Trial Outcomes & Findings for Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma (NCT NCT02860286)

Last Updated: 2021-04-09

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

74 participants

Primary outcome timeframe

Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

Results posted on

2021-04-09

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Part 1 (Pharmacokinetics) 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.	Part 2 (Efficacy) 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.
Overall Study STARTED	13	61
Overall Study COMPLETED	13	61
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Study of the EZH2 Inhibitor Tazemetostat in Malignant Mesothelioma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1 (Pharmacokenitc) n=13 Participants 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.	Part 2 (Efficacy) n=61 Participants 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 n=74 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	6 Participants n=5 Participants	37 Participants n=7 Participants	43 Participants n=5 Participants
Age, Categorical >=65 years	7 Participants n=5 Participants	24 Participants n=7 Participants	31 Participants n=5 Participants
Age, Continuous	64.7 Years STANDARD_DEVIATION 8.58 • n=5 Participants	65.1 Years STANDARD_DEVIATION 10.56 • n=7 Participants	65.0 Years STANDARD_DEVIATION 10.18 • n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	22 Participants n=7 Participants	25 Participants n=5 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	39 Participants n=7 Participants	49 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	5 Participants n=5 Participants	44 Participants n=7 Participants	49 Participants n=5 Participants
Race/Ethnicity, Customized Other	6 Participants n=5 Participants	15 Participants n=7 Participants	21 Participants n=5 Participants
Region of Enrollment United States	8 participants n=5 Participants	15 participants n=7 Participants	23 participants n=5 Participants
Region of Enrollment United Kingdom	2 participants n=5 Participants	35 participants n=7 Participants	37 participants n=5 Participants
Region of Enrollment France	3 participants n=5 Participants	11 participants n=7 Participants	14 participants n=5 Participants
Baseline Disease Characteristics and Prior Therapies Solid Tumor with 1 prior line of systemic Anticancer Therapy	3 Participants n=5 Participants	27 Participants n=7 Participants	30 Participants n=5 Participants
Baseline Disease Characteristics and Prior Therapies Solid Tumor with 2 prior lines of systemic Anticancer Therapy	7 Participants n=5 Participants	13 Participants n=7 Participants	20 Participants n=5 Participants
Baseline Disease Characteristics and Prior Therapies Solid Tumor with 3 prior lines of systemic Anticancer Therapy	1 Participants n=5 Participants	14 Participants n=7 Participants	15 Participants n=5 Participants
Baseline Disease Characteristics and Prior Therapies Solid Tumor with 4 prior lines of systemic Anticancer Therapy	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Baseline Disease Characteristics and Prior Therapies Solid Tumor with >=5 prior lines of systemic Anticancer Therapy	1 Participants n=5 Participants	6 Participants n=7 Participants	7 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and 12 post-dose

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Cmax	933 Ng/mL Standard Deviation 440	—

PRIMARY outcome

Timeframe: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): Tmax	1.1 Hour Interval 1.0 to 4.0	—

PRIMARY outcome

Timeframe: Cycle 1 Day 15: pre-dose, 0.5, 1, 2, 4, 6, 8, 10, and12 post-dose.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-t)	3650 h*ng/mL Standard Deviation 1640	—

PRIMARY outcome

Timeframe: 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-∞)

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): AUC(0-∞)	3410 h*ng/mL Standard Deviation 1640	—

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1: Pharmacokinetics Profile of Tazemetostat and Its Metabolite (Plasma): t1/2	3.06 Hour Standard Deviation 0.307	—

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=61 Participants 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.	Part 2 Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) DCR at 12 weeks	33 Participants	—
Part 2: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) DCR at 24 weeks	20 Participants	—

PRIMARY outcome

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.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 n=61 Participants Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any TEAE	13 Participants	60 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any TEAE Grade 3 or 4	5 Participants	31 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any Treatment-Related TEAE	8 Participants	44 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any Treatment-Related TEAE Grade 3 or 4	3 Participants	9 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any TEAE Leading to Dose Reduction or 4or() {	0 Participants	3 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any TEAE Leading to Study Drug Interruption��	5 Participants	22 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any TEAE Leading to Study Drug Discontinuation	0 Participants	2 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any TESAENR	2 Participants	23 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any Treatment-Related TESAE	1 Participants	2 Participants
Incidence of Treatment-emergent Adverse Events as a Measure of Safety and Tolerability Any Protocol Defined AE of Special Interestion	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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)

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 n=61 Participants Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) Objective Response Rate,	0 Participants	2 Participants
Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) Complete response	0 Participants	0 Participants
Part 1 and 2: Objective Response Rate (ORR; Complete Response + Partial Response [CR + PR]) Partial response	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 n=61 Participants Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Progression-free Survival (PFS)	12 Weeks Interval 5.4 to 34.1	18 Weeks Interval 1.6 to 114.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 n=61 Participants Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1 and 2: Overall Survival (OS)	29.0 Weeks Interval 16.3 to 139.7	41.0 Weeks Interval 1.6 to 120.9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 n=61 Participants Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR DOR great than 6 weeks	0 Participants	0 Participants
Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR DOR great than 12 weeks	0 Participants	0 Participants
Part 1 and 2: To Evaluate the Duration of Response (DOR) in Subjects With Confirmed CR or PR DOR great than 18 weeks	0 Participants	2 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Part 1 (Pharmacokinetics) n=13 Participants 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.	Part 2 Subjects with BAP1-deficientrelapsed or refractorymalignant mesothelioma wereto receive orally administeredtazemetostat 800 mg twicedaily starting on Cycle 1 Day1
Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) DCR at 12 weeks	5 Participants	—
Part 1: To Assess Disease Control Rate (DCR) Defined as Number of Subjects With Complete Response (CR), Partial Response (PR) and Stable Disease (SD) DCR at 24 weeks	1 Participants	—

Adverse Events

Part 1 (Pharmacokinetics)

Serious events: 2 serious events

Other events: 13 other events

Deaths: 1 deaths

Part 2 (Efficacy)

Serious events: 4 serious events

Other events: 59 other events

Deaths: 7 deaths

Serious adverse events

Other adverse events

Additional Information

Kemly Calixte

Epizyme

Phone: 617-500-0608

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Part 1 (Pharmacokinetics) n=13 participants at risk 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.	Part 2 (Efficacy) n=61 participants at risk 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
Infections and infestations Liver abscess	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Peritonitis	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Pneumonia	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Sepsis	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	4.9% 3/61 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Systemic infection	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Investigations Electrocardiogram ST segment elevation	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Investigations Electrocardiogram T wave inversiontion	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Investigations Oxygen saturation decreased	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Metabolism and nutrition disorders Decreased appetite	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer Pain	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Respiratory, thoracic and mediastinal disorders Pleural effusion	15.4% 2/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Respiratory, thoracic and mediastinal disorders Dyspnoea	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Cardiac disorders Pericardial Effusion	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Vascular disorders Embolism	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Vascular disorders Air embolism	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Vascular disorders Deep vein thrombosis	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Abdominal pain	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Ascites	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Incarcerated umbilical hernia	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Intestinal perforation	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Nausea	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Pneumoperitoneum	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Vomiting	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
General disorders General physical health deterioration	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant ascites	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Nervous system disorders Syncope	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Renal and urinary disorders Renal failure	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.

Measure	Part 1 (Pharmacokinetics) n=13 participants at risk 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.	Part 2 (Efficacy) n=61 participants at risk 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
Gastrointestinal disorders Nausea	46.2% 6/13 • Number of events 6 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	24.6% 15/61 • Number of events 22 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Vomiting	15.4% 2/13 • Number of events 4 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	24.6% 15/61 • Number of events 18 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Abdominal Distension	15.4% 2/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	8.2% 5/61 • Number of events 8 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Constipation	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	11.5% 7/61 • Number of events 7 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Abdominal pain	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	6.6% 4/61 • Number of events 5 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Dyspepsia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Gastrooesophageal Reflux Disease	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Ascites	7.7% 1/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Dysphagia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Gastrointestinal disorders Haemorrhoids	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
General disorders Fatigue	30.8% 4/13 • Number of events 4 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	36.1% 22/61 • Number of events 28 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
General disorders Asthenia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	13.1% 8/61 • Number of events 10 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
General disorders Oedema peripheral	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	9.8% 6/61 • Number of events 8 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
General disorders Pyrexia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
General disorders Chills	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Respiratory, thoracic and mediastinal disorders Dyspnoea	53.8% 7/13 • Number of events 13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	23.0% 14/61 • Number of events 19 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Respiratory, thoracic and mediastinal disorders Cough	15.4% 2/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	27.9% 17/61 • Number of events 17 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Respiratory, thoracic and mediastinal disorders Dysphonia	15.4% 2/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	4.9% 3/61 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	7.7% 1/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Respiratory, thoracic and mediastinal disorders Epistaxis	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Throat Irritation	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Lower respiratory tract infection	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	13.1% 8/61 • Number of events 11 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Upper respiratory Tract Infection	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	8.2% 5/61 • Number of events 5 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Oral candidiasis	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	4.9% 3/61 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Infections and infestations Urinary tract infection	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	6.6% 4/61 • Number of events 4 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Metabolism and nutrition disorders Decreased appetite	15.4% 2/13 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	36.1% 22/61 • Number of events 27 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Metabolism and nutrition disorders Hyperglycaemia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	4.9% 3/61 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Metabolism and nutrition disorders Hypophosphataemia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Metabolism and nutrition disorders Hypokalaemia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	23.1% 3/13 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	29.5% 18/61 • Number of events 33 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Nervous system disorders Dysgeusia	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	13.1% 8/61 • Number of events 11 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Nervous system disorders Dizziness	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	6.6% 4/61 • Number of events 5 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Nervous system disorders Neuralgia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Investigations Weight decreased	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	19.7% 12/61 • Number of events 15 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Investigations Lymphocyte count decreased	15.4% 2/13 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	0.00% 0/61 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Skin and subcutaneous tissue disorders Dry skin	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	4.9% 3/61 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Skin and subcutaneous tissue disorders Dermal cyst	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Skin and subcutaneous tissue disorders Night sweats	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Skin and subcutaneous tissue disorders Rash	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	3.3% 2/61 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Skin and subcutaneous tissue disorders Dermatitis acneiform	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Musculoskeletal and connective tissue disorders Back pain	23.1% 3/13 • Number of events 3 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	6.6% 4/61 • Number of events 5 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	9.8% 6/61 • Number of events 8 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Musculoskeletal and connective tissue disorders Arthralgia	7.7% 1/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Blood and lymphatic system disorders Anaemia	0.00% 0/13 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	21.3% 13/61 • Number of events 17 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Injury, poisoning and procedural complications Procedural pain	7.7% 1/13 • Number of events 2 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.
Psychiatric disorders Insomnia	7.7% 1/13 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.	1.6% 1/61 • Number of events 1 • Adverse Events were collected over a period of 2 years. No other adverse events are listed in the CSR.