Part 1 – Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status Part 2 – Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma MedDRA version: 19.1 Level: HLT Classification code 10027414 Term: Mesotheliomas malignant and unspecified System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) M
Conditions
Interventions
Product Name: TAZEMETOSTAT
Product Code: EPZ-6438 (E7438)
Pharmaceutical Form: Tablet
INN or Proposed INN: TAZEMETOSTAT
Current Sponsor
Sponsors
Epizyme, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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: a. Cytotoxic chemotherapy; at least 21 days since last dose b. Non-cytotoxic chemotherapy (e.g., small molecule inhibitor); at least 14 days since last dose c. Monoclonal antibody; at least three half-lives since the last dose d. Non-antibody immunotherapy (e.g., tumor vaccine); at least 42 days since last dose e. Radiotherapy, at least 14 days from last local site radiotherapy f. Hematopoietic growth factor; at least 14 days from last dose g. 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: a. Hemoglobin =9 mg/dL b. Platelets =100,000/mm3 (=100 × 109/L) without platelet transfusion for 7 days c. ANC =1000/mm3 (=1.0 × 109/L) without growth factor support for 14 days d. Coagulation: Prothrombin time (PT) <1.5 × ULN and partial thromboplastin time (PTT) <1.5 × ULN e. Creatinine < 2.0 × ULN f. 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 starti
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Part 1 End of Cycle 1 Part 2 DCR (CR+PR+SD) at Week 12 ; Main Objective: Part 1 (Pharmacokinetics) To assess the pharmacokinetic (PK) and safety profile of single and repeated doses of 800 mg tazemetostat administered as 400 mg tablets in subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status Part 2 (Efficacy) To assess disease control rate (DCR) at 12 weeks [consisting of complete response (CR), partial response (PR) or stable disease (SD)] according to modified RECIST [Nowak, 2005] for thoracic disease or RECIST 1.1 elsewhere in subjects with relapsed or refractory BAP1-deficient malignant mesothelioma treated with tazemetostat ; Secondary Objective: Parts 1 and 2 To assess the safety and tolerability of tazemetostat To assess the overall response rate (ORR) in subjects with relapsed or refractory malignant mesothelioma treated with tazemetostat To determine the progression-free survival (PFS) and overall survival (OS) at 12 weeks, 24 weeks and overall in subjects with relapsed or refractory malignant mesothelioma treated with tazemetostat To evaluate the duration of response (DOR) in subjects with relapsed or refractory malignant mesothelioma achieving a CR or PR according to disease-appropriate criteria treated with tazemetostat Part 1 To assess DCR at 12 weeks (consisting of CR, PR, and SD) in subjects with relapsed or refractory malignant mesothelioma treated with tazemetostat Part 2 To assess the population PK parameters of tazemetostat To investigate the pharmacodynamic (PD) effects of tazemetostat in tumor tissue before and after treatment with tazemetostat (optional) ; | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Part 1 and 2 DCR (CR+PR+SD) at Week 12 and 24 ; Secondary end point(s): Parts 1 and 2 AE and clinical laboratory tests ORR (confirmed CR+PR) to tazemetostat in subjects with relapsed/refractory malignant mesothelioma using disease-appropriate standardized response criteria (modified RECIST or RECIST 1.1) PFS at 12 weeks, 24 weeks, and overall (defined as the time from date of first dose of study treatment to the earlier of the date of first documented disease progression or date of death due to any cause) OS at 12 weeks, 24 weeks, and overall (defined as the time from the date of the first dose of study treatment to the date of death due to any cause) DOR, for the subset of subjects with a confirmed CR or PR (defined as the time from the first documented evidence of CR or PR to the time of first documented disease progression or death due to any cause, using disease-appropriate standardized response criteria) Part 1 DCR (CR+PR+SD) at Week 12 Part 2 Population PK parameters oral clearance (CL/F), oral volume of distribution (Vd/F), and first-order absorption rate constant (Ka) for tazemetostat Changes in H3K27me3 levels between pre- and post-dose tumor tissue | — |
Countries
France, United Kingdom, United States
Contacts
Public ContactClinical Trials Information
Epizyme, Inc.
Outcome results
None listed