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

Inclusion Criteria:

• Patient must have a diagnosis of BRAF^V600E/K-mutated metastatic melanoma

• Patient must have had documented radiographic or clinical evidence of progressivedisease while on combination BRAF/MEK inhibitor therapy. For Phase 2 only, no morethan one intervening therapy since progression on BRAF/MEK inhibitor therapy isallowed. Subjects who have evidence of progression while on, or within 4 weeks ofcompleting, combination BRAF/MEK inhibitor therapy in the adjuvant setting will beeligible

• PHASE 2 ONLY: Patient must have EZH2 alteration (somatic mutation or copy numberalteration). Can be performed on either archival or fresh specimen. EZH2 alterationsneed to be documented by a Clinical Laboratory Improvement Act (CLIA)/ClinicalLaboratory Improvement Program (CLIP)-certified next generation sequencing platform (Foundation One, Tempus, Guardant360, etc.)

• PHASE 2 ONLY: Patient must have measurable disease

• PHASE 2 ONLY: Patient must have at least one tumor lesion amenable to biopsy. Ifpossible, this lesion should be different from the lesion used for following tumormeasurements but is not required

• PHASE 2 ONLY: Patient must agree to planned pre-treatment and planned on-treatmentbiopsy. A pre-treatment biopsy will be optional if patient has an archival tissueblock or 5 formalin-fixed paraffin-embedded (FFPE) slides available from specimenused to document presence of eligible EZH2 alteration that is deemed adequate forevaluation

• Patient must be >= 18 years

• Because no dosing or adverse event data are currently available on the use oftazemetostat in combination with dabrafenib and trametinib in patients < 18years of age, children are excluded from this study

• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)

• Patients with symptomatic central nervous system (CNS) metastases are eligible ifpreviously treated with surgery and/or radiation with no evidence of radiologic CNSrecurrence or progression for 4 weeks and on a stable/tapering dose of steroid forat least one week prior to start of study drug. Patients with new or progressiveasymptomatic CNS metastases are eligible

• Hemoglobin >= 9 g/dL

• Albumin >= 2.5 g/dL

• Leukocytes >= 3,000/mcL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 100,000/mcL

• Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN) except subjectswith known Gilbert's syndrome

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN

• Creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min

• Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2

• Patients with a prior (or concurrent, if enrolling in Phase 1) malignancy whosenatural history or treatment does not have the potential to interfere with thesafety or efficacy assessment of the investigational regimen are eligible for thistrial

• Patient must be able to swallow and retain oral medication and must not have anyclinically significant gastrointestinal abnormalities that may alter absorption suchas malabsorption syndrome or major resection of the stomach or bowels

• Prothrombin time (PT)/international normalized ratio (INR) and partialthromboplastin time (PTT) =< 1.3 x institutional ULN. Prophylactic low dose warfarinmay be given to maintain central catheter patency

• The effects of tazemetostat, and the combination of tazemetostat, dabrafenib andtrametinib on the developing human fetus are unknown. Women of childbearingpotential and all male patients must agree to the following:

• For women of childbearing potential: agreement to remain abstinent (refrainfrom heterosexual intercourse) or use contraceptive methods that result in afailure rate of < 1% per year during the treatment period, for 6 months aftertazemetostat discontinuation, or for 6 months after discontinuation of thecombination of tazemetostat, dabrafenib and trametinib. Should a woman becomepregnant 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 ispostmenarcheal, has not reached a postmenopausal state (>= 12 continuousmonths of amenorrhea with no identified cause other than menopause), andhas not undergone surgical sterilization (removal of ovaries and/oruterus)

• Examples of contraceptive methods with a failure rate of < 1% per yearinclude bilateral tubal ligation, male sterilization, established, properuse of hormonal contraceptives that inhibit ovulation, hormone-releasingintrauterine devices, and copper intrauterine devices

• Due to the potential of enzyme induction with tazemetostat, femalesubjects who use hormonal contraceptives should use an additional barriermethod of birth control while on study treatment and for 6 months afterdiscontinuation of tazemetostat or the combination of tazemetostat,dabrafenib and trametinib

• The reliability of sexual abstinence should be evaluated in relation tothe duration of the clinical study and the preferred and usual lifestyleof the patient. Periodic abstinence (e.g., calendar, ovulation,symptothermal, or post ovulation methods) and withdrawal are notacceptable methods of contraception

• Women of childbearing potential must have a negative urine or serum pregnancytest at screening

• For men: agreement to remain abstinent (refrain from heterosexual intercourse)or use contraceptive measures and agreement to refrain from donating sperm, asdefined below:

• With female partners of childbearing potential or pregnant femalepartners, men must remain abstinent or use a condom during the treatmentperiod and for at least 4 months after the last dose of study drug. Menmust 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 samehormonal contraceptive product for at least 4 weeks before receivingstudy drug) AND a condom (hormonal contraceptives must besupplemented with condoms)

• The reliability of sexual abstinence should be evaluated in relation tothe duration of the clinical study and the preferred and usual lifestyleof the patient. Periodic abstinence and withdrawal are not acceptablemethods of contraception

• Ability to understand and the willingness to sign a written informed consentdocument. Participants with impaired decision-making capacity (IDMC) who have alegally-authorized representative (LAR) and/or family member available will also beeligible

• Have progressed on, been intolerant to, is ineligible for, or has refused priorstandard of care anti-PD-1 based immunotherapy

Exclusion Criteria:

• Previous therapy with a demethylating agent (i.e. decitabine) or previous therapywith an EZH2 inhibitor

• History of second malignancy not treated with curative intent

• History of life-threatening toxicity, including hypersensitivity, related to BRAF orMEK inhibitor therapy, or known immediate or delayed hypersensitivity reaction oridiosyncrasy to drugs chemically related to the study treatments, their excipients,and/or dimethyl sulfoxide (DMSO)

• Active infection requiring intravenous therapy

• Presence of untreated or progressive symptomatic CNS melanoma metastases. Diffuseleptomeningeal carcinomatosis or metastases causing spinal cord compression areexclusionary. Previously treated lesions should be stable for >= 4 weeks (must bedocumented by imaging). Subjects on a stable dose of corticosteroids for > 1 weekcan be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks

• Radiation therapy in the last 14 days. Palliative radiation to a localized areawithout residual toxicity requires a washout of at least 7 days

• Prior systemic anti-cancer therapy (chemotherapy, targeted therapy, immunotherapy,biologic therapy, or vaccine therapy) within the 2 weeks preceding the first dose ofstudy treatment. For Phase 2 only, prior chemotherapy regimens are not permitted

• Use of other investigational drugs within 21 days (or five half-lives, whichever isshorter; with a minimum of 14 days from the last dose) preceding the first dose ofstudy treatment and during the study

• Unresolved toxicity of National Cancer Institute Common Terminology Criteria forAdverse Events, version 5.0 (NCI CTCAE v5.0) grade 2 or higher from previousanti-cancer therapy, except alopecia and other toxicities that have resolved tograde 1 or well controlled with medical management (i.e.: hypothyroidism, adrenalinsufficiency, type 1 diabetes, etc.), at the time of randomization

• Current use of a prohibited medication. Patients must not be treated with anymedications or substances that are strong or moderate inhibitors or inducers ofCYP3A or strong inhibitors or inducers of CYP2C8 within 14 days prior to the firsttreatment through the end of the study. Current use of, or intended ongoingtreatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors orinducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1)should also be excluded

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviraltherapy are ineligible because of the potential for pharmacokinetic interactionswith dabrafenib

• A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with theexception of cleared HBV and HCV infection, which will be allowed)

• History of interstitial lung disease or pneumonitis

• Clinically significant bleeding diathesis or coagulopathy, including known plateletfunction disorders. Patients on anticoagulation with low molecular weight heparin orlow dose warfarin are allowed

• History of myeloid malignancies, including myelodysplastic syndrome (MDS)

• Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) andmultiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testingand deoxyribonucleic acid (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 ofinterval from the current study. Note: Prospective RAS testing is not required.However, if the results of previous RAS testing are known, they must be used inassessing eligibility

• History or evidence of cardiovascular risks including any of the following:

• QT interval corrected for heart rate using Fridericia's formula (QT correctedby Fridericia [QTcF]) >= 450 msec

• History of acute coronary syndromes (including myocardial infarction orunstable angina), coronary angioplasty, or stenting within the past 24 weeksprior to randomization

• History or evidence of current class II, III, or IV heart failure as defined bythe New York Heart Association (NYHA) functional classification system

• Intra-cardiac defibrillators

• Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjectswith grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be enteredon study). Subjects with moderate valvular thickening should not be entered onstudy

• History or evidence of current clinically significant uncontrolled cardiacarrhythmias; clarification: Subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible

• Treatment refractory hypertension defined as a blood pressure of systolic > 140mmHg and/or diastolic > 90 mm Hg which cannot be controlled byanti-hypertensive therapy

• Left ventricular ejection fraction (LVEF) < institutional lower limit of normal (LLN) by ECHO or MUGA

• Known cardiac metastases

• Patients with uncontrolled intercurrent illness

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements

• Pregnant women are excluded from this study because of the potential for teratogenicor abortifacient effects. Because there is an unknown but potential risk for adverseevents in nursing infants secondary to treatment of the mother with tazemetostat /dabrafenib / trametinib, breastfeeding should be discontinued prior to treatment

• Patients with uncontrolled diabetes

• Patients with a history of retinal vein occlusion (RVO), retinal pigment epithelialdetachment (RPED) or other ophthalmologic toxicity