This phase I/II trial investigates the best dose, possible benefits and/or side effects of
tazemetostat 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 in
combination with dabrafenib and trametinib may stabilize BRAFV600 mutated melanoma.
I. 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)
I. 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)
I. 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 II. Patients in the phase II
trial are randomized to Arm I or Arm II.
ARM I: Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-28. Cycles
repeat every 28 days in the absence of disease progression or unacceptable toxicity. At the
time of progression, patients may crossover to Arm II after completion of radiation therapy.
ARM II: Patients receive tazemetostat PO BID, dabrafenib PO BID, and trametinib PO once daily
(QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or
After completion of study treatment, patients are followed up at 30 days, and then annually
Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Malignant Neoplasm in the Central Nervous System, Metastatic Melanoma, Pathologic Stage IV Cutaneous Melanoma AJCC v8
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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