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    Clinical Trial Results:
    A PHASE 1B/2 OPEN-LABEL STUDY EVALUATING TAZEMETOSTAT IN COMBINATION WITH ENZALUTAMIDE OR ABIRATERONE/PREDNISONE IN CHEMOTHERAPY NAIVE SUBJECTS WITH METASTATIC CASTRATION RESISTANT PROSTATE CANCER

    Summary
    EudraCT number
    		 2019-003649-14
    Trial protocol
    		 BE  
    Global end of trial date
    04 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2025
    First version publication date
    19 Nov 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EZH-1101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04179864
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 143032
    Sponsors
    Sponsor organisation name
    Epizyme, Inc.
    Sponsor organisation address
    400 Technology Square, 4th Floor, Cambridge, MA, United States, 02139
    Public contact
    Medical Director, Ipsen, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Ipsen, clinical.trials@ipsen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Nov 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase Ib: To determine the safety and tolerability of each of the combinations (tazemetostat with enzalutamide or tazemetostat with abiraterone/prednisone); To select the recommended phase 2 doses (RP2Ds) of tazemetostat for each combination treatment based on pharmacokinetic (PK) and pharmacodynamic (PD) parameters as well as efficacy and the overall tolerability of each of the combinations (tazemetostat with enzalutamide or tazemetostat with abiraterone/prednisone). Phase II: To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide monotherapy, as assessed by radiographic progression-free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for progression in bone or in soft tissue (the latter by Response Evaluation Criteria in Solid Tumours 1.1 [RECIST 1.1]).
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, following the International Conference on Harmonisation (ICH) Consolidated Guideline on Good Clinical Practice (GCP) and in compliance with IECs/IRBs, informed consent regulations and the sponsor's policy on bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Nov 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    United States: 84
    Worldwide total number of subjects
    102
    EEA total number of subjects
    18
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    29
    From 65 to 84 years
    69
    85 years and over
    4

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This Phase 1b/2, 2-part, open-label study was conducted at 21 sites in asymptomatic or mildly symptomatic participants with progressive, metastatic castration resistant prostate cancer (mCRPC).

    Pre-assignment
    Screening details
    		 The study consisted of 2 parts: Phase 1b (dose-escalation) and Phase 2 (randomized). The study was terminated early as Sponsor decided to discontinue the development of tazemetostat in mCRPC and the primary endpoint was not met for this study. There were no safety concerns.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide
    Arm description
    		 Participants received tazemetostat 400 milligrams (mg) tablet orally twice daily (BID) from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally once daily (OD) from Cycle 1 Day 1 until death, disease progression (PD), development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 400 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg capsule orally OD in continuous 28-day cycles.

    Arm title
    		 Phase 1b: Tazemetostat 600 mg + Enzalutamide
    Arm description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 600 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg capsule orally OD in continuous 28-day cycles.

    Arm title
    		 Phase 1b: Tazemetostat 800 mg + Enzalutamide
    Arm description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 800 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg capsule orally OD in continuous 28-day cycles.

    Arm title
    		 Phase 1b: Tazemetostat 1200 mg + Enzalutamide
    Arm description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 1200 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg capsule orally OD in continuous 28-day cycles.

    Arm title
    		 Phase 1b: Tazemetostat 1600 mg + Enzalutamide
    Arm description
    		 Participants received tazemetostat 1600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 1600 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg capsule orally OD in continuous 28-day cycles.

    Arm title
    		 Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone
    Arm description
    		 Participants received tazemetostat 400 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 400 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received abiraterone 1000 mg tablet orally OD in continuous 28-day cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received prednisone 5 mg tablet orally BID in continuous 28-day cycles.

    Arm title
    		 Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone
    Arm description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 600 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received abiraterone 1000 mg tablet orally OD in continuous 28-day cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received prednisone 5 mg tablet orally BID in continuous 28-day cycles.

    Arm title
    		 Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Arm description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 800 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Abiraterone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received abiraterone 1000 mg tablet orally OD in continuous 28-day cycles.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received prednisone 5 mg tablet orally BID in continuous 28-day cycles.

    Arm title
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide
    Arm description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tazemetostat
    Investigational medicinal product code
    EPZ-6438
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tazemetostat 1200 mg tablet orally BID in continuous 28-day cycles.

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg capsule orally OD in continuous 28-day cycles.

    Arm title
    		 Phase 2: Enzalutamide
    Arm description
    		 Participants received enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Enzalutamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received enzalutamide 160 mg capsule orally OD in continuous 28-day cycles.

    Number of subjects in period 1
    		Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Started
    2
    3
    3
    3
    3
    1
    3
    3
    41
    40
    Completed
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Not completed
    2
    3
    3
    3
    3
    1
    3
    3
    41
    40
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    -
    -
    5
    5
         Physician decision
    -
    -
    -
    -
    -
    -
    -
    -
    1
    2
         Adverse event, non-fatal
    1
    -
    -
    -
    -
    -
    -
    -
    3
    1
         Non- Compliance With Study Drug
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Death
    -
    -
    -
    -
    -
    -
    -
    -
    -
    2
         Progressive Disease
    1
    3
    3
    3
    2
    1
    3
    3
    28
    28
         Study Terminated by Sponsor
    -
    -
    -
    -
    -
    -
    -
    -
    3
    2
         Sponsor Request
    -
    -
    -
    -
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b: Tazemetostat 400 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 400 milligrams (mg) tablet orally twice daily (BID) from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally once daily (OD) from Cycle 1 Day 1 until death, disease progression (PD), development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 600 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 800 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 1200 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 1600 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 400 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 2: Tazemetostat 1200 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 2: Enzalutamide
    Reporting group description
    		 Participants received enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group values
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide Total
    Number of subjects
    		 2 3 3 3 3 1 3 3 41 40 102
    Age categorical
    Units: Subjects
        <65 years
    		 0 1 2 0 2 0 1 0 12 11 29
        >=65 years
    		 2 2 1 3 1 1 2 3 29 29 73
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0 0 0 0 0 0 0 0
        Male
    		 2 3 3 3 3 1 3 3 41 40 102
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 1 0 0 1 1 0 1 5 3 12
        Not Hispanic or Latino
    		 2 2 3 2 2 0 3 2 35 33 84
        Unknown or Not Reported
    		 0 0 0 1 0 0 0 0 1 4 6
    Race
    Units: Subjects
        Black or African American
    		 0 0 1 0 0 0 0 0 0 6 7
        White
    		 2 3 2 3 3 1 3 3 35 31 86
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0 6 3 9

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Phase 1b: Tazemetostat 400 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 400 milligrams (mg) tablet orally twice daily (BID) from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally once daily (OD) from Cycle 1 Day 1 until death, disease progression (PD), development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 600 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 800 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 1200 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 1600 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 400 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 2: Tazemetostat 1200 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 2: Enzalutamide
    Reporting group description
    		 Participants received enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Subject analysis set title
    Phase 1b: Tazemetostat Dose-escalation
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received tazemetostat 400 mg, 600 mg, 800 mg, 1200 mg and 1600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1; Participants received tazemetostat 400 mg, 600 mg and 800 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Subject analysis set title
    Phase 1b: Tazemetostat + Enzalutamide
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received tazemetostat 400 mg, 600 mg, 800 mg, 1200 mg and 1600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Subject analysis set title
    Phase 1b: Tazemetostat + Abiraterone/prednisone
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received tazemetostat 400 mg, 600 mg and 800 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Subject analysis set title
    Phase 2: Tazemetostat 1200 mg + Enzalutamide
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Subject analysis set title
    Phase 2: Enzalutamide
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Primary: Phase 1b: Number of Participants With Treatment-Emergent non-Serious Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Phase 1b: Number of Participants With Treatment-Emergent non-Serious Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [1] [2]
    End point description
    AE:untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily had a causal relationship with this study drug. SAE: AE which occurred during any study phase and at any dose of study drug, that fulfilled 1 or more of following:resulted in death,was life-threatening,required hospitalization or prolongation of existing hospitalization,resulted in disability or incapacity,was a congenital abnormality or birth defect,or was an important medical event that might jeopardize participant or might require medical intervention to prevent one of outcomes listed above.TEAEs:AEs that started or worsened in severity on or after date of first dose of study drug through 30 after end of study drug, or prior to initiation of another investigational agent or cytotoxic chemotherapy. Safety population:all participants who received any dose of study drugs. TE non-serious AEs are presented with a frequency threshold of 5%.
    End point type
    Primary
    End point timeframe
    From first dose of study drug (Day 1) up to either 30 days after last dose of study drug or until the initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint was descriptive in nature, no statistical analysis was reported.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 1b arms.
    End point values
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Number of subjects analysed
    2
    3
    3
    3
    3
    1
    3
    3
    Units: participants
        Treatment-emergent non-serious AEs
    2
    3
    3
    3
    3
    1
    3
    3
        TESAEs
    0
    1
    0
    0
    2
    0
    1
    1
    No statistical analyses for this end point

    Primary: Phase 1b: Recommended Phase 2 Dose of Tazemetostat

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    End point title
    		 Phase 1b: Recommended Phase 2 Dose of Tazemetostat [3]
    End point description
    RP2D was based on PK parameters, PD parameters as well as efficacy and the overall tolerability of each combination (tazemetost with enzalutamide or tazemetostat with abiraterone/prednisone). The safety population included all participants who received any dose of the study drugs.
    End point type
    Primary
    End point timeframe
    From Day 1 up to Day 28 of Cycle 1 (each cycle was 28 days)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint was descriptive in nature, no statistical analysis was reported.
    End point values
    		 Phase 1b: Tazemetostat Dose-escalation
    Number of subjects analysed
    21
    Units: mg
        number (not applicable)
    1200
    No statistical analyses for this end point

    Primary: Phase 2: Radiographic Progression-Free Survival

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    End point title
    		 Phase 2: Radiographic Progression-Free Survival [4] [5]
    End point description
    rPFS was defined as the time from date of randomization (phase 2)/date of first dose of study drug (phase 1b) to the first objective evidence of radiographic progression using RECIST 1.1 (soft tissue) and PCWG3 (bone), or death from any cause, whichever occurred first. The radiographic PD for soft tissue lesion was determined based on computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria and no confirmatory scan was required for soft tissue PD; for bone lesion was determined by 2 or more new bone lesions on bone scan per PCWG3 criteria (i.e., the appearance of 2 or more new bone lesions on bone scan) and the 2 scans (i.e., the confirmatory scan is required for bone disease progression) should be at least 6 weeks apart from each other. The intent-to-treat (ITT) population included all participants who were randomized into the study.
    End point type
    Primary
    End point timeframe
    Assessments performed at screening (within 4 weeks of randomization) and every 8 weeks for first 6 months and then every 12 weeks thereafter, until death, PD, unacceptable toxicity, consent withdrawal, or termination of study. Approximately 200 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint was descriptive in nature, no statistical analysis was reported.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 2 arms.
    End point values
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    41
    40
    Units: months
        median (confidence interval 95%)
    22.1 (16.6 to 27.6)
    11.1 (5.7 to 16.5)
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Percentage of Participants With Confirmed Prostate-Specific Antigen >=50% (PSA50) Response

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    End point title
    		 Phase 1b and 2: Percentage of Participants With Confirmed Prostate-Specific Antigen >=50% (PSA50) Response
    End point description
    Blood samples were collected for evaluation of PSA. Confirmed PSA50 response was defined as >=50% decline of PSA from baseline at any time on study for participants with a baseline PSA >=1.0 microgram per liter (mcg/L) (nanogram/milliliter [ng/mL]) per PCWG3 criteria. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization. Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 (Baseline) up to either 30 days after last dose of study drug or until initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    14
    7
    41
    40
    Units: percentage of participants
        number (confidence interval 95%)
    28.6 (8.39 to 58.10)
    14.3 (0.36 to 57.87)
    19.5 (8.82 to 34.87)
    15.0 (5.71 to 29.84)
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Objective Response Rate (ORR)

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    End point title
    		 Phase 1b and 2: Objective Response Rate (ORR)
    End point description
    ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target lesions, any pathological lymph nodes (LN) must be <10 millimeter (mm) in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study. Only those participants with response are reported.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed at screening (within 4 weeks of randomization) and every 8 weeks for first 6 months and then every 12 weeks thereafter, until death, PD, unacceptable toxicity, consent withdrawal, or termination of study.Approximately 259 weeks
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    6
    1
    10
    14
    Units: percentage of participants
        number (confidence interval 95%)
    16.7 (0.42 to 64.12)
    0.0 (0 to 97.50)
    10.0 (0.25 to 44.50)
    0.0 (0 to 23.16)
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Best Overall Response (BOR)

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    End point title
    		 Phase 1b and 2: Best Overall Response (BOR)
    End point description
    BOR was defined as percentage of participants with CR, PR, stable disease (SD), PD, or not evaluable (NE). CR was defined as disappearance of all target lesions, any pathological LN must be <10 mm in the short axis. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as a reference, baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the drug started. In addition, sum had an absolute increase from nadir of 5 mm. NE: which cannot be classified by 1 of above preceding definitions. Phase 1b: safety population: all participants who received any dose of the study drugs. Phase 2: ITT population: all participants who were randomized into study. Only those participants with response are reported. Percentages are rounded off to the tenth decimal place.
    End point type
    Secondary
    End point timeframe
    Tumor assessments performed at screening (within 4 weeks of randomization) and every 8 weeks for first 6 months and then every 12 weeks thereafter, until death, PD, unacceptable toxicity, consent withdrawal, or termination of study.Approximately 259 weeks
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    6
    1
    10
    14
    Units: percentage of participants
    number (not applicable)
        Complete response
    0.0
    0.0
    0.0
    0.0
        Partial response
    16.7
    0.0
    10.0
    0.0
        Stable disease
    66.7
    100.0
    70.0
    57.1
        Progressive disease
    16.7
    0.0
    20.0
    35.7
        Not evaluable
    0.0
    0.0
    0.0
    7.1
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Disease Control Rate (DCR) at 6 Months

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    End point title
    		 Phase 1b and 2: Disease Control Rate (DCR) at 6 Months
    End point description
    DCR at 6 months (24 weeks) was defined as percentage of participants with measurable soft tissue disease at baseline who had BOR of CR or PR and remaining on study without progression at 23 weeks or with a duration of SD for at least 23 weeks after of randomization (phase 2)/first dose (phase 1b) using overall imaging-based response assessed by RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone). BOR:percentage of participants with CR, PR, SD, PD, or NE.CR: disappearance of all target lesions,any pathological LN must be <10 mm in the short axis.PR:at least a 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters.SD:neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.PD:at least a 20% increase in sum of diameters of target lesions,taking as a reference, smallest sum of diameters recorded since the drug started.In addition, sum had an absolute increase from nadir of 5 mm. Phase 1b: safety, Phase 2: ITT.
    End point type
    Secondary
    End point timeframe
    Baseline and at 6 months (24 weeks)
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    6
    1
    10
    14
    Units: percentage of participants
        number (confidence interval 95%)
    50.0 (11.81 to 88.19)
    100.0 (2.50 to 100)
    40.0 (40.0 to 73.76)
    21.4 (4.66 to 50.80)
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Time to First Skeletal-Related Event (SRE) Per Prostate Cancer Clinical Trials Working Group 3 Criteria

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    End point title
    		 Phase 1b and 2: Time to First Skeletal-Related Event (SRE) Per Prostate Cancer Clinical Trials Working Group 3 Criteria
    End point description
    Time to first SRE per PCWG3 criteria was defined as the time from the date of randomization (phase II)/date of the first dose of study drug (phase Ib) to the date of first SRE. An SRE was defined as radiation therapy or surgery to bone, pathologic bone fracture, or spinal cord compression. Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study. Only those participants with confirmed SRE event are reported. "9999": indicates that the values were not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    6
    3
    7
    9
    Units: months
        median (confidence interval 95%)
    16.2 (4.4 to 9999)
    26.3 (4.0 to 9999)
    9999 (16.9 to 9999)
    9999 (9.0 to 9999)
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Time to Initiation of the Next Systemic Treatment (TTNT) for Prostate Cancer

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    End point title
    		 Phase 1b and 2: Time to Initiation of the Next Systemic Treatment (TTNT) for Prostate Cancer
    End point description
    TTNT was defined as the time from the date of randomization (phase II)/date of the first dose of the study drug (phase Ib) to the date of the first documented administration of systemic treatment for prostate cancer. Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study. Only those participants who initiated the next systemic treatment are reported. "9999": indicates that the values were not estimable due to insufficient number of participants with events.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    13
    5
    27
    21
    Units: months
        median (confidence interval 95%)
    8.2 (2.6 to 13.9)
    13.4 (5.4 to 9999)
    9.0 (6.5 to 17.0)
    10.6 (5.0 to 15.9)
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Time to Prostate-Specific Antigen Progression (TTPP)

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    End point title
    		 Phase 1b and 2: Time to Prostate-Specific Antigen Progression (TTPP)
    End point description
    TTPP was defined as the duration from the date of randomization (phase II)/date of first dose of study drug (phase Ib) to the date of first PSA progression per PCWG3 criteria. PSA progression was defined as a >=25% increase and an absolute increase of >=2 mcg/L (2 ng/mL) above the nadir (or baseline value for participants who did not have a decline in PSA value beyond 12 weeks). Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization. Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study. Only those participants with confirmed PSA progression are reported.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    10
    7
    26
    25
    Units: months
        median (confidence interval 95%)
    4.6 (2.1 to 8.3)
    2.8 (2.8 to 4.6)
    4.6 (3.3 to 11.1)
    3.0 (2.8 to 5.6)
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Percentage of Participants With Reduction in Circulating Tumor Cells (CTC)

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    End point title
    		 Phase 1b and 2: Percentage of Participants With Reduction in Circulating Tumor Cells (CTC)
    End point description
    Blood samples were collected for evaluation of CTC. Reduction in CTC was defined as participants from a state of having a detectable number of CTCs to having an undetectable number of CTCs. Percentage of participants with detectable CTC at baseline and non-detectable CTC are presented. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization. Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 (Baseline) up to either 30 days after last dose of study drug or until initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    14
    7
    41
    40
    Units: percentage of participants
    number (not applicable)
        Detectable CTC at baseline
    64.3
    100.0
    36.6
    52.5
        Non-detectable CTC
    35.7
    0.0
    63.4
    47.5
    No statistical analyses for this end point

    Secondary: Phase 1b and 2: Percentage of Participants With Circulating Tumor Cells Response

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    End point title
    		 Phase 1b and 2: Percentage of Participants With Circulating Tumor Cells Response
    End point description
    Blood samples were collected for evaluation of CTC. CTC response was defined as a >=30% reduction in CTC number from baseline in participants who entered the study. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization. Phase 1b: The safety population included all participants who received any dose of the study drugs. Phase 2: The ITT population included all participants who were randomized into the study.
    End point type
    Secondary
    End point timeframe
    From Cycle 1 Day 1 (Baseline) up to either 30 days after last dose of study drug or until initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively
    End point values
    		 Phase 1b: Tazemetostat + Enzalutamide Phase 1b: Tazemetostat + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    14
    7
    41
    40
    Units: percentage of participants
        number (confidence interval 95%)
    88.9 (51.75 to 99.72)
    100.0 (59.04 to 100.00)
    80.0 (51.91 to 95.67)
    42.9 (21.82 to 65.98)
    No statistical analyses for this end point

    Secondary: Phase 2: Number of Participants With Treatment-Emergent non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events

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    End point title
    		 Phase 2: Number of Participants With Treatment-Emergent non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events [6]
    End point description
    AE:any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily had a causal relationship with this study drug. SAE:AE which occurred during any study phase and at any dose of the study drug,that fulfilled 1 or more of following:resulted in death,was life-threatening,required hospitalization or prolongation of existing hospitalization,resulted in disability or incapacity,was a congenital abnormality or birth defect,or was an important medical event that might jeopardize participant or might require medical intervention to prevent one of outcomes listed above.TEAEs:AEs that started or worsened in severity on or after date of first dose of study drug through 30 after end of study drug,or prior to initiation of another investigational agent or cytotoxic chemotherapy.Safety population:all participants who received any dose of study drugs.TE non-serious AEs are presented with frequency threshold of 5%.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug (Day 1) up to either 30 days after last dose of study drug or until the initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 191 weeks
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 2 arms.
    End point values
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    41
    40
    Units: participants
        Treatment-emergent non-serious AEs
    41
    39
        TESAEs
    13
    10
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Tazemetostat

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    End point title
    		 Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Tazemetostat [7]
    End point description
    Blood samples were collected at specified timepoints for the assessment of AUC0-last of tazemetostat. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "9999": indicates that the values were not estimable as they were below the lower limit of quantification (LLOQ) of 1.00 ng/mL.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 2 and 21 (each cycle was 28 days)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 1b arms.
    End point values
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Number of subjects analysed
    2
    3
    3
    3
    3
    1
    3
    3
    Units: hour*nanograms per milliliter (ng/ mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 2 (n=2, 3, 3, 3, 3, 1, 3, 3)
    1640 ( 150 )
    3350 ( 2020 )
    2860 ( 866 )
    7060 ( 1580 )
    6830 ( 5880 )
    9999 ( 9999 )
    3480 ( 2990 )
    4380 ( 4680 )
        Cycle 1 Day 21 (n=1, 3, 3, 3, 3, 1, 3, 3)
    9999 ( 9999 )
    1230 ( 168 )
    1490 ( 606 )
    2800 ( 2020 )
    1120 ( 620 )
    9999 ( 9999 )
    2290 ( 1100 )
    3500 ( 1570 )
    No statistical analyses for this end point

    Secondary: Phase 1b: Maximum Plasma Concentration (Cmax) of Tazemetostat

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    End point title
    		 Phase 1b: Maximum Plasma Concentration (Cmax) of Tazemetostat [8]
    End point description
    Blood samples were collected at specified timepoints for the assessment of Cmax of tazemetostat. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "9999": indicates that the values were not estimable as they were below the LLOQ of 1.00 ng/mL.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 2 and 21 (each cycle was 28 days)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 1b arms.
    End point values
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Number of subjects analysed
    2
    3
    3
    3
    3
    1
    3
    3
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 2 (n=2, 3, 3, 3, 3, 1, 3, 3)
    341 ( 69.3 )
    911 ( 609 )
    888 ( 97.8 )
    1470 ( 217 )
    1730 ( 1100 )
    9999 ( 9999 )
    851 ( 348 )
    1060 ( 916 )
        Cycle 1 Day 21 (n=1, 3, 3, 3, 3, 1, 3, 3)
    9999 ( 9999 )
    364 ( 36.8 )
    530 ( 436 )
    568 ( 341 )
    254 ( 118 )
    9999 ( 9999 )
    810 ( 327 )
    1140 ( 646 )
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 8 Hours Post-Dose (AUC0-8) of Tazemetostat

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    End point title
    		 Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 8 Hours Post-Dose (AUC0-8) of Tazemetostat [9]
    End point description
    Blood samples were collected at specified timepoints for the assessment of AUC0-8 of tazemetostat. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "9999": indicates that the values were not estimable as they were below the LLOQ of 1.00 ng/mL.
    End point type
    Secondary
    End point timeframe
    8 hours post-dose on Cycle 1 Days 2 and 21 (each cycle was 28 days)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 1b arms.
    End point values
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Number of subjects analysed
    2
    3
    3
    3
    3
    1
    3
    3
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 2 (n=2, 3, 3, 3, 3, 1, 3, 3)
    1240 ( 705 )
    3350 ( 2020 )
    2860 ( 866 )
    7060 ( 1580 )
    6830 ( 5880 )
    9999 ( 9999 )
    3130 ( 2390 )
    4380 ( 4680 )
        Cycle 1 Day 21 (n=1, 3, 3, 2, 2, 1, 2, 3)
    9999 ( 9999 )
    1230 ( 168 )
    1490 ( 606 )
    3770 ( 1590 )
    1440 ( 310 )
    9999 ( 9999 )
    2280 ( 1560 )
    3500 ( 1570 )
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 12 Hours Post-Dose (AUC0-12) of Tazemetostat

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    End point title
    		 Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 12 Hours Post-Dose (AUC0-12) of Tazemetostat [10]
    End point description
    Blood samples were collected at specified timepoints for the assessment of AUC0-12 of tazemetostat. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "9999": indicates that the values were not estimable as they were below the LLOQ of 1.00 ng/mL. "99999": indicates that no participants were analyzed for that category.
    End point type
    Secondary
    End point timeframe
    12 hours post-dose on Cycle 1 Days 2 and 21 (each cycle was 28 days)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 1b arms.
    End point values
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Number of subjects analysed
    1
    2
    2
    1
    1
    1
    2
    1
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 2 (n=1, 0, 1, 1, 1, 1, 2, 1)
    9999 ( 9999 )
    99999 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    9999 ( 9999 )
    4480 ( 3460 )
    9999 ( 9999 )
        Cycle 1 Day 21 (n=0, 2, 2, 0, 0, 1, 1, 0)
    99999 ( 99999 )
    1300 ( 121 )
    1800 ( 863 )
    99999 ( 99999 )
    99999 ( 99999 )
    9999 ( 9999 )
    9999 ( 9999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose (AUC0-24) of Enzalutamide

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    End point title
    		 Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose (AUC0-24) of Enzalutamide [11]
    End point description
    Blood samples were collected at specified timepoints for the assessment of AUC0-24 of enzalutamide. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "9999": indicates that the values were not estimable as they were below the LLOQ of 1.00 ng/mL.
    End point type
    Secondary
    End point timeframe
    24 hours post-dose on Cycle 1 Days 1, 2 and 21 (each cycle was 28 days)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 1b arms.
    End point values
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide
    Number of subjects analysed
    2
    3
    3
    3
    3
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=1, 3, 3, 3, 3)
    9999 ( 9999 )
    33000 ( 15600 )
    28800 ( 5780 )
    36800 ( 6440 )
    27500 ( 5270 )
        Cycle 1 Day 2 (n=2, 3, 3, 3, 3)
    56700 ( 7900 )
    57700 ( 30100 )
    57400 ( 18400 )
    66800 ( 10500 )
    60300 ( 19900 )
        Cycle 1 Day 21 (n=1, 3, 3, 3, 3)
    9999 ( 9999 )
    272000 ( 106000 )
    263000 ( 50400 )
    251000 ( 47400 )
    199000 ( 30800 )
    No statistical analyses for this end point

    Secondary: Phase 2: Maximum Plasma Concentration of Enzalutamide

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    End point title
    		 Phase 2: Maximum Plasma Concentration of Enzalutamide [12]
    End point description
    Blood samples were collected at specified timepoints for the assessment of Cmax of enzalutamide. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "99999": indicates that no participants were analyzed for that category.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2 and 21 (each cycle was 28 days)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 2 arms.
    End point values
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    14
    14
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=0, 14)
    99999 ( 99999 )
    3000 ( 577 )
        Cycle 1 Day 2 (n=14, 0)
    3960 ( 773 )
    99999 ( 99999 )
        Cycle 1 Day 21 (n=13, 0)
    12100 ( 3080 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Enzalutamide

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    End point title
    		 Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Enzalutamide [13]
    End point description
    Blood samples were collected at specified timepoints for the assessment of AUC0-last of enzalutamide. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "99999": indicates that no participants were analyzed for that category.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1, 2 and 21 (each cycle was 28 days)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 2 arms.
    End point values
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    14
    14
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=0, 14)
    99999 ( 99999 )
    30100 ( 9540 )
        Cycle 1 Day 2 (n=14, 0)
    60400 ( 17200 )
    99999 ( 99999 )
        Cycle 1 Day 21 (n=13, 0)
    259000 ( 67300 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose of Enzalutamide

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    End point title
    		 Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose of Enzalutamide [14]
    End point description
    Blood samples were collected at specified timepoints for the assessment of AUC0-24 of enzalutamide. The PK population included all participants in the safety population who had at least 1 post-dose sample collected to allow estimation of the PK parameters. Only those participants with data collected at specified timepoints are reported. Here, n= number of participants analyzed for specified category. "99999": indicates that no participants were analyzed for that category.
    End point type
    Secondary
    End point timeframe
    24 hours post-dose on Cycle 1 Days 1, 2 and 21 (each cycle was 28 days)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 2 arms.
    End point values
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    14
    13
    Units: hour*ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (n=0, 13)
    99999 ( 99999 )
    31400 ( 8430 )
        Cycle 1 Day 2 (n=14, 0)
    60000 ( 17000 )
    99999 ( 99999 )
        Cycle 1 Day 21 (n=13, 0)
    253000 ( 64500 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Prostrate (FACT-P): Functional Wellbeing Subscale (FWB) and Prostate Cancer Subscale (PCS) Scores

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    End point title
    		 Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Prostrate (FACT-P): Functional Wellbeing Subscale (FWB) and Prostate Cancer Subscale (PCS) Scores [15]
    End point description
    FACT-P questionnaire included subscales:physical well-being(PWB)(Questions [Q]GP1 to GP7),social/family wellbeing subscale(SWB)(Q GS1 to GS7),emotional well-being subscale(EWB)(Q GE1 to GE6),functional well-being subscale(FWB) (Q GF1 to GF7) and prostate cancer subscale(PCS)(Q C2, C6, P1 to P8, BL2 and BL5).Each question had 5 responses,0:“not at all”, 1:“a little bit”, 2:"somewhat”, 3:“quite a bit” and 4:“very much”. Scores ranged: 0 (“not at all”) to 4(“very much”) for positively phrased questions.Negatively phrased questions had a reverse scoring,from 0(“very much”) to 4(“not at all”). Q that were reversed (via subtraction of the response from 4)were: GP1-7, GE1, GE3-6, C2, P1-3, P6-P8 and BL2.Total FACT-P score:sum of scores of all sub-scales(PWB, SWB, EWB, FWB and PCS).Higher scores:better quality of life.Baseline:last value recorded for a variable prior to or on date of randomization."9999": standard deviation not estimable for 1 participant. "99999": no participants analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Cycle (C) 3 Day 57, C 5 Day 113, C 7 Day 169, C 10 Day 253, C 13 Day 337, C 14 Day 421, C 15 Day 505, C 16 Day 589, C 17 Day 673, C 18 Day 757, C 19 Day 841, C 20 Day 925, C 21 Day 1009, C 22 Day 1093, C 23 Day 1177 and C 24 Day 1261
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 2 arms.
    End point values
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    33
    36
    Units: score on a scale
    arithmetic mean (standard deviation)
        FWB: Cycle 3 Day 57 (n=33, 36)
    -0.8 ( 4.73 )
    -1.2 ( 6.22 )
        FWB: Cycle 5 Day 113 (n=31, 23)
    -0.8 ( 4.61 )
    -0.6 ( 4.14 )
        FWB: Cycle 7 Day 169 (n=22, 14)
    -0.1 ( 5.68 )
    1.4 ( 5.72 )
        FWB: Cycle 10 Day 253 (n=17, 13)
    -0.6 ( 4.82 )
    -0.6 ( 5.11 )
        FWB: Cycle 13 Day 337 (n=15, 10)
    0.4 ( 3.58 )
    1.1 ( 4.61 )
        FWB: Cycle 14 Day 421 (n=12, 9)
    2.1 ( 4.32 )
    1.0 ( 6.44 )
        FWB: Cycle 15 Day 505 (n=12, 6)
    0.3 ( 2.70 )
    1.7 ( 5.09 )
        FWB: Cycle 16 Day 589 (n=8, 4)
    0.4 ( 3.46 )
    5.0 ( 6.06 )
        FWB: Cycle 17 Day 673 (n=8, 5)
    1.4 ( 3.50 )
    2.0 ( 4.64 )
        FWB: Cycle 18 Day 757 (n=6, 3)
    1.7 ( 1.51 )
    5.0 ( 4.36 )
        FWB: Cycle 19 Day 841 (n=5, 2)
    2.6 ( 3.51 )
    7.5 ( 3.54 )
        FWB: Cycle 20 Day 925 (n=3, 2)
    2.0 ( 4.00 )
    4.0 ( 4.24 )
        FWB: Cycle 21 Day 1009 (n=3, 0)
    1.7 ( 2.31 )
    99999 ( 99999 )
        FWB: Cycle 22 Day 1093 (n=3, 0)
    2.7 ( 4.73 )
    99999 ( 99999 )
        FWB: Cycle 23 Day 1177 (n=2, 0)
    4.5 ( 6.36 )
    99999 ( 99999 )
        FWB: Cycle 24 Day 1261 (n=1, 0)
    7.0 ( 9999 )
    99999 ( 99999 )
        PCS: Cycle 3 Day 57 (n=33, 36)
    -0.8 ( 5.69 )
    -1.3 ( 5.85 )
        PCS: Cycle 5 Day 113 (n=31, 23)
    -0.9 ( 5.12 )
    -0.7 ( 4.60 )
        PCS: Cycle 7 Day 169 (n=23, 14)
    -1.2 ( 6.07 )
    -0.8 ( 5.08 )
        PCS: Cycle 10 Day 253 (n=17, 13)
    0.0 ( 7.62 )
    -0.4 ( 7.89 )
        PCS: Cycle 13 Day 337 (n=15, 10)
    0.8 ( 5.63 )
    -1.8 ( 7.73 )
        PCS: Cycle 14 Day 421 (n=12, 8)
    0.8 ( 6.82 )
    -0.8 ( 5.19 )
        PCS: Cycle 15 Day 505 (n=12, 6)
    2.0 ( 5.02 )
    4.1 ( 2.65 )
        PCS: Cycle 16 Day 589 (n=8, 4)
    2.3 ( 3.49 )
    2.6 ( 6.26 )
        PCS: Cycle 17 Day 673 (n=8, 5)
    1.6 ( 5.50 )
    3.6 ( 3.07 )
        PCS: Cycle 18 Day 757 (n=6, 3)
    1.3 ( 3.72 )
    0.2 ( 6.81 )
        PCS: Cycle 19 Day 841 (n=4, 2)
    1.8 ( 3.50 )
    7.3 ( 1.80 )
        PCS: Cycle 20 Day 925 (n=3, 2)
    3.3 ( 4.73 )
    -1.0 ( 7.07 )
        PCS: Cycle 21 Day 1009 (n=3, 0)
    5.0 ( 1.73 )
    99999 ( 99999 )
        PCS: Cycle 22 Day 1093 (n=3, 0)
    6.0 ( 2.65 )
    99999 ( 99999 )
        PCS: Cycle 23 Day 1177 (n=2, 0)
    6.5 ( 0.71 )
    99999 ( 99999 )
        PCS: Cycle 24 Day 1261 (n=1, 0)
    3.0 ( 9999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Phase 2: Time to Definitive Deterioration (TDD) in Prostate Symptoms as Assessed by the Functional Assessment of Cancer Therapy-Prostrate: Prostate Cancer Subscale Score

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    End point title
    		 Phase 2: Time to Definitive Deterioration (TDD) in Prostate Symptoms as Assessed by the Functional Assessment of Cancer Therapy-Prostrate: Prostate Cancer Subscale Score [16]
    End point description
    TTD:interval from date of randomization until date of first clinically meaningful deterioration(3 points or more decline for subscale score,10 points or more decline for total score)that was confirmed at subsequent visit at least 3 weeks apart with no improvement in between visits or death(by any cause) in absence of a clinically meaningful deterioration,regardless of whether participant discontinued study drug(s) prior to deterioration.PCS included Q C2, C6, P1 to P8, BL2 and BL5.Each question had 5 responses,0:“not at all”,1:“a little bit”,2:“somewhat”,3:“quite a bit” and 4:“very much”. Scores ranged:0(“not at all”) to 4(“very much”) for positively phrased Q.Negatively phrased Q: reverse scoring,from 0(“very much”) to 4(“not at all”).Total FACT-P: sum of scores of all subscales(PWB, SWB, EWB, FWB and PCS). Higher scores:better quality of life.TDD in prostate symptoms as assessed by FACT-P: PCS score is presented. "9999": not estimable due to insufficient participants with events.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Cycle 24 Day 1261
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was evaluated for only Phase 2 arms.
    End point values
    		 Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Number of subjects analysed
    16
    21
    Units: months
        median (confidence interval 95%)
    11.2 (3.9 to 9999)
    3.7 (2.5 to 11.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs:first dose of study drug (Day 1) up to either 30 days after last dose or until initiation of subsequent anticancer therapy or end of treatment.Up to 149 and 191 weeks for Phases 1b and 2 respectively. Deaths:From Day 1 up to approximately 259 weeks.
    Adverse event reporting additional description
    The safety population included all participants who received any dose of the study drugs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Phase 1b: Tazemetostat 400 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 400 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 600 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 800 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 1200 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 1600 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1600 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 400 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 600 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone
    Reporting group description
    		 Participants received tazemetostat 800 mg tablet orally BID from Cycle 1 Day 2 and abiraterone 1000 mg tablet orally OD/prednisone 5 mg tablet orally BID from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 2: Tazemetostat 1200 mg + Enzalutamide
    Reporting group description
    		 Participants received tazemetostat 1200 mg tablet orally BID from Cycle 1 Day 2 and enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Reporting group title
    Phase 2: Enzalutamide
    Reporting group description
    		 Participants received enzalutamide 160 mg capsule orally OD from Cycle 1 Day 1 until death, PD, development of unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 28 days.

    Serious adverse events
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    13 / 41 (31.71%)
    10 / 40 (25.00%)
         number of deaths (all causes)
    2
    2
    2
    3
    0
    1
    2
    3
    7
    18
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Atrioventricular block
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Acquired haemophilia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b: Tazemetostat 400 mg + Enzalutamide Phase 1b: Tazemetostat 600 mg + Enzalutamide Phase 1b: Tazemetostat 800 mg + Enzalutamide Phase 1b: Tazemetostat 1200 mg + Enzalutamide Phase 1b: Tazemetostat 1600 mg + Enzalutamide Phase 1b: Tazemetostat 400 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 600 mg + Abiraterone/prednisone Phase 1b: Tazemetostat 800 mg + Abiraterone/prednisone Phase 2: Tazemetostat 1200 mg + Enzalutamide Phase 2: Enzalutamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    1 / 1 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    41 / 41 (100.00%)
    39 / 40 (97.50%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin cancer
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 41 (4.88%)
    7 / 40 (17.50%)
         occurrences all number
    1
    1
    2
    1
    0
    0
    0
    1
    5
    9
    Hypotension
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 41 (4.88%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    3
    5
    Chills
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 2 (0.00%)
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    1 / 1 (100.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    26 / 41 (63.41%)
    12 / 40 (30.00%)
         occurrences all number
    0
    3
    1
    2
    5
    1
    3
    0
    36
    12
    Influenza like illness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 41 (9.76%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    5
    0
    Injection site bruising
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 41 (2.44%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    1
    2
    3
    Oedema peripheral
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    7 / 41 (17.07%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    3
    7
    1
    Pyrexia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    5
    0
    3
    0
    Thirst
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Reproductive system and breast disorders
    Balanoposthitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Pelvic pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Penile pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 41 (9.76%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    4
    2
    Dyspnoea
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 41 (4.88%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    2
    3
    Dyspnoea at rest
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    0
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    Productive cough
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    0
    0
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    4 / 40 (10.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    1
    5
    Disorientation
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    5 / 41 (12.20%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    5
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Heart rate irregular
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Urine output decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    8 / 41 (19.51%)
    3 / 40 (7.50%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    0
    9
    3
    White blood cell count decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    4 / 41 (9.76%)
    1 / 40 (2.50%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    6
    5
    1
    Skin abrasion
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    3
    Bradycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Nodal rhythm
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    3
    0
    Tachycardia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    6 / 41 (14.63%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    0
    8
    3
    Dysgeusia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    10 / 41 (24.39%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    0
    14
    3
    Headache
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 41 (4.88%)
    4 / 40 (10.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    2
    4
    Neuralgia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    5
    1
    Presyncope
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    2
    Tremor
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    9 / 41 (21.95%)
    3 / 40 (7.50%)
         occurrences all number
    0
    1
    1
    1
    1
    0
    0
    0
    12
    3
    Anaemia macrocytic
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    0
    0
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 41 (9.76%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    7 / 41 (17.07%)
    6 / 40 (15.00%)
         occurrences all number
    0
    2
    1
    1
    0
    1
    2
    0
    7
    7
    Diarrhoea
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    15 / 41 (36.59%)
    8 / 40 (20.00%)
         occurrences all number
    0
    0
    0
    2
    2
    1
    0
    0
    20
    9
    Diverticulum
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 41 (9.76%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    0
    0
    5
    0
    Nausea
         subjects affected / exposed
    1 / 2 (50.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    19 / 41 (46.34%)
    8 / 40 (20.00%)
         occurrences all number
    1
    3
    1
    0
    2
    0
    2
    0
    23
    9
    Oral pruritus
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    5 / 41 (12.20%)
    4 / 40 (10.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    0
    0
    9
    4
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Blister
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    0
    0
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    4 / 40 (10.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    3
    4
    Pollakiuria
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Urine odour abnormal
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    11 / 41 (26.83%)
    9 / 40 (22.50%)
         occurrences all number
    0
    3
    2
    0
    0
    0
    1
    5
    17
    10
    Back pain
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 41 (7.32%)
    8 / 40 (20.00%)
         occurrences all number
    0
    3
    0
    0
    1
    1
    0
    2
    3
    10
    Flank pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    1
    2
    Muscular weakness
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 41 (4.88%)
    5 / 40 (12.50%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    1
    2
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    3
    3
    Myalgia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 41 (4.88%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    0
    2
    2
    Neck pain
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 41 (2.44%)
    3 / 40 (7.50%)
         occurrences all number
    0
    1
    0
    1
    1
    0
    1
    0
    1
    3
    Osteoporosis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 41 (7.32%)
    4 / 40 (10.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    1
    4
    4
    Tendonitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    4 / 41 (9.76%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    0
    0
    4
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Onychomycosis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    2
    Tooth abscess
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    3
    0
    3
    1
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 2 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    12 / 41 (29.27%)
    9 / 40 (22.50%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    0
    0
    16
    9
    Dehydration
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    3 / 41 (7.32%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    1
    0
    3
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    4 / 41 (9.76%)
    3 / 40 (7.50%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    4
    3
    Increased appetite
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 41 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2019
    The potential dose level of tazemetostat was increased up to 1600 mg BID when given in combination with enzalutamide. Addition of death of any cause as an event in the definition of the rPFS endpoint and an assessment of the PK of enzalutamide and abiraterone/prednisone when administered in combination with tazemetostat. Participants with human immunodeficiency virus (HIV) or hepatitis who met specific criteria for immune function and HIV or hepatitis treatment were included. Criteria for dose-limiting toxicities (DLTs) was adjusted. The tazemetostat dose modification levels for combination treatment-related toxicities when administered with abiraterone/prednisone was corrected.
    10 Jan 2020
    The abiraterone/prednisone arm in the phase 2 portion of the study was removed. Clarifications provided regarding participants treated in phase Ib and AEs collection procedures. The location for the phase Ib portion of the study was expanded from the United States to global. Clinical experience information and the anticipated tazemetostat safety profile updated. Secondary objectives pertaining to CTCs, inclusion and exclusion criteria refined and exploratory objectives were expanded. Dose reduction amounts were modified for abiraterone-related toxicity to align with the package insert and clarified dose reduction procedures for tazemetostat. Instructions and guidance added for dosing in case of vomiting investigational drug and for the treatment of overdose and clarified permitted concomitant medications. Mandatory paired pre- and post-treatment biopsies were added for the additional participants to be enrolled at the RP2D in the phase 1 portion and allowed baseline biopsies from archival tumour sample if the sample was obtained less than 1 year before enrolment. PK sampling removed at 10 and 12 hours post-dose and deleted the CTC sample collection at Cycle 6. An optional chest ultrasound at screening and every 8 weeks at the investigator’s discretion and an annual blood sample for PK assessment for tazemetostat-treated participants added. Corrections made in the errors in the schedule of assessments, names and roles of safety committees and removed erroneously stated plans for an independent data monitoring committee. Analysis procedure and wording of record retention requirements revised.
    05 Jun 2020
    Since the original protocol was written, the sponsor had completed aggregate analysis of cumulative safety data for two New Drug Application submissions in the US and their subsequent safety updates. These analyses were supplemented by data from participants enrolled in 5 different dose-escalation cohort levels in the EZH-1101 trial with no observed DLTs. A review of cumulative safety data demonstrates a stable AE profile of tazemetostat managed by dose interruption and, uncommonly, by dose reduction or discontinuation. Based on this data, the sponsor reassessed the need for the additional number of participants considered for this study. Accordingly, the modified 3 + 3 dose-escalation design had been adjusted such that the RP2D could be determined based on the first three participants treated at any dose level if no DLTs occurred among them, without an additional three participants for added safety and PK information. Cohort expansion occurred only if a DLT was observed at any given cohort level. The availability of PK data in this study was adequate to characterize the PK of tazemetostat in the combination setting without additional participants (to a total of 12 at the RP2D) in the phase Ib portion of the study; the addition of these participants, therefore, was removed. The annual PK assessment that had been required for participants receiving tazemetostat was removed. The current information was updated on the medications to be used with caution and prohibited medications. A whole blood sample was added for potential genotype analysis at the 30-day follow-up visit to correct an oversight. Simplified, updated and applied consistency with other Epizyme documents and industry standards in safety reporting definitions, management and instructions.
    27 Dec 2020
    Declared the RP2D of tazemetostat when given in combination with enzalutamide. The total number of participants planned in the phase II randomized component of the study was increased from 32 per arm to 40 per arm (a total increase of 16 participants) in order to achieve 80% power and account for a 10% dropout rate; a critical boundary was also added. Reflection of the prevalence of measurable disease in the population (approximately 60%) was achieved by capping the enrolment of participants without measurable disease at 15 participants per treatment arm, as necessary. Updated to require tumour biopsies, when safe and feasible, from 12-20 participants randomized to receive tazemetostat plus enzalutamide in the phase II portion of the study. Included additional health-related quality of life measures. PK sample collection time points adjusted in phase 2 to coincide with efficacy assessments. Language to clarify safety/adverse event of special interest definitions adjusted. An exploratory objective was added.
    14 Apr 2022
    The name of the responsible medical officer and contact information in case of emergency was updated. The cap of 15 participants per treatment group without measurable disease in phase 2 was removed. Adjusted the phase 2 study duration from approximately 30 months to approximately 38 months and the estimated date of last participant completion from August 2023 to February 2024 and the timeframe for participants who discontinued treatment for reasons other than confirmed radiographic progression from up to 2 years post last dose to up to 18 months post last dose. Follow-up procedures and pregnancy prevention wording for participants’ partners who were females of childbearing potential revised. PK sample collection was specified in phase 2. Added that Epizyme would request available archival tumour samples from all participants who did not provide matched biopsies at screening, to allow randomization of phase 2 participants to occur before Cycle 1 Day 1. Any second-generation androgen targeted agents as a class in phase 2 was excluded. Herbal remedies from the list of prohibited concomitant medications and the 400 mg formulation of tazemetostat from the list of available formulations was removed. The order of presentation was adjusted and additional details clarification was provided concerning secondary and exploratory endpoint definitions and planned statistical analyses. Clarification provided for the detection of myeloid malignancies in study participants. Safety information was updated to align with the current Investigator’s Brochure (IB). Serum chromogranin A assessment at screening and to include a section on the future use of biosamples was removed.
    31 Aug 2022
    Background and clinical information regarding tazemetostat was updated to align with the updated tazemetostat IB (IB v12.0). The requirement of scans for confirmation of progression in soft tissue at Week 9 based on RECIST 1.1 criteria was removed. The list of responsible personnel and emergency contact information was updated. Internal conflict errors introduced in Protocol Amendment #5 was corrected and concomitant medication and supplement advice was clarified.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The study was terminated early as Sponsor decided to discontinue the development of tazemetostat in mCRPC and the primary endpoint was not met for this study. There were no safety concerns.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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