Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

NCT02860286 | Completed Phase 2 Results DMC

• 1 other identifier: EZH-203
• Study Type: interventional
• Target: 74
• Locations: 3 countries
• Sites: 16

Brief Summary

This is a Phase 2, multicenter, open-label, 2-part, single-arm, 2-stage study of tazemetostat 800 mg two times a day (BID) administered orally. Screening of subjects to determine eligibility for the study will be performed within 21 days of the first planned dose of tazemetostat. In Part 1: planned to enroll 12 subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status will be treated and undergo pharmacokinetics (PK) blood sample collection after a single tazemetostat 800 mg. Part 2 plans to include 55 subjects with BAP1-deficient relapsed or refractory malignant mesothelioma. Treatment with tazemetostat will continue until disease progression, unacceptable toxicity or withdrawal of consent, or termination of the study. Response assessment will be evaluated after 6 weeks of treatment and then every 12 weeks thereafter while on study.

Conditions

Mesothelioma; BAP1 Loss of Function

Outcome Measures

Primary Outcomes (7)

• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax

  To assess the pharmacokinetic (PK) and safety profile of single (Cycle 1 day 1) and repeated doses (Cycle 1 day 2 onwards) of 800 mg tazemetostat administered as 400 mg tablets in subjects with relapsed or refractory malignant mesothelioma regardless of BRCA1 associated protein 1 (BAP1) status.

  Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Tmax

  Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.

• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t)

  To assess the pharmacokinetic (PK) and safety profile of single (Cycle 1 day 1) and repeated doses (Cycle 1 day 2 onwards) of 800 mg tazemetostat administered as 400 mg tablets in subjects with relapsed or refractory malignant mesothelioma regardless of BRCA1 associated protein 1 (BAP1) status

  Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.

• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞)

  Pharmacokinetics profile of tazemetostat and its metabolite (plasma) assessing AUC(0-∞)

  Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2

  Results from assessing the half-life of Tazemetostat and its metabolite shown below

  Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

• Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)

  Overall, the disease control rate (DCR) (calculated as subjects with CR + subjects with PR + subjects with SD at 12 weeks in duration), and the DCR at 24 weeks.

  The patients were assessed for DCR for up to 24 weeks

• Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability

  From the first dose of study treatment until the earlier of either 30 days after the discontinuation of study treatment or until the initiation of subsequent anticancer therapy.

Secondary Outcomes (5)

• Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR])

  Assessed every 6 weeks for duration of study participation which is estimated to be 12 months

• Progression-free Survival (PFS)

  The patients were assessed for PFS for up to 24 weeks

• Part 1 and 2: Overall Survival (OS)

  The patients were assessed for PFS for up to 24 weeks

• Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR

  Every 6 weeks up to disease progression or start of new anti-cancer therapy assessed for up to 12 months

• Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)

  The patients were assessed for DCR for up to 24 weeks

Study Arms (1)

Open-Label Tazemetostat

EXPERIMENTAL

Oral Tazemetostat 800mg BID

Drug: Tazemetostat

Interventions

Tazemetostat DRUG

Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.

Also known as: EPZ-6438, E7438

Open-Label Tazemetostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age (at the time of consent) ≥18 years of age
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Has a life expectancy of \>3 months
• Has mesothelioma (pleural, peritoneal, pericardial, tunica vaginalis) of any histology that is relapsed or refractory after treatment with at least one pemetrexed-containing regimen
• Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or equivalent laboratory certification
• Part 2: Molecular evidence of BAP1 loss of function mutation present on local pathology, e.g., lack of nuclear BAP1 staining by immunohistochemistry (IHC) or evidence of loss of function by gene sequencing
• Has sufficient archival tumor tissue (a minimum of 10 slides or tumor block) available for central retrospective testing of BAP1 status
• Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable and not clinically significant, at time of enrollment
• Prior therapy(ies), if applicable, must be completed according to the criteria below prior to first dose of tazemetostat:
• Cytotoxic chemotherapy; at least 21 days since last dose
• Non-cytotoxic chemotherapy (e.g., small molecule inhibitor); at least 14 days since last dose
• Monoclonal antibody; at least three half-lives since the last dose
• Non-antibody immunotherapy (e.g., tumor vaccine); at least 42 days since last dose
• Radiotherapy, at least 14 days from last local site radiotherapy
• Hematopoietic growth factor; at least 14 days from last dose

You may not qualify if:

• Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2)
• Has a history of known central nervous system metastasis
• Has had a prior malignancy other than the malignancies under study Exception: A subject who has been disease-free for 5 years, or a subject with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible.
• Has had major surgery within 3 weeks prior to enrollment (a percutaneous biopsy, pleural catheter insertion, placement of central venous catheter or other minor procedure are permitted)
• Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment throughout their time on study
• Has cardiovascular impairment, history of congestive heart failure greater than NYHA Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months prior to the planned first dose of tazemetostat; or ventricular cardiac arrhythmia requiring medical treatment
• Is currently taking any prohibited medication(s)
• Has an active infection requiring systemic treatment
• Has a congenital or acquired immunodeficiency, including subjects with known history of infection with human immunodeficiency virus (HIV) NOTE: HIV-positive subjects who are taking antiretroviral therapy are ineligible due to potential PK interactions with tazemetostat.
• Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable anti-hepatitis C circulating viral RNA)
• Has had a deep venous thrombosis (DVT) or pulmonary embolism within the 3 months prior to study enrollment.
• NOTE: Subjects with a history of a DVT or pulmonary embolism \>3 months prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study.
• Is pregnant or breastfeeding.

Sponsors & Collaborators

• Epizyme, Inc.: lead

Study Sites (16)

University of California, Los Angeles

Los Angeles, California, 90025, United States

Location

City of Hope National Medical Center

Los Angeles, California, 90301, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Mayo Clinic - Rochester

Rochester, Minnesota, 55905, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Institut Bergonie

Bordeaux, 33076, France

Location

CHRU de Lille

Lille, 59037, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

University of Leicester & Leicester University Hospitals

Leicester, LE1 9HN, United Kingdom

Location

St. Bartholomew's Hospital

London, EC1M 6BQ, United Kingdom

Location

University College Hospital

London, NW1 2PG, United Kingdom

Location

Royal Marsden Hospital - Chelsea

London, SW3 6JJ, United Kingdom

Location

University Hospital of South Manchester

Manchester, M23 9LT, United Kingdom

Location

Royal Marsden Hospital - Surrey

Sutton, SM2 5PT, United Kingdom

Location

Related Publications (1)

• Zauderer MG, Szlosarek PW, Le Moulec S, Popat S, Taylor P, Planchard D, Scherpereel A, Koczywas M, Forster M, Cameron RB, Peikert T, Argon EK, Michaud NR, Szanto A, Yang J, Chen Y, Kansra V, Agarwal S, Fennell DA. EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2022 Jun;23(6):758-767. doi: 10.1016/S1470-2045(22)00277-7. Epub 2022 May 16.

  PMID: 35588752 DERIVED

MeSH Terms

Conditions

Mesothelioma

Interventions

tazemetostat

Condition Hierarchy (Ancestors)

Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial

Results Point of Contact

• Title: Kemly Calixte
• Organization: Epizyme

kcalixte@epizyme.com

617-500-0608

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 27, 2016
• First Posted: August 9, 2016
• Study Start: July 1, 2016
• Primary Completion: June 1, 2018
• Study Completion: May 1, 2019
• Last Updated: April 9, 2021
• Results First Posted: April 9, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (3); US (7); GB (6)