Clinical trial NCT02860286: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Mesothelioma
BAP1 Loss of Function
Lead sponsor: Epizyme, Inc.
Sponsor class: INDUSTRY
First posted: 2016-08-09
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax
timeFrame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose
measure: Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Tmax
timeFrame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.
measure: Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t)
timeFrame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.
measure: Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞)
timeFrame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose
measure: Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2
timeFrame: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose
measure: Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)
timeFrame: The patients were assessed for DCR for up to 24 weeks
measure: Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability
timeFrame: 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.
Secondary outcomes:
measure: Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR])
timeFrame: Assessed every 6 weeks for duration of study participation which is estimated to be 12 months
measure: Progression-free Survival (PFS)
timeFrame: The patients were assessed for PFS for up to 24 weeks
measure: Part 1 and 2: Overall Survival (OS)
timeFrame: The patients were assessed for PFS for up to 24 weeks
measure: Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR
timeFrame: Every 6 weeks up to disease progression or start of new anti-cancer therapy assessed for up to 12 months
measure: Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)
timeFrame: The patients were assessed for DCR for up to 24 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Los Angeles
country: United States
facility: City of Hope National Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Bordeaux Cedex
country: France
facility: Institut Bergonie
city: Lille
country: France
facility: CHRU de Lille
city: Villejuif cedex
country: France
facility: Institut Gustave Roussy
city: Leicester
country: United Kingdom
facility: University of Leicester & Leicester University Hospitals
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital
city: London
country: United Kingdom
facility: University College Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital - Chelsea
city: Manchester
country: United Kingdom
facility: University Hospital of South Manchester
city: Sutton
country: United Kingdom
facility: Royal Marsden Hospital - Surrey
Study officials:
References:
citation: Zauderer MG, Szlosarek PW, Le Moulec S, Popat S, Taylor P, Planchard D, Scherpereel A, Koczywas M, Forster M, Cameron RB, Peikert T, Argon EK, Michaud NR, Szanto A, Yang J, Chen Y, Kansra V, Agarwal S, Fennell DA. EZH2 inhibitor tazemetostat in patients with relapsed or refractory, BAP1-inactivated malignant pleural mesothelioma: a multicentre, open-label, phase 2 study. Lancet Oncol. 2022 Jun;23(6):758-767. doi: 10.1016/S1470-2045(22)00277-7. Epub 2022 May 16.