EZH-202: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Why are we doing this research?

PURPOSE:

This is a Phase II, multicenter, open-label, single arm, 2-stage study of tazemetostat 800 mg BID administered orally. 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-deficient/aberrant tumors, including: Epithelioid sarcoma (ES), Epithelioid malignant peripheral nerve sheath tumor (EMPNST), Extraskeletal myxoid chondrosarcoma (EMC), Myoepithelial carcinoma, Renal medullary carcinoma (RMC), Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval

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.

 

PRIMARY OUTCOME MEASURES:

Number of subjects with objective response using disease appropriate standardized response criteria [ Time Frame: Assessed every 8 weeks for duration of study participation which is estimated to be 24 months ] [ Designated as safety issue: No ]

·         Progression-free survival (PFS) rate for Cohort 2 (Relapsed/Refractory Synovial Sarcoma) [ Time Frame: 16 weeks of treatment ] [ Designated as safety issue: No ]

The number of subjects with CR, PR, or stable disease (SD) at 16 week assessment

 

Study Type: Interventional

Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Who can participate?

AGES ELIGIBLE FOR STUDY: 16 Years and older

ELIGIBILITY CRITERIA

Inclusion Criteria:

  • Age (at the time of consent/assent): ≥16 years of age
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
  • Has a life expectancy of >3 months
  • Has a malignancy:

o    For which there are no standard therapies available (Cohorts 1 & 3)

o    That is relapsed or refractory after treatment with an approved therapy(ies) (Cohort 2)

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

o    Chemotherapy: cytotoxic (At least 21 days since last dose of chemotherapy prior to first dose of tazemetostat)

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

o    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)

o    Monoclonal antibody(ies) (At least 3 half-lives since the last dose of any monoclonal antibody prior to first dose of tazemetostat)

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

o    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)

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

o    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:

o    Hematologic (BM Function):

§  Hemoglobin ≥9 mg/dL

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

§  ANC ≥1,000/mm^3 (≥1.0x10^9/L)

o    Hematologic (Coagulation Factors):

§  PT and PTT <1.5 ULN

§  Fibrinogen >0.5 LLN

o    Renal Function: - Serum creatinine ≤1.5 x ULN

o    Hepatic Function:

§  Conjugated bilirubin <1.5 x ULN

§  AST and ALT <3 x ULN

  • 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
  • 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.

 

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 CNS or leptomeningeal metastasis of primary extra-cranial tumor - NOTE: only subjects with ATRT as a primary CNS tumor are permitted
  • 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
  • Has had major surgery within 3 weeks prior to enrollment
  • 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)
  • Has an active infection requiring systemic treatment
  • Is immunocompromised (i.e. has congenital immunodeficiency), including subjects known history of infection with human immunodeficiency virus (HIV)
  • Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
  • 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
  • For subjects with ATRT only, have ≥3 foci of punctate hemorrhage, any active bleeding, or intratumoral hemorrhage at time of enrollment or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents

Ages

  • years old and above

Conditions

  • Brain Spinal Tumors Medulloblastoma Relapse
  • Brain Spinal Tumor Low Grade Glioma Relapse
  • Brain Spinal Tumor DIPG Relapse
  • Brain and Spinal Tumor Ependymoma Relapse
  • Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Brain Spinal Neurofibromatosis OPG
  • Brain Spinal Other ATRT
  • Brain Spinal Other Craniopharyngioma
  • Brain Spinal Other Germ Cell Tumor
  • Brain Spinal Other Choroid Plexus Tumor
  • Brain Spinal Other All Other
  • Sarcoma Osteosarcoma Relapse
  • Sarcoma Ewing Relapse
  • Sarcoma Rhabdomyosarcoma Relapse
  • Neuroblastoma Relapse - Refractory
  • Liver Relapse - Refractory
  • Kidney Relapse - Refractory
  • Solid Tumor Retinoblastoma Relapse - Refractory
  • Solid Tumor Neurofibromatosis Sarcoma MPNST Relapse - Refractory
  • Solid Tumor Neurofibromatosis OPG Low Grade Glioma
  • Solid Tumor Melanoma Relapse - Refractory
  • Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Solid Tumors - All Other
  • Adult - Brain Spinal Tumors Medulloblastoma Relapse
  • Adult - Brain Spinal Tumor Low Grade Glioma Relapse
  • Adult - Brain Spinal Tumor DIPG Relapse
  • Adult - Brain and Spinal Tumor Ependymoma Relapse
  • Adult - Brain Spinal Neurofibromatosis Sarcoma MPNST Relapse
  • Adult - Brain Spinal Neurofibromatosis OPG
  • Adult - Brain Spinal Other All Other
  • Adult - Brain Spinal Other ATRT
  • Adult - Brain Spinal Other Choroid Plexus Tumor
  • Adult - Brain Spinal Other Craniopharyngioma
  • Adult - Brain Spinal Other Germ Cell Tumor
  • Adult - Sarcoma Ewing Relapse
  • Adult - Sarcoma Osteosarcoma Relapse
  • Adult - Sarcoma Rhabdomyosarcoma Relapse
  • Adult - Neuroblastoma Relapse - Refractory
  • Adult - Liver Relapse - Refractory
  • Adult - Kidney Relapse - Refractory
  • Adult - Solid Tumor Retinoblastoma Relapse - Refractory
  • Adult - Solid Tumor Neurofibromatosis Sarcoma MPNST Relapse - Refractory
  • Adult - Solid Tumor Neurofibromatosis OPG Low Grade Glioma
  • Adult - Solid Tumor Melanoma Relapse - Refractory
  • Adult - Solid Tumor Germ Cell Tumor Relapse - Refractory
  • Adult - Solid Tumors - All Other

Contact

For more information contact:

Cincinnati Children’s Hospital Medical Center
Division of Hematology/Oncology
3333 Burnet Ave., Cincinnati OH 45229-3039

Phone: 513-636-2799

cancer@cchmc.org