Inclusion Criteria:

• Age (at the time of consent/assent): >18years of age.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 (Appendix 1).
  • 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, & 5);
  • That is relapsed or refractory, defined as metastatic or non-resectable, locally advanced disease that has previously been treated with and progressed following approved therapy(ies), if therapy(ies) exists (Cohort 2);
  • That has progressed within 6 months prior to study enrollment (Cohort 5 Expansion and Cohort 6 ONLY).
• Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or other Sponsor-approved laboratory certification.
• For Cohort 1 (subjects with rhabdoid tumors only): The following test results must be available by local laboratory:
  • Morphology and immunophenotypic panel consistent with rhabdoid tumors, and tazemetostat Protocol EZH-202;
  • Loss of INI1 or SMARCA4 confirmed by IHC;
  • 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 test results must be available by local laboratory:
  • Morphology consistent with synovial sarcoma;
  • Cytogenetics or Fluorescence in situ hybridization (FISH) and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11).
• For Cohorts 3, 4, 5, and 7 (subjects with INI1-negative 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);
  • Loss of INI1 confirmed by IHC;
  • Molecular confirmation of tumor bi-allelic INI1 loss or mutation when INI1 IHC is equivocal or unavailable;
  • Molecular evidence of EZH2 GOF mutation.
• For Cohort 6 (subjects with epithelioid sarcoma undergoing mandatory tumor biopsy):
  • Morphology and immunophenotypic panel consistent with epithelioid sarcoma (e.g., CD34, EMA, Keratin, and INI1):
    • Tumor that is accessible for mandatory biopsy.
  • Note: Subjects who are unable to undergo pre-dose (screening biopsy) will not be eligible.
  • 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 4.03 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.
• Prior Therapy Time from Last Prior Therapy:
  • 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 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 stereotactic 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 or allogeneic hematopoietic cell infusion
    • At least 60 days from last infusion prior to first dose of tazemetostat
  • Hematopoietic growth factor in support of anti-cancer therapy
    • 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 as defined in Section 8.5.3.
• Has adequate hematologic (bone marrow [BM] and coagulation factors), renal and hepatic function as defined by criteria below.
• System Laboratory Value > Hematologic (BM Function):
  • Hemoglobin(a) ≥9 g/dL;
  • Platelets(b) ≥100,000/mm3 (≥100 × 109/L);
  • ANC(c) ≥1000/mm3 (≥1.0 × 109/L).
• Hematologic (Coagulation Factors):
  • INR/PTd <1.5 ULN;
  • PTT <1.5 ULN.
• Renal Function:
  • Serum creatininee ≤1.5 × ULN.
• Hepatic Function:
  • Totalf bilirubin <1.5× ULN;
  • ASTg <3 × ULN;
  • ALTg <3 × ULN.
• Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; BM, bone marrow; CrCl, creatinine clearance; LLN, lower limit of normal; PT, prothrombin time; PTT, partial thromboplastin time; ULN, upper limit of normal.
  • May receive transfusion.
  • Should be evaluated after at least 7 days since last platelet transfusion.
  • Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days.
  • INR is the preferred value to be measured. However, if only PT can be performed in the testing laboratory that is acceptable.
  • If creatinine is not <1.5×ULN, then calculate by Cockcroft-Gault methods or local institutional standard and CrCl must be >50 mL/kg/1.73 m2 (see Appendix 3).
  • If attributed to documented Gilbert’s disease, total bilirubin < 2.5 × ULN. Eligibility can be determined by total or conjugated bilirubin.
  • If attributed to tumor involvement, AST and ALT <5×ULN.
  • Subjects a history of hepatitis (Exclusion Criterion No. 11) must have ALT within the normal range.
    • 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 (see Appendix 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 8.5.13.4.1, from start of screening until 30 days 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 8.5.13.4.1);
    • 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 8.5.13.4.2, from first dose of tazemetostat until 30 days following the last dose of tazemetostat; or
  • Have a female partner who is NOT of childbearing potential.
• For French subjects only:  Is either affiliated with or a beneficiary of a social security category.

Exclusion Criteria:

• Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2 (EZH2).
• Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat.
• Has known active CNS or any leptomeningeal metastasis of primary extracranial tumor.  Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging 4 weeks prior to the first dose of study drug and any neurologic symptoms have stabilized), have no  evidence of new or enlarging brain metastases, and are on stable or tapering doses of steroids for at least 7 days prior to first dose of study drug.
  • NOTE: Subjects with asymptomatic brain metastases found on screening MRI may be entered into the study without prior radiation therapy to the brain if they do not require immediate surgical or radiation therapy in the opinion of the treating Investigator and in the opinion of a radiation therapy or neurosurgical consultant.
• Has had a prior malignancy other than the malignancies under study.
  • Exception: 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.
  • NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment..
• Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) pero or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g., del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing.
  • NOTE: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central laboratory.  Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy.
• Has a prior history of T-LBL/T-ALL.
• Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while 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) as described in Section 7.3.
• Has an active infection requiring systemic treatment.
• Is immunocompromised (i.e., has a congenital immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV).
• Has known active infection with hepatitis B virus or hepatitis C virus.
• Subjects with a history of hepatitis B or C with normal ALT and undetectable.
• HBV DNA or HCV RNA are eligible for this study.
• Has had a symptomatic venous thrombosis within 2 weeks prior to study enrollment.
  • NOTE: Subjects with a history of a deep vein thrombosis >2 weeks prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study.
• For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intra-tumoral hemorrhage of more than punctate size on screening MRI obtained within 14 days of starting study drug or known  bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents.
• Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2.
• Is unable to take oral medications, or has malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea or vomiting) that might impair the bioavailability of tazemetostat.
• Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements.
• For female subjects of childbearing potential: Is pregnant or nursing.
• For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 30 days after last dose of tazemetostat.