Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

Study Overview
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Brief Summary
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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.

Official Title
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A Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With Relapsed or Refractory Malignant Mesothelioma With BAP1 Loss of Function

Conditions
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Mesothelioma, BAP1 Loss of Function

Intervention / Treatment
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* Drug: Tazemetostat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Investigational drug; 30 days or five half-lives, whichever is longer, from last dose Has measurable disease based on either modified RECIST [Nowak 2005] for thoracic disease or RECIST 1.1 elsewhere 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 Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec Willing to provide tissue for translational research 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). 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: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-Label Tazemetostat<br>Oral Tazemetostat 800mg BID | Drug: Tazemetostat<br>* Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.<br>* Other names: E7438;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) | 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) | Assessed every 6 weeks for duration of study participation which is estimated to be 12 months | 
| Progression-free Survival (PFS) | 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. | The patients were assessed for PFS for up to 24 weeks | 
| Part 1 and 2: Overall Survival (OS) | 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. | 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 | 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. | 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) | 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 |