Summary

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.

Objectives

PRIMARY OBJECTIVES:
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)

SECONDARY OBJECTIVES:
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)

EXPLORATORY OBJECTIVE:
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 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 and magnetic resonance imaging (MRI) throughout the study. 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 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, multigated acquistion scan (MUGA) or echocardiogram (ECHO) throughout the study.

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

Eligibility

1. Patient must have a diagnosis of BRAF^V600E/K-mutated metastatic melanoma
2. Patient must have had documented radiographic or clinical evidence of progressive disease while on combination BRAF/MEK inhibitor therapy. For Phase 2 only, no more than one intervening therapy since progression on BRAF/MEK inhibitor therapy is allowed. Subjects who have evidence of progression while on, or within 4 weeks of completing, combination BRAF/MEK inhibitor therapy in the adjuvant setting will be eligible
3. PHASE 2 ONLY: Patient must have EZH2 alteration (somatic mutation or copy number alteration). Can be performed on either archival or fresh specimen. EZH2 alterations need to be documented by a Clinical Laboratory Improvement Act (CLIA)/Clinical Laboratory Improvement Program (CLIP)-certified next generation sequencing platform (Foundation One, Tempus, Guardant360, etc.)
4. PHASE 2 ONLY: Patient must have measurable disease
5. PHASE 2 ONLY: Patient must have at least one tumor lesion amenable to biopsy. If possible, this lesion should be different from the lesion used for following tumor measurements but is not required
6. PHASE 2 ONLY: Patient must agree to planned pre-treatment and planned on-treatment biopsy. A pre-treatment biopsy will be optional if patient has an archival tissue block or 5 formalin-fixed paraffin-embedded (FFPE) slides available from specimen used to document presence of eligible EZH2 alteration that is deemed adequate for evaluation
7. Patient must be >=18 years * Because no dosing or adverse event data are currently available on the use of tazemetostat in combination with dabrafenib and trametinib in patients < 18 years of age, children are excluded from this study
8. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
9. Patients with symptomatic central nervous system (CNS) metastases are eligible if previously treated with surgery and/or radiation with no evidence of radiologic CNS recurrence or progression for 4 weeks and on a stable/tapering dose of steroid for at least one week prior to start of study drug. Patients with new or progressive asymptomatic CNS metastases are eligible
10. Hemoglobin >= 9 g/dL
11. Albumin >= 2.5 g/dL
12. Leukocytes >= 3,000/mcL
13. Absolute neutrophil count >= 1,500/mcL
14. Platelets >= 100,000/mcL
15. Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjects with known Gilbert’s syndrome
16. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN
17. Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min
18. Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
19. Patients with a prior (or concurrent, if enrolling in Phase 1) malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
20. Patient must be able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
21. Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN. Prophylactic low dose warfarin may be given to maintain central catheter patency
22. The effects of tazemetostat, and the combination of tazemetostat, dabrafenib and trametinib on the developing human fetus are unknown. Women of childbearing potential and all male patients must agree to the following: * For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period, for 6 months after tazemetostat discontinuation, or for 6 months after discontinuation of the combination of tazemetostat, dabrafenib and trametinib. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately ** A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (>= 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus) ** Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices ** Due to the potential of enzyme induction with tazemetostat, female subjects who use hormonal contraceptives should use an additional barrier method of birth control while on study treatment and for 6 months after discontinuation of tazemetostat or the combination of tazemetostat, dabrafenib and trametinib ** The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception * Women of childbearing potential must have a negative urine or serum pregnancy test at screening * For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm, as defined below: ** With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 4 months after the last dose of study drug. Men must refrain from donating sperm during this same period. In addition, female partners of male subjects should adhere to the following: *** Intrauterine device (IUD) (must provide medical documentation of IUD) *** Hormonal contraceptive (partner must be on a stable dose of the same hormonal contraceptive product for at least 4 weeks before receiving study drug) AND a condom (hormonal contraceptives must be supplemented with condoms) ** The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence and withdrawal are not acceptable methods of contraception
23. Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
24. Have progressed on, been intolerant to is, ineligible for, or has refused prior standard of care anti-PD-1 based immunotherapy