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

Running, not enrolling · Phase 1/Phase 2

Conditions studied: Clinical Stage IV Cutaneous Melanoma AJCC v8, Metastatic Melanoma

In brief

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 from where it first started (primary site) 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.

Key facts

Study ID

NCT04557956

Run by

National Cancer Institute (NCI)

People needed

16

Starts

2021-08-19

Expected to finish

2027-03-11

Last updated by the study team

2026-04-02

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Patient must have a diagnosis of BRAF\^V600E/K-mutated metastatic melanoma
• 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
• 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.)
• PHASE 2 ONLY: Patient must have measurable disease
• 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
• 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
• 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
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
• 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
• 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 subjects with 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 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
• 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
• 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
• 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)

You may not qualify if…

• Previous therapy with a demethylating agent (i.e. decitabine) or previous therapy with an EZH2 inhibitor
• History of second malignancy not treated with curative intent
• History of life-threatening toxicity, including hypersensitivity, related to BRAF or MEK inhibitor therapy, or known immediate or delayed hypersensitivity reaction or idiosyncrasy 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. Diffuse leptomeningeal carcinomatosis or metastases causing spinal cord compression are exclusionary. Previously treated lesions should be stable for >= 4 weeks (must be documented by imaging). Subjects on a stable dose of corticosteroids for > 1 week can 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 area without 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 of study treatment. For Phase 2 only, prior chemotherapy regimens are not permitted
• Use of other investigational drugs within 21 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study treatment and during the study
• Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) grade 2 or higher from previous anti-cancer therapy, except alopecia and other toxicities that have resolved to grade 1 or well controlled with medical management (i.e.: hypothyroidism, adrenal insufficiency, type 1 diabetes, etc.), at the time of randomization
• Current use of a prohibited medication. Patients must not be treated with any medications or substances that are strong or moderate inhibitors or inducers of CYP3A or strong inhibitors or inducers of CYP2C8 within 14 days prior to the first treatment through the end of the study. Current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with dabrafenib
• A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception 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 platelet function disorders. Patients on anticoagulation with low molecular weight heparin or low 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) and multiple primary neoplasms (MPN) (e.g. JAK2 V617F) observed in cytogenetic testing and 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 of interval 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 in assessing eligibility
• History or evidence of cardiovascular risks including any of the following:
• QT interval corrected for heart rate using Fridericia's formula (QT corrected by Fridericia [QTcF]) >= 450 msec
• History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization
• History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
• Intra-cardiac defibrillators
• Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study
• History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: Subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible

Where it is running

• UM Sylvester Comprehensive Cancer Center at Aventura — Aventura, Florida, United States
• UM Sylvester Comprehensive Cancer Center at Coral Gables — Coral Gables, Florida, United States
• UM Sylvester Comprehensive Cancer Center at Deerfield Beach — Deerfield Beach, Florida, United States
• University of Miami Miller School of Medicine-Sylvester Cancer Center — Miami, Florida, United States
• UM Sylvester Comprehensive Cancer Center at Plantation — Plantation, Florida, United States
• Emory University Hospital/Winship Cancer Institute — Atlanta, Georgia, United States
• Northwestern University — Chicago, Illinois, United States
• Siteman Cancer Center at Saint Peters Hospital — City of Saint Peters, Missouri, United States
• Siteman Cancer Center at West County Hospital — Creve Coeur, Missouri, United States
• Washington University School of Medicine — St Louis, Missouri, United States
• Siteman Cancer Center-South County — St Louis, Missouri, United States
• Siteman Cancer Center at Christian Hospital — St Louis, Missouri, United States
• Wake Forest University Health Sciences — Winston-Salem, North Carolina, United States
• University of Pittsburgh Cancer Institute (UPCI) — Pittsburgh, Pennsylvania, United States
• Huntsman Cancer Institute/University of Utah — Salt Lake City, Utah, United States
• University of Wisconsin Carbone Cancer Center - Eastpark Medical Center — Madison, Wisconsin, United States
• University of Wisconsin Carbone Cancer Center - University Hospital — Madison, Wisconsin, United States

Full record on ClinicalTrials.gov

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