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Clinical Trial Results:
A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Summary
EudraCT number	2015-002469-41
Trial protocol	GB DE BE FR IT
Global end of trial date	26 Feb 2024

Results information
Results version number	v1(current)
This version publication date	23 Feb 2025
First version publication date	23 Feb 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

EZH-202

ISRCTN number

US NCT number

NCT02601950

WHO universal trial number (UTN)

Sponsor organisation name

Epizyme, Inc.

Sponsor organisation address

400 Technology Square, 4th Floor, Cambridge, United States, 02139

Public contact

Shefali Agarwal, MBBS, MPH, MIS, Epizyme, Inc., 001 855500-1011, clinicaltrials@epizyme.com

Scientific contact

Shefali Agarwal, MBBS, MPH, MIS, Epizyme, Inc., 001 855500-1011, clinicaltrials@epizyme.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-003055-PIP02-23

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Sep 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Feb 2024

Was the trial ended prematurely?

Main objective of the trial

- To assess the overall response rate (ORR) following oral administration of tazemetostat 800 milligrams (mg) twice daily (BID) in Cohort 1 (rhabdoid tumours), Cohort 3 (other integrase interactor 1 [INI-1]-negative tumours or any solid tumour with enhancer of zeste homologue-2 (EZH2) gain of function [GOF] mutation), Cohort 4 (renal medullary carcinoma [RMC]), Cohort 5 (epithelioid sarcoma [ES]), Cohort 6 (ES with optional tumour biopsy), and Cohort 7 (chordoma). - To determine the progression-free survival (PFS) rate following 16 weeks of oral administration of tazemetostat 800 mg BID in Cohort 2 (relapsed/ refractory synovial sarcoma with SS18-SSX rearrangement). - To assess the safety and tolerability of tazemetostat 1600 mg QD in Cohort 8 (ES treated with tazemetostat 1600 mg once daily [QD]).

Protection of trial subjects

The procedures set out in the study protocol pertaining to the conduct, evaluation, and documentation of this study were designed to ensure that the sponsor and investigators are by Good Clinical Practice as described in the International Conference on Harmonisation Tripartite Guideline E6. Compliance with these regulations also constituted compliance with the ethical principles described in the current revision of the Declaration of Helsinki. The study was also carried out in keeping with local legal and regulatory requirements. Participant confidentiality was strictly held in trust by the sponsor and/or their designee(s), participating Investigators, and site staff.

Background therapy

Evidence for comparator

Actual start date of recruitment

22 Dec 2015

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Belgium: 14

Country: Number of subjects enrolled

Canada: 6

Country: Number of subjects enrolled

France: 32

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 21

Country: Number of subjects enrolled

Taiwan: 13

Country: Number of subjects enrolled

United Kingdom: 20

Country: Number of subjects enrolled

United States: 150

Worldwide total number of subjects

267

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

247

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This Phase II, open-label study was conducted at 28 sites in 9 countries from 22 December 2015 to 26 February 2024.

Screening details

Participants were enrolled into 1 of the 8 cohorts based on tumor type. A total of 267 participants were enrolled in the study.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Rhabdoid Tumors: Cohort 1

Arm description

Participants with rhabdoid tumors (malignant rhabdoid tumor [MRT], rhabdoid tumors of the kidney [RTK], atypical teratoid rhabdoid tumor [ATRT], and selected tumors with rhabdoid features, including small cell carcinoma of the ovary hypercalcemic type [SCCOHT], also known as malignant rhabdoid tumor of the ovary [MRTO]) received tazemetostat 800 milligram (mg) twice daily (BID) orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 800 mg BID orally in continuous 28-day cycles.

Synovial Sarcoma: Cohort 2

Arm description

Participants with relapsed or refractory synovial sarcoma with SS18-SSX rearrangement received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 800 mg BID orally in continuous 28-day cycles.

Other INI1-negative: Cohort 3

Arm description

Participants with other INI-1-negative tumors or any solid tumor with EZH2 GOF mutation, including epithelioid malignant peripheral nerve sheath tumor (EMPNST), extraskeletal myxoid chondrosarcoma (EMC), myoepithelial carcinoma, other INI-1-negative malignant tumors with sponsor approval, any solid tumor with EZH2 GOF mutation including but not limited to Ewing's sarcoma and melanoma received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 800 mg BID orally in continuous 28-day cycles.

RMC: Cohort 4

Arm description

Participants with RMC received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 800 mg BID orally in continuous 28-day cycles.

ES: Cohort 5

Arm description

Participants with ES received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 800 mg BID orally in continuous 28-day cycles.

ES Paired Biopsy: Cohort 6

Arm description

Participants with ES undergoing optional tumor biopsy received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 800 mg BID orally in continuous 28-day cycles.

Chordoma: Cohort 7

Arm description

Participants with poorly differentiated chordoma (or other chordoma with sponsor approval) received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 800 mg BID orally in continuous 28-day cycles.

ES 1600 mg: Cohort 8

Arm description

Participants with ES received tazemetostat 1600 mg once daily (QD) orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Arm type

Experimental

Investigational medicinal product name

Tazemetostat

Investigational medicinal product code

EPZ-6438

Other name

IPN60200

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received tazemetostat 1600 mg QD orally in continuous 28-day cycles.

Number of subjects in period 1	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Started	32	33	32	14	62	69	18	7
Completed	0	0	0	0	0	0	0	0
Not completed	32	33	32	14	62	69	18	7
Participant refused further study treatment	-	1	1	-	2	2	2	1
Disease progression - clinical	3	5	4	2	6	6	5	1
Adverse event (not related to study treatment)	1	-	-	-	-	2	-	-
Death	6	-	3	1	4	1	-	-
Unacceptable toxicity (related to study treatment)	-	-	-	-	-	1	-	-
Non-compliance	-	1	-	-	-	1	1	-
Disease progression - radiological	21	26	22	11	46	52	7	5
Unspecified	-	-	-	-	2	2	1	-
Investigator discretion	1	-	1	-	1	1	1	-
Participant enrolled in rollover study	-	-	1	-	1	1	1	-

Baseline characteristics

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Reporting group title

Rhabdoid Tumors: Cohort 1

Reporting group description

Reporting group title

Synovial Sarcoma: Cohort 2

Reporting group description

Reporting group title

Other INI1-negative: Cohort 3

Reporting group description

Reporting group title

RMC: Cohort 4

Reporting group description

Reporting group title

ES: Cohort 5

Reporting group description

Reporting group title

ES Paired Biopsy: Cohort 6

Reporting group description

Reporting group title

Chordoma: Cohort 7

Reporting group description

Reporting group title

ES 1600 mg: Cohort 8

Reporting group description

Reporting group values	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8	Total
Number of subjects	32	33	32	14	62	69	18	7	267
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	37.9 ( 16.31 )	38.8 ( 9.54 )	46.9 ( 16.94 )	30.7 ( 10.71 )	37.0 ( 15.08 )	41.3 ( 14.00 )	38.9 ( 17.49 )	40.9 ( 15.74 )	-
Gender categorical
Units: Subjects
Female	19	12	17	4	23	26	8	4	113
Male	13	21	15	10	39	43	10	3	154
Race
Units: Subjects
American Indian or Alaska Native	1	0	0	0	0	0	0	0	1
Asian	2	0	1	0	7	9	1	2	22
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	1	0	0	1
Black or African American	3	4	2	11	4	1	1	0	26
White	24	24	28	2	47	54	16	5	200
Unknown or Not Reported	2	5	1	1	4	4	0	0	17
More than one race	0	0	0	0	0	0	0	0	0
Ethnicity
Units: Subjects
Hispanic or Latino	0	5	4	1	7	4	0	0	21
Not Hispanic or Latino	31	28	27	13	53	55	17	7	231
Unknown or Not Reported	1	0	1	0	2	10	1	0	15

End points

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Reporting group title

Rhabdoid Tumors: Cohort 1

Reporting group description

Reporting group title

Synovial Sarcoma: Cohort 2

Reporting group description

Reporting group title

Other INI1-negative: Cohort 3

Reporting group description

Reporting group title

RMC: Cohort 4

Reporting group description

Reporting group title

ES: Cohort 5

Reporting group description

Reporting group title

ES Paired Biopsy: Cohort 6

Reporting group description

Reporting group title

Chordoma: Cohort 7

Reporting group description

Reporting group title

ES 1600 mg: Cohort 8

Reporting group description

Primary: Cohorts 1, 3, 4, 5, 6 and 7: Objective response rate (ORR)

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End point title

Cohorts 1, 3, 4, 5, 6 and 7: Objective response rate (ORR) ^[1] ^[2]

End point description

ORR=percentage of participants who achieved a confirmed complete response (CR) or partial response (PR) based on the investigator review from start of treatment until progressive disease (PD) or start of subsequent anti-cancer therapy or cancer-related surgery, whichever was earlier, per response assessment in neuro-oncology (RANO) criteria for primary brain tumors or response evaluation criteria in solid tumors (RECIST) version(v) 1.1 criteria for all other solid tumors. CR=disappearance of all target and non-target lesions. Any pathological lymph nodes must be <10 millimeter (mm) in short axis. PR=at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. PD=at least a 20% increase in sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since treatment started. Sum must have an absolute increase from nadir of 5 mm. ITT population=all participants who received at least 1 dose of tazemetostat.

End point type

Primary

End point timeframe

Tumor assessment performed at screening and every 8 weeks beginning at Cycle 3 Day 1, until disease progression or the start of subsequent anti-cancer therapy, whichever occurred first, up to 5.75 years (cycle duration: 28 days).

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 primary endpoint only applies to participants in Cohorts 1, 3, 4, 5, 6 and 7.

End point values	Rhabdoid Tumors: Cohort 1	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7
Number of subjects analysed	32	32	14	62	69	18
Units: Percentage of participants
number (confidence interval 95%)	9.4 (2.0 to 25.0)	9.4 (2.0 to 25.0)	0.0 (0.0 to 23.2)	16.1 (8.0 to 27.7)	15.9 (8.2 to 26.7)	5.6 (0.1 to 27.3)

No statistical analyses for this end point

Primary: Cohort 2: Progression-Free Survival (PFS) rate at 16 Weeks of Treatment With Tazemetostat

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End point title

Cohort 2: Progression-Free Survival (PFS) rate at 16 Weeks of Treatment With Tazemetostat ^[3] ^[4]

End point description

PFS was defined as the interval of time between the date of the first dose of study treatment and the earliest date of PD or death due to any cause, whichever comes first, as per RECIST v 1.1 criteria. PFS rate at 16 week was estimated. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. ITT population included all participants who received at least 1 dose of tazemetostat.

End point type

Primary

End point timeframe

At 16 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: As the endpoint was descriptive in nature, no statistical analysis was reported.
[4] - 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: Only participants in Cohort 2 were analyzed for this endpoint.

End point values	Synovial Sarcoma: Cohort 2
Number of subjects analysed	33
Units: Percentage of participants
number (confidence interval 95%)	15.2 (5.1 to 31.9)

No statistical analyses for this end point

Primary: Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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End point title

Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) ^[5] ^[6]

End point description

An AE was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily have a causal relationship with this treatment. An SAE was defined as any untoward medical occurrence that, at 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 medically significant. TEAEs were defined as AEs if one of the following conditions met: emerged after the time of first dose administration, having been absent prior to the first dose; re-emerged, having been present but stopped prior to time of first dose administration; worsened in severity after the time of first dose administration relative to the pretreatment state, when the AE was continuous. Safety population=all participants in ITT population who had at least 1 post-dose safety observation recorded.

End point type

Primary

End point timeframe

From first dose of study treatment (Day 1) up to 30 days after the last dose of study treatment, approximately 148 weeks

Notes
[5] - 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.
[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: Only participants in Cohort 8 were analyzed for this endpoint.

End point values	ES 1600 mg: Cohort 8
Number of subjects analysed	7
Units: Participants
TEAEs	7
TESAEs	2

No statistical analyses for this end point

Secondary: All Cohorts: Duration of Response (DOR)

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End point title

All Cohorts: Duration of Response (DOR)

End point description

DOR was defined as time from the first documented evidence of CR or PR based on investigator review to the time of first documented PD or death due to any cause, whichever came first, as per RECIST v 1.1 criteria. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. ITT population included all participants who received at least 1 dose of tazemetostat. Only those participants with a confirmed CR or PR (responders) were analyzed.

End point type

Secondary

End point timeframe

End point values	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Number of subjects analysed	3	0 ^[7]	3	0 ^[8]	10	11	1	1
Units: Weeks
median (full range (min-max))	29.0 (24.1 to 32.1)	( to )	80.1 (24.1 to 87.6)	( to )	88.0 (7.1 to 224.4)	96.1 (10.3 to 112.3)	151.6 (151.6 to 151.6)	119.4 (119.4 to 119.4)

Notes
[7] - None of the participants experienced a CR or PR.
[8] - None of the participants experienced a CR or PR.

No statistical analyses for this end point

Secondary: All Cohorts: Progression-Free Survival (PFS)

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End point title

All Cohorts: Progression-Free Survival (PFS)

End point description

PFS was defined as the interval of time between the date of the first dose of study treatment and the earliest date of PD or death due to any cause, whichever comes first, as per RECIST v 1.1 criteria. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. ITT population included all participants who received at least 1 dose of tazemetostat. Here, '99999' indicates that upper limit of confidence interval (CI) was not estimable due to insufficient number of participants with events at study closure.

End point type

Secondary

End point timeframe

End point values	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Number of subjects analysed	32	33	32	14	62	69	18	7
Units: Weeks
median (confidence interval 95%)	7.9 (7.7 to 15.1)	8.0 (7.6 to 8.1)	15.7 (7.7 to 31.7)	7.3 (6.3 to 15.1)	23.7 (14.7 to 25.7)	16.1 (8.4 to 16.6)	24.0 (6.3 to 175.3)	39.9 (4.1 to 99999)

No statistical analyses for this end point

Secondary: All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56

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End point title

All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56

End point description

PFS was defined as the interval of time between the date of the first dose of study treatment and the earliest date of PD or death due to any cause, whichever comes first, as per RECIST v 1.1 criteria. PFS rate at 24, 32 and 56 weeks were estimated. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. Estimates were calculated with Kaplan-Meier analysis and 95% CIs using the complementary log-log transformation. ITT population included all participants who received at least 1 dose of tazemetostat.

End point type

Secondary

End point timeframe

At Weeks 24, 32 and 56

End point values	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Number of subjects analysed	32	33	32	14	62	69	18	7
Units: Percentage of participants
number (confidence interval 95%)
Week 24	17.6 (6.5 to 33.1)	15.9 (5.1 to 32.0)	34.4 (18.2 to 51.2)	15.4 (2.5 to 38.8)	42.1 (29.3 to 54.4)	33.8 (22.9 to 45.0)	43.6 (18.2 to 66.7)	53.6 (13.2 to 82.5)
Week 32	14.1 (4.5 to 28.9)	10.6 (2.2 to 26.7)	26.7 (12.3 to 43.5)	15.4 (2.5 to 38.8)	29.1 (17.9 to 41.2)	29.3 (19.1 to 40.4)	43.6 (18.2 to 66.7)	53.6 (13.2 to 82.5)
Week 56	3.5 (0.3 to 15.2)	0.0 (0.0 to 0.0)	13.8 (3.8 to 29.9)	0.0 (0.0 to 0.0)	21.3 (11.6 to 33.0)	22.6 (13.3 to 33.3)	18.2 (1.5 to 50.3)	26.8 (1.3 to 67.0)

No statistical analyses for this end point

Secondary: All Cohorts: Overall Survival (OS)

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End point title

All Cohorts: Overall Survival (OS)

End point description

OS was defined as the interval of time between the date of the first dose of study treatment and the date of death due to any cause. ITT population included all participants who received at least 1 dose of tazemetostat. Here, '99999' indicates that upper limit of CI was not estimable due to insufficient number of participants with events at study closure.

End point type

Secondary

End point timeframe

End point values	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Number of subjects analysed	32	33	32	14	62	69	18	7
Units: Weeks
median (confidence interval 95%)	22.1 (14.4 to 54.6)	43.4 (31.7 to 58.1)	37.9 (23.3 to 104.0)	24.6 (8.4 to 73.6)	82.4 (47.4 to 117.0)	111.4 (63.0 to 99999)	77.7 (32.9 to 99999)	49.6 (19.3 to 99999)

No statistical analyses for this end point

Secondary: All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56

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End point title

All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56

End point description

OS was defined as the interval of time between the date of the first dose of study treatment and the date of death due to any cause. OS rate at 24, 32 and 56 weeks were estimated. Estimates were calculated with Kaplan-Meier analysis and 95% CIs using the complementary log-log transformation. ITT population included all participants who received at least 1 dose of tazemetostat.

End point type

Secondary

End point timeframe

At Weeks 24, 32 and 56

End point values	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Number of subjects analysed	32	33	32	14	62	69	18	7
Units: Percentage of participants
number (confidence interval 95%)
Week 24	45.4 (27.6 to 61.6)	81.4 (63.2 to 91.2)	68.8 (49.7 to 81.8)	50.0 (22.9 to 72.2)	85.5 (73.9 to 92.2)	83.6 (72.3 to 90.6)	88.9 (62.4 to 97.1)	83.3 (27.3 to 97.5)
Week 32	38.6 (21.8 to 55.2)	68.9 (49.9 to 81.9)	56.3 (37.6 to 71.3)	42.9 (17.7 to 66.0)	77.2 (64.6 to 85.8)	75.8 (63.6 to 84.4)	77.8 (51.1 to 91.0)	66.7 (19.5 to 90.4)
Week 56	30.9 (15.5 to 47.7)	37.6 (21.3 to 53.8)	49.6 (31.4 to 65.4)	35.7 (13.0 to 59.4)	57.3 (43.9 to 68.6)	66.5 (53.7 to 76.6)	55.6 (30.5 to 74.8)	44.4 (6.6 to 78.5)

No statistical analyses for this end point

Secondary: All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48

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End point title

All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48

End point description

DCR was defined as the percentage of participants who achieved a confirmed response (CR or PR, as per RECIST v 1.1 criteria) or who have SD lasting at least 32 weeks from the start of treatment until disease progression or the start of subsequent anti-cancer therapy. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. SD was defined neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. ITT population included all participants who received at least 1 dose of tazemetostat.

End point type

Secondary

End point timeframe

At Weeks 12, 24, 32 and 48

End point values	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Number of subjects analysed	32	33	32	14	62	69	18	7
Units: Percentage of participants
number (confidence interval 95%)
Week 12	21.9 (9.3 to 40.0)	15.2 (5.1 to 31.9)	40.6 (23.7 to 59.4)	21.4 (4.7 to 50.8)	45.2 (32.5 to 58.3)	36.2 (25.0 to 48.7)	50.0 (26.0 to 74.0)	42.9 (9.9 to 81.6)
Week 24	12.5 (3.5 to 29.0)	9.1 (1.9 to 24.3)	21.9 (9.3 to 40.0)	14.3 (1.8 to 42.8)	29.0 (18.2 to 41.9)	30.4 (19.9 to 42.7)	33.3 (13.3 to 59.0)	42.9 (9.9 to 81.6)
Week 32	9.4 (2.0 to 25.0)	3.0 (0.1 to 15.8)	18.8 (7.2 to 36.4)	7.1 (0.2 to 33.9)	25.8 (15.5 to 38.5)	29.0 (18.7 to 41.2)	27.8 (9.7 to 53.5)	14.3 (0.4 to 57.9)
Week 48	9.4 (2.0 to 25.0)	3.0 (0.1 to 15.8)	12.5 (3.5 to 29.0)	0.0 (0.0 to 23.2)	24.2 (14.2 to 36.7)	23.2 (13.9 to 34.9)	11.1 (1.4 to 34.7)	14.3 (0.4 to 57.9)

No statistical analyses for this end point

Secondary: Cohorts 2 and 8: Objective Response Rate (ORR)

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End point title

Cohorts 2 and 8: Objective Response Rate (ORR) ^[9]

End point description

ORR was defined as percentage of participants who achieved a confirmed CR or PR based on investigator assessment from start of treatment until PD or start of subsequent anti-cancer therapy or cancer-related surgery, whichever was earlier, as per RANO criteria for primary brain tumors or RECIST v 1.1 criteria for all other solid tumors. CR was defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must be <10 mm in the short axis. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm. ITT population included all participants who received at least 1 dose of tazemetostat.

End point type

Secondary

End point timeframe

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: Only participants in Cohorts 2 and 8 were analyzed for this endpoint.

End point values	Synovial Sarcoma: Cohort 2	ES 1600 mg: Cohort 8
Number of subjects analysed	33	7
Units: Percentage of participants
number (confidence interval 95%)	0 (0.0 to 10.6)	14.3 (0.4 to 57.9)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

TEAEs:Day 1 upto 30 days after last dose of study treatment,approximately 88 weeks(Cohort 1),55 weeks(Cohort 2),148 weeks(Cohorts 3 and 8),48 weeks(Cohort 4),304 weeks(Cohort 5),270 weeks(Cohort 6) and 183 weeks(Cohort 7). Deaths: Day 1 up to 5.75 years.

Adverse event reporting additional description

Safety population included all participants in the ITT population who had at least 1 post-dose safety observation recorded.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Rhabdoid Tumors: Cohort 1

Reporting group description

Participants with rhabdoid tumors (MRT, RTK, ATRT, and selected tumors with rhabdoid features, including SCCOHT, also known as MRTO) received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Reporting group title

Synovial Sarcoma: Cohort 2

Reporting group description

Reporting group title

Other INI1-negative: Cohort 3

Reporting group description

Participants with other INI-1-negative tumors or any solid tumor with EZH2 GOF mutation, including EMPNST, EMC, myoepithelial carcinoma, other INI-1-negative malignant tumors with sponsor approval, any solid tumor with EZH2 GOF mutation including but not limited to Ewing’s sarcoma and melanoma received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Reporting group title

RMC: Cohort 4

Reporting group description

Reporting group title

ES: Cohort 5

Reporting group description

Reporting group title

ES Paired Biopsy: Cohort 6

Reporting group description

Participants with ES undergoing optional tumour biopsy received tazemetostat 800 mg BID orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Reporting group title

Chordoma: Cohort 7

Reporting group description

Reporting group title

ES 1600 mg: Cohort 8

Reporting group description

Participants with ES received tazemetostat 1600 mg QD orally in continuous 28-day cycles until disease progression, development of an unacceptable toxicity, withdrawal of consent, or termination of the study.

Serious adverse events	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Total subjects affected by serious adverse events
subjects affected / exposed	18 / 32 (56.25%)	13 / 33 (39.39%)	11 / 32 (34.38%)	8 / 14 (57.14%)	25 / 62 (40.32%)	19 / 69 (27.54%)	7 / 18 (38.89%)	2 / 7 (28.57%)
number of deaths (all causes)	9	2	5	3	8	6	2	0
number of deaths resulting from adverse events	9	2	5	3	8	6	2	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	2 / 32 (6.25%)	2 / 33 (6.06%)	2 / 32 (6.25%)	0 / 14 (0.00%)	3 / 62 (4.84%)	1 / 69 (1.45%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 3	0 / 0	0 / 3	0 / 2	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
Tumour pain
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Lymphangiosis carcinomatosa
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	1 / 14 (7.14%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Small cell carcinoma
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death
subjects affected / exposed	5 / 32 (15.63%)	0 / 33 (0.00%)	4 / 32 (12.50%)	3 / 14 (21.43%)	4 / 62 (6.45%)	2 / 69 (2.90%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 4	0 / 3	0 / 4	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 5	0 / 0	0 / 4	0 / 3	0 / 4	0 / 2	0 / 2	0 / 0
Fatigue
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Oedema peripheral
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Pain
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Pyrexia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 32 (3.13%)	3 / 33 (9.09%)	3 / 32 (9.38%)	3 / 14 (21.43%)	3 / 62 (4.84%)	3 / 69 (4.35%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 3	0 / 3	0 / 4	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 32 (6.25%)	0 / 33 (0.00%)	2 / 32 (6.25%)	0 / 14 (0.00%)	4 / 62 (6.45%)	2 / 69 (2.90%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 6	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 32 (0.00%)	3 / 33 (9.09%)	0 / 32 (0.00%)	0 / 14 (0.00%)	4 / 62 (6.45%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0	1 / 4	0 / 3	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
Pneumothorax
subjects affected / exposed	0 / 32 (0.00%)	2 / 33 (6.06%)	1 / 32 (3.13%)	0 / 14 (0.00%)	1 / 62 (1.61%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0	0 / 2	0 / 2	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
Pulmonary embolism
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	2 / 14 (14.29%)	1 / 62 (1.61%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 1	0 / 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
Acute respiratory failure
subjects affected / exposed	1 / 32 (3.13%)	2 / 33 (6.06%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	1 / 69 (1.45%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	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
Atelectasis
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Cough
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Haemothorax
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Hypercapnia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Pneumonia aspiration
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Pulmonary haemorrhage
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Pulmonary hypertension
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Mental status changes
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Panic attack
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
C-reactive protein increased
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Ejection fraction decreased
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	1 / 14 (7.14%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Platelet count decreased
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Ankle fracture
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Femur fracture
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Spinal fracture
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Tracheal obstruction
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Wound dehiscence
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Cardiac arrest
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Nervous system disorders
Nervous system disorder
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Aphasia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Brain oedema
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Cerebral haemorrhage
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Cognitive disorder
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Dizziness
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Haemorrhage intracranial
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Neuralgia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Paraparesis
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Seizure
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	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
Spinal cord compression
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Febrile neutropenia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 32 (9.38%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1	0 / 0	0 / 1	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
Constipation
subjects affected / exposed	1 / 32 (3.13%)	2 / 33 (6.06%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 2	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
Ascites
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	1 / 14 (7.14%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	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
Nausea
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 2	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
Vomiting
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Dysphagia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Intra-abdominal haemorrhage
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Large intestinal obstruction
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 2	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
Small intestinal obstruction
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Hyperbilirubinaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	1 / 1	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
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Ureteric obstruction
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Urinary retention
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	1 / 14 (7.14%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	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
Muscular weakness
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Musculoskeletal chest pain
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	1 / 14 (7.14%)	1 / 62 (1.61%)	2 / 69 (2.90%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 1	0 / 2	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
Cellulitis
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	2 / 62 (3.23%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2	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
Pyelonephritis
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	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
Pyelonephritis acute
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 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
Sepsis
subjects affected / exposed	1 / 32 (3.13%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	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
Bacteraemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Biliary tract infection
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
COVID-19 pneumonia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Enterocolitis infectious
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Infection
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Periorbital cellulitis
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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
Pneumonia staphylococcal
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences causally related to treatment / all	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
Skin infection
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Soft tissue infection
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Staphylococcal bacteraemia
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	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 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	1 / 62 (1.61%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	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
Hypercalcaemia
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	1 / 32 (3.13%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Decreased appetite
subjects affected / exposed	0 / 32 (0.00%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	1 / 69 (1.45%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 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
Failure to thrive
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	0 / 14 (0.00%)	0 / 62 (0.00%)	0 / 69 (0.00%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences causally related to treatment / all	0 / 1	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

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Rhabdoid Tumors: Cohort 1	Synovial Sarcoma: Cohort 2	Other INI1-negative: Cohort 3	RMC: Cohort 4	ES: Cohort 5	ES Paired Biopsy: Cohort 6	Chordoma: Cohort 7	ES 1600 mg: Cohort 8
Total subjects affected by non serious adverse events
subjects affected / exposed	27 / 32 (84.38%)	28 / 33 (84.85%)	29 / 32 (90.63%)	12 / 14 (85.71%)	58 / 62 (93.55%)	65 / 69 (94.20%)	16 / 18 (88.89%)	6 / 7 (85.71%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	9 / 32 (28.13%)	8 / 33 (24.24%)	7 / 32 (21.88%)	2 / 14 (14.29%)	19 / 62 (30.65%)	1 / 69 (1.45%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	10	13	9	3	29	1	3	0
Tumour pain
subjects affected / exposed	2 / 32 (6.25%)	1 / 33 (3.03%)	3 / 32 (9.38%)	0 / 14 (0.00%)	1 / 62 (1.61%)	4 / 69 (5.80%)	2 / 18 (11.11%)	1 / 7 (14.29%)
occurrences all number	3	2	3	0	1	7	2	1
Vascular disorders
Hypertension
subjects affected / exposed	0 / 32 (0.00%)	2 / 33 (6.06%)	4 / 32 (12.50%)	0 / 14 (0.00%)	7 / 62 (11.29%)	4 / 69 (5.80%)	0 / 18 (0.00%)	0 / 7 (0.00%)
occurrences all number	0	2	15	0	8	10	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	7 / 32 (21.88%)	10 / 33 (30.30%)	11 / 32 (34.38%)	3 / 14 (21.43%)	24 / 62 (38.71%)	21 / 69 (30.43%)	4 / 18 (22.22%)	3 / 7 (42.86%)
occurrences all number	7	13	12	3	38	26	6	6
Asthenia
subjects affected / exposed	3 / 32 (9.38%)	4 / 33 (12.12%)	3 / 32 (9.38%)	0 / 14 (0.00%)	4 / 62 (6.45%)	9 / 69 (13.04%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	3	8	3	0	6	14	3	0
Oedema peripheral
subjects affected / exposed	3 / 32 (9.38%)	2 / 33 (6.06%)	1 / 32 (3.13%)	2 / 14 (14.29%)	6 / 62 (9.68%)	7 / 69 (10.14%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	4	2	1	2	6	8	0	1
Pyrexia
subjects affected / exposed	2 / 32 (6.25%)	1 / 33 (3.03%)	1 / 32 (3.13%)	1 / 14 (7.14%)	4 / 62 (6.45%)	5 / 69 (7.25%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	2	1	1	1	8	6	1	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 32 (9.38%)	10 / 33 (30.30%)	4 / 32 (12.50%)	3 / 14 (21.43%)	13 / 62 (20.97%)	5 / 69 (7.25%)	2 / 18 (11.11%)	3 / 7 (42.86%)
occurrences all number	4	12	6	3	13	6	3	3
Dyspnoea
subjects affected / exposed	7 / 32 (21.88%)	8 / 33 (24.24%)	4 / 32 (12.50%)	4 / 14 (28.57%)	6 / 62 (9.68%)	7 / 69 (10.14%)	0 / 18 (0.00%)	3 / 7 (42.86%)
occurrences all number	8	9	4	4	7	11	0	9
Pleural effusion
subjects affected / exposed	3 / 32 (9.38%)	3 / 33 (9.09%)	2 / 32 (6.25%)	3 / 14 (21.43%)	4 / 62 (6.45%)	4 / 69 (5.80%)	0 / 18 (0.00%)	4 / 7 (57.14%)
occurrences all number	3	3	4	3	5	5	0	8
Psychiatric disorders
Insomnia
subjects affected / exposed	2 / 32 (6.25%)	2 / 33 (6.06%)	4 / 32 (12.50%)	3 / 14 (21.43%)	5 / 62 (8.06%)	4 / 69 (5.80%)	2 / 18 (11.11%)	0 / 7 (0.00%)
occurrences all number	2	2	4	3	6	4	2	0
Investigations
Weight decreased
subjects affected / exposed	3 / 32 (9.38%)	2 / 33 (6.06%)	2 / 32 (6.25%)	4 / 14 (28.57%)	10 / 62 (16.13%)	6 / 69 (8.70%)	0 / 18 (0.00%)	3 / 7 (42.86%)
occurrences all number	3	5	3	6	22	12	0	4
Weight increased
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	3 / 32 (9.38%)	0 / 14 (0.00%)	6 / 62 (9.68%)	3 / 69 (4.35%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	1	0	3	0	17	4	2	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 32 (12.50%)	5 / 33 (15.15%)	3 / 32 (9.38%)	1 / 14 (7.14%)	11 / 62 (17.74%)	5 / 69 (7.25%)	3 / 18 (16.67%)	0 / 7 (0.00%)
occurrences all number	4	5	5	1	17	6	3	0
Dysgeusia
subjects affected / exposed	3 / 32 (9.38%)	2 / 33 (6.06%)	3 / 32 (9.38%)	0 / 14 (0.00%)	5 / 62 (8.06%)	1 / 69 (1.45%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	3	2	3	0	6	1	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 32 (12.50%)	4 / 33 (12.12%)	4 / 32 (12.50%)	4 / 14 (28.57%)	10 / 62 (16.13%)	8 / 69 (11.59%)	3 / 18 (16.67%)	1 / 7 (14.29%)
occurrences all number	7	8	6	5	34	9	3	2
Gastrointestinal disorders
Nausea
subjects affected / exposed	10 / 32 (31.25%)	9 / 33 (27.27%)	9 / 32 (28.13%)	3 / 14 (21.43%)	23 / 62 (37.10%)	32 / 69 (46.38%)	8 / 18 (44.44%)	3 / 7 (42.86%)
occurrences all number	15	14	18	3	31	43	10	5
Vomiting
subjects affected / exposed	13 / 32 (40.63%)	1 / 33 (3.03%)	9 / 32 (28.13%)	5 / 14 (35.71%)	16 / 62 (25.81%)	9 / 69 (13.04%)	5 / 18 (27.78%)	3 / 7 (42.86%)
occurrences all number	18	2	12	6	23	13	5	5
Constipation
subjects affected / exposed	7 / 32 (21.88%)	4 / 33 (12.12%)	5 / 32 (15.63%)	4 / 14 (28.57%)	13 / 62 (20.97%)	10 / 69 (14.49%)	3 / 18 (16.67%)	3 / 7 (42.86%)
occurrences all number	7	4	5	4	17	10	3	3
Diarrhoea
subjects affected / exposed	6 / 32 (18.75%)	3 / 33 (9.09%)	6 / 32 (18.75%)	0 / 14 (0.00%)	10 / 62 (16.13%)	16 / 69 (23.19%)	3 / 18 (16.67%)	2 / 7 (28.57%)
occurrences all number	8	3	6	0	15	17	4	2
Abdominal pain
subjects affected / exposed	4 / 32 (12.50%)	0 / 33 (0.00%)	2 / 32 (6.25%)	1 / 14 (7.14%)	4 / 62 (6.45%)	7 / 69 (10.14%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	4	0	3	1	7	8	1	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	4 / 32 (12.50%)	0 / 14 (0.00%)	5 / 62 (8.06%)	7 / 69 (10.14%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	1	0	4	0	5	9	1	1
Dry skin
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	2 / 32 (6.25%)	2 / 14 (14.29%)	5 / 62 (8.06%)	5 / 69 (7.25%)	1 / 18 (5.56%)	0 / 7 (0.00%)
occurrences all number	0	1	2	2	6	5	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 32 (12.50%)	1 / 33 (3.03%)	6 / 32 (18.75%)	1 / 14 (7.14%)	7 / 62 (11.29%)	4 / 69 (5.80%)	0 / 18 (0.00%)	1 / 7 (14.29%)
occurrences all number	6	1	6	1	7	6	0	1
Back pain
subjects affected / exposed	1 / 32 (3.13%)	1 / 33 (3.03%)	1 / 32 (3.13%)	2 / 14 (14.29%)	4 / 62 (6.45%)	9 / 69 (13.04%)	1 / 18 (5.56%)	1 / 7 (14.29%)
occurrences all number	1	1	1	3	4	10	1	1
Pain in extremity
subjects affected / exposed	1 / 32 (3.13%)	0 / 33 (0.00%)	0 / 32 (0.00%)	1 / 14 (7.14%)	7 / 62 (11.29%)	7 / 69 (10.14%)	2 / 18 (11.11%)	1 / 7 (14.29%)
occurrences all number	1	0	0	1	7	7	2	1
Musculoskeletal pain
subjects affected / exposed	0 / 32 (0.00%)	2 / 33 (6.06%)	1 / 32 (3.13%)	0 / 14 (0.00%)	1 / 62 (1.61%)	11 / 69 (15.94%)	3 / 18 (16.67%)	0 / 7 (0.00%)
occurrences all number	0	2	1	0	2	11	3	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	0 / 32 (0.00%)	1 / 33 (3.03%)	2 / 32 (6.25%)	0 / 14 (0.00%)	3 / 62 (4.84%)	5 / 69 (7.25%)	1 / 18 (5.56%)	2 / 7 (28.57%)
occurrences all number	0	1	3	0	3	12	1	4
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 32 (9.38%)	4 / 33 (12.12%)	3 / 32 (9.38%)	8 / 14 (57.14%)	15 / 62 (24.19%)	9 / 69 (13.04%)	3 / 18 (16.67%)	2 / 7 (28.57%)
occurrences all number	3	4	4	9	27	9	3	3
Hypophosphataemia
subjects affected / exposed	2 / 32 (6.25%)	3 / 33 (9.09%)	2 / 32 (6.25%)	0 / 14 (0.00%)	1 / 62 (1.61%)	4 / 69 (5.80%)	0 / 18 (0.00%)	2 / 7 (28.57%)
occurrences all number	2	4	5	0	1	5	0	2

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Were there any global substantial amendments to the protocol? Yes

24 Aug 2015

Protocol changes made to reflect regulatory agency requests, to ensure document consistency and further clarify administrative details.

02 Oct 2015

Protocol changes made to clarify eligibility, to ensure document consistency and further clarify administrative details.

02 Mar 2016

To satisfy various regulatory requirements as well as to further expand the criteria for entry into the study and to further simplify and clarify study procedures. Removal of baseline visit (associated assessments to be performed on Day 1 of Cycle 1). Addition of INI-1-negative tumor type cohorts that were exclusively RMC (Cohort 4) and ES (Cohort 5). Participants with previously treated brain metastases might have been included providing they were stable, had no evidence of new or enlarging brain metastases, and were on stable or tapering doses of steroids. Any incidence of secondary lymphoma, even if occurring more than 30 days after the last dose of study treatment, was to be reported to the sponsor. Occurrence of secondary lymphoma added as reason for suspension of enrolment. New section and criteria added detailing removal of participants and study termination. Caution added that participants should avoid prolonged exposure to sunlight and ultraviolet rays while receiving study treatment. Various typographical/ administrative changes made.

25 Oct 2016

Expanded Cohort 5 (ES) due to clinical activity observed. In addition, the participant population was expanded to include participants with any solid tumor with EZH2 GOF mutation and clarifies that participants with SCCOHT, also known as MRTO were eligible. Clarified relapsed or refractory criteria in synovial sarcoma. Added preliminary pharmacokinetic (PK) data related to cytochrome (CYP)3A metabolism. Added 13-week juvenile Sprague-Dawley rat study data. Clarified disease progression with respect to continuation of treatment. Changed coagulation parameters to remove fibrinogen measurements and add international normalized ratio. Clarified tumor biopsy requirements and definition of disease-related events and adverse events of special interest (AESI). Typographical errors were corrected.

07 Aug 2017

Added Cohorts 6 (participants with ES undergoing mandatory tumor biopsy) and 7 (participants with chordoma). In addition, the objectives had been reorganized and updated based on recent data and Food and Drug Administration (FDA) meeting. The number of participants expanded to 130 – 250 and typographical errors corrected.

28 Sep 2018

The protocol was primarily amended with 2 new AESI of T-cell lymphoblastic lymphoma/T-cell acute lymphoblastic leukemia (TLL/T-ALL) and myelodysplastic syndrome, as well as the risk mitigation and monitoring required to minimize the risk of occurrence of these events in participants taking tazemetostat.

12 Sep 2019

To add a new cohort (n=16) of participants with ES that would receive tazemetostat 1600 mg QD, as opposed to all other cohorts receiving 800 mg BID. Rationale for doing so was potential achievement of higher area under the concentration-time curve at steady-state of approximately 7000 nanogram*hour per milliliter due to potentially lower inductive effect of the CYP3A4 enzyme.

21 Oct 2019

To correct 1600 mg QD tazemetostat dose modification column of Table 2: Dose Modifications for Treatment-Related Toxicities. In amendment 7.0, the restart dose for 1600 mg QD tazemetostat was incorrectly mentioned as BID which was now corrected as QD in amendment 8.0.

17 Mar 2020

To address requirements of the approval of tazemetostat by the FDA. As part of the post-marketing requirement Epizyme agreed to add 25 additional participants to cohort 6 with a primary endpoint of ORR and 12 months DOR. The number of participants had been updated approximately. The requirement for mandatory tumor biopsies for Cohort 6 was made optional.

01 Jul 2021

To update the safety profile based on the latest investigator’s brochure (IB) (version 11.0) for tazemetostat. Information regarding special situations (overdose, medication error, misuse, and abuse) was clarified and added based on current safety practices. Language regarding the case of TLL/T-ALL was updated to align with the latest IB. Information regarding a case of B-ALL was added to align with the most recent safety profile. The medical monitor was updated. Annual PK assessments were removed with this protocol amendment as the extra PK sample would not yield a sufficient amount of data to characterize the safety and efficacy of tazemetostat, therefore, the collection is no longer needed. Updates were added to the protocol to clarify which study arms were closed for enrolment and that participants in this study (EZH-202) were eligible to rollover into Study EZH-501. Text regarding FDA-approval for tazemetostat was updated to reflect the approval granted after January 2020.

05 Oct 2022

To update and align background and clinical information about tazemetostat with the updated IB for tazemetostat (IB version 12.0). To update the medical monitor. To update the exploratory objectives and endpoints regarding pharmacodynamics. To remove the requirement for central electrocardiogram readings. To remove the requirements for PK sampling for participants in Cohort 8. To update the requirements for record retention.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical Trial Results:
A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

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Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohorts 1, 3, 4, 5, 6 and 7: Objective response rate (ORR)

Primary: Cohorts 1, 3, 4, 5, 6 and 7: Objective response rate (ORR)

Primary: Cohort 2: Progression-Free Survival (PFS) rate at 16 Weeks of Treatment With Tazemetostat

Primary: Cohort 2: Progression-Free Survival (PFS) rate at 16 Weeks of Treatment With Tazemetostat

Primary: Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Primary: Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Secondary: All Cohorts: Duration of Response (DOR)

Secondary: All Cohorts: Duration of Response (DOR)

Secondary: All Cohorts: Progression-Free Survival (PFS)

Secondary: All Cohorts: Progression-Free Survival (PFS)

Secondary: All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Overall Survival (OS)

Secondary: All Cohorts: Overall Survival (OS)

Secondary: All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48

Secondary: All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48

Secondary: Cohorts 2 and 8: Objective Response Rate (ORR)

Secondary: Cohorts 2 and 8: Objective Response Rate (ORR)

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Clinical trials

Clinical Trial Results: A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohorts 1, 3, 4, 5, 6 and 7: Objective response rate (ORR)

Primary: Cohorts 1, 3, 4, 5, 6 and 7: Objective response rate (ORR)

Primary: Cohort 2: Progression-Free Survival (PFS) rate at 16 Weeks of Treatment With Tazemetostat

Primary: Cohort 2: Progression-Free Survival (PFS) rate at 16 Weeks of Treatment With Tazemetostat

Primary: Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Primary: Cohort 8: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

Secondary: All Cohorts: Duration of Response (DOR)

Secondary: All Cohorts: Duration of Response (DOR)

Secondary: All Cohorts: Progression-Free Survival (PFS)

Secondary: All Cohorts: Progression-Free Survival (PFS)

Secondary: All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Progression-Free Survival (PFS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Overall Survival (OS)

Secondary: All Cohorts: Overall Survival (OS)

Secondary: All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Overall Survival (OS) Rate at Weeks 24, 32 and 56

Secondary: All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48

Secondary: All Cohorts: Disease Control Rate (DCR) at Weeks 12, 24, 32 and 48

Secondary: Cohorts 2 and 8: Objective Response Rate (ORR)

Secondary: Cohorts 2 and 8: Objective Response Rate (ORR)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase II, Multicenter Study of the EZH2 Inhibitor Tazemetostat in Adult Subjects with INI1-Negative Tumors or Relapsed/Refractory Synovial Sarcoma