This phase III trial studies how well initial treatment with ipilimumab and nivolumab followed by dabrafenib and trametinib works and compares it to initial treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab in treating patients with stage III-IV melanoma that contains a mutation known as BRAFV600 and cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as ipilimumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Dabrafenib and trametinib may block tumor growth by targeting the BRAFV600 gene. It is not yet known whether treating patients with ipilimumab and nivolumab followed by dabrafenib and trametinib is more effective than treatment with dabrafenib and trametinib followed by ipilimumab and nivolumab.
PRIMARY OBJECTIVE: I. To determine whether initial treatment with either combination ipilimumab + nivolumab (with subsequent dabrafenib mesylate \[dabrafenib\] in combination with trametinib dimethyl sulfoxide \[trametinib\]) or dabrafenib in combination with trametinib (with subsequent ipilimumab + nivolumab) significantly improves 2 year overall survival (OS) in patients with unresectable stage III or stage IV BRAFV600 mutant melanoma. SECONDARY CLINICAL OBJECTIVES: I. To evaluate the impact of initial treatment on median OS and hazard ratio for death. II. To determine whether initial treatment choice significantly improves 3 year OS. III. To evaluate the anti-tumor activities (Response Evaluation Criteria in Solid Tumors \[RECIST\]-defined response rate, median progression-free survival \[PFS\]) and safety profiles of ipilimumab + nivolumab and dabrafenib-trametinib in a Cooperative Group trial of patients with V600 mutant melanoma. IV. To evaluate the activity (RECIST-defined response rate, median PFS) and safety of dabrafenib + trametinib in patients who have had disease progression on ipilimumab + nivolumab and in comparison to its activity and safety in ipilimumab + nivolumab naive patients. V. To evaluate the activity of ipilimumab + nivolumab (RECIST-defined response rate, median PFS) and safety in patients who have had disease progression on dabrafenib + trametinib and in comparison to its activity and safety in dabrafenib + trametinib naive patients. VI. To assess the feasibility of crossover to the alternative treatment strategy (percentage of patients who are able to crossover from one arm to the other and complete at least an initial course \[12 weeks\] of treatment after cross-over without intervening symptomatic disease progression or treatment limiting toxicity). SECONDARY LABORATORY OBJECTIVES: I. Association of inherited variation with immune mediated adverse events and response to ipilimumab + nivolumab. Ia. To determine the association of inherited genetic variation and immune-associated adverse events in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines, cytokine receptors and within the major histocompatibility complex (MHC) region and an agnostic genome-wide single nucleotide polymorphism (SNP)-based approach; Ib. To investigate the association between inherited genetics and survival in patients with metastatic melanoma treated with ipilimumab containing regimens by completing candidate-based gene and pathway analyses of genes involved in lymphocyte activation, cytokines profile, cytokine receptors and within the MHC region and an agnostic genome-wide SNP-based approach; Ic. To replicate genomic markers identified in the above aims in an independent sample set of patients treated with ipilimumab containing regimens and preliminarily characterize their potential functional role by completing replication of variation as associated with immune-related adverse events (irAEs) and survival and bio-informatic assessment of genomic markers. II. To determine the utility of circulating BRAF levels in determining the response and resistance to either BRAF/MEK directed and/or combination immunotherapy in patients with BRAF mutant melanoma. IIa. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600 mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and resistance to combination BRAF/MEK directed therapy; IIb. To determine if changes in blood BRAF levels utilizing peripheral blood BRAFV600 mutational testing in patients with stage IV BRAF mutant melanoma correlate with response and resistance to combination immunotherapy; IIc. To compare the kinetics of peripheral blood BRAFV600 levels during response and resistance in groups of patients receiving BRAF targeted therapy or combination immunotherapy as initial therapy; IId. To compare the kinetics of peripheral blood BRAFV600 levels during response and resistance to combination BRAF targeted therapy or combination immunotherapy in individual patients (initial treatment versus \[vs\] crossover treatment). SECONDARY PATIENT REPORTED OUTCOMES OBJECTIVES: I. To evaluate differences in overall health between initial treatment arms (dabrafenib + trametinib vs. ipilimumab + nivolumab immunotherapy) at 2 years, accounting for toxicities and overall survival. (Primary) II. To assess differences in overall function over 2 years between initial treatment with dabrafenib + trametinib vs. ipilimumab + nivolumab. (Secondary) III. To document the effects of treatment crossover and treatment administration sequence on symptom burden and overall function. (Secondary) IIIa. To compare differences in function and symptoms by treatment sequence for ipilimumab + nivolumab (arm A vs. D), and dabrafenib + trametinib, (arm B vs. C) at baseline, 6 weeks, 12 weeks, and 6 months after the initiation of each treatment; IIIb. To describe the frequency and severity of treatment toxicities at baseline, 6 weeks, 12 weeks, and 6 months after initiation of each treatment. EXPLORATORY TOBACCO USE OBJECTIVES: I. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events \[both clinical and hematologic\] and dose modifications). II. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms. III. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization. IV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit. EXPLORATORY CORRELATIVE OBJECTIVES: I. To assess serum based biomarkers of efficacy and adverse events due to treatment with immune checkpoint inhibitors. II. To monitor tumor response by comparing changes in circulating cell-free mutant tumor deoxyribonucleic acid (DNA) (ctDNA) as a readout of tumor burden (a) at week 12 relative to baseline before treatment in responders and non-responders; (b) before and during immunosuppressive treatment to control irAEs. III. To monitor organ-specific adverse events (irAEs) using circulating cell-free, tissue-specific methylated DNA (cmeDNA) as a readout of tissue-specific toxicity (a) at the time of grade 3-4 irAE relative to baseline and control patients without irAEs; (b) during immunosuppressive treatment for irAEs. OUTLINE: Patients are randomized to 1 of 2 treatment arms (Arm A or Arm B). ARM A: IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab intravenously (IV) over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Upon disease progression (or before), patients re-register and cross over to Arm C. ARM C: Patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO daily on days 1-42. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression (or before), patients re-register and cross over to Arm D. ARM D: IMMUNOTHERAPY INDUCTION (CYCLES 1-2): Patients receive nivolumab IV over 30-60 minutes and ipilimumab IV over 30-90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 cycles in the absence of disease progression or unacceptable toxicity. IMMUNOTHERAPY MAINTENANCE (CYCLES 3-14): Patients receive nivolumab IV over 30-60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 cycles in the absence of disease progression or unacceptable toxicity. All patients also undergo computed tomography (CT), echocardiography (ECHO) or multigated acquisition scan (MUGA), and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
267
Undergo collection of blood samples
Undergo CT
Given PO
Undergo ECHO
Given IV
Undergo MUGA scan
Given IV
Ancillary studies
Given PO
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Anchorage Associates in Radiation Medicine
Anchorage, Alaska, United States
Anchorage Radiation Therapy Center
Anchorage, Alaska, United States
Alaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
Overall survival (OS) rate
Defined as the proportion of patients alive after 2 years of follow-up time. Will be estimated and compared between the two arms using the Mantel-Haenszel test based (stratified by Eastern Cooperative Oncology Group \[ECOG\] performance status \[PS\] and lactate dehydrogenase \[LDH\]) based on two-sided overall type I error rate of 0.05 adjusting for two-interim analysis. Mantel-Haenszel test will compare the 2-year OS rates while controlling for the stratification factors. The difference in 2-year OS rates in arms A and B will be estimated and presented with 95% repeated confidence interval of Jennison-Turnbull. In addition, OS distribution will be estimated using the Kaplan-Meier method. The distribution of OS will be compared using the stratified log rank test. Hazard of OS will be estimated as a function of time in arm A and in arm B (as randomized in step 1 to arm A versus B) and presented graphically.
Time frame: The time from randomization to death from any cause, assessed for up to 2 years
Progression-free survival (PFS)
Evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Distribution will be estimated using the Kaplan-Meier method. PFS will be compared using the log-rank test.
Time frame: The time from randomization to disease progression or death (whichever occurs first), assessed up to 5 years
Response rate
According to RECIST 1.1. Response rates will be compared using the Mantel-Haenszel test (stratified by ECOG PS and LDH) test in arms A vs. B. Response rate for patients who are treated with ipilimumab/nivolumab before crossover (arm A) vs. for patients who were initially treated with dabrafenib/trametinib and crossed over to ipilimumab/nivolumab will be compared (arm D). Response rates will be compared using the Fisher's exact test.
Time frame: Up to 5 years
Toxicity rate for individual adverse events (AEs)
Will be assessed using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4.0. Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.
Time frame: Up to 5 years
Toxicity rate for categorized AEs
Will be assessed using CTCAE v 4.0. Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.
Time frame: Up to 5 years
Toxicity rate for worst degree AEs
Will be assessed using CTCAE v 4.0. Compared using the chi-square of Fisher's exact test. Two-sided p-values will be reported for these comparisons.
Time frame: Up to 5 years
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