Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

Mesothelioma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02860286
• Other study ID #: EZH-203
• Status: Completed
• Phase: Phase 2
• Start date: July 2016
• Est. completion date: May 2019

Study information

• Verified date: March 2021
• Source: Epizyme, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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: 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 74
• Est. completion date: May 2019
• Est. primary completion date: June 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

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.

Related Conditions & MeSH terms

• BAP1 Loss of Function
• Mesothelioma

Intervention

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

Locations

Country	Name	City	State
France	Institut Bergonie	Bordeaux Cedex
France	CHRU de Lille	Lille
France	Institut Gustave Roussy	Villejuif cedex
United Kingdom	University of Leicester & Leicester University Hospitals	Leicester
United Kingdom	Royal Marsden Hospital - Chelsea	London
United Kingdom	St. Bartholomew's Hospital	London
United Kingdom	University College Hospital	London
United Kingdom	University Hospital of South Manchester	Manchester
United Kingdom	Royal Marsden Hospital - Surrey	Sutton
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	City of Hope National Medical Center	Los Angeles	California
United States	University of California, Los Angeles	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Epizyme, Inc.

Countries where clinical trial is conducted

United States,  France,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax	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.	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose
Primary	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Tmax		Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.
Primary	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t)	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	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.
Primary	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-8)	Pharmacokinetics profile of tazemetostat and its metabolite (plasma) assessing AUC(0-8)	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose
Primary	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2	Results from assessing the half-life of Tazemetostat and its metabolite shown below	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose
Primary	Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)	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.	The patients were assessed for DCR for up to 24 weeks
Primary	Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability		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	Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR])	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)	Assessed every 6 weeks for duration of study participation which is estimated to be 12 months
Secondary	Progression-free Survival (PFS)	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.	The patients were assessed for PFS for up to 24 weeks
Secondary	Part 1 and 2: Overall Survival (OS)	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.	The patients were assessed for PFS for up to 24 weeks
Secondary	Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR	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.	Every 6 weeks up to disease progression or start of new anti-cancer therapy assessed for up to 12 months
Secondary	Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)	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.	The patients were assessed for DCR for up to 24 weeks