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Melanoma

Melanoma, Cutaneous Malignant

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Trametinib

Dabrafenib

Dimethyl Sulfoxide

Protein Kinase Inhibitors

Enzyme Inhibitors

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Antioxidants

Patients 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 tumor biopsy, CT scan and MRI throughout the study. At the time of progression, patients may crossover to Arm II after completion of radiation therapy.

Patients receive tazemetostat orally 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, MUGA or ECHO throughout the study.

Biopsy

Computed Tomography

Dabrafenib Mesylate

Echocardiogram Recording

Magnetic Resonance Imaging

Multigated Acquisition Scan

Tazemetostat Hydrobromide

Trametinib Dimethyl Sulfoxide

Site Public Contact

Leonel F. Hernandez-Aya

Melinda L. Yushak

Jeffrey A. Sosman

Tanner M. Johanns

Pierre L. Triozzi

Diwakar Davar

Siwen Hu-Lieskovan

Mark R. Albertini

Tanner M Johanns

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.

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.

Phase I single-arm trial followed by randomized two-arm phase II trial with cross-over

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

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

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 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.

Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and 95% confidence intervals will be calculated.

Will be estimated in each arm using Kaplan-Meier product limit methods, and its 95% confidence interval will be calculated.

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).

National Cancer Institute (NCI)

Patients undergo a one time assessment of cardiac function by echo, CMR, and the Tonometry-based system system in the clinic over 4-6 hours, and will be asked to perform their home-based measurements within 1-5 days of the clinical assessment, allowing us to directly compare measurements obtained by survivors to those by research personnel. Patients also complete questionnaires at baseline.

Questionnaire Administration

Stress Cardiac Magnetic Resonance Imaging

SphygmoCor® Xcel Oscar 2™ Ambulatory Blood Pressure Monitor

Wireless Synchronized Cardiac Function Monitoring Device

Saro H. Armenian

Saro H Armenian

The clinical trial compares the reproducibility and accuracy of cardiac tonometry-based portable systems that may detect early cardiac dysfunction (SphygmoCor® Xcel and Oscar 2™ ambulatory blood pressure monitor) at home and in the clinic to currently available screening tests for heart failure including echocardiogram (echo) and cardiovascular magnetic resonance (CMR). The SphygmoCor® Xcel and Oscar 2™ systems may help detect cardiac dysfunction earlier than other available screening tests because it can be self-administered outside of the clinic. This study aims to test the accuracy and practicality of these devices in the clinic setting and at home.

Primary Objective(s)

Validate the accuracy of ejection fraction, as measured using a tonometry-based system (SphygmoCor® Xcel), in the clinic setting, and determine the reproducibility (Oscar 2™) at home.

Secondary Objective(s)

Determine the cost-effectiveness of tonometry-based screening in the clinic setting and at home.

Reproducibility and Accuracy of a Portable System for Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors

Assessment of the Reproducibility and Accuracy of a Portable System for Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors

Validate the accuracy of ejection fraction, as measured using a tonometry-based system (SphygmoCor® Xcel), in the clinic setting, and determine the reproducibility (Oscar 2™) at home.

Will apply the sensitivity and specificity of echo, CMR, and the Oscar 2™ ABPM system (clinic, home-based) to compare the number of asymptomatic cardiac dysfunction cases identified via each method. Screening costs for echo and CMR, including costs of clinical services, will be obtained from the 2020 Centers for Medicare \& Medicaid Services (CMS).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	NCT04557956	Clinical Stage ... Metastatic Mela...	Biopsy Computed Tomogr... Dabrafenib Mesy... Echocardiogram ... Magnetic Resona... Multigated Acqu... Tazemetostat Hy... Trametinib Dime...	18 Years -	National Cancer Institute (NCI)
Reproducibility and Accuracy of a Portable System for Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors	NCT05138991	Hematopoietic a... Malignant Solid...	Echocardiogram ... Questionnaire A... Stress Cardiac ... Wireless Synchr...	-	City of Hope Medical Center
Reproducibility and Accuracy of a Portable System for Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors	NCT05138991	Hematopoietic a... Malignant Solid...	Echocardiogram ... Questionnaire A... Stress Cardiac ... Wireless Synchr...	-	City of Hope Medical Center

Spots Global Cancer Trial Database for echocardiogram recording