Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

Phase 2

Completed

• Conditions: Mesothelioma; BAP1 Loss of Function
• Interventions: Drug: Tazemetostat

• Registration Number: NCT02860286
• Lead Sponsor: Epizyme, Inc.

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2016-07
• Study First Submitted: 2016-07-27
• Study First Submitted QC: 2016-08-04
• Study First Posted: 2016-08-09
• Primary Completion: 2018-06
• Study Completion: 2019-05
• Results First Submitted: 2020-11-16
• Status Verified: 2021-03
• Results First Submitted QC: 2021-03-16
• Last Update Submitted: 2021-03-16
• Results First Posted: 2021-04-09
• Last Update Posted: 2021-04-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 74

Inclusion Criteria

1. Age (at the time of consent) ≥18 years of age

2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

3. Has a life expectancy of >3 months

4. Has mesothelioma (pleural, peritoneal, pericardial, tunica vaginalis) of any histology that is relapsed or refractory after treatment with at least one pemetrexed-containing regimen

5. 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

6. 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

7. Has sufficient archival tumor tissue (a minimum of 10 slides or tumor block) available for central retrospective testing of BAP1 status

8. 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

9. 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
   • Investigational drug; 30 days or five half-lives, whichever is longer, from last dose

10. Has measurable disease based on either modified RECIST [Nowak 2005] for thoracic disease or RECIST 1.1 elsewhere

11. Has adequate hematologic (bone marrow and coagulation factors), renal, and hepatic function as defined by criteria below:

    • Hemoglobin ≥9 mg/dL
    • Platelets ≥100,000/mm3 (≥100 × 109/L) without platelet transfusion for 7 days
    • ANC ≥1000/mm3 (≥1.0 × 109/L) without growth factor support for 14 days
    • Coagulation: Prothrombin time (PT) <1.5 × ULN and partial thromboplastin time (PTT) <1.5 × ULN
    • Creatinine < 2.0 × ULN
    • Hepatic function: Conjugated bilirubin <1.5 × ULN and ALT and AST <3 × ULN

12. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec

13. Willing to provide tissue for translational research

14. Female subjects of childbearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study drug; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required and subject also should agree to use an adequate method of contraception starting with screening through 30 days after the last dose of study therapy (if sexually active).

15. Male subjects should agree to use condoms starting with the first dose of study therapy through 30 days after the last dose of study therapy if sexually active with a female of childbearing potential

Exclusion Criteria

1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2)

2. Has a history of known central nervous system metastasis

3. 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.

4. 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)

5. 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

6. 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

7. Is currently taking any prohibited medication(s)

8. Has an active infection requiring systemic treatment

9. 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.

10. 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)

11. 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.

12. Is pregnant or breastfeeding.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-Label Tazemetostat	Tazemetostat	Oral Tazemetostat 800mg BID

Primary Outcome Measures

Name	Time	Method
Part 2: 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	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.
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose	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.
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.
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)	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.	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
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞)	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose	Pharmacokinetics profile of tazemetostat and its metabolite (plasma) assessing AUC(0-∞)
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose	Results from assessing the half-life of Tazemetostat and its metabolite shown below

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	The patients were assessed for PFS for up to 24 weeks	Progression-Free Survival is defined as the interval of time between the date of the first dose of study drug and the earliest date of disease progression or death due to any cause. PFS was analyzed and listed for the ITT population. PFS was calculated using the Kaplan-Meier method.
Part 1 and 2: Overall Survival (OS)	The patients were assessed for PFS for up to 24 weeks	OS was analyzed and listed for the ITT population. Subjects who have not died were censored at the date of last contact which was identified from a visit date, study assessment (physical examination, vital signs, ECOG performance status, electrocardiogram \[ECG\], study drug record, radiological evaluation), AE, medication, or disposition information.; OS was calculated using the Kaplan-Meier method. OS at 12 and 24 weeks along with the associated 2-sided 95% CIs were provided. Median OS, first and third quartiles and associated 95% 2-sided CIs were provided.
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	DOR was calculated for subjects with a confirmed CR or PR. DOR is defined as the time from the date of the initial response (CR/PR) to the date of first documented PD or death due to any cause, whichever occurs first.; DOR censoring rules followed those of the PFS analysis defined in the SAP. DOR was analyzed using the Kaplan-Meier methods and the median DOR, first quartile, and third quartile was presented. The associated 2- sided 95% CIs was estimated.
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	ORR (confirmed CR+PR) to tazemetostat in subjects with relapsed/refractory malignant mesothelioma using disease-appropriate standardized response criteria (modified RECIST or RECIST 1.1)
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	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.

Trial Locations

Locations (16)

University of California, Los Angeles; 🇺🇸 Los Angeles, California, United States

City of Hope National Medical Center; 🇺🇸 Los Angeles, California, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States

Institut Bergonie; 🇫🇷 Bordeaux Cedex, France

University of California San Francisco; 🇺🇸 San Francisco, California, United States

CHRU de Lille; 🇫🇷 Lille, France

Institut Gustave Roussy; 🇫🇷 Villejuif cedex, France

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

University College Hospital; 🇬🇧 London, United Kingdom

University of Leicester & Leicester University Hospitals; 🇬🇧 Leicester, United Kingdom

St. Bartholomew's Hospital; 🇬🇧 London, United Kingdom

Royal Marsden Hospital - Surrey; 🇬🇧 Sutton, United Kingdom

Royal Marsden Hospital - Chelsea; 🇬🇧 London, United Kingdom

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

University Hospital of South Manchester; 🇬🇧 Manchester, United Kingdom