A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

• Age (at the time of consent/assent): ≥18 years of age

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

• Has provided signed written informed consent

• Has a life expectancy of \>3 months

• Has a malignancy:

‣ For which there are no standard therapies available (Cohorts 1, 3, 4 and 5)

⁃ That is relapsed or refractory after treatment with an approved therapy(ies), defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies) (Cohort 2)

• That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion, Cohort 6 and Cohort 8 ONLY)

• 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

• For Cohort 1 (rhabdoid tumors only), the following test results must be available by local laboratory: morphology and immunophenotypic panel consistent with rhabdoid tumors, and loss of INI1 or SMARCA4 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss or mutation when INI1 or SMARCA4 IHC is equivocal or unavailable

• For Cohort 2 (subjects with relapsed/refractory synovial sarcoma only), the following tests must be available by local laboratory: Morphology consistent with synovial sarcomas, and cytogenetics or fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)

• For Cohort 3, 4, 5, 7 and 8 (subjects with INI1-negative/aberrant tumors or any solid tumor with EZH2 GOF mutation only), the following test results must be available by local laboratory: Morphology and immunophenotypic panel consistent with INI1-negative tumors (not applicable for solid tumors with EZH2 GOF mutation), and loss of INI1 confirmed by IHC, or molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable, or molecular evidence of EZH2 GOF mutation

⁃ For Cohort 6 (subjects with ES undergoing optional tumor biopsy) only:

∙ Morphology and immunophenotypic panel consistent with ES (e.g., CD34, EMA, Keratin, and INI1)

⁃ Has all prior treatment (i.e. chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤Grade 1 per CTCAE version 4.0.3 or are clinically stable and not clinically significant, at time of enrollment.

⁃ Prior anti-cancer therapy(ies), if applicable, must be completed according to the criteria below:

∙ Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior to first dose of tazemetostat)

‣ Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas prior to first dose of tazemetostat)

‣ Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days since last dose of non-cytotoxic chemotherapy prior to first dose of tazemetostat)

‣ Monoclonal antibody(ies) (At least 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat)

‣ Immunotherapy (e.g. tumor vaccine) (At least 42 days since last dose of immunotherapy agent(s) prior to first dose of tazemetostat)

‣ Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose of tazemetostat/At least 21 days from stereostatic radiosurgery prior to first dose of tazemetostat/At least 12 weeks from craniospinal, ≥50% radiation of pelvis, or total body irradiation prior to first dose of tazemetostat)

‣ High dose therapy with autologous hematopoietic cell infusion (At least 60 days from last infusion prior to first dose of tazemetostat)

‣ Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat)

⁃ Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing

⁃ Has measurable disease based on either RECIST 1.1 for solid tumors or RANO for CNS tumors

⁃ Has adequate hematologic (bone marrow \[BM\] and coagulation factors), renal and hepatic function.

⁃ For subjects with CNS Tumors only, subject must have seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 21 days prior to the planned first dose of tazemetostat

⁃ Has a shortening fraction of \>27% or an ejection fraction of ≥50% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan and New York Heart Association (NYHA) Class ≤2

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

⁃ Female subjects of childbearing potential must:

∙ Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of screening and within 14 days prior to planned first dose of tazemetostat and

‣ Agree to use effective contraception from a minimum of 7 days prior to first dose until 6 months following the last dose of tazemetostat and have a male partner who uses a condom, or

‣ Practice true abstinence or have a male partner who is vasectomized

⁃ Male subjects with a female partner of childbearing potential must:

∙ Be vasectomized, or

‣ Agree to use condoms as defined in Section 8.6.2, from first dose of tazemetostat until 3 months following the last dose of tazemetostat, or

‣ Have a female partner who is NOT of childbearing potential