Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Dabrafenib

Dimethyl Sulfoxide

Protein Kinase Inhibitors

Enzyme Inhibitors

Protective Agents

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)

Symptoms and General Pathology

Respiratory Tract (Lung and Bronchial) Diseases

Immune System Diseases

Recurrence

Carcinoma

Small Cell Lung Carcinoma

Carcinoma, Small Cell

Lung Neoplasms

Hypersensitivity

Neoplasms, Glandular and Epithelial

Disease Attributes

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Small Cell Lung Cancer

Pembrolizumab

Topotecan

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Topoisomerase I Inhibitors

Patients receive tazemetostat PO BID on days 1-21, pembrolizumab IV over 30 minutes on day 1, and topotecan IV over 30 minutes on days 1-5. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan throughout the study and may also undergo biopsy and collection of blood on study.

Biospecimen Collection

Topotecan Hydrochloride

Jorge J. Nieva

Stephen V. Liu

Zhonglin Hao

Christine L. Hann

Anish Thomas

Jimmy Ruiz

Jonathan E. Dowell

This phase I trial tests the safety, side effects, and best dose of tazemetostat in combination with topotecan and pembrolizumab in treating patients with small cell lung cancer that has come back after a period of improvement (recurrent). Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tazemetostat in combination with topotecan and pembrolizumab may shrink or stabilize recurrent small cell lung cancer.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of tazemetostat hydrobromide (tazemetostat) in combination with topotecan hydrochloride (topotecan) and pembrolizumab in patients with recurrent extensive stage-small cell lung cancer (ES-SCLC), by reviewing dose-limiting toxicities (DLTs) in cycle 1 (21 days). (Dose-Escalation Cohort) II. To select the recommended phase II dose (RP2D) for a combination of tazemetostat, topotecan and pembrolizumab, based on pharmacodynamic (PD) parameters as well as overall efficacy and tolerability. (Dose-Escalation Cohort) III. To evaluate safety and tolerability of tazemetostat in combination with topotecan and pembrolizumab. (Expansion Cohort)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. To determine in a very preliminary fashion, the efficacy of a combination of tazemetostat, topotecan and pembrolizumab in recurrent ES-SCLC by assessing overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS).

EXPLORATORY OBJECTIVES:

I. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to ribonucleic acid (RNA) sequencing (RNA-Seq).

II. To assess modulation of EZH2 targets including SLFN11 and MHC among others. III. To identify potential predictive biomarkers of response. IV. To identify mechanisms of drug sensitivity and resistance using deoxyribonucleic acid (DNA)- and RNA-based assessment platforms.

V. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.

VI. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the National Cancer Institute (NCI) Early-Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank) at Nationwide Children's Hospital.

VII. Characterize circulating cell-free DNA (cfDNA).

OUTLINE: This is a dose-escalation study of tazemetostat followed by a dose-expansion study.

Patients receive tazemetostat orally (PO) twice daily (BID) on days 1-21, pembrolizumab intravenously (IV) over 30 minutes on day 1, and topotecan IV over 30 minutes on days 1-5. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan throughout the study and may also undergo biopsy and collection of blood on study.

After completion of study treatment, patients are followed every 3 months after removal from study treatment until study closure or death, whichever occurs first.

Testing of Tazemetostat in Combination With Topotecan and Pembrolizumab in Patients With Recurrent Small Cell Lung Cancer

Phase I Dose Escalation and Expansion Study of Tazemetostat in Combination With Topotecan and Pembrolizumab in Recurrent Small Cell Lung Cancer

Will be evaluated in more detail by reporting the adverse events noted, by type and grade, for the patients in the expansion cohort.

Will be estimated based on patients evaluable for response and will be presented along with a 95% confidence interval.

Will be estimated using the Kaplan-Meier method, resulting in median survival times with 95% confidence interval.

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)
Testing of Tazemetostat in Combination With Topotecan and Pembrolizumab in Patients With Recurrent Small Cell Lung Cancer	NCT05353439	Extensive Stage... Limited Stage L... Platinum-Resist... Platinum-Sensit... Recurrent Lung ...	Biopsy Biospecimen Col... Computed Tomogr... Pembrolizumab Tazemetostat Hy... Topotecan Hydro...	18 Years -	National Cancer Institute (NCI)
Testing of Tazemetostat in Combination With Topotecan and Pembrolizumab in Patients With Recurrent Small Cell Lung Cancer	NCT05353439	Extensive Stage... Limited Stage L... Platinum-Resist... Platinum-Sensit... Recurrent Lung ...	Biopsy Biospecimen Col... Computed Tomogr... Pembrolizumab Tazemetostat Hy... Topotecan Hydro...	18 Years -	National Cancer Institute (NCI)
Testing of Tazemetostat in Combination With Topotecan and Pembrolizumab in Patients With Recurrent Small Cell Lung Cancer	NCT05353439	Extensive Stage... Limited Stage L... Platinum-Resist... Platinum-Sensit... Recurrent Lung ...	Biopsy Biospecimen Col... Computed Tomogr... Pembrolizumab Tazemetostat Hy... Topotecan Hydro...	18 Years -	National Cancer Institute (NCI)

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