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

Official Title:

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

Basic Trial Information

Phase Type Age Sponsor Protocol IDs Status
Phase 2 Interventional 16 Years and older Epizyme, Inc. EZH-202
NCT02601950
Enrolling patients

Study Design:


Principal Investigator

Professor of Medicine
Chair, Data and Safety Monitoring Committee
Bonnie J. and Anthony Addario Endowed Chair in Thoracic Oncology
UCSF Helen Diller Family Comprehensive Cancer Center

Clinical Research Coordinator

UCSF Helen Diller Family Comprehensive Cancer Center
(415) 514-6241 Phone
(415) 353-9721 Fax

Trial 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

Important

Final eligibility is determined by the health professionals conducting the trial and the protocol approved by the Committee on Human Resources (CHR) at the University of California, San Francisco (UCSF). The Patient Consent Form for this trial is available upon request. For more information about this trial, please see the full posting at ClinicalTrials.gov.

Information about this trial was obtained from the NIH Clinical Trials website, http://clinicaltrials.gov on 4/28/2017. UCSF specific information including the PI (Principal Investigator), trial enrollment status, and UCSF Study ID, supplement the ClinicalTrials.gov study posting.
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