Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

Official Title:

A Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects With Relapsed or Refractory Malignant Mesothelioma With BAP1 Loss of Function

Basic Trial Information

Phase Type Age Sponsor Protocol IDs Status
Phase 2 Interventional 18 Years and older Epizyme, Inc. EZH-203
NCT02860286
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 2, multicenter, open-label, 2-part, single-arm, 2-stage study of tazemetostat 800 mg two times a day (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.

In Part 1, 12 subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status will be treated and undergo pharmacokinetics (PK) blood sample collection after a single tazemetostat 800 mg.

Part 2 will include subjects with BAP1-deficient relapsed or refractory malignant mesothelioma.

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 6 weeks of treatment and then every 12 weeks thereafter while on study.

Eligibility

Inclusion Criteria:

     1. Age (at the time of consent) ≥18 years of age
     2. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
     3. Has a life expectancy of >3 months
     4. Has mesothelioma (pleural, peritoneal, pericardial, tunica vaginalis) of any
         histology that is relapsed or refractory after treatment with at least one
         pemetrexed-containing regimen
     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. Part 2: Molecular evidence of BAP1 loss of function mutation present on local
         pathology, e.g., lack of nuclear BAP1 staining by immunohistochemistry (IHC) or
         evidence of loss of function by gene sequencing
     7. Has sufficient archival tumor tissue (a minimum of 10 slides or tumor block)
         available for central retrospective testing of BAP1 status
     8. 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
     9. Prior therapy(ies), if applicable, must be completed according to the criteria below
         prior to first dose of tazemetostat:
    - Cytotoxic chemotherapy; at least 21 days since last dose
    - Non-cytotoxic chemotherapy (e.g., small molecule inhibitor); at least 14 days
       since last dose
    - Monoclonal antibody; at least three half-lives since the last dose
    - Non-antibody immunotherapy (e.g., tumor vaccine); at least 42 days since last
       dose
    - Radiotherapy, at least 14 days from last local site radiotherapy
    - Hematopoietic growth factor; at least 14 days from last dose
    - Investigational drug; 30 days or five half-lives, whichever is longer, from last
       dose
     10. Has measurable disease based on either modified RECIST [Nowak 2005] for thoracic
         disease or RECIST 1.1 elsewhere
     11. Has adequate hematologic (bone marrow and coagulation factors), renal, and hepatic
         function as defined by criteria below:
    - Hemoglobin ≥9 mg/dL
    - Platelets ≥100,000/mm3 (≥100 × 109/L) without platelet transfusion for 7 days
    - ANC ≥1000/mm3 (≥1.0 × 109/L) without growth factor support for 14 days
    - Coagulation: Prothrombin time (PT) <1.5 × ULN and partial thromboplastin time
       (PTT) <1.5 × ULN
    - Creatinine < 2.0 × ULN
    - Hepatic function: Conjugated bilirubin <1.5 × ULN and ALT and AST <3 × ULN
     12. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec
     13. Willing to provide tissue for translational research
     14. Female subjects of childbearing potential must have a negative urine or serum
         pregnancy within 72 hours prior to receiving the first dose of study drug; if the
         urine test is positive or cannot be confirmed as negative, a serum pregnancy test
         will be required and subject also should agree to use an adequate method of
         contraception starting with screening through 30 days after the last dose of study
         therapy (if sexually active).
     15. Male subjects should agree to use condoms starting with the first dose of study
         therapy through 30 days after the last dose of study therapy if sexually active with
         a female of childbearing potential
Exclusion Criteria:

     1. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste
         homologue-2 (EZH2)
     2. Has a history of known central nervous system metastasis
     3. 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.
     4. Has had major surgery within 3 weeks prior to enrollment (a percutaneous biopsy,
         pleural catheter insertion, placement of central venous catheter or other minor
         procedure are permitted)
     5. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the
         diet and all foods that contain those fruits from time of enrollment throughout their
         time on study
     6. 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
     7. Is currently taking any prohibited medication(s)
     8. Has an active infection requiring systemic treatment
     9. Has a congenital or acquired immunodeficiency, including subjects with known history
         of infection with human immunodeficiency virus (HIV) NOTE: HIV-positive subjects who
         are taking antiretroviral therapy are ineligible due to potential PK interactions
         with tazemetostat.
     10. Has known history of chronic infection with hepatitis B virus (hepatitis B surface
         antigen positive) or hepatitis C virus (detectable anti-hepatitis C circulating viral
         RNA)
     11. Has had a deep venous thrombosis (DVT) or pulmonary embolism within the 3 months
         prior to study enrollment.
         NOTE: Subjects with a history of a DVT or pulmonary embolism >3 months prior to study
         enrollment who are on anticoagulation therapy with low molecular weight heparin are
         eligible for this study.
     12. Is pregnant or breastfeeding.

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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