This is a single arm phase II trial focused on how dabrafenib and trametinib before and after surgery works in treating patients with stage IIIB-C melanoma that has a specific mutation in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib and trametinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving dabrafenib and trametinib after surgery may kill any remaining tumor cells.
Name: Dabrafenib
Description: Given POType: DrugTreatment (dabrafenib, trametinib, surgery)
Name: Laboratory Biomarker Analysis
Description: Correlative studiesType: OtherTreatment (dabrafenib, trametinib, surgery)
Name: Therapeutic Conventional Surgery
Description: Undergo surgeryType: ProcedureTreatment (dabrafenib, trametinib, surgery)
Name: Trametinib
Description: Given POType: DrugTreatment (dabrafenib, trametinib, surgery)
Description: RFS will be compared between patients with a pathologic complete response (pCR) and patients without a pCR using a two-sided log-rank test.
Measure: Relapse-free survival (RFS) Time: Up to 12 monthsDescription: The association between RFS and OS and covariates of interest will be assessed using Cox proportional hazards regression analysis.
Measure: Overall survival (OS) Time: Up to 1 yearDescription: Logistic regression will be used to assess the association between the probability of complete pathologic response and clinical and disease covariates of interest.
Measure: Complete pathologic response Time: Up to 1 yearDescription: Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.
Measure: Incidence of adverse events Time: Up to 1 yearSingle Group Assignment
There are 2 SNPs
Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.. Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E ---
uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E ---
uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency BRAF V600E Mutation Present BRAF V600K Mutation Present Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Study enrollment was stopped in April 2016 due to a substantial improvement in RFS in Arm B vs Arm A treated patients. --- V600E ---
Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.. Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E --- --- V600K ---
uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency Inclusion Criteria: - Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form - Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable; multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team - Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team - BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory - Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 - Eastern Cooperative Oncology Group (ECOG) performance status 0-1 - Absolute neutrophil count (ANC) >= 1.5 x 10^9/L - Hemoglobin >= 9.5 g/dL - Platelets >= 100 x 10^9/L - Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) - Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN ^1 - Albumin >= 2.5 g/dL - Creatinine =< 1.5 x ULN 2 OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min - Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. --- V600E --- --- V600K ---
uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) - Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs - Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug - Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) - Uncontrolled arrhythmias - Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Pregnant or lactating female - Unwillingness or inability to follow the procedures required in the protocol - Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity - Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency BRAF V600E Mutation Present BRAF V600K Mutation Present Stage IIIB Cutaneous Melanoma AJCC v7 Stage IIIC Cutaneous Melanoma AJCC v7 Melanoma Skin Neoplasms PRIMARY OBJECTIVES: I. Study enrollment was stopped in April 2016 due to a substantial improvement in RFS in Arm B vs Arm A treated patients. --- V600E --- --- V600K ---