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.

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.

To be determined.