Testing the Addition of the Anti-cancer Drug, Tazemetostat, to the Usual Treatment (Dabrafenib and Trametinib) for Metastatic Melanoma That Has Progressed on the Usual Treatment

PRIMARY OBJECTIVES:

1. To identify a maximum tolerated dose for the EZH2 inhibitor, tazemetostat hydrobromide (tazemetostat), when used in combination with dual BRAF inhibitor (dabrafenib mesylate [dabrafenib]) and MEK inhibitor (trametinib dimethyl sulfoxide [trametinib]) therapy in BRAF/MEK inhibitor-resistant, BRAF^V600-mutated metastatic melanoma. (Phase 1) II. To determine if the addition of the EZH2 inhibitor, tazemetostat, to BRAF and MEK inhibitor therapy improves progression-free survival over single-agent EZH2 inhibitor therapy in patients with BRAF/MEK inhibitor-resistant, BRAF^V600-mutated melanomas harboring an EZH2 alteration. (Phase 2)

SECONDARY OBJECTIVES:

1. To observe and record anti-tumor activity. (Phase 1) II. To determine the overall response rate of single-agent EZH2 inhibitor therapy (tazemetostat) and triplet EZH2 inhibitor (tazemetostat), BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) therapy in patients with BRAF/MEK inhibitor-resistant BRAF^V600-mutated melanomas harboring an EZH2 alteration. (Phase 2)

EXPLORATORY OBJECTIVE:

1. To explore alterations in the gene expression profile (ribonucleic acid [RNA]-sequencing), H3K27 methylome (immunohistochemistry [IHC], chromatin immunoprecipitation [ChIP]-Sequencing), and open chromatin landscape (assay for transposase accessible chromatin [ATAC]-sequencing) with EZH2 inhibition in fresh clinical or patient derived xenograft (PDX)-derived tumor samples, which may reveal underlying transcriptional/epigenetic pathways mediating response to treatment.

OUTLINE: This is a phase I, dose-escalation trial of tazemetostat followed by a phase II trial. Patients in the phase I trial receive treatment as in Arm 2. Patients in the phase II trial are randomized to Arm 1 or Arm 2.

Phase I

Dose Level 1: Patients receive tazemetostat 400 mg orally (PO) twice daily (BID), dabrafenib 150 mg PO BID, and trametinib 2 mg PO once daily (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI), and multigated acquisition scan (MUGA) or echocardiography (ECHO) throughout the study.

Dose Level 2: Patients receive tazemetostat 600 mg PO BID, dabrafenib 150 mg PO BID, and trametinib 2 mg PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, and MUGA or ECHO throughout the study.

Dose Level 3: Patients receive tazemetostat 800 mg PO BID, dabrafenib 150 mg PO BID, and trametinib 2 mg PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, and MUGA or ECHO throughout the study.

Phase II

ARM 1: Patients receive tazemetostat PO BID on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan and MRI throughout the study. At the time of progression, patients may crossover to Arm 2 after completion of radiation therapy.

ARM 2: Patients receive tazemetostat PO BID, dabrafenib PO BID, and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, and MUGA or ECHO throughout the study.

After completion of study treatment, patients are followed up at 30 days, and then annually thereafter.