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 NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair subject is considered to be ambulatory for the purpose of assessing their performance status.

⁃ 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 epithelioid sarcoma undergoing optional tumor biopsy):

⁃ Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1)

⁃ If providing optional biopsy: Willingness to provide informed consent to undergo pre- and post-dose biopsy

⁃ 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 of IHC and/or cytogenetics/FISH and/or DNA mutation analysis (required for study entry but enrollment based on local results)

⁃ 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 as defined by criteria below:

⁃ Hematologic (BM Function):

⁃ Hemoglobin ≥9 mg/dL

⁃ Platelets ≥100,000/mm^3 (≥100x10^9/L)

⁃ ANC ≥1,000/mm^3 (≥1.0x10^9/L)

⁃ Hematologic (Coagulation Factors):

⁃ INR/PT₫ <1.5 ULN

⁃ PTT>1.5 ULN

⁃ Renal Function:

• Serum creatinine ≤1.5 x ULN

⁃ Hepatic Function:

⁃ Total bilirubin <1.5 x ULN(Eligibility can be determined by conjugated or total bilirubin)

⁃ AST and ALT <3 x ULN NOTE: Laboratory results obtained during screening should be used to determine eligibility criteria. In situations where laboratory results are outside the permitted range, the Investigator may retest the subject and the subsequent within range screening result may be used to determine the subject's eligibility.

⁃ 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 NOTE: Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS symptoms prior to enrollment; however, subjects should receive a stable or tapering dose for at least 7 days prior to 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 (urine or serum test is acceptable however, positive urine tests must be confirmed with serum testing), and

⁃ Agree to use effective contraception, as defined in Section 8.6.1, 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 (when this is in line with the preferred and usual lifestyle of the subject, see Section 8.6.1), 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