Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

• Sponsor: Epizyme, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02860286
• Collaborator: (none)
• Enrollment: 74
• Locations: 16
• Arm: 1
• Duration (Months): 34
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Mesothelioma; BAP1 Loss of Function	Drug: Tazemetostat	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: Jul 1, 2016
• Actual Primary Completion Date: Jun 1, 2018
• Actual Study Completion Date: May 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open-Label Tazemetostat Oral Tazemetostat 800mg BID	Drug: Tazemetostat; Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.; Other Names: EPZ-6438 E7438

Outcome Measures

Primary Outcome Measures

1. Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax [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.

2. 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.]

3. Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t) [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

4. Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞) [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-∞)

5. Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2 [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

6. Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) [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.

7. 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 Outcome Measures

1. Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) [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)

2. Progression-free Survival (PFS) [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.

3. Part 1 and 2: Overall Survival (OS) [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.

4. Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR [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.

5. Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. Has measurable disease based on either modified RECIST [Nowak 2005] for thoracic disease or RECIST 1.1 elsewhere

2. 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

1. Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec

2. Willing to provide tissue for translational research

3. 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).

4. 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.

1. Is pregnant or breastfeeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Los Angeles	Los Angeles	California	United States	90025
2	City of Hope National Medical Center	Los Angeles	California	United States	90301
3	University of California San Francisco	San Francisco	California	United States	94143
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
6	Mayo Clinic - Rochester	Rochester	Minnesota	United States	55905
7	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
8	Institut Bergonie	Bordeaux Cedex		France	33076
9	CHRU de Lille	Lille		France	59037
10	Institut Gustave Roussy	Villejuif cedex		France	94805
11	University of Leicester & Leicester University Hospitals	Leicester		United Kingdom	LE1 9HN
12	St. Bartholomew's Hospital	London		United Kingdom	EC1M 6BQ
13	University College Hospital	London		United Kingdom	NW1 2PG
14	Royal Marsden Hospital - Chelsea	London		United Kingdom	SW3 6JJ
15	University Hospital of South Manchester	Manchester		United Kingdom	M23 9LT
16	Royal Marsden Hospital - Surrey	Sutton		United Kingdom	SM2 5PT

Sponsors and Collaborators

• Epizyme, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 27, 2017

More Information

Publications

None provided.

• Responsible Party: Epizyme, Inc.
• ClinicalTrials.gov Identifier: NCT02860286
• Other Study ID Numbers: EZH-203
• First Posted: Aug 9, 2016
• Last Update Posted: Apr 9, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Mesothelioma; Mesothelioma, Malignant

Study Results

Participant Flow

Recruitment Details

Study EZH-203 was conducted at 16 clinical sites in France, UK, and USA. Subjects were screened for eligibility within 21 days of the planned date of the first dose of tazemetostat. Eligible subjects were enrolled into 2 different parts: Part 1 - Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status Part 2 - Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma.

Pre-assignment Detail

Seventy-four subjects were enrolled and treated with study drug (13 subjects in Part 1 and 61 subjects in Part 2). No patients were excluded due to unmet study eligibility criteria.

Arm/Group Title	Part 1 (Pharmacokinetics)	Part 2 (Efficacy)
Arm/Group Description	Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status were to be treated and PK blood samples collected after a single tazemetostat 800 mg dose on Cycle 1 Day 1 and after repeated twice daily doses of tazemetostat 800 mg on Cycle 1 Day 15. Subjects were to receive a single oral 800 mg tazemetostat dose on Cycle 1 Day 1. Starting on Cycle 1 Day 2, tazemetostat was orally administered at a dose of 800 mg twice daily.	subjects with BAP1-deficient relapsed or refractory malignant mesothelioma were to receive orally administered tazemetostat 800 mg twice daily starting on Cycle 1 Day 1.
Period Title: Overall Study
STARTED	13	61
COMPLETED	13	61
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Part 1 (Pharmacokenitc)	Part 2 (Efficacy)	Total
Arm/Group Description	Subjects enrolled in Part 1were to receive a single 800 mg tazemetostat dose on Cycle 1 Day 1. Starting on Cycle 1 Day 2, tazemetostat was to be administered at a dose of 800 mg twice daily. PK blood samples were to be collected after administration of a single dose of 800 mg tazemetostat on Cycle 1 Day 1 and after repeated twice daily doses of tazemetostat 800 mg on Cycle 1 Day 15. Plasma samples were to be analyzed for tazemetostat after each set of 6 subjects completed the PK sampling procedures on Cycle 1 Day 15.	In Part 2, subjects with BAP1-deficient relapsed or refractory malignant mesothelioma were to receive orally administered tazemetostat 800 mg twice daily starting on Cycle 1 Day 1. A 2-stage Green-Dahlberg design was utilized with a stopping rule to allow early termination at the end of Stage 1 if there was strong evidence of lack of efficacy based on results from the first 30 treated subjects who completed at least the 12-week assessment, completed the final study visit, or terminated early from the study, whichever was sooner. If early stopping criteria were met, enrollment was to be stopped. To avoid disruptions in the study, enrollment and treatment of subjects were not halted in order to conduct the interim analysis.	Total of all reporting groups
Overall Participants	13	61	74
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	6 46.2%	37 60.7%	43 58.1%
>=65 years	7 53.8%	24 39.3%	31 41.9%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	64.7 (8.58)	65.1 (10.56)	65.0 (10.18)
Sex: Female, Male (Count of Participants)
Female	3 23.1%	22 36.1%	25 33.8%
Male	10 76.9%	39 63.9%	49 66.2%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	2 15.4%	2 3.3%	4 5.4%
Not Hispanic or Latino	5 38.5%	44 72.1%	49 66.2%
Other	6 46.2%	15 24.6%	21 28.4%
Region of Enrollment (participants) [Number]
United States	8 61.5%	15 24.6%	23 31.1%
United Kingdom	2 15.4%	35 57.4%	37 50%
France	3 23.1%	11 18%	14 18.9%
Baseline Disease Characteristics and Prior Therapies (Count of Participants)
Solid Tumor with 1 prior line of systemic Anticancer Therapy	3 23.1%	27 44.3%	30 40.5%
Solid Tumor with 2 prior lines of systemic Anticancer Therapy	7 53.8%	13 21.3%	20 27%
Solid Tumor with 3 prior lines of systemic Anticancer Therapy	1 7.7%	14 23%	15 20.3%
Solid Tumor with 4 prior lines of systemic Anticancer Therapy	1 7.7%	1 1.6%	2 2.7%
Solid Tumor with >=5 prior lines of systemic Anticancer Therapy	1 7.7%	6 9.8%	7 9.5%

Outcome Measures

1. Primary Outcome

Title	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax
Description	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.
Time Frame	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1 (Pharmacokinetics)
Arm/Group Description	Assessment of 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.
Measure Participants	13
Mean (Standard Deviation) [Ng/mL]	933 (440)

2. Primary Outcome

Title	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1 (Pharmacokinetics)
Arm/Group Description	Assessment of 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.
Measure Participants	13
Median (Inter-Quartile Range) [Hour]	1.1

3. Primary Outcome

Title	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t)
Description	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
Time Frame	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1 (Pharmacokinetics)
Arm/Group Description	Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status were to be treated and PK blood samples collected after a single tazemetostat 800 mg dose on Cycle 1 Day 1 and after repeated twice daily doses of tazemetostat 800 mg on Cycle 1 Day 15. Subjects were to receive a single oral 800 mg tazemetostat dose on Cycle 1 Day 1. Starting on Cycle 1 Day 2, tazemetostat was orally administered at a dose of 800 mg twice daily.
Measure Participants	13
Mean (Standard Deviation) [h*ng/mL]	3650 (1640)

4. Primary Outcome

Title	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞)
Description	Pharmacokinetics profile of tazemetostat and its metabolite (plasma) assessing AUC(0-∞)
Time Frame	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1 (Pharmacokinetics)
Arm/Group Description	Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status were to be treated and PK blood samples collected after a single tazemetostat 800 mg dose on Cycle 1 Day 1 and after repeated twice daily doses of tazemetostat 800 mg on Cycle 1 Day 15. Subjects were to receive a single oral 800 mg tazemetostat dose on Cycle 1 Day 1. Starting on Cycle 1 Day 2, tazemetostat was orally administered at a dose of 800 mg twice daily.
Measure Participants	13
Mean (Standard Deviation) [h*ng/mL]	3410 (1640)

5. Primary Outcome

Title	Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2
Description	Results from assessing the half-life of Tazemetostat and its metabolite shown below
Time Frame	Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1(Pharmacokinetics)
Arm/Group Description	Oral Tazemetostat 800mg BID Tazemetostat: Tazemetostat (EPZ-6438) is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2 gene.
Measure Participants	13
Mean (Standard Deviation) [Hour]	3.06 (0.307)

6. Primary Outcome

Title	Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)
Description	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.
Time Frame	The patients were assessed for DCR for up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 2
Arm/Group Description	Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma.
Measure Participants	61
DCR at 12 weeks	33 253.8%
DCR at 24 weeks	20 153.8%

7. Primary Outcome

Title	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1	Part 2
Arm/Group Description	Subjects with relapsed orrefractory malignantmesothelioma regardless ofBAP1 status were to be treatedand PK blood samplescollected after a singletazemetostat 800 mg dose onCycle 1 Day 1 and afterrepeated twice daily doses oftazemetostat 800 mg on Cycle1 Day 15. Subjects were toreceive a single oral 800 mgtazemetostat dose on Cycle 1Day 1. Starting on Cycle 1 Day2, tazemetostat was orallyadministered at a dose of 800mg twice daily.	Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Measure Participants	13	61
Any TEAE	13 100%	60 98.4%
Any TEAE Grade 3 or 4	5 38.5%	31 50.8%
Any Treatment-Related TEAE	8 61.5%	44 72.1%
Any Treatment-Related TEAE Grade 3 or 4	3 23.1%	9 14.8%
Any TEAE Leading to Dose Reduction or 4or() {	0 0%	3 4.9%
Any TEAE Leading to Study Drug Interruption��	5 38.5%	22 36.1%
Any TEAE Leading to Study Drug Discontinuation	0 0%	2 3.3%
Any TESAENR	2 15.4%	23 37.7%
Any Treatment-Related TESAE	1 7.7%	2 3.3%
Any Protocol Defined AE of Special Interestion	0 0%	0 0%

8. Secondary Outcome

Title	Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR])
Description	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)
Time Frame	Assessed every 6 weeks for duration of study participation which is estimated to be 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1	Part 2
Arm/Group Description	Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status	Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma
Measure Participants	13	61
Objective Response Rate,	0 0%	2 3.3%
Complete response	0 0%	0 0%
Partial response	0 0%	2 3.3%

9. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	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.
Time Frame	The patients were assessed for PFS for up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1	Part 2
Arm/Group Description	Part 1 - Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status Part 2: Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma	Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma
Measure Participants	13	61
Median (Inter-Quartile Range) [Weeks]	12	18

10. Secondary Outcome

Title	Part 1 and 2: Overall Survival (OS)
Description	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.
Time Frame	The patients were assessed for PFS for up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1	Part 2
Arm/Group Description	Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status	Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma
Measure Participants	13	61
Median (Inter-Quartile Range) [Weeks]	29.0	41.0

11. Secondary Outcome

Title	Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR
Description	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.
Time Frame	Every 6 weeks up to disease progression or start of new anti-cancer therapy assessed for up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part 1	Part 2
Arm/Group Description	Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 statu	Subjects with relapsed or refractory BAP1-deficient malignant mesothelioma
Measure Participants	13	61
DOR great than 6 weeks	0 0%	0 0%
DOR great than 12 weeks	0 0%	0 0%
DOR great than 18 weeks	0 0%	2 3.3%

12. Secondary Outcome

Title	Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD)
Description	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.
Time Frame	The patients were assessed for DCR for up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part
Arm/Group Description	Subjects with relapsed or refractory malignant mesothelioma regardless of BAP1 status
Measure Participants	13
DCR at 12 weeks	5 38.5%
DCR at 24 weeks	1 7.7%

Adverse Events

Time Frame	Adverse Events were collected over a period of 2 years.
Adverse Event Reporting Description	No other adverse events are listed in the CSR.
Arm/Group Title	Part 1 (Pharmacokinetics)		Part 2 (Efficacy)
Arm/Group Description	Assessed 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.		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
All Cause Mortality
	Part 1 (Pharmacokinetics)		Part 2 (Efficacy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/13 (7.7%)		7/61 (11.5%)
Serious Adverse Events
	Part 1 (Pharmacokinetics)		Part 2 (Efficacy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/13 (15.4%)		4/61 (6.6%)
Cardiac disorders
Pericardial Effusion	0/13 (0%)	0	2/61 (3.3%)	2
Gastrointestinal disorders
Abdominal pain	0/13 (0%)	0	1/61 (1.6%)	1
Ascites	0/13 (0%)	0	1/61 (1.6%)	1
Incarcerated umbilical hernia	0/13 (0%)	0	1/61 (1.6%)	1
Intestinal perforation	0/13 (0%)	0	1/61 (1.6%)	1
Nausea	0/13 (0%)	0	1/61 (1.6%)	1
Pneumoperitoneum	0/13 (0%)	0	1/61 (1.6%)	1
Vomiting	0/13 (0%)	0	1/61 (1.6%)	1
General disorders
General physical health deterioration	0/13 (0%)	0	1/61 (1.6%)	1
Infections and infestations
Liver abscess	0/13 (0%)	0	1/61 (1.6%)	1
Peritonitis	0/13 (0%)	0	1/61 (1.6%)	1
Pneumonia	0/13 (0%)	0	2/61 (3.3%)	2
Sepsis	0/13 (0%)	0	3/61 (4.9%)	3
Systemic infection	0/13 (0%)	0	1/61 (1.6%)	1
Investigations
Electrocardiogram ST segment elevation	0/13 (0%)	0	1/61 (1.6%)	1
Electrocardiogram T wave inversiontion	0/13 (0%)	0	1/61 (1.6%)	1
Oxygen saturation decreased	0/13 (0%)	0	1/61 (1.6%)	1
Metabolism and nutrition disorders
Decreased appetite	0/13 (0%)	0	1/61 (1.6%)	1
Hyperglycaemia	0/13 (0%)	0	1/61 (1.6%)	1
Hyponatraemia	0/13 (0%)	0	2/61 (3.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer Pain	0/13 (0%)	0	1/61 (1.6%)	1
Malignant ascites	0/13 (0%)	0	1/61 (1.6%)	1
Squamous cell carcinoma of skin	0/13 (0%)	0	1/61 (1.6%)	1
Nervous system disorders
Syncope	0/13 (0%)	0	1/61 (1.6%)	1
Renal and urinary disorders
Renal failure	0/13 (0%)	0	1/61 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion	2/13 (15.4%)	2	1/61 (1.6%)	1
Dyspnoea	1/13 (7.7%)	1	2/61 (3.3%)	2
Vascular disorders
Embolism	1/13 (7.7%)	1	1/61 (1.6%)	1
Air embolism	0/13 (0%)	0	1/61 (1.6%)	1
Deep vein thrombosis	0/13 (0%)	0	1/61 (1.6%)	1
Other (Not Including Serious) Adverse Events
	Part 1 (Pharmacokinetics)		Part 2 (Efficacy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		59/61 (96.7%)
Blood and lymphatic system disorders
Anaemia	0/13 (0%)	0	13/61 (21.3%)	17
Gastrointestinal disorders
Nausea	6/13 (46.2%)	6	15/61 (24.6%)	22
Vomiting	2/13 (15.4%)	4	15/61 (24.6%)	18
Abdominal Distension	2/13 (15.4%)	2	5/61 (8.2%)	8
Constipation	0/13 (0%)	0	7/61 (11.5%)	7
Abdominal pain	1/13 (7.7%)	1	4/61 (6.6%)	5
Dyspepsia	1/13 (7.7%)	1	2/61 (3.3%)	2
Gastrooesophageal Reflux Disease	1/13 (7.7%)	1	1/61 (1.6%)	1
Ascites	1/13 (7.7%)	2	0/61 (0%)	0
Dysphagia	1/13 (7.7%)	1	0/61 (0%)	0
Haemorrhoids	1/13 (7.7%)	1	0/61 (0%)	0
General disorders
Fatigue	4/13 (30.8%)	4	22/61 (36.1%)	28
Asthenia	1/13 (7.7%)	1	8/61 (13.1%)	10
Oedema peripheral	1/13 (7.7%)	1	6/61 (9.8%)	8
Pyrexia	1/13 (7.7%)	1	2/61 (3.3%)	3
Chills	1/13 (7.7%)	1	0/61 (0%)	0
Infections and infestations
Throat Irritation	1/13 (7.7%)	1	0/61 (0%)	0
Lower respiratory tract infection	0/13 (0%)	0	8/61 (13.1%)	11
Upper respiratory Tract Infection	1/13 (7.7%)	1	5/61 (8.2%)	5
Oral candidiasis	1/13 (7.7%)	1	3/61 (4.9%)	3
Urinary tract infection	0/13 (0%)	0	4/61 (6.6%)	4
Injury, poisoning and procedural complications
Procedural pain	1/13 (7.7%)	2	1/61 (1.6%)	1
Investigations
Weight decreased	0/13 (0%)	0	12/61 (19.7%)	15
Lymphocyte count decreased	2/13 (15.4%)	3	0/61 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	2/13 (15.4%)	3	22/61 (36.1%)	27
Hyperglycaemia	1/13 (7.7%)	1	3/61 (4.9%)	3
Hypophosphataemia	1/13 (7.7%)	1	1/61 (1.6%)	1
Hypokalaemia	1/13 (7.7%)	1	0/61 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	3/13 (23.1%)	3	4/61 (6.6%)	5
Muscle spasms	0/13 (0%)	0	6/61 (9.8%)	8
Arthralgia	1/13 (7.7%)	2	1/61 (1.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	3/13 (23.1%)	3	18/61 (29.5%)	33
Nervous system disorders
Dysgeusia	0/13 (0%)	0	8/61 (13.1%)	11
Dizziness	0/13 (0%)	0	4/61 (6.6%)	5
Neuralgia	1/13 (7.7%)	1	0/61 (0%)	0
Psychiatric disorders
Insomnia	1/13 (7.7%)	1	1/61 (1.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	7/13 (53.8%)	13	14/61 (23%)	19
Cough	2/13 (15.4%)	2	17/61 (27.9%)	17
Dysphonia	2/13 (15.4%)	2	3/61 (4.9%)	3
Pleural Effusion	1/13 (7.7%)	2	2/61 (3.3%)	2
Epistaxis	1/13 (7.7%)	1	0/61 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	1/13 (7.7%)	1	3/61 (4.9%)	3
Dermal cyst	1/13 (7.7%)	1	2/61 (3.3%)	2
Night sweats	1/13 (7.7%)	1	2/61 (3.3%)	2
Rash	1/13 (7.7%)	1	2/61 (3.3%)	3
Dermatitis acneiform	1/13 (7.7%)	1	1/61 (1.6%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.