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

This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID administered orally in continuous 28 day cycles. Screening of subjects to determine eligibility for the study will be performed within 21 days of the first planned dose of tazemetostat. Eligible subjects will be enrolled into one of three cohorts based on tumor type: - Cohort 1: MRT, RTK, ATRT, or selected tumors with rhabdoid features - Cohort 2: Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement - Cohort 3: Other INI1 negative tumors, including: Epithelioid malignant peripheral nerve sheath tumor (EMPNST), Extraskeletal myxoid chondrosarcoma (EMC), Myoepithelial carcinoma,Other INI1-negative malignant tumors with Sponsor approval (e.g., dedifferentiated chordoma) - Cohort 4: Renal medullary carcinoma (RMC) - Cohort 5: Epithelioid sarcoma (ES) 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 8 weeks of treatment and then every 8 weeks thereafter while on study.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

Overall PI:

Site-responsible Investigators:

Contacts:

Eligibility Criteria

Inclusion Criteria:

  1. Age (at the time of consent/assent): ≥16 years of age

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

  3. Has a life expectancy of >3 months

  4. 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)
  (Cohort 2)

  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. 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

  7. 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)

  8. For Cohort 3 to 5 (subjects with INI1-negative/aberrant tumor only), the following
     test results must be available by local laboratory: Morphology and immunophenotypic
     panel consistent with INI1-negative tumors, 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

  9. Prior therapy(ies), if applicable, must be completed according to the criteria below:

       -  Chemotherapy: cytotoxic (At least 21 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 3 half-lives 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)

 10. 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)

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

 12. 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):

    -  PT and PTT <1.5 ULN

    -  Fibrinogen >0.5 LLN

       -  Renal Function:

  - Serum creatinine ≤1.5 x ULN

       -  Hepatic Function:

    -  Conjugated bilirubin <1.5 x ULN

    -  AST and ALT <3 x ULN

 13. For subjects with ATRT 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

 14. 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

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

Exclusion Criteria:

  1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste
     homologue-2 (EZH2)

  2. 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

  3. Has known active CNS or any leptomeningeal metastasis of primary extra-cranial tumor
     - NOTE: 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.

  4. 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

  5. Has had major surgery within 3 weeks prior to enrollment

  6. 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

  7. 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

  8. Is currently taking any prohibited medication(s)

  9. Has an active infection requiring systemic treatment

 10. Is immunocompromised (i.e. has congenital immunodeficiency), including subjects known
     history of infection with human immunodeficiency virus (HIV)

 11. Has known history of chronic infection with hepatitis B virus (hepatitis B surface
     antigen positive) or hepatitis C virus (detectable HCV RNA)

 12. Has had a symptomatic venous thrombosis within the 3 months prior to study enrollment
     - NOTE: Subjects with a history of a deep vein thrombosis >3 months prior to study
     enrollment who are on anticoagulation therapy with low molecular weight heparin are
     eligible for this study

 13. For subjects with CNS involvement (primary tumor or metastatic disease), have any
     active bleeding or new intratumoral hemorrhage of more than punctuate size of
     screening MRI obtained within 14 days of starting study drug or known bleeding
     diathesis or treatment with anti-platelet or anti-thrombotic agents