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
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT04557956|
Recruitment Status : Not yet recruiting
First Posted : September 22, 2020
Last Update Posted : January 15, 2021
|Condition or disease||Intervention/treatment||Phase|
|Clinical Stage IV Cutaneous Melanoma AJCC v8 Metastatic Malignant Neoplasm in the Central Nervous System Metastatic Melanoma Pathologic Stage IV Cutaneous Melanoma AJCC v8||Drug: Dabrafenib Mesylate Drug: Tazemetostat Hydrobromide Drug: Trametinib Dimethyl Sulfoxide||Phase 1 Phase 2|
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, BRAFV600-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, BRAFV600-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 BRAFV600-mutated melanomas harboring an EZH2 alteration. (Phase 2)
I. To explore alterations in the gene expression profile (RNA-sequencing), H3K27 methylome (IHC, ChIP-Sequencing), and open chromatin landscape (ATAC-sequencing) with EZH2 inhibition in fresh clinical or 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 PO 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 QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and then annually thereafter.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||18 participants|
|Intervention Model:||Sequential Assignment|
|Intervention Model Description:||Phase I single-arm trial followed by randomized two-arm phase II trial with cross-over|
|Masking:||None (Open Label)|
|Official Title:||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|
|Estimated Study Start Date :||February 1, 2021|
|Estimated Primary Completion Date :||September 1, 2023|
|Estimated Study Completion Date :||September 1, 2023|
Active Comparator: ARM I (tazemetostat) phase II
Patients receive tazemetostat PO 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.
Drug: Tazemetostat Hydrobromide
Experimental: ARM II (tazemetostat, dabrafenib, trametinib) phase I/phase II
Patients receive tazemetostat orally PO BID, dabrafenib PO BID, and trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Dabrafenib Mesylate
Drug: Tazemetostat Hydrobromide
Drug: Trametinib Dimethyl Sulfoxide
- Recommended phase 2 dose (R2PD) (Phase 1) [ Time Frame: Up to 30 days ]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.
- Median progression-free survival (PFS) (Phase 2) [ Time Frame: At 6 and 12 months ]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.
- Overall response rates (complete response [CR], partial response [PR]) [ Time Frame: Up to 3 years ]Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and 95% confidence intervals will be calculated.
- Overall survival [ Time Frame: Up to 3 years ]Will be estimated in each arm using Kaplan-Meier product limit methods, and its 95% confidence interval will be calculated.
- Incidence of adverse events [ Time Frame: Up to 3 years ]Toxicity evaluation will be descriptive, and standard toxicity definitions and criteria will be used as outlined in the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity. If appropriate, confidence intervals will be used to characterize the precision of the estimate. A complete listing of adverse events will also be tabulated, and will provide details including severity, relationship to treatment, onset, duration, and outcome. Laboratory data measured on a continuous scale will be characterized by summary statistics (mean and standard deviation).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04557956
|Principal Investigator:||Tanner M Johanns||Duke University - Duke Cancer Institute LAO|