Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

• ClinicalTrials.gov Identifier: NCT02860286
• Recruitment Status: Completed
• First Posted: August 9, 2016
• Results First Posted: April 9, 2021
• Last Update Posted: April 9, 2021
• Sponsor: Epizyme, Inc.
• Information provided by (Responsible Party): Epizyme, Inc.

Tracking Information

• First Submitted Date: July 27, 2016
• First Posted Date: August 9, 2016
• Results First Submitted Date: November 16, 2020
• Results First Posted Date: April 9, 2021
• Last Update Posted Date: April 9, 2021
• Study Start Date: July 2016
• Actual Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 16, 2021)

• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax [ Time Frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose ]
  To assess the pharmacokinetic (PK) and safety profile of single (Cycle 1 day 1) and repeated doses (Cycle 1 day 2 onwards) of 800 mg tazemetostat administered as 400 mg tablets in subjects with relapsed or refractory malignant mesothelioma regardless of BRCA1 associated protein 1 (BAP1) status.
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Tmax [ Time Frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose. ]
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t) [ Time Frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose. ]
  To assess the pharmacokinetic (PK) and safety profile of single (Cycle 1 day 1) and repeated doses (Cycle 1 day 2 onwards) of 800 mg tazemetostat administered as 400 mg tablets in subjects with relapsed or refractory malignant mesothelioma regardless of BRCA1 associated protein 1 (BAP1) status
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞) [ Time Frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose ]
  Pharmacokinetics profile of tazemetostat and its metabolite (plasma) assessing AUC(0-∞)
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2 [ Time Frame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose ]
  Results from assessing the half-life of Tazemetostat and its metabolite shown below
• Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) [ Time Frame: The patients were assessed for DCR for up to 24 weeks ]
  Overall, the disease control rate (DCR) (calculated as subjects with CR + subjects with PR + subjects with SD at 12 weeks in duration), and the DCR at 24 weeks.
• Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability [ Time Frame: From the first dose of study treatment until the earlier of either 30 days after the discontinuation of study treatment or until the initiation of subsequent anticancer therapy. ]

Original Primary Outcome Measures (submitted: August 4, 2016)

• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax [ Time Frame: Days 1 and 15 ]
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Tmax [ Time Frame: Days 1 and 15 ]
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t) [ Time Frame: Days 1 and 15 ]
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞) [ Time Frame: Days 1 and 15 ]
• Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2 [ Time Frame: Days 1 and 15 ]
• Part 1: Incidence of treatment-emergent adverse events as a measure of safety and tolerability [ Time Frame: Adverse events assessed from first dose through 30 days post last dose ]
• Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) [ Time Frame: 12 weeks ]

Current Secondary Outcome Measures (submitted: March 16, 2021)

• Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) [ Time Frame: Assessed every 6 weeks for duration of study participation which is estimated to be 12 months ]
  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)
• Progression-free Survival (PFS) [ Time Frame: The patients were assessed for PFS for up to 24 weeks ]
  Progression-Free Survival is defined as the interval of time between the date of the first dose of study drug and the earliest date of disease progression or death due to any cause. PFS was analyzed and listed for the ITT population. PFS was calculated using the Kaplan-Meier method.
• Part 1 and 2: Overall Survival (OS) [ Time Frame: The patients were assessed for PFS for up to 24 weeks ]
  OS was analyzed and listed for the ITT population. Subjects who have not died were censored at the date of last contact which was identified from a visit date, study assessment (physical examination, vital signs, ECOG performance status, electrocardiogram [ECG], study drug record, radiological evaluation), AE, medication, or disposition information. OS was calculated using the Kaplan-Meier method. OS at 12 and 24 weeks along with the associated 2-sided 95% CIs were provided. Median OS, first and third quartiles and associated 95% 2-sided CIs were provided.
• Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR [ Time Frame: Every 6 weeks up to disease progression or start of new anti-cancer therapy assessed for up to 12 months ]
  DOR was calculated for subjects with a confirmed CR or PR. DOR is defined as the time from the date of the initial response (CR/PR) to the date of first documented PD or death due to any cause, whichever occurs first. DOR censoring rules followed those of the PFS analysis defined in the SAP. DOR was analyzed using the Kaplan-Meier methods and the median DOR, first quartile, and third quartile was presented. The associated 2- sided 95% CIs was estimated.
• Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) [ Time Frame: The patients were assessed for DCR for up to 24 weeks ]
  Overall, the disease control rate (DCR) (calculated as subjects with CR + subjects with PR + subjects with SD at 12 weeks in duration), and the DCR at 24 weeks.

Original Secondary Outcome Measures (submitted: August 4, 2016)

• Part 1 and 2: Incidence of treatment-emergent adverse events as a measure of safety and tolerability [ Time Frame: Adverse events assessed from first dose through 30 days post last dose ]
• Part 1 and 2: Overall response rate (ORR; complete response + partial response [CR + PR]) [ Time Frame: Assessed every 6 weeks for duration of study participation which is estimated to be 12 months ]
• Part 1 and 2: Progression-free survival (PFS) [ Time Frame: 12 weeks and 24 weeks as the time from the date of the first dose of study treatment to the date of death due to any cause ]
• Part 1 and 2: Overall Survival (OS) [ Time Frame: 12 weeks and 24 weeks as the time from the date of the first dose of study treatment to the date of death due to any cause assessed for up to 24 months ]
• Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR [ Time Frame: Every 6 weeks up to disease progression or start of new anti-cancer therapy assessed for up to 12 months ]
• Part 1: Disease Control Rate (DCR) [ Time Frame: 12 weeks ]
• Part 2: Population PK parameters: Cmax [ Time Frame: Days 1 and 15 of Cycle 1, and Days 1 of Cycles 2 through 4, where each cycle is 21 days ]
• Part 2: Population PK parameters: Tmax [ Time Frame: Days 1 and 15 of Cycle 1, and Days 1 of Cycles 2 through 4, where each cycle is 21 days ]
• Part 2: Population PK parameters: AUC(0-t) [ Time Frame: Days 1 and 15 of Cycle 1, and Days 1 of Cycles 2 through 4, where each cycle is 21 days ]
• Part 2: Population PK parameters: AUC(0-∞) [ Time Frame: Days 1 and 15 of Cycle 1, and Days 1 of Cycles 2 through 4, where each cycle is 21 days ]
• Part 2: Population PK parameters: t1/2 [ Time Frame: Days 1 and 15 of Cycle 1, and Days 1 of Cycles 2 through 4, where each cycle is 21 days ]
• Part 2: Changes in H3K27me3 levels in tumor tissue as assessed by IHC [ Time Frame: 6 or 12 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

Brief 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: planned to enroll 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 plans to include 55 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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Mesothelioma
• BAP1 Loss of Function

Intervention

Drug: Tazemetostat

Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.

Other Names:

• EPZ-6438
• E7438

Study Arms

Experimental: Open-Label Tazemetostat

Oral Tazemetostat 800mg BID

Intervention: Drug: Tazemetostat

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 23, 2019): 74
• Original Estimated Enrollment (submitted: August 4, 2016): 67
• Actual Study Completion Date: May 2019
• Actual Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)

Eligibility 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:

   • 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, United Kingdom, United States

Administrative Information

• NCT Number: NCT02860286
• Other Study ID Numbers: EZH-203
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: To be determined.

• Responsible Party: Epizyme, Inc.
• Study Sponsor: Epizyme, Inc.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Epizyme, Inc.
• Verification Date: March 2021