SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT02097225

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

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
MeSH: Neoplasms Melanoma Skin Neoplasms
HPO: Cutaneous melanoma Melanoma Neoplasm Neoplasm of the skin

5 Interventions

Name: Dabrafenib

Description: Given PO

Type: Drug

Treatment (dabrafenib, trametinib, onalespib)

Name: Laboratory Biomarker Analysis

Description: Correlative studies

Type: Other

Treatment (dabrafenib, trametinib, onalespib)

Name: Onalespib

Description: Given IV

Type: Drug

Treatment (dabrafenib, trametinib, onalespib)

Name: Pharmacological Study

Description: Correlative studies

Type: Other

Treatment (dabrafenib, trametinib, onalespib)

Name: Trametinib

Description: Given PO

Type: Drug

Treatment (dabrafenib, trametinib, onalespib)


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)

Purpose: Treatment

Single Group Assignment


There are 2 SNPs

SNPs


1 V600E

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 ---


2 V600K

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 --- --- V600K ---



HPO Nodes


HPO:
Cutaneous melanoma
Genes 11
BRAF HRAS XPC CDKN2A POLH ERCC3 BAP1 CXCR4 MC1R NRAS WRN
Melanoma
Genes 64
RAD51 RAD51C TYR RAD51D CDKN2A KRAS CDKN2B RAF1 CDKN2D MRE11 CYSLTR2 ERCC2 KLLN PTPN11 ERCC3 BRIP1 ERCC4 ERCC5 ERCC6 SF3B1 NRAS MGMT BRCA1 MBTPS2 BRAF ACD BRCA2 PIK3CA CXCR4 CTSC POLH POT1 MC1R MITF WRN CHEK2 HRAS BARD1 NBN AKT1 SLC45A2 GNA11 TRPV3 XPA OCA2 XPC GNAQ PTEN MDM2 TERT DDB2 RNF43 PALLD PALB2 TERF2IP SEC23B TP53 SDHB SDHC SDHD SMAD4 BAP1 CDK4 RAD50
Neoplasm
Genes 762
CDKN1A CDKN1B CDKN1C CDKN2A HFE CDKN2B CDKN2C GDF5 TSR2 CDKN2D H19-ICR TMEM67 RPL26 RPL27 TREX1 ASXL1 ERBB2 SCN11A POU6F2 ERCC2 RPL35A ERCC3 BRIP1 ERCC4 ABL1 ERCC5 CEBPA ERCC6 PDE6D GCM2 CEL PDGFB PDGFRA PDGFRL MNX1 PDGFRB LEMD3 ENPP1 CTSC ESR1 HLA-DRB1 SLC26A4 MAX APC2 RPS7 TMC6 TMEM216 TRPS1 ACTB RPS10 MC1R MC2R BLNK RPS14 RPS15A ACTG2 ETV6 TCIRG1 DNAJC21 EVC HMBS L2HGDH RPS17 MCM4 RPS19 RPS20 TSC1 TSC2 EWSR1 EXT1 EXT2 RPS24 RPS26 RPS27 ACVR1 EYA1 RPS28 RPS29 MAGT1 ACVRL1 MDH2 MDM2 ADA HNF4A ADAR TRIP13 LYST PICALM ALX4 F13A1 TERF2IP PHF21A F13B RYR1 MAP3K1 AXIN1 TBC1D24 AXIN2 BAP1 CHRNG TWIST1 MEN1 TNFRSF4 FANCA FANCC FANCD2 FANCE TYR GFI1B FAH MET TYROBP FANCB FANCF FANCG SERPINA1 ARID1B SAMD9L AP2S1 MGAT2 DLC1 ICOS DMRT3 SFTPA2 PIGA MGMT MBTPS2 CLCNKB HOXD13 PIK3CA PIK3R1 ACAN FDPS HPGD JAG1 RNASEH2C RECQL4 SCN4A HACE1 RAD54B NR0B1 MITF AHCY GPC4 SCN9A SCN10A HRAS MLF1 MLH1 CTHRC1 TJP2 GTF2H5 FGF3 CC2D2A ANTXR1 LMOD1 PLAG1 FGF8 COL14A1 AKT1 NOP10 ASPSCR1 FGFR1 PLCB4 FGFR3 PLCD1 FGFR2 HAX1 MMP1 MAD2L2 UROD FH MN1 ALK HSPA9 SEC23B SEC23A CARD14 SDHA RAD54L SDHB SDHC SDHD FOXI1 COL1A1 FOXC2 COL2A1 FOXE1 MPL VEGFC ALX3 PMS1 FOXO1 VHL COL4A5 FLI1 MRE11 HSPG2 FLNA KLF11 COL7A1 PIGL SEMA3C BIN1 FLT3 PMS2 FLT4 COL11A2 CIB1 CCDC22 WAS COMP FN1 WIPF1 OFD1 KLF6 ADAMTS3 RNASEH2A LIN28B SFTPC CTC1 PUF60 WHCR NSD2 PPM1D NELFA MAP3K8 INPP5E POLD1 POLE WNT5A POLH GNPTAB SH3GL1 POT1 SH3KBP1 FERMT1 POLR1C WRN TUBB KCNAB2 WT1 APC IKBKG SHH PORCN SHOX BIRC3 POU2AF1 XIAP NLRP1 SAMHD1 XPA MSH2 CHD7 XPC MSH3 ZSWIM6 IDH1 MINPP1 IDH2 TMEM107 TXNRD2 XRCC2 XRCC4 SIX1 SIX3 FANCM SKI FAS FCN3 NHP2 FASLG CR2 CTSA TMEM127 CREB1 CREBBP AR ZAP70 ABCC6 CRKL ZIC2 FAN1 MSR1 MST1 PPP2R1B SETD2 C2CD3 MLH3 PIEZO2 IGF2 ARSA IGF2R MTAP MMEL1 STS GNA14 PMVK SLC12A3 COX1 COX2 UBE2T COX3 IGH SLC17A9 DYNC2LI1 PRCC ELMO2 ASCL1 PRF1 TP63 SLCO2A1 IGHM MTM1 ND1 SETBP1 ND4 ND5 ND6 SNAI2 PTCH2 RNR1 MPLKIP PRKAR1A SMARCB1 ABCB11 WNT10A FLCN SMARCD2 APPL1 PRKCD FOXP1 TRNF C11ORF95 CTBP1 SMO NR5A1 TRNH CTLA4 TRNK IGLL1 TRNL1 ATM RERE MAPK1 CTNNB1 TRNP TRNQ TRNS1 TRNS2 TRNW KDSR SUFU MAP2K1 MAP2K2 CEP57 FZD2 PRDM16 IL2RG G6PC SLC37A4 STAG3 PALLD TRIM37 SLX4 PRLR MUTYH H19 MVD IL7 MVK IL7R SOS1 MYC SOX2 GABRD CYLD MYCN TET2 SOX9 MYD88 IL12A IL12RB1 MYF6 TCTN3 ATP6V1B2 INTU MYH8 MYH11 SAMD9 ATP7A DIS3L2 ATP7B PSAP WWOX MYLK HDAC4 ATR SPIB ACD ATRX SPINK1 ING1 TNFSF12 RTEL1 INHBA PSENEN INS GJB4 CYP11B1 CYP11B2 GJB6 ARHGAP26 KIF1B MAFA RNF113A SRC GAS1 GATA1 CPLX1 GATA2 GATA4 PDX1 BARD1 GBA CDH23 SRP54 FGFRL1 IRF1 NBN SRP72 IRF5 DAXX SRY GCGR CCND1 BCL2 SMARCAD1 GCK NDP KEAP1 TNFRSF10B BCL6 RB1CC1 DCC GPR101 PTCH1 PTEN GDF2 SSX1 BCR SSX2 ADA2 NSUN2 NEK9 DDB2 GDNF DPM1 GINS1 RNF43 GFI1 PTH1R STAR BDNF NAGS STAT1 ITK STAT3 KIAA0753 NOD2 BLK BLM NUTM1 JAK2 STK4 IFIH1 GJA1 STK11 MALT1 NEK1 PTPN3 FAM20C BMPR1A BMPR1B GJB2 GJB3 CCM2 PTPN11 ARL6IP6 KARS NEUROD1 NF1 ANTXR2 DHH GPC3 BRCA1 BRAF BRCA2 NF2 TINF2 SDHAF2 WASHC5 KCNH1 CXCR4 SQSTM1 GLI1 GLI2 GLI3 ABCC8 NBEAL2 DHCR7 DHCR24 KCNJ10 NFKB1 BTK KCNJ11 NFKB2 BUB1 CYP26C1 BUB1B VAMP7 TMC8 MFN2 DKC1 KCNQ1 C1S GNA11 KDR TRPV3 BCL10 DLEC1 GNAI3 GNAQ CDC73 BMPER GNAS SEMA4A GNB1 NME1 TMEM231 FOXH1 PHOX2B CPLANE1 MAPRE2 NODAL TAL1 KIT TAL2 KCNQ1OT1 TNFSF15 DNASE1L3 NOTCH1 NOTCH3 KIF11 CDON DNM2 DNMT3A PNP RAD21 TBX2 RAD51 RAD51C RNASEH2B RAD51D KRAS NPM1 RAF1 KRT1 RAG1 RAG2 CACNA1S KRT5 TCF4 KRT6B EFL1 HNF1A FAT4 HNF1B KRT9 TCF3 CYSLTR2 KRT10 KRT14 EVC2 KCNE3 RARA RPGRIP1L KRT16 CARMIL2 NRAS SRD5A3 KRT17 SASH1 RASA1 RHBDF2 SH2B3 USB1 RB1 TCOF1 NRTN DOCK8 DYNC2H1 CALR GPR35 SLC26A2 NTHL1 NTRK1 MYO1H NUMA1 DVL1 ASCC1 DVL3 NSD1 LAMA3 AGGF1 GPR143 CASP8 B3GALT6 LAMB3 CASP10 GJC2 NR4A3 CASR LAMC2 FANCL RELA OCA2 TDGF1 NUP214 OCRL AIP REST RET MLLT10 RUNX1 WRAP53 CBFB ECE1 GPC6 DLL1 TEK CBL TERC ECM1 AAGAB TERT OGG1 TFAP2A DICER1 WDPCP PALB2 EDN1 LETM1 OPCML MSTO1 EDN3 EDNRB TFE3 ZFPM2 RFWD3 KRIT1 KIF7 SIX6 TG RAD50 ESCO2 VANGL2 RMRP TBX18 TGFBR2 POLR1D SLC22A18 TGIF1 MSH6 COL18A1 USP8 RASGRP1 LIG4 SEMA3D GTF2E2 KLLN RNASEL THPO SF3B1 HMGA2 ALX1 LMNA RNF6 CD19 MS4A1 MTMR14 EGFR LMO1 DCLRE1C ABCA5 LZTS1 LMX1B CD27 TRIM28 CD28 VANGL1 CCBE1 SBDS FANCI BRD4 SLC25A13 MRAP ARMC5 LPP SLC49A4 CHEK2 TREM2 TNFRSF13C FIBP LRRC8A ELANE TNFRSF13B LRP5 CD70 SPRED1 CD79A CD79B CD81 SLC45A2 PRKN PARN HABP2 TAF15 PAX3 EIF2AK4 PAX4 RPL35 PAX6 GREM1 PAX7 SPRTN TNFRSF1B BUB3 KAT6B HBB PDCD10 RNF139 SH2D1A ENG CDH1 EPCAM RSPO1 NNT RPL5 TNPO3 CD96 EP300 DISP1 TOP2A TP53 RPL10 RPL11 SMAD4 RPL15 CDK4 RPL18
Neoplasm of the skin
Genes 171
VEGFC ALX3 CDKN1A PMS1 CDKN1B CYLD CDKN2A KRAS CDKN2B CDKN2C KRT1 KRT5 COL7A1 KRT6B KRT9 TCF3 PMS2 ERCC2 FLT4 KRT14 ERCC3 CIB1 ERCC4 ERCC5 KRT16 CARMIL2 WWOX NRAS KRT17 SASH1 RASA1 PDGFB PDGFRA ING1 PDGFRB DOCK8 PSENEN GJB4 NTHL1 CTSC GJB6 POLH RNF113A TMC6 FERMT1 MC1R WRN BLNK APC IKBKG LAMA3 GPR143 PORCN LAMB3 CASP10 NLRP1 GJC2 LAMC2 RPS20 TSC1 TSC2 XPA MSH2 OCA2 XPC MSH3 OCRL KEAP1 TNFRSF10B DCC PTCH1 WRAP53 PTEN MDM2 FAS FCN3 FASLG TERC ECM1 TERT DDB2 DICER1 STAT1 BAP1 MEN1 FAN1 TNFRSF4 BLM TYR NUTM1 STK4 RMRP TGFBR2 GJA1 MSH6 RASGRP1 BMPR1A GTF2E2 GJB2 GJB3 KLLN MLH3 NF1 GNA14 PMVK MBTPS2 LMNA BRAF RNF6 NF2 TINF2 DCLRE1C SLC17A9 LZTS1 PIK3CA CD28 CXCR4 PIK3R1 FDPS HPGD SLCO2A1 IGHM BRD4 RECQL4 SNAI2 CHEK2 TMC8 HRAS PTCH2 MLH1 MPLKIP PRKAR1A GTF2H5 LRRC8A WNT10A DKC1 FLCN PRKCD SPRED1 CD79A CD79B AKT1 SLC45A2 SMO TRPV3 FGFR1 CTLA4 PLCD1 IGLL1 MMP1 SEMA4A CTNNB1 TNFRSF1B FH KDSR SUFU KIT EPCAM RSPO1 SLX4 SEC23B MUTYH MVD TP53 IL7 MVK NOTCH3 SDHB SDHC SDHD COL1A1