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    Clinical Trial Results:
    A Phase 1b/3 Global, Randomized, Double-blind, Placebo-Controlled Trial of Tazemetostat in Combination With Doxorubicin as Frontline Therapy for Advanced Epithelioid Sarcoma

    Summary
    EudraCT number
    		 2019-003648-55
    Trial protocol
    		 GB   CZ   BE   PL  
    Global end of trial date
    24 Jun 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 May 2026
    First version publication date
    01 May 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EZH-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04204941
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Epizyme, Inc.
    Sponsor organisation address
    One Main St, 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
    24 Jun 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2025
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Phase 1b: Evaluate the safety and tolerability of tazemetostat in combination with doxorubicin in participants with advanced soft tissue sarcoma and select a dose for further evaluation in Phase 3 (the recommended Phase 3 dose [RP3D]). Phase 3: Evaluate and compare the progression-free survival (PFS) by Independent Review Committee (IRC) in participants with advanced epithelioid sarcoma (ES) treated with tazemetostat + doxorubicin versus placebo + doxorubicin.
    Protection of trial subjects
    The study was conducted under the provisions of the Declaration of Helsinki, in accordance with the International Conference on Harmonisation Consolidated Guideline on good clinical practice and in compliance with Institutional Review Board/Independent Ethics Committee and informed consent regulations and the Sponsor's policy on bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Dec 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
    Canada: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    25
    EEA total number of subjects
    0
    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)
    19
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase (Ph) 1b/3, 2-part study was conducted at 8 sites in 3 countries in participants with advanced ES. The study consisted of 2 parts: Phase 1b (dose escalation [esc] and dose expansion [exp]) and Phase 3. A total of 25 participants were enrolled in Phase 1b (dose escalation) of the study.

    Pre-assignment
    Screening details
    		 Following consultation with Food and Drug Administration(FDA),study was terminated due to feasibility concerns related to inability to meet required enrollment targets. Decision was made after completion of Ph1b(dose esc) & prior to initiation of Ph1b (dose exp) & Ph3. At termination, no participants enrolled in Ph1b (dose exp) & Ph3 not initiated.

    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: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg
    Arm description
    		 Participants received doxorubicin 75 milligram per square meter (mg/m^2) intravenous (IV) injection on Day 1 of Cycles 1 to 6 and tazemetostat 400 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and twice daily (BID) from Day 2 Cycle 1 until disease progression (PD), unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6.

    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 single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1.

    Arm title
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg
    Arm description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 600 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6.

    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 single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1.

    Arm title
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Arm description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 800 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6.

    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 single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1.

    Number of subjects in period 1
    		Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Started
    4
    6
    15
    Completed
    0
    0
    1
    Not completed
    4
    6
    14
         Consent withdrawn by subject
    -
    -
    1
         Completion of 2 years post treatment follow-up
    -
    2
    5
         Death
    4
    4
    7
         Unspecified
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg
    Reporting group description
    		 Participants received doxorubicin 75 milligram per square meter (mg/m^2) intravenous (IV) injection on Day 1 of Cycles 1 to 6 and tazemetostat 400 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and twice daily (BID) from Day 2 Cycle 1 until disease progression (PD), unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg
    Reporting group description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 600 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Reporting group description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 800 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Reporting group values
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg Total
    Number of subjects
    		 4 6 15 25
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 73.3 ( 6.99 ) 50.5 ( 13.63 ) 46.9 ( 12.14 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 5 9 16
        Male
    		 2 1 6 9
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 4 2 6
        Not Hispanic or Latino
    		 4 2 13 19
        Unknown or Not Reported
    		 0 0 0 0
    Race
    Units: Subjects
        White
    		 4 5 14 23
        American Indian or Alaska Native
    		 0 1 0 1
        Other
    		 0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg
    Reporting group description
    		 Participants received doxorubicin 75 milligram per square meter (mg/m^2) intravenous (IV) injection on Day 1 of Cycles 1 to 6 and tazemetostat 400 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and twice daily (BID) from Day 2 Cycle 1 until disease progression (PD), unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg
    Reporting group description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 600 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Reporting group description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 800 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Subject analysis set title
    Phase 1b: Dose Exp: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants planned to receive doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 800 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was planned to be 21 days.

    Subject analysis set title
    Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants planned to receive doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 800 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was planned to be 21 days.

    Subject analysis set title
    Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Participants planned to receive doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and placebo matched to tazemetostat tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was planned to be 21 days.

    Primary: Phase 1b: Dose Escalation and Dose Expansion: Number of Participants With Dose-Limiting Toxicities (DLTs)

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    End point title
    		 Phase 1b: Dose Escalation and Dose Expansion: Number of Participants With Dose-Limiting Toxicities (DLTs) [1]
    End point description
    DLT:study drug related adverse event(AE) graded using Common Terminology Criteria for Adverse Events version 5.0:hematological toxicity:Grade(G)4 neutropenia >=7 days;G3 neutropenia >=14 days;any G neutropenia with normal absolute neutrophil count with fever (>38.5 degree Celsius);G4 thrombocytopenia >=7 days;G3 thrombocytopenia >=14 days with bleeding requiring intervention;anemia >=G3 requiring transfusion;non-hematological:any drug-related AE >=G3,G3 fatigue,or 2-point decline in Eastern Cooperative Oncology Group performance status >7 days,G3 aspartate aminotransferase (AST)/G3 alanine aminotransferase(ALT),elevation of >3 days,or G4 AST or ALT of any duration;>=G3 neurotoxicity or cardiotoxicity;G2 hypersensitivity reaction;nausea,vomiting,or diarrhea >=72 hours with adequate antiemetic & other supportive care;any participant meeting Hy’s law criteria;any G3 or higher non-hematological toxicity.DLT population.Due to early study termination,Phase 1b(dose expansion)never initiated.
    End point type
    Primary
    End point timeframe
    From the first dose of study drug (Day 1) up to Day 21 of Cycle 1 (each cycle was 21 days) (dose escalation)
    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.
    End point values
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg Phase 1b: Dose Exp: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Number of subjects analysed
    4
    6
    6
    0 [2]
    Units: participants
    0
    1
    1
    Notes
    [2] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Primary: Phase 3: Progression-Free Survival Assessed by Independent Review Committee

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    End point title
    		 Phase 3: Progression-Free Survival Assessed by Independent Review Committee [3]
    End point description
    PFS was planned to be assessed in Phase 3. PFS as assessed by IRC was defined as the time from the date of randomization into the study to the first observation of documented PD or death due to any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the study drug started (percent change from nadir, where nadir was defined as the smallest sum of diameters recorded since study drug started). In addition, the sum must have an absolute increase from nadir of 5 millimeter (mm). Due to early study termination, Phase 3 was never initiated.
    End point type
    Primary
    End point timeframe
    Assessments were planned to be performed within 7 days prior to Day 1 of odd numbered cycles until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Approximately 287.7 weeks
    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: PFS was a primary endpoint for the Phase 3 element of the study. As the study was terminated before the Phase 3 element was started, this endpoint was not assessed.
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [4] - Due to early study termination, no participants were analyzed.
    [5] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 1b: Dose Escalation and Dose Expansion: Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of Tazemetostat

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    End point title
    		 Phase 1b: Dose Escalation and Dose Expansion: Area Under the Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate AUC0-24 of tazemetostat. The study was early terminated prior to the data collection and analysis of the pharmacokinetic (PK) parameters for Phase 1b (dose escalation and dose expansion).
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour on Days -1, 1, 8 and 21 of Cycle 1; 0, 0.5, 1, 1.5, 2, 4, 6, 8 and 24 hours post-dose on Days -1, 1, and 21 of Cycle 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg Phase 1b: Dose Exp: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    Units: hour*nanogram per milliliter (h*ng/mL)
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [6] - Due to early study termination, no participants were analyzed.
    [7] - Due to early study termination, no participants were analyzed.
    [8] - Due to early study termination, no participants were analyzed.
    [9] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 1b: Dose Escalation and Dose Expansion: Area Under the Concentration-Time Curve From Time 0 to Last Measurement (AUC0-last) of Tazemetostat

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    End point title
    		 Phase 1b: Dose Escalation and Dose Expansion: Area Under the Concentration-Time Curve From Time 0 to Last Measurement (AUC0-last) of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate AUC0-last of tazemetostat. The study was early terminated prior to the data collection and analysis of the PK parameters for Phase 1b (dose escalation and dose expansion).
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour on Days -1, 1, 8 and 21 of Cycle 1; 0, 0.5, 1, 1.5, 2, 4, 6, 8 and 24 hours post-dose on Days -1, 1, and 21 of Cycle 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg Phase 1b: Dose Exp: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Number of subjects analysed
    0 [10]
    0 [11]
    0 [12]
    0 [13]
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [10] - Due to early study termination, no participants were analyzed.
    [11] - Due to early study termination, no participants were analyzed.
    [12] - Due to early study termination, no participants were analyzed.
    [13] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 1b: Dose Escalation and Dose Expansion: Maximum Concentration (Cmax) of Tazemetostat

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    End point title
    		 Phase 1b: Dose Escalation and Dose Expansion: Maximum Concentration (Cmax) of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate Cmax of tazemetostat. The study was early terminated prior to the data collection and analysis of the PK parameters for Phase 1b (dose escalation and dose expansion).
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour on Days -1, 1, 8 and 21 of Cycle 1; 0, 0.5, 1, 1.5, 2, 4, 6, 8 and 24 hours post-dose on Days -1, 1, and 21 of Cycle 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg Phase 1b: Dose Exp: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Number of subjects analysed
    0 [14]
    0 [15]
    0 [16]
    0 [17]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [14] - Due to early study termination, no participants were analyzed.
    [15] - Due to early study termination, no participants were analyzed.
    [16] - Due to early study termination, no participants were analyzed.
    [17] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Overall Survival (OS)

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    End point title
    		 Phase 3: Overall Survival (OS)
    End point description
    OS was planned to be assessed in Phase 3. OS was defined as the number of months elapsed between the date of randomization and the date of death (whatever the cause). Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned from the first dose of study drug (Day 1) up to date of death due to any cause, approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [18]
    0 [19]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [18] - Due to early study termination, no participants were analyzed.
    [19] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Phase 3: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
    End point description
    TEAEs and TESAEs were planned to be assessed in Phase 3. An AE was 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. An SAE was any AE that any dose, resulted in death, was life threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect, or was an important medical event. A TEAE was an AE that started or worsened in severity on or after the date of the first dose of tazemetostat (study day -1) through 30 days after the end of study drug (doxorubicin or tazemetostat, whichever was dosed last). Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned from first dose of study drug (tazemetostat) (Day -1) up to approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [20]
    0 [21]
    Units: participants
    Notes
    [20] - Due to early study termination, no participants were analyzed.
    [21] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Progression-Free Survival Assessed by Investigator

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    End point title
    		 Phase 3: Progression-Free Survival Assessed by Investigator
    End point description
    PFS was planned to be assessed in Phase 3. PFS as assessed by Investigator was defined as the time from the date of randomization into the study to the first observation of documented PD or death due to any cause, whichever occurred first. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the study drug started (percent change from nadir, where nadir was defined as the smallest sum of diameters recorded since study drug started). In addition, the sum must have an absolute increase from nadir of 5 mm. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned to be performed within 7 days prior to Day 1 of odd numbered cycles until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [22]
    0 [23]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [22] - Due to early study termination, no participants were analyzed.
    [23] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Disease Control Rate (DCR)

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    End point title
    		 Phase 3: Disease Control Rate (DCR)
    End point description
    DCR was planned to be assessed in Phase 3. DCR was defined as percentage of participants with best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD) lasting 24 or more weeks. BOR was defined as CR, PR, SD, PD, or not evaluable (NE) which occurred between date of randomization and date of documented PD or date of subsequent therapy. CR was defined as disappearance of all target lesions, any pathological lymph nodes must be <10 mm in short axis. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned to be performed within 7 days prior to Day 1 of odd numbered cycles until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [24]
    0 [25]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [24] - Due to early study termination, no participants were analyzed.
    [25] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Objective Response Rate (ORR)

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    End point title
    		 Phase 3: Objective Response Rate (ORR)
    End point description
    ORR was planned to be assessed in Phase 3. ORR was defined as the percentage of participants with BOR of CR or PR. BOR was defined as CR, PR, SD, PD, or NE which occurred between date of randomization and date of documented PD or date of subsequent therapy. CR was defined as disappearance of all target lesions, any pathological lymph nodes must be <10 mm in short axis. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned to be performed within 7 days prior to Day 1 of odd numbered cycles until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [26]
    0 [27]
    Units: percentage of participants
        number (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [26] - Due to early study termination, no participants were analyzed.
    [27] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Duration of Response (DOR)

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    End point title
    		 Phase 3: Duration of Response (DOR)
    End point description
    DOR was planned to be assessed in Phase 3. DOR was defined as the time from first documented evidence of CR or PR (whichever response was observed first) to the time of first documented PD or death, whichever occurred first. CR was defined as disappearance of all target lesions, any pathological lymph nodes must be <10 mm in short axis. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. PD was defined at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, smallest sum of diameters recorded since study drug started. In addition, sum must have an absolute increase from nadir of 5 mm. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned to be performed within 7 days prior to Day 1 of odd numbered cycles until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [28]
    0 [29]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [28] - Due to early study termination, no participants were analyzed.
    [29] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Change From Baseline in European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30): Physical Function, Role Function, and Global Health Status Domains

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    End point title
    		 Phase 3: Change From Baseline in European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30): Physical Function, Role Function, and Global Health Status Domains
    End point description
    EORTC-QLQ-C30 was planned to be assessed in Phase 3. EORTC-QLQ-C30 measured cancer participants’ physical, psychological, and social functions. It consisted of 30 questions incorporated into 5 functional domains (physical,role,social,emotional,and cognitive functioning),9 symptom scales (pain,fatigue,financial impact,appetite loss,nausea and vomiting,diarrhea,constipation,sleep disturbance,and quality of life [QoL]) and a single global QoL/global health status score.Items in functional and symptom scale used raw participant response of 1-4; 1:“not at all” and 4:“very much”. 2 global items contained responses ranging from 1:“very poor” to 7:“excellent”.All domain scores were transformed in range from 0 to 100;higher functional score indicated more favorable outcomes and higher score on symptom domains indicated a less favorable participant outcome.Baseline:last non-missing assessment prior to starting tazemetostat. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned at baseline (Day -1) and up to approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [30]
    0 [31]
    Units: score on a scale
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [30] - Due to early study termination, no participants were analyzed.
    [31] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Progression-Free Survival 2 (PFS2)

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    End point title
    		 Phase 3: Progression-Free Survival 2 (PFS2)
    End point description
    PFS2 was planned to be assessed in Phase 3. PFS2 was defined as time from the date of the first dose of the next-line therapy to the first observation of PD or death due to any cause, whichever occurred first. PD was defined at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, smallest sum of diameters recorded since study drug started. In addition, sum must have an absolute increase from nadir of 5 mm. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned to be performed within 7 days prior to Day 1 of odd numbered cycles until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [32]
    0 [33]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [32] - Due to early study termination, no participants were analyzed.
    [33] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Time to First Subsequent Therapy (TFST)

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    End point title
    		 Phase 3: Time to First Subsequent Therapy (TFST)
    End point description
    TFST was planned to be assessed in Phase 3. TFST was defined as the time from the date of randomization to date of fifirst documented administration of a new anti-cancer therapy. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned to be performed within 7 days prior to Day 1 of odd numbered cycles until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Approximately 287.7 weeks
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [34]
    0 [35]
    Units: months
        median (confidence interval 95%)
    ( to )
    ( to )
    Notes
    [34] - Due to early study termination, no participants were analyzed.
    [35] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Oral Clearance (CL/F) of Tazemetostat

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    End point title
    		 Phase 3: Oral Clearance (CL/F) of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate CL/F of tazemetostat. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour, 0.5 to 2 and 3 to 6 hours post-dose on Days 1 and 8 of Cycles 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [36]
    0 [37]
    Units: liter/h
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [36] - Due to early study termination, no participants were analyzed.
    [37] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Oral Volume of Distribution (Vss) of Tazemetostat

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    End point title
    		 Phase 3: Oral Volume of Distribution (Vss) of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate Vss of tazemetostat. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour, 0.5 to 2 and 3 to 6 hours post-dose on Days 1 and 8 of Cycles 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [38]
    0 [39]
    Units: liter
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [38] - Due to early study termination, no participants were analyzed.
    [39] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Area Under the Concentration-Time Curve at Steady State (AUCss) of Tazemetostat

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    End point title
    		 Phase 3: Area Under the Concentration-Time Curve at Steady State (AUCss) of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate AUCss of tazemetostat. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour, 0.5 to 2 and 3 to 6 hours post-dose on Days 1 and 8 of Cycles 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [40]
    0 [41]
    Units: h*ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [40] - Due to early study termination, no participants were analyzed.
    [41] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Trough Concentration (Ctrough) of Tazemetostat

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    End point title
    		 Phase 3: Trough Concentration (Ctrough) of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate Ctrough of tazemetostat. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour, 0.5 to 2 and 3 to 6 hours post-dose on Days 1 and 8 of Cycles 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [42]
    0 [43]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [42] - Due to early study termination, no participants were analyzed.
    [43] - Due to early study termination, no participants were analyzed.
    No statistical analyses for this end point

    Secondary: Phase 3: Maximum Concentration of Tazemetostat

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    End point title
    		 Phase 3: Maximum Concentration of Tazemetostat
    End point description
    Blood samples were planned to be collected at specified timepoints to evaluate Cmax of tazemetostat. Due to early study termination, Phase 3 was never initiated.
    End point type
    Secondary
    End point timeframe
    Assessments were planned at 0 hour, 0.5 to 2 and 3 to 6 hours post-dose on Days 1 and 8 of Cycles 1 and on Day 1 of Cycle 2; 0 hour on Day 1 of Cycles 3 and 5
    End point values
    		 Phase 3: Doxorubicin 75 mg/m^2 + Tazemetostat 800 mg Phase 3: Doxorubicin 75 mg/m^2 + Placebo
    Number of subjects analysed
    0 [44]
    0 [45]
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    Notes
    [44] - Due to early study termination, no participants were analyzed.
    [45] - Due to early study termination, no participants were analyzed.
    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 (tazemetostat) (Day -1) up to 30 days after last dose of study drug, up to 107 weeks for phase 1b (dose esc). Deaths: First dose of study drug (tazemetostat) (Day -1) up to approximately 287.7 weeks (phase 1b [dose esc]).
    Adverse event reporting additional description
    The safety population included all participants who received any dose of study drug. Due to early study termination, Phase 1b (dose expansion) and Phase 3 were never initiated.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28.0
    Reporting groups
    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg
    Reporting group description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 400 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg
    Reporting group description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 600 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Reporting group title
    Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Reporting group description
    		 Participants received doxorubicin 75 mg/m^2 IV injection on Day 1 of Cycles 1 to 6 and tazemetostat 800 mg tablet orally single dose on Days -1 and 1 of Cycle 1, Day 1 of Cycle 2 and BID from Day 2 Cycle 1 until PD, unacceptable toxicity, withdrawal of consent, or termination of the study. Each cycle duration was 21 days.

    Serious adverse events
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    5 / 6 (83.33%)
    8 / 15 (53.33%)
         number of deaths (all causes)
    4
    4
    8
         number of deaths resulting from adverse events
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy acute
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 6 (50.00%)
    3 / 15 (20.00%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Neutropenic sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection staphylococcal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 400 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 600 mg Phase 1b: Dose Esc: Doxorubicin 75 mg/m^2+Tazemetostat 800 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    15 / 15 (100.00%)
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Hot flush
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    1
    Fatigue
         subjects affected / exposed
    3 / 4 (75.00%)
    5 / 6 (83.33%)
    9 / 15 (60.00%)
         occurrences all number
    4
    8
    12
    Oedema peripheral
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    0
    2
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 6 (50.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    4
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    0
    2
    Hiccups
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    1
    Hypoxia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    3
    Confusional state
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Delirium
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 15 (20.00%)
         occurrences all number
    1
    1
    3
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    6 / 15 (40.00%)
         occurrences all number
    0
    0
    12
    Platelet count decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    4
    Weight decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    2
    White blood cell count decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    5 / 15 (33.33%)
         occurrences all number
    1
    0
    13
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Wound secretion
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    4 / 15 (26.67%)
         occurrences all number
    0
    1
    4
    Headache
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    9 / 15 (60.00%)
         occurrences all number
    1
    4
    11
    Taste disorder
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 6 (66.67%)
    10 / 15 (66.67%)
         occurrences all number
    6
    29
    20
    Leukopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    2
    Neutropenia
         subjects affected / exposed
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    8 / 15 (53.33%)
         occurrences all number
    11
    15
    18
    Thrombocytopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    10
    6
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    2 / 15 (13.33%)
         occurrences all number
    1
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    3
    Constipation
         subjects affected / exposed
    3 / 4 (75.00%)
    5 / 6 (83.33%)
    6 / 15 (40.00%)
         occurrences all number
    3
    5
    7
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    5 / 15 (33.33%)
         occurrences all number
    1
    3
    7
    Dyspepsia
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 6 (33.33%)
    6 / 15 (40.00%)
         occurrences all number
    2
    2
    7
    Dysphagia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    2
    Haemorrhoids
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    Mouth ulceration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    3
    Nausea
         subjects affected / exposed
    4 / 4 (100.00%)
    4 / 6 (66.67%)
    14 / 15 (93.33%)
         occurrences all number
    5
    5
    29
    Oral pain
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    3 / 15 (20.00%)
         occurrences all number
    0
    2
    3
    Stomatitis
         subjects affected / exposed
    3 / 4 (75.00%)
    4 / 6 (66.67%)
    9 / 15 (60.00%)
         occurrences all number
    7
    10
    17
    Vomiting
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 6 (66.67%)
    7 / 15 (46.67%)
         occurrences all number
    4
    7
    13
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    4 / 15 (26.67%)
         occurrences all number
    0
    2
    4
    Dermatitis acneiform
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    3
    Night sweats
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Rash
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    3 / 15 (20.00%)
         occurrences all number
    1
    2
    4
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 15 (20.00%)
         occurrences all number
    2
    2
    5
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    3
    Joint swelling
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    Myalgia
         subjects affected / exposed
    2 / 4 (50.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    2
    2
    1
    Pain in extremity
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    4 / 15 (26.67%)
         occurrences all number
    0
    2
    5
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    3 / 15 (20.00%)
         occurrences all number
    1
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 6 (50.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    6
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 4 (75.00%)
    3 / 6 (50.00%)
    2 / 15 (13.33%)
         occurrences all number
    3
    3
    2
    Dehydration
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 6 (50.00%)
    1 / 15 (6.67%)
         occurrences all number
    3
    3
    1
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 4 (50.00%)
    4 / 6 (66.67%)
    4 / 15 (26.67%)
         occurrences all number
    2
    12
    6
    Hypomagnesaemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    1 / 15 (6.67%)
         occurrences all number
    3
    6
    2
    Hyponatraemia
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 6 (33.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    2
    0
    Hypophosphataemia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    1 / 15 (6.67%)
         occurrences all number
    2
    5
    2
    Malnutrition
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2019
    Added PK sampling windows and adjusted timing of samples which were to be collected on Day 1 of Cycles 3 and 5 (instead of Cycles 4 and 6) to coincide with 6-week tumor measurements. Moved baseline clinical laboratory tests from Day 1 to Day -1 (to occur before the first dose of tazemetostat) and corrected inconsistencies in clinical laboratory test days and test facility (local or central). Changed EORTC-QLQ-C30 questionnaire to Day 1 of all Cycles (instead of just Cycles 1, 2, 4, and 6) in the Phase 3 portion of the study, removed it from Day 8 of Cycles 1 and 2, and specified the domains that would be analyzed. Specified that unblinding would take place at the end of the study except in case of emergency or related adverse event of special interest (AESI) (as intended), rather than at PD. Modified first and second tazemetostat dose reduction levels for combination treatment related toxicities to be consistent with the 200 mg tablet strength. Specified doxorubicin dosing over 3 to 10 minutes or up to approximately 30 minutes to reflect both label instructions and standard of care. Required that any archival tumor tissue samples be obtained less than 1 year before enrolment. Revised categories for AE causality assessments. Corrected inconsistencies between different sections of the protocol, added clarity and enhanced readability.
    24 Jan 2020
    Updated inclusion criteria to include immunophenotypic panel (for example: cluster of differentiation (CD34), epithelial membrane antigen, Keratin, and integrase interactor 1) for epithelioid sarcoma as a diagnostic criterion. Updated exclusion criteria to remove human immunodeficiency virus and human T-cell lymphotropic virus 1. Updated Response Evaluation Criteria in Solid Tumors criteria version. Updated prohibited medications to restrict dexrazoxane administration during Cycle 1. Provided clarity regarding doxorubicin administration for Cycles 1-6. Updated Phase 3 sample size determination. Updated decision rules for interim analysis.
    03 Jul 2020
    Responded to agency request dated 02 July 2020 regarding eligibility age in Phase 1b dose escalation, Phase 1b dose expansion, and Phase 3 portions of the study. Clarified and updated dose modifications for tazemetostat, “study drug” (blinded Phase 3), and study drug + doxorubicin, modifications for doxorubicin-related toxicity and modifications for combination treatment related toxicities. Updated contraception requirement. Updated restrictions during study treatment.
    10 Mar 2021
    Incorporated the RP3D. Included the rationale for RP3D. Updated inclusion and exclusion criteria. Updated dose modifications, interruptions, and discontinuations. Updated study schema and schedule of events for Phase 1b and Phase 3 study. Updated statistical analysis section.
    29 Mar 2022
    Corrected statements concerning the Sponsor’s response in the event of a new, adult case of related AESI of myelodysplastic syndrome/acute myeloid leukemia or events like myeloproliferative neoplasm. Added that eligible participants enrolled in the open-label Phase 1b portion of the study might be transferred to long-term rollover study EZH-501 at the discretion of the Investigator and Medical Monitor. Modified the electrocardiogram frequency following combination therapy. Modified the duration of monotherapy treatment following combination therapy in the event of surgical resection. Clarified when complete peripheral blood smears were conducted during treatment. Updated language concerning AESIs and safety monitoring by the Sponsor. Made clarifications concerning toxicity management and prophylactic use of hematopoietic colony stimulating factors during the study.
    21 Mar 2023
    Supplemented the Phase 1b expansion cohort with approximately 7 additional participants diagnosed with advanced ES, and who would be treated with granulocyte-colony stimulating factor (GCSF) prophylactically in Cycles 1-6. Required prophylactic treatment with GCSF in Cycles 1-6 for all Phase 3 participants. Updated contraception language and information regarding AEs under investigation or of special interest with tazemetostat to align with the current tazemetostat Investigator’s Brochure, version 12.0. Included a window of +/-7 days for the 12-week follow-up visits. Updated the list of responsible personnel and emergency contact information. Updated the supplier of doxorubicin to allow sourcing from commercial supply. Added a subsection to define prior and concomitant medications and adjusted the timing of collection to those administered within 30 days before the first study drug dose. Added specifications for data protection and remote source data verification. Added the Sponsor to the list of those at whose discretion participants might be transferred to long-term rollover study EZH-501.

    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.
    Following consultation with FDA, study was terminated due to feasibility concerns related to inability to meet required enrollment targets. Decision made after completion of Ph1b (dose esc) & prior to initiation of Ph1b (dose exp) & Ph3.
    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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