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
Phase 1/2 Study of an EZH2 Inhibitor (Tazemetostat) in Combination With Dual BRAF/MEK Inhibition in Patients With BRAF- Mutated Metastatic Melanoma Who Progressed on Prior BRAF/MEK Inhibitor Therapy
5 other identifiers
interventional
16
1 country
17
Brief 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 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Aug 2021
Longer than P75 for phase_1
17 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 18, 2020
CompletedFirst Posted
Study publicly available on registry
September 22, 2020
CompletedStudy Start
First participant enrolled
August 19, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
October 15, 2025
CompletedStudy Completion
Last participant's last visit for all outcomes
March 11, 2027
ExpectedApril 2, 2026
March 1, 2026
4.2 years
September 18, 2020
April 1, 2026
Conditions
Outcome Measures
Primary Outcomes (2)
Recommended phase 2 dose (Phase I)
Data analysis will be descriptive in nature, and will be determined using the standard 3+3 algorithm. Toxicities by grade, number of cycles administered, and response to treatment will be listed for each dose level.
Up to 30 days
Median progression-free survival (PFS) (Phase II)
Median PFS in each arm will be assessed using Kaplan-Meier product limit methods and the randomized arms will be compared using log-rank test (at 0.15 one-sided significance level) when 36 PFS events are observed.
At 6 and 12 months
Secondary Outcomes (3)
Overall response rates (complete response, partial response)
Up to 3 years
Overall survival
Up to 3 years
Incidence of adverse events
Up to 3 years
Study Arms (2)
Phase I; Phase II Arm 2 (tazemetostat, dabrafenib, trametinib)
EXPERIMENTALPatients 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.
Phase II, Arm 1 (tazemetostat)
ACTIVE COMPARATORPatients 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.
Interventions
Undergo tumor biopsy
Undergo CT scan
Given PO
Undergo ECHO
Undergo MRI
Undergo MUGA
Given PO
Given PO
Eligibility Criteria
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
- +21 more criteria
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
- 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
- +17 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (17)
UM Sylvester Comprehensive Cancer Center at Aventura
Aventura, Florida, 33180, United States
UM Sylvester Comprehensive Cancer Center at Coral Gables
Coral Gables, Florida, 33146, United States
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Deerfield Beach, Florida, 33442, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, 33136, United States
UM Sylvester Comprehensive Cancer Center at Plantation
Plantation, Florida, 33324, United States
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322, United States
Northwestern University
Chicago, Illinois, 60611, United States
Siteman Cancer Center at Saint Peters Hospital
City of Saint Peters, Missouri, 63376, United States
Siteman Cancer Center at West County Hospital
Creve Coeur, Missouri, 63141, United States
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Siteman Cancer Center-South County
St Louis, Missouri, 63129, United States
Siteman Cancer Center at Christian Hospital
St Louis, Missouri, 63136, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, 27157, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, 15232, United States
Huntsman Cancer Institute/University of Utah
Salt Lake City, Utah, 84112, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
Madison, Wisconsin, 53718, United States
University of Wisconsin Carbone Cancer Center - University Hospital
Madison, Wisconsin, 53792, United States
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Tanner M Johanns
Yale University Cancer Center LAO
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- NIH
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
September 18, 2020
First Posted
September 22, 2020
Study Start
August 19, 2021
Primary Completion
October 15, 2025
Study Completion (Estimated)
March 11, 2027
Last Updated
April 2, 2026
Record last verified: 2026-03
Data Sharing
- IPD Sharing
- Will share
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