There are 11 clinical trials
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.
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 ---
Description: Area under the ROC curve of the mutation percentage obtained from plasma ccfDNA analysis
Measure: Area under ROC curve Time: 12 monthThe purpose of this study is to determine if it is safe to add multiple immunotherapies to standard chemotherapy and radiation for treating pancreatic cancer tumors that cannot be completely removed by surgery. 1. GI-4000 Vaccination: The first involves a "vaccine," which is an injection (shot) that teaches your immune system to attack foreign invaders. The vaccine we will use is called "GI-4000" - a vaccine composed of yeast that is made to carry the same proteins (called "mutated Ras proteins") found in some pancreatic cancer cells. 2. Adoptive T-cell Transfer: The second type of immunotherapy in this study is called "adoptive T-cell transfer." This involves collecting a specific type of white blood cells from you (called "T-cells")and growing T-cells grown in a lab which may help the research participants' immune systems recover more quickly after chemotherapy, and possibly improved response to other immunotherapies. We hope that studying these agents together will teach us how to help the immune system fight pancreatic cancer.
1. Histologically-confirmed pancreatic adenocarcinoma that expresses one of the GI-4000-related k-ras oncoproteins (G12V, G12C, G12D, Q61L, or Q61R) 2. Locally advanced disease, (stages I-III, i.e no evidence of metastasis outside the pancreas and its regional lymph nodes). --- G12V --- --- G12C ---
Evaluate the safety, tolerability, drug levels, molecular effects, and clinical activity of MRTX849 in patients with advanced solid tumors that have a KRAS G12C mutation.
A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients With Advanced Solid Tumors With KRAS G12C Mutation. --- G12C ---
MRTX849 in Patients With Cancer Having a KRAS G12C Mutation Evaluate the safety, tolerability, drug levels, molecular effects, and clinical activity of MRTX849 in patients with advanced solid tumors that have a KRAS G12C mutation. --- G12C ---
MRTX849 in Patients With Cancer Having a KRAS G12C Mutation Evaluate the safety, tolerability, drug levels, molecular effects, and clinical activity of MRTX849 in patients with advanced solid tumors that have a KRAS G12C mutation. --- G12C --- --- G12C ---
Characterize the safety of MRTX849 in patients having advanced solid tumor malignancies with KRAS G12C mutation. --- G12C ---
Inclusion Criteria: - Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation - Unresectable or metastatic disease - Standard treatment is not available or patient declines - Adequate organ function Exclusion Criteria: - Active brain metastases - History of intestinal disease or major gastric surgery or inability to swallow oral medications - Other active cancer Inclusion Criteria: - Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation - Unresectable or metastatic disease - Standard treatment is not available or patient declines - Adequate organ function Exclusion Criteria: - Active brain metastases - History of intestinal disease or major gastric surgery or inability to swallow oral medications - Other active cancer Advanced Cancer Metastatic Cancer Malignant Neoplastic Disease Neoplasm Metastasis Neoplasms Evaluate the safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumors with a KRAS G12C mutation. --- G12C ---
Inclusion Criteria: - Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation - Unresectable or metastatic disease - Standard treatment is not available or patient declines - Adequate organ function Exclusion Criteria: - Active brain metastases - History of intestinal disease or major gastric surgery or inability to swallow oral medications - Other active cancer Inclusion Criteria: - Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation - Unresectable or metastatic disease - Standard treatment is not available or patient declines - Adequate organ function Exclusion Criteria: - Active brain metastases - History of intestinal disease or major gastric surgery or inability to swallow oral medications - Other active cancer Advanced Cancer Metastatic Cancer Malignant Neoplastic Disease Neoplasm Metastasis Neoplasms Evaluate the safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumors with a KRAS G12C mutation. --- G12C --- --- G12C ---
Inclusion Criteria: - Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation - Unresectable or metastatic disease - Standard treatment is not available or patient declines - Adequate organ function Exclusion Criteria: - Active brain metastases - History of intestinal disease or major gastric surgery or inability to swallow oral medications - Other active cancer Inclusion Criteria: - Histologically confirmed diagnosis of a solid tumor malignancy with KRAS G12C mutation - Unresectable or metastatic disease - Standard treatment is not available or patient declines - Adequate organ function Exclusion Criteria: - Active brain metastases - History of intestinal disease or major gastric surgery or inability to swallow oral medications - Other active cancer Advanced Cancer Metastatic Cancer Malignant Neoplastic Disease Neoplasm Metastasis Neoplasms Evaluate the safety, tolerability, pharmacokinetics, metabolites, pharmacodynamics, and clinical activity of MRTX849 in patients with advanced solid tumors with a KRAS G12C mutation. --- G12C --- --- G12C --- --- G12C ---
MRTX849 is an orally-available small molecule inhibitor of KRAS G12C. --- G12C ---
Description: Number of participants with treatment related adverse events
Measure: Characterize the safety of MRTX849 in patients having advanced solid tumor malignancies with KRAS G12C mutation Time: 20 monthsDescription: Blood plasma concentration
Measure: Evaluate the pharmacokinetics of MRTX849 Time: 20 monthsDescription: Number of participants with dose limiting toxicity
Measure: Establish maximum tolerated dose Time: 12 monthsDescription: Objective response rate in accordance with Response Evaluation Criteria in Solid Tumors (RECIST)
Measure: Evaluate clinical activity of MRTX849 Time: 20 monthsThis study will determine the safety and tolerability and establish a preliminary recommended Phase 2 dose of V941(mRNA-5671/V941) as a monotherapy and in combination with pembrolizumab infusion.
T-cell receptor (TCR) clonality and diversity in the periphery and tumor.. Inclusion Criteria: Part 1 Only - Has a histologically confirmed advanced or metastatic KRAS 4MUT+ (G12D, G12V, G13D or G12C) (4 prevalent KRAS mutant antigens in solid tumors) solid tumor confirmed by central laboratory testing, and who have received, or been intolerant to, or ineligible for all treatment known to confer clinical benefit. --- G12D --- --- G12V --- --- G13D --- --- G12C ---
Part 2 Only - Has a histologically confirmed advanced or metastatic non-small cell lung cancer (NSCLC), adenocarcinoma of the colon or rectum, or pancreatic adenocarcinoma, central laboratory confirmed Human Leukocyte Antigen (HLA) (HLA-A*11 and/or HLA-C*08 allele and mutated KRAS 4MUT+ (G12D, G12V, G13D or G12C) who have received, or been intolerant to or ineligible for all treatment known to confer clinical benefit) All - A male participant must agree to use study-approved contraception during the treatment period and for at least 120 days after the last dose of study intervention and refrain from donating sperm during this period. --- G12D --- --- G12V --- --- G13D --- --- G12C ---
Inclusion Criteria: Part 1 Only - Has a histologically confirmed advanced or metastatic KRAS 4MUT+ (G12D, G12V, G13D or G12C) (4 prevalent KRAS mutant antigens in solid tumors) solid tumor confirmed by central laboratory testing, and who have received, or been intolerant to, or ineligible for all treatment known to confer clinical benefit. --- G12D --- --- G12V --- --- G13D --- --- G12C ---
Description: The following toxicities graded for severity using NCI Common Terminology for Adverse Events (CTCAE), Version 4.0 will be considered a DLT if judged by the investigator to be possibly related to study investigational products: 1) Grade 4 nonhematologic toxicity (ie. not a laboratory finding). 2) Grade 4 hematologic toxicity lasting ≥ 7 days, except thrombocytopenia: 3) Grade 4 thrombocytopenia of any duration 4) Grade 3 thrombocytopenia associated with clinically significant bleeding 5) Any nonhematologic AE ≥ Grade 3 in severity, with some exceptions 6) Any Grade 3 or Grade 4 nonhematologic laboratory value that meets one of the study criteria 7) Febrile neutropenia Grade 3 or Grade 4 8) Prolonged delay (> 2 weeks) in initiating Cycle 2 due to treatment-related toxicity. 9) Any treatment-related toxicity that causes the participant to discontinue treatment during Cycle 1. 10) Grade 5 toxicity 11) Any other clinically significant toxicity judged to be a DLT by the investigator.
Measure: Dose-Limiting Toxicities (DLTs) Time: Cycle 1 (Up to 21 days)Description: Number of participants who experienced an AE. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Measure: Adverse Events (AEs) Time: Up to approximately 25 monthsDescription: Number of participants who discontinued from study due to an AE. An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study.
Measure: Discontinuations Time: Up to approximately 24 monthsDescription: ORR is assessed by the investigator based on Response Rate Assessed by Modified Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) and RECIST for immune-based therapeutics (iRECIST) following administration of V941 in combination with pembrolizumab. Objective response is a confirmed complete response (CR) or partial response (PR).
Measure: Objective Response Rate (ORR) Time: Up to approximately 24 monthsDescription: Presence of and changes in the quantity of mutant KRAS specific T cells in the periphery.
Measure: Mutant KRAS Specific T cells Time: Up to approximately 24 monthsDescription: T-cell receptor (TCR) clonality and diversity in the periphery and tumor.
Measure: T-cell receptor (TCR) Time: Up to approximately 24 monthsThis research study is designed to evaluate the effects of a dendritic cell (kind of white blood cell) vaccine for pancreatic cancer.
Inclusion Criteria: - Pathologically-confirmed KRAS(G12D-), KRAS(G12V-), KRAS(G12R-) or KRAS(G12C-mutated) pancreatic ductal adenocarcinoma who are at high risk of relapse and have no evidence of disease. --- G12D --- --- G12V --- --- G12R --- --- G12C ---
This study is a Phase Ib, multi-center, open-label study of TNO155 in combination with spartalizumab or ribociclib with a dose escalation part followed by a dose expansion part in adult subjects with advanced solid tumors. These two treatment arms will enroll subjects in parallel to characterize the safety, tolerability, PK, PD and preliminary antitumor activity. The study treatment will be administered until the subject experiences unacceptable toxicity, progressive disease, and/or has treatment discontinued at the discretion of the Investigator or the subject, or due to withdrawal of consent.
For TNO155 plus spartalizumab combination: i. Advanced EGFR WT, ALK WT, KRAS G12C NSCLC after progression on or intolerance to platinum-containing combination chemotherapy and after progression on anti-PD-1 or anti-PD-L1 therapy. --- G12C ---
Description: Incidence of dose limiting toxicities (DLTs) during the first cycle of combination treatment during the dose escalation part
Measure: DLT incidence Time: 1 yearDescription: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment
Measure: AE and SAE incidence Time: 3 yearsDescription: Dose tolerability
Measure: Dose interruptions, reductions and dose intensity, by treatment Time: 3 yearsDescription: Cmax for TNO155, spartalizumab, and ribociclib
Measure: Pharmacokinetics (PK): Cmax Time: 3 yearsDescription: Tmax for TNO155, spartalizumab, and ribociclib
Measure: Pharmacokinetics (PK): Tmax Time: 3 yearsDescription: AUClast for TNO155, spartalizumab, and ribociclib
Measure: Pharmacokinetics (PK): AUClast Time: 3 yearsDescription: AUCtau for TNO155, spartalizumab, and ribociclib
Measure: Pharmacokinetics (PK): AUCtau Time: 3 yearsDescription: Overall response rate (ORR) per RECIST v1.1, by treatment
Measure: Efficacy measurements per RECIST v1.1: ORR Time: 3 yearsDescription: Disease control rate (DCR) per RECIST v1.1, by treatment
Measure: Efficacy measurements per RECIST v1.1: DCR Time: 3 yearsDescription: Progression-free survival (PFS) per RECIST v1.1, by treatment
Measure: Efficacy measurements per RECIST v1.1: PFS Time: 3 yearsDescription: Duration of response (DOR) per RECIST v1.1, by treatment
Measure: Efficacy measurements per RECIST v1.1: DOR Time: 3 yearsDescription: Overall response rate (ORR) per iRECIST for TNO155 in combination with spartalizumab
Measure: Efficacy measurements per iRECIST: ORR Time: 3 yearsDescription: Disease control rate (DCR) per iRECIST for TNO155 in combination with spartalizumab
Measure: Efficacy measurements per iRECIST: DCR Time: 3 yearsDescription: Progression-free survival (PFS) per iRECIST for TNO155 in combination with spartalizumab
Measure: Efficacy measurements per iRECIST: PFS Time: 3 yearsDescription: Duration of response (DOR) per iRECIST for TNO155 in combination with spartalizumab
Measure: Efficacy measurements per iRECIST: DOR Time: 3 yearsDescription: Overall survival (OS) by treatment
Measure: Overall Survival Time: 3 yearsThe purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74699157 in participants with advanced solid tumors harboring a kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation (Part 1: Dose escalation) and to determine the safety and preliminary antitumor activity of JNJ-74699157 at the RP2D regimen in participants with advanced solid tumors harboring a KRAS G12C mutation (Part 2: Dose expansion).
A First-in-Human Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of JNJ-74699157 in Participants With Advanced Solid Tumors Harboring the KRAS G12C Mutation. --- G12C ---
First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74699157 in participants with advanced solid tumors harboring a kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation (Part 1: Dose escalation) and to determine the safety and preliminary antitumor activity of JNJ-74699157 at the RP2D regimen in participants with advanced solid tumors harboring a KRAS G12C mutation (Part 2: Dose expansion). --- G12C ---
First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74699157 in participants with advanced solid tumors harboring a kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation (Part 1: Dose escalation) and to determine the safety and preliminary antitumor activity of JNJ-74699157 at the RP2D regimen in participants with advanced solid tumors harboring a KRAS G12C mutation (Part 2: Dose expansion). --- G12C --- --- G12C ---
First-in-Human Study of JNJ-74699157 in Participants With Tumors Harboring the KRAS G12C Mutation The purpose of this study is to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of JNJ-74699157 in participants with advanced solid tumors harboring a kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation (Part 1: Dose escalation) and to determine the safety and preliminary antitumor activity of JNJ-74699157 at the RP2D regimen in participants with advanced solid tumors harboring a KRAS G12C mutation (Part 2: Dose expansion). --- G12C --- --- G12C --- --- G12C ---
AUC (0-last) is the area under the plasma concentration-time curve from time zero to last observed quantifiable concentration.. Part 1 and 2: Percentage of KRAS G12C Protein in Tumor Tissue Covalently Bound with JNJ-74699157 or its Metabolites. --- G12C ---
Percentage of kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) protein in tumor tissue covalently bound with JNJ-74699157 or its metabolites will be evaluated using mass spectroscopy.. Part 1: Overall Response Rate. --- G12C ---
Change from baseline in QTcF intervals will be assessed.. Inclusion Criteria: - Kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation in tumor tissue or blood - Histological documentation of disease: Part 1: Histologically or cytologically confirmed solid tumor malignancy that is metastatic or unresectable, Part 2: (a) unresectable, locally advanced (Stage IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC), (b) Solid tumor malignancy other than NSCLC that is metastatic or unresectable - Received or was ineligible for standard treatment options. --- G12C ---
Participants who have had complete surgical resection of or received stereotactic radiosurgery to less than or equal to (<=) 3 metastatic lesions will be permitted to enroll in the study within 14 days of such treatment if they have recovered from treatment, are clinically stable, and do not require prolonged systemic corticosteroid therapy as noted above - Prior treatment with an inhibitor specific to KRAS G12C - Prior solid organ transplantation - History of malignancy (other than the disease under study) within 2 years before the first administration of study drug. --- G12C ---
If any of these conditions exist, the investigator should discuss with the sponsor to determine participant eligibility Inclusion Criteria: - Kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) mutation in tumor tissue or blood - Histological documentation of disease: Part 1: Histologically or cytologically confirmed solid tumor malignancy that is metastatic or unresectable, Part 2: (a) unresectable, locally advanced (Stage IIIB) or metastatic (Stage IV) non-small cell lung cancer (NSCLC), (b) Solid tumor malignancy other than NSCLC that is metastatic or unresectable - Received or was ineligible for standard treatment options. --- G12C ---
This study will evaluate JNJ-74699157, a potent and specific, orally bioavailable inhibitor of the glycine-to-cysteine (G12C) mutant KRAS protein, which is found in non-small cell lung cancers and other solid tumor types. --- G12C ---
This study will enroll participants with advanced solid tumors harboring the KRAS G12C mutation and will be conducted in 2 parts. --- G12C ---
Description: DLTs are defined as certain non-hematologic and hematologic toxicities of Grade 3 or higher.
Measure: Part 1: Number of Participants with Dose-Limiting Toxicity (DLT) Time: Up to 2 yearsDescription: An AE is any untoward medical occurrence in a participant who received study drug without regard to causal relationship.
Measure: Part 1 and Part 2: Number of Participants with Adverse Events (AEs) Time: Up to 4 yearsDescription: Severity of AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) criteria: Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life threatening consequences; Grade 5: Death.
Measure: Part 1 and Part 2: Number of Participants with AE's by Severity Time: Up to 4 yearsDescription: ORR is defined as the percentage of participants who have a partial response (PR) or better response as per RECIST v.1.1. PR criteria in solid tumors (RECIST) is greater than or equal to (>=) 30 percent (%) decrease in the sum of the diameters of all index lesions compared with baseline in 2 observations at least 4 weeks apart, in absence of new lesions or unequivocal progression of non-index lesions.
Measure: Part 2: Overall Response Rate (ORR) Time: Up to 4 yearsDescription: Cmax is the maximum observed plasma concentration.
Measure: Part 1 and Part 2: Maximum Observed Plasma Concentration (Cmax) of JNJ-74699157 Time: Up to 4 yearsDescription: Tmax is defined as actual sampling time to reach maximum observed plasma concentration.
Measure: Part 1 and Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-74699157 Time: Up to 4 yearsDescription: AUC (0-last) is the area under the plasma concentration-time curve from time zero to last observed quantifiable concentration.
Measure: Part 1 and 2: Area Under Plasma-concentration Time Curve from Time 0 to Time of Last Quantifiable Concentration (AUC [0-last]) Time: Up to 4 yearsDescription: Percentage of kirsten rat sarcoma virus homolog (KRAS) glycine-to-cysteine (G12C) protein in tumor tissue covalently bound with JNJ-74699157 or its metabolites will be evaluated using mass spectroscopy.
Measure: Part 1 and 2: Percentage of KRAS G12C Protein in Tumor Tissue Covalently Bound with JNJ-74699157 or its Metabolites Time: Up to 4 YearsDescription: ORR is defined as the percentage of participants who have a PR or better response as per RECIST v.1.1. PR criteria in solid tumors (RECIST) is >=30 percent % decrease in the sum of the diameters of all index lesions compared with baseline in 2 observations at least 4 weeks apart, in absence of new lesions or unequivocal progression of non-index lesions.
Measure: Part 1: Overall Response Rate Time: Up to 4 yearsDescription: DOR is defined as the duration from the date of initial documentation of a response (PR or better) to the date of first documented evidence of progressive disease (PD), as defined in the RECIST v1.1, or death due to any cause, whichever occurs first. PD is assessed if the sum of the diameters has increased by >=20% and >=5 millimeter (mm) from nadir (including baseline if it is the smallest sum).
Measure: Part 1 and Part 2: Duration of Response (DOR) Time: Up to 4 yearsDescription: Change from baseline in QTcF intervals will be assessed.
Measure: Change From Baseline in QTc Interval Based on the Fridericia Correction (QTcF) Method Time: Baseline up to 4 yearsLung cancer tumors become resistant to the first generation epidermal growth factor receptor (EGFR) inhibitors erlotinib or gefitinib by changing and increasing the activity of two cell signaling pathways: the cMET pathway and the EGFR pathway. Both resistance mechanisms can occur at the same time, in the same patient and even in the same tumor. This study combines a second generation EGFR inhibitor and a cMET inhibitor to block both these pathways in order to overcome resistance and treat this disease.
Sample analyses were performed in accordance to Good Laboratory Practice (GLP) guidance and included mutation detection for EGFR gene.. Number of Participants With KRAS Mutation (GLY12CYS) at Baseline. --- GLY12CYS ---
Description: AE was any untoward medical occurrence with study drug/ device in a trial participant. Serious adverse event (SAE) was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE) v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Measure: Overview of Treatment-emergent All Causalities Adverse Events (AEs) in Escalation Phase Time: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)Description: AE was any untoward medical occurrence with study drug/ device in a trial participant. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Measure: Overview of Treatment-emergent All Causalities AEs in Expansion Phase Time: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)Description: An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Measure: Overview of Treatment-emergent, Treatment-related AEs in Escalation Phase Time: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)Description: An AE was any untoward medical occurrence attributed to study treatment in a participant who received study treatment. SAE was an AE resulting in death, initial or prolonged inpatient hospitalization, life-threatening experience, persistent or significant disability/incapacity, congenital anomaly. Treatment-emergent AEs were those with initial onset or that worsen in severity after the first dose of study medication. AEs were reported from signing of informed consent until 28 days after the last dose of study medication. SAEs were reported after this time frame if considered to be treatment related. The severity of AEs were graded by the investigator using NCI CTCAE v.4.02 and was assessed as Grade 0: no change from normal or reference range; Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening or disabling; Grade 5: death related to AE. However the below table included Grade 3, 4, and 5 AEs.
Measure: Overview of Treatment-emergent, Treatment-related AEs in Expansion Phase Time: Up to Maximum of treatment duration + 28 days for each participant (could be 295 days)Description: DLTs were those AEs which occurred in Cycle 1 of treatment in Dose Escalation Phase which may be attributed to study drug [combined Crizotinib (PF-02341066) plus Dacomitinib (PF-00299804)] without a clear alternative explanation and despite the use of adequate/maximal medical intervention as dictated by local institutional clinical practices or the judgment of the investigator. The following events were considered DLTs (using CTCAE version 4.02);1. Grade ≥4 hematologic events. 2. Grade ≥3 non-hematological events (except Grade 3/4 asymptomatic hypophosphatemia and Grade 3/4 hyperuricemia without signs and symptoms of gout). Nausea, vomiting or diarrhea had to have persisted at Grade 3 or 4 despite maximal medical therapy. Grade 3 hypertension will be considered a DLT only if the event is unmanageable by standard approved pharmacologic agents or if the symptomatic sequelae are identified despite appropriate medical intervention.
Measure: Number of Participants With Dose Limiting Toxicities (DLTs) in Escalation Phase Time: Cycle 1 (4 weeks)Description: If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) - 1.1 as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.
Measure: Number of Participants With Stable Disease and Stable Disease Duration in Escalation Phase Time: From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)Description: If a participant had not achieved an objective response with confirmed complete response (CR) or partial response (PR) according to RECIST (1.1) as determined by the investigators, relative to the response evaluable population, but remained stable for at least 6 weeks after first dose, then the best overall response for such a participant was considered as stable disease.
Measure: Number of Participants With Stable Disease and Stable Disease Duration in Expansion Phase Time: From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)Description: ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.
Measure: Number of Participants With Objective Response Rate (ORR) in Escalation Phase Time: From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)Description: ORR was defined as the percent of participants with CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) determined by study physicians, relative to the response evaluable population. Participants were considered non-responders until proven otherwise. Thus, participants who: 1) Did not have CR or PR while on study, or 2) Did not have a post-baseline tumor evaluation, or 3) Received anti-tumor treatment other than the study medication prior to reaching a CR or PR, or 4) Died, in progress, or drop out for any reason prior to reaching a CR or PR, were counted as non-responders in the assessment of ORR. To be assigned a status of PR or CR, changes in tumor measurements in participants with responding tumors were confirmed by repeated tumor assessment that were performed 4 weeks after the criteria for response were first met.
Measure: Number of Participants With ORR in Expansion Phase Time: From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)Description: This outcome measure presented the duration of response for one participant in expansion cohort 1 who showed partial response.
Measure: Duration of Response for the Only Participant Shown Partial Response in Expansion Phase Time: From objective response to date of progression or death due to any cause, whichever occurs first (up to post treatment follow-up as 28-35 days after last dose of study treatment)Description: PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.
Measure: Progression Free Survival (PFS) in Escalation Phase Time: From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment)Description: PFS was defined as the time from the date of the first dose to the date of the first documentation of objective tumor progression according to RECIST 1.1 or death on study due to any cause, whichever occurred first. If tumor progression data included more than 1 date, the first date was used.
Measure: Progression Free Survival (PFS) in Expansion Phase Time: From randomization to objective tumor progression or death (up to post treatment follow-up as 28-35 days after last dose of study treatment)Description: Tumor biomarkers such as HGF, EGFR, and c-Met were analyzed in tumor cells (neoplastic compartment) of tumor specimens from both expansion cohorts 1 and 2 by IHC. The H score was derived by summing the percentages of cells staining at each intensity multiplied by the weighted intensity of staining (0, 1+, 2+, 3+, where 3+ indicates the strongest staining, 2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no staining). Minimum calculated score of 0 to maximum calculated score of 300, where 0 correspond to no expression and maximum score of 300 indicates the strongest expression. However, the biomarker expression level (higher or lower) was not a predictor of outcome.
Measure: Expression Analysis of Tumor Biomarkers (HGF, EGFR, and c-Met ) at Baseline Using Immunohistochemistry (IHC) Method Time: BaselineDescription: Expression of tumor biomarkers EGFR and cMet at Baseline (using FISH method) are presented in this outcome measure.
Measure: Expression Analysis of Tumor Biomarkers (EGFR, and c-Met) at Baseline Using Fluorescent in Situ Hybridization (FISH) Method Time: BaselineDescription: Participants showed amplification of c-Met, HER2, and EGFR in the tumor cells and gene rearrangement of ALK are presented in this outcome measure.
Measure: Number of Participants With c-Met, HER2, EGFR Amplification and ALK Rearrangement at Baseline Using FISH Method Time: BaselineDescription: This outcome measure presented the plasma concentration of sMet at different study visits. s-Met was analyzed using an enzyme-linked immunosorbent assay (ELISA).
Measure: Plasma Concentration of sMet by Study Visits Time: At screening and Cycle 1 Day 1 (C1D1) (6 hours post dose), and C1D15, C2D1, C2D15 (all predose).Description: Sample analyses were performed in accordance to Good Laboratory Practice (GLP) guidance and included mutation detection for EGFR gene.
Measure: Number of Participants With EGFR Mutation at Baseline Time: BaselineDescription: Sample analyses were performed in accordance to GLP guidance and included mutation detection for KRAS gene.
Measure: Number of Participants With KRAS Mutation (GLY12CYS) at Baseline Time: BaselineDescription: Sample analyses were performed in accordance to GLP guidance and included mutation detection for PIK3CA gene.
Measure: Number of Participants With PIK3CA Mutation at Baseline Time: BaselineDescription: Sample analyses were performed in accordance to GLP guidance and included translocation detection (RNA based) for ROS1 gene.
Measure: Number of Participants With ROS1 Gene Translocation at Baseline Time: BaselineDescription: At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for crizotinib and PF-06260182. AUClast was calculated using Linear/Log trapezoidal method.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Profile From Time Zero to the Last Quantifiable Concentration (AUClast) Time: Cycle 1 (C1)/Day 1 (D1), C1D15Description: At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). AUC10 was calculated using Linear/Log trapezoidal method. The below analysis table included geometric Mean and Geometric Coefficient of Variation of AUC10 for crizotinib and PF-06260182. Arithmetic mean was presented if the n=2.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Area Under the Plasma Concentration-time Curve 10 (AUC10) Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for crizotinib and PF-06260182. Cmax was observed directly from data.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Maximum Plasma Concentration (Cmax) Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for crizotinib and PF-06260182. Tlast was observed directly from data.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase - Time of Last Quantifiable Concentration (Tlast) Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for pharmacokinetic (PK) analysis of crizotinib and its metabolite, PF 06260182 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for crizotinib and PF-06260182. Tmax was observed directly from data as time of first occurrence.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Escalation Phase -Time to Maximum Plasma Concentration (Tmax) Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUClast for dacomitinib and PF-05199265. AUClast was calculated using Linear/Log trapezoidal method.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUClast Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included AUC24 for dacomitinib and PF-05199265. AUC24 was calculated using Linear/Log trapezoidal method.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - AUC24 Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Cmax for dacomitinib and PF-05199265. Cmax was observed directly from data.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Cmax Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tlast for dacomitinib and PF-05199265. Tlast was observed directly from data.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tlast Time: C1D1, C1D15Description: At each designated time point, blood samples (3 mL) for PK analysis of dacomitinib and its metabolite, PF 05199265 were collected in appropriately labeled collection tubes containing dipotassium ethylenediamine tetra-acetic acid (K2EDTA). The below analysis table included Tmax for dacomitinib and PF-05199265. Tmax was observed directly from data as time of first occurrence.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Escalation Phase - Tmax Time: C1D1, C1D15Description: Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUClast. AUClast was calculated using Linear/Log trapezoidal method.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUClast Time: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)Description: Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for AUC10. AUC10 was calculated using Linear/Log trapezoidal method.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - AUC10 Time: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)Description: Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmin. Cmin was observed directly from data.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmin Time: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)Description: Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Cmax. Cmax was observed directly from data.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Cmax Time: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)Description: Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tlast. Tlast was observed directly from data.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tlast Time: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)Description: Participants were evaluated for the effect of dacomitinib on steady-state PK of crizotinib. PK of crizotinib alone was evaluated on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) after a lead in period of continuous BID dosing of crizotinib for approximately 12 days (±2 days). PK of crizotinib and dacomitinib in combination treatment was evaluated on Day 1 of Cycle 2. Blood samples for crizotinib full PK were to be collected on Day -1 and Day 1 of Cycle 2. The below table included PK data for Tmax. Tmax was observed directly from data as time of first occurrence.
Measure: Plasma Crizotinib and PF-06260182 Pharmacokinetic Parameter in Expansion Cohort 1 With or Without Co-administration of Dacomitinib - Tmax Time: Day -1 (crizotinib alone), C2D1 (crizotinib + dacomitinib)Description: PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUClast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUClast was calculated using Linear/Log trapezoidal method.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUClast Time: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)Description: PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (AUC24) following dacomitinib alone and in combination with crizotinib are summarized in the below table. AUC24 was calculated using Linear/Log trapezoidal method.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - AUC24 Time: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)Description: PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmin) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmin was observed directly from data.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmin Time: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)Description: PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Cmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Cmax was observed directly from data.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Cmax Time: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)Description: PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tlast) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tlast was observed directly from data.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tlast Time: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)Description: PK samples for full PK evaluation of dacomitinib were drawn on Day -1 (one day before C1D1 on which the combination treatment of crizotinib and dacomitinib started) and on C2D1. Dacomitinib and PF-05199265 PK parameter (Tmax) following dacomitinib alone and in combination with crizotinib are summarized in the below table. Tmax was observed directly from data as time of first occurrence.
Measure: Plasma Dacomitinib and PF-05199265 Pharmacokinetic Parameter in Expansion Cohort 2 With or Without Co-administration of Dacomitinib - Tmax Time: Day -1 (dacomitinib alone), C2D1 (crizotinib + dacomitinib)This phase II trial studies how well trametinib and docetaxel work in treating patients with stage IV KRAS mutation positive non-small cell lung cancer or cancer that has come back. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, 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 trametinib with docetaxel may work better in treating non-small cell lung cancer.
Response rate (confirmed and unconfirmed complete and partial responses) in all KRAS mutant patients (both those with G12C mutations and those with non-G12C mutations). --- G12C ---
Response rate (confirmed and unconfirmed complete and partial responses) in all KRAS mutant patients (both those with G12C mutations and those with non-G12C mutations). --- G12C --- --- G12C ---
Response rate in patients with a G12C mutation. --- G12C ---
SECONDARY OBJECTIVES: I. To evaluate if trametinib plus docetaxel is consistent with promise of activity measured by the response rate in G12C KRAS mutation positive NSCLC patients following one or two prior systemic therapies. --- G12C ---
To assess the response rate of this combination in non-G12C KRAS mutation positive NSCLC patients. --- G12C ---
To assess progression-free survival within the G12C and non-G12C KRAS positive subgroups and the entire study population. --- G12C ---
To assess progression-free survival within the G12C and non-G12C KRAS positive subgroups and the entire study population. --- G12C --- --- G12C ---
V. To assess overall survival within G12C positive patients, non-G12C positive patients, and the entire study population. --- G12C ---
V. To assess overall survival within G12C positive patients, non-G12C positive patients, and the entire study population. --- G12C --- --- G12C ---
Description: Progression free survival estimates will be calculated using the method of Kaplan-Meier. 95% confidence for the medians will be constructed using the method of Brookmeyer-Crowley.
Measure: Progression free survival 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 yearsDescription: Overall survival estimates will be calculated using the method of Kaplan-Meier. 95% confidence for the medians will be constructed using the method of Brookmeyer-Crowley.
Measure: Overall survival Time: Up to 3 yearsDescription: Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (CTCAE version 5.0 will be utilized for serious adverse event reporting only). Toxicity rates can be estimated to within +/- 14% with 95% confidence.
Measure: Incidence of toxicity Time: Up to 3 yearsDescription: The response rate between patients with dysfunctional p53 will be compared to the response rate in patients without p53 dysfunction.
Measure: Response rates in the presence of p53 mutations Time: Up to 3 yearsDescription: The response rate between patients with LKB1 disruption will be compared to the response rate in patients without LKB1 disruption. The response rate will be estimated by LKB1 disruption status (yes/no), along with 95% confidence intervals around the estimated proportions. This analysis will evaluate if disruption in LKB1 is associated with a lower probability of response.
Measure: Response rates in the presence of LKB1 mutations Time: Up to 3 yearsThe purpose of this first in human (FIH) trial is to characterize the safety and tolerability of the SHP2 inhibitor TNO155 and identify a recommended dose for future studies in adult patients with advanced solid tumors in selected indications.
(Exceptions are KRAS G12C CRC and KRAS G12C NSCLC) 2. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. 3. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures. --- G12C ---
(Exceptions are KRAS G12C CRC and KRAS G12C NSCLC) 2. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. 3. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures. --- G12C --- --- G12C ---
Advanced EGFRmutant NonSmallSellLungCancer (NSCLC),KRAS G12C NSCLC,CRC,Esophageal SquamousCellCancer (SCC),Head/Neck SCC,RAS/RAF Wild-type Other Solid Tumor This study has been designed as a Phase I, open-label, dose finding study with a dose escalation part and a dose expansion part in adult patients with selected advanced solid tumors. --- G12C ---
Description: All patients participating in this study will be assessed for incidence and severity of adverse events (AEs) and serious AEs, including changes in laboratory values, vital signs, electrocardiograms, cardiac imaging and ophthalmological assessments
Measure: Number of participants with adverse events Time: up to 3 years; at least once per treatment cycleDescription: Incidence and nature of dose limiting toxicities (DLTs) in the dose escalation part. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first treatment cycle (either 21 days or 28 days, depending on the cohort's treatment schedule) with TNO155
Measure: Number of participants with dose limiting toxicities Time: up to 28-day cycleDescription: Area under the plasma concentration time curve of TNO155
Measure: Area under the curve Time: 30 monthsDescription: To evaluate the preliminary anti-tumor activity of TNO155, e.g., overall response rate per RECIST 1.1
Measure: Overall response rate Time: From start of treatment for 34 monthsDescription: On treatment versus baseline comparison of pharmacodynamic markers e.g., pERK (Phosphorylated form of Extracellular signal-regulated kinase) on newly obtained tumor samples by IHC
Measure: pERK Time: At screening and between Cycle 1 and Cycle 3 on treatment for 30 monthsDescription: highest observed plasma concentration of TNO155
Measure: Cmax Time: 30 monthsDescription: Time of highest observed plasma concentration of TNO155
Measure: tmax Time: 30 monthsDescription: terminal elimination half-life of TNO155
Measure: apparent terminal elimination half-life Time: 30 monthsThe purpose of this study is to determine whether carboplatin-paclitaxel-bevacizumab results in a prolonged progression free survival compared to cisplatin-pemetrexed as first line treatment in patients with KRAS mutated non-small cell lung cancer.
Stratification for KRAS mutation (G12V versus G12C versus other). --- G12V --- --- G12C ---
outcome between G12V versus G12C versus other subtypes of KRAS mutations (mutational analysis on plasma and blood platelets).. --- G12V --- --- G12C ---
The two most common KRAS types are G12C in about 40% of cases, G12V in 18% and G12D in 15% of cases. --- G12C ---
Stratification for KRAS mutation (G12V versus G12C versus other) at randomization.. response by Crabb criteria (if applicable). --- G12V --- --- G12C ---
Description: Stratification for KRAS mutation (G12V versus G12C versus other)
Measure: overall survival Time: date of randomization to the date of death from any cause, assessed up to 60 months.Description: The two most common KRAS types are G12C in about 40% of cases, G12V in 18% and G12D in 15% of cases. Subgroup analyses are planned to explore treatment effect in these different KRAS mutations groups. At baseline the metastatic patterns of these subgroups will be described. KRAS mutations in NSCLC occur mainly in codon 12 and 13. Stratification for KRAS mutation (G12V versus G12C versus other) at randomization.
Measure: outcome between G12V versus G12C versus other subtypes of KRAS mutations (mutational analysis on plasma and blood platelets). Time: date of randomization to the date of death from any cause, assessed up to 60 months.