Last updated on November 2018

Dabrafenib and Trametinib Followed by Ipilimumab and Nivolumab or Ipilimumab and Nivolumab Followed by Dabrafenib and Trametinib in Treating Patients With Stage III-IV BRAFV600 Melanoma


Brief description of study

This randomized 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. Ipilimumab and nivolumab may block tumor growth by targeting certain cells. 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.

Detailed Study Description

PRIMARY OBJECTIVES:

I. To determine whether initial treatment with either combination ipilimumab + nivolumab (with subsequent dabrafenib in combination with 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 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 of treatment after cross-over without intervening symptomatic disease progression or treatment limiting toxicity).

VII. Association of inherited variation with immune mediated adverse events and response to ipilimumab + nivolumab.

VIII. 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.

IX. 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.

X. 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.

XI. 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.

XII. 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.

XIII. 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.

XIV. 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.

XV. 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 vs crossover treatment).

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) IV. 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.

V. To describe the frequency and severity of treatment toxicities at baseline, 6 weeks, 12 weeks, and 6 months after initiation of each treatment.

TERTIARY 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.

OUTLINE: Patients are randomized to 1 of 2 treatment arms (Arm A or Arm B).

ARM A:

IMMUNOTHERAPY INDUCTION (COURSES 1-2): Patients receive nivolumab intravenously (IV) over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm C.

ARM C: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive dabrafenib PO BID and trametinib PO daily on days 1-42. Courses repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Upon disease progression, patients re-register and cross over to Arm D.

ARM D:

IMMUNOTHERAPY INDUCTION (COURSES 1-2): Patients receive nivolumab IV over 60 minutes and ipilimumab IV over 90 minutes on days 1 and 22. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

IMMUNOTHERAPY MAINTENANCE (COURSES 3-14): Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29. Treatment repeats every 6 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Clinical Study Identifier: NCT02224781

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UPMC Washington Hospital Radiation Oncology
Washington, PA United States
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