This phase I/II trial investigates the best dose and side effects of tazemetostat and how well it works in combination with dabrafenib and trametinib in treating patients with melanoma that has a specific mutation in the BRAF gene (BRAFV600) and that has spread to other places in the body (metastatic). Tazemetostat, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving tazemetostat with dabrafenib and trametinib may help treat patients with BRAFV600 mutated melanoma.
Name: Dabrafenib Mesylate
Name: Tazemetostat Hydrobromide
Name: Trametinib Dimethyl Sulfoxide
Description: Data analysis will be descriptive in nature, and will be determined using the standard 3+3 algorithm. Toxicities by grade, number of cycles administered, and response to treatment will be listed for each dose level.
Measure: Recommended phase 2 dose (R2PD) (Phase 1) Time: Up to 3 yearsDescription: Median PFS in each arm will be assessed using Kaplan-Meier product limit methods and the randomized arms will be compared using log-rank test (at 0.15 one-sided significance level) when 36 PFS events are observed.
Measure: Median progression-free survival (PFS) in Arm 1 and 2 (Phase 2) Time: At 6 and 12 monthsDescription: Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and 95% confidence intervals will be calculated.
Measure: Overall response rates (complete response [CR], partial response [PR]) Time: Up to 3 yearsDescription: Will be estimated in each arm using Kaplan-Meier product limit methods, and its 95% confidence interval will be calculated.
Measure: Overall survival Time: Up to 3 yearsDescription: Toxicity evaluation will be descriptive, and standard toxicity definitions and criteria will be used as outlined in the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity. If appropriate, confidence intervals will be used to characterize the precision of the estimate. A complete listing of adverse events will also be tabulated, and will provide details including severity, relationship to treatment, onset, duration, and outcome. Laboratory data measured on a continuous scale will be characterized by summary statistics (mean and standard deviation).
Measure: Incidence of adverse events Time: Up to 3 yearsAllocation: Randomized
Sequential Assignment
There is one SNP
JAK2 V617F) observed in cytogenetic testing and DNA sequencing - History of T-lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) - Patients with history of RAS mutation-positive tumors are not eligible regardless of interval from the current study. --- V617F ---