Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

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

Summary: 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 fivecohorts based on tumor type:
  -  Cohort 1: MRT, RTK, ATRT, or selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type [SCCOHT], also known as malignant rhaboid tumor of the ovary [MRTO]
  -  Cohort 2: Relapsed or refractory synovial sarcoma with SS18-SSX rearrangement
  -  Cohort 3: Other INI1 negative tumors or any solid tumor with an EZH2 gain of function (GOF) mutation, 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) any solid tumor with an EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma
  -  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.


Eligibility: 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), 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 ONLY)
  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 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
  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 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 >2 weeks 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

Relevance to patient case: not relevant