SNPMiner Trials by Shray Alag


SNPMiner Trials: Mutation Report


Report for Mutation V600E

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

There are 204 clinical trials

Clinical Trials


1 Evaluating BRAF Mutations as Predictors of Efficacy in Cetuximab-Treated Colorectal Cancer Patients: A Retrospective Study of Tissues From CALGB / SWOG

RATIONALE: Studying samples of tissue in the laboratory from patients who received cetuximab may help doctors understand and predict how well patients will respond to treatment. PURPOSE: This research study is studying biomarkers in predicting response to cetuximab in patients with advanced colorectal cancer.

NCT01243372 Colorectal Cancer Genetic: mutation analysis Other: laboratory biomarker analysis
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

DISEASE CHARACTERISTICS: - Participation in CALGB-C80405 - Have KRAS WT or KRAS mut tumor - Randomized to treatment with either bevacizumab or cetuximab alone - Patients randomized to the combination therapy are not eligible - Available specimens at the PCO for BRAF mutation detection - Patient consent for use of samples DISEASE CHARACTERISTICS: - Participation in CALGB-C80405 - Have KRAS WT or KRAS mut tumor - Randomized to treatment with either bevacizumab or cetuximab alone - Patients randomized to the combination therapy are not eligible - Available specimens at the PCO for BRAF mutation detection - Patient consent for use of samples Colorectal Cancer Colorectal Neoplasms OBJECTIVES: Primary - To determine, among patients with advanced CRC, whether the effect of treatment (cetuximab vs bevacizumab) on progression-free survival (PFS) depends on tumor BRAF V600E mutational status. --- V600E ---

Secondary - To study the relationships between tumor BRAF V600E mutational status, OS, and tumor response. --- V600E ---

Previously collected formalin-fixed and paraffin-embedded baseline tumor samples are analyzed for BRAF V600E mutation. --- V600E ---

Primary Outcomes

Measure: Progression-free survival as measured by RECIST

Time: Up to 36 months

Secondary Outcomes

Measure: overall survival

Time: Up to 36 months

Measure: tumor response as measured by RECIST

Time: Up to 36 months

2 A Phase III Randomized, Open-label Study Comparing GSK1120212 to Chemotherapy in Subjects With Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma

This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. All subjects must have a BRAF mutation-positive tumour sample. Subjects who have received up to one prior regimen of chemotherapy in the advanced or metastatic melanoma setting will be enrolled into the study. Subjects with any prior BRAF or MEK inhibitor use will be excluded. Approximately 297 subjects will be enrolled with 2:1 randomization (198 subjects into the GSK1120212 arm and 99 subjects into the chemotherapy arm). The primary endpoint for the statistical analysis will be a comparison of progression free survival for subjects receiving GSK1120212 compared to chemotherapy. Subjects who have progression on chemotherapy will be offered the option to receive GSK1120212.

NCT01245062 Melanoma Drug: GSK1120212 Drug: Chemotherapy
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

A Phase III Randomized, Open-label Study Comparing GSK1120212 to Chemotherapy in Subjects With Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma. --- V600E ---

GSK1120212 vs Chemotherapy in Advanced or Metastatic BRAF V600E/K Mutation-positive Melanoma This is a two-arm, open-label, randomized Phase III study comparing single agent GSK1120212 to chemotherapy (either dacarbazine or paclitaxel) in subjects with Stage IIIc or Stage IV malignant cutaneous melanoma. --- V600E ---

Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review. --- V600E ---

Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.. Progression-free Survival in All Participants. --- V600E ---

Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered.. PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator. --- V600E ---

PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.. PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator. --- V600E ---

Overall survival was defined as the time from the date of randomization to the date of death due to any cause.. Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases. --- V600E ---

NA indicates data was not available.. Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review. --- V600E ---

Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.. Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator. --- V600E ---

Only participants who received at least one dose of Trametinib were included in this population.. Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review. --- V600E ---

NA indicates data was not available.. DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review. --- V600E ---

PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.. Inclusion Criteria: - ≥18 years of age - Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory - Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. --- V600E ---

- Intraocular pressure > 21 mm Hg as measured by tonography Inclusion Criteria: - ≥18 years of age - Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory - Received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. --- V600E ---

Primary Outcomes

Description: Progression-free survival (PFS) is defined as the time from randomization to the first documented occurrence of disease progression (PD) or death. PFS for investigator-assessed and blinded, independent, central review committee (BRIC)-assessed responses was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer participants improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Primary Efficacy Population included all participants with BRAF V600E mutation-positive melanoma without a history of brain metastases.

Measure: Progression-free Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases as Assessed by the Investigator and Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Secondary Outcomes

Description: PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed and BRIC-assessed PFS were summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Intend-To-Treat (ITT) Population included all randomized participants regardless of whether or not treatment was administered.

Measure: Progression-free Survival in All Participants

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Measure: PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and Without Prior Chemotherapy as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: PFS is defined as the time from the date of randomization to the first documented occurrence of PD or death. Investigator-assessed PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Measure: PFS in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases and With Prior Chemotherapy as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

Measure: Overall Survival in All Participants

Time: Day 1 until death due to any cause (average of 20.3 months)

Description: Overall survival was defined as the time from the date of randomization to the date of death due to any cause. NA indicates data was not available.

Measure: Overall Survival in BRAF V600E Mutation-positive Participants Without a History of Brain Metastases

Time: Day 1 until death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (CR; disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

Measure: Number of BRAF V600E Mutation-positive Participants Without a History of Brain Metastases With Overall Response (OR) as Assessed by the Investigator and Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator and an independent review per RECIST, Version 1.1.

Measure: Number of Participants With OR as Assessed by the Investigator and Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

Measure: Number of BRAF V600E Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of complete response (CR; disappearance of all extranodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or partial response (PR: at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator per RECIST, Version 1.1.

Measure: Number of BRAF V600K Mutation-positive Participants Classified as Confirmed Responders (CR and PR) as Assessed by the Investigator

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: OR is defined as the number of participants with evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 millimeters in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) evaluated by the Investigator in participants following cross-over to Trametinib. The evaluation was carried out by the Investigator per RECIST, Version 1.1. Cross-over Population included the subset of participants who were randomized to CT and who elected to cross-over to Trametinib following disease progression on CT. Only participants who received at least one dose of Trametinib were included in this population.

Measure: Number of Participants With OR Following Cross-over to Trametinib

Time: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the investigator-assessed (INVA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: Duration of Response (DoR) for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Investigator Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD (at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation) or death due to any cause. DoR for the independently-assessed (INDA) response data were summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All BRAF V600E Mutation-positive Participants Without a Prior History of Brain Metastases Classified as Confirmed Responders (CR or PR) as Assessed by the Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INVA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All Confirmed Responders (CR or PR) as Assessed by the Investigator Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all target lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR for the INDA response data was summarized per RECIST, Version 1.1. Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All Confirmed Responders (CR or PR) as Assessed by the Independent Review

Time: Day 1 until the earliest date of disease progression or death due to any cause (average of 20.3 months)

Description: DoR is defined as the time from the first documented evidence of CR (disappearance of all extra nodal lesions. Any pathological lymph node must be less than 10 mm in the short axis) or PR (at least a 30% decrease in the sum of the diameters of target lesions) until PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation. DoR data were summarized per RECIST, Version 1.1Only those participants with confirmed response (CR and PR) were analyzed. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available.

Measure: DoR for All Responders (CR or PR) Following Cross-over to Trametinib as Assessed by the Investigator

Time: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)

Description: PFS is defined as the time from the first dose of cross-over therapy to the first documented occurrence of PD or death. PFS was summarized per RECIST, Version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

Measure: PFS Following Cross-over to Trametinib as Assessed by the Investigator

Time: Day 1 of cross-over therapy until the earliest date of disease progression or death due to any cause (average of 18.3 months)

3 A Phase 1 Study of a RAF Inhibitor (BMS-908662) Administered in Combination With Immunotherapy (Ipilimumab) in Subjects With Unresectable Stage III or Stage IV Melanoma

The purpose of the study is to identify a safe and tolerable dose of BMS-908662 in combination with ipilimumab; and then to evaluate the anti-tumor response to BMS-908662 when administered in combination with ipilimumab.

NCT01245556 Melanoma Drug: BMS-908662 Drug: BMS-908662 Drug: Ipilimumab Drug: Ipilimumab
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Melanoma Melanoma null --- V600E ---

Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Inclusion: - Male and female subjects ≥ 18 years of age with a histologic or cytologic diagnosis of Stage III or Stage IV (unresectable) melanoma - Enrollment to cohort expansion will be limited to only those subjects whose tumors demonstrate the B-Raf V600E mutation - ECOG ≤ 1 - Adequate organ & marrow function Exclusion: - Uncontrolled or significant cardiovascular disease - Cohort expansion: Prior therapy with a RAF inhibitor Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Measure: Toxicity will be evaluated according to the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 3

Time: Assessments approximately every 3 weeks throughout the duration of the trial

Secondary Outcomes

Measure: Efficacy as determined by estimates of objective response rates and response duration

Time: Efficacy measured every 6 weeks until week 48, then every 12 weeks

Measure: PK for BMS-908662 as determined by minimum and maximum observed concentrations, time of maximum observed concentration, area under the concentration curve for one dosing interval and the accumulation index

Time: PK measured during first 4 weeks on study

Measure: PD will be assessed by evaluating markers of RAS/RAF pathway activity

Time: PD assessed during the first 4 weeks on study

4 A SINGLE ARM, OPEN LABEL, EXPANDED ACCESS STUDY OF RG7204 IN PREVIOUSLY TREATED PATIENTS WITH METASTATIC MELANOMA

This is an open-label, non-comparative, multicenter, expanded access study of RO5185426 in patients who have received prior systemic therapy for metastatic melanoma and who have no other satisfactory treatment options.

NCT01248936 Malignant Melanoma Drug: RO5185426
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Participants were assessed for best overall response by investigator as per RECIST v1.1.. Inclusion Criteria: - Histologically confirmed metastatic melanoma with documented BRAF V600E mutation, determined by the cobas BRAF V600 mutation test - Patients with either measurable or non-measurable disease - Adequate recovery from most recent systemic or local treatment for metastatic melanoma - Adequate organ function - For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of RO5185426 - For men with female partners of childbearing potential, agreement to use a latex condom, and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of RO5185426 - Negative serum or urine pregnancy test within 7 days of commencement of treatment in premenopausal women. --- V600E ---

Women who are either surgically sterile or have been post-menopausal for at least 1 year are eligible to participate in this study - Agreement not to donate blood or blood products during the study and for at least 6 months after discontinuation of RO5185426; for male patients, agreement not to donate sperm during the study and for at least 6 months after discontinuation of RO5185426 Exclusion Criteria: - Pregnant or breast-feeding - Concurrent anti-tumor therapy - Uncontrolled medical illness - History of congenital prolonged QT syndrome or patients with a mean QTc interval greater than 470 milliseconds at baseline, or ongoing grade 2 or greater cardiac arrhythmia Inclusion Criteria: - Histologically confirmed metastatic melanoma with documented BRAF V600E mutation, determined by the cobas BRAF V600 mutation test - Patients with either measurable or non-measurable disease - Adequate recovery from most recent systemic or local treatment for metastatic melanoma - Adequate organ function - For women of childbearing potential, agreement to the use of two acceptable methods of contraception, including one barrier method, during the study and for 6 months after discontinuation of RO5185426 - For men with female partners of childbearing potential, agreement to use a latex condom, and to advise their female partner to use an additional method of contraception during the study and for 6 months after discontinuation of RO5185426 - Negative serum or urine pregnancy test within 7 days of commencement of treatment in premenopausal women. --- V600E ---

Primary Outcomes

Description: An Adverse Event (AE) is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs will be graded according to the 'National Cancer Institute Common Terminology Criteria for Adverse Events' (NCI CTCAE, v4.0). However Laboratory data will be summarized by grade using the NCI CTCAE, v4.0 toxicity grade.

Measure: Number of Participants With Any Adverse Event, Adverse Events With Severity, Adverse Events Leading to Discontinuation

Time: Up to 1 year

Description: Serious Adverse Event (SAEs) is defined as those events that were fatal or immediately life-threatening, and those events that resulted in hospitalization; prolonged an existing hospitalization; resulted in disability; or was a congenital anomaly. Number of participants who died and the cause of death are also recorded.

Measure: Number of Participants With Any Serious Adverse Event, Death and Cause of Death

Time: Up to 1 year

Secondary Outcomes

Description: The best overall response (unconfirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed. Participants were assessed for best overall response by investigator as per 'Response Evaluation Criteria in Solid Tumors' (RECIST v1.1).

Measure: Number of Participants With Best Overall Response (Unconfirmed)

Time: Up to 1 year

Description: The best overall response recorded from the start of the treatment until disease progression/recurrence which was unconfirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair >50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. This endpoint was tumor response category according to investigator assessment per RECIST v1.1 for efficacy assessment. The 'n' is number of participants with ECOG performance status in each criteria.

Measure: Number of Participants With Best Overall Response (Unconfirmed) by ECOG Performance

Time: Up to 1 year

Description: The best overall response (confirmed) is the best response recorded from the start of the treatment until disease progression/recurrence which was confirmed. Participants were assessed for best overall response by investigator as per RECIST v1.1.

Measure: Number of Participants With Best Overall Response (Confirmed)

Time: Up to 1 year

Description: The best overall response recorded from the start of the treatment until disease progression/recurrence which was confirmed in patients with Eastern Cooperative Oncology Group (ECOG) performance status 2 or 3/0 or 1. Following are ECOG grades. 0: Fully active, perform all pre-disease activities without restriction. 1: Restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2: Ambulatory, capable of selfcare, unable to carry out any work activities, up and about more than (>) 50% of waking hours. 3: Capable of limited selfcare, confined to bed or chair >50% of waking hours. 4: Completely disabled, not capable of any selfcare, totally confined to bed or chair. 5: Dead. Participants were assessed for best overall response by investigator as per RECIST v1.1. The 'n' is number of participants with ECOG performance status in each criteria.

Measure: Number of Participants With Best Overall Response (Confirmed) by ECOG Performance

Time: Up to 1 year

Description: Mean time to Complete Response (CR)/Partial Response(PR) (confirmed or unconfirmed was assessed). Participants were assessed for best overall response by investigator as per RECIST v1.1.

Measure: Mean Time to Complete Response/Partial Response

Time: Up to 1 year

5 A Phase II, Randomised, Open Label Study of Neoadjuvant Dabrafenib, Trametinib and / or Pembrolizumab in BRAF V600 Mutant Resectable Stage IIIB/C Melanoma

This study aims to determine which of 3 drug combinations best reduces the size of tumour prior to surgery for advanced melanoma and prevents the recurrence of melanoma after surgery.

NCT02858921 Melanoma Drug: Dabrafenib Drug: Trametinib Drug: Pembrolizumab
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

A positive V600E immunohistochemistry stain at study entry should be formally quantified with a local molecular test following study entry (e.g. --- V600E ---

Allocation of treatment will be concealed prior to randomisation which will be performed via a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF V600E mutation (i.e. --- V600E ---

Allocation of treatment will be concealed prior to randomisation which will be performed via a web based system in permuted blocks and stratified by BRAF V600E mutation versus non BRAF V600E mutation (i.e. --- V600E --- --- V600E ---

Primary Outcomes

Description: Proportion of patients with complete absence of residual melanoma cells in the planned resected tumour site(s) at week 6 surgery.

Measure: Pathological response rate

Time: From baseline to 6 weeks

Secondary Outcomes

Description: Proportion of patients with complete and partial responses at 6 weeks compared to baseline per RECIST guidelines for each treatment arm.

Measure: Objective clinical (RECIST) response rate

Time: From baseline to 6 weeks

Description: The amount of time that patients are disease free from the time of surgery at 6 weeks from study entry

Measure: Relapse free survival

Time: 5 years

Description: The proportion of patients who are alive from the time of study entry

Measure: Overall survival

Time: 5 years

Description: The number of patients (and the number of episodes) who develop a post operative infection of the surgical wound requiring intravenous antibiotics and/or wound drainage

Measure: Incidence of post operative infection

Time: 6 weeks

Description: The number of patients (and the number of episodes) who develop a seroma at the surgical site that requires any intervention and the volume of seroma drainage

Measure: Incidence of post operative seroma formation

Time: 6 weeks

Description: The number of days that a wound drain remains in situ from the time of surgery

Measure: Duration of post operative wound drainage time

Time: 6 weeks

Description: The number of patients (and the number of episodes) who have a bleed from the post operative surgical wound that requires a blood transfusion or return to theatre to stop the bleeding

Measure: Incidence of post operative bleeding requiring return to theatre or transfusion

Time: 6 weeks

Description: The change, if any, in the surgeon's assessment of 'operability' from baseline opinion (based on clinical and imaging examination) to time of operation

Measure: Comparison of surgeon's opinion of operability evaluated at baseline to time of surgery

Time: Baseline and 6 weeks

Description: The number of study treatment related adverse events of all Common Terminology Criteria for Adverse Events (CTCAE) grades from the time of starting study treatment to the time of permanent discontinuation of study treatment

Measure: Incidence of any treatment-emergent adverse events

Time: 52 weeks

Description: The effects of study treatment on the body's immune cells within the tumour tissue prior to surgery

Measure: Characterisation of the immunophenotype of tumour infiltrating cells in melanoma tissue

Time: Baseline, Week 1, Week 2, Week 6

Description: The effects of study treatment on the degree of necrosis and genetic markers in tumour tissue prior to surgery

Measure: Description of the morphological assessment of melanoma tissue

Time: Baseline, Week 1, Week 2, Week 6

Description: The effects of study treatment on the baseline function of RNA expression in tumour tissue prior to surgery

Measure: Description of the RNA expression profile of melanoma tumour

Time: Baseline, Week 1, Week 2, Week 6

Description: The effects of study treatment on the number and type of white cells in the blood

Measure: Measurement of leucocyte subpopulations in peripheral blood

Time: Baseline, Week 1, Week 2, Week 6

Description: The levels of melanoma DNA that is circulating in the blood stream and the changes during study treatment

Measure: Measurement of circulating tumour DNA

Time: Baseline, Week 1, Week 2, Week 6

Other Outcomes

Description: The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the findings from the pathological examination of completely excised tumour tissue

Measure: Concordance of metabolic response measured by pathological response

Time: 6 weeks

Description: The activity of melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

Measure: Concordance of metabolic response measured by RECIST response

Time: 52 weeks

Description: he findings from the pathological examination of completely excised tumour tissue and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

Measure: Concordance of pathological response measured by RECIST response

Time: 6 weeks

Description: The activity of recurrent melanoma tissue assessed by the uptake of fludeoxyglucose (18F) in tumour cells viewed using positron emission tomography (PET) and how well this corresponds to the assessment of tumour size and extent using computed tomography and magnetic resonance imaging scans

Measure: Concordance of metabolic response with RECIST response at relapse

Time: 52 weeks

Description: The application of two different criterion to establish the tumour burden as assessed with computed tomorgraphy and magnetic resonanse imaging

Measure: Concordance of immune related response criteria (irRC) with RECIST response

Time: Weeks 6 and 52

Description: Characterisation of the bacterial diversity and composition in stool samples at baseline, prior to surgery at week 6, week 24 and at relapse.

Measure: Correlation of the gut microbiome with RECIST response to immunotherapy.

Time: Baseline, Week 6, week 24, at relapse if this occurs within 5 years from study entry

Description: Diet plays a significant role in shaping the intestinal microbiome. Nutrition may influence the gut microbiome and response to immunotherapy.

Measure: Characterisation of self-reported dietary habits (including use of oral probiotics) and correlation with the gut microbiome.

Time: Baseline

6 A Phase 1 Study of an ERK1/2 Inhibitor (LY3214996) Administered Alone or in Combination With Other Agents in Advanced Cancer

The purpose of this study is to determine the safety of an extracellular signal regulated kinase (ERK1/2) inhibitor LY3214996 administered alone or in combination with other agents in participants with advanced cancer.

NCT02857270 Advanced Cancer Metastatic Melanoma Metastatic Non-small Cell Lung Cancer Metastatic Pancreatic Ductal Adenocarcinoma Colorectal Cancer Drug: LY3214996 Drug: Midazolam Drug: Abemaciclib Drug: Nab-paclitaxel Drug: Gemcitabine Drug: Encorafenib Drug: Cetuximab
MeSH: Carcinoma, Non-Small-Cell Lung Colorectal Neoplasms Adenocarcinoma
HPO: Neoplasm of the large intestine Non-small cell lung carcinoma

- Part E: Metastatic BRAF V600E colorectal cancer (dose escalation and dose expansion). --- V600E ---

Primary Outcomes

Measure: Number of Participants with LY3214996 Dose Limiting Toxicities (DLTs)

Time: Cycle 1 (21 Days)

Secondary Outcomes

Measure: Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC) of LY3214996 Administered as Monotherapy and when Administered in Combination with Nab-Paclitaxel Plus Gemcitabine, Abemaciclib and Encorafenib Plus Cetuximanb

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 28 Day Cycles)

Measure: PK: AUC of Gemcitabine when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 1 Day 15 (28 Day Cycles)

Measure: PK: AUC of Nab-Paclitaxel when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 1 Day 15 (28 Day Cycles)

Measure: PK: AUC of Abemaciclib and its Metabolites when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles)

Measure: PK: AUC of Encorafenib when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles)

Measure: PK: AUC of Cetuximab when Administered with LY3214996

Time: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles)

Measure: PK: AUC of Midazolam and its 1'-Hydroxymidazolam Metabolite when Administered Alone and in Combination with LY3214996

Time: Cycle 1 Day 1 through Cycle 1 Day 16 (21 Day Cycles)

Measure: Objective Response Rate (ORR): Percentage of Participants With a Complete (CR) or Partial Response (PR)

Time: Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Estimated up to 6 Months)

Measure: Duration of Response (DoR)

Time: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 12 Months)

Measure: Time to First Response (TTR)

Time: Baseline to Date of CR or PR (Estimated up to 6 Months)

Measure: Progression Free Survival (PFS)

Time: Baseline to Progressive Disease or Death of Any Cause (Estimated up to 12 Months)

Measure: Disease Control Rate (DCR): Percentage of Participants who Exhibit Stable Disease (SD), CR or PR

Time: Baseline through Measured Progressive Disease (Estimated up to 6 Months)

Measure: Overall Survival (OS) (Dose Expansion Arms Only)

Time: Baseline to Date of Death from Any Cause (Estimated up to 2 Years)

7 A Randomized, Phase III Study of Fotemustine Versus the Combination of Fotemustine and Ipilimumab or the Combination of Ipilimumab and Nivolumab in Patients With Metastatic Melanoma With Brain Metastasis

This Phase 3, open-label, triple arm study aims to evaluate the overall survival (OS) of fotemustine versus the combination of ipilimumab and fotemustine or the combination of Ipilimumab and nivolumab in patients with metastatic melanoma with brain metastasis.

NCT02460068 Brain Metastases Drug: Fotemustine Drug: Fotemustine and Ipilimumab Drug: Ipilimumab and nivolumab
MeSH: Melanoma Neoplasm Metastasis Neoplasms, Second Primary Brain Neoplasms
HPO: Brain neoplasm Cutaneous melanoma Melanoma

- Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard. --- V600E ---

- Subjects must have known BRAF V600E mutation status or consent to BRAF V600E mutation testing per local institutional standard. --- V600E --- --- V600E ---

Primary Outcomes

Description: To compare the efficacy of the combination of ipilimumab and fotemustine or the Combination of ipilimumab and nivolumab versus fotemustine in terms of overall survival (OS) in patients with metastatic melanoma with brain metastasis.Overall Survival (OS) is defined as the time from randomization until the date of death. For those subjects who have not died, OS will be censored at the recorded last date of subject contact, and for subjects with a missing recorded last date of contact, OS will be censored at the last date the subject was known to be alive.

Measure: Overall Survival (OS)

Time: 2 years

Secondary Outcomes

Description: Reporting of safety, extent of exposure, concomitant medications and discontinuation of study therapy will be based on all treated subjects; for on-study laboratory test results, all treated subjects with at least one on-study laboratory measurement available will be included in the analysis. The reporting period for safety data will be from the date of first dose received on this study to 70 days (5 half-lives) after the last dose is received. Serious adverse events are reported from the time of consent forward for all subjects.All subjects who receive at least 1 dose of study treatment will be evaluated for safety parameters

Measure: safety (adverse events)

Time: 2 years

Description: m-WHO and immune-related is the proportion of treated subjects with a ir-BOR of confirmed irCR, confirmed irPR or irSD in and outside the brain.

Measure: m-WHO and immune-related Disease Control Rate (DCR) in and outside the brain

Time: Weeks 24

Description: Immune-related progression free survival (irPFS) per irRC will be defined as the time between the date of randomization and the date of progression per irRC or death, whichever occurs first. A subject who dies without reported progression per irRC will be considered to have progressed on the date of death.

Measure: Immune-related Progression-free Survival (irPFS)

Time: 2 years

Description: Progression-free survival (PFS) per mWHO criteria will be defined as the time between the date of randomization and the date of progression per mWHO criteria or death, whichever occurs first. A subject who dies without reported progression per mWHO criteria will be considered to have progressed on the date of death.

Measure: m-WHO Progression-free Survival (irPFS)

Time: 2 years

Description: is the proportion of treated subjects with a BOR of confirmed CR or confirmed PR.

Measure: Objective Response Rate (ORR)

Time: Weeks 24

Description: is the proportion of treated subjects with a irBOR of confirmed irCR or confirmed irPR.

Measure: Immune-related Objective Response Rate (irORR)

Time: Weeks 24

Description: Time to Response (TTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of PR or CR (whichever status comes first, and provided it is subsequently confirmed).

Measure: Time to Response (TTR)

Time: Weeks 24

Description: Immune-related Time to Response (irTTR) is defined as the time from first dosing date until the measurement criteria are first met for overall response of irPR or irCR (whichever status comes first, and provided it is subsequently confirmed).

Measure: Immune-related Time to Response (irTTR)

Time: Weeks 24

Description: Duration of Response (DoR) is defined as the time between the date the measurement criteria are first met for an CR or PR (whichever status comes first and provided it is subsequently confirmed) and the date of PD or death (whichever comes first). For a subject who undergoes tumor resection following response but prior to disease progression, DOR will be censored at the date of the last evaluable TA on or prior to the date of resection. For subjects who remain alive and have no progressive disease as assessed by the investigator using RC, DOR will be censored on the date of last evaluable tumor assessment.

Measure: Duration of Response (DoR)

Time: 2 years

Description: Immune-related Duration of Response (irDoR) for the subjects whose irBOR is irCR or irPR will be defined as the time between the date of response of confirmed irCR or confirmed irPR (whichever occurs first) and the date of irPD or death (whichever occurs first). The onset of a confirmed irCR or irPR is determined by the initial assessment of response, not by the confirmatory assessment. Note that if an assessment of irPR occurs before confirmation of irCR, the duration of immune-related response endpoint will not begin at the time that the irBOR of irCR is shown but rather at the earlier time-point showing irPR. For subjects who remain alive and have not progressed following response, irDoR will be censored on the date of last evaluable TA.

Measure: Immune-related Duration of Response (irDoR)

Time: 2 years

Description: Brain progression-free survival (Brain-PFS) (3 and 6 months rates) is defined as the time from randomization date to the date of progression as per MRI of existing brain lesions, or of occurrence as per MRI of a new lesion located in the brain, or of death, whichever occurs first. For subjects who remain alive and have not progressed as per definition above, Brain-PFS will be censored at the day of last evaluable brain imaging assessment.

Measure: Brain progression-free survival (Brain-PFS)

Time: 6 months

8 Phase II Trial of Hyd-sulfate AZD6244 [NSC 748727] in Patients With BRAF or NRAS Mutated Melanomas

This phase II trial is studying how well MEK inhibitor AZD6244 works in treating patients with stage III or stage IV melanoma. MEK inhibitor AZD6244 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT00866177 Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Other: Laboratory Biomarker Analysis Drug: Selumetinib
MeSH: Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the skin

Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Determine the response in patients with V600E or V600K BRAF-mutated or NRAS-mutated stage III or stage IV melanoma with low or high phospho-pAKT expression treated with MEK inhibitor AZD6244. --- V600E ---

Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Determine the response in patients with V600E or V600K BRAF-mutated or NRAS-mutated stage III or stage IV melanoma with low or high phospho-pAKT expression treated with MEK inhibitor AZD6244. --- V600E --- --- V600K --- --- V600E ---

Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Inclusion Criteria: - Histologically or cytologically confirmed melanoma - Stage IV or stage III disease not potentially curable with surgery - Documented tumor progression - Must have a V600E or V600K BRAF-mutated tumor, or a NRAS mutation at condons 12, 13, or 61 - Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan - Must have tumor tissue (block or unstained slides) available for IHC studies - No primary uveal or mucosal melanoma - No active or untreated brain metastases - Treated brain metastases allowed provided they have been stable for ≥ 3 months - ECOG performance status 0-1 - Life expectancy > 3 months - WBC ≥ 3,000/mcL - Absolute neutrophil count ≥ 1,500/mcL - Platelet count ≥ 100,000/mcL - Hemoglobin ≥ 9.0 g/dL (no requirement for transfusions within the past 2 weeks) - Total bilirubin ≤ 1.5 times upper limit of normal (ULN) - AST/ALT ≤ 2.5 times ULN - Creatinine ≤ 1.5 mg/dL - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use effective contraception during and for 16 weeks after completion of study treatment - No refractory nausea and vomiting, chronic gastrointestinal disease (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption - No concurrent uncontrolled illness, including, but not limited to, any of the following: - Ongoing or active infection or bleeding - Symptomatic congestive heart failure - Unstable angina pectoris - Cardiac arrhythmia - Psychiatric illness/social situation that would limit compliance with study requirements - No history of allergic reactions attributed to compounds of similar chemical or biologic composition to MEK inhibitor AZD6244 - Any number of prior therapies allowed - At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C) and recovered - At least 4 months since prior anti-CTLA4 monoclonal antibody therapy - At least 4 weeks since other prior systemic therapy - No other concurrent investigational agents - No concurrent antiretroviral therapy for HIV-positive patients - No concurrent vitamin E supplementation or multivitamin supplements that provide a total daily dose in excess of 100% of the recommended daily dose of vitamin E - No concurrent anticancer chemotherapy or other systemic drugs - Concurrent palliative radiotherapy allowed Recurrent Melanoma Stage III Skin Melanoma Stage IV Skin Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Determine the response in patients with V600E or V600K BRAF-mutated or NRAS-mutated stage III or stage IV melanoma with low or high phospho-pAKT expression treated with MEK inhibitor AZD6244. --- V600E --- --- V600K --- --- V600E --- --- V600K --- --- V600E ---

Primary Outcomes

Description: Anti-tumor response defined as either a Complete Response, Partial Response, or Stable Disease as defined by RECIST

Measure: Anti-tumor Response Defined as Either a CR, PR, or SD as Defined by RECIST

Time: Up to 4 weeks

9 Phase I Study of INCB039110 in Combination With Dabrafenib and Trametinib in Patients With BRAF-mutant Melanoma and Other Solid Tumors.

This research study is studying a combination of drugs as a possible treatment for BRAF-mutant melanoma. The drugs involved in this study are: - Itacitinib (INCB039110) - Dabrafenib - Trametinib

NCT03272464 Melanoma Drug: Trametinib Drug: Dabrafenib Drug: INCB039110
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Inclusion Criteria: - For Dose-Escalation Phase: Patients must have histologically confirmed, BRAF-mutant (V600E/K) malignancy (molecularly confirmed using Cobas assay or a comparable FDA-approved assay (for exceptions, see below*) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy or not previously received BRAF targeted therapy, and for which standard curative or palliative measures do not exist or are no longer effective. --- V600E ---

- For Dose-Expansion Phase: Patients must have histologically confirmed, BRAF-mutant (V600E/K) melanoma (molecularly confirmed using Cobas assay or a comparable FDA-approved assay (for exceptions, see below*) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF targeted therapy. --- V600E ---

Current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded Inclusion Criteria: - For Dose-Escalation Phase: Patients must have histologically confirmed, BRAF-mutant (V600E/K) malignancy (molecularly confirmed using Cobas assay or a comparable FDA-approved assay (for exceptions, see below*) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy or not previously received BRAF targeted therapy, and for which standard curative or palliative measures do not exist or are no longer effective. --- V600E ---

Primary Outcomes

Description: Doses at which fewer than one third of patients have severe toxicity

Measure: Maximum Tolerated Dose

Time: 2 years

Secondary Outcomes

Description: Proportion of patients with tumor shrinkage that meets standard criteria for response

Measure: Objective Response Rate

Time: 2 years

Description: Time until worsening of cancer

Measure: Progression Free Survival

Time: 6 Months

Description: Time until death from cancer

Measure: Overall Survival

Time: 1 year

Description: Proportion of patients with complete tumor shrinkage

Measure: Complete response rate

Time: 2 years

Description: Proportion of patients with less than complete tumor shrinkage

Measure: Partial Response Rate

Time: 2 years

Description: Proportion of patients with no change in tumor size

Measure: Stable Disease

Time: 2 years

Description: Proportion of patients with worsening of cancer at or before first response assessment

Measure: Progressive Disease

Time: 2 years

10 A Multicenter, Open-Label Phase 1 Study of DS-1205c in Combination With Osimertinib in Subjects With Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer

This study has two parts: dose escalation and dose expansion. The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population - For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population In Dose Escalation, after a 7-day run in period (Cycle 0), there will be 21-day cycles (Cycle 1 onward). In Dose Expansion, there will be 21-day cycles. The number of treatment cycles is not fixed in this study. Participants will continue study treatment for 36 months unless they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity).

NCT03255083 Non-small Cell Lung Cancer (NSCLC) Drug: DS-1205c Drug: Osimertinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

2. Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, BRAF V600E mutation, rearranged during transfection (RET) rearrangement, human epidermal growth factor receptor 2 (HER2) mutation, or MET exon 14 skipping mutation. --- V600E ---

Primary Outcomes

Measure: Number of participants with dose-limiting toxicities (DLTs) when taking DS-1205c in combination with osimertinib during dose escalation

Time: within 28 days

Description: Categories: during dose escalation, during dose expansion

Measure: Number of participants with clinically significant safety measures when taking DS-1205c in combination with osimertinib

Time: within 36 months

Secondary Outcomes

Description: DS-1205a is the free form of DS-1205c when DS-1205c is administered alone

Measure: Area under the plasma concentration time curve (AUC) for DS-1205a

Time: during Cycle 0 of the dose escalation period (within 28 days)

Measure: Maximum observed analyte concentration (Cmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Actual sampling time to reach Cmax (Tmax) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Area under the analyte concentration versus time curve during a dosing interval (AUCtau) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Measure: Minimum observed analyte concentration prior to the beginning, or at the end, of a dosing interval (Ctrough) of DS-1205a

Time: during Cycle 0 of the dose escalation period (7 days)

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Cmax during a dosing interval (Tau) at steady state (Cmax,ss)

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Plasma concentration of DS-1205a versus time

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Tmax

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites (AZ5104 and AZ7550)

Measure: Ctrough

Time: during the dose expansion period, within 36 months

Description: Categories: DS-1205a, osimertinib, and osimertinib active metabolites

Measure: AUCtau

Time: during the dose expansion period, within 36 months

Description: Objective response rate is calculated as the number of participants with best objective response [complete response (CR) or partial response (PR) determined by Investigator assessment based on Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1], divided by the number of participants in the analysis population.

Measure: Objective response rate (ORR), graded according to RECIST version 1.1

Time: within 36 months

Measure: Change from baseline in size of target lesion(s)

Time: within 36 months

Description: DOR is defined as the time from documentation of tumor response [either CR or PR] to disease progression

Measure: Duration of response (DOR)

Time: within 36 months

Description: DCR is defined as the sum of CR rate, PR rate, and stable disease (SD) rate

Measure: Disease control rate (DCR)

Time: first dose to 36 months

Description: PFS is defined as the time from the date of the first dose to the earlier of the dates of the first objective documentation of radiographic PD, or death due to any cause

Measure: Progression-free survival (PFS)

Time: baseline to objective disease progression or death from any cause (within 36 months)

Measure: Overall survival (OS)

Time: baseline to death from any cause (within 36 months)

11 A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer

Dabrafenib is a potent and selective inhibitor of BRAF kinase activity. This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib administered as a single agent and in combination with trametinib in stage IV disease to subjects with BRAF mutant advanced non-small cell lung cancer. Subjects will receive dabrafenib 150 mg twice daily (BID) in monotherapy treatment and dabrafenib 150 mg bid and trametinib 2 mg once daily in combination therapy and continue on treatment until disease progression, death, or unacceptable adverse event.

NCT01336634 Cancer Drug: Dabrafenib Device: Trametinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

A Phase II Study of the BRAF Inhibitor Dabrafenib as a Single Agent and in Combination With the MEK Inhibitor Trametinib in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. --- V600E ---

Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. --- V600E ---

Subjects in Cohort C will be required to have not received prior systemic anti-cancer therapies for metastatic disease (i.e., dabrafenib/trametinib will be 1st line treatment for metastatic disease); - Measurable disease according to Response Evaluation Criteria in Solid Tumors [RECIST 1.1]; - At least 18 years of age; - Anticipated life expectancy of at least three months; - Presence of a BRAF V600E mutation in lung cancer tissue. --- V600E ---

Primary Outcomes

Description: ORR is defined as the percentage of par. with a confirmed complete response (CR) or partial response (PR) by investigator assessment as per Response Evaluation Criteria In Solid Tumors evaluates the response on the basis of target and non-target lesions, and best over all response. The response rate was analyzed every 6 weeks (wks) after initiation of study treatment until Week 36 and then every 12 wks until discharge or crossover. Percentage of par. analyzed as number of par. having overall response on the date of analysis from Baseline multiply by 100. The Second Line Plus All Treated Population used for cohort A and B consisted of all par. in the All Treated Population who had received at least one line of prior anti-cancer therapy for advanced/metastatic disease. The First-Line All Treated Population used for cohort C consisted of all par. in the All Treated Population who had not received any prior anti-cancer therapy for advanced/metastatic disease.

Measure: Percentage of Participants With Overall Response Rate (ORR) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Secondary Outcomes

Description: DoR is defined for the subset of participants with confirmed CR or PR, as the time from first documented evidence of CR or PR until time of first documented disease progression or death due to any cause. The response was analyzed every 6 weeks after initiation of study treatment until Week 36 and then every 12 wks. Disease progression will be based on radiological assessments [magnetic resonance imaging (MRI) or computed tomography (CT)]. Confidence Intervals (CIs) estimated using the Brookmeyer Crowley method. Upper limit of confidence interval was not reached as data were not yet mature. A value of NA indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in that population (27 percent).

Measure: Duration of Response (DoR) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. The target and non-target lesions were identified at time of screening and the same lesions were re-assessed by a contrast-enhanced brain magnetic resonance imaging (MRI) or Computed tomography (CT) every 6 wks after initiation of study treatment until Week 36 and then every 12 wks. CI estimated using the Brookmeyer Crowley method. A value of NA indicates where no data is available or not able to determine the value for Arm 3 due to a low event rate in the population (36 percent).

Measure: Progression Free Survival (PFS) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: OS defined as the time from first dose until death due to any cause. CI estimated using the Brookmeyer Crowley method. A value of NA indicates where no data is available or not able to determine the value. The upper bound of the 95 percent CI for the median was not reached due to insufficient event rates for Arm 2 (58 percent) and Arm 3 (28 percent).

Measure: Overall Survival (OS) at the Date of Analysis

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: Number of participants with abnormal values of vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and temperature were evaluated. Participants with worst case post-Baseline vital sign values were presented at the given timepoints. Only those participants with data available at the specified data points were analyzed. All treated population was used for monotherapy cohort which comprised of all participants in the monotherapy cohort who receive at least one dose of study treatment. HR: <60 bpm clinical concern-low; >100 bpm Clinical concern-high Temperature: <=35 °C clinical concern - low; >=38 °C clinical concern - high For SBP change from baseline, the following categories will be used: Grade 0: <120 mm Hg; Grade 1: >=120-<140 mmHg; Grade 2: >=140-<160 mmHg; Grade 3: >=160 mmHg; For DBP change from baseline, the following categories will be used: Grade 0: <80 mm Hg; Grade 1: >=80-<90 mmHg; Grade 2: 90-<100 mmHg; Grade 3: >=100mmHg

Measure: Number of Participants With Abnormal Vital Signs Values

Time: Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months

Description: Single measurements of 12-lead ECGs were obtained at given time points using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and corrected QT (QTc) interval. ECG values at worst case post-Baseline were categorized as 'clinically significant change from Baseline' and 'not a clinically significant change'.

Measure: Number of Participants With Abnormal Electrocardiogram (ECG) Values

Time: Week 3, Week 6, Week 15 and then every 9 weeks until discharge, for an average of 13.8 months

Description: Echocardiography scans were obtained at given time points using an echocardiogram and the findings for left ventricular ejection fraction (LVEF) were obtained. LVEF values at worst case post-Baseline were recorded as any increase and any decrease values.

Measure: Number of Participants With Abnormal Echocardiogram Findings

Time: Week 6, Week 15 and then every 9 weeks until discharge, for an average of 13.8 months

Description: Blood samples were collected from participants for evaluation of clinical chemistry parameters by worst case post-Baseline increase. The clinical chemistry parameters included creatinine, phosphate and high and low calcium, glucose, magnesium, potassium and sodium. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Measure: Number of Participants With Abnormal Clinical Chemistry Values

Time: Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months

Description: Blood samples were collected from participants for evaluation of hematology parameters by worst case post-Baseline increase. The hematology parameters included leukocytes, neutrophils, platelets and high and low hemoglobin and lymphocytes. Participants were counted in the category that their values shows any grade increase , Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles).

Measure: Number of Participants With Abnormal Hematology Values

Time: Up to Week 12 and then every 3 weeks until discharge, for an average of 13.8 months

Description: An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth effect, other situations and is associated with liver injury or impaired liver function.

Measure: Number of Participants With AEs and Serious AEs (SAEs)

Time: Up to Week 12 and then every 3 weeks up to follow up, for an average of 13.8 months

Description: Blood samples from participants were collected for population pharmacokinetic analysis including CL/F following oral dosing of dabrafenib and trametinib.

Measure: Apparent Clearance (CL/F) of Dabrafenib and Trametinib

Time: Week 3, Week 6, Week 12 and Week 18

Description: Blood samples from participants were collected for population pharmacokinetic analysis including V/F following oral dosing of dabrafenib and trametinib.

Measure: Volume of Distribution (V/F) of Dabrafenib and Trametinib

Time: Week 3, Week 6, Week 12 and Week 18

12 A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5- Fluorouracil (5-FU)/Folinic Acid (FA) /Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer

This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.

NCT02928224 BRAF V600E-mutant Metastatic Colorectal Cancer Drug: Encorafenib Drug: Binimetinib Drug: Cetuximab Drug: Irinotecan Drug: Folinic Acid Drug: 5-Fluorouracil
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5- Fluorouracil (5-FU)/Folinic Acid (FA) /Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer. --- V600E ---

Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA)/Irinotecan (FOLFIRI)/Cetuximab With a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. --- V600E ---

Key Inclusion Criteria: - Age ≥ 18 years at time of informed consent - Histologically- or cytologically-confirmed CRC that is metastatic - Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory - Progression of disease after 1 or 2 prior regimens in the metastatic setting - Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1 - Adequate bone marrow, cardiac, kidney and liver function - Able to take oral medications - Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential - Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up Key Exclusion Criteria: - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors - Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks - Symptomatic brain metastasis or leptomeningeal disease - History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) - Known history of acute or chronic pancreatitis - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization - Uncontrolled blood pressure despite medical treatment - Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) - Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli - Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) - Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy - Known history of HIV infection - Active hepatitis B or hepatitis C infection - Known history of Gilbert's syndrome - Known contraindication to receive cetuximab or irinotecan at the planned doses Key Inclusion Criteria: - Age ≥ 18 years at time of informed consent - Histologically- or cytologically-confirmed CRC that is metastatic - Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory - Progression of disease after 1 or 2 prior regimens in the metastatic setting - Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1 - Adequate bone marrow, cardiac, kidney and liver function - Able to take oral medications - Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential - Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up Key Exclusion Criteria: - Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors - Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks - Symptomatic brain metastasis or leptomeningeal disease - History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) - Known history of acute or chronic pancreatitis - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization - Uncontrolled blood pressure despite medical treatment - Impaired GI function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption) - Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli - Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) - Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy - Known history of HIV infection - Active hepatitis B or hepatitis C infection - Known history of Gilbert's syndrome - Known contraindication to receive cetuximab or irinotecan at the planned doses BRAF V600E-mutant Metastatic Colorectal Cancer Colorectal Neoplasms null --- V600E ---

Primary Outcomes

Measure: (Safety Lead-in) Incidence of dose-limiting toxicities (DLTs)

Time: Cycle 1 (up to 28 days)

Measure: (Safety Lead-in) Incidence and severity of adverse events (AEs) and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Incidence of dose interruptions, dose modifications and discontinuations due to adverse events (AEs)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Response Rate (ORR) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Secondary Outcomes

Measure: (Safety Lead-in) Response Rate (ORR)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Duration of Response (DOR)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Time to Response

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Progression-free Survival (PFS)

Time: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm and Triplet Arm vs. Doublet Arm

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Progression-free Survival (PFS) in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Objective Response Rate (ORR) in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Duration of Response (DOR) in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of Time to Response in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Incidence and severity of adverse events (AEs) and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Phase 3) Comparison of the Quality of Life in study arms

Time: Duration of Phase 3, approximately 6 months (up to 28 days per cycle)

Measure: (Safety Lead-in) Evaluation of the area under the concentration-time curve (AUC) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the maximum concentration (Cmax) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the time of maximum observed concentration (Tmax) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

Measure: (Safety Lead-in) Evaluation of the steady-state concentration measured just before the next dose of study drug (Ctrough) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib

Time: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2

13 A Phase 1 Study of RGX-104, a Small Molecule LXR Agonist, With or Without Nivolumab in Patients With Advanced Solid Malignancies and Lymphoma With an Expansion in Select Malignancies

Study RGX-104-001 is a Phase 1, first-in-human, dose escalation and expansion study of RGX-104, an oral small molecule targeting the liver X receptor (LXR), as a single agent and in combination with nivolumab. RGX-104 activates LXR, resulting in depletion of both myeloid-derived suppressor cells (MDSCs) as well as tumor blood vessels. MDSCs block the ability of T-cells and other cells of the immune system from attacking tumors. During the dose escalation stage, multiple doses and schedules of orally administered RGX-104 with or without nivolumab (single agent or combination therapy) will be evaluated in patients with advanced solid tumors and lymphoma (i.e., locally advanced and unresectable, or metastatic) who have had progressive disease (PD) on available standard systemic therapies or for which there are no standard systemic therapies of relevant impact. In the expansion stage of the study, additional patients with epithelial ovarian carcinoma (EOC), melanoma, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), renal cell cancer (RCC), bladder cancer (BLC), or triple negative breast cancer (TNBC) will be treated at the MTD (or maximum tested dose if no MTD is identified, or dose below the MTD if there is evidence suggesting a more favorable risk/benefit profile). This stage will provide further characterization of the safety, efficacy, PK, and pharmacodynamics, including biomarkers of immunologic activity and LXR target activation, of RGX-104 as a single agent (EOC) and in combination with nivolumab (melanoma, NSCLC, SCLC, RCC, BLC, and TNBC).

NCT02922764 Malignant Neoplasms Drug: RGX-104 Drug: Nivolumab
MeSH: Lymphoma Neoplasms
HPO: Lymphoma Neoplasm

ROS rearrangement, BRAF V600E mutation) for which FDA-approved targeted therapy is available and, if positive, the patient should have received such therapy prior to study entry. --- V600E ---

- In the absence of relevant EGFR mutation, ALK translocation, ROS rearrangement or BRAF V600E mutation, the patient must have received first-line therapy with a platinum-based regimen, be intolerant to, or refused such treatment. --- V600E ---

- A patient with a tumor with an EGFR mutation, ALK translocation, ROS rearrangement, or BRAF V600E mutation may have received appropriate inhibitors of EGFR, ALK, ROS or BRAF in addition to 3 prior lines of therapy for metastatic disease. --- V600E ---

Primary Outcomes

Measure: Maximum tolerated dose (MTD), or the maximum tested dose at which multiple dose-limiting toxicities (DLTs) are not observed, of RGX-104 as a single agent, and separately, in combination with nivolumab.

Time: 6 months

Measure: Overall response rate associated with RGX-104 treatment as a single agent, and separately, in combination with nivolumab.

Time: 24 months

Measure: Progression-free survival associated with RGX-104 treatment as a single agent, and separately, in combination with nivolumab.

Time: 24 months

Measure: Number of participants with treatment-emergent adverse events with severity as determined by CTCAE v4.03 associated with RGX-104 treatment as a single agent, and separately, in combination with nivolumab.

Time: 24 months

Secondary Outcomes

Measure: Pharmacokinetics: Maximum Plasma Concentration (Cmax) of RGX-104.

Time: 24 months

Measure: Pharmacokinetics: Area Under the Curve (AUC) of RGX-104.

Time: 24 months

14 Molecular Disease Profile of Haematological Malignancies. A Prospective Registry Study by the Rete Ematologica Lombarda (REL) Clinical Network

In this prospective multicentric study, the University of Pavia together with the Fondazione IRCCS Policlinico San Matteo, Pavia and the IRCCS Fondazione Maugeri, Pavia, Italy will provide a systematic analysis of gene mutations in hematological malignancies by using NGS techniques. Patients with a conclusive diagnosis of haematological malignancies according to WHO criteria referred to the Rete Ematologica Lombarda clinical network (REL, www.rel-lombardia.net) will be enrolled. The investigators will analyse genomic DNA extracted from hematopoietic cells at different time points of patient disease. The study contemplates the use of molecular platforms (Next Generation Sequencing, NGS) aimed at the identification of recurrent mutations in myeloid and lymphoid neoplasms, respectively. Screening of gene mutations by NGS will be prospectively implemented in the context of REL clinical network. Patient samples will be analyzed at diagnosis and sequentially during the course of the disease at specific timepoints. The researchers will analyze the correlations between somatic mutations, specific clinical phenotypes (according to the WHO classification) and disease evolution. This will allow to: 1) identify new recurrent genetic mutations involved in the molecular pathogenesis of hematological malignancies; 2) define the role of mutated genes, distinguishing between genes which induce a clonal proliferation of hematopoietic stem cells, and genes which determine the clinical phenotype of the disease; 3) identify mutations which are responsible for disease evolution; 4) define the diagnostic/prognostic role of the identified mutations, and update the current disease classifications and prognostic scores by including molecular parameters. A systematic biobanking of biological material will be provided.

NCT02459743 Hematological Malignancies
MeSH: Neoplasms
HPO: Neoplasm

Moreover in last years, researchers from the University of Pavia gave a significant contribution in the definition of the molecular basis of lymphoid neoplasms (i.e., BRAF V600E mutation in Hairy cell Leukemia, MYD88 L265P mutation in Waldenstrom disease, and SF3B1 mutations in Chronic Lymphocytic Leukemia). --- V600E ---

Primary Outcomes

Measure: Cumulative incidence of gene mutations in principal clone and subclones in each hematological malignancy

Time: 3 years

Secondary Outcomes

Measure: Genotype-phenotype correlations between clinical characteristics and mutational status

Time: 3 years

Measure: Overall survival and disease-free survival according to clinical and biological risk factors at diagnosis and during disease evolution

Time: 3 years

15 A Phase I Study to Evaluate the Pharmacokinetics and Safety of Repeat Oral Doses of Dabrafenib and the Combination of Dabrafenib With Trametinib in Chinese Subjects With Melanoma

Present clinical study will be conducted in China to evaluate the pharmacokinetics (PK) of single and repeat oral doses of dabrafenib alone and dabrafenib and trametinib in combination, the safety profile and the clinical activity of dabrafenib in combination with trametinib in Chinese melanoma subjects with BRAF V600E/K mutation. Approximately 20 evaluable subjects will be enrolled in the study, out of which, the first 10 subjects will be enrolled into cohort A (Part I and II) and remaining 10 subjects will be enrolled in cohort B. Subjects in cohort A (Part I) will receive dabrafenib 150 mg twice daily (BID) and subjects in cohort A (Part II) and Cohort B will receive combination of dabrafenib 150 mg BID and trametinib 2 mg once daily (QD). Study treatment will continue until disease progression, death or unacceptable toxicity. After disease progression, all enrolled subjects will be followed up for overall survival. The study will be completed after all subjects have died or surviving subjects have had at least 5 years of follow-up, whichever occurs first.

NCT02447939 Melanoma Drug: Dabrafenib Drug: Trametinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Pharmacokinetics of Repeat Oral Doses of Dabrafenib and the Combination of Dabrafenib and Trametinib in Chinese Subjects With Melanoma Present clinical study will be conducted in China to evaluate the pharmacokinetics (PK) of single and repeat oral doses of dabrafenib alone and dabrafenib and trametinib in combination, the safety profile and the clinical activity of dabrafenib in combination with trametinib in Chinese melanoma subjects with BRAF V600E/K mutation. --- V600E ---

- Histologically confirmed cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV (metastatic), and BRAF V600E/K mutation-positive from the designated qualified laboratory for this study. --- V600E ---

Primary Outcomes

Description: Maximum observed plasma concentration (Cmax), time to Cmax (Tmax) and area under the concentration-time curve over the dosing interval [AUC(0-tau)] will be calculated for dabrafenib and its metabolites.

Measure: Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) dose: Cmax,Tmax and AUC(0-tau)

Time: At Day 1: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Description: Tmax, minimum concentration at steady state (Css_min), maximum concentration at steady state (Css_max), average concentration at steady state (Css_av), AUC(0-tau) will be calculated for dabrafenib and its metabolites.

Measure: A Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) dose : Tmax, Css_min, Css_max, Css_av and AUC(0-tau)

Time: At Day 21: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Accumulation ratio of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) dose

Time: At Day 21.

Measure: Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose: Cmax, Tmax, AUC(0-tau)

Time: At Day 1: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Composite of PK parameters of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose : Tmax, Css_min, Css_max, Css_av, AUC(0-tau)

Time: At Day 21: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Accumulation ratio of dabrafenib and its metabolites following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose

Time: At Day 21.

Measure: Composite of PK parameters of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose: Cmax, Tmax, AUC(0-tau)

Time: At Day 1: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Composite of PK parameters of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose : Tmax, Css_min, Css_max, Css_av, AUC(0-tau)

Time: At Day 21: Pre dose, 1,2, 3, 4, 6, 8, 12 and 24 h post dose.

Measure: Accumulation ratio of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose

Time: At Day 21.

Measure: Effective half-life of trametinib following single and repeat dabrafenib (150 mg BID) and trametinib (2 mg QD) dose

Time: At Day 21.

Secondary Outcomes

Description: Physical examination will include assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and skin, genitourinary (pelvic) and rectal exams.

Measure: Composite of Physical examination assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Description: Vital sign measurements will include systolic and diastolic blood pressure, body temperature and pulse rate.

Measure: Composite of Safety and tolerability as assessed by vital signs assessment: blood pressure, temperature and pulse rate

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Description: 12-lead ECGs will be obtained at each time point using an ECG machine that automatically to calculate the heart rate and measures PR, QRS, QT and corrected QT interval duration (QTc intervals).

Measure: Electrocardiogram (ECG) assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Description: ECHO assessment will include an evaluation for left ventricular ejection fraction.

Measure: Echocardiogram (ECHO) assessment

Time: At week 4, week 8, and then every 8 weeks until treatment discontinuation.

Description: Eye exam will include indirect fundoscopic examination,visual acuity, visual field examination, and tonometry, with special attention to retinal abnormalities.

Measure: Eye exams assessment

Time: At screening, and when clinical indicated until treatment discontinuation.

Measure: Chemistry laboratory values assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Measure: Number of subjects with Adverse events (AEs)

Time: Up to 5 years.

Measure: Number of subjects with Serious Adverse events (SAEs)

Time: Up to 5 years.

Description: ORR defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation

Measure: Objective response rate (ORR)

Time: Up to 5 years.

Description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.

Measure: Progression free survival(PFS)

Time: Up to 5 years.

Description: OS defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact.

Measure: Overall survival(OS)

Time: Up to 5 years.

Measure: Hematology laboratory values assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

Measure: Urinalysis laboratory values assessment

Time: Up to 30 days of the subject's last dose (assessed up to 5 years).

16 Comparison of KRAS/BRAF Mutational Status Between Tumor Tissue Section Analysis With Conventional Techniques and Plasma Samples Analysis (KPLEX2)

The goal of this multicenter prospective study is to validate, and ultimately translate in routine clinical practice, the use of plasma analysis of ccfDNA for the determination of KRAS mutation status in mCRC patients.

NCT02784639 Colorectal Cancer Other: Plasma Analysis of circulating cell free DNA Other: Tumor tissue analysis of circulating cell free DNA
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

As a consequence, the method was adapted to detect the six more frequent KRAS mutations in CRC (G12D, G12V, G13D, G12S, G12C, G12A) and the BRAF V600E. --- G12D --- --- G12V --- --- G13D --- --- G12S --- --- G12C --- --- G12A --- --- V600E ---

CcfDNA analysis showed 100% specificity and sensitivity for the BRAF V600E mutation. --- V600E ---

Primary Outcomes

Description: Area under the ROC curve of the mutation percentage obtained from plasma ccfDNA analysis

Measure: Area under ROC curve

Time: 12 month

17 Prognostic Impact of Immunohistochemical and Molecular Expression of the Endocytosis Receptor LRP1 in Colonic Adenocarcinomas

Colorectal cancer (CRC) is a major public health problem in France and worldwide. CRC is the third most common cancer in incidence and mortality in France. The vast majority of these cancers are adenocarcinomas that arise sporadically and develop from precursor lesions: adenoma. All CCR with the same disease stage do not have the same prognosis. Various parameters have been identified as factors influencing the prognosis and allows adjustment of the treatment. The poor histoprognostic factors are vessels and nerves invasion by the tumor or the mucinous adenocarcinoma subtype. At the molecular level, the presence of microsatellite instability (MSI) improves the prognosis, while the presence of a BRAF mutation is an independent poor prognostic factor. LRP-1 is a multifunctional endocytic receptor that belongs to the family of LDL receptors. It is involved in the clearance of matrix proteases. A loss of expression or a decrease of the LRP-1 activity is correlated with an increase of aggressiveness of cancer cells. This effect was demonstrated in vitro in vesicular thyroid carcinomas after LRP-1 blocking. The decrease in the immunohistochemical expression and LRP-1 genomic in hepatocellular carcinomas and lung adenocarcinomas was correlated with a decrease in the overall survival. In CRC, only one immunohistochemical expression study of LRP-1 in colonic adenocarcinoma has been published to date. This study shows that tumor cells express LRP-1, but in nearly half the cases, weaker than in normal colonic cells. The clinical and prognostic impact of LRP-1 expression in colon cancer and its association with a particular molecular or morphological profile has not been studied to date. In this work, the investigators will study the immunohistochemical and genic expression of LRP-1 in a series of colorectal cancers.

NCT02788669 Colon Cancer Adenocarcinoma
MeSH: Adenocarcinoma Colonic Neoplasms
HPO: Colon cancer Neoplasm of the colon

- Immunohistochemical analysis on formalin fixed and paraffin embedded tissue will be performed: - qualitative and semi-quantitative evaluation of LRP1 immunoexpression with anti-5A6 and 8G1 antibodies - RER phenotype research (MLH1, MSH2, MSH6 and PMS2 immunohistochemistry) and BRAF V600E immunohistochemistry - Molecular analyzes: - analysis of LRP-1 gene expression on frozen tissue - for selected cases: search for microsatellite instability, search for BRAF V600E, KRAS (exon 2, 3 and 4) and NRAS (exons 2, 3 and 4) mutation on formalin fixed and paraffin embedded tissue Statistical analysis: - Data description: mean and standard deviation for quantitative variables; number and percentage for categorical variables. --- V600E ---

- Immunohistochemical analysis on formalin fixed and paraffin embedded tissue will be performed: - qualitative and semi-quantitative evaluation of LRP1 immunoexpression with anti-5A6 and 8G1 antibodies - RER phenotype research (MLH1, MSH2, MSH6 and PMS2 immunohistochemistry) and BRAF V600E immunohistochemistry - Molecular analyzes: - analysis of LRP-1 gene expression on frozen tissue - for selected cases: search for microsatellite instability, search for BRAF V600E, KRAS (exon 2, 3 and 4) and NRAS (exons 2, 3 and 4) mutation on formalin fixed and paraffin embedded tissue Statistical analysis: - Data description: mean and standard deviation for quantitative variables; number and percentage for categorical variables. --- V600E --- --- V600E ---

Primary Outcomes

Measure: LRP1 molecular expression

Time: between 2006 and 2012

18 Adoptive T Cell Immunotherapy for Advanced Melanoma Using Engineered Lymphocytes: A Phase 1b Study

Phase I clinical trial to determine the Phase II dose of autologous TIL 1383I TCR gene modified T Cells using a retrovirus. This is a novel National Cancer Institute (NCI) funded investigator initiated therapy for patients with advanced melanoma.

NCT02870244 Melanoma Biological: Escalating Doses
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

- Patients with V600E mutations are eligible if they have failed an approved BRAF inhibitor or MEK inhibitor therapy or have refused treatment with an approved BRAF inhibitor or MEK inhibitor. --- V600E ---

Primary Outcomes

Description: Establish a recommended phase II dose of autologous T cell receptor transduced T cells by evaluating unexpected Grade 2 adverse events through Grade 5 regardless of attribution, all toxicities attributed to the cells, and all incidences of intubation including the duration and reason for intubation.

Measure: Approximately 18 patients with Grade 2 through Grade 5 Adverse Events that are related to study drug, graded according to NCI CTCAE Version 4.0

Time: 4 weeks

Secondary Outcomes

Description: Change in T cell count from baseline to 4 weeks.

Measure: Immunologic changes in T cell count

Time: Baseline and 4 weeks

Description: Potential auditory changes from baseline to 4 weeks.

Measure: Audiologic changes of Grade 2 or higher as related to study drug, graded according to NCI CTCAE Version 4.0

Time: Baseline and 4 weeks

Description: Potential visual changes from baseline to 4 weeks.

Measure: Ophthalmologic changes or development of Uveitis of Grade 2 or higher as related to study drug, graded according to NCI CTCAE Version 4.0

Time: Baseline and 4 weeks

Description: CT scan or physical examination will be used to evaluate for a clinical objective response in patients who have received transduced T Cells at scheduled time points.

Measure: CT scans or physical examination from approximately 18 patients will be used to evaluate for a clinical objective response using RECIST Guideline Version 1.1

Time: Baseline and 4 weeks

19 A Phase I, Randomized, Open-label, Multi-center, Two Period Crossover Study to Investigate the Effect of Food on the Pharmacokinetics of a Single Oral Dose of RO5185426, Followed by Administration of 960 mg RO5185426 Twice Daily to BRAF V600E Positive Metastatic Melanoma Patients

This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. Patients will be randomized to receive in a crossover design single oral doses of RO5185426 with or without food, with a 10-day washout period between doses. Following the crossover periods, patients will receive RO5185426 orally twice daily on a continuous basis until disease progression or unacceptable toxicity occurs.

NCT01264380 Malignant Melanoma Drug: RO5185426 Drug: RO5185426 Drug: RO5185426
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

A Phase I, Randomized, Open-label, Multi-center, Two Period Crossover Study to Investigate the Effect of Food on the Pharmacokinetics of a Single Oral Dose of RO5185426, Followed by Administration of 960 mg RO5185426 Twice Daily to BRAF V600E Positive Metastatic Melanoma Patients. --- V600E ---

A Study of the Effect of Food on the Pharmacokinetics of Single Dose RO5185426 And the Safety And Efficacy of Continuous Administration in Patients With BRAF V600E Mutation-Positive Metastatic Melanoma This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. --- V600E ---

A Study of the Effect of Food on the Pharmacokinetics of Single Dose RO5185426 And the Safety And Efficacy of Continuous Administration in Patients With BRAF V600E Mutation-Positive Metastatic Melanoma This randomized, open-label, two period crossover study will evaluate the effect of food on the pharmacokinetics of a single dose of RO5185426 and the efficacy and safety of continuous administration in patients with BRAF V600E mutation-positive metastatic melanoma. --- V600E --- --- V600E ---

OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Malignant Melanoma Melanoma null --- V600E ---

OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.. Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Inclusion Criteria: - Adult patients, >/= 18 years of age - Histologically confirmed metastatic melanoma (Stage IV, American Joint Committee on Cancer) - Positive BRAF V600E mutation result determined by Cobas 4800 BRAF V600 Mutation Test - Previously treated patients must have failed at least one prior treatment regimen; if patients have received prior systemic treatments for metastatic melanoma, the time elapsed from previous therapy must be >/= 28 days; patients must have recovered fully from toxicities of all prior therapy - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Evaluable disease (measurable for disease progression according to RECIST criteria) - Adequate hematological, renal and liver function Exclusion Criteria: - Active CNS lesions - History of or known spinal cord compression or carcinomatous meningitis - Anticipated or ongoing administration of anti-cancer therapies other than those administered in this study - Previous malignancy within the past 5 years except for basal or squamous cell carcinoma of the skin, melanoma in-situ and carcinoma in-situ of the cervix - Previous treatment with BRAF inhibitor (sorafenib allowed) or MEK inhibitor - Refractory nausea or vomiting, malabsorption, external biliary shunt, or history of any type of gastrointestinal surgery that would preclude adequate absorption of study drug Malignant Melanoma Melanoma null --- V600E --- --- V600E ---

Primary Outcomes

Description: Pharmacokinetic (PK) analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC [0-inf]) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 hours (h) post-dose (pd) on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Sample With Last Measurable Concentration (AUC[0-last]) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Maximal Observed Plasma Concentration (Cmax) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: Single dose Pre-dose concentration is referred as Cmin here. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Minimum Observed (Trough) Plasma Concentration (Cmin) in the Fasted and Fed States

Time: Pre-dose on Periods A and B

Description: PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Time to Reach Maximal Plasma Concentration (Tmax) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: T1/2 is the time required for the concentration of the drug to reach half of its original value. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Terminal Elimination Half-Life (t1/2) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Description: Apparent first-order terminal elimination rate constant (kel), was calculated as the negative slope of the linear regression of the terminal phase in plasma vemurafenib concentration-time profile using specific appropriate time points. PK analyses was performed after the completion of Period A and Period B of this study for all participants.

Measure: Apparent First-order Terminal Elimination Rate Constant (Kel) in the Fasted and Fed States

Time: Period A: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 1; 24, 36, 48, 72, 96, 144, 192, and 240 h pd and Period B: pre-dose, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16 h pd on Day 11; 24, 36, 48, 72, 96, 144, 192, and 240 h pd

Secondary Outcomes

Description: BOR was defined as the best objective response assessed by investigator during the treatment period according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. BOR was the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. It is defined as the number of participants whose best objective response was complete response (CR) or partial response (PR) divided by the total number of efficacy evaluable participants. CR: disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes (whether target or non-target) were non-pathological in size (less than [<] 10 millimeter [mm] short axis). PR: at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Percentage of Participants With Best Objective Response (BOR) as Complete Response (CR) or Partial Response (PR)

Time: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until disease progression or death (Up to Week 124)

Description: OS was defined as the time, in months, from the date of the first study drug to the date of death, regardless of the cause of death.

Measure: Overall Survival (OS)

Time: From Baseline then Day 1 of Cycle 3 and 5 (21-day cycle) at Period C thereafter every 2 cycles until Cycle 12 followed by every 4 cycles from Cycle 13 until death (Up to Week 124)

20 BRF113929: An Open-Label, Two-Cohort, Multicentre Study of GSK2118436 as a Single Agent in Treatment Naïve and Previously Treated Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. Subjects in Cohort A will not have received any local brain therapy, and subjects in Cohort B will have received prior local therapy for brain metastases. Subjects will continue on treatment until disease progression, death, or unacceptable adverse event.

NCT01266967 Melanoma and Brain Metastases Drug: GSK2118436
MeSH: Melanoma Neoplasm Metastasis
HPO: Cutaneous melanoma Melanoma

A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. --- V600E ---

Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator. --- V600E ---

Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.. Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator. --- V600E ---

Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.. Duration of Intracranial Response for the Subset of V600E Mutation-positive Participants. --- V600E ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Duration of Overall Response for the Subset of V600E Mutation-positive Participants. --- V600E ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Progression-free Survival in V600E Mutation-positive Participants. --- V600E ---

If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters [e.g., percent change from Baseline]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.. Overall Survival of V600E Mutation-positive Participants. --- V600E ---

- Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation. --- V600E ---

Primary Outcomes

Description: OIR is defined as the number of participants whose intracranial response was a confirmed complete response (CR) or partial response (PR) assessed by investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR is defined as disappearance of all lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters (e.g., percent change from Baseline). For the primary analysis, OIR was measured when all participants in both treatment arms had two post-Baseline disease assessments. Participants who had an intracranial response of not evaluable or a missing response were treated as non-responders. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.

Measure: Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)

Secondary Outcomes

Description: OR is defined as the number of participants achieving either a CR (the disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) per modified RECIST, version 1.1. To determine the OR, the extracranial response was combined with the intracranial response. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol-scheduled assessment. Participants who had an overall response of not evaluable or a missing response were treated as non-responders.

Measure: Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 24 weeks)

Description: OR is defined as the number of participants achieving either a CR (the disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) per modified RECIST, version 1.1. To determine the OR, the extracranial response was combined with the intracranial response. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol-scheduled assessment. Participants who had an overall response of not evaluable or a missing response were treated as non-responders.

Measure: Number of Participants With V600K Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 17 weeks)

Description: OIR is defined as the number of participants whose intracranial response was a confirmed complete response (CR) or partial response (PF) assessed by investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters (e.g., percent change from Baseline). For the primary analysis, OIR was measured when all participants in both treatment arms had two post-Baseline disease assessments. Participants who had an intracranial response of not evaluable or a missing response were treated as non-responders. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.

Measure: Number of Participants With V600K Mutation-positive Melanoma With OIR, as Assessed by the Investigator

Time: From the time of the Baseline assessment until disease progression or end of study treatment (average of 16 weeks)

Description: Duration of Intracranial Response is defined as the time from the first documented evidence of intracranial CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented intracranial disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Intracranial Response for the Subset of V600E Mutation-positive Participants

Time: Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 27 weeks)

Description: Duration of Intracranial Response is defined as the time from the first documented evidence of intracranial CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented intracranial disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Intracranial Response for the Subset of V600K Mutation-positive Participants

Time: Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 31 weeks)

Description: Duration of Overall Response is defined as the time from the first documented evidence of overall CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Overall Response for the Subset of V600E Mutation-positive Participants

Time: Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 28 weeks)

Description: Duration of Overall Response is defined as the time from the first documented evidence of overall CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) until the time of the first documented disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).

Measure: Duration of Overall Response for the Subset of V600K Mutation-positive Participants

Time: Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 31 weeks)

Description: PFS is defined as the time from the first dose of study medication to the earliest of death or progression (at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters [e.g., percent change from Baseline]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Measure: Progression-free Survival in V600E Mutation-positive Participants

Time: Time from the first dose of study medication to the earliest of death or progression (average of 23 weeks)

Description: PFS is defined as the time from the first dose of study medication to the earliest of death or progression (at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters [e.g., percent change from Baseline]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Measure: Progression-free Survival in V600K Mutation-positive Participants

Time: Time from the first dose of study medication to the earliest of death or progression (average of 17 weeks)

Description: Overall survival (OS) is defined as the time from the first dose of study medication until death due to any cause. OS was censored using the date of last known contact for those participants who were alive at the time of analysis.

Measure: Overall Survival of V600E Mutation-positive Participants

Time: Time from the first dose of study medication until death due to any cause (average of 35 weeks)

Description: Overall survival (OS) is defined as the time from the first dose of study medication until death due to any cause. OS was censored using the date of last known contact for those participants who were alive at the time of analysis.

Measure: Overall Survival in V600K Mutation-positive Participants

Time: Time from the first dose of study medication until death due to any cause (average of 26 weeks)

Description: An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

Measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Clinical chemistry data were summarized at each scheduled assessment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade (G) 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death related to toxicity. Blood sample was collected for the assessment of glucose, potassium, magnesium, sodium, phosphorus, potassium. aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, total bilirubin, albumin, amylase, cholesterol, creatine kinase, gamma glutamyl transferase (GGT), lipase, blood pH, and triglycerides.

Measure: Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Clinical Chemistry Parameters

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Blood samples were collected for the assessment of hepatobiliary parameters. ALT=alanine aminotranserase; AST=aspartate aminotransferase; ALP=alkaline phosphatase; BIL=total bilirubin; INR=international normalized ratio; ULN=upper limit of normal. Hepato-cellular injury is defined as (ALT/ULN)/(ALP/ULN) >=5.

Measure: Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Hematology data were summarized at each scheduled assessment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe, Grade 4, life threatening, Grade 5, death related to toxicity. Blood sample was collected for the assessment of hemoglobin, white blood cells, and platelet count.

Measure: Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Hematology Parameters

Time: From Screening until the conclusion of the study (up to 103 weeks)

Description: Systolic and diastolic blood pressure were measured for all treated participants.

Measure: Mean Blood Pressure at Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36

Time: Baseline; Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36

Description: An increase in the QTc interval corrected using Bazett's formula (Bazett's QTc) was recorded for all treated participants. Grade 1 (450-480 milliseconds [msec]), Grade 2 (481-500 msec), Grade 3/4 (>=501 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade.

Measure: Number of Participants With a Worst-case On-therapy Increase From Baseline in Bazett's QTc Reading in the 12-lead Electrocardiogram (ECG)

Time: Baseline; Weeks 4, 12, 20, 28, 40, 52, and 64

Description: Echocardiograms (ECHO) were measured for all treated participants. An echocardiogram test gives information about the structure and function of the heart. LLN=lower limit of normal (determined by the institution).

Measure: Number of Participants With Abnormal Echocardiograms (ECHO) at Weeks 4 and 12

Time: Weeks (W) 4 and 12

Description: Summary statistics were calculated for each time point by cohort. The population pharmacokinetics were determined using a non-linear mixed effects modeling approach after pooling the data with other studies. These results are reported separately.

Measure: Median Concentrations of GSK2118436 and Its Metabolites Including GSK2285403, GSK2298683, and GSK2167542

Time: Week 4 (pre-dose and 1-3 hours post-dose) and Weeks 8, 16, 24, and 32 (either pre-dose in the morning or in the afternoon at 4-8 hours post-dose)

Description: This outcome measure could not be analyzed because too few participants participated in the dexamethasone study.

Measure: Composite of Pharmacokinetic Parameters of GSK2118436 in a Subset of Participants Receiving Dexamethasone

Time: Day 15

Description: The BRAF screening assay determines the specific BRAF mutational status (V600 E and K) in participants with metastatic melanoma who may benefit from treatment with GSK2118436. Per RECIST, version 1.1, CR is defined as the disappearance of all lesions. PR is defined as a >=30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline (BL) sum of the diameters (e.g., percent change from BL). Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as a >=20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir [smallest sum of diameters recorded since treatment start]). In addition, the sum must have an absolute increase from nadir of 5 millimeters. Not evaluable: cannot be classified by a preceding definition.

Measure: Number of Response Genetics Incorporated (RGI) Investigational Use Only (IUO) Assay Mutation Positive Participants and THxID BRAF Assay Mutation Positive Participants With the Indicated Best Intracranial Response

Time: Screening

21 A Phase 2 Trial of Oxaliplatin and Sorafenib Combination in Patients With Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma, Relapsed After a Cisplatin Based Treatment

In Spain, the gastric carcinoma is the 5th most frequent malignant tumor in women and the 6th in men, and represents the 3rd cause of cancer-related deaths amongst women and the 4th amongst men. The average of 5-year survival rate in Spain is under 30%. The main reason of it is that, despite carrying out an adjuvant treatment, more than the 50% will present relapsed disease. Sorafenib has been the first RAF inhibitor, both of RAF-1 and B-rRAF and its b-RAF variant V600E. Moreover, it has shown its ability to inhibit other tyrosin-quinase receptors as VEGFR 2 and 3, c-kit, Flt-3 or PDGFR. Its activity has been clearly proven in clear cell renal carcinoma. The mechanism by which Sorafenib seems to act is not because of the existence of a mutation of RAS or RAF, but because as there is a VHL shortage the HIP produces a VEGF, bFGF or TGF overexpression that produces in turn a hyper-stimulation on the RAF/ERK/MEK pathway. The RAF/MEK/ERK pathway and angiogenesis seem to be clearly involved in the gastric carcinoma tumorigenesis and progression. Because of that, it seems interesting to associate Sorafenib to an oxaliplatin-based chemotherapy, which has shown its effectiveness in relapsed patients after receiving cisplatin-based schemes. Moreover, there is a phase 1 trial confirming the tolerance of the oxaliplatin and Sorafenib association, describing partial responses amongst gastric cancer patients previously treated with cisplatin.

NCT01262482 Advanced or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (Relapsed After a Cisplatin Based Treatment) Drug: Oxaliplatin Drug: Sorafenib
MeSH: Adenocarcinoma Esophageal Neoplasms
HPO: Esophageal neoplasm

Sorafenib has been the first RAF inhibitor, both of RAF-1 and B-rRAF and its b-RAF variant V600E. --- V600E ---

Primary Outcomes

Description: Measurements according to RECIST criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan and Magnetic Resonance Imaging (MRI)

Measure: Progression free survival

Time: anticipated 3 years

Secondary Outcomes

Description: Measurements according to RECIST criteria (Response Evaluation Criteria in Solid Tumors). Main techniques: CT-scan and Magnetic Resonance Imaging (MRI)

Measure: Tumoral response

Time: anticipated 3 years

Description: Duration of the partial or total response to the treatment. Evaluation and classification according to RECIST criteria (Response Evaluation Criteria in Solid Tumors)

Measure: Response duration

Time: anticipated 3 years

Measure: Overall survival

Time: anticipated 3 years

Measure: Toxicity

Time: anticipated 3 years

22 A Phase Ib/II Clinical Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies

This is an open label, single arm phase 1 dose escalation study and phase 2 study of BBI608 in combination with paclitaxel in patients with advanced malignancies. Currently the study is only enrolling patients with thymic carcinoma.

NCT01325441 Cancer Drug: BBI608 Drug: Paclitaxel

If melanoma is positive for the V600E or V600K BRAF mutation, must have received at least one line of prior therapy with a BRAF-specific inhibitor; either alone or in combination. --- V600E ---

Primary Outcomes

Measure: Safety by reporting the adverse events and serious adverse events

Time: 6 months

Measure: Determination of the Recommended Phase 2 Dose by assessing dose-limiting toxicities (DLTs)

Time: 6 months

Secondary Outcomes

Measure: Preliminary anti-tumor activity of BBI608 when administered in combination with paclitaxel in patients with advanced malignancies by performing tumor assessments every 8 weeks

Time: 6 months

Measure: Pharmacokinetic profile of BBI608 and paclitaxel assessed by area under the plasma concentration versus time curve

Time: On Day 3 and Day 17 of the first cycle prior to dosing and 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 8.5, 9, 10, 11, 24 and 27 hours after first dose

23 A Phase 1 Safety and Tolerability Study of Personalized Live, Attenuated, Double-Deleted Listeria Monocytogenes (pLADD) Immunotherapy in Adults With Metastatic Colorectal Cancer

This study will evaluate the safety and tolerability of a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD) treatment in adults with metastatic colorectal cancer.

NCT03189030 Colorectal Neoplasms Biological: pLADD
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Colorectal Neoplasms Colorectal Neoplasms This single arm study is designed to evaluate the safety and tolerability of a personalized treatment in adults with metastatic colorectal cancer by first analyzing the expression of tumor-associated antigens and then treating the patients with a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD)-based immunotherapy. --- V600E ---

Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Inclusion Criteria: - metastatic colorectal cancer (mCRC) that is microsatellite stable (MSS) - able to provide adequate tumor tissue from at least 1 accessible tumor site - completed or have developed intolerance to a course of oxaliplatin- or irinotecan-based frontline therapy at Screening - on maintenance standard-of-care chemotherapies or on treatment holiday - Eastern Cooperative Oncology Group (ECOG) 0 or 1 - adequate organ function - progression of disease at the time of Enrollment Exclusion Criteria: - BRAF V600E mutation - known allergy to both penicillin and sulfa drugs - implanted devices that cannot be easily removed - immunodeficiency, immune compromised state or receiving immunosuppressive therapy Colorectal Neoplasms Colorectal Neoplasms This single arm study is designed to evaluate the safety and tolerability of a personalized treatment in adults with metastatic colorectal cancer by first analyzing the expression of tumor-associated antigens and then treating the patients with a personalized live, attenuated, double-deleted Listeria monocytogenes (pLADD)-based immunotherapy. --- V600E --- --- V600E ---

Primary Outcomes

Description: Number of patients with treatment-related adverse events as assessed by CTCAE v 4.0

Measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)

Time: Through study completion, an average of 12 months

24 ENABLE-NGS: Enhancing Diagnosis in Chronic B-cell Lymphoproliferative Disorders Using Next-Generation Sequencing

To enhance the diagnosis of unclassifiable, non-CLL B-LPDs using next-generation sequencing technology.

NCT03344809 Lymphoma
MeSH: Lymphoproliferative Disorders
HPO: Lymphoproliferative disorder

While some of these mutations, such as the BRAF V600E mutation in Hairy Cell Leukaemia (HCL)2, are now accepted as disease defining mutations, others such as MYD88 and NOTCH1/2 mutations are found in more than one subtype of B-LPD3. --- V600E ---

Primary Outcomes

Description: This will be reported as a percentage of the total number of cases sequenced

Measure: Proportion of cases where a definite category and/or detectable mutation can be identified.

Time: 2 years

Secondary Outcomes

Description: Age and sex distribution will be reported along with the proportion of cases in each immunomorphologic category

Measure: Demographics and distribution in each immunomorphological category

Time: 2 years

Description: The distribution of mutations within each immunomorphological category will be reported descriptively.

Measure: Correlation of each immunomorphological category with the mutation profile.

Time: 2 years

25 A Phase 1b Trial of Talimogene Laherparepvec in Combination With Dabrafenib and Trametinib in Advanced Melanoma With an Activating BRAF Mutation

The purpose of the study is to determine safety and tolerability of the combination of talimogene laherparepvec in combination with dabrafenib and trametinib in BRAF mutated advanced melanoma.

NCT03088176 Melanoma BRAF Gene Mutation Drug: Talimogene Laherparepvec 1 Million Pfu/Ml Inj,Susp,1Ml,Vil Drug: Talimogene Laherparep 100 Mil Pfu/Ml 1Ml Drug: Dabrafenib Drug: Trametinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Primary or recurrent Stage IIIB to IVM1c melanoma for whom surgery is not recommended 3. Activating BRAF mutation (limited to V600E or V600K mutations if being treated first-line, but can include any well-defined BRAF mutation after failure of prior immunotherapy) 4. Measurable disease defined as follows: At least one melanoma lesion that can be accurately and serially measured in one dimension and for which the longest diameter is ≥10 mm as measured by calipers, CT scan, or MRI. --- V600E ---

Primary Outcomes

Description: Number of DLT seen in the subject population

Measure: Rate of Dose Limiting Toxicities (DLT)

Time: 2 years

Secondary Outcomes

Description: per RECIST 1.1

Measure: Progression Free Survival

Time: 4 years

Description: per RECIST 1.1

Measure: Objective Response Rate

Time: 4 years

Description: Best change in tumor diameters

Measure: Change in tumor burden

Time: 4 years

Description: In responding patients, time from first dose to achieving objective response

Measure: Time to Response

Time: 4 years

Description: In responding patients, time from first evidence of objective response until progression or end of study

Measure: Duration of Response

Time: 4 years

Other Outcomes

Description: Change in diameters of individual lesions

Measure: Lesion-level objective response

Time: 4 years

Description: Exploratory analysis including number of participants with changes in CD8+ tumor infiltrating lymphocytes between pre-study and on-study biopsies

Measure: Biomarker analysis

Time: 4 years

26 A Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma

BRF113683 is a Phase III, randomized, open-label study comparing the efficacy, safety, and tolerability of GSK2118436 to dacarbazine (DTIC), in subjects with BRAF mutant advanced (Stage III) or metastatic (Stage IV) melanoma. Subjects will be randomized to receive 150 mg of GSK2118436 twice daily or 1000 mg/m2 DTIC every 3 weeks and continue on treatment until disease progression, death, or unacceptable adverse event. Subjects who progress on DTIC will be allowed to crossover to an optional extension arm of the study to receive GSK2118436.

NCT01227889 Cancer Drug: GSK2118436 Drug: Dacarbazine (DTIC)
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

The number of participants with non-melanoma skin lessions was assessed from the time of Screening until study completion or discontinuation from the study for any reason.. Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay. --- V600E ---

Multiple specimen per participant were analyzed.. Inclusion Criteria: - Adults at least 18 years of age - Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E) - Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed. --- V600E ---

- Certain cardiac abnormalities Inclusion Criteria: - Adults at least 18 years of age - Has advanced (unresectable Stage III) or metastatic (Stage IV) melanoma that is BRAF mutation positive (V600E) - Is treatment naive for advanced (unresectable) or metastatic melanoma, with the exception of Interleukin 2 (IL-2) which is allowed. --- V600E ---

Primary Outcomes

Description: PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). For participants who did not progress or die, PFS was censored at the date of last contact. Data are presented as median and 96% confidence interval.

Measure: Progression-free Survival (PFS) as Assessed by the Investigator

Time: Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)

Description: PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by an independent radiologist according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.

Measure: Progression-free Survival (PFS) as Assessed by an Independent Radiologist: Randomized Phase

Time: Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)

Secondary Outcomes

Description: Overall survival is defined as the interval of time between the date of randomization and the date of death due to any cause. For participants who did not die, overall survival was censored at the date of last contact.

Measure: Overall Survival

Time: Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months)

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

Measure: Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Randomized Phase

Time: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks)

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an independent radiologist per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

Measure: Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase

Time: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks)

Description: Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

Measure: Duration of Response as Assessed by the Investigator: Randomized Phase

Time: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 65.6 weeks)

Description: Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. NA indicates that data is not available.

Measure: Duration of Response as Assessed by an Independent Radiologist: Randomized Phase

Time: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 7.4 months)

Description: PFS2 is defined as the time from the first dose of GSK2118436, in participants randomized to DTIC who crossed over to GSK2118436 after initial progression, to the earliest date of radiographic or photographic disease progression or death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST version 1.1. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.

Measure: Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase

Time: Time from first dose of GSK2118436 in participants who crossover after initial progression to the earliest date of radiographical or photographical PD or death due to any cause (up to 6.4 months)

Description: A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.

Measure: Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Crossover Phase

Time: From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months)

Description: Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of PD or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.

Measure: Duration of Response as Assessed by the Investigator: Crossover Phase

Time: Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 6.4 months)

Description: Dermatological examinations were performed by the investigator, or at the discretion of the investigator, referred to a dermatologist. The number of participants with non-melanoma skin lessions was assessed from the time of Screening until study completion or discontinuation from the study for any reason.

Measure: Number of Participants With Non-melanoma Skin Lesions: Randomized Phase

Time: From Screening until study completion or discontinuation from the study (up to 9.9 months)

Description: Analytical and clinical validation of the companion diagnostic (cDx) assay was performed to determine the extent of agreement between the bioMerieux cDx assay (THxID BRAF Assay) and the Clinical Trial Assay (CTA) to detect BRAF mutations to determine participant eligibility into the study. Skin tissue samples collected at the Screening visit were used for this analysis. Multiple specimen per participant were analyzed.

Measure: Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay

Time: Screening

27 Randomized Controlled Trial of Total Thyroidectomy With and Without Prophylactic Central Neck Lymph Node Dissection in Patients With Low-risk Papillary Thyroid Cancer

Background: - Papillary thyroid cancer (PTC) often spreads to lymph nodes in the neck. This can be hard to detect. People often have lymph nodes removed anyway, and researchers want to study if this is a good idea. Objective: - To compare the effectiveness of removing lymph nodes in the neck that show no evidence of cancer along with the thyroid, or removing only the thyroid. Eligibility: - Adults age 18 and older with PTC or thyroid nodules suspicious for PTC, with no evidence that the disease has spread in the body. Design: - Participants will be screened with medical history, physical exam, blood tests, scans, and x-rays. - Participants will: - Answer questions. They may have a tumor biopsy. - Have a flexible laryngoscopy. A small tube will pass through the nose to the vocal cords. - Group 1: have surgery to remove the thyroid gland only. Lymph nodes in the neck will be removed if the cancer has spread. - Group 2: have surgery to remove the thyroid and lymph nodes in the neck. - At all post-surgery visits, participants will answer questions and have blood drawn. In addition: - 1 day: laryngoscopy. - 2 weeks: possible laryngoscopy. - 3 months: ultrasound of the thyroid and neck. - Discuss whether to try hormone treatment and/or radioactive iodine. - Possible diagnostic whole body radioiodine scan (WBS). Participants will swallow a capsule or liquid and lie under a camera. - 6 months: ultrasound and maybe laryngoscopy. - 1 year: diagnostic WBS and ultrasound. Participants may get thyroid stimulating hormone. - Participants will have annual follow-up visits for 10 years. They will have a physical exam, blood drawn, scans, and may complete a questionnaire.

NCT02408887 Low-risk Papillary Thyroid Cancer Endocrine Malignancy Thyroid Cancer Procedure: Total Thyroidectomy (TT) Procedure: Prophylactic central neck lymph node dissection(pCND)
MeSH: Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary
HPO: Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Correlation between BRAF V600E of tumor and median amount of time before disease progression. --- V600E ---

but less than or equal to 4 cm measured in greatest dimension and confirmed by the Laboratory of Pathology, NCI or confirmed by the pathology laboratory of the enrolling institution: - Indeterminate thyroid biopsy per Bethesda System for reporting thyroid cytopathology with BRAF V600E mutation or RET/PTC rearrangement - Cytologically or histologically suspicious or confirmed PTC per Bethesda System for reporting thyroid cytopathology. --- V600E ---

but less than or equal to 4 cm. in size with either: - inconclusive thyroid cytology positive for BRAF V600E mutation or RET/PTC rearrangement or - cytologically suspicious for or consistent with PTC - Absence of extrathyroidal extension or lymphadenopathy suggesting metastatic PTC on physical examination and neck ultrasound. --- V600E ---

Primary Outcomes

Description: Proportion of patients that have biochemical cure after totalthyroidectomy (TT) with and without pCND

Measure: Biochemical cure rates undergoing total thyroidectomy (TT) with and without pCND as measured by postoperative TSH-stimulated serum thyroglobulin (stim-Tg) at 3 months (prior to RAI treatment)

Time: 3 months

Secondary Outcomes

Description: Proportion of patients that have biochemical cure after TT with andwithout pCND

Measure: Biochemical cure rates in patients undergoing total thyroidectomy with and without pCND by postoperative TSH-stimulated serum thyroglobulin (stim-Tg) at 1 year postoperatively in patients who will not receive RAI or 1 year post remnant ablation

Time: 1 year

Description: Proportion of patients that have improvement in quality of life afterTT with and without pCND

Measure: The QOL of patients

Time: 10 years

Description: Proportion of patients that have improvement in voice quality,swallowing impairment after TT with and without pCND

Measure: Subjective voice quality, swallowing impairment

Time: 6 month

Description: Rate and duration hypoparathyroidism

Measure: Rate and duration of both symptomatic and asymptomatic hypoparathyroidism

Time: 6 month

Description: Proportion of patients that have cervical wound complications

Measure: Rate of cervical wound complications

Time: 3 month

Description: Correlation between BRAF V600E of tumor and median amount of time before disease progression

Measure: Correlation between BRAF V600E of tumor and median amount of time before disease progression

Time: at progression

Description: Proportion of patients that have less neck pain

Measure: Neck pain

Time: 6 month

28 Biopsy- and Biology-driven Optimization of Targeted Therapy of Metastatic Melanoma in BRAF Inhibitor Non-pretreated and Pretreated Subjects With Advanced, Non-resectable (STAGE IIIC) or Metastatic (StAGE IV) BRAF Mutation-positive Melanoma

This is an open-label, multi-center, clinical phase II study to explore the correlation of the genetic make-up of the treated tumor before start of therapy and to correlate clinical response at 8 weeks as well as metabolic response at 2 and 8 weeks with genetic features of the tumor. It will be conducted as a rationale optimization of targeted therapy in BRAF naïve and pretreated patients. Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B)

NCT02410863 Malignant Melanoma Drug: Dabrafenib Drug: Trametinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Prerequisite for all patients is the availability of tumor sample at start of treatment in order to determine the underlying driver mutation (BRAF mutational status) as well as molecular composition by next generation sequencing (NGS) and assessable lesions for biopsy at week 2. Melanoma patients in stage III (non-resectable) and stage IV are sorted into Cohort A or B according to their previous BRAF-treatment and treated with dabrafenib and trametinib (cohort A and B) Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.. To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.. Correlation of the tumor´s molecular composition to metabolic responses. --- V600E ---

3. Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-positive by the central laboratory. --- V600E ---

Primary Outcomes

Description: To broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial or complete response according to RECIST) at week 8 of targeted therapy in different pre-treated patients with advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.

Measure: Correlation of clinical response at week 8 of targeted therapy with molecular results of the biopsies.

Time: Week 8

Secondary Outcomes

Description: To correlate the tumor´s molecular composition to metabolic responses and biological effects on the downstream signaling cascade in order to get first insights into an adaptive mechanism in the downstream signaling of an oncogenic driver mutation upon its selective inhibition.

Measure: Correlation of the tumor´s molecular composition to metabolic responses

Time: Baseline, week 2 and 8

Description: Occurrence of adverse events and reactions

Measure: Safety / toxicity according to the Common Toxicity Criteria (CTC, Version 4.0)

Time: 1 year

Description: Proportion of patients with PFS after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs first.

Measure: Progression free survival rate

Time: 6 and 12 months

Description: Time after date of the first dose of study medication until documented date of death

Measure: Overall survival

Time: 6 and 12 months

Description: Time after date of the first dose of study medication until the first documented tumor progression date or date of death, whichever occurs

Measure: Progression free survival according to RECIST criteria

Time: 6 and 12 months

Description: Proportion of patients with PR and CR

Measure: Overall response rate according to RECIST criteria

Time: 6 and 12 months

Description: Proportion of patients with SD, PR and CR

Measure: Disease control rate according to RECIST criteria

Time: 6 and 12 months

29 An Open Label Non Randomized Access Study of Trametinib for Patients With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma

This is a single arm open label, multicenter, non randomized, access study of trametinib for subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV). Trametinib may be given as monotherapy or in combination since first line metastatic melanoma as per inclusion criteria. Subjects who received prior BRAF inhibitor may be included if they have not progressed under such treatment or if they have presented limited progression as per eligibility criteria. It is estimated that between 250 and 400 subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV) will be enrolled.

NCT02416232 Melanoma Drug: Trametinib Drug: Dabrafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

An Open Label Non Randomized Access Study of Trametinib for Patients With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma. --- V600E ---

Access Study of Trametinib for Subjects With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma This is a single arm open label, multicenter, non randomized, access study of trametinib for subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV). --- V600E ---

Access Study of Trametinib for Subjects With Advanced Unresectable (Stage IIIc) or Distant Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma This is a single arm open label, multicenter, non randomized, access study of trametinib for subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV). --- V600E --- --- V600E ---

It is estimated that between 250 and 400 subjects with histologically confirmed cutaneous melanoma with a BRAF V600E/K positive mutation that is either advanced unresectable (stage IIIc) or distant metastatic (stage IV) will be enrolled. --- V600E ---

- Has histologically confirmed cutaneous melanoma BRAF V600E/K positive mutation either unresectable (stage IIIc) or distant metastatic (stage IV). - Is not eligible for enrolment in any other ongoing relevant hypothesis testing clinical study for metastatic melanoma or, if eligible, is so geographically distant from a participating site that attending frequent clinic visits is not feasible. --- V600E ---


30 Phase 2 Study With COmbination of Vemurafenib With Cobimetinib in B-RAF V600E/K Mutated Melanoma Patients to Normalize LDH and Optimize Nivolumab and Ipilimumab therapY

Rationale: The combination of ipilimumab and nivolumab induces relatively high response rates and promising response depth in late stage melanoma. Nevertheless, it takes time till responses occur and still a significant number of patients do not benefit from treatment, due to rapid progressive disease or resistance to therapy. In contrast to immunotherapies targeted therapies (BRAF or MEK inhibitors), can induce faster and higher response rates, but often of shorter duration, even when combined. Initial attempts of combining vemurafenib or dabrafenib + trametinib with ipilimumab failed due to toxicity. Patients with elevated levels of serum LDH are less likely to respond to immunotherapy compared to patients with normal LDH levels. This does not mean that such patients do not benefit at all from immunotherapy. This raises the question, whether response rates upon immunotherapy can be improved by upfront reduction of tumor burden and normalization of LDH. The investigators postulate that induction therapy with combined BRAF+MEK inhibition, and subsequent LDH normalization, can improve response rates to the rates seen in LDH normal patients. To address this question the investigators have setup a randomized phase 2 trial in metastatic melanoma patients with elevated serum LDH comparing the response rates upon ipilimumab + nivolumab versus ipilimumab + nivolumab preceded by 6 weeks of vemurafenib + cobimetinib induction. Furthermore, less than half of the patients treated with the combination of ipilimumab and nivolumab received maintenance nivolumab, and approximately 40% of all patients discontinued treatment for toxicity. In 70% of patients responses were ongoing despite discontinuation of treatment due to toxicity. This raises the question, to what extent does maintenance therapy add clinical benefit to an ongoing immune response. Preclinical data indicate even that continuous restimulation of T cells can result in activation induced non-responsiveness (anergy). Therefore, a secondary objective of this trial will be, to test a response-driven nivolumab scheme Objectives: Primary Objective • To compare efficacy of induction vemurafenib + cobimetinib followed by ipilimumab + nivolumab (Arm A) versus upfront ipilimumab + nivolumab treatment (Arm B). Secondary Objectives - To describe duration of response and overall survival induced by vemurafenib + cobimetinib followed by the combination of ipilimumab + nivolumab (Arm A) as compared to ipilimumab + nivolumab (Arm B) - To describe the rate and quality of toxicity observed in the two study arms - To describe the rate of ongoing responses upon response-driven flat dose (240mg, q2w) nivolumab maintenance - To determine the immune-activating capacity of induction therapy with vemurafenib + cobimetinib followed by the combination of ipilimumab + nivolumab. - To evaluate the changes in systemic immune competence Study design: This is a two-arm phase 2 study consisting of 200 BRAFV600E/K mutation-positive late-stage melanoma patients with an elevated baseline LDH level (> ULN, < 3xULN) randomized 1:1 (stratified according to LDH) to receive either vemurafenib + cobimetinib directly followed by ipilimumab + nivolumab (Arm A) or standard first line ipilimumab + nivolumab (Arm B). Subsequently, patients in both arms will receive flat dose (240mg, q2w) nivolumab maintenance in a response-driven manner. Study population: Stage IV, or unresectable stage III, BRAFV600E/K mutation positive melanoma patients, naïve for BRAF/MEK, PD-1/PD-L1 or CTLA-4 targeting therapy, 18 years and older. Intervention: Patients will be randomized 1:1 to receive either 6 weeks vemurafenib 960 mg bid + cobimetinib 60 mg QD 21-day on, 7-day off (21/7) schedule, directly followed by 4 courses of ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm A) or first line standard 4 courses of ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm B). Subsequently, patients in both arms will receive nivolumab maintenance flat dose (240mg, q2w) in a response-driven manner according to their response at week 18. Main study parameters/endpoints: Primary Endpoints • Compare the best overall response rate (BORR) according to RECIST 1.1 of both arms at week 18 from start of treatment. Secondary Endpoints - Progression-free survival (PFS) according to RECIST 1.1 - Overall survival (OS) - Percentage of grade 3/4 toxicities according to CTCv4.03 - Percentage of ongoing response, percentage of patients requiring re-induction, response percentage upon re-induction - Changes in tumor-specific T cell responses

NCT02968303 Melanoma, Malignant, of Soft Parts Drug: Vemurafenib and Cobimetinib
MeSH: Melanoma Sarcoma, Clear Cell
HPO: Cutaneous melanoma Melanoma

Phase 2 Study With COmbination of Vemurafenib With Cobimetinib in B-RAF V600E/K Mutated Melanoma Patients to Normalize LDH and Optimize Nivolumab and Ipilimumab therapY. --- V600E ---

Inclusion Criteria: - Adults 18 years and older - World Health Organization (WHO) Performance Status 0-2 - Histologically or cytologically confirmed Stage IV, or unresectable stage III, BRAF V600E/K mutated melanoma - Measurable disease according to RECIST 1.1 - Signed and dated informed consent form - No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 - No prior BRAFi and/ or MEKi therapy - No immunosuppressive medications - Screening laboratory values must meet the following criteria and should be obtained within 10 days prior to randomization: - WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.0 mmol/L - Creatinine ≤ 2x ULN or creatinine clearance (CrCl) ≥ 40 ml/min - AST, ALT ≤ 3.0 x ULN (≤5 x ULN for patients with liver metastases) - Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL ) - LDH > ULN, < 5.0 x ULN - No symptomatic brain metastases (asysmptomatic brain metastases, accidentally found during screening can be included) - No leptomeningeal metastases - No active autoimmune disease requiring systemic treatment in the past 3 months or a documented history of autoimmune disease, or history of syndrome that required systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or immunosuppressive medications. --- V600E ---

- No underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events Inclusion Criteria: - Adults 18 years and older - World Health Organization (WHO) Performance Status 0-2 - Histologically or cytologically confirmed Stage IV, or unresectable stage III, BRAF V600E/K mutated melanoma - Measurable disease according to RECIST 1.1 - Signed and dated informed consent form - No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 - No prior BRAFi and/ or MEKi therapy - No immunosuppressive medications - Screening laboratory values must meet the following criteria and should be obtained within 10 days prior to randomization: - WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 5.0 mmol/L - Creatinine ≤ 2x ULN or creatinine clearance (CrCl) ≥ 40 ml/min - AST, ALT ≤ 3.0 x ULN (≤5 x ULN for patients with liver metastases) - Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL ) - LDH > ULN, < 5.0 x ULN - No symptomatic brain metastases (asysmptomatic brain metastases, accidentally found during screening can be included) - No leptomeningeal metastases - No active autoimmune disease requiring systemic treatment in the past 3 months or a documented history of autoimmune disease, or history of syndrome that required systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or immunosuppressive medications. --- V600E ---

Primary Outcomes

Measure: Best overall response rate (BORR) according to RECIST 1.1

Time: Week 18 from start of treatment

Secondary Outcomes

Measure: Progression-free survival (PFS) according to RECIST 1.1

Time: 1 and 2 years from start of treatment

Measure: Overall survival (OS)

Time: 1 and 2 years from start of treatment

Measure: Grade 3/4 toxicities according to CTCv4.03

Time: Week 18 from start of treatment

Measure: Percentage of ongoing response

Time: 1 and 2 years from start of treatment

Measure: Response percentage upon re-induction

Time: Week 18 from start of treatment

Measure: Changes in tumor-specific T cell responses

Time: Week 18 from start of treatment

31 An Open-label Multicenter Study on the Efficacy of Continuous Oral Dosing of Vemurafenib on Tumour Response in Previously Treated Patients With Metastatic Melanoma

This open-label single arm study will assess the efficacy, safety and tolerability of Vemurafenib in previously treated patients with metastatic melanoma. Patients will receive oral Vemurafenib [RG7204; PLEXXIKON: PLX4032] at a dose of 960 mg b.i.d. continuously until disease progression or withdrawal from study and will be assessed at regular intervals for tumour response and tolerability. Target sample size is <100 patients.

NCT00949702 Malignant Melanoma Drug: vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

DTIC, temozolomide, etc.) - BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay) - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active CNS metastases on CT/MRI within 28 days prior to enrollment - history of or known carcinomatous meningitis - previous treatment with BRAF (sorafenib allowed) or MEK inhibitor - cardiac dysrhythmias >2 NCI CTCAE or treatment with drugs with dysrhythmic potential - uncontrolled hypertension(>150/100mmHg) despite optimal medical therapy - infectious disease including HIV, HBV and HCV Inclusion Criteria: - adult patients >/=18 years of age - histologically confirmed metastatic melanoma (Stage IV, AJCC) - patients must have completed and failed at least one prior standard of care regimen (e.g. --- V600E ---

DTIC, temozolomide, etc.) - BRAF V600E positive mutation (by Roche CoDx BRAF mutation assay) - measurable disease by RECIST criteria - negative pregnancy test and, for fertile men and women, effective contraception during treatment and for 6 months after completion Exclusion Criteria: - active CNS metastases on CT/MRI within 28 days prior to enrollment - history of or known carcinomatous meningitis - previous treatment with BRAF (sorafenib allowed) or MEK inhibitor - cardiac dysrhythmias >2 NCI CTCAE or treatment with drugs with dysrhythmic potential - uncontrolled hypertension(>150/100mmHg) despite optimal medical therapy - infectious disease including HIV, HBV and HCV Malignant Melanoma Melanoma null --- V600E ---

Primary Outcomes

Description: BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.

Measure: Best Overall Response (BOR) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Secondary Outcomes

Description: BOR was defined as a complete response (CR) or partial response (PR) confirmed per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Patients who never received study treatment and treated patients without any post-baseline tumor assessments were considered as non-responders. CR: Disappearance of all target lesions, all non-target lesions, and no new lesion. Any pathological lymph nodes must have had reduction in the short axis to <10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesion.

Measure: Best Overall Response (BOR) Assessed by the Investigator Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: Duration of response was defined as the time interval between the date of the earliest qualifying response and the date of disease progression (PD) or death, only for those patients whose best overall response was complete response or partial response. PD: At least 20% increase in the sum of diameters of target lesions compared to Nadir (smallest sum of diameters on-study), unequivocal progression of existing non-target lesions, or presence of new lesion. For patients who were alive without progression, duration of response was censored on the date of the last evaluable tumor assessment.

Measure: Duration of Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: Time to response was defined as the interval between the date of the first treatment and the date of the first documentation of confirmed complete response (CR) or partial response (PR), whichever occurred first.

Measure: Time to Response Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: PFS was defined the time interval between the date of the first treatment and the date of progression or death from any cause, whichever occurred first. Deaths that occurred in patients without disease progression were considered to be a PFS event on the date of death. Patients who neither progressed nor died were censored on the date of the last evaluable tumor assessment prior to the data cutoff date.

Measure: Progression Free Survival (PFS) Assessed by an Independent Review Committee Using Response Evaluation Criteria In Solid Tumors (RECIST 1.1)

Time: From first treatment through September 27, 2010

Description: Overall survival was defined as the time from the date of the first treatment to the date of death, regardless of the cause of death. For patients who were alive at the time of analysis, overall survival was censored at the last date the patient was known to be alive prior to the data cutoff date.

Measure: Overall Survival

Time: From first treatment through September 27, 2010

Description: Three parameters were measured. (1) Improvement in the Physician's Assessment of Global Performance status on a 7-point scale (1=very much better to 7=very much worse). (2) Improvement in oxygen saturation requirements, defined as a clinically meaningful increase in oxygen saturation requirement (from a baseline value < 95% to ≥ 95% saturation using a pulse oximeter). (3) A decrease in total dose and frequency of narcotic pain analgesics. The percentage of patients showing improvement (1 and 2) or a decrease (3) are reported.

Measure: Improvement in Physical Symptoms (Improvement in Physician's Assessment of Global Performance Status and Oxygen Saturation Requirements, and Decrease in Total Dose and Frequency of Narcotic Pain Analgesics) During Treatment in Comparison to Baseline

Time: From first treatment through September 27, 2010

Description: Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin).

Measure: Maximum Plasma Concentration (Cmax) of Vemurafenib on Day 15 of Cycle 1

Time: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1

Description: Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and at 2, 4, 6, and 8 hours post-dose on Day 15 of Cycle 1. Pharmacokinetic parameters were estimated by non-compartmental analysis (Win Non-Lin). AUC0-8h was calculated using the linear trapezoidal rule.

Measure: Vemurafenib Plasma Level Area Under the Curve From 0 to 8 Hours (AUC0-8h) on Day 15 of Cycle 1

Time: Pre-dose to 8 hours post-dose on Day 15 of Cycle 1

Description: Blood samples for assessing the concentration of vemurafenib in plasma were drawn before the morning dose and 4 hours post-dose at Day 1 of Cycles 1, 2, 3, 4, 6, 8, and 10. Each Cycle was 3 weeks in duration.

Measure: Vemurafenib Plasma Levels at Various Treatment Cycles

Time: Pre-dose Cycle 1 Day 1 to 4 hours post-dose Cycle 10 Day 1

Description: Three electrocardiograms (ECG) were obtained pre-dose and 2, 4, 6, and 8 hours post-dose at Days 1 and 15 of Cycle 1 and again pre-dose and 4 hours post-dose at various Cycles throughout treatment. Five baseline triplicate ECGs were obtained before the start of treatment at the same time points used during treatment. Reported is the largest mean time-matched QTcP change from baseline. QTcP=QT/(60/heart rate)^β (β=mean [calculated separately for males and females] log-transformed QT versus log-transformed RR regression slopes using all available pre-treatment (baseline) ECG values.

Measure: Time-matched Change From Baseline in the Study Specific Corrected QT Interval (QTcP)

Time: Pre-dose Cycle 1 Day 1 to pre-dose Cycle 6 Day 1

Description: The intensity of adverse events was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) on a 5-point scale (Grade 1 to 5: Mild, Moderate, Severe, Life-threatening, and Death).

Measure: Percentage of Patients With Adverse Event

Time: From first treatment through September 27, 2010

32 A Multicenter, Open-label, Dose-escalation, Phase I Study of TAK-733, an Oral MEK Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies

The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics and maximum tolerated dose of TAK-733 in patients with advanced, nonhematologic tumors. The expansion stage of the study will evaluate evidence of antitumor activity of TAK-733 in patients with advanced metastatic melanoma.

NCT00948467 Advanced Non-hematologic Malignancies Advanced Metastatic Melanoma Drug: TAK-733
MeSH: Melanoma Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm

- Melanoma patients should have the V600E BRAF mutation status of their tumor documented, if available, and tumor tissue must be provided for confirmatory genotyping by a central laboratory. --- V600E ---

Primary Outcomes

Measure: Safety profile, dose-limiting toxicities, maximum tolerated dose and recommended phase 2 dose of TAK-733

Time: 12 months

Measure: Pharmacokinetic characterization of TAK-733

Time: 12 months

Secondary Outcomes

Measure: Effect of food on the pharmacokinetics of TAK-733

Time: 12 months

Measure: Antitumor activity of TAK-733 in patients with advanced nonhematologic malignancies

Time: 12 months

Measure: Antitumor activity of TAK-733 in melanoma patients

Time: 12 months

33 A Randomized Discontinuation, Blinded, Placebo-Controlled Phase II Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma

Uveal melanoma is the most common primary intra-ocular malignancy in adults with an incidence of 0.6 - 0.7 per 100,000 per year. Prognosis of metastatic uveal melanoma is poor. In retrospective analyses a median survival time after detection of metastases of 5 months (Flaherty et al, 1998) and 7 months (Kath et al, 1993) was reported. For patients receiving no treatment reported median survival was 2.0 months compared with 5.2 months for those receiving treatment for metastases (Gragoudas et al, 1991). Up to now there is no established treatment of metastatic uveal melanoma. Some therapeutic approaches with locoregional treatment or systemic chemotherapy have been undertaken: In case of metastatic disease which is confined to the liver in about 85% of patients with uveal melanoma surgical resection led to a median survival of 14 months (Mariani et al, 2009) or 19 months and a 5-year survival rate of 22% in a selected patient population (Adam et al, 2006). As locoregional treatment option treatment with fotemustine via direct intra-arterial hepatic infusion was investigated and led to a median survival of 15 months (Peters et al, 2006). This was not a randomized trial, but a report on 101 consecutive treated patients. Additional debulking surgery was performed whenever feasible. A randomized phase III trial comparing intra-arterial hepatic fotemustine administration with intravenous systemic fotemustine and overall survival as primary endpoint is still ongoing (EORTC 18021). Thus, no systemic chemotherapy is approved for metastatic uveal melanoma. Although no specific genes have been linked to the pathogenesis of uveal melanoma, preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Thus, sorafenib as inhibitor of b-Raf and Raf-1 (c-Raf or c-Raf-1), pro-angiogenic vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) may potentially lead to a benefit for patients with metastatic uveal melanoma in terms of disease control and prolongation of survival.

NCT01377025 Uveal Melanoma Drug: Placebo Drug: Sorafenib Drug: Sorafenib
MeSH: Melanoma Uveal Neoplasms
HPO: Cutaneous melanoma Melanoma

Thus, sorafenib as oral multi-kinase inhibitor that targets the Raf/MEK/ERK signaling pathway (CRAF, BRAF, V600E BRAF) in the cell and receptor tyrosine kinases (RTKs) such as VEGFR-2, VEGFR-3, and PDGFR-ß involved in tumor cell proliferation and angiogenesis may potentially lead to a benefit for patients with metastatic uveal melanoma in terms of disease control and prolongation of survival. --- V600E ---

Primary Outcomes

Measure: Progression Free Survival

Time: Every 8 weeks for 1 year

Secondary Outcomes

Measure: Number of patients with adverse events

Time: Every 8 weeks for 1 year

Measure: Overall Survival

Time: Every 8 weeks for 2 years

34 Combination of Targeted Therapy (Encorafenib and Binimetinib) Followed by Combination of Immunotherapy (Ipilimumab and Nivolumab) vs Immediate Combination of Immunotherapy in Patients With Unresectable or Metastatic Melanoma With BRAF V600 Mutation : an EORTC Randomized Phase II Study (EBIN)

This is a multicenter, 2-arm open-label, randomized comparative phase II study. The objective of this trial is to prospectively evaluate whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves progression free survival compared to combination immunotherapy nivolumab + ipilimumab alone in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

NCT03235245 Unresectable Stage III Melanoma Stage IV Melanoma Drug: Nivolumab + Ipilimumab Drug: Encorafenib + Binimetinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Inclusion Criteria: - Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma - Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment - Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E ---

Note: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on binimetinib treatment - Impaired cardiovascular function or clinically significant cardiovascular diseases - Uncontrolled hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100mmHg, despite current therapy - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to starting study treatment - History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including stroke, transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis Inclusion Criteria: - Histologically or cytologically confirmed unresectable stage III or IV cutaneous or mucosal melanoma - Presence of BRAF V600E or V600K mutation in tumor tissue prior to enrolment as per local assessment - Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses. --- V600E ---

Primary Outcomes

Description: PRS is defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. Progression will be assessed according to the RECIST criteria (version 1.1)

Measure: Progression Free Survival (PFS)

Time: 4.1 years from first patient in

Secondary Outcomes

Description: OS is defined as the time from the date of randomization to the date of death, whatever the cause.

Measure: Overall Survival (OS)

Time: 6 years from first patient in

Description: CR will be assessed according to the RECIST criteria (version 1.1)

Measure: Complete Response (CR) rate

Time: 4.1 years from first patient in

Description: Time to CR is defined as the time from the date of randomization until the occurrence of first CR.

Measure: Time to Complete Response (CR)

Time: 4.1 years from first patient in

Description: Duration of CR will be measured from the time measurement criteria for CR are first met until the first date that recurrence is objectively documented.

Measure: Duration of Complete Response (CR)

Time: 4.1 years from first patient in

Description: Best overall response will be assessed according to the RECIST criteria (version 1.1)

Measure: Best overall response rate

Time: 4.1 years from first patient in

Description: Time to best response is defined as the time from the date of randomization until the occurrence of the best response (CR or PR, whichever comes first). CR and PR will be assessed according to the RECIST criteria (version 1.1)

Measure: Time to best response

Time: 4.1 years from first patient in

Description: Best response duration will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. CR and PR will be assessed according to the RECIST criteria (version 1.1)

Measure: Duration of best response

Time: 4.1 years from first patient in

Description: This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.

Measure: Occurrence of adverse events

Time: 4.1 years from first patient in

Description: PFS2 is defined as the time from randomization to second objective disease progression, or death from any cause, whichever first. The second objective disease progression will be assessed according to the RECIST criteria (version 1.1)

Measure: Progression-free survival 2 (PFS2)

Time: 4.1 years from first patient in

35 Phase Ib Study to Test the Safety and Potential Synergy of Pembrolizumab (Anti-PD-1) and AMG386 (Angiopoietin-2 (Ang-2) in Patients With Advanced Solid Tumor

This research study is studying an investigational combination of drugs as a possible treatment for advanced solid tumors: melanoma, ovarian, renal, or colorectal cancer. The drugs involved in this study are: - Pembrolizumab - AMG386

NCT03239145 Advanced Solid Tumor Drug: Pembrolizumab Drug: Trebananib

Melanoma patients with BRAF V600E or V600K mutation-positive melanoma who have previously received a BRAF inhibitor with or without a MEK inhibitor) are eligible. --- V600E ---

Primary Outcomes

Measure: Dose Limiting Toxicity

Time: 2 years

Secondary Outcomes

Measure: Objective Response Rate

Time: 2 years

Measure: Progression Free Survival

Time: 2 years

Measure: Overall Survival

Time: 2 years

36 The TRIPLETE Study RANDOMIZED PHASE III STUDY OF TRIPLET mFOLFOXIRI PLUS PANITUMUMAB Versus mFOLFOX6 PLUS PANITUMUMAB AS INITIAL THERAPY FOR UNRESECTABLE RAS AND BRAF WILDTYPE METASTATIC COLORECTAL CANCER PATIENTS

- The association of FOLFOX (5-fluoruracil, folinic acid, and oxaliplatin) and pan is a standard option for the first-line treatment of unresectable RAS and BRAF wt mCRC patients. - The phase III TRIBE trial recently demonstrated that FOLFOXIRI (5-fluoruracil, folinic acid, oxaliplatin and irinotecan) plus bev significantly prolongs PFS and OS and increases RECIST response rate, ETS and DoR, as compared to FOLFIRI (5-fluoruracil folinic acid, and irinotecan) plus bev. The advantage provided by the intensification of the upfront chemotherapy backbone is independent of RAS and BRAF mutational status. - Some phase II trials recently assessed the safety and activity of the combination of three-drugs chemotherapy regimens with an anti-EGFR monoclonal antibody. Promising activity results in terms of RECIST response rate and R0 resection rate have been achieved, with some safety concerns with special regards to gastrointestinal toxicity. - In the phase II randomized MACBETH study the combination of a modified schedule of FOLFOXIRI with cetuximab determined remarkable activity results, with an acceptable and manageable safety profile. - The optimal duration of the upfront treatment with chemotherapy plus anti-EGFRs is not established. The phase II MACRO-2 trial suggested that interrupting FOLFOX after 4 months while continuing cet alone as maintenance, is a reasonable option. - Activity parameters (RECIST response rate, ETS, DoR) are clinically relevant endpoints, associated with longer survival, in particular with anti-EGFR moAb-based treatment. On the basis of these considerations, we designed the present phase III randomized trial of first-line mFOLFOXIRI plus pan versus mFOLFOX6 plus pan in RAS and BRAF wt unresectable mCRC patients.

NCT03231722 Metastatic Colorectal Cancer Drug: Panitumumab Drug: Irinotecan Drug: Oxaliplatin Drug: l-leucovorin Drug: 5-fluorouracil
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

- RAS (codons 12, 13, 59, 61, 117 and 146 of KRAS and NRAS genes) and BRAF (V600E mutation) wt status of primary colorectal cancer or related metastasis (local or central laboratory assessment). --- V600E ---

Primary Outcomes

Description: the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria

Measure: Overall response rate

Time: 12 months

Secondary Outcomes

Description: the percentage of patients, relative to the total of enrolled subjects, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 4.0)

Measure: Overall Toxicity Rate

Time: 24 months

Description: the percentage of patients, relative to the total of enrolled subjects, experiencing a specific adverse event of grade 3/4, according to National Cancer Institute Common Toxicity Criteria (version 4.0)

Measure: Toxicity Rate

Time: 24 months

Description: the time from randomization to the first documentation of objective disease progression or death due to any cause, whichever occurs first. Documentation of disease progressive disease is defined as per RECIST 1.1 criteria based on investigator assessment

Measure: Progression Free Survival

Time: 24 months

Description: the time from randomization to the date of death due to any cause

Measure: Overall Survival

Time: 48 months

Description: the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR) or partial (PR) response, according to RECIST 1.1 criteria based on central re-evaluation of CT scan images.

Measure: Centrally assessed Overall response rate

Time: 12 months

Description: the percentage of patients, relative to the total of the enrolled subjects, achieving a ≥20% decrease in the sum of diameters of RECIST target lesions at week 8 compared to baseline.

Measure: Early Tumour Shrinkage Rate

Time: up to 2 months from randomization

Description: the relative change in the sum of longest diameters of RECIST target lesions at the nadir, in the absence of new lesions or progression of non-target lesions, when compared with baseline.

Measure: Deepness of Response

Time: 12 months

Description: the percentage of patients, relative to the total of enrolled subjects, undergoing secondary R0 resection of metastases

Measure: R0 Resection Rate

Time: 12 months

37 Phase I/II Study of Nivolumab and Ipilimumab Combined With Nintedanib in Non Small Cell Lung Cancer

The main purpose of this study is to see if the combination of nivolumab, ipilimumab and nintedanib is effective in people with non- small cell lung cancer. Researchers also want to find out if the combination of nivolumab, ipilimumab and nintedanib is safe and tolerable.

NCT03377023 Non Small Cell Lung Cancer Lung Cancer, Nonsmall Cell Non Small Cell Lung Cancer Metastatic Drug: Nivolumab Drug: Ipilimumab Drug: Nintedanib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy. --- T790M --- --- V600E ---

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy. --- T790M --- --- V600E ---

Patients with NSCLC tumor known to harbor a genomic aberration for which FDA approved treatment is available (i.e, non-resistant EGFR mutations, EGFR T790M mutation, ALK rearrangement, ROS rearrangement, BRAF V600E mutation) are allowed to enroll if they have received prior treatment with the FDA approved targeted therapy - At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. --- T790M --- --- V600E ---

Primary Outcomes

Description: Dose escalation to determine the MTD and Recommended Phase 2 Dose (RP2D) of concurrent administration of nivolumab, ipilimumab, and nintedanib. The maximum tolerated dose (MTD) is defined as the dose with the dose limiting toxicity (DLT) rate of 30%.

Measure: Phase 1 - Maximum Tolerated Dose (MTD)

Time: Up to 12 months

Description: Objective response is defined as confirmed CR or confirmed PR based on modified RECIST guidelines version 1.1. The ORR will be estimated by calculating the proportion of patients who achieve OR; the 80% Confidence Interval (CI) and 95% CI for the OR rate will be estimated using the exact binomial distribution. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Measure: Phase 2 - Objective Response Rate (ORR) per Treatment Arm

Time: Up to 36 months

Secondary Outcomes

Description: Disease control is defined as CR, PR, or SD based on RECIST guidelines version 1.1 with modifications. The disease control rate (DCR) will be estimated by the proportion of patients who achieve DC, and its 80% CI and 95% CI will be estimated using the exact binomial distribution. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Measure: Phase 2: Disease Control Rate (DCR)

Time: Up to 36 months

Description: Overall survival will be determined as the time from the start of treatment with nivolumab plus ipilimumab plus nintedanib until death due to any cause. For patients who are alive at the time of data cut-off, OS will be censored on the last date when patients are known to be alive. The Kaplan-Meier method will be used to estimate the OS curve and the OS rate at time points of interest.

Measure: Phase 2: Overall Survival (OS)

Time: Up to 36 months

Description: Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

Measure: Phase 2: Progression-free Survival (PFS)

Time: Up to 36 months

38 A Phase 2 Study of AZD6244 in Biliary Cancers

This phase II trial is studying how well selumetinib works in treating patients with biliary cancer that cannot be removed by surgery. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT00553332 Liver and Intrahepatic Biliary Tract Cancer Recurrent Extrahepatic Bile Duct Cancer Unresectable Extrahepatic Bile Duct Cancer Drug: selumetinib Other: laboratory biomarker analysis
MeSH: Biliary Tract Neoplasms Bile Duct Neoplasms Cholangiocarcinoma
HPO: Biliary tract neoplasm Cholangiocarcinoma

To genotype tumors for the presence of RAS mutations (i.e., NRAS, KRAS, HRAS) and BRAF mutations (e.g., V600E) in biliary tumor samples from these patients. --- V600E ---

Primary Outcomes

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR

Measure: Objective Response Rate (CR and PR)

Time: Every 8 weeks

Secondary Outcomes

Description: Toxicitity will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 3.0

Measure: Toxicity Profile of AZD6244

Time: From the time of first treatment with AZD6244, assessed up to 4 weeks

Description: Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

Measure: Median Progression Free Survival for Patients

Time: Up to 6 months

Measure: Overall Survival

Time: Up to 12 months

Measure: RAS/RAF/MEK/ERK Signaling Pathway Activation

Time: At baseline

Description: Measure the proteins levels of RAS/RAF/MEK/ERK signaling pathway activation to AZD6244

Measure: Protein Levels of RAS/RAF/MEK/ERK Signaling Pathway Activation

Time: At baseline

39 Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression for Patients With Non-small Cell Lung Cancers Harboring Major Oncogenic Drivers

This phase II trial studies how well targeted therapy works in treating patients with incurable non-small cell lung cancer with a genetic mutation. Giving drugs that target other genetic mutations or other specific proteins may work better when a patient has cancer caused by a driver mutation and the treatment that targets that mutation stops working.

NCT02949843 EGFR Activating Mutation Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Drug: Chemotherapy Biological: Immunotherapy Other: Laboratory Biomarker Analysis Biological: Nivolumab Biological: Pembrolizumab Drug: Targeted Molecular Therapy Drug: Tyrosine Kinase Inhibitor
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

These tests will be performed overall and then separately in the three arms.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued EGFR Activating Mutation Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To estimate the objective response rate among patients with high PD-L1 expressing cancers after failure of targeted therapy. --- V600E ---

These tests will be performed overall and then separately in the three arms.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued Inclusion Criteria: - Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1 - Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene - Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial - Eastern Cooperative Oncology Group (ECOG) performance status of 0-3 - Total bilirubin =< 1.5 X institutional upper limit of normal - Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal - Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document Exclusion Criteria: - Emergent need for palliative radiation - Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer - Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded; breastfeeding should be discontinued EGFR Activating Mutation Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer Lung Neoplasms Carcinoma, Non-Small-Cell Lung PRIMARY OBJECTIVES: I. To estimate the objective response rate among patients with high PD-L1 expressing cancers after failure of targeted therapy. --- V600E --- --- V600E ---

Primary Outcomes

Description: A Simon's two-stage design will be used.

Measure: Objective response rate in patients with high PD-L1 expressing cancers after failure of targeted therapy defined as complete or partial response according to the investigator's assessment

Time: Up to 3 years

Secondary Outcomes

Description: Toxicities for each group will be estimated and described using counts and frequencies by grade, location and relatedness.

Measure: Incidence of adverse events measured using Common Terminology Criteria for Adverse Events version 4.0

Time: Up to 30 days after the last dose of study treatment

Measure: Incidence of mutations in secondary genes for patients with PD-L1 expression < 50%

Time: Up to 3 years

Description: Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table).

Measure: Objective response rates for patients without high PD-L1 expressing cancers

Time: Up to 3 years

Description: Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table).

Measure: Objective response rates for the combined population to historical controls receiving second or third line targeted agents

Time: Up to 3 years

Description: Estimated using Kaplan-Meier methods and survival rates will be compared using log-rank tests.

Measure: Overall survival

Time: From date of progression on primary targeted treatment to death, assessed up to 3 years

Measure: Rate of tobacco use and mutation burden based on PD-L1 expression at time of progression

Time: Up to 3 years

Description: Whether smoking status is related to the prevalence of any mutations identified (present/absent) will be examined using Cochran-Maentel Haenzel tests. These tests will be performed overall and then separately in the three arms.

Measure: Smoking status defined as current, former, never

Time: At baseline

40 An Exploratory Study of the Immunological Effects of Vemurafenib and Cobimetinib, Administered Alone and in Combination, in Subjects With Advanced BRAF V600E/K Mutant Melanoma

This trial explores the immunologic effects of vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), administered alone and in combination, to patients with advanced BRAF V600E/K mutant melanoma.

NCT02427893 Melanoma Drug: Cobimetinib Drug: Vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

An Exploratory Study of the Immunological Effects of Vemurafenib and Cobimetinib, Administered Alone and in Combination, in Subjects With Advanced BRAF V600E/K Mutant Melanoma. --- V600E ---

Trial of Vemurafenib and Cobimetinib in Patients With Advanced BRAFV600 Mutant Melanoma This trial explores the immunologic effects of vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), administered alone and in combination, to patients with advanced BRAF V600E/K mutant melanoma. --- V600E ---

Primary Outcomes

Description: compare immunologic changes described above with the development of study treatment-related adverse events. For example, severity or extent of rash from cobimetinib (a well-described dermatologic toxicity of MEK inhibitors) may be compared to levels of intratumoral immune activation assessed by one or more of the parameters.

Measure: Safety and tolerability of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma.

Time: 2 years

Secondary Outcomes

Description: compare immunologic changes described above with therapeutic outcomes, including CR, PR, SD, and PD measured by RECIST 1.1. For example, tumor regression may be correlated with levels of intratumoral immune activation or expression of immune checkpoints assessed by one or more of the parameters

Measure: Anti-tumor activity of cobimetinib monotherapy and combination vemurafenib/cobimetinib in subjects with advanced melanoma.

Time: 2 years

41 Phase II Study of Clofarabine in Patients With Recurrent or Refractory Langerhans Cell Histiocytosis and LCH-related Disorders

This research study is evaluating a drug called clofarabine as a possible treatment for Langerhans Cell Histiocytosis (LCH) and and other histiocytic disorders.

NCT02425904 Langerhans Cell Histiocytosis Drug: Clofarabine
MeSH: Histiocytosis Histiocytosis, Langerhans-Cell
HPO: Histiocytosis

ECD patients who have confirmed BRAF V600E mutation must have failed treatment with a BRAF inhibitor or are not considered to be eligible for such treatment. --- V600E ---

Primary Outcomes

Description: Responses will be assessed using the standard criteria proposed by the Histiocyte Society

Measure: Overall Response Rate

Time: Week 7

Secondary Outcomes

Measure: Progression Free Survival

Time: At three and five years

Measure: Overall Survival

Time: At three and five years

Measure: The proportion of patients who experience a toxicity-event requiring stopping clofarabine

Time: Baseline, Up to 24 weeks

Measure: Proportion of participants with grade 3-4 toxicity

Time: Baseline, Up to 24 Weeks

42 Immunohistochemical Detection of the BRAFV600E Mutation on Cytological Specimen in PTC

Immunohistochemical detection of the BRAF-V600E mutation on pre-operative fine needle aspiration biopsy (FNAB) from patients suspected for papillary thyroid carcinoma, using the mutation specific antibody VE1.

NCT02561533 Papillary Thyroid Carcinoma Other: BRAF detection on fine needle aspiration biopsy (FNAB)
MeSH: Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary
HPO: Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Detection of BRAF Mutation on FNAB From Papillary Thyroid Carcinoma Immunohistochemical detection of the BRAF-V600E mutation on pre-operative fine needle aspiration biopsy (FNAB) from patients suspected for papillary thyroid carcinoma, using the mutation specific antibody VE1. --- V600E ---

Therefore, pre-operative detection of the BRAF-V600E mutation may be of clinical interest in order to individualize treatment of patients with BRAF positive PTC. --- V600E ---

FNABs are performed immediately before the thyroid operation, and BRAF-V600E detection using VE1 is performed on clots. --- V600E ---

Primary Outcomes

Description: Mutations status correlated to histological diagnoses and mutation status on histological samples

Measure: Immunohistochemical detection of BRAF mutation on fine needle aspiration biopsy (FNAB)

Time: 1 day

43 Dose-seeking Study of Pembrolizumab Plus Vemurafenib and Cobimetinib for Therapy of Advanced Melanoma

The study plans to treat patients with pembrolizumab and thus blocking the PD-1/PD-L1 axis would render tumor-infiltrating lymphocytes (TILs) in the tumor parenchyma more functional as a consequence of BRAF inhibition, such that T cell activation by BRAFi would not be dampened by the PD-1/PD-L1 interaction. This combination would reverse dysfunction among T cells in the tumor parenchyma, maximizing T cell mediated immune anti-tumor efficacy. Progression free survival (PFS) with pembrolizumab in KEYNOTE-001 was 57% at 6 months, and 46.4% in the more recently reported phase III trial. PFS with vemurafenib treatment in BRIM-3 was ~50% at 6 months. Combined treatment with pembrolizumab, cobimetinib and vemurafenib for BRAF mutant melanoma is hypothesized to be safe and to improve the PFS compared to these recent historical controls. Because this combination has not yet been tested, and because the primary objective is to assess safety, the investigators are staging accrual in the first phase of the trial. The study aims to accrue up to 30 patients to the mTPI design of this study with the expectation that there will be at least 30 patients treated at RP2D. In case there are less than 30 patients on the RP2D, additional patients will be accrued. Patients will continue to receive treatment with pembrolizumab, vemurafenib and cobimetinib until disease progression or dose limiting toxicity. Patients with treatment response and no dose limiting toxicity may receive treatment with pembrolizumab for up to 24 months.

NCT02818023 Melanoma Drug: Pembrolizumab Drug: Vemurafenib Drug: Cobimetinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Only patients with BRAF V600E or V600K mutated tumors will be enrolled. --- V600E ---

Primary Outcomes

Description: determine the safety and maximum tolerated dose of vemurafenib and cobimetinib with pembrolizumab

Measure: Percentage of participants that experience a dose-limiting toxicity

Time: Up to 2 years

Secondary Outcomes

Measure: overall response rate (ORR)

Time: Up to 2 years

Measure: progression free survival

Time: Up to 2 years

Measure: overall survival

Time: up to 2 years

Other Outcomes

Measure: assessment of tumor microenvironment and immune response via biomarker level measurement

Time: Up to 2 years

44 A Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of PLX4032 in Patients With Solid Tumors

The primary objective of this FIH study is to assess the safety and pharmacokinetics of PLX4032 in patients with solid tumors. The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation.

NCT00405587 Malignant Melanoma Colorectal Carcinoma Drug: PLX4032
MeSH: Melanoma Colorectal Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the large intestine

The secondary objective is to assess the pharmacodynamic activity in paired biopsy specimens obtained from patients with malignant melanoma who have the V600E BRAF oncogenic mutation. --- V600E ---

Two extension cohorts of patients with confirmed V600E mutations will be recruited, consisting of advanced melanoma and metastatic colorectal carcinoma. --- V600E ---

Primary Outcomes

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Area Under the Plasma Concentration-Time Curve (AUC) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Peak Concentration (Cmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Peak Concentration (Cmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose on Day 15, pre-morning dose on Day 16

Measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 1 - Dose Escalation: Original Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Time to Peak Concentration (Tmax) of RO5185426 on Day 15 - Dose Escalation: Original Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, pre-morning dose on Day 16

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

Measure: Mean RO5185426 Accumulation Ratios - Dose Escalation: MBP Formulation

Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Description: Accumulation ratio is the ratio of AUC (0-8 hour) on Day 15 / AUC (0-8 hour) on Day 1.

Measure: Mean RO5185426 Accumulation Ratios - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Day 1 and Day 15: pre-morning dose and at 0.5, 1, 2, 4, and 8 hours post-morning dose

Measure: Cmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Cmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Measure: Tmax of RO5185426 on Day 1 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Tmax of RO5185426 on Day 15 - Dose Escalation: MBP Formulation

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals zero (0) to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: AUC of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Cmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Cmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- Positive CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15 and pre-morning dose on Day 16

Measure: Tmax of RO5185426 on Day 1 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1, pre-morning dose on Day 2 and Day 8

Measure: Tmax of RO5185426 on Day 15 - Extension: BRAFV600E- Positive Melanoma and BRAFV600E- CRC

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 15, and pre-morning dose on Day 16

Description: BOR of confirmed /unconfirmed (total) response was defined as CR or PR recorded from baseline until disease progression/recurrence according to Response Evaluation Criteria In Solid Tumors (RECIST) v 1.0 criteria. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30 percent (%) decrease in the sum of longest diameters of the TLs, taking as a reference the baseline (BL) sum of longest diameters. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With a Confirmed and an Unconfirmed Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) According to RECIST Version (v) 1.0 - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Confirmed responses were those which were confirmed by repeat assessments performed no less than four weeks after the criteria for response are first met Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Extension: BRAFV600E- Positive CRC

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: Original Formulation

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: BOR of CR or PR was recorded from baseline until disease progression/recurrence according to RECIST v 1.0 criteria. For TLs, CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the sum of longest diameters of the TLs, taking as a reference the BL sum of longest diameters. For NTLs, CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. Percentage of participants with best overall response rate was calculated as the (number of participants with CR or PR) divided by (total number of participants in the cohort), and then multiplied by 100. The 95% Cl was determined using the Pearson-Clopper method.

Measure: Percentage of Participants With BOR of CR or PR According to RECIST v1.0 - Dose Escalation: MBP Formulation

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Secondary Outcomes

Description: Duration of response for participants with confirmed CR or PR was the period of time measured between the date that the criteria for objective CR or PR (whichever status was recorded first) was met, and the first date that recurrent or PD was objectively documented (or death if before progression). PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). In the event of no disease progression or documented death prior to study termination, analysis cutoff, or initiation of confounding anticancer therapy, duration of response was censored at the date of the last evaluable tumor assessment.

Measure: Duration of CR or PR Using RECIST v 1.0 - Extension BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 337 days)

Description: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was defined according to the RECIST criteria (v 1.0) as increase by at least 20% in the sum of the longest diameters of each TL, taking as a reference the smallest sum of the longest diameters, reported since the start of treatment, or appearance of one or more new lesions. For Non-TLs, PD was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs.

Measure: Percentage of Participants With Progression-Free Survival (PFS) Using RECIST v 1.0 - Melanoma Extension Cohort

Time: Month 1, 3, 4, 6, 9, and Last event (350) days

Description: PFS was the period of time measured from the date of initiation of therapy to the date of the appearance of new metastatic lesions, objective tumor progression, or death if before progression. PD was at least a 20% increase in the sum of longest diameters of TLs taking as reference the smallest sum of longest diameters recorded since the baseline measurements, or the appearance of one or more new lesion(s). For Non-TLs, disease progression was defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-TLs. In the event of no disease progression or documented death prior to study termination, analysis cutoff, or start of confounding anticancer therapy, PFS was censored at the date of the last evaluable tumor assessment.

Measure: PFS Using RECIST v1.0 - Extension BRAFV600E Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to data cutoff (up to 421 days)

Measure: Percentage of Participants Who Died - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Description: OS was the period of time measured from the date of initiation of therapy to the date of the death. In the event of no death prior to study termination or analysis data cutoff, OS was censored at the last known date that the patient was alive as documented on the follow-up case report form. If this date was not available, then the last known alive date from the database was used.

Measure: Overall Survival (OS) - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, until PD, or end of efficacy follow-up, up to 444 days

Description: Time to CR or PR was defined as the interval between the date of the first treatment to the date of the first documentation of confirmed CR or PR whichever occurred first, and not the date of confirmation at the subsequent tumor assessment. Time to response = Date of first response - initial dose date + 1.

Measure: Time to CR or PR Using RECIST v1.0 - Extension: BRAFV600E- Positive Melanoma

Time: Screening, BL, and up to 168 days

Description: AUC (0-8 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 8 hours post-dose. AUC (0-24 hour) was defined as the area under the plasma concentration-time curve from time equals 0 to 24 hours post-dose. AUC (0-8 hour) and AUC (0-24 hour) were computed using the linear trapezoidal rule.

Measure: Mean Dose-Normalized Steady-State AUC of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma

Time: Pre-morning dose and at 0.5, 1, 2, 4, and 8, and 24 hours post-morning dose

Measure: Mean Dose-Normalized Steady-State Cmax of RO5185426 80 mg and 120 mg Capsules - Dose Escalation: MBP Formulation and Extension: BRAFV600E- Positive Melanoma

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2 and Day 8, and Day 16

Description: Tumor uptake of FDG was assessed by means of positron-emission tomography (PET)

Measure: Decrease in Tumor Uptake of 18F-fluorodeoxyglucose (FDG)

Time: BL and Day 15

Measure: Cmax of RO5185426 - Food Effect

Time: Pre-morning dose, 0.5, 1, 2, 4, and 8 hour post-morning dose on Day 1 and 15, pre-morning dose on Day 2, Day 8, and Day 16

Description: The immunohisto-chemical analyses of the expression of phosphorylated ERK, cyclin D1, and Ki-67 in tumor-biopsy specimens was performed using hematoxylin and eosin staining.

Measure: Tumor Levels of Phosphorylated Extracellular Signal-Regulated Kinapse (ERK), Cyclin D1, and Ki-67

Time: BL and Day 15

45 A Phase 1 and Phase II and Re-Treatment Study of AZD6244 for Recurrent or Refractory Pediatric Low Grade Glioma

This phase I/II trial studies the side effects and the best dose of selumetinib and how well it works in treating or re-treating young patients with low grade glioma that has come back (recurrent) or does not respond to treatment (refractory). Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01089101 Low Grade Glioma Recurrent Childhood Pilocytic Astrocytoma Recurrent Neurofibromatosis Type 1 Recurrent Visual Pathway Glioma Refractory Neurofibromatosis Type 1 Refractory Visual Pathway Glioma Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Selumetinib
MeSH: Glioma Astrocytoma Neurofibromatoses Neurofibromatosis 1 Neurofibroma Optic Nerve Glioma
HPO: Astrocytoma Glioma Neurofibromas Optic nerve glioma Subependymal giant-cell astrocytoma

It is unlikely that sufficient numbers of subjects will be followed until death to statistically support estimation of the survival distributions but survival estimation will also be considered.. Presence or absence of BRAF V600E mutations or BRAF KIAA1549 fusion as assessed by immunohistochemistry and fluorescence in situ hybridization, respectively (phase II). --- V600E ---

To assess the sustained response rate of AZD6244 administered at 25 mg/m^2/dose twice daily (BID), in a single arm Phase II setting in patients assigned to strata based on neurofibromatosis (NF)-1 status and presence or absence of v-raf murine sarcoma viral oncogene homolog B (BRAF) aberrations, specifically BRAF V600E mutations and/or BRAF KIAA1549 fusion identified by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively. --- V600E ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Measure: Maximum tolerated dose and recommended phase 2 dose of selumetinib determined by dose-limiting toxicities (phase I)

Time: 28 days

Description: For each stratum separately exact confidence interval estimates will be provided for the true, unknown rates of objective response. In addition, the confirmed sustained objective response rate observed during treatment by cumulative incidence functions will be estimated. This provides not only an overall estimate of the response rate but also an estimate of the timing of responses as a function of number of months of treatment.

Measure: Stratum-specific objective response (complete response + partial response) rate sustained for 8 weeks (phase II)

Time: 40 weeks

Description: Exact confidence interval estimates will be provided.

Measure: Objective response (objective response = complete response + partial response) (re-treatment study)

Time: Up to 48 weeks

Description: Disease stabilization rates will be measured.

Measure: Disease stabilization rates (re-treatment study)

Time: At 1 year

Secondary Outcomes

Description: Plasma drug concentrations and pharmacokinetic parameters volume of the central compartment, elimination rate constant, half-life, apparent oral clearance, and area under the plasma concentration time curve.

Measure: Plasma drug concentrations and pharmacokinetic parameters (Phase I)

Time: Day 1 of course 1

Description: Kaplan-Meier estimates of distributions of PFS all eligible subjects who received at least one dose of selumetinib will be provided separately for each stratum. It is unlikely that sufficient numbers of subjects will be followed until death to statistically support estimation of the survival distributions but survival estimation will also be considered.

Measure: Stratum-specific progression-free survival distribution (PFS) (phase II)

Time: From the date of initial treatment to the earliest date of disease progression, second malignancy or death for subjects who fail; and to the date of last contact for subjects who remain at risk for failure assessed for up to 30 days

Description: Frequency tables summarizing the presence and absence of BRAF aberrations in all patients from whom tissue is available will be provided. The association of presence/absence and type of BRAF aberrations versus PFS will be explored via Kaplan-Meier-plots. Log-rank tests and/or Cox regression models may also be used to assess statistical associations between BRAF and PFS provided more than 10 events are observed in a given strata to make such assessments meaningful.

Measure: Presence or absence of BRAF V600E mutations or BRAF KIAA1549 fusion as assessed by immunohistochemistry and fluorescence in situ hybridization, respectively (phase II)

Time: Up to 30 days

Description: Kaplan-Meier estimates of progression-free survival distributions for all eligible patients will be provided. Exact confidence interval estimates will be provided.

Measure: Progression-free survival (retreatment study)

Time: From the date of re-treatment initiation to the earliest date of disease progression, second malignancy or death for patients who fail; and the last contact for patients who remain at risk for failure, assessed up to 30 days

46 A Phase 1/2 Study of BMS-908662 (XL281) Alone or in Combination With Cetuximab in Subjects With K-RAS or B-RAF Mutation Positive Advanced or Metastatic Colorectal Cancer

The purpose of the study is to identify a safe and tolerable dose of BMS-908662 in combination with cetuximab; and then to evaluate the tumor response to BMS-908662 when administered alone or in combination with cetuximab

NCT01086267 Colorectal Cancer Drug: BMS-908662 Drug: BMS-908662 Drug: Cetuximab
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

Inclusion Criteria: - Subjects with K-RAS (codon 12 or 13) or B -RAF (V600E) mutation positive advanced or metastatic colorectal cancer who have relapsed or are refractory to 2 or more standard systemic anticancer regimes for metastatic disease, or are intolerant to existing therapies. --- V600E ---

Primary Outcomes

Measure: Toxicity will be evaluated according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 3

Time: Assessments every 1-2 weeks while receiving study drug

Secondary Outcomes

Measure: Efficacy as determined by estimates of objective response rates and response duration

Time: Efficacy measured at least every 8 weeks while receiving study drug

Measure: Pharmacodynamics (PD) will be assessed by evaluating markers of RAS/RAF pathway activity

Time: PD assessed during the first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by minimum observed concentrations [Cmin].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by maximum observed concentrations [Cmax].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by time of maximum observed concentration [Tmax].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by area under the concentration-curve for one dosing interval [AUC(TAU)].

Time: PK measured during first 4 weeks on study

Measure: Pharmacokinetics (PK) for BMS-908662 as determined by accumulation index [AI].

Time: PK measured during first 4 weeks on study

47 Association Between BRAF V600E and Redifferentiation Therapy in Patients With Radioiodine-refractory Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) is the most common neoplasia in the thyroid gland. The combination of surgery, followed by radioiodine therapy (RIT) and thyroid-stimulating hormone (TSH) suppressive therapy is usually a curative option for differentiated thyroid cancer (DTC). Although DTC has a good prognosis generally, it is problematic when dedifferentiation is suspected and radioiodine refractoriness presumed. One possible therapy option for redifferentiation is the pretreatment with retinoids. From 2008 to 2014 there were 13 patients with PTC who were treated with retinoids after thyroidectomy before a further course of radioiodine. A recent study has shown that the efficacy of Selumetinib, another option for redifferentiation depends on the mutational status of the treated patient. In this retrospective study the investigators looked for a similar association between BRAF V600E and redifferentiation therapy with retinoids. As retinoids have fewer side effects compared to TKI, it is worth performing studies to assess the importance of genetic marker for the response and to estimate the chances of this specific patient collective. BRAF V600E seems to be associated with better long-term response after redifferentiation therapy with 13-cis RA in RAI-R PTC. Therefore, evaluation of BRAF mutational status prior to redifferentiation therapy could be beneficial for predicting response.

NCT03363347 Thyroid Cancer Drug: Redifferentiation with retinoid acid
MeSH: Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary
HPO: Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Association Between BRAF V600E and Redifferentiation Therapy in Patients With Radioiodine-refractory Papillary Thyroid Cancer. --- V600E ---

BRAF V600E and Redifferentiation Therapy in Radioiodine-refractory Papillary Thyroid Cancer Papillary thyroid cancer (PTC) is the most common neoplasia in the thyroid gland. --- V600E ---

In this retrospective study the investigators looked for a similar association between BRAF V600E and redifferentiation therapy with retinoids. --- V600E ---

BRAF V600E seems to be associated with better long-term response after redifferentiation therapy with 13-cis RA in RAI-R PTC. --- V600E ---

Primary Outcomes

Description: Redifferentiation therapy was performed using 13-cis RA (Isotretinoin, Roaccutan®) with a daily dose of orally 1,5mg/kg for up to two months. For assessment of clinical outcome of 13-cis retinoic acid treatment three parameters, tumor size, thyroglobulin levels and radioiodine uptake were considered in a graduated model.

Measure: Response to radioiodine therapy after redifferentiation

Time: 7 years

Secondary Outcomes

Description: Tumor size was evaluated form CT, MRI, or FDG-PET/CT imaging, comparing results before and after redifferentiation and RIT, results were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST).

Measure: Parameter tumor size

Time: 7 years

Description: Non-stimulated serum Tg level (in ng/ml) before redifferentiation therapy was compared with the first Tg level after redifferentiation and RIT. A stable Tg level was defined as ≤10% difference.

Measure: Parameter thyroglobulin levels (serum Tg)

Time: 7 years

Description: Recovery of RI-Uptake was evaluated from the post-therapy whole body scan in comparison to the lesions in CT, MRI, or FDG-PET/CT imaging before redifferentiation. Optimal uptake was defined as intensive accumulation of radioiodine in all tumor lesions. When not all lesions accumulate radioiodine or the signal was weak it was considered as suboptimal uptake.

Measure: Parameter radioiodine-uptake (RI-Uptake)

Time: 7 years

48 S1613, A Randomized Phase II Study of Trastuzumab and Pertuzumab (TP) Compared to Cetuximab and Irinotecan (CETIRI) in Advanced/Metastatic Colorectal Cancer (mCRC) With HER-2 Amplification

This randomized phase II trial studies how well trastuzumab and pertuzumab work compared to cetuximab and irinotecan hydrochloride in treating patients with HER2/neu amplified colorectal cancer that has spread from where it started to other places in the body and cannot be removed by surgery. Monoclonal antibodies, such as trastuzumab and pertuzumab, may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as cetuximab and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trastuzumab and pertuzumab may work better compared to cetuximab and irinotecan hydrochloride in treating patients with colorectal cancer.

NCT03365882 Colon Adenocarcinoma ERBB2 Gene Amplification Rectal Adenocarcinoma Recurrent Colon Carcinoma Recurrent Rectal Carcinoma Stage III Colon Cancer AJCC v7 Stage III Rectal Cancer AJCC v7 Stage IIIA Colon Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Colon Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Colon Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IV Colon Cancer AJCC v7 Stage IV Rectal Cancer AJCC v7 Stage IVA Colon Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Colon Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7 Biological: Cetuximab Drug: Irinotecan Hydrochloride Other: Laboratory Biomarker Analysis Biological: Pertuzumab Biological: Trastuzumab Device: HER-2 testing
MeSH: Carcinoma Colorectal Neoplasms Adenocarcinoma Rectal Neoplasms Colonic Neoplasms
HPO: Carcinoma Colon cancer Neoplasm of the colon Neoplasm of the large intestine Neoplasm of the rectum

The associations between HER-2/CEP17 signal ratio and response will be explored via Logistic regression.. Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Colon Adenocarcinoma ERBB2 Gene Amplification Rectal Adenocarcinoma Recurrent Colon Carcinoma Recurrent Rectal Carcinoma Stage III Colon Cancer AJCC v7 Stage III Rectal Cancer AJCC v7 Stage IIIA Colon Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Colon Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Colon Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IV Colon Cancer AJCC v7 Stage IV Rectal Cancer AJCC v7 Stage IVA Colon Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Colon Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7 Carcinoma Colorectal Neoplasms Adenocarcinoma Rectal Neoplasms Colonic Neoplasms PRIMARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP compared to control arm (Arm 2) of cetuximab and irinotecan hydrochloride (irinotecan) (CETIRI). --- V600E ---

The associations between HER-2/CEP17 signal ratio and response will be explored via Logistic regression.. Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Inclusion Criteria: - STEP 1 INITIAL REGISTRATION: HER2 TESTING - Patients must have histologically or cytologically documented adenocarcinoma of the colon or rectum that is metastatic or locally advanced and unresectable - Mutation results: - All patients must have molecular testing performed in a Clinical Laboratory Improvement Act (CLIA) certified lab which includes which includes KRAS and NRAS gene and exon 15 of BRAF gene (BRAF V600E mutation); patients with any known activating mutation in exon 2 [codons 12 and 13], exon 3 [codons 59 and 61] and exon 4 [codons 117 and 146]) of KRAS/NRAS genes and in exon 15 (BRAFV600E mutation) of BRAF gene are not eligible - Patients must not have been treated with any of the following prior to step 1 initial registration: - Cetuximab, panitumumab, or any other monoclonal antibody against EGFR or inhibitor of EGFR - HER-2 targeting for treatment of colorectal cancer; patients who have received prior trastuzumab or pertuzumab for other indications such as prior history of adjuvant or neoadjuvant breast cancer treatment prior to the development of advanced colorectal cancer are eligible - Patients must not have had history of severe toxicity and intolerance to or hypersensitivity to irinotecan or any other study drug; patients must not have had a severe infusion-related reaction during any prior therapy with pertuzumab or trastuzumab - Patients must have tumor slides available for submission for HER-2 testing; HER-2 testing must be completed by the central lab prior to step 2 randomization - Patients must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines; for step 1 initial registration, the appropriate consent form is the step 1 consent form - As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2 RANDOMIZATION - Patients must have HER-2 amplification as determined by central testing (3+ or 2+ by immunohistochemistry and HER-2 gene amplification by in situ hybridization with a ratio of HER-2 gene signals to centromere 17 signals >= 2.0) - Patients must have measurable disease that is metastatic or locally advanced and unresectable; imaging used to assess all disease per RECIST 1.1 must have been completed within 28 days prior to step 2 randomization; all disease must be assessed and documented on the Baseline Tumor Assessment Form - Patients must have had at least one prior regimen of systemic chemotherapy for metastatic or locally advanced, unresectable disease; patients must have progressed following the most recent therapy; prior treatment with irinotecan is allowed; for patients that received adjuvant chemotherapy: prior treatment for metastatic disease is not required for patient who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy; if the patient received one line of adjuvant treatment and had disease recurrence after 6 months of completing chemotherapy, patients will only be eligible after failing one additional line of chemotherapy used to treat the metastatic or locally advanced, unresectable disease; patients who have received >= 3 lines of systemic chemotherapy for metastatic or locally advanced, unresectable disease are not eligible - Patients must have completed prior chemotherapy, immunotherapy, or radiation therapy at least 14 days prior to step 2 randomization and all toxicity must be resolved to Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 grade 1 (with the exception of CTCAE v4.0 grade 2 neuropathy) prior to step 2 randomization - Brain metastases are allowed if they have been adequately treated with radiotherapy or surgery and stable for at least 30 days prior to step 2 randomization; eligible patients must be neurologically asymptomatic and without corticosteroid treatment for at least 7 days prior to step 2 randomization - Patients must have a Zubrod performance status of 0 or 1 - Patients must have a complete physical examination and medical history within 28 days prior to step 2 randomization - Absolute neutrophil count (ANC) >= 1,500/mcL - Platelets >= 75,000/mcL - Hemoglobin >= 9 g/dL - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 5 x institutional upper limit of normal (IULN) - Bilirubin =< 1.5 mg/dL - Calculated creatinine clearance > 30 ml/min within 14 days prior to step 2 randomization - Patients who have had an echocardiogram performed within 6 months prior to step 2 randomization must have ventricular ejection fraction (left ventricular ejection fraction [LVEF]) >= 50% or >= within normal limits for the institution - Patients must not have an uncontrolled intercurrent illness including, but not limited to diabetes, hypertension, severe infection, severe malnutrition, unstable angina, class III-IV New York Heart Association (NYHA) congestive heart failure, ventricular arrhythmias, active ischemic heart disease, or myocardial infarction within 6 months prior to step 2 randomization - Patients must not have any known previous or concurrent condition suggesting susceptibility to hypersensitivity or allergic reactions, including, but not limited to: known hypersensitivity to any of the study treatments or to excipients of recombinant human or humanized antibodies; patients with mild or seasonal allergies may be included after discussion with the study chairs - Patients must not be planning treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type - No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, ductal carcinoma in situ, other low grade lesions such as incidental appendix carcinoid, or any other cancer from which the patient has been disease and treatment free for two years; prostate cancer patients on active surveillance are eligible - Patients must not be pregnant or nursing; females of child-bearing potential must have a negative serum pregnancy test within 7 days prior to registration; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for at least 7 months after the last dose of study treatment; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures - Patients must be given the opportunity to consent to the optional submission of tissue for future research - Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 2 RANDOMIZATION: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have documented disease progression while on CETIRI (Arm 2) on this protocol; the Follow-up Tumor Assessment Form documenting disease progression must be submitted to Southwest Oncology Group (SWOG) prior to step 3 crossover registration; registration to step 3 crossover must be within 28 days of discontinuation of CETIRI protocol treatment; patients going off treatment for any other reason are not eligible - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a Zubrod performance status of 0 or 1 - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): ANC >= 1,500/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Platelets >= 75,000/mcL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Hemoglobin >= 9 g/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): AST and ALT both =< 5 x institutional upper limit of normal (IULN) - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Bilirubin =< 1.5 mg/dL - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Calculated creatinine clearance > 30 ml/min within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have left ventricular ejection fraction (LVEF) >= 50% or >= lower limit of normal for the institution by echocardiogram within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must have a magnesium, potassium, calcium, sodium, bicarbonate, and chloride performed within 14 days prior to step 3 crossover registration - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines; the appropriate consent form for this registration is the step 2 consent form - STEP 3 CROSSOVER REGISTRATION (OPTIONAL): As a part of the OPEN registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Colon Adenocarcinoma ERBB2 Gene Amplification Rectal Adenocarcinoma Recurrent Colon Carcinoma Recurrent Rectal Carcinoma Stage III Colon Cancer AJCC v7 Stage III Rectal Cancer AJCC v7 Stage IIIA Colon Cancer AJCC v7 Stage IIIA Rectal Cancer AJCC v7 Stage IIIB Colon Cancer AJCC v7 Stage IIIB Rectal Cancer AJCC v7 Stage IIIC Colon Cancer AJCC v7 Stage IIIC Rectal Cancer AJCC v7 Stage IV Colon Cancer AJCC v7 Stage IV Rectal Cancer AJCC v7 Stage IVA Colon Cancer AJCC v7 Stage IVA Rectal Cancer AJCC v7 Stage IVB Colon Cancer AJCC v7 Stage IVB Rectal Cancer AJCC v7 Carcinoma Colorectal Neoplasms Adenocarcinoma Rectal Neoplasms Colonic Neoplasms PRIMARY OBJECTIVES: I. To evaluate the efficacy of trastuzumab and pertuzumab (TP) (Arm 1) in HER-2 amplified metastatic colorectal cancer (mCRC) by comparing progression-free survival (PFS) on TP compared to control arm (Arm 2) of cetuximab and irinotecan hydrochloride (irinotecan) (CETIRI). --- V600E --- --- V600E ---

Primary Outcomes

Description: Analysis of PFS will be conducted using the stratified log rank test upon the observation of 115 PFS events. PFS among patients who register to Arm 3 will be summarized using descriptive statistics.

Measure: Progression-free survival (PFS)

Time: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Secondary Outcomes

Description: Evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Measure: Incidence of adverse events

Time: Up to 3 years

Description: ORR including confirmed complete and partial responses per Response Evaluation Criteria in Solid Tumors 1.1 will be compared using using the Cochran-Mantel-Haenszel test. ORR among patients who register to Arm 3 will be summarized using descriptive statistics.

Measure: Overall response rate (ORR)

Time: Up to 3 years

Description: Distributions of OS in each arm will be estimated using the method of Kaplan-Meier and compared using the stratified log-rank test. OS among patients who register to Arm 3 will be summarized using descriptive statistics.

Measure: Overall survival (OS)

Time: From date of registration to date of death due to any cause, assessed up to 3 years

Other Outcomes

Description: The associations between GCN and PFS will be explored via Kaplan-Meier curves and Cox regression.

Measure: Association between HER-2 gene copy number (GCN) and PFS

Time: Up to 3 years

Description: The associations between GCN and response will be explored via logistic regression.

Measure: Association between HER-2 gene copy number (GCN) and response

Time: Up to 3 years

Description: The associations between HER-2/CEP17 signal ratio and PFS will be explored via Kaplan-Meier curves and Cox regression.

Measure: Association between HER-2/CEP17 signal ratio and PFS

Time: Up to 3 years

Description: The associations between HER-2/CEP17 signal ratio and response will be explored via Logistic regression.

Measure: Association between HER-2/CEP17 signal ratio and response

Time: Up to 3 years

49 A Phase 2 Study of Trametinib for Patients With Pediatric Glioma or Plexiform Neurofibroma With Refractory Tumor and Activation of the MAPK/ERK Pathway.

This is a phase 1/2, open-label, interventional clinical trial that will study the response rate of pediatric glioma and plexiform neurofibroma (PN) to oral administration of trametinib. Patients meeting all inclusion criteria for a given study group will receive the study medication at a daily dose of 0.025 mg/kg up to a total of 18 cycles, in 28-day cycles. A total of 150 patients will be recruited as part of this clinical study. Patients aged between 1 month (corrected age) and 25 years old will be eligible, in order to include a maximum of patients affected by low-grade glioma (LGG) and PN. This study includes four groups: patients with neurofibromatosis type 1 (NF1) and LGG, NF1 patients with PN, patients with LGG with a B-Raf Serine/Threonine-protein Kinase/Proto-oncogene Encoding B-Raf (BRAF) fusion and patients with glioma of any grade with activation of the Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinases (MAPK/ERK) pathway. All patients except patients with PN must have failed at least one line of treatment. The study will also explore the molecular mechanisms behind tumor development, progression and resistance to treatment. Furthermore, this study will also explore important aspects for patients with brain tumors by including assessment of quality of life and neuropsychological evaluation.

NCT03363217 Low-grade Glioma Plexiform Neurofibroma Central Nervous System Glioma Drug: Trametinib
MeSH: Glioma Neurofibroma Neurofibromatoses Neurofibroma, Plexiform
HPO: Glioma Neurofibromas Plexiform neurofibroma

5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation. --- V600E ---

5. Tumor with BRAF V600E mutation Patients with a tumor presenting a positive BRAF V600E mutation. --- V600E --- --- V600E ---

Primary Outcomes

Description: Determination of the objective response rate of daily trametinib as a single agent for treatment of progressing/refractory low-grade tumors with MAPK/ERK pathway activation.

Measure: Objective Response Rate

Time: From date of study inclusion until the date of first documented progression, up to 504 treatment days.

Secondary Outcomes

Description: Time from registration to progression, or censored at the date of last disease evaluation for those without progression reported. Applicable to group 1-2-3-4.

Measure: Time to Progression (time from registration to progression)

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at the date of last disease evaluation. Applicable to group 1-2-3-4.

Measure: Progression Free Survival (time from registration to the earlier of progression or death).

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Time from registration to death due to any cause, or censored at date last known alive. Applicable to group 1-2-3-4.

Measure: Overall Survival (time from registration to death)

Time: Every 6 months up to 3 years following completion of treatment (504 treatment days).

Description: Determination of the safety and tolerability of trametinib by assessment of toxicity associated with trametinib (Adverse Events (AEs), Serious Adverse Events (SAEs)). Applicable to group 1-2-3-4.

Measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability).

Time: At treatment week 2, 3, 4, 5, 9, 13, 17, 21, 25, 48, 72; at the end of 504 treatment days and every 6 months for up to 3 years.

Description: Determination of the serum level of trametinib by assessment of the through level. Applicable to group 1-2-3-4.

Measure: Determination of the Serum Level of Trametinib.

Time: At day 22 and at tumor progression up to the end of treatment day 504.

Description: Evaluation of the quality of life during treatment with the PedsQL cancer/brain tumor modules. Applicable to group 1-2-3-4.

Measure: Evaluation of the Quality of Life During Treatment.

Time: At screening, week 13, week 25, week 37, week 49, week 61 and at the end of treatment day 504.

Other Outcomes

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib. The areas of development assessed to calculate the composite score are: cognition, communication, physical, social/emotional and adaptative. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 1 and 42 months using the Bayley Scales of Infant and Toddlers Development, Third Edition (Bailey-III).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 2 years and 6 years using the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, visual spatial, fluid reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 6 years and 16 years and 11 months using the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determine if there are cognitive changes in patients with NF1 during treatment with trametinib.The areas of cognition assessed to calculate the composite score are: verbal comprehension, perceptual reasoning, working memory and processing speed. This scale ranges from a score of 40 to 160 with a mean score of 100, where higher scores are desirable.

Measure: Neurocognitive assessment of NF1 patients between 16 years 11 months and 25 years using the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV).

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Determination of trametinib usefulness in patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1. Applicable to group 4

Measure: Response rate of patients with refractory glioma with activation of the MAPK pathway other than BRAF fusion and NF1

Time: At study inclusion and at the end of treatment (up to treatment day 504).

Description: Comparison of the best response rate using the RECIST 1.1 criteria and volumetric measurement. Applicable to group 2.

Measure: Comparison of responses with RECIST 1.1 and volumetric measurement for plexiform neurofibroma

Time: At the achievement of best response to treatment up to treatment day 504.

Description: Gene expression profiling on fresh frozen tissue and mutational analysis on paraffin-embedded tissue. Circulating tumor DNA (ctDNA) evolution through treatment.

Measure: Investigation and correlation of biological features to tumor response.

Time: Within 14 days prior to treatment start for investigations of tumor tissue. At screening, week 13, week 25, week 37, week 49, week 61, at the end of treatment day 504 and every 6 months up to 3 years for ctDNA evaluation.

50 A Phase II Trial of Rechallenge With Panitumumab Driven by RAS Clonal-mediated Dynamic of Resistance

Open label, single-arm, multiple centers, Phase II trial. The trial has been designed to prove or disprove whether a third line rechallenge with panitumumab can achieve an objective response rate (ORR= CR+PR) of 30% or more in a population of RAS wild type mCRC patients selected on the basis of RAS extended clonal evolution in their plasma.

NCT03227926 Colorectal Cancer Drug: Panitumumab 20 MG/ML Intravenous Solution [VECTIBIX]
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

INCLUSION CRITERIA Molecular Screening - Histologically confirmed diagnosis of metastatic colorectal cancer; - Age ≥ 18 years; - Documented WT RAS exons 2, 3 and 4 (KRas and NRas) and WT BRAF V600E; - Complete or partial response to frontline chemotherapy including anti-EGFR mAb. --- V600E ---

Primary Outcomes

Measure: Overall response rate (ORR) to panitumumab according to RECIST v1.1.

Time: Tumor assessments every 8 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

Secondary Outcomes

Measure: Progression Free Survival

Time: every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

Measure: Overall Survival

Time: every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

Measure: Toxicity according to CTCAE version 4.03.

Time: every 2 weeks from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months

51 VECODUE A Phase II Trial of Vemurafenib Plus Cobimetinib in Patients Treated With Prior First-line Systemic Immunotherapy for Inoperable Locally Advanced or Metastatic Melanoma

In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. In the same setting, combined use of vemurafenib and cobimetinib, a selective inhibitor of MEK, yielded a significant improvement in PFS and response rate, compared to vemurafenib monotherapy, along with an advantage in OS, which did not cross the pre-specified significance bounderies (COBRIM trial). In treatment-naïve patients with mutated BRAF, both anti PD-1-based immunotherapy and BRAF-targeted agents are feasible therapeutic options, with the former and latter agents being associated with more durable and earlier responses, respectively. As suggested by National Comprehensive Cancer Network (NCCN) guidelines, the use of combined BRAF and MEK inhibitors in patients with progressive disease after immunotherapy, is also feasible, but it is not supported by category 1 evidence, in view of the lack of studies conducted in this setting. The main objective of this phase II trial is to evaluate the efficacy and safety of the combined use of vemurafenib plus cobimetinib in advanced melanoma patients who have received first-line systemic immunotherapy for inoperable locally advanced / metastatic disease.

NCT03224208 Melanoma Melanoma (Skin) Melanoma Stage Drug: Vemurafenib Drug: Cobimetinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Vemurafenib Plus Cobimetinib in Advanced or Metastatic Melanoma Patients In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged overall survival (OS) and progression-free survival (PFS) compared to dacarbazine. --- V600E ---

Melanoma Melanoma (Skin) Melanoma Stage Melanoma In the BRIM-3 trial, which was conducted in patients with previously untreated advanced melanoma harboring the BRAF V600E mutation, vemurafenib, a potent inhibitor of mutated BRAF, was associated with prolonged OS and PFS compared to dacarbazine. --- V600E ---

As evidenced above, vemurafenib inhibits the BRAF V600E kinase, (this mutation is found in 50% to 60% of melanomas), and enables a remarkable clinical response rate, more than 50% and a statistically significant improvement in OS in patients with unresectable stage III and IV melanoma. --- V600E ---

Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. --- V600E ---

Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. --- V600E --- --- V600E ---

Multiple mechanisms underlie the development of BRAF-I resistance in BRAF V600E melanoma cells including point mutations in MEK1, amplification of mutant BRAF V600E, elevated closely related serinethreonine kinase activity, activating NRAS mutations, increased levels of COT/Tpl2, aberrantly spliced BRAF V600E and growth factor receptor upregulation. --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: OS will be calculated from the first day of treatment until the date of death from any cause.Any patient not know to have died at the time of data analysis will be censored at the time of the last recorded date on which the patient was know to be alive.

Measure: Overall Survival

Time: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

Secondary Outcomes

Description: PFS will be defined as the time from initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first.PFS will be calculated based on disease status evaluated bythe investigator according to RECIST v1.1

Measure: PFS

Time: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

Description: ORR, defined as the proportion of patients with a best overall response of either complete response (CR) or partial response (PR), will be calculated based on disease status evaluated by the investigator accordingto RECIST v1.1

Measure: ORR

Time: Patients enrolled will receive study medication until disease progression, unaccettable toxicity, withdrawal of consent or death, whichever comes first, assested up to 24 month

52 Phase II Trial of BRAF/MEK Inhibitors in Papillary Craniopharyngiomas

This phase II trial studies how well vemurafenib and cobimetinib work in treating patients with BRAF V600E mutation positive craniopharyngioma. Vemurafenib and cobimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03224767 BRAF V600E Mutation Present Papillary Craniopharyngioma Drug: Vemurafenib Drug: Cobimetinib Other: Laboratory Biomarker Analysis Other: Quality-of-Life Assessment
MeSH: Craniopharyngioma Adamantinoma
HPO: Craniopharyngioma

Vemurafenib and Cobimetinib in Treating Patients With BRAF V600E Mutation Positive Craniopharyngioma This phase II trial studies how well vemurafenib and cobimetinib work in treating patients with BRAF V600E mutation positive craniopharyngioma. --- V600E ---

Vemurafenib and Cobimetinib in Treating Patients With BRAF V600E Mutation Positive Craniopharyngioma This phase II trial studies how well vemurafenib and cobimetinib work in treating patients with BRAF V600E mutation positive craniopharyngioma. --- V600E --- --- V600E ---

Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.. - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E ---

Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.. - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E --- --- V600E ---

- Prior treatment - Cohort A: No prior therapy received other than surgery - Cohort B: Prior radiation therapy required (any type of prior radiation is allowed) - For patients treated with external beam radiation therapy, interstitial brachytherapy or radiosurgery, an interval of >= 3 months must have elapsed from completion of radiation therapy to registration - Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity attributed to radiation with exception of alopecia, fatigue - For patients enrolling on Cohort A or Cohort B: - For patients treated with surgery, an interval of >= 21 days must have elapsed prior to registration - No prior treatment with BRAF or MEK inhibitors - Steroid dosing stable for at least 4 days prior to registration - Not pregnant and not nursing; for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required - ECOG performance status =< 2 - Comorbid conditions - No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) =< 8 weeks prior to registration - No evidence of intracranial hemorrhage =< 4 weeks prior to registration - Patients who have experienced thromboembolic event within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 4 weeks prior to registration - No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration - No current unstable angina or uncontrolled arrhythmia - No uncontrolled hypertension at time of registration (blood pressure [BP] > 150/95 despite antihypertensive therapy) - No known history of prolonged QT syndrome - No known history of ventricular arrhythmia within 6 months of registration - No known history of uveitis or iritis =< 4 weeks prior to registration - No known history of or evidence of retinal pathology that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration within 12 months of registration - No known history of chronic lung disease - Concomitant medications - Chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Chronic concomitant treatment with CYP1A2 substrate is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Absolute neutrophil count >= 1500/mm^3 - Platelets >= 100,000/mm^3 - Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45mL/min - Bilirubin =< 1.5 upper limit of normal (ULN) - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 ULN - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E ---

- Prior treatment - Cohort A: No prior therapy received other than surgery - Cohort B: Prior radiation therapy required (any type of prior radiation is allowed) - For patients treated with external beam radiation therapy, interstitial brachytherapy or radiosurgery, an interval of >= 3 months must have elapsed from completion of radiation therapy to registration - Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity attributed to radiation with exception of alopecia, fatigue - For patients enrolling on Cohort A or Cohort B: - For patients treated with surgery, an interval of >= 21 days must have elapsed prior to registration - No prior treatment with BRAF or MEK inhibitors - Steroid dosing stable for at least 4 days prior to registration - Not pregnant and not nursing; for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required - ECOG performance status =< 2 - Comorbid conditions - No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) =< 8 weeks prior to registration - No evidence of intracranial hemorrhage =< 4 weeks prior to registration - Patients who have experienced thromboembolic event within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 4 weeks prior to registration - No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration - No current unstable angina or uncontrolled arrhythmia - No uncontrolled hypertension at time of registration (blood pressure [BP] > 150/95 despite antihypertensive therapy) - No known history of prolonged QT syndrome - No known history of ventricular arrhythmia within 6 months of registration - No known history of uveitis or iritis =< 4 weeks prior to registration - No known history of or evidence of retinal pathology that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration within 12 months of registration - No known history of chronic lung disease - Concomitant medications - Chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Chronic concomitant treatment with CYP1A2 substrate is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Absolute neutrophil count >= 1500/mm^3 - Platelets >= 100,000/mm^3 - Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45mL/min - Bilirubin =< 1.5 upper limit of normal (ULN) - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 ULN - Pre-registration: Patients must have local diagnosis of papillary craniopharyngioma and have tissue slides available for submission to central pathology review; central pathology review will include immunohistochemistry (IHC) testing for BRAF V600E mutation (VE1 clone) and beta-catenin IHC (membranous, non-nuclear pattern) if needed to confirm diagnosis of papillary craniopharyngioma - Histologically proven papillary craniopharyngioma as documented by central pathology review with positive BRAF V600E mutation by IHC - Measurable disease and/or non-measurable disease - Measurable disease, defined as bidimensionally measurable lesions with clearly defined margins by magnetic resonance imaging (MRI) scans, with a minimum diameter of 10 mm in both dimensions - Progressive disease required in cohort B, defined as an increase in the bidirectional area by 25% within the past 13 months after surgery or radiation; progressive or recurrent disease is not required in cohort A, but is allowed provided it is a new diagnosis and patient has not received prior treatment. --- V600E --- --- V600E ---

- Prior treatment - Cohort A: No prior therapy received other than surgery - Cohort B: Prior radiation therapy required (any type of prior radiation is allowed) - For patients treated with external beam radiation therapy, interstitial brachytherapy or radiosurgery, an interval of >= 3 months must have elapsed from completion of radiation therapy to registration - Recovered to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less toxicity attributed to radiation with exception of alopecia, fatigue - For patients enrolling on Cohort A or Cohort B: - For patients treated with surgery, an interval of >= 21 days must have elapsed prior to registration - No prior treatment with BRAF or MEK inhibitors - Steroid dosing stable for at least 4 days prior to registration - Not pregnant and not nursing; for women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required - ECOG performance status =< 2 - Comorbid conditions - No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of red blood) =< 8 weeks prior to registration - No evidence of intracranial hemorrhage =< 4 weeks prior to registration - Patients who have experienced thromboembolic event within 6 months prior to registration must be on stable therapeutic anticoagulation for at least 4 weeks prior to registration - No symptomatic congestive heart failure (New York Heart Association class II, III, or IV) within 6 months prior to registration - No current unstable angina or uncontrolled arrhythmia - No uncontrolled hypertension at time of registration (blood pressure [BP] > 150/95 despite antihypertensive therapy) - No known history of prolonged QT syndrome - No known history of ventricular arrhythmia within 6 months of registration - No known history of uveitis or iritis =< 4 weeks prior to registration - No known history of or evidence of retinal pathology that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration within 12 months of registration - No known history of chronic lung disease - Concomitant medications - Chronic concomitant treatment with strong CYP3A4 inducers or CYP3A4 inhibitors is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Chronic concomitant treatment with CYP1A2 substrate is not allowed; patients must discontinue the drug at least 14 days prior to study registration - Absolute neutrophil count >= 1500/mm^3 - Platelets >= 100,000/mm^3 - Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45mL/min - Bilirubin =< 1.5 upper limit of normal (ULN) - Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 ULN BRAF V600E Mutation Present Papillary Craniopharyngioma Craniopharyngioma Adamantinoma PRIMARY OBJECTIVES: I. To determine the activity of BRAF and MEK inhibitor combination in untreated papillary craniopharyngiomas as measured by best response at any time during the first four cycles of BRAF and MEK inhibitor treatment. --- V600E ---

Primary Outcomes

Description: Defined as the number of responses achieved during treatment with BRAF and MEK inhibitors divided by the total number of evaluable patients and assessed by contrast-enhanced magnetic resonance imaging or computed tomography. Point estimates will be generated for response rates within each cohort with corresponding 95% binomial confidence intervals. Simon's two-stage design with one interim analysis for futility will be applied to evaluate response rate within each cohort.

Measure: Response rate

Time: Up to 5 years

Secondary Outcomes

Description: Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.

Measure: Progression-free survival

Time: Up to 5 years

Description: Will be summarized for each cohort within each cohort with Kaplan-Meier curves and estimates.

Measure: Overall survival

Time: Up to 5 years

53 QUILT-3.055: A Phase IIb, Single-Arm, Multicohort, Open-Label Study of ALT-803 in Combination With PD-1/PD-L1 Checkpoint Inhibitor in Patients Who Have Disease Progression Following an Initial Response to Treatment With PD-1/PD-L1 Checkpoint Inhibitor Therapy

This is a Phase IIb, single-arm, multicohort, open-label multicenter study of ALT-803 in combination with an FDA-approved PD-1/PD-L1 checkpoint inhibitor in patients with advanced cancers who have progressed following an initial response to treatment with PD-1/PD-L1 checkpoint inhibitor therapy. All patients will receive the combination treatment of PD-1/PD-L1 checkpoint inhibitor plus ALT-803 for up to 16 cycles. Each cycle is six weeks in duration. All patients will receive ALT-803 once every 3 weeks. Patients will also receive the same checkpoint inhibitor that they received during their previous therapy. Radiologic evaluation will occur at the end of each treatment cycle. Treatment will continue for up to 2 years, or until the patient experiences confirmed progressive disease or unacceptable toxicity, withdraws consent, or if the Investigator feels it is no longer in the patient's best interest to continue treatment. Patients will be followed for disease progression, post-therapies, and survival through 24 months past administration of the first dose of study drug.

NCT03228667 Non-Small Cell Lung Cancer Small Cell Lung Cancer Urothelial Carcinoma Head and Neck Squamous Cell Carcinoma Merkel Cell Carcinoma Melanoma Renal Cell Carcinoma Gastric Cancer Cervical Cancer Hepatocellular Carcinoma Microsatellite Instability Mismatch Repair Deficiency Colorectal Cancer Drug: ALT-803 + Pembrolizumab Drug: ALT-803 + Nivolumab Drug: ALT-803 + Atezolizumab Drug: ALT-803 + Avelumab
MeSH: Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Melanoma Colorectal Neoplasms Carcinoma, Squamous Cell Carcinoma, Hepatocellular Stomach Neoplasms Uterine Cervical Neoplasms Carcinoma, Renal Cell Small Cell Lung Carcinoma Carcinoma, Transitional Cell Squamous Cell Carcinoma of Head and Neck Carcinoma, Merkel Cell Microsatellite Instability Brain Neoplasms Neoplastic Syndromes, Hereditary
HPO: Brain neoplasm Carcinoma Cervical polyp Cervix cancer Clear cell renal cell carcinoma Cutaneous melanoma Hepatocellular carcinoma Melanoma Merkel cell skin cancer Neoplasm of the large intestine Neoplasm of the lung Neoplasm of the stomach Non-small cell lung carcinoma Papillary renal cell carcinoma Renal cell carcinoma Small cell lung carcinoma Squamous cell carcinoma

Patients with BRAF V600E mutation-positive melanoma were not required to have received prior BRAF inhibitor therapy; OR unresectable or metastatic melanoma with progression, refractory to ≥ 2 doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutation-positive, a BRAF or MEK inhibitor, and disease progression within 24 weeks following the last dose of ipilimumab. --- V600E ---

Primary Outcomes

Description: Assess the anti-tumor activity of ALT-803 in combination with a PD-1/PD-L1 checkpoint inhibitor in patients with advanced cancers who have progressed following an initial response to treatment with PD-1/PD-L1 checkpoint inhibitors.

Measure: Objective Response Rate

Time: 24 months

Secondary Outcomes

Description: Assess time from first treatment to death resulting from cancer.

Measure: Disease-specific Survival

Time: 24 months

Description: Assess time from first treatment to death resulting from any cause.

Measure: Overall Survival

Time: 24 months

Description: Assess time to response

Measure: Time to Response

Time: 24 months

Description: Assess duration of response

Measure: Duration of Response

Time: 24 months

Description: Assess incidence of adverse events.

Measure: Incidence of Adverse Events

Time: 24 months

Description: Compare changes in QOL scores from baseline.

Measure: Quality of Life (QOL)

Time: 24 months

Description: Assess amount of time disease does not get worse after first treatment.

Measure: Progression-free Survival

Time: 24 months

54 Study of Tilsotolimod in Combination With Nivolumab and Ipilimumab for the Treatment of Solid Tumors

A Phase 2 study intended to see efficacy of tilsotolimod in combination with immunotheraphy drugs ipilimumab and nivolumab in different solid tumors.

NCT03865082 Solid Tumor Drug: Tilsotolimod Drug: Nivolumab Drug: Ipilimumab

2. Subjects with BRAF V600E mutations. --- V600E ---

Primary Outcomes

Description: Efficacy measure by overall response rate (ORR)

Measure: Demonstrate the efficacy of intratumoral tilsotolimod in combination with ipilimumab and nivolumab for each cohort

Time: ORR defined as a CR or partial response (PR) according to RECIST v1.1, confirmed by imaging ≥ 4 weeks after the initial documentation of response (to occur up to 24 months).

Secondary Outcomes

Description: Number of subjects with adverse events as a measure of safety and tolerability including changes in vital signs, electrocardiograms(ECGs), safety and laboratory parameters as assessed by CTCAE v4.03 or higher.

Measure: Safety and tolerability of the combination of tilsotolimod with nivolumab and ipilimumab

Time: At every study visit (up to 48 months)

Description: Serum concentrations will be determined for tilsotolimod, nivolumab, and ipilimumab

Measure: Evaluate serum concentrations of tilsotolimod, nivolumab, and ipilimumab using sparse blood sampling

Time: Screening, Day -7, Cycle 1 Day 1 and Cycle 3 Day 1 (up to 17 weeks). Each cycle is 28 days

Description: Anti-drug anitbody measures of tilsotolimod when combined with nivolumab and ipilimumab

Measure: Immunogenicity of tilsotolimod in combination with nivolumab and ipilimumab

Time: Screening, Day -7, Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1 and Cycle 7 Day 1, (up to 32 weeks). Each cycle is 28 days

55 An Open-label Phase 1 Study to Evaluate Drug-Drug Interactions of Agents Co-Administered With Encorafenib and Binimetinib in Patients With BRAF V600-mutant Unresectable or Metastatic Melanoma or Other Advanced Solid Tumors

This is an open-label, 3-arm, fixed-sequence study to evaluate the effect of single and multiple oral doses of encorafenib in combination with binimetinib on the single oral dose pharmacokinetics (PK) of cytochrome P450 (CYP) enzyme probe substrates using a probe cocktail, on an organic anion-transporting polypeptide/breast cancer resistance protein (OATP/BCRP) substrate using rosuvastatin and on a CYP2B6 substrate using bupropion. The effect of multiple oral doses of the moderate cytochrome P450 (CYP) inhibitor modafinil on encorafenib in combination with binimetinib will also be assessed. The study will have 2 treatment phases, a drug-drug interaction (DDI) phase followed by a post-DDI phase.

NCT03864042 Advanced Solid Tumors Metastatic Melanoma Drug: losartan Drug: dextromethorphan Drug: caffeine Drug: omeprazole Drug: midazolam Drug: rosuvastatin Drug: bupropion immediate release (IR) Drug: encorafenib Drug: binimetinib Drug: modafinil
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E ---

Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K --- --- V600E ---

- Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; - ARM 1 ONLY: Positive urine cotinine test at screening - ARM 3 ONLY: - History of psychosis, depression or mania; - History of angioedema; - History of mitral valve prolapse; - History of left ventricular hypertrophy; Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E ---

- Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein occlusion; - ARM 1 ONLY: Positive urine cotinine test at screening - ARM 3 ONLY: - History of psychosis, depression or mania; - History of angioedema; - History of mitral valve prolapse; - History of left ventricular hypertrophy; Key Inclusion Criteria - Patients must meet all of the inclusion criteria to be eligible for enrollment into the study: - Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant advanced solid tumors - Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to enrollment, as determined using a local test; - Evidence of measurable or non-measurable lesions - Patient with unresectable locally advanced or metastatic melanoma who has received no prior treatment or progressed on or after prior systemic therapy; Note: Prior therapy with a BRAF proto-oncogene serine-threonine protein kinase (BRAF) inhibitor and/or a mitogen-activated protein (MAP) kinase (MEK) inhibitor is permitted except in the regimen immediately prior to study entry - Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced solid tumors who has progressed on standard therapy or for whom there are no available standard therapies; Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted except in the regimen immediately prior to study entry - Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 - Adequate bone marrow, hepatic and renal function as specified in the protocol - ARM 1 ONLY: Non-smoker who has not used nicotine containing products for at least 3 months prior to the first dose. --- V600E --- --- V600K --- --- V600E ---

Primary Outcomes

Measure: Probe substrate peak plasma concentration (Cmax) in Arms 1 and 2

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Probe substrate concentration from time zero to the time of last quantifiable concentration (AUClast) in Arms 1 and 2

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Changes in the amount of probe eliminated via urine over an 8-hour period (Ae0-8) in Arm 1

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Changes in plasma encorafenib and LHY746 Cmax and area under the concentration time curve (AUC) in Arm 3.

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 (Drug-Drug Interaction (DDI) phase)

Secondary Outcomes

Measure: Metabolite ratio (MRAUC) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Metabolite ratio (MRCmax) for 1-OH midazolam/midazolam, paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole, hydroxybupropion/bupropion and LHY746/encorafenib

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: Metabolite ration (MRAe0-8) for E-3174/losartan and dextrorphan/dextromethorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (time to reach Cmax [Tmax]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUC from time zero extrapolated to infinity [AUCinf]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (percent of AUC extrapolated [AUC%extrap]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent terminal elimination half-life [T1/2]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent terminal elimination rate constant [Kel]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent total body clearance after extravascular administration [CL/F]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (apparent total volume of distribution after extravascular administration [Vz/F]) in plasma for midazolam, 1-OH midazolam, caffeine, paraxanthine, omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (urine concentration [Curine]) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day-7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (quantity of urine excreted during each collection interval) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (cumulative amount excreted in urine during each collection interval [CumA]e) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (percentage of dose recovered in urine [Fe] %) for losartan, E-3174, dextromethorphan and dextrorphan

Time: multiple timepoints over 8 hours post dose on Day -7, Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 1 and Day 14 in Arms 1 and 2 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Cmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUClast) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Tmax) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUCinf,) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (AUC%extrap) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Kel) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (CL/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (T1/2) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: PK parameter (Vz/F) for encorafenib, LHY746, binimetinib and AR00426032

Time: multiple timepoints over 8 hours post dose on Day 15 and Day 21 in Arm 3 (Drug-Drug Interaction (DDI) phase)

Measure: Safety will be evaluated by monitoring adverse events (AEs)

Time: From first dose of study intervention/treatment until the end of DDI phase (through 28 days)

56 A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600 Mutation Positive Lesions in Erdheim Chester Disease

This phase II trial studies the side effects and how well dabrafenib and trametinib work in treating patients with Erdheim Chester disease that have BRAF V600 gene mutations. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03794297 BRAF NP_004324.2:p.V600X Erdheim-Chester Disease Drug: Dabrafenib Mesylate Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Trametinib Dimethyl Sulfoxide
MeSH: Erdheim-Chester Disease

These potential risks may also apply to other agents used in this study - History of retinal vein occlusion (RVO) - Interstitial lung disease or pneumonitis not secondary to ECD - Central serous retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or visible pathology (e.g., evidence of optic disc cupping, evidence of new visual field defects on automated perimetry, or intraocular pressure > 21 mmHg as measured by tonography) as assessed by ophthalmic examination - Inability to travel to the treating center - Patients with confirmed diagnosis of ECD that are asymptomatic and with no visceral involvement are not eligible for this trial (patients with no target lesions as per RECIST 1.1 criteria) BRAF NP_004324.2:p.V600X Erdheim-Chester Disease Erdheim-Chester Disease PRIMARY OBJECTIVES: I. To study the efficacy and safety of dabrafenib mesylate (dabrafenib) and trametinib dimethyl sulfoxide (trametinib) as combination therapy in patients with BRAF V600E positive Erdheim Chester disease. --- V600E ---

To determine the clinical response rate to dabrafenib and trametinib combination therapy in patients with BRAF V600E positive Erdheim Chester disease. --- V600E ---

V. To establish duration of treatment-endpoints in patients with BRAF V600E positive Erdheim-Chester disease (ECD) lesions. --- V600E ---

Primary Outcomes

Description: Measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Response to therapy will be evident on follow up imaging studies revealing a decrease in lesion size of 30% or more, which is defined as a partial response as per RECIST criteria, when compared to baseline studies.

Measure: Clinical response rate

Time: Up to 48 weeks after completion of study treatment

Description: Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Measure: Incidence of toxicities

Time: Up to 48 weeks after completion of study treatment

Secondary Outcomes

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Time to response

Time: Up to 48 weeks after completion of study treatment

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Duration of response

Time: From the time measurement criteria are met for complete or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 48 weeks after completion of study treatment

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Progression-free survival

Time: From start of treatment to time of progression or death, whichever occurs first, assessed up to 48 weeks after completion of study treatment

Description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.

Measure: Overall survival

Time: Up to 48 weeks after completion of study treatment

Measure: Degree of histiocytic infiltration using fludeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and bone scans

Time: Up to 48 weeks after completion of study treatment

Measure: Levels of C-reactive protein

Time: Up to 48 weeks after completion of study treatment

Measure: Levels of estrogen receptor (ESR)

Time: Up to 48 weeks after completion of study treatment

Measure: Levels of cytokines

Time: Up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the multi-dimensional fatigue inventory.

Measure: Change in fatigue

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the 6 minute walk test, single leg stance, and functional reach and grip strength using a dynamometer.

Measure: Change in level of functioning

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the human activity profile and activity card sort.

Measure: Change in ability to perform routine activities

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the comparative pain scale.

Measure: Change in pain

Time: Baseline up to 48 weeks after completion of study treatment

Description: Patients will be evaluated using the the group peg board test.

Measure: Change in fine motor dexterity

Time: Baseline up to 48 weeks after completion of study treatment

Description: Improvement of patients' overall quality of life will be evidence of response, and assessments will be made at baseline and throughout the trial, as well as at the conclusion of the trial, to evaluate for any improvement in quality of life. Patients will be evaluated using the National Institute of Neurological Disorders and Stroke-Neuro-Quality of Life scale.

Measure: Change in overall quality of life

Time: Baseline up to 48 weeks after completion of study treatment

Description: Resistance to therapy will be evaluated through imaging studies and patient follow up for at least one year, but this is not expected with the combination therapy.

Measure: Resistance to therapy

Time: Up to 1 year

57 Phase I/II Study of the Human Anti-Mesothelin Antibody Drug Conjugate Anetumab Ravtansine (AR), Combined With the PD-L1 Inhibitor Atezolizumab in Non-Small Cell Lung Cancer

This phase I/II trial studies the best dose and side effects of anetumab ravtansine when given together with atezolizumab and how well they work in treating participants with non-small cell lung cancer that has spread to other places in the body. Monoclonal antibodies, such as anetumab ravtansine and atezolizumab, may interfere with the ability of tumor cells to grow and spread.

NCT03455556 Mesothelin Positive Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Stage IV Non-Small Cell Lung Cancer AJCC v7 Biological: Anetumab Ravtansine Biological: Atezolizumab Other: Laboratory Biomarker Analysis
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

INCLUSION CRITERIA - Phase I only: Diagnosis of advanced/metastatic NSCLC for which no standard treatment option; Phase II only: Advanced NSCLC patients who have received at least 1 platinum-based systemic chemotherapy regimen - Patients with tumors having actionable genomic alterations should have received prior therapy with Food and Drug Administration (FDA) approved agents targeting these aberrations (ie EGFR, ALK, ROS1, BRAF V600E) - Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 - Phase II only: Must have at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria - Ability to understand and the willingness to sign a written informed consent document - Histological or cytologically confirmed NSCLC that shows moderate or stronger mesothelin expression in 30% of tumor cells by a companion assay; MSLN expression score using Ventana immunohistochemistry (IHC) SP74 assay; Phase I only: In addition 5- 30% tumor cells and 1, 2, or 3+ MSLN score; Phase II only: 30% tumor cells and either 2+/3+ - Life expectancy of >= 12 weeks - Absolute neutrophil count >= 1.5 ? --- V600E ---

Primary Outcomes

Description: Will be examined in an exploratory and hypothesis-generating fashion.

Measure: Maximum tolerated dose (MTD) of anetumab ravtansine combined with atezolizumab defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients) (Phase I)

Time: Up to 21 days

Description: Defined as a patient who has achieved a partial response (PR) or complete response (CR) on two consecutive evaluations at least 4 weeks apart. Will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.

Measure: Rate of confirmed response (Phase II)

Time: 6 months

Secondary Outcomes

Description: Will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population.

Measure: Clinical activity (Phase I)

Time: Up to 6 months

Description: The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population.

Measure: Incidence of adverse events according to Common Terminology Criteria for Adverse Events version 4.0 (Phase I)

Time: Up to 21 days after last dose

Description: Defined as the time from registration to death due to any cause. The distribution of overall survival will be estimated using the method of Kaplan-Meier.

Measure: Overall survival (Phase II)

Time: Up to 2 years

Description: Defined as the time from registration to the earliest date of documentation of disease progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan Meier. Will also report the 1-year progression free survival (PFS) rate for the combination of anetumab ravtansine and atezolizumab in 2nd-line non-small cell lung cancer (NSCLC).

Measure: Progression-free survival (Phase II)

Time: 1 year and up to 2 years

58 A Phase I/II Study of MCS110 With BRAF/MEK Inhibition in Patients With Melanoma After Progression on BRAF/MEK Inhibition

This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation. The interventions involved in this study are: - MCS110 - Dabrafenib - Trametinib

NCT03455764 Melanoma Drug: MCS110 Drug: Dabrafenib Drug: Trametinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

MCS110 With BRAF/MEK Inhibition in Patients With Melanoma This research study is studying a combination of targeted therapies as a possible treatment for advanced melanoma that was found to have a BRAF V600E or BRAF V600K genetic mutation. --- V600E ---

Inclusion Criteria: - For enrollment to the phase I portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective. --- V600E ---

- For enrollment to the phase II portion: participants must have a histologically confirmed melanoma with a BRAF V600E or BRAF V600K mutation (identified via NextGen sequencing using the DFCI/BWH OncoPanel or any CLIA-certified method) and have had progression of disease on prior BRAF and MEK inhibitor therapy. --- V600E ---

Primary Outcomes

Description: Any side effects or severe side effects that require the drug to be held or reduced

Measure: Dose Limiting Toxicity

Time: 2 years

Secondary Outcomes

Description: The percentage of patients that have a reduction of their disease on imaging that meets RECIST criteria

Measure: Overall Response Rate

Time: 2 years

Description: The percentage of patients who have a reduction of their disease on imaging to the point that it can no longer be measured.

Measure: Complete Response rate

Time: 2 years

Description: The percentage of patients who have meet RECIST criteria for having a reduction in their disease on imaging but still have measurable disease.

Measure: Partial Response rate

Time: 2 years

Description: The length of time between participants starting study treatment and having growth of their disease

Measure: Progression Free Survival

Time: 2 years

Description: The amount of time between participants starting study therapy and death

Measure: Overall Survival

Time: 2 years

Description: Any side effects or severe side effects associated with study therapy

Measure: Toxicity

Time: 2 years

59 An Open Label, Multicenter, Phase I Extension Study of an Oral Cdk Inhibitor P1446A-05 Administered With an Oral BRAF Inhibitor Vemurafenib (Zelboraf®) in Patients With Advanced or Inoperable Malignant Melanoma With BRAF Mutation

- An Open Label, Multicenter, Phase I Extension Study of an Oral Cdk Inhibitor P1446A-05 Administered with an Oral BRAF Inhibitor Vemurafenib (Zelboraf®) in Patients with Advanced or Inoperable Malignant Melanoma with BRAF Mutation - The primary objective is to determine the safety, maximum tolerated dose (MTD), and dose limiting toxicity (DLT) of the co-administration of P1446A-05 with vemurafenib, in melanoma patients with BRAF mutation

NCT01841463 Advanced or Inoperable Malignant Melanoma With BRAF Mutation Drug: P1446A-05 Drug: Vemurafenib (Zelboraf®)
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

In the 'Extension' phase, sixty patients with BRAF V600E/K mutations (forty patients naïve to selective BRAF inhibitor therapy, and twenty progressing on selective BRAF inhibitor therapy) will be treated at the MTD on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity to determine efficacy of the co-administration.. Tumor Response. --- V600E ---

Primary Outcomes

Description: The study will be conducted in two phases- Phase I (Dose escalation phase), and Extension phase. In the Dose escalation' phase patients will be co-administered P1446A-05 (150, 250, 350 mg qd) and vemurafenib (720, 960 mg bid) in a cohort of three to six patients on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity. Escalation to the next higher dose during the dose escalation phase will depend upon demonstrated safety in the previous dose group. The maximum tolerated dose (MTD) of P1446A-05 and vemurafenib co-administered will be determined. In the 'Extension' phase, sixty patients with BRAF V600E/K mutations (forty patients naïve to selective BRAF inhibitor therapy, and twenty progressing on selective BRAF inhibitor therapy) will be treated at the MTD on a 28-day cycle, until the occurrence of disease progression or unacceptable toxicity to determine efficacy of the co-administration.

Measure: Maximum Tolerated Dose and Dose Limiting Toxicity

Time: Until disease progression or unacceptable toxicity (expected to be 6-8 months)

Secondary Outcomes

Description: - To determine best Overall Response Rate (ORR), Duration of response (DOR), Progression Free Survival (PFS), and Overall Survival (OS) of the co-administration of P1446A 05 and vemurafenib using RECIST version 1.1 in melanoma patients with BRAF mutation

Measure: Tumor Response

Time: Until disease progression or unacceptable toxicity (expected to be 6-8 months)

Description: PK parameters such as Cmax, Tmax, AUC0-t, AUC0-inf, Kel, CL, Vz and t1/2 will be determined using standard non-compartmental and population pharmacokinetic approach (wherever possible). Blood samples (6 mL at each time point) for pharmacokinetic assessment will be collected at the following time points in Dose Escalation Phase- Cycle 1- Day 15: pre-dose (within 30 min before swallowing the capsule/s, 1, 2, 4, 6, 8hr; Day 19: pre-dose (within 30 min before swallowing the capsule/s, 1, 2, 4, 8hr; and within one hour post dose on Day 22. Additionally, blood samples for PK analysis may be collected should patient develop SAE at the earliest feasible time point.

Measure: Pharmacokinetic (PK)

Time: Cycle1 (Day 15 and 22) and Cycle 2 (Day1,15 and 28)

Description: The biomarkers will be assessed pre- and post-treatment and will focus on (a) inhibition of the MAPK pathway as a target of vemurafenib, a RAF inhibitor; (b) cell cycle pathways as an effect of P1446A-05, a Cdk inhibitor; (c) mechanisms of resistance; and (d) markers for senescence and apoptosis as evidence of target engagement/drug response. During phase I dose escalation, optional tumor samples will be collected at screening, within 4 to 6 hours of drug administration on Day 14 of Monotherapy and between Cycle 1 Day 15 and Cycle 1 Day 21, and at disease progression After the MTD is determined, 10 additional patients will be enrolled in "Serial Tumor biopsy cohort" During the Extension phase, tumor samples will be collected at screening, Cycle 1 Day 15 and Cycle 1 Day 21 within 4 to 6 hours of drug administration, and at disease progression.

Measure: Biomarker Analysis

Time: Until disease progression or unacceptable toxicity (expected to be 6-8 months)

60 A 2-part Phase III Randomized, Open Label, Multicenter Study of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

This is 2-part, randomized, open label, multi-center, parallel group, phase III study comparing the efficacy and safety of LGX818 plus MEK162 to vemurafenib and LGX818 monotherapy in patients with locally advanced unresectable or metastatic melanoma with BRAF V600 mutation. A total of approximately 900 patients will be randomized. Part 1: Patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms: 1. LGX818 450 mg QD plus MEK162 45 mg BID (denoted as Combo 450 arm) 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm) or 3. vemurafenib 960 mg BID (denoted as vemurafenib arm) Part 2: Patients will be randomized in a 3:1 ratio to one of the 2 treatment arms: 1. LGX818 300 mg QD plus MEK162 45 mg BID (denoted as Combo 300 arm) or 2. LGX818 300 mg QD monotherapy (denoted as LGX818 arm)

NCT01909453 Melanoma Drug: LGX818 Drug: MEK162 Drug: vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Change from baseline in the EQ-5D.. Inclusion Criteria: - Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV) - Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization - Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. --- V600E ---

IFN, IL-2 therapy, any other immunotherapy, radiotherapy or chemotherapy), except the administration of BRAF or MEK inhibitors - Evidence of at least one measurable lesion as detected by radiological or photographic methods - ECOG performance status of 0 or 1 - Adequate bone marrow, organ function, cardiac and laboratory parameters - Normal functioning of daily living activities Exclusion Criteria: - Any untreated central nervous system (CNS) lesion - Uveal and mucosal melanoma - History of leptomeningeal metastases - History of or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or history of retinal degenerative disease - Any previous systemic chemotherapy treatment, extensive radiotherapy or investigational agent other than immunotherapy, or patients who have received more than one line of immunotherapy for locally advanced unresectable or metastatic melanoma; Ipilimumab (adjuvant) or other immunotherapy treatment must have ended at least 6 weeks prior to randomization - History of Gilbert's syndrome - Prior therapy with a BRAF inhibitor and/or a MEK- inhibitor - Impaired cardiovascular function or clinically significant cardiovascular diseases - Uncontrolled arterial hypertension despite medical treatment - HIV positive or active Hepatitis B, and/or active Hepatitis C - Impairment of gastrointestinal function - Patients with neuromuscular disorders that are associated with elevated CK - Pregnant or nursing (lactating) women - Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: - Diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma (AJCC Stage IIIB, IIIC, or IV) - Presence of BRAF V600E or V600K mutation in tumor tissue prior to randomization - Naïve untreated patients or patients who have progressed on or after prior first line immunotherapy for resectable locally advanced or metastatic melanoma; prior adjuvant therapy is permitted (e.g. --- V600E ---

Primary Outcomes

Description: PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. The local Investigator's assessments will be used as supportive analyses.

Measure: Progression free survival (PFS)

Time: Approximately 2 years after first patient randomized

Secondary Outcomes

Description: OS is calculated as the time from date of randomization to date of death due to any cause.

Measure: Overall Survival (OS)

Time: Up to approximately 5 years after first patient randomized

Description: PFS is defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause, whichever occurs first. PFS will be determined based on tumor assessment (RECIST version 1.1 criteria) as per Blinded Independent Review Committee (BIRC) and survival information. The local Investigator's assessments will be used as supportive analyses.

Measure: Progression Free Survival (PFS)

Time: Approximately 2 years with update around 3 years after first patient randomized

Description: ORR calculated as the proportion of patient with a best overall response of complete response (CR) or partial response (PR). ORR will be calculated for confirmed and unconfirmed responses separately.

Measure: Objective Response Rate (ORR)

Time: Approximately 2 years after first patient randomized

Description: TTR calculated as the time from date of randomization until first documented complete response (CR) or partial response (PR).

Measure: Time To Response (TTR)

Time: Approximately 2 years after first patient randomized

Description: DCR calculated as the proportion of patient with a best overall response of CR, PR or stable disease (SD).

Measure: Disease Control Rate (DCR)

Time: Approximately 2 years after first patient randomized

Description: DOR calculated as the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer.

Measure: Duration of objective response (DOR)

Time: Approximately 2 years after first patient randomized

Description: Number of patients with adverse events and serious adverse events, changes in laboratory values, vital signs, electrocardiograms (ECGs), MUGA (Multi Gated Acquisition Scan)/ echocardiogram and assessment of physical,dermatological and ocular examinations graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.

Measure: Safety and tolerability of combination and LGX818

Time: Up to approximately 4 years after first patient randomized

Description: Change from baseline in the ECOG PS.

Measure: ECOG Performance status (PS)

Time: Approximately 2 years after first patient randomized

Description: Time to definitive 1 point deterioration in the ECOG PS is defined as the time form date of randomization to definitive deterioration, where deterioration is considered as definitive if no improvement in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.

Measure: Time to definitive 1 point deterioration in ECOG performance status

Time: Approximately 2 years after first patient randomized

Description: Plasma concentration-profiles of LGX818 and MEK162 and model based PK parameters.

Measure: Pharmacokinetics of LGX818 and MEK162

Time: Approximately 2 years after first patient randomized

Description: Time to definitive 10% deterioration in the global health status score of the EORTC QLQ-C30 is the time from the date of randomization to the date of at least 10% relative to baseline worsening with no later improvement above this threshold observed during the course of the study or death due to any cause.

Measure: Time to definitive 10% deterioration in global health status (EORTC QLQC30)

Time: Approximately 2 years after first patient randomized

Description: Change from baseline in the global health status score of the EORTC QLQ-C30.

Measure: Global health status (EORTC QLQC30)

Time: Approximately 2 years after first patient randomized

Description: Time to definitive 10% deterioration in the FACT-M melanoma (subscale) is the time from the date of randomization to the date of at least 10% relative to baseline worsening with no later improvement above this threshold observed during the course of the study or death due to any cause.

Measure: Time to definitive 10% deterioration in the FACT-M melanoma subscale

Time: Approximately 2 years after first patient randomized

Description: Change from baseline in the EQ-5D.

Measure: Global health status (EQ-5D)

Time: Approximately 2 years after first patient randomized

61 A Single Center Phase II Trial of Vemurafenib (R05185426) in Poor Performance Status Patients With Unresectable Locally Advanced or Metastatic Melanoma Harboring a V600E/K Mutation

The purpose of this study is to find out what effects, good and/or bad, vemurafenib has on the patient and the melanoma. Specifically, the investigators want to know how well vemurafenib shrinks melanoma. The investigators also want to find out how well vemurafenib can improve how well the patient functions.

NCT01474551 Melanoma Drug: vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

A Single Center Phase II Trial of Vemurafenib (R05185426) in Poor Performance Status Patients With Unresectable Locally Advanced or Metastatic Melanoma Harboring a V600E/K Mutation. --- V600E ---

Vemurafenib (R05185426) in Poor Performance Status Patients With Unresectable Locally Advanced or Metastatic Melanoma Harboring a V600E/K Mutation The purpose of this study is to find out what effects, good and/or bad, vemurafenib has on the patient and the melanoma. --- V600E ---

Primary Outcomes

Description: The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 will be used to determine treatment response. In order to be considered evaluable for response, a patient must have completed at least 1 cycle of therapy. Patients who do not complete a cycle of therapy can be replaced.

Measure: Overall Objective Response

Time: 2 years

62 Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436

Radioactive iodine therapy is often part of the standard treatment for Papillary Thyroid Carcinoma (PTC) patients. However, in many patients, tumors develop a resistance or no longer respond to radioactive iodine therapy (iodine-refractory). Several lines of evidence suggest that blocking the BRAF gene may help to re-sensitize the tumors to radioactive iodine. BRAF is a protein that plays a central role in the growth and survival of cancer cells in some types of PTC. The investigational drug GSK2118436 may work by blocking the BRAF protein in cancer cells lines and tumors that have a mutated BRAF gene. In this research study, the investigators are looking to see if GSK2118436 can re-sensitize iodine-refractory PTC to radioactive iodine therapy. The investigators are also looking at the safety of adding GSK2118436 to radioactive iodine therapy.

NCT01534897 Papillary Thyroid Carcinoma Drug: GSK2118436
MeSH: Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary
HPO: Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436. --- V600E ---

Re-differentiation of Radioiodine-Refractory BRAF V600E-mutant Papillary Thyroid Carcinoma With GSK2118436 Radioactive iodine therapy is often part of the standard treatment for Papillary Thyroid Carcinoma (PTC) patients. --- V600E ---

Number of patients with radioiodine-refractory metastatic BRAF V600E-mutant PTC who have increased radioiodine uptake in their disease sites while on dabrafenib. --- V600E ---

To determine the feasibility of: (a) administering GSK2118436 for 28 days in patients with BRAF V600E-mutant PTC, prior to whole body iodine scanning (all patients); and (b) administering GSK2118436 for an additional 14 days, prior to administering treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake after 28 days of treatment).. Clinical Benefit as Measured by Change in Thyroglobulin Level. --- V600E ---

Rising thyroglobulin is generally indicative of tumor growth.. Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Papillary Thyroid Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary You will take GSK2118436 capsules by mouth for 28 straight days. --- V600E ---

Rising thyroglobulin is generally indicative of tumor growth.. Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Inclusion Criteria: - Histologically confirmed papillary thyroid carcinoma, including its variants, such as tall cell PTC or poorly differentiated thyroid carcinoma, that is metastatic or unresectable AND harbors a BRAF V600E mutation - Evaluable disease, as defined by at least one lesion that can be accurately measured in at least one dimension on CT scan or ultrasound, if present in the neck - Radioiodine-refractory disease - Life expectancy > 6 months - Able to swallow and retain oral medication - Normal organ and marrow function Exclusion Criteria: - Pregnant or breastfeeding - Previous treatment with a specific BRAF or MEK inhibitor - Receiving any other study agents - Known brain metastases - History of allergic reactions attributed to compounds of similar chemical or biologic composition to GSK2118436, bovine TSH, mannitol or iodine - Active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs - History of known glucose-6-phosphate dehyrogenase (G6PD) deficiency - Corrected QT interval >/= 480 msecs; history of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; Class II, III, or IV heart failure, abnormal cardiac valve morphology; or history of known cardiac arrhythmias - Taking herbal remedies - Subjects with significant symptoms from their thyroid cancer, or have a large burden of rapidly progressive iodine-refractory PTC who are in need of other systemic therapy, as judged by their treating physician - Uncontrolled current illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or psychiatric illness/social situations that would limit compliance with study requirements - History of a different malignancy unless disease-free for at least 5 years and deemed to be at low risk for recurrence - HIV-positive on combination antiretroviral therapy Papillary Thyroid Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary You will take GSK2118436 capsules by mouth for 28 straight days. --- V600E --- --- V600E ---

Primary Outcomes

Description: Number of patients with radioiodine-refractory metastatic BRAF V600E-mutant PTC who have increased radioiodine uptake in their disease sites while on dabrafenib. Radioiodine uptake is assessed by whole body scan and areas of interest are identified by nuclear medicine physicians.

Measure: Increased Radioiodine Uptake

Time: 25 days after start of Dabrafenib (GSK2118436)

Secondary Outcomes

Description: To evaluate the safety and tolerability, as determined by adverse event and serious adverse event reporting, of GSK2118436 in combination with whole body iodine scans (all patients) and treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake).

Measure: Safety Analysis as Number of Participants With Adverse Events

Time: 2 years

Description: To evaluate clinical benefit as measured by objective response rate per modified RECIST 1.1, which assesses changes in size of measurable tumors. (per RECIST, a partial response (PR) = at least 30% decrease in size of tumor; progressive disease (PD) = at least 20% increase in size of tumor; stable disease (SD) = neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD).

Measure: Clinical Benefit as Measured by Change in Tumor Size

Time: 2 years

Description: To determine the feasibility of: (a) administering GSK2118436 for 28 days in patients with BRAF V600E-mutant PTC, prior to whole body iodine scanning (all patients); and (b) administering GSK2118436 for an additional 14 days, prior to administering treatment doses of radioactive iodine (patients whose tumors demonstrate significant iodine uptake after 28 days of treatment).

Measure: Number of Participants Who Complete the Study With Minimal Delays and no Dose Reductions

Time: 2 years

Description: To evaluate clinical benefit as measured by change in serum tumor marker, thyroglobulin. Rising thyroglobulin is generally indicative of tumor growth.

Measure: Clinical Benefit as Measured by Change in Thyroglobulin Level

Time: 3 months after radioiodine therapy

63 A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma

This randomized phase II trial studies how well dabrafenib and trametinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery and contains a B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02196181 BRAF V600E Mutation Present BRAF V600K Mutation Present Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma Drug: Dabrafenib Drug: Trametinib
MeSH: Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the skin

A Randomized Phase II Trial of Intermittent Versus Continuous Dosing of Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAF V600E/K Mutant Melanoma. --- V600E ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E ---

Cox regression analyses will be used to evaluate biomarkers' associations with PFS.. Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment Inclusion Criteria: - Patients must have histologically or cytologically confirmed stage IV or unresectable stage III BRAF V600E or BRAF V600K mutant melanoma - Patients must have BRAF V600E or BRAF V600K mutation identified by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; acceptable analytic techniques include but are not restricted to DNA sequencing, pyrosequencing, polymerase chain reaction (PCR), melting point assays, and immunohistochemistry - Contrast-enhanced computed tomography (CT) scans of the neck, chest, abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT scan with diagnostic quality images and intravenous iodinated contrast may be used in lieu of a contrast enhanced CT of the neck, chest, abdomen and pelvis; contrast may be omitted if the treating investigator believes that exposure to contrast poses an excessive risk to the patient; patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; all measurable lesions must be assessed within 28 days prior to registration; tests to assess non-measurable disease must be performed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (RECIST 1.1) - Patients must not have received a prior BRAF or mitogen-activated protein kinase kinase (MEK) inhibitor - Patients with a history of brain metastases are eligible if the patient is asymptomatic with no residual neurological dysfunction and has not received enzyme-reducing anti-epileptic drugs or corticosteroids for at least 7 days prior to registration - Patients must not have received any anti-cancer drug within 28 days prior to registration, and must not have received any nitrosoureas or mitomycin C within 42 days prior to registration - Patients must not have received any major surgery or immunotherapy within 28 days prior to registration - Patients must not have any unresolved toxicity greater than National Cancer Institute (NCI)-CTCAE version (v) 4.0 grade 1 from previous anti-cancer therapy except alopecia within 7 days prior to registration - Absolute neutrophil count (ANC) >= 1,200/ul (obtained within 28 days prior to registration) - Platelets >= 100,000/ul (obtained within 28 days prior to registration) - Hemoglobin >= 9 g/dL (obtained within 28 days prior to registration) - Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (or =< 2.5 x upper limit of normal [ULN] with Gilbert's syndrome) (obtained within 28 days prior to registration) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (or < 5 x IULN for patients with known liver metastases) (obtained within 28 days prior to registration) - Serum albumin >= 2.5 g/dL (obtained within 28 days prior to registration) - Serum creatinine =< 1.5 x mg/dL OR measured or calculated creatinine clearance >= 50 mL/min; creatinine measurements must be obtained within 28 days prior to registration - Patients must have lactate dehydrogenase (LDH) obtained within 28 days prior to registration in order to obtain baseline stratification information - Patients must have a left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (ILLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) within 28 days prior to registration - Patients must have corrected QT (QTc) =< 480 msec by electrocardiogram (ECG) (corrected using the Bazett's formula) within 28 days prior to registration - Patients with known history or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) are not eligible: - History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. --- V600E --- --- V600K --- --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment BRAF V600E Mutation Present BRAF V600K Mutation Present Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To compare progression-free survival with intermittent dosing and continuous dosing of dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma. --- V600E ---

ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) - Patients receiving anticoagulation treatment are allowed to participate with international normalized ratio (INR) established within the therapeutic range - Patients must not have a history of pneumonitis or interstitial lung disease - Patients must not have any grade II/III/IV cardiac disease as defined by the New York Heart Association criteria (i.e., patients with cardiac disease resulting in marked limitation of physical activity or resulting in inability to carry on any physical activity without discomfort), unstable angina pectoris, myocardial infarction within 6 months, or serious uncontrolled cardiac arrhythmia; abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be entered on study; patients with a history of atrial fibrillation must have atrial fibrillation controlled for at least 30 days prior to registration - Patients with known hepatitis B or hepatitis C are not eligible, regardless of concomitant antiretroviral therapy or current viral load - Patients with known human immunodeficiency virus (HIV) may be eligible providing they meet the following additional criteria: - Cluster of differentiation (CD)4 cells >= 500/uL - Serum HIV viral load of < 25,000 IU/ml - No current antiretroviral therapy - Tests must be obtained within 28 days prior to registration; patients who are HIV positive (+) and do not meet all of these criteria are not eligible for this study (HIV/hepatitis testing are not required for patients without known infection) - Pre-study history and physical must be obtained with 28 days prior to registration - Patients must have dermatology exam obtained within 28 days prior to registration to obtain baseline measurement; exam to be performed by treating physician or designated dermatologist - Patients must have Zubrod performance status of 0, 1 or 2 - No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years; exception: patients with known history of colon cancer, cancer of the pancreas, or any cancer known to harbor an activating RAS mutation are ineligible regardless of stage or time since diagnosis - Patients must not be pregnant or nursing because of the risk of fetal harm; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures; hormonal contraception is not allowed due to drug interactions which can render hormonal contraceptives ineffective - Patients must be offered the opportunity to participate in specimen banking - Patients with cutaneous or superficial lesions that do not require imaging guidance for biopsy must be willing to undergo biopsies for tissue submission and blood draws for translational medicine - Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines - As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system - STEP 2: RANDOMIZATION - After completing one cycle of therapy, patients will be registered for randomization between intermittent and continuous dosing, provided that they were eligible for the initial step 1 registration and satisfy the following criteria - Patients must not have unequivocal disease progression (by RECIST v1.1) during the first cycle; patients must have disease assessed using the same method as baseline within +/- 5 days of the day 56 scheduled assessment (between days 51-55 of cycle 1, or days 1-5 of cycle 2); all disease must be assessed and documented on the follow-up tumor assessment form (RECIST 1.1) - Patients must be registered to step 2: randomization within +/- 5 days of starting cycle 2; patients MUST NOT be registered prior to the day 56 disease assessment BRAF V600E Mutation Present BRAF V600K Mutation Present Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Melanoma Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To compare progression-free survival with intermittent dosing and continuous dosing of dabrafenib and trametinib among patients with metastatic BRAF V600E/K mutant melanoma. --- V600E --- --- V600K --- --- V600E ---

Primary Outcomes

Description: Testing of the superiority of intermittent dosing of dabrafenib and trametinib compared to continuous dosing with these two same agents will be based on progression-free survival. Stratified Cox regression models stratified by stratification factors will be used for all analyses.

Measure: Progression-free survival (PFS)

Time: Measured from date of randomization, assessed up to 5 years

Secondary Outcomes

Description: Overall survival between patients on each arm and survival after progression will be compared using Cox regression models.

Measure: Overall survival

Time: Up to 5 years

Description: Response rates between arms will be compared using Fisher's exact test.

Measure: Response rates

Time: Up to 5 years

Description: Defined as >= grade 3 per Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 with attribution possibly, probably, or definitely related to treatment; or any >= grade 1 per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment with chills, dehydration, hypotension, dizziness, or muscle weakness per CTCAE v4.0 with attribution possibly, probably, or definitely related to treatment reported during the same course. Rates of fever between arms will also be compared using Fisher's exact test.

Measure: Rates of fever

Time: Up to 5 years

Other Outcomes

Description: Compared between patients of the two treatment groups.

Measure: Molecular events leading to reactivation of the MAPK pathway

Time: Up to 5 years

Description: Cox regression analyses will be used to evaluate biomarkers' associations with PFS.

Measure: Change in biomarkers associated with PFS of archived tissue

Time: Baseline up to 5 years

Description: Cox regression analyses will be used to evaluate biomarkers' associations with PFS.

Measure: Interaction between baseline biomarkers and treatment arm

Time: Baseline up to 5 years

64 A Phase II Study of Cetuximab Rechallenge in Combination With Irinotecan in Advanced Metastatic Colorectal Cancer Without KRAS or NRAS or BRAF Mutation (All Wild Type) for Patients Pretreated With FOLFIRI and Cetuximab in First Line With Stopping Cetuximab for Progressive Disease After a Previous Response (Partial Response or Complete Response) and After Treatment With a Fluoropyrimidine, Oxaliplatin Plus Bevacizumab Regimen

The main objective of this study is to evaluate the objective response rate at two months (complete disappearance of the disease and partial disappearance of the disease) obtained after administration of combination therapy with cetuximab and irinotecan in the patients with metastatic colorectal cancer. Secondaries objectives will be assessed progression-free survival, overall survival, toxicity, quality of life.

NCT02316496 Colorectal Cancer Metastatic Drug: cetuximab Drug: Irinotecan
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Colorectal Cancer Metastatic Colorectal Neoplasms null --- V600E ---

Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Inclusion Criteria: - Signed and dated informed consent - Histologically confirmed metastatic adenocarcinoma of the colon or rectum - All Wild Type KRAS (exon 2 [codons 12-13], exon 3 [codons - 61]; exon 4 [codon 146]), NRAS (exon 2 [ codons 12-13] and exon 3 [codon 61) and BRAF (V600E) tumor ( local assessment performed either on primary tumor or metastasis) - First line chemotherapy regimen with a fluoropyrimidine and Irinotecan (FOLFIRI) + cetuximab with initial partial or complete response and progressive disease (PD) with PD ≤ 6 weeks after the last administration of cetuximab - Other line(s) of therapy(ies) including the following drugs: second line oxaliplatin based chemotherapy with fluoropyrimidines (5FU or capecitabine) + bevacizumab and eventually regorafenib (possible but not mandatory) and progression or limiting toxicity to the last therapy with a minimum of 4 months between last injection of cetuximab and inclusion in this study - At least one measurable lesion ≥ 10 mm as assessed by CT-scan or MRI (Magnetic Resonance Imaging) according to RECIST v1.1 (All sites must be evaluated ≤ 28 days prior to the enrolment) - Age ≥18 years - World Health Organization (WHO) Performance status (PS) 0-2 - The patient has adequate organ function, defined as : Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, hemoglobin ≥ 9 g/dL, and platelets ≥ 100 x 109/L.Total bilirubin ≤ 1.5 times upper limit of normal value (ULN), serum alkaline phosphatase level < 5 times ULN, Serum creatinine level <150μM/l - For female patients of childbearing potential, negative pregnancy test within 7 days before starting the study drug - Men and women are required to use adequate birth control during the study (when applicable) and until 6 months after the end of study treatment - Registration in a national health care system (CMU included) Exclusion Criteria: - Previous chemotherapy other than adjuvant therapy with different combinations than those scheduled in first and second line treatment - Presence of any KRAS, BRAF or NRAS mutation by allelic discrimination on tumor DNA - Significant cardiovascular disease including unstable angina or myocardial infarction within 12 months before initiation of study treatment or a history of ventricular arrhythmia (treated or not) - History or evidence of central nervous system metastasis (systematic CT-scan or MRI not mandatory if no clinical symptoms) - Known allergy or hypersensitivity to cetuximab - Previous or concurrent malignancy except for basal or squamous cell skin cancer, in situ carcinoma of the cervix, low-risk prostate cancer according to d'Amico classification or other solid tumors treated curatively and without evidence of recurrence for at least 5 years prior to the study - Active or uncontrolled clinically serious infection - Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness - Other serious and uncontrolled non-malignant disease - Pregnancy - Breast feeding - Treatment with any other investigational medicinal product within 28 days prior to study entry - Known Gilbert's syndrome - Concomitant administration of live, attenuated virus vaccine such as yellow fever vaccine - Concomitant use with St John's Wort - Chronic inflammatory bowel disease and/or Bowel obstruction Colorectal Cancer Metastatic Colorectal Neoplasms null --- V600E --- --- V600E ---

Primary Outcomes

Measure: Objective response rate (ORR)

Time: At 2 months

Secondary Outcomes

Description: Best response observed during investigational treatment combination. From the start of treatment until treatment failure

Measure: Objective response rate (ORR)

Time: up to 27 months

Description: The proportion of patients with tumor response (Complete response or partial response) or tumor stabilization as best response during study treamtent

Measure: Disease control rate (DCR)

Time: up to 27 months

Description: Time from the date of inclusion to the date of the first progressive disease (RECIST criteria) or death (any cause)

Measure: Progression-free survival (PFS)

Time: up to 27 months

Description: Only for patients with tumor response (complete reposne or partial response) , from first confirmed response to first observed progression (PD) or death due to PD during study treatment

Measure: Duration of response (DOR)

Time: up to 27 months

Description: Time from the date of inclusion to the date of the first confirmed CR or PR during study treatment

Measure: Time to response (TTR)

Time: up to 27 months

Description: Time from the date of inclusion to the date of the first obseved progression (PD), or death due to progression during the study treatment

Measure: Time to progression (TTP)

Time: up to 27 months

Description: Time from the date of inclusion to the date the decision was made to end the study treatment for any reason

Measure: Time to treatment failure (TTF)

Time: up to 27 months

Description: Only for patient with a stable disease (SD) as best response during the study treatment, from date of inclusion to the first observed progression (PD) or death due to progression

Measure: Duration of stable disease (DoSD)

Time: up to 27 months

Description: From the date of inclusion to the date of patient death, due to any cause, or to the last date the patient was known to be alive

Measure: Overall survival (OS)

Time: up to 27 months

Measure: Adverse Events (CTCAE v.4.03)

Time: Up to 27 months

Description: Using EORTC Quality of Life Questionnaire - C30 (QLQ-C30) and the Dermatology Life Quality Index (DLQI ) questionnaires

Measure: Quality of life

Time: Up to 27 months

Description: RAS and BRAF status in circulating tumoral DNA

Measure: Respose rate

Time: up to 27 months

Description: RAS and BRAF status in circulating tumoral DNA

Measure: PFS

Time: up to 27 months

65 Phase II Biomarker Study Evaluating The Upfront Combination Of BRAF Inhibitor Dabrafenib With MEK Inhibitor Trametinib Versus The Combination After Eight Weeks Of Monotherapy With Dabrafenib Or Trametinib In Patients With Metastatic And Unresectable Stage III Or IV Melanoma Harbouring An Activating BRAF Mutation

This is a three-arm, open-label, randomised Phase II study to evaluate whether the different sequencing of dabrafenib and trametinib monotherapies and the upfront combination has an impact on translational or clinical activity in subjects with BRAF mutant metastatic unresectable stage IIIc or IV melanoma. Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and in combination in BRAF-mutant melanoma. However, duration of responses seem to be limited due to acquired drug resistance. The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition on skin, blood and tumour biomarkers and to study the correlation between biomarkers and response to treatment and intrapatient toxicity. Approximately 54 eligible subjects will be randomised in the ratio of 1:1:1 to one of the three treatment arms.

NCT02314143 Melanoma Drug: Dabrafenib Drug: Trametinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

- BRAF (proto-oncogene B-Raf) V600E/K mutation-positive confirmed by a local laboratory. --- V600E ---

Primary Outcomes

Description: Intra-tumoral expression levels of ERK measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 [no staining], 1+ [weak staining], 2+ [medium staining] and 3+ [strongest staining]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for combination therapy calculated from Week 0 to Week 2. The analysis was based on the biomarker Population which included all participants with biopsy performed at screening and at least once during treatment.

Measure: Number of Participants With Percentage Change From Baseline in Extracellular Signal-regulated Kinase (ERK) Phosphorylation (p-ERK) H Score From Week 0 to Week 2

Time: Baseline (Week 0) and up to 2 weeks

Description: Intra-tumoral expression levels of ERK were measured using immunohistochemistry methods. The H score value ranged from 0 to a maximum score of 300 (strongest expression) was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0 [no staining], 1+ [weak staining], 2+ [medium staining] and 3+ [strongest staining]). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. The data has been presented for dabrafenib followed by combination therapy and trametinib followed by combination therapy, calculated from Week 8 to Week 10.

Measure: Number of Participants With Percentage Change in p-ERK H Score From Week 8 to Week 10

Time: Week 8 and up to 10 weeks

Secondary Outcomes

Description: Clinical response was evaluated by ORR, which was defined as the number of participants with a confirmed or an unconfirmed complete response (CR) or partial response (PR) at any time per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR was defined as disappearance of all target lesions. PR was defined as at least a 30 percent decrease in the sum of the diameters of target lesions. Number of participants with ORR (CR+PR) has been presented. The analysis was based on the Intent-to-Treat Population (ITT) which included all the randomized participants whether or not randomized treatment was administered.

Measure: Number of Participants With Overall Response Rate (ORR)

Time: Up to 3.2 years

Description: Vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP) and heat rate (HR) were measured. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus the Baseline value. The number of participants with heart rate "decrease to < 60" and "increase to >100" have been presented. For SBP and DBP, "any grade increase" have been presented. Any grade increase in SBP, including grade 0 (<120), grade 1 (120-139), grade 2 (140-159), grade 3 (>=160) and DBP including grade 0 (<80), grade 1 (80-89), grade 2 (90-99), grade 3 (>=100) have been presented. The analysis was based on the Safety Population which included all participants who received at least one dose of randomized treatment and was based on the actual treatment received. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

Measure: Number of Participants With Change in Vital Signs From Baseline

Time: Baseline and up to 3.2 years

Description: Complete physical examination included assessments of eyes, neurological and cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. This analysis was planned but data was not captured in the database. Abnormal changes were captured as adverse events if they were clinically significant.

Measure: Number of Participants With Clinically Significant Abnormal Findings Undergoing Physical Examinations

Time: Up to 3.2 years

Description: The ECOG scale of performance status describes the level of functioning of participants in terms of their ability to care for themselves, daily activity, and physical ability. The ECOG performance was recorded as per ECOG performance status grades ranging from 0 (fully active, able to carry on all pre-disease performance without restriction) to 5 (dead). Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The Baseline performance status of participants with respect to worst-case on-therapy performance status has been presented.

Measure: Number of Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Scores From Baseline

Time: Baseline and up to 3.2 years

Description: Single measurements of 12-lead ECGs were obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, corrected QT interval (QTc), Bazett's Corrected QT interval (QTcB), Friderica's Corrected QT interval (QTcF). Number of participants with abnormal ECG findings (Abnormal - Not Clinically Significant and Abnormal - Clinically Significant ) at any time post-Baseline visit have been presented.

Measure: Number of Participants With Abnormal Electrocardiograms (ECG) Findings

Time: Up to 3.2 years

Description: Echocardiograms (ECHO) was performed to assess cardiac ejection fraction and cardiac valve morphology. Baseline was defined as the most recent non-missing value prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on-therapy value has been presented.

Measure: Number of Participants With Absolute Change in Left Ventricular Ejection Fraction From Baseline

Time: Baseline and up to 3.2 years

Description: Blood samples were collected for evaluation of clinical chemistry parameters including sodium, potassium, calcium, albumin, total protein, blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GCT), phosphate, C-reactive protein (CRP), hypercalcemia, hyperkalemia, hypernatremia, hypocalcemia, hypokalemia, hyponatremia, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total bilirubin, direct bilirubin and estimated creatinine clearance (CRTCE). Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in clinical chemistry parameters for has been presented. Only those participants available at specified time point were analyzed (represented by n=x in category titles).

Measure: Number of Participants With Change in Clinical Chemistry Parameters From Baseline

Time: Baseline and up to 3.2 years

Description: Blood samples were collected for evaluation of hematology parameters including hemoglobin, white blood cell (WBC), platelet count, basophils, eosinophils, lymphocytes, monocytes, total neutrophils, lymphocytopenia and lymphocytosis. Baseline was defined as the most recent non-missing value from a central laboratory prior to the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The worst-case on therapy value for number of participants with any grade increase in hematology parameters for has been presented.

Measure: Number of Participants With Change in Hematology Parameters From Baseline

Time: Baseline and up to 3.2 years

Description: The safety profile of dabrafenib and trametinib in monotherapy as well as in combination therapy was characterized by determining the number of participants with incidence of squamous cell carcinoma and keratoacanthoma.

Measure: Number of Participants With Incidence of Squamous Cell Carcinoma and Keratoacanthoma

Time: Up to 3.2 years

Description: An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function.

Measure: Number of Participants With On-treatment Serious Adverse Events (SAEs) and Non-SAEs

Time: Up to 3.2 years

Description: Blood samples were collected for pharmacokinetic analysis of trametinib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.

Measure: Plasma Pharmacokinetic Concentration of Trametinib

Time: 4 to 8 hours post-dose at Weeks 2, 8 and 10

Description: Blood samples were collected for pharmacokinetic analysis of Dabrafenib at indicated time points. Pharmacokinetic analysis was performed using standard non-compartmental method.

Measure: Plasma Pharmacokinetic Concentration of Dabrafenib

Time: 4 to 8 hours post-dose at Weeks 2, 8 and 10

66 BRAF, Autophagy and MEK Inhibition in Metastatic Melanoma: A Phase I/2 Trial of Dabrafenib, Trametinib and Hydroxychloroquine in Patients With Advanced BRAF Mutant Melanoma

The primary purpose of this study is to determine the maximum tolerated dose (MTD) and preliminary safety of hydroxychloroquine (HCQ) when administered in conjunction with oral dabrafenib and trametinib (D+T) in patients with advanced BRAF mutant melanoma.

NCT02257424 Advanced BRAF Mutant Melanoma Drug: Trametinib 2 mg daily Drug: hydroxychloroquine (HCQ) Drug: dabrafenib 150 mg orally twice a day
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

- Patients must have histologically confirmed diagnosis of Stage IV metastatic melanoma positive for BRAF V600E or V600K by a CLIA approved assay. --- V600E ---

Primary Outcomes

Description: Phase 1: Maximum tolerated dose (MTD) = a) the dose producing Dose Limiting Toxicity (DLT) in 2/6 patients, or b) the dose level below the dose which produced DLT in ≥ 2/3 patients, or in ≥ 3/6 patients

Measure: Phase 1: To determine the maximum tolerated dose

Time: 5 weeks

Description: Phase 2: Progression free survival (PFS) is defined as the duration of time from start of treatment to time of first progression, death due to any cause or last patient contact alive and progression-free

Measure: Phase 2: To assess the clinical efficacy of HCQ+D+T by 1 year PFS rate.

Time: 1 year

67 Culture and Characterization of Circulating Tumor Cells (CTC) From Patients With Malignant Melanoma and Other Cancers

The purpose of this study is to determine if circulating tumor cells (CTC) can be accurately detected and isolated from the blood of participants with melanoma using novel laboratory techniques. Blood samples will be collected from participants with melanoma, and also from participants with other solid tumor cancers and healthy volunteers for purposes of comparison. Relevant information will be collected from participant's medical record and stored in a coded manner in a password-protected format. This information will be used to look for correlations of research results on blood samples to participant's medical condition. Test results will not be given to participants or their physicians. In some cases, CTC may be grown for long-term cell lines for further research.

NCT01528774 Melanoma Other: Blood Draw
MeSH: Melanoma Neoplastic Cells, Circulating
HPO: Cutaneous melanoma Melanoma

- Isolate plasma RNA and DNA to assess expression tumor-specific markers (e.g., tyrosinase, B-FRAF, V600E, etc.) and metastasis-associated genes (e.g., MSH-1, thymidylate synthase, etc.). --- V600E ---

B-RAF V600E in melanoma patients) mitotic rate of tumor, date of tumor diagnosis, treatment history, date of regional and metastatic progression and date of death (if applicable). --- V600E ---

Primary Outcomes

Measure: Circulating tumor cell (CTC) isolation and colony counts

Time: 2 years

Secondary Outcomes

Measure: Immunophenotyping, somatic (tumor-specific) DNA mutation analysis

Time: 2 years

68 A Phase 1, Open-label, Dose-escalation, Safety and Pharmacokinetic Study of CDX-1127 in Patients With Selected Refractory or Relapsed Hematologic Malignancies or Solid Tumors

This is a study of CDX-1127, a therapy that targets the immune system and may act to promote anti-cancer effects. The study enrolls patients with hematologic cancers (certain leukemias and lymphomas), as well as patients with select types of solid tumors.

NCT01460134 CD27 Expressing B-cell Malignancies for Example Hodgkin's Lymphoma Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Marginal Zone B Cell Lymphoma) Any T-cell Malignancy Solid Tumors (Metastatic Melanoma, Renal (Clear) Cell Carcinoma Hormone-refractory Prostate Adenocarcinoma, Ovarian Cancer Colorectal Adenocarcinoma, Non-small Cell Lung Cancer) Burkett's Lymphoma Primary Lymphoma of the Central Nervous System Drug: CDX-1127 Drug: CDX-1127 Drug: CDX-1127
MeSH: Lymphoma Neoplasms Carcinoma, Non-Small-Cell Lung Melanoma Adenocarcinoma Ovarian Neoplasms Carcinoma, Ovarian Epithelial Leukemia, Lymphoid Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, B-Cell Hodgkin Disease Lymphoma, Mantle-Cell Lymphoma, B-Cell, Marginal Zone Prostatic Neoplasms
HPO: B-cell lymphoma Chronic lymphatic leukemia Cutaneous melanoma Hodgkin lymphoma Lymphoid leukemia Lymphoma Melanoma Neoplasm Non-small cell lung carcinoma Ovarian neoplasm Prostate cancer Prostate neoplasm

4. Tumor must be recurrent or treatment refractory with no remaining alternative, approved therapy options, with the following exception: melanoma patients enrolled in the expansion phase must have previously received ipilimumab and, for patients with the BRAF V600E mutation, vemurafenib, or have been offered such therapies and refused, and patients must have progressive disease subsequent to previous therapies. --- V600E ---

Primary Outcomes

Description: Analysis of adverse events along with the results of vital sign measurements, physical examinations, and clinical laboratory tests will be used to determine the safety profile of CDX-1127.

Measure: Characterize the adverse events associated with CDX-1127 administration

Time: Safety follow up is 70 days from last dose.

Secondary Outcomes

Measure: Levels of anti-CD27 antibodies in circulating blood.

Time: Until end of treatment

Measure: Levels of CDX-1127 in circulating blood.

Time: Until end of treatment

Description: Determine the anti-malignant cell activity of CDX-1127 based on change from baseline in tumor measurements every 12 weeks.

Measure: Activity Evaluations

Time: Until disease progression

Measure: Immune system effects (eg: lymphoid cell populations and serum cytokine levels)

Time: Until end of treatment

69 A Multicenter Phase II Study of the Combination of AZD6244 Hydrogen Sulfate and MK-2206 in Patients With Refractory Advanced Biliary Cancers

This phase II trial studies how well selumetinib and Akt inhibitor MK-2206 work in treating patients with refractory or advanced gallbladder or bile duct cancer that cannot be removed by surgery. Selumetinib and Akt inhibitor MK-2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01859182 Adenocarcinoma of the Gallbladder Adenocarcinoma With Squamous Metaplasia of the Gallbladder Adult Primary Cholangiocellular Carcinoma Advanced Adult Primary Liver Cancer Cholangiocarcinoma of the Extrahepatic Bile Duct Localized Unresectable Adult Primary Liver Cancer Metastatic Extrahepatic Bile Duct Cancer Recurrent Adult Primary Liver Cancer Recurrent Extrahepatic Bile Duct Cancer Stage II Gallbladder Cancer Stage IIIA Gallbladder Cancer Stage IIIB Gallbladder Cancer Stage IVA Gallbladder Cancer Stage IVB Gallbladder Cancer Unresectable Extrahepatic Bile Duct Cancer Drug: selumetinib Drug: Akt inhibitor MK2206 Other: laboratory biomarker analysis Other: pharmacogenomic studies Procedure: quality-of-life assessment
MeSH: Adenocarcinoma Liver Neoplasms Cholangiocarcinoma Gallbladder Neoplasms Bile Duct Neoplasms Metaplasia
HPO: Cholangiocarcinoma Neoplasm of the gallbladder Neoplasm of the liver

To determine the presence of genetic mutations of phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) signaling pathway genes (other than v-raf murine sarcoma viral oncogene homolog [BRAF] V600E) relevant to biliary cancer and how these correlate with and may predict objective response to treatment with AZD6244 hydrogen sulfate and MK-2206. --- V600E ---

Primary Outcomes

Description: Calculated with corresponding 95% binomial confidence intervals.

Measure: Proportion of patients who have a response (PR or CR), assessed by the RECIST v1.1

Time: 6 months

Secondary Outcomes

Description: Frequency and severity of adverse events and tolerability of the regimen in each of the patient groups will be collected and summarized by descriptive statistics.

Measure: Frequency and severity of adverse events as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

Time: Up to 4 weeks

Description: Changes in overall quality of life will be explored in relation to severe toxicity incidence and in particular to incidence of cachexia. Graphical analyses will be used to assess patterns in these patient reported outcomes in relation to the clinical and tolerability outcomes of incidence.

Measure: Changes in QOL evaluated using the Functional Assessment of Cancer Therapy - General (FACT-G)

Time: Baseline to 8 weeks

70 Predictive Value of Progastrin Titer at Diagnosis and of Progastrin Kinetics During Treatment in Cancer Patients

Progastrin is a pro-hormone that, in physiological conditions, is maturated in gastrin in G cells of the stomach. The role of the gastrin is to stimulate the secretion of gastric acids during digestion. It is also important for the regulation of cell growth of the gastric mucosal. In a healthy person, progastrin is not detectable in the peripheral blood. However, progastrin is abnormally released in the blood of patients with different cancers (colorectal, gastric, ovarian, breast, cervix uterus, melanoma…) The gene GAST coding for progastrin is a direct target gene of the WNT/ß-catenin oncogenic pathway. The activation of this oncogenic pathway is an early event in cancer development. Chronic activation of the WNT/ß-catenin oncogenic pathway occurs in almost all human solid tumors and is a central mechanism in cancer biology that induces cellular proliferation, blocking of differentiation leading to primary tumor growth and metastasis formation. Progastrin measured in the peripheral blood of patients on treatments, could be a new powerful marker for diagnosis and prognosis at different stages.

NCT03787056 Cancer Breast Cancer Gastric Cancer Renal Cancer Prostate Cancer Melanoma Lung Cancer Hepatocellular Cancer Colorectal Cancer Head and Neck Cancer Pancreatic Cancer Ovarian Cancer Glioblastoma Endometrial Cancer Bladder Cancer Esophageal Cancer B-cell Lymphoma Other: Blood draws
MeSH: Colorectal Neoplasms Pancreatic Neoplasms Glioblastoma Lymphoma, B-Cell Head and Neck Neoplasms Urinary Bladder Neoplasms Esophageal Neoplasms Endometrial Neoplasms Kidney Neoplasms Carcinoma, Renal Cell Liver Neoplasms Carcinoma, Hepatocellular
HPO: B-cell lymphoma Bladder neoplasm Clear cell renal cell carcinoma Endometrial carcinoma Esophageal neoplasm Glioblastoma multiforme Hepatocellular carcinoma Neoplasm of head and neck Neoplasm of the large intestine Neoplasm of the liver Neoplasm of the pancreas Papillary renal cell carcinoma Renal cell carcinoma Renal neoplasm

Lung carcinoma: - SCLC for curative-intent cohort - Stage IV NSCLC with EGFR activating mutation, BRAF V600E mutation, ALK or ROS1 fusion. --- V600E ---

Primary Outcomes

Description: Progastrin concentration in plasma samples will be measured with an ELISA Kit (CancerREAD LAB) provided by ECS Progastrin.

Measure: ROC curve AUC regarding diagnostic accuracy of progastrin levels at baseline in cancer patients compared to non-cancer controls

Time: At baseline

Secondary Outcomes

Description: A nonlinear mixed effect model will be used to model the progastrin measurements done during treatments and follow-up of patients.The effect of each event (chemotherapy, surgery…) on the progastrin value and in the inter-individual variability of production and/or elimination rates of progastrin will be analyzed. Progastrin will be measured by ELISA, and the values will be expressed in pM. Measures will be done depending on the treatment received. Chemotherapy, every 3 or 4 weeks. Oral treatments: every 3 to 12 weeks. Surgery or radiotherapy: before and after the treatment. Follow up: concomitantly to the visits scheduled for the regular follow up of the patients.

Measure: Longitudinal kinetic of progastrin values during treatments, assessed by modeled kinetic parameters of interest

Time: 6 years

Description: 24 patients will be selected, upon their agreement and serum high levels, to enter in nychtemer (12 patients) or weekly (12 patients) cohorts. For the Nychtemer cohort, progastrin will be assayed at d1 at 8:00 am; 11:00 am; 2:00 pm; 5:00 pm; 8:00 pm and at d2 at 8:00 For the weekly cohort, progastrin will be assayed Day 1; Day 8; Day 15 and +/- Day 22; ideally on the same hour times. Progastrin will be measured by ELISA, and the values will be expressed in pM.

Measure: Nycthemeral and weekly progastrin variations

Time: every 3 hours within 24 hours for the Nycthemeral cohort, and every week for 2 or 3 weeks for the weekly cohort

Description: A nonlinear mixed effect model will be used to correlate individual values of progastrin (expressed in pM) with individual characteristic on the patient (hepatic function, as measured by the concentration of AST, ALT and bilirubin). Measures will be done Chemotherapy, every 3 or 4 weeks. Oral treatments: every 3 to 12 weeks. Surgery or radiotherapy: before and after the treatment. Follow up: concomitantly to the visits scheduled for the regular follow up of the patients

Measure: Determinants of progastrin serum values: hepatic function

Time: 6 years

Description: A nonlinear mixed effect model will be used to correlate individual values of progastrin (expressed in pM) with individual characteristic on the patient (renal function, as measured by creatinin concentration and creatinin clearance). Measures will be done Chemotherapy, every 3 or 4 weeks. Oral treatments: every 3 to 12 weeks. Surgery or radiotherapy: before and after the treatment. Follow up: concomitantly to the visits scheduled for the regular follow up of the patients

Measure: Determinants of progastrin serum values: renal function

Time: 6 years

Description: A nonlinear mixed effect model will be used to correlate the individual characteristics of the patient (age and gender) with progastrin concentration at the inclusion.

Measure: Determinants of progastrin serum values: age

Time: at the inclusion

Description: A nonlinear mixed effect model will be used to correlate genders with progastrin concentrations at the inclusion.

Measure: Determinants of progastrin serum values: gender

Time: at the inclusion

Description: The relationships between the progastrin kinetics during and after treatment and overall survival will be analyzed. Analyses will be performed separately on patients with curative intent treatment and on patients with palliative intent treatment. Measures wil be done At the end of the study (6 years for patients enrolled in curative intent and 5 years for patients enrolled in non-curative intent) or alternatively at the occurrence of progression or relapse.

Measure: Overall survival

Time: 6 years

Description: The relationships between the progastrin kinetics during and after treatment and recurrence free survival will be analyzed. Analyses will be performed separately on patients with curative intent treatment and on patients with palliative intent treatment. Measures wil be done At the end of the study (6 years for patients enrolled in curative intent and 5 years for patients enrolled in non-curative intent) or alternatively at the occurrence of progression or relapse.

Measure: recurrence free survival

Time: 6 years

Description: The relationships between the progastrin kinetics during and after treatment and progression free survival will be analyzed. Analyses will be performed separately on patients with curative intent treatment and on patients with palliative intent treatment. Measures wil be done At the end of the study (6 years for patients enrolled in curative intent and 5 years for patients enrolled in non-curative intent) or alternatively at the occurrence of progression or relapse.

Measure: progression free survival

Time: 6 years

Description: The size of the tumor will be correlated to progastrin concentration at the time of cancer diagnosis

Measure: The tumor size at cancer diagnosis

Time: At baseline

Description: The ability of progastrin kinetics during the neoadjuvant period to predict the outcome of the surgery (complete or not) will be analyzed by a ROC curve. If applicable.

Measure: Complete surgery

Time: 6 years

Description: The ability of the progastrin kinetics to predict recurrence free survival (curative cohorts), will be based on parameters estimated with a PK/PD model able to characterize the early kinetics of progastrin during and after the end of treatment and during follow up.

Measure: time to recurrence (for patients enrolled in curative intent cohorts).

Time: 6 years

Description: The ability of the progastrin kinetics to predict progression-free survival (non-curative cohorts) will be based on parameters estimated with a PK/PD model able to characterize the early kinetics of progastrin during and after the end of treatment and during follow up

Measure: time to progression (for patients enrolled in non-curative intent cohorts)

Time: 6 years

Description: The ability of the progastrin kinetics to predict time to death will be based on parameters estimated with a PK/PD model able to characterize the early kinetics of progastrin during and after the end of treatment and during follow up

Measure: time to death (whenever it occurred)

Time: 6 years

Description: The ROC AUC will be compared between classical markers and the prograstrin. Logistic regression will be used to combine the classical marker(s) and the progastrin in order to estimate the diagnostic value of the marker combination. progastrin, CA15-3, CA19-9, CA125, CEA, PSA and AFP concentration will be measured on blood sample taken at the inclusion.

Measure: Comparison of the initial values and of the kinetics of other serum tumor markers (CA15-3, CA 19-9, CA125, CEA, PSA, AFP) with those of progastrin

Time: at the baseline

71 A Multicenter, Open-label Phase 1b Study of the Combination of Binimetinib and Encorafenib in Adolescent Patients With Unresectable or Metastatic BRAF V600-mutant Melanoma

This is a multicenter Phase 1b, open-label study to evaluate the pharmacokinetic, safety and efficacy of binimetinib and encorafenib co-administered to adolescent patients with BRAF V600-mutant advanced/metastatic melanoma. The study consists of a Safety Run-in Phase to determine the RDE (recommended dose in expansion), followed by an Expansion Phase.

NCT03878719 Melanoma Drug: binimetinib Drug: encorafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

- Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous melanoma or unknown primary melanoma American Joint Committee on Cancer Stage IIIB, IIIC, or IV. - Presence of BRAF V600E or V600K mutation in tumor tissue as determined by a local or central laboratory - Adequate cardiac function: - Left ventricular ejection fraction (LVEF) ≥ 50% as determined by ECHO or multi-gated acquisition (MUGA) scan and above the institutional lower limit of normal (LLN); - Triplicate average baseline QTcF value ≤ 450 ms. - Adequate bone marrow, organ function, and laboratory parameters: - Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; - Hemoglobin ≥ 9 g/dL with or without transfusions; - Platelets ≥ 75 × 10⁹/L without transfusions; - Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN); in patients with liver metastases ≤ 5 × ULN; - Total bilirubin ≤ 1.5 × ULN and < 2 mg/dL; OR total bilirubin >1.5 × ULN with indirect bilirubin < 1.5 × ULN; - Creatinine ≤ 1.5 × institutional ULN for age, or calculated creatinine clearance ≥ 70 mL/min/1.73 --- V600E ---

Primary Outcomes

Measure: Pharmacokinetic (PK) parameter (time to reach the maximum observed plasma concentration Cmax [Tmax]) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (time of last PK sample [Tlast]) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (area under the plasma concentration-time curve from time zero to Tlast [AUClast]) for binimetinib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tmax) for binimetinib's active metabolite (AR00426032)

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for AR00426032

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tlast) for AR00426032

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (AUClast) for AR00426032

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tmax) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tlast) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (AUClast) for encorafenib

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tmax) for encorafenib's metabolite (LHY746)

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Cmax) for LHY746

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Tlast) for LHY746

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (AUClast) for LHY746

Time: Day 1 and Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (trough concentration [Ctrough]) for binimetinib

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (trough concentration [Ctrough]) for binimetinib

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (trough concentration [Ctrough]) for binimetinib

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Measure: PK parameter (Ctrough) for AR00426032

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Ctrough) for AR00426032

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (Ctrough) for AR00426032

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Measure: PK parameter (Ctrough) for encorafenib

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Ctrough) for encorafenib

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (Ctrough) for encorafenib

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Measure: PK parameter (Ctrough) for LHY746

Time: at time zero Day 15 of Cycle 1, 28 day cycles

Measure: PK parameter (Ctrough) for LHY746

Time: at time zero Day 1 of Cycle 2, 28 day cycles

Measure: PK parameter (Ctrough) for LHY746

Time: at time zero Day 1 of Cycle 3, 28 day cycles

Secondary Outcomes

Measure: Incidence and severity of adverse events (AEs)

Time: From informed consent up to 30 days following last dose of study drug

Measure: Incidence of dose-limiting toxicities (DLTs)

Time: Duration of treatment for safety run-in phase, approximately 6 months, 28 day cycles

Description: Five-point Hedonic scale from 1 to 5, 5=really good

Measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for binimetinib

Time: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles

Description: Five-point Hedonic scale from 1 to 5, 5=really good

Measure: Palatability score for the pediatric formulations as assessed by an age-appropriate questionnaire for encorafenib

Time: Through Cycle 3 Day 1 in patients receiving the pediatric formulations in the Expansion Phase, 28 day cycles

Measure: Objective response rate (ORR) assessed by the investigator, based on Response Criteria Evaluation in Solid Tumors (RECIST) v1.1

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Duration of response (DOR)

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Time to response

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Progression-free survival (PFS)

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: One-year survival rate

Time: From first dose up to 1 year after treatment initiation

Measure: Change from Baseline in bone densitometry based on dual energy X-ray absorptiometry (DEXA) scan.

Time: Duration of treatment, approximately 6 months, 28 day cycles

Measure: Change from Baseline in calcium-phosphorus product (Ca × P)

Time: Duration of treatment, approximately 6 months, 28 day cycles

72 LUNGMAP: A Master Protocol To Evaluate Biomarker-Driven Therapies And Immunotherapies In Previously-Treated Non-Small Cell Lung Cancer (Lung-Map Screening Study)

This screening and multi-sub-study randomized phase II/III trial will establish a method for genomic screening of similar large cancer populations followed by assigning and accruing simultaneously to a multi-sub-study hybrid Master Protocol (Lung-MAP). The type of cancer trait (biomarker) will determine to which sub-study, within this protocol, a participant will be assigned to compare new targeted cancer therapy, designed to block the growth and spread of cancer, or combinations to standard of care therapy with the ultimate goal of being able to approve new targeted therapies in this setting. In addition, the protocol includes non-match sub-studies which will include all screened patients not eligible for any of the biomarker-driven sub-studies.

NCT03851445 Previously Treated Non-Small Cell Lung Cancer Drug: Screening Platform
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Patients must agree to have any tissue that remains after testing retained for the use of sub-study Translational Medicine (TM) studies at the time of consent the patient is enrolled in. 5. Patients with known EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, or BRAF V600E mutation are not eligible unless they have progressed following all standard of care targeted therapy. --- T790M --- --- V600E ---

Primary Outcomes

Description: The tissue submission will be measured by the proportion of patients who register to this screening study for whom a tissue sample is submitted.

Measure: Screening Success (Tissue Submission)

Time: Up to 3 years

Description: Adequate tissue will be measured by the proportion of patients who submitted a specimen for whom genomic results were successfully obtained, if multiple platforms are being used (e.g. both FMI and IHC), these rates will be summarized by the individual assays and combined. These rates are summarized for the entire screened population and by screening type (screened at progression versus pre-screened prior to progression). The rates are evaluated for both the initial submission success rates and the overall success rate accounting for new tissue submissions following an unsuccessful result.

Measure: Screening Success (Adequate Tissue)

Time: Up to 3 years

Description: Pre-screening-to-sub-study assignment will be measured among pre-screened patients and the proportion of patients assigned to a sub-study (which is triggered by the submission of the notice of progression form, see Section 14.0). Note: Patients screened at progression are notified of their sub-study assignment within 1 day of the biomarker results being reported to SWOG.

Measure: Screening Success (Prescreening-to-sub-study Assignment)

Time: Up to 3 years

Description: Screening success will be measured by the reasons for non-participation collection on the LungMAP Notice of Intention not to Register Form. The proportions of patients with this form submitted are summarized overall and by screening type. The reasons for submission are summarized overall and by screening type.

Measure: Screening Success (Notice of Intention Not to Register Submission)

Time: Up to 3 years

Description: Match to Biomarker-Driven Sub-Study will be measured by successful biomarker screening, the proportion assigned to a biomarker-driven substudy.

Measure: Screening Success (Match to Biomarker-Driven Sub-Study)

Time: Up to 3 years

Description: Assignment Success will be measured by the proportion of patients assigned to a sub-study who are registered to a sub-study, these rates are summarized overall and among biomarker-driven and non-match sub-study assignments, separately. In addition, these rates are summarized by screening type.

Measure: Screening Success (Assignment Success)

Time: Up to 3 years

73 A Phase IIb Study of RAMucirumab in Combination With TAS102 vs. TAS102 Monotherapy in Chemotherapy Refractory Metastatic Colorectal Cancer Patients

Interventional, prospective, randomized (1:1), controlled, open label, multicenter phase IIb study in patients with advanced metastatic colorectal cancer. The scope of the trial is to evaluate overall survival of either regimen (TAS102 +/- Ramucirumab) and evaluate safety and tolerability.

NCT03520946 Colorectal Cancer Drug: Ramucirumab Drug: TAS 102
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

Intolerance is defined as a permanent discontinuation of the respective treatment resulting from toxicity 2. Signed informed consent before start of specific protocol procedure 3. Histologically or cytologically documented diagnosis of adenocarcinoma of the colon or rectum 4. Presence of at least one measurable site of disease following RECIST 1.1 criteria 5. ECOG (Eastern Cooperative Oncology Group) performance 0-1 6. Known RAS and BRAF V600E mutational status 7. Life expectancy of at least 3 months 8. Adequate hematological, hepatic and renal function parameters: 1. Leukocytes ≥3000/mm³, platelets ≥100,000/mm³, neutrophil count (ANC) ≥1500/μL, hemoglobin ≥9 g/dL (5.58 mmol/L) 2. Adequate coagulation function as defined by International Normalized Ratio (INR) ≤1.5, and a partial thromboplastin time (PTT) ≤5 seconds above the ULN (upper limit of normal) (unless receiving anticoagulation therapy). --- V600E ---

Patients will be stratified by the duration of previous anti-angiogenic therapy ≥ or <12 months in total, BRAF V600E mutation status (mutation vs. wildtype), RAS mutation status (mutation vs. wildtype), and randomized 1:1 to receive either ramucirumab/TAS102 (arm A) or TAS102 (arm B). --- V600E ---

Primary Outcomes

Description: Overall survival according to Kaplan-Meier

Measure: Overall survival

Time: Up to 3 years

Secondary Outcomes

Description: ORR defined as the proportion of patients with complete or partial remission according to RECIST 1.1

Measure: Overall response rate (ORR)

Time: Up to 3 years

Description: DCR defined as the proportion of patients with complete or partial remission and stable disease according to RECIST 1.1

Measure: Disease control rate (DCR)

Time: Up to 3 years

Description: PFS, defined as the time from enrollment/randomization to the first occurrence of progression, as determined by the investigator using CT criteria, or death from any cause

Measure: Progression-free survival (PFS)

Time: Up to 3 years

Description: OS rate at 6 and 12 months, defined as patients who are alive after at 6 and 12 months, respectively

Measure: Overall survival (OS) at different time points

Time: 6 months and 1 year

Description: Efficacy (ORR) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

Measure: Efficacy (ORR)

Time: Up to 3 years

Description: Efficacy (PFS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

Measure: Efficacy (PFS)

Time: Up to 3 years

Description: Efficacy (OS) in patients who develop neutropenia grade ≥2 (ANC ≤1500/μl) in cycle 1

Measure: Efficacy (OS)

Time: Up to 3 years

Description: Quality of life (QoL) as measured by EORTC-QLQ-C30 at d1 of each cycle and on EOT (end of treatment).

Measure: Quality of life I (QoL)

Time: Up to 1 year

Description: Quality of life (QoL) as measured by EQ-5D-5L at d1 of each cycle and on EOT.

Measure: Quality of life II (QoL)

Time: Up to 1 year

Other Outcomes

Description: ORR according to gene expression, mutational profiles and plasma biomarkers

Measure: Explorative: Overall response rate (ORR)

Time: Up to 3 years

Description: OS according to gene expression, mutational profiles and plasma biomarkers

Measure: Explorative: Overall survival (OS)

Time: Up to 3 years

Description: PFS according to gene expression, mutational profiles and plasma biomarkers

Measure: Explorative: Progression-free survival (PFS)

Time: Up to 3 years

74 An Open-Label, Phase 1/1b, Single-Agent Study of RXDX-105 in Patients With Advanced Solid Tumors

This is a first-in-human, multicenter, open-label study consisting of 2 phases. Phase 1 is a dose escalation study of RXDX-105 (formerly known as CEP-32496) in patients with advanced solid tumors aimed at defining the recommended Phase 2 dose (RP2D) and schedule for administration. Phase 1b is a dose expansion in approximately 90 patients with advanced solid tumors with specific histologies and/or molecular alterations of interest. Patients in Phase 1b will be treated at the RP2D determined in Phase 1.

NCT01877811 Solid Tumors Drug: RXDX-105

Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E ---

Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E ---

Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E --- --- V600E ---

Known hypersensitivity to any of the components of RXDX-105 Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E ---

Known hypersensitivity to any of the components of RXDX-105 Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E ---

Known hypersensitivity to any of the components of RXDX-105 Inclusion Criteria for Phase 1b: 1. Patients must have histologically or cytologically confirmed advanced solid tumors with a histology and/or molecular alteration of interest as defined in Section 4, detected by a CLIA-certified or equivalently accredited diagnostic laboratory • Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) patients must have archival tissue available for analysis by Ignyta; all other patients must send tissue to Ignyta, if tissue is available 2. Prior Treatment: - Patients with BRAF V600E mutations must be TKI-naïve; any number of other prior therapies are allowed - NSCLC patients with RET alterations who have had a prior RET inhibitor or are RET inhibitor-naïve will be enrolled; (any number of other prior therapies are allowed); all other histologies with RET alterations must be RET inhibitor-naïve - Patients with Squamous NSCLC and Non-squamous NSCLC (no known RET alterations or BRAF V600E mutations) may have had prior TKIs and any number of other prior therapies 3. Measurable disease according to RECIST v1.1 for all patients except patients with RET altered tumors; patients with RET altered tumors must have evaluable disease, but are not required to have measurable disease 4. Patients with treated, stable CNS metastases, including leptomeningeal carcinomatosis are allowed. --- V600E --- --- V600E --- --- V600E ---

Primary Outcomes

Description: From signing of the informed consent up to approximately 12 months

Measure: Phase 1: Dose Limiting Toxicities

Time: Approximately 12 months

Description: From signing of the informed consent up to approximately 12 months

Measure: Phase 1: Occurrence of Adverse Events

Time: Approximately 12 months

Description: To further assess the safety profile and tolerability of RXDX-105 at the RP2D

Measure: Phase 1b: Occurrence of Adverse Events

Time: Approximately 12 months

Secondary Outcomes

Measure: Phase 1: Maximum observed plasma drug concentration (Cmax)

Time: Day 1 to Day 16

Measure: Phase 1: Time of maximum observed plasma drug concentration (tmax)

Time: Day 1 to Day 16

Measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to infinity (AUC0-∞)

Time: Day 1 to Day 16

Measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to the last measureable drug concentration (AUC0-t)

Time: Day 1 to Day 16

Measure: Phase 1: Area under the plasma drug concentration versus time curve from time 0 to 24 hours after study drug administration (AUC0-24)

Time: Day 1 to Day 16

Measure: Phase 1: Terminal elimination rate constant (λz)

Time: Day 1 to Day 16

Measure: Phase 1: Terminal elimination half-life (t1/2)

Time: Day 1 to Day 16

Measure: Phase 1: Apparent clearance of study drug from plasma (CL/F)

Time: Day 1 to Day 16

Description: Objective response rate is defined as the proportion of patients with advanced solid tumors achieving best overall response of complete response (CR), or partial response (PR), as assessed using RECIST v1.1

Measure: Phase 1b: Objective Response Rate

Time: Approximately 12 months

Description: The duration of objective response is defined as the time interval from the date of first documented response (CR or PR) to disease progression or death, whichever occurs first

Measure: Phase 1b: Duration of Objective Response

Time: Approximately 12 months

Description: Clinical benefit rate is defined as the proportion of patients achieving a complete response (CR), partial response (PR) or stable disease (SD) for 6 months

Measure: Phase 1b: Clinical Benefit Rate

Time: Approximately 12 months

75 Phase III, Randomized, Double-Blind, Multicenter Trial of Autologous Dendritic Cells and Irradiated Autologous Tumor Cells In Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) vs. Autologous Peripheral Blood Mononuclear Cells (PBMCs) In GM-CSF for The Treatment Of Metastatic Melanoma

The purpose of this research is to evaluate the safety and effectiveness of tumor cell therapy. This research study is evaluating if a patient-specific experimental therapy for metastatic melanoma will lengthen survival with minimal harmful effects. It is called an experimental therapy (or "study therapy") because it is not yet approved by the U.S. Food and Drug Administration (FDA). This research study will use the patient's own tumor cells,the patient's own dendritic cells (a type of immune cell), and a granulocyte-macrophage colony stimulating factor (GM-CSF, a type of growth factor). GM-CSF is a natural growth factor that stimulates growth of white blood cells in the body. Since 1991, GM-CSF has been used as a standard treatment to help increase the number of white blood cells after chemotherapy. The patient's dendritic cells are grown in a test-tube with the patient's tumor cells and the growth factor. The resulting solution is called the study therapy. The intent of the study therapy is to make the dendritic cells more effective at fighting the tumor when they are injected back into the patient.

NCT01875653 Stage IV Melanoma Stage III Melanoma Biological: Autologous Dendritic Cell-Tumor Cell Immunotherapy (DC-TC) Biological: Autologous PBMCs in GM-CSF (MC)
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

2. Patients with multiple depots of distant metastatic disease must have previously received at least one or more of the following standard treatments: interleukin 2 (IL-2), or ipilimumab, or vemurafenib (if tumor expresses the V600E mutation), or dacarbazine or temozolomide, if not mutated for the V600E mutation, and not felt to be medically appropriate for IL-2 or ipilimumab. --- V600E ---

2. Patients with multiple depots of distant metastatic disease must have previously received at least one or more of the following standard treatments: interleukin 2 (IL-2), or ipilimumab, or vemurafenib (if tumor expresses the V600E mutation), or dacarbazine or temozolomide, if not mutated for the V600E mutation, and not felt to be medically appropriate for IL-2 or ipilimumab. --- V600E --- --- V600E ---

Primary Outcomes

Description: The time frames are estimated time in months (rounded up to the nearest month) from the start of study. The time estimates for the analyses are based on enrolling approximately 250 patients over a 34.8 months period and having a follow up of approximately 17 months after the last patient is enrolled.

Measure: Overall survival

Time: 52 months

Secondary Outcomes

Description: Adverse Events monitoring to assess safety and tolerability History & physical examination, vital signs, clinical laboratory tests (safety), and other tests as clinically indicated adverse event monitoring to assess safety and toxicity

Measure: Adverse Events as a Measure of Safety and Tolerability

Time: 52 months

76 A Phase 2 Study of Neoadjuvant Vemurafenib in Melanoma Patients With Untreated Brain Metastases, Whose Tumors Harbor B-raf Mutations

The purpose of this trial is to study the activity of vemurafenib in untreated melanoma brain metastases harboring B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations that are not amenable to stereotactic radiosurgery based on size, number of lesions or location, to measure cerebrospinal fluid (CSF) levels of vemurafenib as an indicator of central nervous system penetrance and to measure levels of vemurafenib in normal brain tissue and brain metastases in those in whom surgical management is feasible.

NCT01781026 Melanoma Drug: Vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.. Inclusion Criteria: - Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations. --- V600E ---

Inclusion Criteria: - Biopsy proven metastatic melanoma with the B-raf V600E or V600K mutations. --- V600E ---

Primary Outcomes

Description: Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Measure: Activity of Vemurafenib in Untreated Brain Metastases

Time: 1 year

77 APPLICATION OF MOLECULAR TECHNIQUES FOR IMPROVING THE DIAGNOSIS AND TREATMENT OF NODULAR THYROID LESIONS.

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System)

NCT02323724 Papillary Thyroid Carcinoma Genetic: BRAF V600E mutation by pyrosequencing technique
MeSH: Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary
HPO: Abnormality of the thyroid gland Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System) Improvement in diagnosis. --- V600E ---

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System).. Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Papillary Thyroid Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary Aim of the study To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System). --- V600E ---

To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System).. Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Inclusion Criteria: - Cases with histological diagnosis of papillary carcinoma (CP) and previous cytological diagnosis in groups III, IV and V Bethesda, collected between October 1989 and July 2014 in Corporació Parc Taulí Exclusion Criteria: - Non available cytological or histological material Papillary Thyroid Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary Aim of the study To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System). --- V600E --- --- V600E ---

Methodology: - Identification of cases - Detection of BRAF V600E mutation, initially in histological material from the surgical specimen, and if present, detection in cytological material. --- V600E ---

Primary Outcomes

Description: To determine the improvement in diagnosis of papillary carcinoma by detecting mutation V600E BRAF in retrospective cases with inconclusive cytologic diagnosis (categories III, IV and V of Bethesda System).

Measure: Improvement in diagnosis

Time: 6 months

78 A Prospective Study of Plasma Genotyping as a Noninvasive Biomarker for Genotype-directed Cancer Care

Tumor genotyping has become an essential biomarker for the care of advanced lung cancer and melanoma, and is currently used to identify patients for treatment with targeted kinase inhibitors like erlotinib and vemurafenib. However, tumor genotyping can be slow and cumbersome, and is limited by availability of tumor biopsy tissue for testing. The aim of this study is to prospectively evaluate a blood-based genotyping tool that can quantify the presence of oncogenic mutations (EGFR, KRAS, BRAF) in patients with lung cancer and melanoma. This assay is being studied both as a diagnostic tool for classifying patient genotype, and a serial measurement tool for quantification of response and progression on therapy.

NCT02279004 NSCLC Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.. Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- L858R --- --- T790M --- --- V600E ---

T790M, etc) Exclusion Criteria - Participants who are unable to provide informed consent - Participants who are 18 years of age or younger - Participants who are unable to comply with the study procedures Inclusion Criteria To participate in this study a participant must meet the eligibility of one of the following cohorts: Cohort 1: Cancers beginning initial treatment - One of the following diagnoses: - Cohort 1A (CLOSED): ---Advanced non-squamous NSCLC (including adenosquamous) - Cohort 1B: - Stage II-III non-squamous NSCLC (including adenosquamous) - Stage IIIB-IV melanoma - Patient must be planned to begin initial therapy, or completely resected before or after receiving adjuvant therapy - For patients with NSCLC, EGFR and KRAS genotype may be known or unknown - For patients with melanoma, BRAF and NRAS genotype may be known or unknown - For patients without tumor genotyping, there must be a plan for genotyping including either: - Archived tumor tissue available and planned for genotyping - A biopsy at some future time is anticipated and will be available for genotyping Cohort 2: Cancers with acquired resistance to targeted therapy - One of the following diagnoses: - Cohort 2A (CLOSED): ---Advanced NSCLC harboring a known EGFR mutation - Cohort 2B: - Advanced NSCLC harboring a targetable genotype other than EGFR - Advanced melanoma harboring a known tumor genotype - Clinical determination of progression targeted therapy, as evidence by plans to start a new systemic treatment regimen, or obtain a biopsy to plan a new treatment regimen - New systemic treatment regimen planned OR - Re-biopsy for resistance genotyping planned - Note, date of targeted therapy start and clinical progression must be provided Cohort 3: Cancers with a known genotype starting palliative systemic therapy Cohort 3A (CLOSED): - Advanced NSCLC harboring one of the following mutations: - EGFR exon 19 deletion - EGFR L858R - EGFR T790M - KRAS G12X - BRAF V600E - Patients must be initiating palliative systemic therapy, either on or off a clinical trial Cohort 4: Paired plasma NGS and ddPCR - Cohort 4A (CLOSED): - Advanced NSCLC, newly diagnosed or with progression following treatment. --- T790M --- --- L858R --- --- T790M --- --- V600E ---

Primary Outcomes

Description: We will determine the accuracy of a droplet digital PCR (ddPCR)-based plasma genotyping assay in performing noninvasive tumor genotyping.

Measure: Accuracy of Plasma Genotyping Assay

Time: 2 years

Secondary Outcomes

Description: The amount of time required to perform this noninvasive genotyping assay.

Measure: Turnaround Time of Plasma Genotyping Assay

Time: 2 years

Description: The ability of serial quantitative ddPCR-based plasma genotyping to predict early treatment failure in patients initiating a new line of therapy.

Measure: Early Treatment Failure

Time: 2 years

Description: We will determine the accuracy of plasma NGS in performing noninvasive genotyping compared to tumor NGS and paired ddPCR.

Measure: Accuracy of Plasma NGS

Time: 2 years

79 A Pilot Study of Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer

The purpose of this study is to test a new drug combination consisting of two drugs, vemurafenib (also known as ZelborafTM) and panitumumab (also known as VectibixTM). This treatment is being tested in a subgroup of patients with colorectal cancer whose tumors have changes in the BRAF gene that may make them more likely to respond to this new drug combination.

NCT01791309 Metastatic Colorectal Cancer Drug: combination panitumumab and vemurafenib
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

A Pilot Study of Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer. --- V600E ---

Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer The purpose of this study is to test a new drug combination consisting of two drugs, vemurafenib (also known as ZelborafTM) and panitumumab (also known as VectibixTM). --- V600E ---

using pre- and post-vemurafenib tumor biopsies obtained from the first 10 patients participating in this trial.. Inclusion Criteria: - Patient must have metastatic colorectal cancer with a V600E BRAF mutation that has been histologically or cytologically-confirmed at MSKCC and has failed to respond to appropriate standard therapy regimens. --- V600E ---

Inclusion Criteria: - Patient must have metastatic colorectal cancer with a V600E BRAF mutation that has been histologically or cytologically-confirmed at MSKCC and has failed to respond to appropriate standard therapy regimens. --- V600E ---

Primary Outcomes

Description: Overall response will be estimated based on best response to this combination in six months of treatment.

Measure: objective response rate (ORR)

Time: 6 months

Secondary Outcomes

Description: Progression free survival (PFS) is defined as the period elapsing between the date of initiation of therapy and the date of either disease progression or date of death, whichever is earlier.

Measure: progression-free survival (PFS)

Time: 2 years

Description: OS is defined as the interval between the time of initiation of therapy and the date of death from any cause. Patients who are alive at the time of study completion will be censored at the time the patient was last known to be alive.

Measure: overall survival (OS)

Time: 2 years

Description: The safety endpoints will include all types of adverse experiences, laboratory safety measurements, ECOG performance scale status, and vital signs. Adverse experiences will be graded and recorded throughout the study according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0.

Measure: safety, tolerability, and adverse event profile

Time: 1 year

Description: using pre- and post-vemurafenib tumor biopsies obtained from the first 10 patients participating in this trial.

Measure: efficacy

Time: 2 years

80 A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).

This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part).

NCT01928940 Solid Tumours Drug: dabrafenib Drug: trametinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E --- --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E --- --- V600E --- --- V600E ---

A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).. Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part) This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Solid Tumours Melanoma This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E ---

Solid Tumours Melanoma This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). --- V600E --- --- V600E ---

Phase I part is designed to primarily assess the safety and tolerability of GSK2118436 and GSK1120212 combination therapy in subjects with BRAF V600E/K mutation positive advanced solid tumors. --- V600E ---

Phase II part is designed to primarily evaluate ORR of the combination as first-line therapy in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation positive cutaneous melanoma. --- V600E ---

Primary Outcomes

Description: An AE is defined as any untoward medical occurrence (MO) in a part. temporally associated with the use of a medicinal product (MP), whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. SAE is defined as any untoward MO that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect and protocol-specific SAEs:ALT>=3xupper limit of normal(ULN) and bilirubin>=2xULN(>35% direct) (or ALT>=3xULN, international normalized ratio>1.5), any new primary cancers, treatment emergent malignancies except basal cell carcinoma, symptomatic or asymptomatic LVEF decrease, retinal pigment epithelial detachment or retinal vein occlusion, pyrexia with hypotension,or dehydration or renal insufficiency,or severe (>=G3) rigor/chills.

Measure: Phase I: Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)

Time: From the start of study treatment until 30 days after study treatment discontinuation (average of 1.38 year)

Description: A DLT was defined as an event occurred during the first 21 days after the first dose of study drugs and met any of the following criteria, according to National Cancer Institutes (NCI) common terminology criteria for AE (CTCAE) grade (G) version 4.0: G4 hematological toxicity; G3 or G4 non-hematologic toxicity (including rash, nausea, vomiting and diarrhea only if uncontrolled with supportive therapy); rash >=G3 that required dose reduction despite supportive care; a G2 or greater non-hematological toxicity that in the judgment of the investigator and medical monitor; dose interruption of greater than 14 consecutive days due to unresolved toxicity; any new G2 or greater valvular heart disease and significant alteration in cardiac valve morphology from Baseline.

Measure: Phase I: Number of Participants With a Dose-limiting Toxicity (DLT)

Time: From the start of study treatment until 21 days

Description: CCPs were graded according to NCI CTCAE grade version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters (para) for which an increase to G3 or G4 from BL G occurred. CCPs that were not G according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those para for which the category decreased to Low or increased to High relative to the BL category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. CCPs included: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, calcium, creatinine, glucose, potassium, magnesium, sodium, inorganic phosphorus, chloride, lactate dehydrogenase (LDH), total protein, urea/blood urea nitrogen (BUN) and uric acid.

Measure: Phase I: Number of Participants With the Indicated Worst-case Change From Baseline (BL) in the Indicated Clinical Chemistry Parameters (CCPs)

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Hematology parameters were summarized according to NCI CTCAE G, version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 from Baseline G occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those parameters for which the category decreased to Low or increased to High relative to the Baseline category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Hematology parameters included: hemoglobin, lymphocytes, total neutrophils, platelet count, white blood cell (WBC) counts, basophils, eosinophils, hematocrit, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), monocytes and red blood cell (RBC) count.

Measure: Phase I: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Hematology Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Urine samples were collected for urine dipstick analysis at Baseline and at the post-treatment Visit. The number of participants with negative (absence) and positive (presence: trace, 1+, 2+, 3+, 4+ or 5+) results for urine occult blood (UOB), urine glucose (UGLU), urine ketones (UKET), urine protein (UP) and urine urobilinogen (UUBIL) were summarized. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase I: Number of Participants With the Indicated Urinalysis Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: The ECOG pef status 5-point scale is used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the par. and to determine appropriate treatment and prognosis: G0, fully active, able to carry on all pre-disease pef without restriction. G1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, example, light house work, office work. G2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about >50 percent (%) of waking hrs. G3, capable of only limited selfcare; confined to bed or chair >50% of waking hrs. G4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. G5, dead. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Number of par. who improved, had no change, or deteriorated in pef status from BL is summarized.

Measure: Phase I: Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance (Pef) Status

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Systolic blood pressure (SBP) and diastolic blood pressure (DBP) values were graded using (NCI CTCAE version 4.0). SBP was categorized as: G1 (Increase to >=120 to 140 millimeters of mercury [mmHg]), G2 (Increase to >=140 to <160 mmHg), and G3 (Increase to >=160 mmHg). DBP was categorized as: G1 (Increase to >=80 to <90 mmHg), G2 (Increase to >=90 to <100 mmHg), and G3 (Increase to >=100 mmHg). The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of G0.

Measure: Phase I: Number of Participants With Worst-case On-therapy Increase From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Change from Baseline in heart rate is categorized as decrease to <60 beats per minute (bpm), change to normal or no change, and increase to >100 bpm relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant's heart rate value decreased to <60 bpm and increased to >100 bpm post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Heart Rate

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Change from Baseline in temperature is categorized as a decrease to <=35 degrees celsius (C), change to normal or no change as 35-38 degrees C, and increase to >=38 degrees C relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant temperature value decreased to <=35 degrees C and increased to >=38 degrees C post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Temperature

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Oxygen saturation measures the capacity of blood to transport oxygen to other parts of the body. Oxygen binds to hemoglobin in red blood cells when moving through the lungs. A pulse oximeter uses two frequencies of light (red and infrared) to determine the percentage of hemoglobin in the blood that is saturated with oxygen,that is called as blood oxygen saturation or SpO2. Change from Baseline was calculated as the individual post-Baseline value (Days 8,15; Weeks 3 to 136 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase I: Change From Baseline in Oxygen Saturation (SpO2) Measured Via Pulse Oxymetry at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Mean change in body weight from Baseline was determined. Change from Baseline was calculated as the individual post-Baseline value (Weeks 3 to 136 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase I: Change From Baseline in Weight at the Indicated Time Points

Time: From Baseline until the post-treatment Visit ( average of 1.38 year)

Description: Single twelve (12)-lead ECGs were perfomred at Baseline, Weeks 3 to 132 and post-treatment Visit. ECG findings were categorized as: normal, abnormal - clinically significant (CS), or abnormal - not clinically significant (NCS), as determined by the investigator.

Measure: Phase I: Number of Participants With the Indicated Electrocardiogram (ECG) Findings at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 year)

Description: Absolute change from Baseline in LVEF were summarized at each scheduled assessment time and in the worst-case post Baseline. Only the post Baseline assessments that used the same method (ECHO or Multi Gated Acquisition Scan [MUGA]) as the Baseline assessments were used to derive the change from Baseline. The change from Baseline was categorized as: any increase; no change; 0-<10 Decrease, 10-19 Decrease, >=20 Decrease, >=10 Decrease and >= lower limit of normal (LLN), >=10 Decrease and below LLN, >=20 Decrease and >=LLN and >=20 Decrease and below LLN. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram (ECHO)

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Confirmed overall response (ORR) is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). ORR was assessed by investigator and blinded independent central review (BICR).

Measure: Phase II: Number of Participant With Confirmed Overall Response

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Secondary Outcomes

Description: Blood samples were collected from each par. at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr post-dose on Day 21 (repeat dose) for PK analysis. GSK2118436 metabolites included GSK2285403, GSK2298683, and GSK2167542. AUC from time zero to last quantifiable concentration (concn) (AUC[0-t]) was determined using the linear trapezoidal rule for increasing concn and the logarithmic trapezoidal rule for decreasing. The AUC from time zero extrapolated to infinity (AUC[0-inf] was calculated, where data permit, as the sum of AUC(0-t) and Ct/z, where Ct is the observed plasma concn obtained from the log-linear regression analysis of the last quantifiable time-point and z is the terminal phase rate constant. Area under the concentration-time curve over 12 hr and 24 hr dosing interval is called AUC[0-12] and AUC[0-24]. AUC(0-inf) was calculated only at Day 1.

Measure: Phase I: Area Under the Plasma Concentration Versus Time Curve (AUC) of GSK2118436 and Metabolites, and GSK1120212 After Single and Repeat Dose

Time: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)

Description: Blood samples were collected from each participant at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr post-dose on Day 21 (repeat dose) for PK analysis. GSK2118436 metabolites included GSK2285403, GSK2298683 and GSK2167542. Cmax was determined from the raw concentration-time data.

Measure: Phase I: Maximum Plasma Concentration (Cmax) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose

Time: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)

Description: Trough concentration is the lowest level that a drug is present in the body. Pre-dose (trough) blood samples were collected on Day 8, Day 15, Weeks 3, 8, 16 and 24 for estimating plasma trough concentration. GSK2118436 metabolites included GSK2285403, GSK2298683, and GSK2167542. Ctau was determined from the raw concentration-time data.

Measure: Phase I: Plasma Trough Concentration (Ctau) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose

Time: At pre-dose on Day 8, Day 15, Weeks 3, 8, 16 and 24

Description: Blood samples were collected from each participant at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr post-dose on Day 21 (repeat dose) for PK analysis. GSK2118436 metabolites included GSK2285403, GSK2298683, and GSK2167542. Tmax is defined as the time of occurrence of Cmax. Tmax was determined directly from the raw concentration-time data. The apparent terminal elimination half-life (t1/2) obtained as the ratio of ln2/lamdaz, where lamdaz is the terminal phase rate constant estimated by linear regression analysis of the log transformed concentration-time data. . T1/2 was calculated only at Day 1.

Measure: Phase I: Time of Occurrence of Cmax (Tmax) and Terminal Phase Half Life (t1/2) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose

Time: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)

Description: Confirmed ORR is defined as the percentage of participants with a confirmed CR or PR according to RECIST, version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). ORR was assessed by investigator and BICR.

Measure: Phase I: Number of Participants With Confirmed Overall Response Rate

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Description: ORR is defined as the percentage of participants with an unconfirmed CR or PR according to RECIST version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). Unconfirmed ORR was assessed by investigator and BICR.

Measure: Phase I: Number of Participants With Unconfirmed Overall Response Rate

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Description: PFS is defined as the time from the first dose of study treatment to the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or disease progression minus the date of first dose plus one day. The date of documented disease progression is defined as the date of disease progression based on radiologic evidence. Participants with documented date of disease progresssion or death and who had not received subsequent anticancer treatment prior to the date of documented disease progression or death were included in the analysis of PFS. PFS was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase I: Progression Free Survival (PFS)

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: Duration of response is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause among participants with confirmed CR or PR. The participant who showed a CR or PR was included in the analysis of duration of response. Duration of response was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase I: Duration of Response

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: ORR is defined as the percentage of participants with an unconfirmed CR or PR according to RECIST version 1.1. RECIST is a set of rules that define when tumors in cancer participants improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment. CR is defined as disappearance of all target lesions. Partial response is defined as at least a 30% decrease in the sum of the diameters of target lesions after treatment from Baseline (before study drug administration). Unconfirmed ORR was assessed by investigator and BICR.

Measure: Phase II: Number of Participants With Unconfirmed Overall Response

Time: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)

Description: PFS is defined as the time from the first dose of study treatment to the earliest date of disease progression or death due to any cause. The length of this interval is estimated as the date of death or disease progression minus the date of first dose plus one day. The date of documented disease progression is defined as the date of disease progression based on radiologic evidence. Participants with documented date of disease progresssion or death and who had not received subsequent anticancer treatment prior to the date of documented disease progression or death were included in the analysis of PFS. PFS was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase II: Progression Free Survival (PFS)

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: Duration of response is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause among participants with confirmed CR or PR. The participant who showed a CR or PR was included in the analysis of duration of response. Duration of response was assessed by investigator and BICR. Please note the values of the Full Range (min, max) are described irregardless of censoring at data cut-off.

Measure: Phase II: Duration of Response

Time: From start of the treatment until disease progression or death (average of 1.38 years)

Description: An AE is defined as any untoward MO in a part. temporally associated with the use of a MP, whether or not considered related to the MP and can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with its use. SAE is defined as any untoward MO that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, a congenital anomaly/birth defect and protocol-specific SAEs:ALT>=3xULN and bilirubin>=2xULN(>35% direct) (or ALT>=3xULN, international normalized ratio>1.5), any new primary cancers, treatment emergent malignancies except basal cell carcinoma, symptomatic or asymptomatic LVEF decrease, retinal pigment epithelial detachment or retinal vein occlusion, pyrexia with hypotension,or dehydration or renal insufficiency,or severe (>=G3) rigor/chills.

Measure: Phase II: Number of Participants With Any Adverse Event and Any Serious Adverse Event

Time: From the start of study treatment until 30 days after study treatment discontinuation (average of 1.38 years)

Description: CCPs were graded according to NCI CTCAE garde version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 from Baseline grade occurred. CCPs that were not graded according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those parameters for which the category decreased to Low or increased to High relative to the Baseline category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. CCPs included: albumin, alkaline phosphatase, ALT, AST, total bilirubin, calcium, creatinine, glucose, potassium, magnesium, sodium, inorganic phosphorus, chloride, LDH, total protein, urea/BUN and uric acid.

Measure: Phase II: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Clinical Chemistry Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Hematology parameters were summarized according to NCI CTCAE G, version 4.0 as: G1, Mild; G2, Moderate; G3, Severe; G4, Life-threatening or disabling; G5, Death. Data are presented for only those parameters for which an increase to G3 or G4 from Baseline G occurred. For hematology parameters that were not graded according to NCI CTCAE criteria, were categorized as High and Low with respect to the normal range. Data are presented only for those parameters for which the category decreased to Low or increased to High relative to the Baseline category. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Hematology parameters included: hemoglobin, lymphocytes, total neutrophils, platelet count, WBC counts, basophils, eosinophils, hematocrit, MCHC, MCH, MCV, monocytes and RBC count.

Measure: Phase II: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Hematology Parameters

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Urine samples were collected for urine dipstick analysis at Baseline and at the post-treatment Visit. The number of participants with negative (absence) and positive (presence: trace, 1+, 2+, 3+, 4+ or 5+) results for UOB, UGLU, UKET, UP and UUBIL were summarized. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase II: Number of Participants With the Indicated Urinalysis Results

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: The ECOG pef status 5-point scale is used to assess how a participant's disease is progressing, to assess how the disease affects the daily living abilities of the par. and to determine appropriate treatment and prognosis: G0, fully active, able to carry on all pre-disease pef without restriction. G1, restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, example, light house work, office work. G2, ambulatory and capable of all selfcare, but unable to carry out any work activities; up and about >50% of waking hrs. G3, capable of only limited selfcare; confined to bed or chair >50% of waking hrs. G4, completely disabled; cannot carry on any selfcare; totally confined to bed or chair. G5, dead. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. Number of par. who improved, had no change, or deteriorated in pef status from BL is summarized.

Measure: Phase II: Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in ECOG Perormance Status

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: SBP and DBP values were graded using (NCI CTCAE version 4.0). SBP was categorized as: G1 (Increase to >=120 to 140 mmHg), G2 (Increase to >=140 to <160 mmHg), and G3 (Increase to >=160 mmHg). DBP was categorized as: G1 (Increase to >=80 to <90 mmHg), G2 (Increase to >=90 to <100 mmHg), and G3 (Increase to >=100 mmHg). The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments. An increase is defined as an increase in the CTCAE grade relative to the Baseline grade. Participants with missing Baseline values were assumed to have a Baseline value of G0.

Measure: Phase II: Number of Participants With Worst-case On-therapy Increase From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Change from Baseline in heart rate is categorized as decrease to <60 bpm, change to normal or no change, and increase to >100 bpm relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant's heart rate value decreased to <60 bpm and increased to >100 bpm post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Heart Rate

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Change from Baseline in temperature is categorized as a decrease to <=35 degrees C, change to normal or no change as 35-38 degrees C, and increase to >=38 degrees C relative to the Baseline value. Participants with a missing Baseline value are assumed to have a normal Baseline value. Participants were counted twice if the participant temperature value decreased to <=35 degrees C and increased to >=38 degrees C post-Baseline. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Temperature

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Oxygen saturation measures the capacity of blood to transport oxygen to other parts of the body. Oxygen binds to hemoglobin in red blood cells when moving through the lungs. A pulse oximeter uses two frequencies of light (red and infrared) to determine the percentage of hemoglobin in the blood that is saturated with oxygen, that is called as blood oxygen saturation, or SpO2. Change from Baseline was calculated as the individual post-Baseline value (Days 8 and 15; Weeks 3 to 132 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase II: Change From Baseline in Oxygen Saturation Measured Via Pulse Oxymetry at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Mean change in body weight from baseline was determined. Change from Baseline was calculated as the individual post-Baseline value (Weeks 3 to 132 and post-treatment Visit) minus the Baseline value. The Baseline value is defined as the last pre-treatment value observed.

Measure: Phase II: Change From Baseline in Weight at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Single 12-lead ECGs were performed at Baseline, Weeks 3 to 132 and post-treatment Visit. ECG findings were categorized as: normal, abnormal - CS, or abnormal - NCS, as determined by the investigator.

Measure: Phase II: Number of Participants With the Indicated Electrocardiogram Findings at the Indicated Time Points

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

Description: Absolute change from Baseline in LVEF were summarized at each scheduled assessment time and in the worst-case post Baseline. Only the post Baseline assessments that used the same method (ECHO or MUGA) as the Baseline assessments were used to derive the change from Baseline. The change from Baseline was categorized as: any increase; no change; 0-<10 Decrease, 10-19 Decrease, >=20 Decrease, >=10 Decrease and >= LLN, >=10 Decrease and below LLN, >=20 Decrease and >=LLN and >=20 Decrease and below LLN. The worst-case during the on-therapy period was determined taking into account both scheduled and unscheduled assessments.

Measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction as Assessed by Echocardiogram

Time: From Baseline until the post-treatment Visit (average of 1.38 years)

81 A Multi-center Phase II Study of AUY922 in Patients With Stage IV Non-small Cell Lung Cancer (NSCLC) With Driver Molecular Alterations Other Than Sensitive EGFR Mutation, Who Have Progressed After One Line of Systemic Therapy

This is an open-label, single-arm, multicenter phase II trial in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC.

NCT01922583 Non-small Cell Lung Cancer (NSCLC) Drug: AUY922
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

V600E) or in exon 11; point mutation (e.g. --- V600E ---

Primary Outcomes

Description: To define the by RECIST 1.1 of AUY922 in patients with stage IV EGFR T790M, EGFR exon 20 and other uncommon, HER2, or BRAF-mutated; ALK, ROS1, or RET-rearranged NSCLC

Measure: Objective response rate

Time: Patients will be followed up for 2 years(post disease progression)

Secondary Outcomes

Description: Patients will be followed for progression-free survival (PFS) and overall survival (OS) which will be analyzed by using a Kaplan-Meier curve. Patients will be followed up for PFS and OS for 2 years.

Measure: Efficacy, progression-free survival (PFS)

Time: Patients will be followed up for PFS and OS for 2 years.(post disease progression)

Description: Patients will be followed for overall survival (OS)

Measure: overall survival (OS)

Time: Patients will be followed up for OS for 2 years.(post disease progression)

82 Phase II Study of Pembrolizumab in Combination With Binimetinib and Bevacizumab in Patients With Refractory Colorectal Cancer

This is an open-label, single-center, single-arm phase II clinical trial evaluating the combination of pembrolizumab, binimetinib, and bevacizumab in patients with metastatic colorectal adenocarcinoma who have not responded to prior therapy.

NCT03475004 Colorectal Cancer Metastatic Cancer Drug: Pembrolizumab, Bevacizumab, and Binimetinib
MeSH: Colorectal Neoplasms Neoplasm Metastasis
HPO: Neoplasm of the large intestine

- Patients with BRAF V600E mutations are not elgible for the study. --- V600E ---

Primary Outcomes

Description: Overall Response Rate based on CT imaging and how it compares to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1)

Measure: Determine the effectiveness pembrolizumab, binimetinib, and bevacizumab on the response rate of colorectal cancer

Time: Study beginning to study end; 12 months

Secondary Outcomes

Description: Kaplan-Meier product-limit method will be used to summarize the time to event results

Measure: Determine the effectiveness of pembrolizumab, binimetinib, and bevacizumab on progression free survival of colorectal cancer

Time: Study start date to first sign of disease progression or death, whichever comes first, assessed up to 100 weeks

Description: Kaplan-Meier product-limit method will be used to summarize the time to event results

Measure: Determine the effectiveness of pembrolizumab, binimetinib, and bevacizumab on overall survival of colorectal cancer

Time: Study start to first sign of disease progression or death. whichever comes first, assessed up to 100 weeks

Description: Grade 1, 2, 3, or 4 toxicities as defined by CTCAE v4 will be evaluated

Measure: Evaluation of the safety and tolerability of pembrolizumab, binimetinib, and bevacizumab when given together

Time: Study beginning to study end, 12 months

83 A Phase II Study of Rucaparib in Patients With Genomic LOH High and/or Deleterious BRCA1/2 Mutation Stage IV or Recurrent Non-Small Cell Lung Cancer (LUNG-MAP Sub-Study)

This phase II Lung-MAP trial studies how well rucaparib works in treating patients with genomic loss of heterozygosity (LOH) high and/or deleterious BRCA1/2 mutation stage IV non-small cell lung cancer or that has come back. Rucaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT03845296 Deleterious BRCA1 Gene Mutation Deleterious BRCA2 Gene Mutation Loss of Heterozygosity Lung Non-Small Cell Squamous Carcinoma Recurrent Large Cell Lung Carcinoma Recurrent Lung Adenocarcinoma Recurrent Lung Non-Small Cell Carcinoma Recurrent Non-Squamous Non-Small Cell Lung Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Drug: Rucaparib
MeSH: Carcinoma Lung Neoplasms Carcinoma, Non-Small-Cell Lung Adenocarcinoma Adenocarcinoma of Lung Carcinoma, Squamous Cell
HPO: Carcinoma Neoplasm of the lung Non-small cell lung carcinoma Squamous cell carcinoma

- Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy. --- T790M --- --- V600E ---

Primary Outcomes

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times.

Measure: Investigator assessed progression free survival (PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Response will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. Response rates and associated confidence intervals will be calculated. Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times. Response rates can be estimated within 16% with 95% confidence.

Measure: Duration of response (DoR)

Time: From date of first documentation of response (complete response [CR] or partial response [PR]) to date of first documentation of progression assessed by local review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. The Brookmeyer-Crowley method will be used to calculate confidence intervals for median times.

Measure: Overall survival

Time: From date of sub-study registration to date of death due to any cause, assessed up to 3 years

Measure: Time to death

Time: From date of sub-study registration to date of death due to any cause, assessed up to 3 years

Description: Toxicity will be evaluated among all patients enrolled on the study (combining the squamous and non-squamous cohorts). Toxicity can be estimated to within 11% with 95% confidence.

Measure: Incidence of adverse events

Time: Up to 3 years

84 A Phase Ib/II, Open-Label Study of M7824 in Combination With Chemotherapy in Participants With Stage IV Non-small Cell Lung Cancer

The main purpose of the study is to evaluate the safety and tolerability of M7824 in combination with chemotherapy.

NCT03840915 Carcinoma, Non-Small-Cell Lung Drug: Cisplatin Drug: Carboplatin Drug: Pemetrexed Drug: Nab-paclitaxel Drug: Gemcitabine Drug: Docetaxel Drug: M7824 Drug: Carboplatin Drug: Carboplatin Drug: M7824
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Fresh biopsies should be collected if archived tumor material is not available - Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study entry and date of first dose Exclusion Criteria: - The participant's tumor harbors an epidermal growth factor receptor (EGFR) sensitizing (activating) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 rearrangement, or BRAF V600E mutation, if targeted therapy is locally approved - Mixed small cell with non-small cell lung cancer histology - Has received major surgery within 4 weeks prior to the first dose of study intervention; received thoracic radiation therapy (RT) of > 30 gray (Gy) within 6 months prior to the first dose of study intervention - Previous malignant disease (other than the target malignancy to be investigated in this study) within the last 3 years - Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. --- V600E ---

Primary Outcomes

Measure: Incidence of Dose Limiting Toxicities (DLTs)

Time: Day 1 to Day 21 (Cycle 1)

Measure: Incidence of Treatment Emergent Adverse Events (TEAEs) and Treatment Related Adverse Events

Time: Up to 3 years

Secondary Outcomes

Measure: Confirmed Objective Response as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Time: Up to 3 years

Measure: Progression-Free Survival (PFS) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Time: Up to 3 years

Measure: Overall Survival (OS)

Time: Up to 3 years

Measure: Duration of Response (DOR) According to Response Evaluation Criteria in Solid Tumors Version (RECIST) 1.1

Time: Up to 3 years

Measure: Concentration of M7824 Observed Immediately at the End of Infusion (Ceoi)

Time: Up to 3 years

Measure: Concentration of M7824 Observed Immediately Before Next Dosing (Ctrough)

Time: Up to 3 years

Measure: Area Under the Serum Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of M7824

Time: Up to 3 years

Measure: Area Under the Serum Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of M7824

Time: Up to 3 years

Measure: Maximum Observed Serum Concentration (Cmax) of M7824

Time: Up to 3 years

Measure: Time to Reach Maximum Serum Concentration (Tmax) of M7824

Time: Up to 3 years

Measure: Apparent Terminal Half-life (t1/2) of M7824

Time: Up to 3 years

Measure: Immunogenicity of M7824, as Assessed by Anti-drug Anti-body (ADA) Assay

Time: Up to 3 years

85 BRAF-/MEK-Inhibition With Dabrafenib and Trametinib in Melanoma Patients in the Adjuvant Setting: a Non-interventional Observatory Study

Adjuvant therapy with dabrafenib plus trametinib in melanoma was approved in 2018 by the EMA (EUropean Medicines Agency). The purpose of this non-interventional study is to assess the usage of adjuvant dabrafenib and trametinib in clinical practice, where the patient population may differ from study population.

NCT03944356 Melanoma Drug: Dabrafenib and Trametinib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

- V600E/K mutation-positive cutaneous melanoma - Adjuvant treatment with combination therapy of Dabrafenib (Tafinlar®) and Trametinib (Mekinist®) as indicated in the SmPC (Summary of Product Characteristics) and by prescription, that has been started no longer that 4 weeks before inclusion of the patient into the study or which will be initiated directly after inclusion - Age ≥ 18 years - Signed written informed consent Exclusion Criteria: - Lack of basic demographics and staging information - Current or planned participation within a clinical trial. --- V600E ---

Treatment with the BRAF inhibitor dabrafenib plus the MEK (Mitogen-activated protein kinase kinase) inhibitor trametinib showed improved overall survival in patients with unresectable or metastatic BRAF V600E/K-mutant melanoma (COMBI-d and COMBI-v studies). --- V600E ---

Primary Outcomes

Description: Median time on adjuvant dabrafenib + trametinib treatment defined as the interval between start of treatment and permanent discontinuation of treatment.

Measure: Median time on treatment

Time: Date of first dose up to 12 months

Secondary Outcomes

Description: Rate of permanent study drug discontinuation due to any reason.

Measure: Permanent study drug discontinuation due to any reason

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Rate of permanent study drug discontinuation due to adverse drug reactions (ADRs).

Measure: Permanent study drug discontinuation due to adverse drug reactions

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Occurrence of pyrexia and related symptoms, listing the grade, number of episodes, and time to resolution.

Measure: Pyrexia and related symptoms

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Type of adverse drug reaction (ADR) management applied for pyrexia and correlation with occurrence/persistence of pyrexia.

Measure: Adverse drug reaction management: pyrexia

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: ADRs persisting/emerging up to 3 months post-treatment.

Measure: Adverse drug reactions in Follow-up

Time: From date of first treatment until the date of treatment end plus 3 months of follow-up, assessed up to 15 months

Description: Assessment of health-related quality of life (HRQoL), measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30). The EORTC QLQ-C30 consists of the folowing scales, with each dimension specifying five levels of severity [not at all (level 1), a little (level 2), quite a bit (level 3), very much (level 4)]: functional scales (Physical, Role, Cognitive, Emotional, Social Functioning) symptom scales (Fatigue, Pain and Nausea/Vomiting) single item scales (Dyspnoea, Insomnia, Appetite Loss, Constipation, Diarrhoea and Financial Difficulties). Additionally the Global Health Status and QoL scales are incorporated, specifying on a scale from 1 (very poor) to 7 (excellent).

Measure: Health-related quality of life

Time: Over the course of treatment plus 3 months safety follow up, assessed up to 15 months

Description: Relapse free survival (RFS) time and rate

Measure: Relapse free survival

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Distant metastasis free survival (DMFS) time.

Measure: Distant metastasis free survival time

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Distant metastasis free survival (DMFS) rate.

Measure: Distant metastasis free survival rate

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Overall survival (OS) time.

Measure: Overall survival time

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Overall survival (OS) rate.

Measure: Overall survival rate

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

Description: Correlation between time on treatment and efficacy endpoints (RFS, DMFS, OS).

Measure: Time on treatment and efficacy endpoints

Time: From date of first treatment until the date of treatment end, assessed up to 12 months

86 Association Of Prognosis And BRAF V600E Mutations In Papillary Thyroid Carcinoma

The purpose of this study is to determine whether BRAF V600E mutation in our patients with papillary thyroid cancer has an association with poor prognosis.

NCT01417442 Papillary Thyroid Carcinoma Genetic: BRAF V600E POSITIVITY
MeSH: Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary
HPO: Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Association Of Prognosis And BRAF V600E Mutations In Papillary Thyroid Carcinoma. --- V600E ---

BRAF V600E Mutations In Papillary Thyroid Carcinoma The purpose of this study is to determine whether BRAF V600E mutation in our patients with papillary thyroid cancer has an association with poor prognosis. --- V600E ---

BRAF V600E Mutations In Papillary Thyroid Carcinoma The purpose of this study is to determine whether BRAF V600E mutation in our patients with papillary thyroid cancer has an association with poor prognosis. --- V600E --- --- V600E ---

BRAF V600E MUTATION. --- V600E ---

Inclusion Criteria: - Patients with papillary thyroid cancer Exclusion Criteria: - Patients who do not want to be a part of this study Inclusion Criteria: - Patients with papillary thyroid cancer Exclusion Criteria: - Patients who do not want to be a part of this study Papillary Thyroid Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms Thyroid Cancer, Papillary Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy and BRAF V600E mutation is the most common genetic alteration identified in PTC, ranging from 25 to 80%, with the average rate about 45%. --- V600E ---

Various studies demonstrated a relationship between BRAF V600E mutation and aggressive characteristics of the cancer, including the worse patient prognosis. --- V600E ---

So the investigators will examine BRAF V600E mutation in our patients with PTC and try to assess the role of this mutation in prognosis and further management of the patients. --- V600E ---

Primary Outcomes

Measure: BRAF V600E MUTATION

Time: 2 years

87 Clinical and Pathophysiological Investigations Into Erdheim-Chester Disease

Background: - Erdheim Chester Disease (ECD) is a very rare disease in which abnormal white blood cells start growing and affect the bones, kidneys, skin, and brain. ECD can cause severe lung disease, kidney failure, heart disease, and other complications that lead to death. Because ECD is a rare disease, found mostly in men over 40 years of age, there is no standard treatment for it. More information is needed to find out what genes can cause ECD and how best to treat it. Objectives: - To collect study samples and medical information on people with Erdheim Chester Disease. Eligibility: - Individuals 2 to 80 year of age who have been diagnosed with Erdheim Chester Disease. Design: - Participants will be screened with a physical exam and medical history. - Participants will have a study visit to provide samples for study, including blood, urine, and skin tissue samples. Participants will also have lung, heart, and muscle function tests; imaging studies of the brain, chest, and whole body; a treadmill running stress test; an eye exam; and other tests as needed by the study doctors. - Participants will be asked to return for a similar set of tests every 2 years, and to remain in contact for possible treatment options....

NCT01417520 Myelofibrosis Gaucher Disease Pulmonary Fibrosis Hermansky-Pudlak Syndrome (HPS) Cancer
MeSH: Primary Myelofibrosis Pulmonary Fibrosis Gaucher Disease Erdheim-Chester Disease Hermanski-Pudlak Syndrome
HPO: Pulmonary fibrosis

We will analyze the data with the assistance of an NIH statistician using parametric and non-parametric methods to assess overall trends in survival, and to look for patterns in organ involvement, patterns in response to various therapeutic regimens, and, lastly, to look for an association between the BRAF V600E mutation and disease severity. --- V600E ---

Primary Outcomes

Description: To comprehensively describe the natural history of ECD, including genetic and epidemiological aspects, its associated complications, and responses to various treatments.

Measure: To comprehensively describe the natural history of ECD, including genetic and epidemiological aspects, its associated complications, and responses to various treatments.

Time: 1 day

Description: To identify molecular markers important for diagnosis and treatment.

Measure: To identify molecular markers important for diagnosis and treatment.

Time: 1 day

88 Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)

This is a single arm phase II trial focused on how dabrafenib and trametinib before and after surgery works in treating patients with stage IIIB-C melanoma that has a specific mutation in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib and trametinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving dabrafenib and trametinib after surgery may kill any remaining tumor cells.

NCT02231775 BRAF V600E Mutation Present BRAF V600K Mutation Present Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Drug: Dabrafenib Other: Laboratory Biomarker Analysis Procedure: Therapeutic Conventional Surgery Drug: Trametinib
MeSH: Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the skin

Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.. Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E ---

uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E ---

uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency BRAF V600E Mutation Present BRAF V600K Mutation Present Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Study enrollment was stopped in April 2016 due to a substantial improvement in RFS in Arm B vs Arm A treated patients. --- V600E ---

Primary Outcomes

Description: RFS will be compared between patients with a pathologic complete response (pCR) and patients without a pCR using a two-sided log-rank test.

Measure: Relapse-free survival (RFS)

Time: Up to 12 months

Secondary Outcomes

Description: The association between RFS and OS and covariates of interest will be assessed using Cox proportional hazards regression analysis.

Measure: Overall survival (OS)

Time: Up to 1 year

Description: Logistic regression will be used to assess the association between the probability of complete pathologic response and clinical and disease covariates of interest.

Measure: Complete pathologic response

Time: Up to 1 year

Description: Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.

Measure: Incidence of adverse events

Time: Up to 1 year

89 A Pilot Study of Dabrafenib and Trametinib for Patients With BRAF Mutated Ameloblastoma

This pilot clinical trial studies dabrafenib and trametinib in treating patients with ameloblastoma and a specific mutation (change) in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02367859 Ameloblastoma BRAF Gene Mutation Drug: Dabrafenib Other: Laboratory Biomarker Analysis Drug: Trametinib
MeSH: Ameloblastoma Adamantinoma

The results of the immunohistochemical analysis will be expressed as both raw data in addition to a ratio between pre- and post- treatment.. Inclusion Criteria: - Histological diagnosis of ameloblastoma; all stages are eligible; patients must have evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria - B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E or other known dabrafenib sensitive BRAF mutation in tumor by any Clinical Laboratory Improvement Amendments (CLIA) certified lab; may include, for example, Sanger sequencing, SNaPshot platform, immunohistochemistry, Foundation One tests, etc.) - Life expectancy > 3 months - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Absolute neutrophil count (ANC) > 1.5 x10^9/L - Platelet (PLT) > 99 x 10^9/L - Hemoglobin > 8 g/dL - Total bilirubin (Tbili) < 1.6 x upper limit of normal (ULN) - Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.6 x ULN - Alkaline phosphatase (alk phos) < 2.6 x ULN - Serum creatinine < 1.6 x ULN or creatinine clearance > 50 ml/min - Ability to understand and the willingness to sign a written informed consent document - Patients of childbearing potential must agree to use effective contraception until at least 6 months after treatment with dabrafenib - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Left ventricular ejection fraction equal to or greater than normal Exclusion Criteria: - No prior treatment with agents targeting BRAF mutant tyrosine kinases or radiation of target lesions - Invasive malignancy other than ameloblastoma within 3 years, excluding curatively treated basal cell carcinoma, and other highly curable cancers such as early stage cutaneous squamous cell carcinoma (T1 NO) cervical carcinoma in situ (CIS), early stage prostate cancer, thyroid cancer or breast cancer - Uncontrolled hypertension, chronic heart failure (CHF), or other major medical illness - Prior allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib - Concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) - Concomitant use of proton pump inhibitors, H2-receptor antagonists, antacids - Known glucose-6-phosphate dehydrogenase (G6PD) deficiency - Pregnant or nursing patients; women of childbearing potential must have a negative pregnancy test within 14 days of enrollment - Electrocardiogram (EKG) with QTcB (Bazett's formula) > 480 ms done within 14 days of enrollment - Interstitial lung disease or pneumonitis - A history of retinal vein occlusion (RVO) - Congestive heart failure NYHA class III or worse (Marked limitation of physical activity. --- V600E ---

Less than ordinary activity causes fatigue, palpitation, or dyspnea.) - A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months Inclusion Criteria: - Histological diagnosis of ameloblastoma; all stages are eligible; patients must have evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria - B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E or other known dabrafenib sensitive BRAF mutation in tumor by any Clinical Laboratory Improvement Amendments (CLIA) certified lab; may include, for example, Sanger sequencing, SNaPshot platform, immunohistochemistry, Foundation One tests, etc.) - Life expectancy > 3 months - Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 - Absolute neutrophil count (ANC) > 1.5 x10^9/L - Platelet (PLT) > 99 x 10^9/L - Hemoglobin > 8 g/dL - Total bilirubin (Tbili) < 1.6 x upper limit of normal (ULN) - Aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.6 x ULN - Alkaline phosphatase (alk phos) < 2.6 x ULN - Serum creatinine < 1.6 x ULN or creatinine clearance > 50 ml/min - Ability to understand and the willingness to sign a written informed consent document - Patients of childbearing potential must agree to use effective contraception until at least 6 months after treatment with dabrafenib - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Left ventricular ejection fraction equal to or greater than normal Exclusion Criteria: - No prior treatment with agents targeting BRAF mutant tyrosine kinases or radiation of target lesions - Invasive malignancy other than ameloblastoma within 3 years, excluding curatively treated basal cell carcinoma, and other highly curable cancers such as early stage cutaneous squamous cell carcinoma (T1 NO) cervical carcinoma in situ (CIS), early stage prostate cancer, thyroid cancer or breast cancer - Uncontrolled hypertension, chronic heart failure (CHF), or other major medical illness - Prior allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib - Concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John's wort) of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) - Concomitant use of proton pump inhibitors, H2-receptor antagonists, antacids - Known glucose-6-phosphate dehydrogenase (G6PD) deficiency - Pregnant or nursing patients; women of childbearing potential must have a negative pregnancy test within 14 days of enrollment - Electrocardiogram (EKG) with QTcB (Bazett's formula) > 480 ms done within 14 days of enrollment - Interstitial lung disease or pneumonitis - A history of retinal vein occlusion (RVO) - Congestive heart failure NYHA class III or worse (Marked limitation of physical activity. --- V600E ---

Primary Outcomes

Description: RECIST v1.1 response rate

Measure: Response rate according to RECIST version (v)1.1

Time: 6 weeks

Secondary Outcomes

Description: Routine Hematoxylin and Eosin slide review will measure extent of tumor necrosis. Percentage of tumor necrosis by volume assessed. The biopsy slide of the resection specimen examined and the volume of the necrosis compared to the volume of the total tumor determined by the centrally reviewing pathologists and percentage readouts of tumor necrosis, in increments of 10%, will be determined. In addition to measuring tumor necrosis the slide review will estimate therapy effect on intact cells by estimating the percent cells with therapy-associated nuclear atypia.

Measure: Percent tumor necrosis

Time: At the time of endpoint biopsy or surgical resection

Description: Proliferation index evaluation will be performed in the laboratory on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen. Ki-67 immunohistochemistry will be scored by at least two pathologists using percentage positive cells as the primary metric. The results of the immunohistochemical analysis will be expressed as both raw data in addition to a ratio between pre- and post- treatment.

Measure: Change in percent proliferation index by Ki67 immunohistochemistry

Time: Baseline to time of endpoint biopsy or surgical resection

Description: Immunohistochemistry evaluation for MEK/ERK will be performed on the initial pre-treatment biopsy and either the endpoint biopsy or the resection specimen. Immunohistochemistry will be scored by at least two pathologists using percentage positive cells and intensity of staining as the primary metrics. The results of the immunohistochemical analysis will be expressed as both raw data in addition to a ratio between pre- and post- treatment.

Measure: Change in expression of phosphorylation of MEK and ERK by immunohistochemistry

Time: Baseline to time of endpoint biopsy or surgical resection

90 COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection

This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]) combination therapy or two placebos for 12 months.

NCT01682083 Melanoma Drug: Dabrafenib Drug: Trametinib Drug: Placebos
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. --- V600E ---

In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.. Key Inclusion Criteria: - Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. --- V600E ---

- History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR) Key Inclusion Criteria: - Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. --- V600E ---

Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. --- V600E ---

Primary Outcomes

Description: Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.

Measure: Relapse-free Survival (RFS)

Time: Approximately 3.5 years

Secondary Outcomes

Description: Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo

Measure: Overall Survival

Time: approximately 3.5 years

Description: Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.

Measure: Distant Metastasis-free Survival

Time: approximately 3.5 years

Description: Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.

Measure: Freedom From Relapse

Time: approximately 3.5 years

91 A Phase I Trial of Vemurafenib and Ipilimumab in Subjects With V600 BRAF Mutation-positive Metastatic Melanoma

Treatment of subjects who have metastatic melanoma that expresses an activated mutant form of the BRAF oncogene (V600E) with a combination of the specific BRAF inhibitor, Vemurafenib, and the Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) inhibitor mAb Ipilimumab will be safe and feasible and will show preliminary evidence of anti-tumor efficacy and survival in comparison to historical results following treatment with either agent alone.

NCT01400451 Melanoma Drug: Ipilimumab (BMS-734016) Drug: Vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Ph I Ipilimumab Vemurafenib Combo in Patients With v-Raf Murine Sarcoma Viral Oncogene Homolog B1 (BRAF) Treatment of subjects who have metastatic melanoma that expresses an activated mutant form of the BRAF oncogene (V600E) with a combination of the specific BRAF inhibitor, Vemurafenib, and the Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) inhibitor mAb Ipilimumab will be safe and feasible and will show preliminary evidence of anti-tumor efficacy and survival in comparison to historical results following treatment with either agent alone. --- V600E ---

Primary Outcomes

Description: AEs graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Lead In Period: between the first vemurafenib dose and the day prior to the first ipilimumab dose.

Measure: During the Lead In Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Vemurafenib Alone

Time: From first vemurafenib dose to day prior to first ipilimumab dose (28 days); Patients who never progressed from Lead-in to combination treatment (720 mg Alone): first dose to last dose + 90 days (approximately 2 years)

Description: AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. AEs: onset on or after ipilimumab start and within 90 days of last dose. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Day 1=first dose of ipilimumab.

Measure: During the Combination Treatment Period: Number of Participants With Adverse Events (AEs), AEs Leading to Drug Discontinuation, Serious Adverse Events (SAEs), and Deaths in Participants Treated With Concurrent Ipilimumab and Vemurafenib

Time: Combination drugs: Day 1 to last dose of drug + 90 days (approximately 2 years)

Description: DLT defined as a >= Grade 3 drug-related AE during induction with ipilimumab in combination with vemurafenib excluding: Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites of known or suspected tumor); Grade 3 cutaneous squamous cell carcinoma; Grade 3 photosensitivity that resolved to a Grade 1 or baseline within 15 days; Grade 3 immune-mediated events of the skin (rash, pruritis) or endocrine systems (hypothyroidism, hyperthyroidism, hypopituitarism, adrenal insufficiency, hypogonadism and cushingoid) that resolved to a Grade 1 or baseline within 28 days; a transient (resolving within 6 hours of onset) Grade 3 infusion-related AE. Hepatic=elevated aspartate aminotransferase and alanine aminotransferase. Maximum tolerable dose (MTD) was defined as the maximum dose of combination treatment that could be given to 6 subjects such that no more than 2 subjects experience DLT. Day 1=first day of concurrent therapy with ipilimumab and vemurafenib.

Measure: Number of Participants With Hepatic Dose Limiting Toxicities (DLT) in Participants Treated With Concurrent Ipilimumab and Vemurafenib

Time: Day 1 to last dose of drug + 90 (approximately 2 years)

92 A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF V600 - Dependent Advanced Solid Tumors

This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and the triple combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to assess the clinical efficacy and to further assess the safety of the combinations in selected patient populations. Oral LGX818 and MEK162 will be administered on a continuous schedule. Oral LEE011 will be administered once daily on a three weeks on, one week off schedule. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. A cycle is defined as 28 days. The dose escalation parts of the trial will be conducted in adult patients with BRAF V600-dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. The dose escalation will be guided by a Bayesian logistic regression model (BLRM). Following MTD/RP2D declaration, patients will be enrolled in three Phase II arms for the dual combination and one Phase II arm for the triple combination. All patients will be followed for 30 days for safety assessments after study drugs discontinuation. All patients enrolled in the Phase II part of the study will be followed for survival.

NCT01543698 Solid Tumors Harboring a BRAF V600 Mutation Drug: LGX818 Drug: MEK162 Drug: LEE011

Inclusion Criteria: Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available - Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation - Evidence of measurable disease as determined by RECIST v1.1 - World Health Organization (WHO) Performance Status ≤ 2 - Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential Exclusion Criteria: Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors - Symptomatic or untreated leptomeningeal disease - Symptomatic brain metastases. --- V600E ---

Other protocol-defined inclusion/exclusion criteria may apply Inclusion Criteria: Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available - Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation - Evidence of measurable disease as determined by RECIST v1.1 - World Health Organization (WHO) Performance Status ≤ 2 - Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential Exclusion Criteria: Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors - Symptomatic or untreated leptomeningeal disease - Symptomatic brain metastases. --- V600E ---

Primary Outcomes

Description: To estimate the MTD(s) and/or recommended phase 2 dose(s) (RP2D(s)) of oral LGX818 in combination with oral MEK162, and of oral LGX818 in combination with oral MEK162 and oral LEE011 in patients with BRAF V600-dependent advanced solid tumors by measuring the incidence of DLTs as defined by the protocol.

Measure: Phase Ib: Estimation of Maximum Tolerated Dose (MTD) by measuring incidence of dose limiting toxicities (DLT)

Time: up to 8 months

Description: Assess clinical efficacy of the LGX818 and MEK162 dual combination and LGX818 and MEK162 and LEE011 triple combination in the Phase II populations by evaluating the disease control rate (DCR) and objective response rate (ORR) as per RECIST 1.1

Measure: Phase II: Clinical efficacy

Time: up to 14 months

Secondary Outcomes

Description: To characterize the safety and tolerability of LGX818 and MEK162 in combination, and LGX818 and MEK162 and LEE011 in combination by evaluating the incidence and severity (as per CTCAE grading) of AEs in all patients enrolled in the study.

Measure: Safety and tolerability of LGX818 and MEK162 dual combination, and LGX818 and MEK162 and LEE011 triple combination by evaluating the incidence and severity of adverse events (AE).

Time: up to 17 months

Description: To determine the single and multiple dose PK profile of the LGX818 and MEK162 combination and LGX818 and MEK162 and LEE011 combination, by measuring plasma concentrations of MEK162 and LGX818 and LEE011 resp. at different timepoints prior and post study drug combination dosing on several days within cycle 1 and subsequent cycles.

Measure: Determination of single and multiple dose of Pharmacokinetics (PK) profile by measuring plasma concentrations versus time after study drug combination dosing (Phase Ib)

Time: up to 8 months

Description: To assess preliminary anti-tumor activity of the LGX818 and MEK162 combination, and the LGX818 and MEK162 and LEE011 combination by evaluating the ORR as per RECIST 1.1. Safety Issue?: (FDAAA) No

Measure: Preliminary clinical anti-tumor activity by evaluating the objective response rate (Phase Ib)

Time: up to 8 months

Description: To further assess clinical efficacy of the LGX818 and MEK162 combination and the LGX818 and MEK162 and LEE011 combination in the Phase II populations by measuring progression free survival (PFS) as per RECIST 1.1

Measure: Further clinical efficacy (phase II)

Time: up to 14 months

93 cKIT, BRAF/NRAS Mutations in Advanced Melanoma : Clinical Outcome in Response to Tyrosine-kinase Inhibitors - KitMel Project

Background: Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients. Until now, available therapies were few and unreliable, but recent understanding of melanomas' molecular pathways has improve their classification and new clinical strategies have been proposed. Initial studies showed that B-Raf/N-Ras mutations (respectively V600E and Q61) are the most frequent alteration being present in 70 to 80% of melanomas, characterizing non Chronic Sun-induced Damage skins (CSD). These include Superficial Spreading Melanomas (SSM) and Nodular Melanomas (NM). Other studies showed that c-Kit mutations are presently the predominant activating mutation (20 - 40 %) in Acro-Lentiginous Melanomas (ALM), Mucous Melanomas (MM) and in melanomas arising on CSD skin. c-Kit mutation pattern is more complex with four exons being affected leading to different mutations, which incidence and biological impact are less documented. BRAF/NRAS genetics alterations drive constantly cell growth, being thus attractive targets. Spectacular results have indeed been obtained with the BRAF inhibitor that targets the V600E BRAF-mutated form. Data from GIST disease revealed that the different c-Kit mutations modulate differently c-Kit function and the response to targeted therapies. Because c-Kit targeted therapy is a critical clinical issue, the investigators aimed to identify the most frequent mutations present in our population to propose appropriate screening test and adapt the therapy. Methods: 250 melanoma samples corresponding to an homogeneous white-Caucasian population (Brittany, France) will be screened. c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible). c-Kit copy number will be quantified by q-PCR and level of c-Kit determined by immunohistochemistry (IHC, CD117). Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing). Expected Results: Taken together, the investigators anticipate that the present genetic analysis of the tumours from patients with advanced melanoma will first document the type and frequency of cKit mutations, will confirm or not that BRAF, NRAS and cKit mutations are mutually exclusive and document their repartition in the melanomas sub-types. Finally this study will clue researchers in to how well patients will respond to a therapy that targets the growth-promoting proteins BRAF/NRAS and cKIT.

NCT01543113 Melanoma Other: sequencing
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Initial studies showed that B-Raf/N-Ras mutations (respectively V600E and Q61) are the most frequent alteration being present in 70 to 80% of melanomas, characterizing non Chronic Sun-induced Damage skins (CSD). --- V600E ---

Spectacular results have indeed been obtained with the BRAF inhibitor that targets the V600E BRAF-mutated form. --- V600E ---

Primary Outcomes

Description: c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible)

Measure: c-Kit exons 11, 13, 17 and 18 will be sequenced (direct sequencing and pyrosequencing when possible)

Time: Day 1

Secondary Outcomes

Description: level of c-Kit determined by immunohistochemistry

Measure: level of c-Kit determined by immunohistochemistry

Time: Day 1

Description: Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing).

Measure: Samples will also be analyzed for B-Raf mutations in codon 464, 466, 469 and 600, and for N-Ras mutations in codon 12, 13 and 61 (Pyrosequencing).

Time: Day 1

94 An Open-Label, Multicentre, Corollary Study of Pre-Operative Therapy With Dabrafenib and the Combination of Dabrafenib With Trametinib in Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.

NCT01978236 Melanoma and Brain Metastases Drug: Dabrafenib 150 mg Drug: Trametinib 2.0 mg
MeSH: Melanoma Neoplasm Metastasis
HPO: Cutaneous melanoma Melanoma

Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. --- V600E ---

The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. --- V600E ---

It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. --- V600E ---

Inclusion Criteria: - Signed written informed consent - Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. --- V600E ---

multiple sclerosis) - A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection - Current acute infection requiring intravenous antibiotics - A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency - The history or evidence of following cardiac abnormalities: - Corrected QT (QTc) interval using Bazett's Formula; (QTcB) >= 480 msecs - A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - Coronary angioplasty or stenting within the past 12 weeks - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Abnormal cardiac valve morphology (>= Grade 2) documented by echocardiogram (ECHO) - History of or evidence of clinically significant uncontrolled cardiac arrhythmias - Treatment refractory hypertension defined as a blood pressure of systolic >140 mmHg and/or diastolic >90 mm Hg which cannot be controlled by anti-hypertensive therapy - Subjects with intra-cardiac defibrillators or permanent pacemakers - Pregnant, lactating or breastfeeding females - Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures - Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2118436 or excipients that contraindicate their participation Inclusion Criteria: - Signed written informed consent - Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. --- V600E ---

Primary Outcomes

Description: Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib were collected on day of surgical resection of the brain metastasis(es), Two samples were collected before surgery and 2 samples after surgery with one hour gap in between. Upon collection blood was placed on wet ice. Plasma was isolated within 60 minutes of collection and frozen at -20 degree celsius.

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma)

Time: Pre-surgery and post-surgery on Day 15

Description: Concentrations of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib, and possibly other drug-related species were quantified in the pharmacokinetic tissue sample by an investigative Liquid chromatography- mass spectrometry (LC-MS)/MS method. The spatial distribution of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib and possibly other drug-related species in the tissue samples were determined using an investigative matrix assisted laser desorption ionization (MALDI) analysis method. Parenchymal brain metastases and extracranial metastases using MALDI imaging was not determined for all participants (completed by GSK for the first two participants enrolled)

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Parenchymal Brain Metastases

Time: Day 15

Description: Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib and trametinib (as appropriate), were planned but not collected.

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) and Trametinib (Cohort B Only) in CSF Samples.

Time: Pre-surgery and post-surgery on Day 15

Secondary Outcomes

Description: Concentrations of dabrafenib, its metabolites hydroxy-, carboxy- and desmethyl-dabrafenib) and trametinib in CSF (in participants who agree for optional collection of CSF at the time of brain tumor resection). Optional collection of CSF was obtained in the operating room on the day of brain metastasis resection. CSF samples for only one participant were collected and analyzed.

Measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) in Cerebrospinal Fluid (CSF) Samples

Time: Day 15

Description: Changes in MAPK pathway markers in paired extracranial biopsies taken pre-treatment, during craniotomy, and at disease progression, and changes in markers between post-operative intracranial and extracranial biopsies was planned but not performed as the study was terminated due to low enrollment.

Measure: Number of Participants With Changes in Mitogen-activated Protein Kinase (MAPK) Pathway Markers

Time: Up to Day 15

Description: Changes in the radiographic characteristics of the tumors were planned to be compared to (1) levels of dabrafenib, its metabolites and trametinib (where appropriate) in the brain metastases, plasma, and CSF, and (2) MAPK pathway activation status in tumors at the time of surgery. Results were planned to be compared to the analysis of early clinical responses in extracranial metastases, as determined by the Positron emission tomography (PET-CT) imaging. This analysis was planned but not performed as the study was terminated due to low enrollment

Measure: Number of Participants With Changes in Radiographic Tumors

Time: Up to 2 years

Description: The change from Baseline to the pre-surgery intracranial disease assessment in the SLD of intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

Measure: Percent Change From Baseline to Pre-surgery in the Sum of the Longest Diameters (SLD) of Intracranial Target Lesions

Time: Up to 2 years

Description: The maximum change from Baseline in the SLD of unresected intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

Measure: Maximum Percent Change From Baseline in the SLD of Unresected Intracranial Target Lesions

Time: Up to 2 years

Description: Overall Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime as per modified Response Evaluation Criteria in Solid Tumors (RECIST). The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence and is determined programmatically based on the investigator's assessment of response at each time point. Overall Extracranial Response Rate was planned but not analyzed as the study was terminated due to low enrollment.

Measure: Percentage of Participants With Overall Extracranial Response Rate in Unresected Lesions

Time: Approximately 2 years or death whichever occurs first

Description: Overall survival, defined as the time from first dose of study treatment to death for any reason, was planned to summarize using Kaplan-Meier quartile estimates along with two sided 95% confidence intervals. But were not performed as the study was terminated due to low enrollment.

Measure: Percentage of Participants With Overall Survival

Time: Approximately 2 years or death whichever occurs first

Description: Vital sign measurements including temperature, respiratory rate, systolic and diastolic blood pressure, and pulse rate were planned to be performed but were neither summarized nor listed as the study was terminated.

Measure: Number of Participants With Abnormal Vital Signs

Time: Up to 2 years

Description: A complete physical examination was planned which included assessments of the head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and extremities. Height and weight was also planned to be measured and recorded. A complete physical exam including a thorough genitourinary examination for female participants, inspection of the head and neck region, and digital rectal examination for both male and female participants was planned to be performed at Screening, and Month 12 or at discontinuation if discontinuation occurs prior to Month 12. If the participants had a genitourinary and rectal exam within 6 months of screening, these assessments need not to be repeated at screening. But data for physical examinations were not summarized and listed as the study was terminated.

Measure: Number of Participants With Abnormal Physical Examinations

Time: Up to 2 years

Description: 112-lead ECGs were planned to be obtained at screening during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. At each assessment a 12-lead ECG was planned to be performed by qualified personnel at the site after at least a five-minute rest with the participants in a semi-recumbent or supine position. But data for 12-lead ECGs were not summarized and listed as the study was terminated.

Measure: Number of Participants With Abnormal 12-lead Electrocardiograms (ECG)

Time: Screening

Description: ECHO include an evaluation for Left ventricular ejection fraction (LVEF) and both right- and left-sided valvular lesions. ECHO was planned to be performed at screening, Week 8 and every 16 weeks till discontinuation. data for ECHO was not summarized and listed as the study was terminated.

Measure: Number of Participants With Abnormal Echocardiogram (ECHO)

Time: Up to 2 years

Description: Laboratory assessments included parameters like Hematology, Standard Chemistry, Coagulation, Serum Pregnancy. Assessment of these parameters were planned to be performed by the central laboratory on screening, Day prior to surgery, Every 4 weeks after restart and Discontinuation, but were not analyzed as the study was terminated due to low enrollment.

Measure: Number of Participants With Abnormal Clinical Laboratory Assessments

Time: Up to 2 years

Description: AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE were collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy using Medical Dictionary for Regulatory Activities (MedDRA)

Measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

Time: Up to 2 years

95 Phase II Study of Durvalumab (MEDI4736) (Anti-PD-L1) and Trametinib (MEKi) in MSS Metastatic Colon Cancer

The goal of this clinical research study is to learn if durvalumab and trametinib can help to control microsatellite stable (MSS) colorectal cancer. The safety of these drugs will also be studied. This is an investigational study. Durvalumab is FDA approved and commercially available for the treatment of previously treated advanced bladder cancer. Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K. It is investigational to use durvalumab and trametinib to treat MSS colorectal cancer. Up to 56 participants will be enrolled in this study. All will take part at MD Anderson.

NCT03428126 Malignant Neoplasms of Digestive Organs Colorectal Cancer Colon Cancer Drug: Durvalumab Drug: Trametinib
MeSH: Colorectal Neoplasms Colonic Neoplasms Neoplasms
HPO: Colon cancer Neoplasm Neoplasm of the colon Neoplasm of the large intestine

Trametinib is FDA approved in combination with another drug called dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or BRAF V600K. --- V600E ---

Primary Outcomes

Description: MTD defined as highest dose level with less than 2 patients with dose limiting toxicity (DLT) out of at least six patients in the cohort. DLT defined as any adverse event (AE) of severity grade 3 or 4 (including serious or life-threatening) considered possibly, probably or definitely related to the combination of Durvalumab and Trametinib determined by NCI CTCAEv4.03.

Measure: Maximum Tolerated Dose (MTD) of Durvalumab and Trametinib in MSS Metastatic Colon Cancer

Time: 28 days

Measure: Best Overall Response (CR+PR) Determined by Immune Response Criteria

Time: Baseline up to 2 months

96 With or withoutA140 + mFOLFOX6 Treat 1st Line mCRC in RAS Wide Type, Multicenter, Double-blind, Randomized, Controlled Phase III Trial

The study is an double blind, randomized, multicenter phase 3 trial. The efficacy analyses are based on 570 Chinese patients with RAS wt mCRC treated with mFOLFOX-6 ± cetuximab. Study treatment continues until disease progression or unacceptable toxicity (ie, not for a fixed number of courses). The primary endpoint of the study is progression-free survival (PFS) time according to RECIST 1.0; key secondary endpoints include overall survival (OS) time, overall response rate (ORR), and safety/tolerability.

NCT03426371 Metastatic Colorectal Cancer Drug: KL-140 Drug: Placebo
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

Quality of life score is defined of questionnaire EORTC QLQ-C30.. Inclusion Criteria: - Signed written informed consent - Male or female subjects, 18-75 years of age - Medically accepted effective contraception if procreative potential exists - Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum - RAS wild-type and BRAF-V600E wild-type status in tumor tissue - At least one measurable lesion by computer tomography (CT) or magnetic resonance imaging (MRI) according to RECIST - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - Life expectancy of at least 12 weeks - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - White blood cell count >= 3 × 10x9/L with neutrophils >= 1.5 × 10x9/L, platelet count >=75 × 10x9/L and hemoglobin >= 8 g/dL; Total bilirubin <= 1.5 × upper limit of reference range, Aspartate transaminase (AST) and alanine transaminase (ALT) <= 2.5 × upper limit of reference range or <= 5 × upper reference range in subjects with liver metastasis;Serum creatinine <= 1.5 × upper limit of reference range Exclusion Criteria: - Known hypersensitivity or allergic reactions against any of the components of the trial treatments - Radiotherapy or surgery (excluding prior diagnostic biopsy) in the 28 days before trial treatment - Known brain metastasis and/or leptomeningeal disease. --- V600E ---

cardiac failure of New York Heart Association classes III-IV, uncontrolled coronary artery disease, cardiomyopathy, uncontrolled arrhythmia, uncontrolled hypertension, or history of myocardial infarction in the last 5 years, or left ventricular ejection fraction below the institutional range of normal on a baseline multiple gated acquisition scan or echocardiogram - Renal replacement therapy - Peripheral neuropathy > grade 1 - History of organ allograft, autologous stem cell transplantation, or allogeneic stem cell transplantation - Previous malignancy other than CRC in the last 5 years except basal cell cancer of the skin or preinvasive cancer of the cervix - Known and declared history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C - Known severe coagulation disorders - Previous chemotherapy for CRC except adjuvant treatment if terminated > 12 months (oxaliplatin-based chemotherapy) or > 6 months (non-oxaliplatin-based chemotherapy) before the start of treatment in this trial - Previous treatment with anti-EGFR monoclonal antibody therapy - Other non-permitted concomitant anticancer therapies, chronic systemic immune therapy or hormone therapy - Granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) within 3 weeks of trial entry,blood transfusion,or blood components transfusion - Pregnancy (absence to be confirmed by serum β-human chorionic gonadotropin test) or breastfeeding - Ongoing alcohol or drug abuse - Known neurological or psychiatric diseases - Participation in another clinical trial within the past 4 weeks - Legal incapacity or limited legal capacity - Other significant disease that in the investigator's opinion should exclude the subject from the trial Inclusion Criteria: - Signed written informed consent - Male or female subjects, 18-75 years of age - Medically accepted effective contraception if procreative potential exists - Diagnosis of histologically confirmed adenocarcinoma of the colon or rectum - RAS wild-type and BRAF-V600E wild-type status in tumor tissue - At least one measurable lesion by computer tomography (CT) or magnetic resonance imaging (MRI) according to RECIST - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - Life expectancy of at least 12 weeks - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at trial entry - White blood cell count >= 3 × 10x9/L with neutrophils >= 1.5 × 10x9/L, platelet count >=75 × 10x9/L and hemoglobin >= 8 g/dL; Total bilirubin <= 1.5 × upper limit of reference range, Aspartate transaminase (AST) and alanine transaminase (ALT) <= 2.5 × upper limit of reference range or <= 5 × upper reference range in subjects with liver metastasis;Serum creatinine <= 1.5 × upper limit of reference range Exclusion Criteria: - Known hypersensitivity or allergic reactions against any of the components of the trial treatments - Radiotherapy or surgery (excluding prior diagnostic biopsy) in the 28 days before trial treatment - Known brain metastasis and/or leptomeningeal disease. --- V600E ---

Primary Outcomes

Description: PFS was defined as the duration (in months) from randomization until the first progressive disease (PD) observation as assessed by the investigators according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.0, or death due to any cause when death occurred within 90 days of randomization or the last tumor assessment, whichever was later. PD was defined as at least a 20% increase in the sum of longest diameter (LD) of the target lesions, taking as references the smallest sum LD since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.

Measure: Progression Free Survival (PFS) Time

Time: Time Frame: Baseline up to 128 weeks

Secondary Outcomes

Description: OS was defined as the time (in months) from randomization to death. For subjects who were still alive at the analysis data cut-off date or who lost to follow-up, survival was censored at the last recorded date that the subject was known to be alive.

Measure: Overall Survival (OS) Time

Time: Time Frame: Baseline up to 258 weeks

Description: The Best ORR was defined as the percentage of subjects having achieved complete response (CR) or partial response (PR) according to RECIST version 1.0 as determined by the IRC. CR: defined as disappearance of all target and all non-target lesions and no new lesions. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters, no progression of non-target lesions and no new lesions. The Best ORR was defined as the percentage of subjects having achieved complete response (CR) or partial response (PR) according to RECIST version 1.0 as determined by the investigators. CR: defined as disappearance of all target and all non-target lesions and no new lesions. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters, no progression of non-target lesions and no new lesions.

Measure: Best Overall Response Rate (ORR)

Time: Time Frame: Baseline up to 128 weeks

Description: TTF was defined as time from randomization to date of the first occurrence of radiologically confirmed PD. Clinical PD according to the Investigator's assessment , discontinuation of treatment due to progression or adverse event, start of new anticancer therapy, withdrawal of consent, or death within 90 days of last tumor assessment or randomization. Subjects without event were censored on the date of last tumor assessment.

Measure: Time to Treatment Failure (TTF)

Time: Time Frame: Baseline up to 128 weeks

Description: Quality of life score is defined of questionnaire EORTC QLQ-C30.

Measure: quality of life score

Time: Time Frame: Baseline up to 258 weeks

97 A Prospective, Open-lable, Multicenter, Randomized, Controlled Phase II Clinical Trial to Evaluate the Efficacy of Irinotecan Versus Oxaliplatin in the First-line Treatment of Refractory Metastatic Colorectal Cancer

This is a prospective, open-lable, multicenter, randomized, controlled, phase II clinical study. The aim is to evaluate the efficacy of Irinotecan versus Oxaliplatin in the first-line treatment of refractory metastatic colorectal cancer.

NCT03567629 mCRC Drug: Irinotecan Drug: Oxaliplatin
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

3. Subjects with BRAF V600E mutation. --- V600E ---

Primary Outcomes

Description: Evaluation of the Progression-free Survival of Irinotecan-based regimen versus Oxaliplatin-based regimen in refractory metastatic colorectal cancer patients.

Measure: Progression-free Survival: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first.

Time: assessed up to 10 months

Secondary Outcomes

Description: Evaluation of the Overall Survival of Irinotecan-based regimen versus Oxaliplatin-based regimen in refractory metastatic colorectal cancer patients.

Measure: Overall Survival : From date of enrollment until the date of death.

Time: 2 years

Description: flurouracil drugs:fluorouracil、S1、Capecitabine

Measure: Evaluation of PFS in patients with different fluorouracil drugs and different genotyping subgroups.

Time: 10months

Description: flurouracil drugs:fluorouracil、S1、Capecitabine

Measure: Evaluation of OS in patients with different fluorouracil drugs and different genotyping subgroups.

Time: 2 years

Description: Adverse reactions evaluation is based on the National Cancer Institute adverse event General terminology Standard [CTCAE] 4.0 version

Measure: The incidence of treatment related emergent adverse events(Safety and Tolerance)

Time: Until 28 days after the deadline of enrollment

98 Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations

This is a single-centre, open-label Phase II study of the investigational drugs binimetinib and encorafenib that will be taken my mouth (orally) daily in adult patient with advanced and/or metastatic solid tumors for which no other standard therapy is available. The main purpose is to evaluate the objective response rate (ORR) of the study drugs in the growth of the cancer in patients with class 2 and 3 BRAF mutations.

NCT03839342 Solid Tumor Drug: Binimetinib Drug: Encorafenib

Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations. --- V600E ---

Binimetinib and Encorafenib for the Treatment of Advanced Solid Tumors With Non-V600E BRAF Mutations This is a single-centre, open-label Phase II study of the investigational drugs binimetinib and encorafenib that will be taken my mouth (orally) daily in adult patient with advanced and/or metastatic solid tumors for which no other standard therapy is available. --- V600E ---

Number of identified molecular mechanisms of acquired resistance to binimetinib and encorafenib in tumors with non-V600E BRAF mutations, measured by analysis of molecular profiles and validated with PDX models in vitro and in vivo.. null. --- V600E ---

Any patient with a tumor expressing a BRAF V600E mutation 2. Any patient with melanoma whose tumor expresses a BRAF V600K mutation 3. Prior therapy with any BRAF inhibitor (e.g., encorafenib, dabrafenib, vemurafenib) and/or any MEK inhibitor (e.g., binimetinib, trametinib, cobimetinib). --- V600E ---

This study will look at participants in these classes (non-V600E BRAF mutations). --- V600E ---

Primary Outcomes

Measure: Objective response rate defined as per RECIST v1.1.

Time: 2.5 years

Secondary Outcomes

Measure: Number of participants with toxicities as per NCI CTCAE v5.0.

Time: 2.5 years

Measure: Disease progression defined as per RECIST v1.1 and monitored throughout the study period. Progression Free Survival defined as time from study registration to disease progression or death from any cause.

Time: 2.5 years

Measure: Disease Control Rate defined in accordance with RECIST v1.1, as the percentage of patients who achieve a complete response, partial response or stable disease after 24 weeks of treatment.

Time: 2.5 years

Measure: Overall survival measured as the length of time from the first day of treatment to the day of death. Median OS will be reported.

Time: 2.5 years

Measure: Change in circulating tumor DNA (ctDNA) profiles measured by serial analysis of ctDNA profiles at baseline, mid-cycle 1, with each subsequent cycle, and at progression, validated by comparison to molecular profiles of corresponding fresh tumor biopsies

Time: 2.5 years

Measure: Number of fresh tumor biopsies collected, frozen, and stored for subsequent development of patient derived xenografts.

Time: 2.5 years

Measure: Number of identified molecular mechanisms of acquired resistance to binimetinib and encorafenib in tumors with non-V600E BRAF mutations, measured by analysis of molecular profiles and validated with PDX models in vitro and in vivo.

Time: 2.5 years

99 A Phase I Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic Thyroid Cancer

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

NCT03975231 BRAF NP_004324.2:p.V600E BRAF V600K Mutation Present Thyroid Gland Anaplastic Carcinoma Drug: Dabrafenib Radiation: Intensity-Modulated Radiation Therapy Drug: Trametinib
MeSH: Thyroid Diseases Thyroid Neoplasms Thyroid Carcinoma, Anaplastic Carcinoma
HPO: Abnormality of the thyroid gland Anaplastic thyroid carcinoma Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

- Presence of BRAF mutation (V600E or V600K) in tumor tissue. --- V600E ---

Primary Outcomes

Measure: Maximum tolerated dose of combination therapy of dabrafenib and trametinib administered concurrently with intensity-modulated radiation therapy (IMRT)

Time: 1 year

Secondary Outcomes

Description: Will be defined as the proportion of patients who have a partial response (PR), or complete response (CR) within the first 4 weeks of IMRT. Complete response (CR) and partial response (PR) will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be calculated with the exact binomial 95% confidence intervals.

Measure: Objective response rate

Time: 1 year

Description: Will be evaluated by RECIST criteria for disease limited to the radiation field (neck) following the first set of scans after completion of IMRT. Estimated by Kaplan-Meier method.

Measure: Time to progression for local disease recurrence

Time: 1 year

Description: Estimated by Kaplan-Meier method.

Measure: Overall survival

Time: From the start date of the treatment to the date of death, assessed up to 1 year

Description: Estimated by Kaplan-Meier method.

Measure: Progression free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

100 A Phase II Study of Binimetinib in Combination With Encorafenib in Adults With Recurrent BRAF V600-Mutated High-Grade Astrocytoma or Other Primary Brain Tumor

The goal of this study is to estimate the efficacy of encorafenib and binimetinib as measured by radiographic response in recurrent high-grade primary brain tumors.

NCT03973918 High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Drug: Encorafenib Drug: Binimetinib Biological: Research Bloods Biological: Tumor Tissue
MeSH: Glioblastoma Glioma Astrocytoma Gliosarcoma Brain Neoplasms
HPO: Astrocytoma Brain neoplasm Glioblastoma multiforme Glioma Subependymal giant-cell astrocytoma

High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Glioblastoma Glioma Astrocytoma Gliosarcoma Brain Neoplasms Primary Objective Estimate the efficacy of combination treatment with encorafenib and binimetinib, as measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs). --- V600E ---

High Grade Glioma BRAF V600E BRAF V600K Anaplastic Astrocytoma Anaplastic Pleomorphic Xanthoastrocytoma Gliosarcoma Glioblastoma Glioblastoma Glioma Astrocytoma Gliosarcoma Brain Neoplasms Primary Objective Estimate the efficacy of combination treatment with encorafenib and binimetinib, as measured by response rate (RANO criteria), in patients with recurrent BRAF V600E/K-mutated malignant glioma (MG) and anaplastic pleomorphic xanthoastrocytoma (PXAs). --- V600E --- --- V600K --- --- V600E ---

Secondary Objectives 1. Estimate efficacy as measured by progression-free survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug. 2. Evaluate duration of response in subjects who have a partial or complete response. --- V600E ---

4. Estimate efficacy as measured by overall survival in subjects with recurrent malignant glioma or anaplastic PXA containing a BRAF-V600E/K mutation who receive drug. 5. Characterize the toxicity profile of the combination of encorafenib and binimetinib in this patient population. --- V600E ---

Primary Outcomes

Description: Number of participants from each treatment cohort with response as defined by Response Assessment in Neuro-oncology (RANO) criteria: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Measure: Tumor radiographic response per RANO for 3 treatment cohorts

Time: 1 year

Secondary Outcomes

Description: Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status

Measure: Progression free survival for 3 treatment cohorts

Time: up to 1 year

Description: median overall survival

Measure: Overall Survival

Time: up to 2 years

Description: Time from response to progression. Response is defined by RANO: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= <50% reduction to <25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

Measure: Duration of response

Time: up to 1 year

Measure: Number of participants with adverse events as defined by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0)

Time: 1 year

101 A Phase II Randomized Study of Ramucirumab Plus MK3475 (Pembrolizumab) Versus Standard of Care for Patients Previously Treated With Immunotherapy for Stage IV or Recurrent Non-Small Cell Lung Cancer (Lung-MAP Non-Matched Sub-Study)

This phase II Lung-MAP non-Match treatment trial studies how well ramucirumab and pembrolizumab work versus standard of care in treating patients with non-small cell lung cancer that is stage IV or has come back. Immunotherapy with monoclonal antibodies, such as ramucirumab and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in standard of care chemotherapy for non-small cell lung cancer, such as docetaxel, gemcitabine hydrochloride, and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ramucirumab and pembrolizumab together may work better in treating patients with non-small lung cancer compared to standard of care.

NCT03971474 Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Stage IVB Lung Cancer AJCC v8 Drug: Docetaxel Drug: Gemcitabine Drug: Gemcitabine Hydrochloride Biological: Pembrolizumab Drug: Pemetrexed Drug: Pemetrexed Disodium Biological: Ramucirumab
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

Patients who were screened under S1400 (legacy screening/pre-screening study) must have had prior PD-L1 testing by the Dako 22C3 PharmDx immunohistochemistry (IHC) assay, and must have results available for stratification purposes - Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS 1 gene rearrangement, and BRAF V600E mutation unless they have progressed following all standard of care targeted therapy - Patients must not have an active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). --- T790M --- --- V600E ---

Primary Outcomes

Description: Will be compared between patients previously treated with platinum-based chemotherapy and immunotherapy for stage IV or recurrent non-small cell lung cancer randomized to ramucirumab and MK-3475 (pembrolizumab) versus standard of care (SoC). Will be estimated using the method of Kaplan-Meier.

Measure: Overall survival (OS)

Time: Up to 3 years

Secondary Outcomes

Description: Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average hazard ratio (HR) will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.

Measure: Investigator assessed-progression-free survival (IA-PFS)

Time: From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration, or death due to any cause, assessed up to 3 years

Description: Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average HR will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.

Measure: Duration of response (DOR)

Time: From date of first documentation of response (CR or PR), or death due to any cause among patients who achieve a response (CR or PR), assessed up to 3 years

Description: Binary proportions will be summarized with associated confidence intervals. Will be compared with toxicities using a chi-squared test at the 1-sided 0.05 level.

Measure: Response rates (RR)

Time: Up to 3 years

Description: Will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Binary proportions will be summarized with associated confidence intervals. Will be compared with RR using a chi-squared test at the 1-sided 0.05 level.

Measure: Incidence of adverse events

Time: Up to 3 years

102 An Open-label, Multicenter, Phase II Study of Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation

This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib and trametinib in stage IV disease to subjects with BRAF V600E mutant advanced non-small cell lung cancer. Subjects will receive dabrafenib 150 mg bid and trametinib 2 mg once daily in combination therapy and continue on treatment until disease progression, death, or unacceptable adverse event.

NCT03543306 Cancer Lung Cancer Metastatic BRAF V600E Drug: daborafenib plus trametinib
MeSH: Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Neoplasm of the lung Non-small cell lung carcinoma

An Open-label, Multicenter, Phase II Study of Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation. --- V600E ---

Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib and trametinib in stage IV disease to subjects with BRAF V600E mutant advanced non-small cell lung cancer. --- V600E ---

Dabrafenib and Trametinib in Patients With Non-small Cell Lung Cancer Harboring V600E BRAF Mutation This is a Phase II, non-randomized, open-label study to assess the efficacy, safety, and tolerability of dabrafenib and trametinib in stage IV disease to subjects with BRAF V600E mutant advanced non-small cell lung cancer. --- V600E --- --- V600E ---

Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed Cancer Lung Cancer Metastatic BRAF V600E Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- V600E ---

Primary Outcomes

Description: ORR is a proportion of patients with a best overall response defined as complete response or partial response by RECIST1.1

Measure: Objective response rate

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Secondary Outcomes

Description: DOR is calculated as the time from the date of the first document of complete remission (CR) or partial remission (PR) to the first documented preogressive disease (PD) or death due to any cause for patients with PR or CR.

Measure: Duration of response

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: . PFS is defined as time from the first dose of investigational products (IPs) to progression or death due to any cause. OS is defined as time from the first dose of IPs to death due to any cause.

Measure: Progression-free survival

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Measure: Overall survival

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

Description: DCR is calculated as the proportion of patients with best response of CR, PR and SD.

Measure: Disease control rate

Time: At Week 6 then every 6 weeks up to Week 36.and then every 12 weeks until discharge, for an average of 13.8 months

103 A Phase 1, Open-Label, Multicenter, Multi-Dose Escalation Study of CM-24 (MK-6018) as Monotherapy and In Combination With Pembrolizumab (MK-3475) in Subjects With Selected Advanced or Recurrent Malignancies

The purpose of this study is to evaluate the safety and tolerability of humanized IgG4 (kappa) isotype monoclonal antibody against CEACAM1 (CM-24 [MK-6018]), administered intravenously as monotherapy and in combination with Pembrolizumab (MK-3475), in participants with selected advanced or recurrent malignancies. Escalating multiple doses will be evaluated to determine the recommended dose for Phase 2 clinical studies.

NCT02346955 Non-small Cell Lung Carcinoma (NSCLC) Melanoma Bladder Cancer Colorectal Cancer Gastric Cancer Ovarian Cancer Biological: CM-24 (MK-6018) Biological: Pembrolizumab (MK-3475)
MeSH: Colorectal Neoplasms Urinary Bladder Neoplasms Lung Neoplasms Carcinoma, Non-Small-Cell Lung
HPO: Bladder neoplasm Neoplasm of the large intestine Neoplasm of the lung Non-small cell lung carcinoma

- Participants in the Monotherapy Expansion Cohort must have one of the following advanced or recurrent malignancies: cutaneous melanoma showing primary progression following treatment with an anti-programmed cell death (PD) or anti-PDL1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Participants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Melanoma with BRAF V600E or V600K mutation-positive melanoma must have progressed on, or were intolerant to, prior BRAF- or MEK-inhibitor therapy - Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with progressing or new tumors since last antitumor therapy - Must have adequate hematologic, renal, and liver function - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Females must not be pregnant (negative human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) or breastfeeding - Women of childbearing potential and male participants must agree to use adequate contraception throughout the study and for up to 180 days after study treatment - An estimated life expectancy of at least 3 months - Must consent to provide an archival tumor biopsy sample at any time point from screening to study exit - Must consent to allow the acquisition of new tissue biopsy samples during the study Exclusion Criteria: - History of severe hypersensitivity reactions or immune related adverse events to other monoclonal antibodies - History of other active malignancy within the prior 2 years - History of insulin-dependent or uncontrolled Diabetes Mellitus - History of inflammatory bowel disease - Autoimmune disorders - Known HIV and/or Hepatitis B or C infections - Known systemic bleeding or platelet disorder - Receipt of live vaccines with 4 weeks (28 days) of study - History or evidence of non-infectious pneumonitis that required steroids or current pneumonitis Inclusion Criteria: - Males and females ≥18 years of age - Participants in the Dose Escalation portion must have one of the following advanced or recurrent malignancies: gastrointestinal (colorectal or gastric); ovarian; melanoma; non-small cell lung adenocarcinoma; or bladder. --- V600E ---

- Participants in the Monotherapy Expansion Cohort must have one of the following advanced or recurrent malignancies: cutaneous melanoma showing primary progression following treatment with an anti-programmed cell death (PD) or anti-PDL1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Participants in the Combination Expansion Cohorts must have one of the following advanced or recurrent malignancies: non-small cell lung adenocarcinoma or cutaneous melanoma showing primary progression following treatment with an anti-PD1 or anti-PD-L1 regimen; or anti-PD1 or anti-PD-L1 treatment-naïve colorectal or gastric cancer, including gastroesophageal junction cancer of Siewert Type II and Type III. - Melanoma with BRAF V600E or V600K mutation-positive melanoma must have progressed on, or were intolerant to, prior BRAF- or MEK-inhibitor therapy - Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 with progressing or new tumors since last antitumor therapy - Must have adequate hematologic, renal, and liver function - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Females must not be pregnant (negative human chorionic gonadotropin test within 72 hours prior to receiving the first dose of study medication) or breastfeeding - Women of childbearing potential and male participants must agree to use adequate contraception throughout the study and for up to 180 days after study treatment - An estimated life expectancy of at least 3 months - Must consent to provide an archival tumor biopsy sample at any time point from screening to study exit - Must consent to allow the acquisition of new tissue biopsy samples during the study Exclusion Criteria: - History of severe hypersensitivity reactions or immune related adverse events to other monoclonal antibodies - History of other active malignancy within the prior 2 years - History of insulin-dependent or uncontrolled Diabetes Mellitus - History of inflammatory bowel disease - Autoimmune disorders - Known HIV and/or Hepatitis B or C infections - Known systemic bleeding or platelet disorder - Receipt of live vaccines with 4 weeks (28 days) of study - History or evidence of non-infectious pneumonitis that required steroids or current pneumonitis Non-small Cell Lung Carcinoma (NSCLC) Melanoma Bladder Cancer Colorectal Cancer Gastric Cancer Ovarian Cancer Colorectal Neoplasms Urinary Bladder Neoplasms Lung Neoplasms Carcinoma, Non-Small-Cell Lung null --- V600E ---

Primary Outcomes

Measure: Number of participants with Adverse Events (AEs)

Time: From time of first dose until the end of follow-up (up to 123 weeks)

Measure: Number of participants discontinuing study drug due to AEs

Time: From time of first dose until the end of follow-up (up to 105 weeks)

Measure: Number of participants with a Dose Limiting Toxicity (DLT)

Time: From time of first dose until the end of follow-up (up to 12 weeks)

Secondary Outcomes

Measure: Maximum drug concentration in serum/plasma (Cmax)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Time to reach Cmax in serum/plasma (Tmax)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Terminal-phase elimination half-life in serum/plasma (t1/2)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Area under the plasma/serum concentration versus time curve from time zero to the last measured time (AUC 0-T)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Area under the plasma/serum concentration versus time curve from time zero to infinity (AUC 0-∞)

Time: For Cycles 1-35: all infusions at pre-infusion. For Cycle 1 first & fourth infusion: at end of infusion; 1, 4, 8 hours post-infusion; and Days 2, 3, 5, 8 post-infusion. For Cycle 1 fourth infusion also at Days 15, 22, 36 post-infusion.

Measure: Objective Response Rate (ORR) defined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

Time: From time of screening until the end of follow-up (up to 123 weeks)

Measure: Time from ORR to disease progression or death (DOR)

Time: From time of screening until the end of follow-up (up to 123 weeks)

104 A Phase I/II Study of Concurrent Ipilimumab and Dabrafenib in Unresectable Stage III or Stage IV Melanoma

Phase I/II study of ipilimumab concurrent ipilimumab and dabrafenib as first line treatment in Stage III or IV melanoma. Assessing safety of Ipilimumab and dabrafenib in combination. Also, assessing disease control rates.

NCT02200562 Stage III or IV Melanoma Drug: ipilimumab and dabrafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Severity of the AEs will be graded according to the CTCAE version 4.0.. Inclusion Criteria: - For Phase I: Locally advanced or metastatic BRAF V600E/K/R positive melanoma that is either treatment-naïve or treatment-experienced. --- V600E ---

- For phase II: Histological diagnosis of BRAF V600E/K melanoma, unresectable stage III or stage IV, according to the AJCC Staging Manual, 7th Edition, 2011. --- V600E ---

- The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of the drugs in this protocol or place the subject at undue risk for treatment complications - Pregnancy or breast feeding - A history of a severe hypersensitivity reaction to ipilimumab or dabrafenib - Any reason why, in the opinion of the investigator, the patient should not participate Inclusion Criteria: - For Phase I: Locally advanced or metastatic BRAF V600E/K/R positive melanoma that is either treatment-naïve or treatment-experienced. --- V600E ---

Primary Outcomes

Description: All patients who receive any study treatment will be included in the final summaries and listings of safety data. Detailed information collected for each AE will include a description of the event, duration, severity, relatedness to study drugs, action taken, and clinical outcome. Severity of the AEs will be graded according to the CTCAE version 4.0.

Measure: Safety of ipilimumab and dabrafenib in combination

Time: Safety analysis will be measured based on frequency and severity of adverse events experienced by patients during the study treatment period which is expected to last about 24 weeks.

105 An Open Label Multicenter, Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma With BRAFv600 Mutated and CDKN2A Loss and Expression of Rb and Treated by Vemurafenib

An open label multicentre, phase I-II study with tumour molecular pharmacodynamics (MPD) evaluation and pharmacokinetics of PD-0332991 added to vemurafenib in patients suffering metastatic melanoma with BR. The main objective is to establish the Maximum Tolerated Dose (MTD) of PD-0332991 when added to standard vemurafenib therapy (960 mg BID). The estimated MTD is defined as the dose of PD-0332991 combined with vemurafenib that will be associated with a prespecified proportion of patients experiencing a Dose-Limiting Toxicity (DLT), ie, 1/3.

NCT02202200 Melanoma BRAF V600E/K Mutated CDNKN2A Loss Defined Drug: PD- 0332991
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Changes from baseline of ANC and platelet levels Efficiency on the cell-cycle machinery and proliferation (tumor sample) Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology) Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).. Inclusion Criteria: - Age > 18 years - Stage IV or un-resectable stage III melanoma - Presence of BRAF V600E/K mutation and CDNKN2A loss and expression of Rb using immunohistochemistry in a recent metastatic sample (< 6 months) - A previous exposure to BRAF inhibitor or combination of BRAF and MEK inhibitors therapy is allowed unless it has been stopped more than 3 months before study enrolment(This will defined the two strata of the trial) - No previous therapy by MEK inhibitor unless associated with BRAF inhibitors - No previous therapy with the AKT/PI3K pathway inhibitor - Patients should have a tumour available for repeated biopsies for pharmacodynamics evaluation - Life expectancy of > 3 months - ECOG performance status <2 - Signed informed consent - Patient with health insurance coverage - No patient under guardianship or curators Exclusion Criteria: - Inadequate hepatic function defined as serum bilirubin>25 μmol/l, transaminases > 3.0 times the upper limit of normal (ULN) or 5ULN in cases of liver metastases; - Inadequate bone marrow function defined as absolute neutrophil count<1500/mcl, platelets<150000/mcl and haemoglobin<8g/dL - Inadequate renal function with serum creatinine>2.0mg/dl) --- V600E ---

- Chemotherapy, immunotherapy within 4 weeks - Drugs interfering with PD-0332991 and vemurafenib metabolism - Malabsorption syndrome or other condition that would interfere with enteral absorption - Congenital long QT syndrome or screening QTc > 470 msec - Need for chronic corticosteroid therapy of ≥10 mg of prednisone per day Inclusion Criteria: - Age > 18 years - Stage IV or un-resectable stage III melanoma - Presence of BRAF V600E/K mutation and CDNKN2A loss and expression of Rb using immunohistochemistry in a recent metastatic sample (< 6 months) - A previous exposure to BRAF inhibitor or combination of BRAF and MEK inhibitors therapy is allowed unless it has been stopped more than 3 months before study enrolment(This will defined the two strata of the trial) - No previous therapy by MEK inhibitor unless associated with BRAF inhibitors - No previous therapy with the AKT/PI3K pathway inhibitor - Patients should have a tumour available for repeated biopsies for pharmacodynamics evaluation - Life expectancy of > 3 months - ECOG performance status <2 - Signed informed consent - Patient with health insurance coverage - No patient under guardianship or curators Exclusion Criteria: - Inadequate hepatic function defined as serum bilirubin>25 μmol/l, transaminases > 3.0 times the upper limit of normal (ULN) or 5ULN in cases of liver metastases; - Inadequate bone marrow function defined as absolute neutrophil count<1500/mcl, platelets<150000/mcl and haemoglobin<8g/dL - Inadequate renal function with serum creatinine>2.0mg/dl) --- V600E ---

- Chemotherapy, immunotherapy within 4 weeks - Drugs interfering with PD-0332991 and vemurafenib metabolism - Malabsorption syndrome or other condition that would interfere with enteral absorption - Congenital long QT syndrome or screening QTc > 470 msec - Need for chronic corticosteroid therapy of ≥10 mg of prednisone per day Melanoma BRAF V600E/K Mutated CDNKN2A Loss Defined Melanoma null --- V600E ---

Primary Outcomes

Description: DLTs, serious adverse events and adverse events leading to treatment discontinuations will be determined as follows: Any grade 3 or more non-haematological toxicity excluding: Grade 3 asymptomatic increase in liver function tests (AST, ALT, ALP) reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement. Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. 5HT3 antagonists and corticosteroids). Grade 3 diarrhoeas if encountered despite adequate and optimal anti diarrhoea therapy. Confirmed grade 3 QTc prolongation (QTc >500 msec) that persists after correction of other possible causes such as electrolyte imbalance Grade 4 hyperlipidemia if it is encountered despite adequate and optimal therapy. Any grade 4 neutropenia of > 5 days duration, or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia > 1 day, or grade 3 with bleeding.

Measure: Occurrence within the first 2 cycles of treatment of a DLT

Time: 42 Days

Secondary Outcomes

Description: Occurrence of clinical benefit (defined as Complete Response (CR), Partial Response (PR) or stable disease (SD)) and progressive disease based on the best overall response which depends on the tumour evaluations assessed using RECIST at the end of each 2 cycles.

Measure: Efficacy

Time: 42 Days

Description: survival

Measure: 1 year survival rate

Time: 1 year

Description: Occurrence of clinically significant changes in a laboratory parameter and/or vital signs judged to be related to the trial medication within the first 6 months.

Measure: Tolerance

Time: 6 months

Other Outcomes

Description: Changes from baseline of ANC and platelet levels Efficiency on the cell-cycle machinery and proliferation (tumor sample) Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology) Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).

Measure: Pharmacodynamic

Time: 42 days

106 Phase I Study of AT13387 in Combination With Dabrafenib and Trametinib in Patients With BRAF-Mutant Melanoma and Other Solid Tumors

This phase I trial studies the side effects and best dose of onalespib when given together with dabrafenib and trametinib in treating patients with BRAF-mutant melanoma or solid tumors that have spread to another place in the body (metastatic) or cannot be removed by surgery. Onalespib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT02097225 BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Malignant Solid Neoplasm Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Solid Neoplasm Drug: Dabrafenib Other: Laboratory Biomarker Analysis Drug: Onalespib Other: Pharmacological Study Drug: Trametinib
MeSH: Neoplasms Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm Neoplasm of the skin

Will be performed to assess how changes in the expression of the key signaling proteins relate to patient response.. Inclusion Criteria: - Patients must have histologically confirmed, BRAF-mutant (V600E/K) solid tumor (molecularly confirmed using Cobas assay or a comparable Food and Drug Administration [FDA]-approved assay) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF targeted therapy, and for which standard curative measures do not exist or are no longer effective - If test at Clinical Laboratory Improvement Act (CLIA)-certified laboratory (lab) used a non-FDA approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; patients may have received any number of prior lines of therapy, including treatment with a BRAF and/or MEK inhibitor - All prior anti-cancer treatment-related toxicities must be less than or equal to grade 1 according to the Common Terminology Criteria for Adverse Events version 5 (CTCAE version 5.0; National Cancer Institute [NCI], 2017) at the time of enrollment; a notable exception are endocrinopathies caused by immune checkpoint inhibitors that are appropriately treated with medical management (e.g. --- V600E ---

m^2 - Potassium > 3 and < 5.5 mEq/L - Magnesium > 1.2 and < 2.5 mEq - Left ventricular >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) ejection fraction - Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) from 14 days prior to randomization, throughout the treatment period, and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Ability to understand and the willingness to sign a written informed consent document - Able to swallow and retain oral medication, and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Exclusion Criteria: - Patients who received prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to day 1 of cycle 1; patients are permitted to be on dabrafenib and trametinib standard of care at start of therapy without wash-out period prior to day 1 of cycle 1; dosing will change to protocol determined dose levels on day 1 of cycle 1 - Patients must not have received prior HSP90 inhibitor therapy - Patients who are receiving any other investigational agents; patients who have taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization - Patients with history of activating RAS mutation positive tumors regardless of interval from current study; however, patients may have concurrent BRAFV600 and RAS mutations in the tumor to be treated with protocol therapy - Patients must have no clinical evidence of leptomeningeal or brain metastasis causing spinal cord compression that are symptomatic or untreated or not stable for >= 4 weeks (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History of known immediate or delayed hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to AT13387, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO) - Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the mother being treated with the study drugs - Patients known to be human immunodeficiency virus (HIV)-positive patients and on combination antiretroviral therapy are ineligible - History of another malignancy other than the study indication under this trial within 5 years of study enrollment; does not apply to subjects who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, in situ breast cancer, or other in situ cancers - Exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History of interstitial lung disease or pneumonitis - History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): - History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm mercury (Hg) - History or evidence of cardiovascular risk including any of the following: - An average of the three most recent QT intervals corrected for heart rate using the Bazett's formula QTcB >= 460 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - Prior placement of an implantable defibrillator - History of or identification on screening imaging of intracardiac metastases - No known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV); patients with chronic or cleared HBV infection and HCV infection are eligible - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded Inclusion Criteria: - Patients must have histologically confirmed, BRAF-mutant (V600E/K) solid tumor (molecularly confirmed using Cobas assay or a comparable Food and Drug Administration [FDA]-approved assay) that is metastatic or unresectable, have received and tolerated prior BRAF or BRAF and MEK inhibitor (BRAF targeted) therapy at full dose or not previously received BRAF targeted therapy, and for which standard curative measures do not exist or are no longer effective - If test at Clinical Laboratory Improvement Act (CLIA)-certified laboratory (lab) used a non-FDA approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test) - Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Prior therapy is allowed; patients may have received any number of prior lines of therapy, including treatment with a BRAF and/or MEK inhibitor - All prior anti-cancer treatment-related toxicities must be less than or equal to grade 1 according to the Common Terminology Criteria for Adverse Events version 5 (CTCAE version 5.0; National Cancer Institute [NCI], 2017) at the time of enrollment; a notable exception are endocrinopathies caused by immune checkpoint inhibitors that are appropriately treated with medical management (e.g. --- V600E ---

m^2 - Potassium > 3 and < 5.5 mEq/L - Magnesium > 1.2 and < 2.5 mEq - Left ventricular >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) ejection fraction - Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) from 14 days prior to randomization, throughout the treatment period, and for 4 months after the last dose of study treatment; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Ability to understand and the willingness to sign a written informed consent document - Able to swallow and retain oral medication, and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels Exclusion Criteria: - Patients who received prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks prior to day 1 of cycle 1; patients are permitted to be on dabrafenib and trametinib standard of care at start of therapy without wash-out period prior to day 1 of cycle 1; dosing will change to protocol determined dose levels on day 1 of cycle 1 - Patients must not have received prior HSP90 inhibitor therapy - Patients who are receiving any other investigational agents; patients who have taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to randomization - Patients with history of activating RAS mutation positive tumors regardless of interval from current study; however, patients may have concurrent BRAFV600 and RAS mutations in the tumor to be treated with protocol therapy - Patients must have no clinical evidence of leptomeningeal or brain metastasis causing spinal cord compression that are symptomatic or untreated or not stable for >= 4 weeks (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History of known immediate or delayed hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to AT13387, dabrafenib, or trametinib, or excipients or to dimethyl sulfoxide (DMSO) - Uncontrolled intercurrent illness including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued prior to the mother being treated with the study drugs - Patients known to be human immunodeficiency virus (HIV)-positive patients and on combination antiretroviral therapy are ineligible - History of another malignancy other than the study indication under this trial within 5 years of study enrollment; does not apply to subjects who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, in situ breast cancer, or other in situ cancers - Exception: patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History of interstitial lung disease or pneumonitis - History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): - History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm mercury (Hg) - History or evidence of cardiovascular risk including any of the following: - An average of the three most recent QT intervals corrected for heart rate using the Bazett's formula QTcB >= 460 msec - History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible) - History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization - History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system - Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy - Abnormal cardiac valve morphology (>= grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - Prior placement of an implantable defibrillator - History of or identification on screening imaging of intracardiac metastases - No known active infection with hepatitis B virus (HBV), or hepatitis C virus (HCV); patients with chronic or cleared HBV infection and HCV infection are eligible - Current use of a prohibited medication; the following medications or non-drug therapies are prohibited: - Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed) - Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis - The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Malignant Solid Neoplasm Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Solid Neoplasm Neoplasms Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD), toxicity, and safety profile of onalespib (AT13387) given weekly in combination with dabrafenib and trametinib in patients with BRAF-mutant metastatic or unresectable solid tumors. --- V600E ---

Primary Outcomes

Description: Toxicities will be graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0. Toxicity rates will be summarized with a 90% exact binomial confidence interval.

Measure: Maximum tolerated dose of onalespib in combination with dabrafenib and trametinib, defined as the highest dose level at which 0 or 1 of six patients has experienced a dose limiting toxicity

Time: 28 days

Secondary Outcomes

Description: The response rate will be presented as a point estimate with a 90% exact binomial confidence interval.

Measure: Objective response rate, defined as the proportion of patients with complete or partial response as their best response to therapy assessed according to Response Evaluation Criteria in Solid Tumors version 1.1

Time: The date of first dose of trial therapy and the date of objectively documented disease progression or cessation of trial therapy, whichever occurs first, assessed up to 28 days after end of treatment

Description: The distribution of progression-free survival will be summarized using the product-limit method of Kaplan-Meier.

Measure: Progression-free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 28 days after end of treatment

Description: Median times for each endpoint will be presented with two-sided, 90% confidence intervals estimated using log(-log[survival]) methodology. Kaplan-Meier estimates of 6-month progression-free survival will also be presented with two-sided, 90% confidence intervals.

Measure: Progression-free survival

Time: Time from start of treatment to time of progression or death, whichever occurs first, assessed at 6 months

Description: The distribution of overall survival will be summarized using the product-limit method of Kaplan-Meier. Kaplan-Meier estimates of 1-year overall survival will also be presented with two-sided, 90% confidence intervals.

Measure: Overall survival

Time: 1 year

Description: The one-year disease-free survival after treatment will be estimated using the product-limit methods of Kaplan-Meier, and presented with 90% confidence intervals.

Measure: Disease-free survival

Time: 1 year

Other Outcomes

Description: Descriptive statistics including mean, standard deviation, coefficient of variation, geometric mean, median, minimum and maximum will be computed for each pharmacokinetic variable; descriptive statistics for natural-log transformed pharmacokinetic variables will also be provided.

Measure: Pharmacokinetic parameters (maximal plasma or serum concentration, area under the curve to the last collection point, area under the curve for dose interval, and time of maximal concentration)

Time: Course 1, days 1 and 15 (pre-dose, 1, 2, 4, 6, 8, 24 hour post-dose) and day 1 in courses 2, 4, 8, and 12 (pre-dose)

Description: Will be performed to assess how changes in the expression of the key signaling proteins relate to patient response.

Measure: Changes in the expression of the key signaling proteins

Time: Baseline to 7 days (1 week)

107 A Phase I Study of the Anti-PD-1 Antibody Nivolumab in Combination With Dabrafenib and/or Trametinib in Patients With BRAF or NRAS-mutated Metastatic Melanoma

This study evaluates nivolumab in combination drug treatments involving 1) nivolumab and dabrafenib 2) nivolumab and trametinib and 3) nivolumab, dabrafenib and trametinib in patients with BRAF or NRAS-mutated metastatic melanoma.

NCT02357732 Metastatic Melanoma Drug: Nivolumab Drug: Trametinib Drug: Dabrafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.. Inclusion Criteria: - Histologically confirmed metastatic melanoma (Stage IV) or unresectable Stage III melanoma with BRAF V600E/K or NRAS mutations. --- V600E ---

Inclusion Criteria: - Histologically confirmed metastatic melanoma (Stage IV) or unresectable Stage III melanoma with BRAF V600E/K or NRAS mutations. --- V600E ---

Primary Outcomes

Description: It is planned to determine the maximum tolerable dose with a modified version of the standard "up and down" (3+3) dose-finding method using cohorts of 3 patients. At the start of the trial, three patients will be placed on dose level 1. The decision rules based on the observed dose limiting toxicities (DLTs) in this and subsequent cohorts are given. Only DLTs observed in a patient during the first cycle (28 days) will be used for the dose escalation decisions. Patients will be considered evaluable for toxicity if they receive 1 complete cycle of therapy, or if they experience DLT; in-evaluable patients will be replaced.

Measure: To determine the Maximally Tolerated Dose and/or Recommended Phase II Dose (RP2D) of nivolumab in combination with dabrafenib and/or trametinib in patients with BRAF- or NRAS-mutated metastatic melanoma

Time: The first four weeks of dosing

Secondary Outcomes

Description: Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) and by the Immune Related Response Criteria. Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.

Measure: Antitumor Effects and Immune Related Response

Time: Every twelve weeks for three years while on study drug

108 Study of Circulating Tumor Cells Before and After Treatment in Patients With Metastatic Melanoma.

Circulating tumor cells (CTC) are the subject of increasing interest in clinical oncology as a prognostic factor and predictor of therapeutic response. The detection of CTC by immunomagnetic method has proved its reliability and its usefulness for monitoring breast cancer, colon and prostate in the metastatic and immunomagnetic detection system (CellSearch, Veridex LLC) was approved by the FDA in these indications. However, to date there is no reliable method to detect CTCs in melanoma (CMC). Studies based on PCR amplification of mRNA by reverse specific melanoma is disappointing. Recently, a new detection system of CMC immunomagnetic was presented (CellSearch, Veridex LLC, United States). This system has the advantage of combining immunomagnetic selection step and a step of identifying by immunofluorescence. A preclinical study on serial dilutions of melanoma cells has shown encouraging results. The investigators propose a prospective study of the CellSearch system in patients with melanoma. Primary objective: To determine the effect of treatment on the number of circulating melanoma cells in patients with metastatic melanoma. Secondary objectives: - determine the percentage of patients with metastatic melanoma with melanoma cells circulating - seek a relationship between the number of circulating melanoma cells and prognosis in patients with metastatic melanoma - seek a relationship between the change in the number of circulating melanoma cells before / after treatment and tumor response in patients with metastatic melanoma

NCT01573494 Melanoma Other: Sampling of blood
MeSH: Melanoma Neoplastic Cells, Circulating
HPO: Cutaneous melanoma Melanoma

Difference in tumor response between patients according to the variation of circulating melanoma cells/ml before and after treatment.. Inclusion Criteria: - Patients > or = 18 years - Patients with advanced melanoma stage IIIC (unresectable) or stage IV - Patient not treated or not responding to chemotherapy with chemotherapy session last> 1 month - Patients who signed informed consent - Patients presenting no socio-economic, psychological, familial or geographical allow proper understanding of the information leaflet of the protocol or the regular monitoring in the department of dermatology - Patients with a life expectancy greater than 3 months - Patients with melanoma measurable by RECIST version 1.1 - Patients with venous good for venipuncture Exclusion Criteria: - Patients with contraindication for treatment with chemotherapy or V600E BRAF inhibitor or ipilimumab or have conditions concomitant heavy may interfere with the treatment of metastatic melanoma - Pregnant women or nursing - People vulnerable detainees, adults under guardianship or curatorship, minors. --- V600E ---

Inclusion Criteria: - Patients > or = 18 years - Patients with advanced melanoma stage IIIC (unresectable) or stage IV - Patient not treated or not responding to chemotherapy with chemotherapy session last> 1 month - Patients who signed informed consent - Patients presenting no socio-economic, psychological, familial or geographical allow proper understanding of the information leaflet of the protocol or the regular monitoring in the department of dermatology - Patients with a life expectancy greater than 3 months - Patients with melanoma measurable by RECIST version 1.1 - Patients with venous good for venipuncture Exclusion Criteria: - Patients with contraindication for treatment with chemotherapy or V600E BRAF inhibitor or ipilimumab or have conditions concomitant heavy may interfere with the treatment of metastatic melanoma - Pregnant women or nursing - People vulnerable detainees, adults under guardianship or curatorship, minors. --- V600E ---

Primary Outcomes

Description: Measuring the number of circulating melanoma cells/ml in the peripheral blood by the test before and after treatment CellSearch.

Measure: Measuring the number of circulating melanoma cells/ml in blood

Time: baseline and 3 months

Secondary Outcomes

Description: Calculating the number of patients who test positive detection of circulating melanoma cells measured in peripheral blood with the CellSearch test before and after treatment.

Measure: number of patients who test positive detection of circulating melanoma cells measured in peripheral blood with the CellSearch test

Time: 3 months

Description: Difference in survival between patients depending on the number of circulating melanoma cells/ml before treatment, according to Kaplan-Meier method.

Measure: Difference in survival

Time: baseline and 6 months

Description: Difference in tumor response between patients according to the variation of circulating melanoma cells/ml before and after treatment.

Measure: Difference in tumor response

Time: 6 months

109 FOLFOXIRI Plus Bevacizumab as First-line Treatment for BRAF V600E Mutant Metastatic Colorectal Cancer: a Prospective Evaluation

The purpose of this study is to prospectively verify if FOLFOXIRI plus bevacizumab as first-line treatment could be considered a promising approach to improve the outcome of BRAF mutant metastatic colorectal cancer patients

NCT01437618 Metastatic Colorectal Cancer Drug: FOLFOXIRI plus bevacizumab
MeSH: Colorectal Neoplasms
HPO: Neoplasm of the large intestine

FOLFOXIRI Plus Bevacizumab as First-line Treatment for BRAF V600E Mutant Metastatic Colorectal Cancer: a Prospective Evaluation. --- V600E ---

Inclusion Criteria: - Histologically confirmed colorectal adenocarcinoma; - Availability of formalin-fixed paraffin embedded tumor block from primary and/or metastasis; - BRAF V600E mutant status of primary colorectal cancer and/or related metastasis; - Unresectable and measurable metastatic disease according to RECIST criteria; - Male or female, aged > 18 years and < 75 years; - ECOG PS < 2 if aged < 71 years; - ECOG PS = 0 if aged 71-75 years; - Life expectancy of more than 3 months; - Adequate haematological function: ANC ≥ 1.5 x 10^9/L; platelets ≥ 100 x 10^9/L, Hb ≥ 9 g/dL; - Adequate liver function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases ≤ 5 x ULN); - Serum creatinine ≤ 1.5 x ULN; - Previous adjuvant chemotherapy is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse; - At least 6 weeks from prior extended radiotherapy and 4 weeks from surgery; - Written informed consent to experimental treatment and molecular analyses. --- V600E ---

Primary Outcomes

Measure: Progression-Free Survival

Time: About 24-30 months (From treatment initiation to evidence of progression or death from any cause)

110 A Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LGX818 in Adult Patients With Locally Advanced or Metastatic BRAF Mutant Melanoma

CLGX818X2101 is a first-time in-human, phase I study to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of daily administered LGX818 (daily, twice daily and/or every-other-day), a RAF kinase inhibitor. Patients with locally advanced or metastatic melanoma harboring the BRAF V600 mutation (during dose escalation phase and expansion phase) and patients with metastatic colorectal cancer harboring the BRAF V600 mutation (during the expansion phase) will be enrolled. The study consists of a dose escalation part were cohorts of patients will receive escalating oral doses of LGX818, followed by a safety dose expansion part were patients will be treated with oral dose of LGX818 given at the MTD or RP2D.

NCT01436656 Melanoma and Metastatic Colorectal Cancer Drug: LGX818
MeSH: Melanoma Colorectal Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the large intestine

2. Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation. --- V600E ---

Primary Outcomes

Measure: Incidence of Dose Limiting Toxicities

Time: Approximately every 8 weeks (up to 2 years)

Secondary Outcomes

Measure: Number and nature of Adverse events and clinical activity

Time: Approximately 3 years

Description: LGX818 Plasma concentration

Measure: Pharmacokinetic profile of LGX818

Time: Approximately 2 years

Description: This includes duration of response, time to response, progression free survival and overall survival.

Measure: Tumor response per RECIST

Time: Approximately 3 years

Description: Baseline molecular status (mutation/ amplification/ expression) in tumor tissue of potential predictive markers

Measure: Baseline molecular status

Time: Approximately 3 years

111 Dose-seeking and Efficacy Study of the Combination of the BRAF Inhibitor Vemurafenib and High-dose Interferon Alfa-2b for Therapy of Advanced Melanoma

This is a dose-seeking and efficacy study of combined BRAF Inhibitor Vemurafenib and High-dose Interferon alfa-2b for therapy of advanced melanoma.

NCT01943422 Melanoma Drug: High-dose Interferon alfa-2b Drug: Vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

- BRAF V600E and V600K mutated - Cutaneous squamous cell carcinomas (SCC) lesions identified at baseline must be excised. --- V600E ---

Primary Outcomes

Description: At each dose level, the number of patients experiencing Adverse Events over their course of treatment will be characterized by type of Adverse Event and grade using NCI CTCAE (v4.0), and by time of onset in relation to the first day of therapy.

Measure: Number of Participants with Adverse Events to determine Ph II dose

Time: 12-24 months from study start

Secondary Outcomes

Description: •Progression Free Survival will be evaluated at 6 months using the Kaplan-Meier method. Overall Survival will be measured from the initial date of treatment to the recorded date of death, and analyzed similarly to Progression Free Survival. Overall Survival will also be analyzed with the Kaplan-Meier method. The complete response rate and partial response rate will be estimated by the proportion of patients with a best response respectively by RECIST criteria.

Measure: Progression Free and overall survival (Efficacy)

Time: 48 months

Other Outcomes

Description: Melanoma metastases removed from patients pretreatment, post-BRAFI alone and Post B-RAF+ will be analyzed for expression of IFNAR1 and immunologically relevant molecules such as HLA antigens, APM components and MA; these results will be correlated with T cell infiltration. In addition the metastases will be tested for extent of melanoma cell proliferation and apoptosis.

Measure: Improve tumor STAT signaling

Time: 48 months

112 A Phase 1 Study of Dabrafenib in Combination With Lapatinib in BRAF Mutant Thyroid Cancer

This phase I trial studies the side effects and best dose of lapatinib ditosylate when given together with dabrafenib in treating patients with thyroid cancer that cannot be removed by surgery and has not responded to previous treatment. Dabrafenib and lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

NCT01947023 BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Thyroid Gland Carcinoma Unresectable Thyroid Gland Carcinoma Drug: Dabrafenib Other: Laboratory Biomarker Analysis Drug: Lapatinib Ditosylate Other: Pharmacological Study
MeSH: Carcinoma Thyroid Diseases Thyroid Neoplasms
HPO: Abnormality of the thyroid gland Carcinoma Neoplasm of the thyroid gland Thyroid adenoma Thyroid carcinoma Thyroid follicular adenoma

Mean percentage change is calculated and compared with respect to each genotype.. Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8 - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8 - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective - Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E or V600K (c. --- V600E ---

1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering (MSK); only tumors with a BRAFV600E or BRAFV600K mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory; BRAF status may also be tested with any Food and Drug Administration (FDA)-approved test (such as Cobas 4800 BRAF V600 Mutation Test) - The tumor is considered to be radioactive-iodine refractory by any of the following criteria: - Total lifetime dose of radioactive iodine > 600 mCi - Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician) - Progression of disease (by imaging or thyroglobulin) within 6 months of radioactive iodine treatment - Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan - No recent treatment for thyroid cancer as defined as: - No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy - No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol - No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy - Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60% - Life expectancy of greater than 2 months - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L, within 2 weeks of the first dose of study treatment - Hemoglobin >= 9 g/dL, within 2 weeks of the first dose of study treatment - Platelets >= 100 x 10^9/L, within 2 weeks of the first dose of study treatment - Bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome, within 2 weeks of the first dose of study treatment - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN, within 2 weeks of the first dose of study treatment - Blood creatinine =< 1.5 mg/dL (if blood creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min), within 2 weeks of the first dose of study treatment - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with PT/INR/PTT established within the therapeutic range prior to randomization; subjects will be eligible if it is determined by a hematologist that the cause is not associated with clinical bleeding (e.g., deficiency of factor XII), within 2 weeks of the first dose of study treatment - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO), within 2 weeks of the first dose of study treatment - Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - Ability to understand and the willingness to sign a written informed consent document - Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if: - Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event) - Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation - Consent of the principal investigator (PI) not to have a biopsy done - A minimum of 8 subjects must participate in the biopsy part of the study Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded; it is important to regularly consult a frequently-updated list of these agents; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product - Prohibited: strong inducers of CYP3A or CYP2C8 - Antibiotics: rifamycin class agents (e.g., rifampin, rifabutin, rifapentine) - Anticonvulsant: carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin - Miscellaneous: bosentan, St. John's wort - Prohibited: strong inhibitors of CYP3A or CYP2C8 - Antibiotics: clarithromycin, telithromycin, troleandomycin - Antidepressant: nefazodone - Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole - Hyperlipidemia: gemfibrozil - Antiretroviral: ritonavir, saquinavir, atazanavir - Miscellaneous: conivaptan - Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia; in specific cases, will be allowed with permission from the principal investigator - Human immunodeficiency virus (HIV)-positive patients on antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment except for carcinoma in situ CIS, squamous cell carcinomas of the skin, or basal cell carcinoma of the skin; a diagnosis of an invasive malignancy within 3 years is allowed if both the cure rate is felt to be > 80% and there has been no evidence of disease in the past year - Patients with a history of RAS mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however if the results of previous RAS testing are known, they must be used in assessing eligibility - Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks - History or evidence of cardiovascular risks including any of the following: - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Medical or psychiatric illness/social situations that would limit compliance with study requirements - Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Thyroid Gland Carcinoma Unresectable Thyroid Gland Carcinoma Carcinoma Thyroid Diseases Thyroid Neoplasms PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of lapatinib (lapatinib ditosylate) that can be used in combination of dabrafenib. --- V600E ---

Primary Outcomes

Description: MTD is defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity.

Measure: Maximum tolerated dose (MTD) of lapatinib ditosylate, in combination with the established dose of dabrafenib, defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity

Time: First 42 days of treatment

Secondary Outcomes

Description: Tissues such as phosphorylated mitogen-activated protein kinase 1 (ERK), human epidermal growth factor receptor (HER) 2, HER3, epidermal growth factor receptor (EGFR), platelet derived growth factor (PDGF), or protein kinase B (AKT) will be examined. Mean percent change will be calculated and compared.

Measure: Mean percent change in the post-treatment tissues relative to pre-treatment tissues for the phosphorylated protein targets examined

Time: Baseline to day 7 of course 1

Description: Genes including sodium/iodide symporter (NIS), dual-specificity phosphatase 5 (DUSP5), and plasminogen activator (PLAT) will be examined. Mean percentage change is calculated and compared with respect to each genotype.

Measure: Mean percentage change in transcript levels in the post-treatment tissues relative to pre-treatment tissues for several genes analyzed by reverse-transcriptase-polymerase chain reaction

Time: Baseline to day 7 of course 1

113 The Effect of BRAF Inhibition With Vemurafenib On The Innate and Adaptive Immune Systems in Patients With Unresectable Stage III or Stage IV Melanoma Expressing a V600 BRAF Mutation

Approximately 40-60 % of cutaneous melanomas select for a mutation in a protein called BRAF which is part of a signaling pathway called the Mitogen Activated Protein Kinase (MAPK) pathway. When BRAF is mutated the MAPK pathway remains active allowing for melanoma to grow. Vemurafenib is an oral treatment which blocks the activity of BRAF which leads to decreasing the activity of the MAPK pathway. When patients with melanoma expressing specific mutation in BRAF are treated with vemurafenib approximately 50% will develop a response to treatment with shrinkage of tumor. When compared to a standard chemotherapy called dacarbazine used to treat melanoma, treatment with vemurafenib leads to a statistically significant overall survival or living longer benefit. Because of this survival benefit vemurafenib was Food and Drug Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF mutation called V600E BRAF. There is increasing evidence that the immune system can also be important in affecting melanoma growth and survival and there are immune treatments FDA approved for the treatment of metastatic melanoma. There is some limited evidence that blocking BRAF with vemurafenib may affect the activity of components of the immune system. It is important to better characterize and understand the effects of vemurafenib treatment on various components of the immune system. The purpose of this study is to systematically evaluate the effects of vemurafenib treatment (at FDA approved dosing regimen) on parts of the immune systems called the innate and adaptive immune systems. The hypothesis is that vemurafenib treatment will affect the immune system.

NCT01942993 Melanoma Drug: Vemurafenib
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

Because of this survival benefit vemurafenib was Food and Drug Administration (FDA) approved for the treatment of metastatic melanoma expressing a BRAF mutation called V600E BRAF. --- V600E ---

Over 90% of mutations in BRAF occur at position V600 with the most common being a V600E mutation. --- V600E ---

The response rate to treatment with vemurafenib in patients with stage IV melanoma expressing a V600E BRAF mutation is approximately 50%. --- V600E ---

Based on this survival benefit vemurafenib was FDA approved for treatment of stage IV melanoma expressing a V600E BRAF mutation. --- V600E ---

Primary Outcomes

Description: Immuno-fluorescence and flow cytometry will be performed on blood specimens obtained to determine changes in the immune cell signature in the blood on day 8 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the immune cellular signature in the blood circulation

Time: baseline and day 8

Description: Immuno-fluorescence and flow cytometry will be performed on blood specimens obtained to determine changes in the immune cell signature in the blood on day 57 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the immune cellular signature in the blood circulation

Time: baseline and day 57

Secondary Outcomes

Description: Immuno-fluorescence and flow cytometry will be performed on tumor specimens obtained to determine changes in the immune cell signature in the tumor on day 8-10 after initiation of vemurafenib treatment as compared to baseline

Measure: Changes in the immune cellular signature in the tumor

Time: baseline and day 8-10

Description: Global changes in the blood transcriptome in response to vemurafenib therapy will be performed using gene expression arrays. Change in the blood transcriptosome on day 8 as compared to baseline.

Measure: Changes in Transcriptional Profile in the blood

Time: baseline and day 8

Description: Global changes in the blood transcriptome in response to vemurafenib therapy will be performed using gene expression arrays. Change in the blood transcriptosome on day 57 as compared to baseline.

Measure: Changes in Transcriptional Profile in the blood

Time: baseline and day 57

Description: Global changes in the transcriptosome of tumor associated immune cells in response to therapy will be performed using gene expression arrays. The transcriptosome in tumor will be compared on purified tumor immune cells obtained from a pretreatment tumor biopsy performed at baseline and a second biopsy obtained after starting treatment and obtained between days 8-10.

Measure: Change in Transcriptional Profile in Tumor

Time: baseline and day 8-10

Description: change in dendritic cell function at day 8 as compared to baseline

Measure: Changes in Dendritic Cell function in Blood

Time: baseline and day 8

Description: change in dendritic cell function at day 57 as compared to baseline

Measure: Changes in Dendritic Cell function in Blood

Time: baseline and day 57

Description: Changes in dendritic cell function in tumor on day 8-10 as compared to baseline

Measure: Changes in Dendritic Cell function in Tumor

Time: baseline and day 8-10

Description: Changes in macrophage function in blood at day 8 as compared to baseline

Measure: Changes in Macrophage Function in Blood

Time: baseline and day 8

Description: Changes in macrophage function in blood at day 57 as compared to baseline

Measure: Changes in Macrophage Function in Blood

Time: baseline and day 57

Description: changes in macrophage function in tumor on day 8-10 as compared to baseline

Measure: Changes in Macrophage Function in Tumor

Time: baseline and day 8-10

Description: changes in global T cell function in blood on day 8 as compared to baseline

Measure: Changes in Global T cell function in Blood

Time: baseline and day 8

Description: changes in global T cell function in blood on day 57 as compared to baseline

Measure: Changes in Global T cell function in Blood

Time: baseline and day 57

Description: Changes in Global T cell function in Tumor on day 8 as compared to baseline

Measure: Changes in Global T cell function in Tumor

Time: baseline and day 8-10

Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 8 as compared to baseline

Measure: Changes in Tumor Antigen Specific T cell Function in blood

Time: baseline and day 8

Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 15 as compared to baseline

Measure: Changes in Tumor Antigen Specific T cell Function in blood

Time: baseline and day 15

Description: Changes in Tumor Antigen Specific T cell Function using CD154 induction assay on day 126 as compared to baseline

Measure: Changes in Tumor Antigen Specific T cell Function in blood

Time: baseline and day 126

Description: Changes in Histocytometry of tumor on day 8-10 as compared to baseline. Histocytometry is a novel microscopic analytical method (Gerner et al. 2012) which combines the advantages of flow cytometry and Microscopic techniques. This techniques allows for the visualization and quantification of phenotypically complex cellular subsets and provides spatial and cell-cell interactions.

Measure: Changes in Histocytometry of tumor

Time: baseline and day 8-10

Description: changes in tumor burden using CT or MRI imaging studies

Measure: response to vemurafenib treatment

Time: up to 57 days

Description: development of cutaneous squamous cell carcinomas assessment

Measure: Development of Cutaneous Squamous Cell Carcinomas

Time: up to one year

114 A Sequential Safety and Biomarker Study of BRAF-MEK Inhibition on the Immune Response in the Context of Combined CTLA-4 Blockade and PD-1 Blockade for BRAF Mutant Melanoma

This randomized phase I trial studies the side effects and best way to give ipilimumab with or without dabrafenib, trametinib and/or nivolumab in treating patients with melanoma that has spread to other parts of the body (metastatic) or cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may interfere with the ability of cancer cells to grow and spread. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether ipilimumab works better with or without dabrafenib, trametinib, and/or nivolumab in treating melanoma.

NCT01940809 BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Drug: Dabrafenib Biological: Ipilimumab Other: Laboratory Biomarker Analysis Biological: Nivolumab Drug: Trametinib
MeSH: Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm of the skin

For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.. Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis Inclusion Criteria: - Study participants must have histologically or cytologically confirmed unresectable or metastatic malignant melanoma - Study participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam - Study participants must have completed any prior treatment at least 3 weeks prior to treatment on this protocol; prior treatments may have included chemotherapy however may not have included BRAF or MEK inhibitors or immunotherapies (interleukin-2, ipilimumab, anti-programmed death [PD]1 antibodies etc.) excluding vaccine therapy; prior treatment with interferon in the adjuvant setting is allowed, though prior treatment with ipilimumab in the adjuvant setting is not; prior radiation therapy is allowed though must have included no more than 3000 centigray (cGy) to fields including substantial marrow - Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%) - Absolute neutrophil count (ANC) >= 1.2 x 10^9/L - Hemoglobin >= 9 g/dL - Platelets >= 100 x 10^9/L - Albumin >= 2.5 g/dL - Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert's syndrome - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN - Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min - Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization - Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) - Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels - Patients must have BRAFV600E or BRAFV600K mutations, identified by a Food and Drug Administration (FDA)-approved test at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (lab); if test at CLIA-certified lab used a non-FDA approved method, information about the assay must be provided - Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency - Women of child-bearing potential must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed) for the duration of study participation, and for at least 2 weeks after treatment with dabrafenib or for 6 months after dabrafenib in combination with trametinib; should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately - All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of randomization - Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: - Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks preceding the first dose of study treatment - Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study - Study participants with a history of prior treatment with BRAF or MEK inhibitors - Study participants who had prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways - Patients with active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids, should be excluded; these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded; patients with vitiligo, endocrine deficiencies including thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible; patients with rheumatoid arthritis and other arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible - Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event) - Study participants who have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses < 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if < 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted - Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study - Study participants with known immune impairment who may be unable to respond to anti-cytotoxic T-lymphocyte antigen 4 (CTLA 4) antibody and/or anti-PD-1 antibody - Study participants with brain metastases are excluded unless these have been definitively treated and are radiographically stable for at least 1 month; the study participant must also demonstrate a stable physical exam and must have discontinued systemic steroids for treatment of edema related to brain metastases or treatment for over 7 days - Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO) - Current use of a prohibited medication; patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible - A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of cleared HBV and HCV infection, which will be allowed) - Patients with history of rat sarcoma (RAS) mutation-positive tumors are not eligible regardless of interval from the current study; Note: prospective RAS testing is not required; however, if the results of previous RAS testing are known, they must be used in assessing eligibility - History or evidence of cardiovascular risks including any of the following: - QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec - History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization - History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Intra-cardiac defibrillators - Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study - History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible - Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy - Any condition which in the investigator's opinion makes the subject unsuitable for study participation - History of retinal vein occlusion (RVO) - History of interstitial lung disease or pneumonitis BRAF V600E Mutation Present BRAF V600K Mutation Present Metastatic Melanoma Stage III Cutaneous Melanoma AJCC v7 Stage IIIA Cutaneous Melanoma AJCC v7 Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of ipilimumab (part 1) or ipilimumab plus nivolumab (part 2) following lead-in of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors, either alone or in combination, in patients with BRAFV600 mutant melanoma. --- V600E ---

Primary Outcomes

Description: Presented with 90% confidence intervals calculated using exact binomial methods.

Measure: Incidence of grade 3 or higher immune-related adverse events (irAEs), graded according to the National Cancer Institute (NCI) CTCAE v4.0

Time: Up to 3 weeks after end of ipilimumab induction

Secondary Outcomes

Description: Presented with 90% confidence intervals calculated using exact binomial methods by randomized treatment arm.

Measure: Proportion of patients receiving dabrafenib and trametinib with grade 3 or higher irAEs after disease progression on ipilimumab, according to the NCI CTCAE v4.0

Time: Up to 4 weeks after completion of study treatment

Description: Summarized by treatment arm and presented with 90% exact binomial confidence intervals. Fisher's exact test will be used.

Measure: Response rate for the total treatment period according to Response Evaluation Criteria in Solid Tumors v1.1

Time: Up to 4 weeks after completion of study treatment

Description: Summarized by treatment arm and presented with 90% exact binomial confidence intervals. Fisher's exact test will be used.

Measure: Disease-control rate

Time: Up to 4 weeks after completion of study treatment

Other Outcomes

Description: The relationship between pre-treatment marker levels and response will be assessed according to expression cut-off between positive and negative. Fisher's exact test will be used to detect an increase in response rate and a secondary, sensitivity analysis will use a stratified Fisher's exact test.

Measure: Biomarker expression levels

Time: Baseline

Description: Biomarkers measured on a continuous scale will be summarized and compared across response categories using the Wilcoxon rank-sum test. For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.

Measure: Fold-changes in biomarkers

Time: Baseline to 3 weeks after fourth ipilimumab dose

Description: Biomarkers measured on a continuous scale will be summarized and compared across response categories using the Wilcoxon rank-sum test. For biomarkers measured categorically, pre/post response combinations will be compared between responders and non-responders using Fisher's exact test.

Measure: Change in immune activation, measured by changes in biomarker levels

Time: Baseline to 3 weeks after fourth ipilimumab dose

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