Ignite Creation Date:
2025-12-24 @ 11:35 PM
Ignite Modification Date:
2025-12-25 @ 9:24 PM
Study NCT ID:
NCT04557956
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2025-10-24
First Post:
2020-09-18
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
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
Sponsor:
National Cancer Institute (NCI)
Organization:
Study Overview
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
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2025-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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.
Detailed Description:
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 2. Patients in the phase II trial are randomized to Arm 1 or Arm 2.
ARM 1: 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 computed tomography (CT) scan and magnetic resonance imaging (MRI) throughout the study. At the time of progression, patients may crossover to Arm 2 after completion of radiation therapy.
ARM 2: 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, and multigated acquisition scan (MUGA) or echocardiography (ECHO) throughout the study.
After completion of study treatment, patients are followed up at 30 days, and then annually thereafter.
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 2. Patients in the phase II trial are randomized to Arm 1 or Arm 2.
ARM 1: 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 computed tomography (CT) scan and magnetic resonance imaging (MRI) throughout the study. At the time of progression, patients may crossover to Arm 2 after completion of radiation therapy.
ARM 2: 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, and multigated acquisition scan (MUGA) or echocardiography (ECHO) throughout the study.
After completion of study treatment, patients are followed up at 30 days, and then annually thereafter.
Study Oversight
Has Oversight DMC:
False
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
Secondary ID Infos
| Secondary ID | Type | Domain | Link | View |
|---|---|---|---|---|
| NCI-2020-07044 | REGISTRY | CTRP (Clinical Trial Reporting Program) | View | |
| 202103077 | None | None | View | |
| 10285 | OTHER | Yale University Cancer Center LAO | View | |
| 10285 | OTHER | CTEP | View | |
| UM1CA186689 | NIH | None | https://reporter.nih.gov/quic… | View |
| UM1CA186704 | NIH | None | https://reporter.nih.gov/quic… | View |