This phase II trial studies the side effects and how well nivolumab with trametinib and dabrafenib, or encorafenib and binimetinib work in treating patients with BRAF-mutated stage III-IV melanoma that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Trametinib, dabrafenib, encorafenib, and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known if nivolumab with trametinib and dabrafenib, or encorafenib and binimetinib may work better in treating patients with BRAF-mutated melanoma.
PRIMARY OBJECTIVE: I. To determine the safety, tolerability, and efficacy (objective response rates by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) of nivolumab in combination with dabrafenib and trametinib or encorafenib and binimetinib in patients with BRAF-mutated metastatic melanoma. SECONDARY OBJECTIVES: I. Safety and tolerability of the nivolumab, dabrafenib, and trametinib triplet combination (NDT). II. Safety and tolerability of the nivolumab, binimetinib and encorafenib. III. Efficacy of the combination as measured by the depth and duration of response by RECIST 1.1 and modified RECIST 1.1 (to include intracranial response). IV. Pharmacodynamic evaluation of combination on circulating markers (immune monitoring). V. Pharmacodynamic evaluation of combination on tumor tissues. VI. Progression- free survival and overall survival. OUTLINE: Patients are assigned to 1 of 3 arms. ARM A (NDT, CLOSED): Patients receive nivolumab intravenously (IV) over 30 minutes on day 1, dabrafenib orally (PO) twice daily (BID) on days 1-28, and trametinib PO once daily (QD) on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. ARM B (NT, CLOSED TO ACCRUAL): Patients receive nivolumab IV over 30 minutes on day 1 and 15, and trametinib PO QD on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. ARM C (NEB): Patients receive nivolumab IV over 30 minutes on day 1 and 15, encorafenib PO QD on days 1-28, and binimetinib PO BID on days 1-28. Cycles repeats every 28 days for up to 3 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days then every 3 months for up to 3 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
52
Given PO
Given PO
Given PO
Correlative studies
Given IV
Correlative studies
Given PO
M D Anderson Cancer Center
Houston, Texas, United States
Objective response rate (ORR) as measured by Response Evaluation Criteria in Solid Tumors version 1.1 on both arms
The ORR for each treatment group will be computed along 95% credible intervals.
Time frame: From the time of initial response until documented tumor progression, assessed up to 3 years
Incidence of adverse events assessed using National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0
The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade. Will describe all dose limiting toxicities and other serious (\>= grade 3) on a patient-by-patient basis; descriptions will include dose level and any relevant baseline data. Statistics on the number of cycles received by patients and any dose reductions will be tabulated.
Time frame: Up to 3 years
Complete response
Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
Time frame: Up to 3 years
Partial response
Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
Time frame: Up to 3 years
Incidence of stable disease
Will be tabulated by disease diagnosis and by dose level; no formal statistical analyses are planned.
Time frame: From the start of the treatment until the criteria for progression are met, assessed up to 3 years
Overall survival (OS)
The Kaplan-Meier method will be used to estimate OS. Associations between OS and clinical measures of interest will be determined using Cox proportional hazards regression models.
Time frame: From treatment start date to last known vital sign, assessed up to 3 years
Progression-free survival (PFS)
The Kaplan-Meier method will be used to estimate PFS. Associations between PFS and clinical measures of interest will be determined using Cox proportional hazards regression models.
Time frame: From treatment start date to date of disease progression or death or the last evaluation date, assessed up to 3 years
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