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Clinical Trial Results:
A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

Summary
EudraCT number	2015-002468-18
Trial protocol	GB DK DE NL IT
Global end of trial date	19 Jun 2021

Results information
Results version number	v1(current)
This version publication date	11 Jan 2022
First version publication date	11 Jan 2022
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-102

ISRCTN number

US NCT number

NCT02601937

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-PIP01-21

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

22 Oct 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

19 Jun 2021

Global end of trial reached?

Yes

Global end of trial date

19 Jun 2021

Was the trial ended prematurely?

Main objective of the trial

Dose Escalation: To determine the MTD or the RP2D of tazemetostat when administered as an oral suspension BID in pediatric subjects with relapsed/refractory rhabdoid tumors, INI1-negative tumors or synovial sarcoma Dose Expansion: To evaluate the antitumor activity of tazemetostat as assessed by overall response rate (ORR) in pediatric subjects with relapsed/refractory atypical teratoid rhabdoid tumor (ATRT) (Cohort 1), non-ATRT rhabdoid tumors (Cohort 2), INI1-negative tumors (Cohort 3), and tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Cohort 4) using disease-appropriate standardized response criteria

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 (GCP) as described in the International Conference on Harmonisation (ICH) 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. Subject 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

07 Jan 2016

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

2 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 3

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

Denmark: 12

Country: Number of subjects enrolled

France: 14

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

United States: 55

Country: Number of subjects enrolled

Canada: 3

Worldwide total number of subjects

109

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

07 January 2016 – 19 June 2021; Medical clinics, hospitals, and academic research centers.

Screening details

A signed, written informed consent (and assent, if applicable) must be obtained prior to any study-specific assessments or procedures being performed. All Screening assessments must be performed within 14 days prior to enrollment (Screening Period extends from Day -14 to Day -1).

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

Dose Escalation Level 1

Arm description

240 mg/m2 BID (starting dose) = 480 mg/m2/day

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Subjects received tazemetostat oral suspension. The amount of tazemetostat oral suspension per dose is calculated based on the subject’s body surface area (BSA) and the assigned dose level. Subjects received oral suspension at the assigned dose twice daily.

Dose Escalation Level 2

Arm description

300 mg/m2 BID = 600 mg/m2/day

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Escalation Level 3

Arm description

400 mg/m2 BID = 800 mg/m2/day

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Escalation Level 4

Arm description

520 mg/m2 BID = 1040 mg/m2/day

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Escalation Level 5

Arm description

700 mg/m2 BID = 1400 mg/m2/day

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Escalation Level 6

Arm description

900 mg/m2 BID = 1800 mg/m2/day

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Escalation Level 7

Arm description

1200 mg/m2 BID = 2400 mg/m2/day

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Expansion Cohort 1

Arm description

Subjects with ATRT

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Expansion Cohort 2

Arm description

Subjects with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Expansion Cohort 3

Arm description

Subjects with INI1-negative tumors

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Suspension for oral suspension

Routes of administration

Oral use

Dosage and administration details

Dose Expansion Cohort 4

Arm description

Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

Arm type

Experimental

Investigational medicinal product name

Tazemostat

Investigational medicinal product code

EPZ-6438

Other name

E7438

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects in Dose Expansion Cohort 4 received tazemetostat tablet formulation, 800 mg/m2 three times daily (2400 mg/m2/day equivalent to 1200 mg/m2 BID).

Number of subjects in period 1	Dose Escalation Level 1	Dose Escalation Level 2	Dose Escalation Level 3	Dose Escalation Level 4	Dose Escalation Level 5	Dose Escalation Level 6	Dose Escalation Level 7	Dose Expansion Cohort 1	Dose Expansion Cohort 2	Dose Expansion Cohort 3	Dose Expansion Cohort 4
Started	8	6	6	7	6	6	7	19	20	18	6
Completed	0	0	0	1	0	1	0	1	0	0	1
Not completed	8	6	6	6	6	5	7	18	20	18	5
Consent withdrawn by subject	1	-	-	-	-	-	1	2	-	-	-
Physician decision	-	-	-	-	-	-	-	-	-	1	1
death	-	-	-	-	-	-	-	-	1	-	-
unknown	-	-	-	-	-	-	-	-	2	2	-
Adverse event, non-fatal	-	-	-	-	-	1	-	-	-	1	-
Unacceptable toxicity	-	-	1	-	-	-	-	-	-	-	-
Disease Progression	7	6	5	6	6	4	6	16	17	14	4

Baseline characteristics

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Reporting group title

Dose Escalation Level 1

Reporting group description

240 mg/m2 BID (starting dose) = 480 mg/m2/day

Reporting group title

Dose Escalation Level 2

Reporting group description

300 mg/m2 BID = 600 mg/m2/day

Reporting group title

Dose Escalation Level 3

Reporting group description

400 mg/m2 BID = 800 mg/m2/day

Reporting group title

Dose Escalation Level 4

Reporting group description

520 mg/m2 BID = 1040 mg/m2/day

Reporting group title

Dose Escalation Level 5

Reporting group description

700 mg/m2 BID = 1400 mg/m2/day

Reporting group title

Dose Escalation Level 6

Reporting group description

900 mg/m2 BID = 1800 mg/m2/day

Reporting group title

Dose Escalation Level 7

Reporting group description

1200 mg/m2 BID = 2400 mg/m2/day

Reporting group title

Dose Expansion Cohort 1

Reporting group description

Subjects with ATRT

Reporting group title

Dose Expansion Cohort 2

Reporting group description

Subjects with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features

Reporting group title

Dose Expansion Cohort 3

Reporting group description

Subjects with INI1-negative tumors

Reporting group title

Dose Expansion Cohort 4

Reporting group description

Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

Reporting group values	Dose Escalation Level 1	Dose Escalation Level 2	Dose Escalation Level 3	Dose Escalation Level 4	Dose Escalation Level 5	Dose Escalation Level 6	Dose Escalation Level 7	Dose Expansion Cohort 1	Dose Expansion Cohort 2	Dose Expansion Cohort 3	Dose Expansion Cohort 4	Total
Number of subjects	8	6	6	7	6	6	7	19	20	18	6	109
Age categorical
Units: Subjects
Infants and toddlers (28 days-23 months)	4	1	1	1	0	1	2	2	5	0	0	17
Children (2-11 years)	4	0	4	6	4	5	4	15	13	5	2	62
Adolescents (12-17 years)	0	5	1	0	2	0	1	2	2	12	2	27
Adults (18-64 years)	0	0	0	0	0	0	0	0	0	1	2	3
Gender categorical
Units: Subjects
Female	4	4	5	5	2	4	2	12	7	11	3	59
Male	4	2	1	2	4	2	5	7	13	7	3	50

End points

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Reporting group title

Dose Escalation Level 1

Reporting group description

240 mg/m2 BID (starting dose) = 480 mg/m2/day

Reporting group title

Dose Escalation Level 2

Reporting group description

300 mg/m2 BID = 600 mg/m2/day

Reporting group title

Dose Escalation Level 3

Reporting group description

400 mg/m2 BID = 800 mg/m2/day

Reporting group title

Dose Escalation Level 4

Reporting group description

520 mg/m2 BID = 1040 mg/m2/day

Reporting group title

Dose Escalation Level 5

Reporting group description

700 mg/m2 BID = 1400 mg/m2/day

Reporting group title

Dose Escalation Level 6

Reporting group description

900 mg/m2 BID = 1800 mg/m2/day

Reporting group title

Dose Escalation Level 7

Reporting group description

1200 mg/m2 BID = 2400 mg/m2/day

Reporting group title

Dose Expansion Cohort 1

Reporting group description

Subjects with ATRT

Reporting group title

Dose Expansion Cohort 2

Reporting group description

Subjects with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features

Reporting group title

Dose Expansion Cohort 3

Reporting group description

Subjects with INI1-negative tumors

Reporting group title

Dose Expansion Cohort 4

Reporting group description

Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

Primary: Dose limiting toxicities (DLTs)

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End point title

Dose limiting toxicities (DLTs) ^[1] ^[2]

End point description

A DLT is a significant adverse reaction (with the exception of tumor progression) that meets any of the following criteria: • Non-hematologic toxicity: any other Grade 3 or greater non-hematologic toxicity except: • alopecia • fatigue/asthenia • transient myalgia/arthralgia • Grade 3 vomiting or diarrhea that resolves to ≤Grade 2 within 48 hours (with or without supportive care) • Grade 3 nausea that resolves (with or without supportive care) to ≤Grade 2 within 7 days • Grade 3 anorexia requiring enteral or parenteral nutrition • Hematologic toxicity: myelosuppression, defined as: • Grade 4 thrombocytopenia of any duration, or Grade 3 thrombocytopenia with bleeding or lasting >7 days • Grade 4 neutropenia for five consecutive days. • Treatment delay of more than 14 days due to delayed recovery from a toxicity related to treatment with tazemetostat

End point type

Primary

End point timeframe

A DLT was determined in the first treatment cycle only (Day 1 to Day 28) of dose escalation. From the start of study treatment until the end of the first cycle (Day 28) of treatment. It was graded according to the CTCAE version 4.03.

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: Summary statistics were provided for this study. This was a signal findings study that was not powered to make statistical comparisons.
[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: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.

End point values	Dose Escalation Level 1	Dose Escalation Level 2	Dose Escalation Level 3	Dose Escalation Level 4	Dose Escalation Level 5	Dose Escalation Level 6	Dose Escalation Level 7
Number of subjects analysed	8	6	6	7	6	6	7
Units: number	0	1	0	0	0	1	0

No statistical analyses for this end point

Primary: Overall response rate (ORR)

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End point title

Overall response rate (ORR) ^[3] ^[4]

End point description

ORR is defined as the percentage of subjects achieving a confirmed complete response (CR) or partial response (PR) from the start of treatment until disease progression or the start of new anticancer therapy, whichever occurs first.

End point type

Primary

End point timeframe

From start of treatment until disease progression or the start of new anticancer therapy, whichever occurs first.

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: Summary statistics were provided for this study. This was a signal findings study that was not powered to make statistical comparisons.
[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: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.

End point values	Dose Expansion Cohort 1	Dose Expansion Cohort 2	Dose Expansion Cohort 3	Dose Expansion Cohort 4
Number of subjects analysed	19	20	18	6
Units: Number of objective responders	5	0	3	1

No statistical analyses for this end point

Secondary: Overall response rate (ORR)

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End point title

Overall response rate (ORR) ^[5]

End point description

End point type

Secondary

End point timeframe

From start of treatment until disease progression or the start of new anticancer therapy, whichever occurs first.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.

End point values	Dose Escalation Level 1	Dose Escalation Level 2	Dose Escalation Level 3	Dose Escalation Level 4	Dose Escalation Level 5	Dose Escalation Level 6	Dose Escalation Level 7
Number of subjects analysed	8	6	6	7	6	6	7
Units: Number of objective responders	0	0	0	1	1	1	0

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS)

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End point title

Progression Free Survival (PFS) ^[6]

End point description

The PFS is defined as the interval of time (in weeks) from the date of first dose of study drug and the earliest date of disease progression or death, from any cause.

End point type

Secondary

End point timeframe

From first dose of study drug until the earliest date of disease progression or death, from any cause.

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.

End point values	Dose Expansion Cohort 1	Dose Expansion Cohort 2	Dose Expansion Cohort 3	Dose Expansion Cohort 4
Number of subjects analysed	19	20	18	6
Units: Number of patients
median (confidence interval 95%)	7.9 (6.0 to 24.3)	7.7 (3.4 to 8)	15.9 (8.0 to 21.3)	28.3 (7.9 to 145.4)

No statistical analyses for this end point

Secondary: Overall survival (OS)

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End point title

Overall survival (OS) ^[7]

End point description

The OS is defined as the interval of time (in weeks) between the date of first dose of study drug and the date of death from any cause.

End point type

Secondary

End point timeframe

From first dose of study drug until the earliest date of death from any cause.

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: There are 8 different phases in the trial (7 dose escalation phases and the dose expansion phase with 4 cohorts) within the same period (overall study). All 8 phases are encompassed within the baseline period but the dose escalation and dose expansion phases have different end points.

End point values	Dose Expansion Cohort 1	Dose Expansion Cohort 2	Dose Expansion Cohort 3	Dose Expansion Cohort 4
Number of subjects analysed	19	20	18	6
Units: Number of patients
median (confidence interval 95%)	21.4 (11.0 to 50.3)	14.1 (6.9 to 22.4)	41.8 (18.6 to 55.6)	103.1 (12.3 to 185.6)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse event monitoring starts from the time the patient consents to the study until they complete the trial.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Dose Escalation Level 1

Reporting group description

240 mg/m2 BID (starting dose) = 480 mg/m2/day

Reporting group title

Dose Escalation Level 2

Reporting group description

300 mg/m2 BID = 600 mg/m2/day

Reporting group title

Dose Escalation Level 3

Reporting group description

400 mg/m2 BID = 800 mg/m2/day

Reporting group title

Dose Escalation Level 4

Reporting group description

520 mg/m2 BID = 1040 mg/m2/day

Reporting group title

Dose Escalation Level 5

Reporting group description

700 mg/m2 BID = 1400 mg/m2/day

Reporting group title

Dose Escalation Level 6

Reporting group description

900 mg/m2 BID = 1800 mg/m2/day

Reporting group title

Dose Escalation Level 7

Reporting group description

1200 mg/m2 BID = 2400 mg/m2/day

Reporting group title

Dose Expansion Cohort 1

Reporting group description

Subjects with ATRT

Reporting group title

Dose Expansion Cohort 2

Reporting group description

Subjects with malignant rhabdoid tumor (MRT)/ rhabdoid tumor of kidney (RTK)/select tumors with rhabdoid features

Reporting group title

Dose Expansion Cohort 3

Reporting group description

Subjects with INI1-negative tumors

Reporting group title

Dose Expansion Cohort 4

Reporting group description

Subjects with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

Serious adverse events	Dose Escalation Level 1	Dose Escalation Level 2	Dose Escalation Level 3	Dose Escalation Level 4	Dose Escalation Level 5	Dose Escalation Level 6	Dose Escalation Level 7	Dose Expansion Cohort 1	Dose Expansion Cohort 2	Dose Expansion Cohort 3	Dose Expansion Cohort 4
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 8 (50.00%)	1 / 6 (16.67%)	3 / 6 (50.00%)	2 / 7 (28.57%)	3 / 6 (50.00%)	4 / 6 (66.67%)	2 / 7 (28.57%)	12 / 19 (63.16%)	10 / 20 (50.00%)	9 / 18 (50.00%)	3 / 6 (50.00%)
number of deaths (all causes)	3	3	4	0	1	2	1	6	8	2	2
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	1	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Second primary malignancy
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	1 / 20 (5.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0
Rhabdoid tumour
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Superior vena cava syndrome
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 6 (33.33%)	0 / 7 (0.00%)	1 / 19 (5.26%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	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	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	2 / 20 (10.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	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	0 / 1	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Apnoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract inflammation
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Platelet count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Unintentional medical device removal
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Hydrocephalus
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	4 / 19 (21.05%)	0 / 20 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrospinal fluid leakage
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Visual impairment
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 19 (10.53%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Urinary tract obstruction
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	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	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	2 / 19 (10.53%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
CNS ventriculitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Laryngitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Mastoid abscess
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Oral herpes
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis externa
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Otitis media
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Pneumococcal bacteraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal bacteraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0
Vascular device infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vulval abscess
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	1 / 20 (5.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Dose Escalation Level 1	Dose Escalation Level 2	Dose Escalation Level 3	Dose Escalation Level 4	Dose Escalation Level 5	Dose Escalation Level 6	Dose Escalation Level 7	Dose Expansion Cohort 1	Dose Expansion Cohort 2	Dose Expansion Cohort 3	Dose Expansion Cohort 4
Total subjects affected by non serious adverse events
subjects affected / exposed	8 / 8 (100.00%)	5 / 6 (83.33%)	6 / 6 (100.00%)	7 / 7 (100.00%)	6 / 6 (100.00%)	6 / 6 (100.00%)	6 / 7 (85.71%)	19 / 19 (100.00%)	19 / 20 (95.00%)	18 / 18 (100.00%)	6 / 6 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	1	0	0	0	0	0	0
Tumour pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 19 (10.53%)	2 / 20 (10.00%)	3 / 18 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	1	1	0	1	0	0	2	2	3	0
Vascular disorders
Hypertension
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 19 (5.26%)	3 / 20 (15.00%)	2 / 18 (11.11%)	1 / 6 (16.67%)
occurrences all number	1	1	0	0	0	0	1	1	3	2	1
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 8 (0.00%)	3 / 6 (50.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 7 (14.29%)	4 / 19 (21.05%)	2 / 20 (10.00%)	5 / 18 (27.78%)	2 / 6 (33.33%)
occurrences all number	0	3	2	1	2	3	1	4	2	5	2
Pyrexia
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 7 (28.57%)	3 / 6 (50.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)	4 / 19 (21.05%)	5 / 20 (25.00%)	7 / 18 (38.89%)	0 / 6 (0.00%)
occurrences all number	0	1	1	2	3	2	1	4	5	7	0
Oedema peripheral
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 19 (10.53%)	1 / 20 (5.00%)	5 / 18 (27.78%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	1	5	0
Asthenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	1 / 20 (5.00%)	1 / 18 (5.56%)	3 / 6 (50.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	1	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 8 (0.00%)	2 / 6 (33.33%)	1 / 6 (16.67%)	0 / 7 (0.00%)	3 / 6 (50.00%)	3 / 6 (50.00%)	2 / 7 (28.57%)	6 / 19 (31.58%)	4 / 20 (20.00%)	6 / 18 (33.33%)	3 / 6 (50.00%)
occurrences all number	0	2	1	0	3	3	2	6	4	6	3
Nasal congestion
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 7 (28.57%)	2 / 19 (10.53%)	1 / 20 (5.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)
occurrences all number	1	1	0	2	0	1	2	2	1	2	0
Dyspnoea
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	1 / 20 (5.00%)	0 / 18 (0.00%)	3 / 6 (50.00%)
occurrences all number	0	1	0	0	2	0	0	1	1	0	3
Hypoxia
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	2 / 20 (10.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences all number	1	1	1	0	0	0	0	1	2	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	3 / 18 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	3	1
Psychiatric disorders
Irritability
subjects affected / exposed	3 / 8 (37.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0	0	0	1	0	0	0	0
Insomnia
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	3 / 18 (16.67%)	1 / 6 (16.67%)
occurrences all number	1	1	0	0	0	1	0	1	0	3	1
Investigations
Platelet count decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 6 (0.00%)	3 / 6 (50.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	1	0	3	0	0	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	2 / 19 (10.53%)	1 / 20 (5.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	1	0	1	0	1	1	2	1	0	1
Lymphocyte count decreased
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	2 / 19 (10.53%)	3 / 20 (15.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)
occurrences all number	1	0	0	1	0	1	1	2	3	2	0
Weight decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	3 / 20 (15.00%)	0 / 18 (0.00%)	2 / 6 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1	3	0	2
Blood bromide increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 19 (10.53%)	1 / 20 (5.00%)	1 / 18 (5.56%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	2	1	1	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 6 (16.67%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	2	0	0	0	0	0	0	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 19 (5.26%)	2 / 20 (10.00%)	1 / 18 (5.56%)	1 / 6 (16.67%)
occurrences all number	1	0	1	0	0	1	0	1	2	1	1
Nervous system disorders
Headache
subjects affected / exposed	0 / 8 (0.00%)	2 / 6 (33.33%)	3 / 6 (50.00%)	2 / 7 (28.57%)	2 / 6 (33.33%)	2 / 6 (33.33%)	1 / 7 (14.29%)	4 / 19 (21.05%)	1 / 20 (5.00%)	7 / 18 (38.89%)	3 / 6 (50.00%)
occurrences all number	0	2	3	2	2	2	1	4	1	7	3
Dizziness
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	1	0	0	0	1	1	0	0	0	0
Paraesthesia
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	1	1	0	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 6 (16.67%)	2 / 7 (28.57%)	4 / 19 (21.05%)	8 / 20 (40.00%)	5 / 18 (27.78%)	0 / 6 (0.00%)
occurrences all number	1	1	1	1	1	1	2	4	8	5	0
Lymphopenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 19 (5.26%)	0 / 20 (0.00%)	0 / 18 (0.00%)	3 / 6 (50.00%)
occurrences all number	1	0	0	0	1	0	1	1	0	0	3
Thrombocytopenia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	1 / 18 (5.56%)	2 / 6 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	2
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 8 (12.50%)	2 / 6 (33.33%)	3 / 6 (50.00%)	2 / 7 (28.57%)	3 / 6 (50.00%)	2 / 6 (33.33%)	6 / 7 (85.71%)	11 / 19 (57.89%)	9 / 20 (45.00%)	11 / 18 (61.11%)	5 / 6 (83.33%)
occurrences all number	1	2	3	2	3	2	6	11	9	11	5
Nausea
subjects affected / exposed	0 / 8 (0.00%)	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 7 (14.29%)	3 / 6 (50.00%)	2 / 6 (33.33%)	1 / 7 (14.29%)	6 / 19 (31.58%)	5 / 20 (25.00%)	11 / 18 (61.11%)	3 / 6 (50.00%)
occurrences all number	0	2	3	1	3	2	1	6	5	11	3
Constipation
subjects affected / exposed	1 / 8 (12.50%)	2 / 6 (33.33%)	3 / 6 (50.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 7 (14.29%)	2 / 19 (10.53%)	4 / 20 (20.00%)	3 / 18 (16.67%)	2 / 6 (33.33%)
occurrences all number	1	2	3	1	1	1	1	2	4	3	2
Diarrhoea
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	0 / 6 (0.00%)	2 / 7 (28.57%)	4 / 6 (66.67%)	2 / 6 (33.33%)	1 / 7 (14.29%)	7 / 19 (36.84%)	3 / 20 (15.00%)	7 / 18 (38.89%)	2 / 6 (33.33%)
occurrences all number	0	1	0	2	4	2	1	7	3	7	2
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	3 / 6 (50.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 19 (5.26%)	4 / 20 (20.00%)	3 / 18 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1	3	1	0	1	4	3	1
Stomatitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	1 / 20 (5.00%)	3 / 18 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	3	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	0	0	0	1	1	0	0	0	0
Erythema
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	1 / 7 (14.29%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0	0	0	0
Pruritus
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	3 / 20 (15.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	3	2	0
Alopecia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	0 / 20 (0.00%)	3 / 18 (16.67%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	1	0	3	1
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	4 / 18 (22.22%)	2 / 6 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	2
Pain in extremity
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	2 / 20 (10.00%)	1 / 18 (5.56%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	1	2	1	1
Infections and infestations
Otitis media
subjects affected / exposed	1 / 8 (12.50%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 19 (0.00%)	0 / 20 (0.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	1	0	1	1	1	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	2 / 7 (28.57%)	1 / 6 (16.67%)	1 / 6 (16.67%)	1 / 7 (14.29%)	2 / 19 (10.53%)	1 / 20 (5.00%)	3 / 18 (16.67%)	0 / 6 (0.00%)
occurrences all number	0	0	0	2	1	1	1	2	1	3	0
Rhinitis
subjects affected / exposed	0 / 8 (0.00%)	1 / 6 (16.67%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	1 / 19 (5.26%)	2 / 20 (10.00%)	1 / 18 (5.56%)	1 / 6 (16.67%)
occurrences all number	0	1	1	0	0	1	0	1	2	1	1
Urinary tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	2 / 20 (10.00%)	1 / 18 (5.56%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	2	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	2 / 6 (33.33%)	3 / 7 (42.86%)	1 / 6 (16.67%)	0 / 6 (0.00%)	1 / 7 (14.29%)	5 / 19 (26.32%)	4 / 20 (20.00%)	4 / 18 (22.22%)	1 / 6 (16.67%)
occurrences all number	1	0	2	3	1	0	1	5	4	4	1
Hypokalaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 6 (16.67%)	0 / 7 (0.00%)	3 / 19 (15.79%)	2 / 20 (10.00%)	0 / 18 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	1	0	0	1	0	3	2	0	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 19 (10.53%)	1 / 20 (5.00%)	2 / 18 (11.11%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	1	2	0
Hypophosphataemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	1 / 20 (5.00%)	1 / 18 (5.56%)	2 / 6 (33.33%)
occurrences all number	0	0	0	0	0	0	0	1	1	1	2
Hypermagnesaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	1 / 19 (5.26%)	1 / 20 (5.00%)	1 / 18 (5.56%)	1 / 6 (16.67%)
occurrences all number	0	0	0	0	0	0	0	1	1	1	1
Hypoalbuminaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 6 (0.00%)	0 / 7 (0.00%)	2 / 19 (10.53%)	2 / 20 (10.00%)	0 / 18 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	2	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

13 Jul 2015

Original Protocol submitted to FDA, never submitted to sites.

24 Aug 2015

Amendment v1.0 – submitted to all sites. Key changes: - Added a dose level to start at a lower dose (240mg/m2 vs. original 300mg/m2) and effectively increasing the dose escalation phase numbers from 18 to 24 subjects. - Additional details on blood sampling volumes added. - Removed mandatory requirement to collect date of birth.

02 Oct 2015

Amendment v2.0 – submitted to all sites. Key changes: - Added selected tumors with rhabdoid features that responses were seen in Phase 1 (SMARCA4 loss in MRTO or SCCOHT). - Removed requirement for fasting based upon data in food-effect study. - Removed restriction for pregnancy prevention 30 days prior to entry.

12 Oct 2015

Amendment v2.1 – Country-specific for Germany Key changes: - Upper age limit changes to <12 years old due to inability to do Panorex films in Germany (radiation exposure an issue). - Removed MUGA scan as it is not performed in Germany. - Removed bone monitoring and Karnofsky performance due to age change.

03 Dec 2015

Amendment v2.2 – Country-specific for United Kingdom Key changes: - Lower age limit increased to >1 year old (vs. 6 mos for rest of world). - No subjects <5 years old in UK will be enrolled until 4 subjects study wide have received at least 4 weeks of study drug. - Pregnancy prevention in females and males updated to reflect UK law.

31 Mar 2016

Amendment v2.3 – Country-specific for Germany Key changes: - Removal of synovial and other INI1-negative/SMARCA4 negative tumors

11 May 2016

Amendment v3.0 – submitted to all sites. Key changes: - Changes to include treated brain mets. - Remove Panorex. - Remove baseline visit and other changes made to 202. - Add cohorts - Cohort 1: atypical teratoid rhabdoid tumor (ATRT), Cohort 2: non-ATRT rhabdoid tumors and Cohort 3: INI1-negative tumors or synovial sarcoma.

22 Jun 2016

Amendment v3.1 – Country-specific for Germany Key changes: - Incorporating all changes from amendment v3.0

13 Jul 2016

Amendment v3.2 – Country-specific for United Kingdom Key changes: - Incorporating all changes from amendment v3.0

27 Jul 2016

Amendment v4.0 – submitted to all sites Key changes: - Four dose expansion levels added. - Number of subjects changed from 84 to 108. - Allow replacement of subjects who discontinue in absence of a dose-limiting toxicity [DLT] prior to the completing of the DLT evaluation period.

02 Aug 2016

Amendment v4.1 – Country-specific for Germany Key changes: - All changes from v4.0 incorporated

21 Oct 2016

Amendment v4.3 – Country-specific for United Kingdom Key changes: - All changes from v4.0 incorporated

20 Jul 2017

Amendment v5.0 – submitted to all sites Key changes: - RP2D was determined to be 1200 mg/m2 BID and will be used in the dose expansion portion of the study. - New cohort 4 added for subjects ≥10 years to ≤21 years to receive tazemetostat tablets. - Number of subjects changed from 108 to 120. - Information on hydrobromide salt, hyperchloremia and potential associated toxicities added. - Cycle length and study procedure timings changed for Cycles 13 and beyond to 21 days.

26 Jul 2017

Amendment v5.3 – Country-specific for United Kingdom Key changes: - Tablet formulation cohort added; this cohort (Cohort 4) will not enroll subjects in Germany - The RP2D was determined to be 1200 mg/m2 BID and will be the dose used in the dose expansion portion of the study - New cohort added to Dose Expansion phase of study (outside of Germany): Cohort 4 to received tazemetostat tablets 800 mg/m2 TID [2400 mg/m2/day]); Subjects are to be ≥10 years to ≤21 years with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement and able to swallow tablets) - Information on hydrobromide salt, hyperchloremia, and potential associated toxicities had been added; also, bromide measurements have been added - Number of subjects increased from 108 to 120 - Additional preliminary PK data added - Additional prohibited medications added - Cycle length for Cycles 13 and beyond changed to 21 days. - Study procedure timings updated for Cycles 13 and beyond to reflect 21-day cycle - Dose modification information has been updated - Expansion of requirements for additional biopsies for subjects who progress to include all subjects (including SD) not just subjects who experienced PR or better. - Safety section has been updated - New appendix added for Cohort 4 dosing and dose modification - Minor corrections

03 Aug 2017

Amendment v5.1 – Country-specific for Germany Key changes: - Tablet formulation cohort added; this cohort (Cohort 4) will not enroll subjects in Germany - The RP2D was determined to be 1200 mg/m2 BID and will be the dose used in the dose expansion portion of the study - New cohort added to Dose Expansion phase of study (outside of Germany): Cohort 4 to received tazemetostat tablets 800 mg/m2 TID [2400 mg/m2/day]); Subjects are to be ≥10 years to ≤21 years with one of the tumor types defined in Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement and able to swallow tablets) - Information on hydrobromide salt, hyperchloremia, and potential associated toxicities had been added; also, bromide measurements have been added - Number of subjects increased from 108 to 120 - Additional preliminary PK data added - Additional prohibited medications added - Cycle length for Cycles 13 and beyond changed to 21 days. - Study procedure timings updated for Cycles 13 and beyond to reflect 21-day cycle - Dose modification information has been updated - Expansion of requirements for additional biopsies for subjects who progress to include all subjects (including SD) not just subjects who experienced PR or better. - Safety section has been updated - New appendix added for Cohort 4 dosing and dose modification - Minor corrections

31 Oct 2017

Amendment v5.4 – Country-specific for France Key changes: - Updated text on phototoxicity. - Updated text to clarify chloride levels are assessed at every visit locally and centrally and bromide levels will be analyzed centrally. - Added additional prohibited meds. - Removed PD samples at C13 and beyond. - Correct inconsistency in Exclusion criteria #11 in two different sections of the protocol. - Remove PD blood sample collection from procedures and assessments conducted at Cycle 13 and beyond. Add language about stopping PD sample collection after 20 evaluable PD samples are collected through Day 15 upon Sponsor notification. - Minor corrections

01 Feb 2018

Amendment v5.5 – Country-specific for France Key changes: - Option to change from suspension to tablets

28 Sep 2018

Amendment v6.0 – submitted to all sites Key changes: - All changes from v5.5 - Updated with 2 new AESIs – T-LBL/T-ALL and MDS. - Added exclusion criteria to exclude patients with thrombocytopenia, neutropenia, anemia of Grade ≥3 and history of MDS and T-LBL and MDS. - Hold treatment to either modify or discontinue if patient develop MDS/AML. - Patients have a maximum of cumulative 2 years on the study. - Updated dose modification or discontinuation section. - Changed age from ≤21 years to <18 years. - Addition of assessments – blood smear morphology and annual PK. - Removed Cycle 13 and beyond study design. - Allow patients to change to tablet dosing after completion of Cycle 1

10 Oct 2018

Amendment v6.2 – Country-specific for United Kingdom - All changes from v6.0 incorporated

07 Nov 2018

Amendment v6.1 – Country-specific for Germany - All changes from v6.0 incorporated

13 Dec 2018

Amendment v7.2 – Country-specific for United Kingdom - All changes from v7.0 incorporated

17 Dec 2018

Amendment v7.0 – submitted to all sites. Key changes: - Addition of the option to discontinue treatment if the Investigator determines the dose of tazemetostat must be modified for subjects enrolled in the dose expansion part of the study. - Alignment of the disease assessment frequency of bone scans with the RECIST guidelines in Appendix 4. - Update of dose rationale language with the starting dose of 520 mg/m2 BID for newly enrolled subjects with non-ATRT tumors to align with the new dosing requirements. - Cohort 1 enrollment has been closed as there has been sufficient data collected in pediatric subjects with ATRT. - Cohort 4 enrollment has been closed as there has been sufficient pharmacokinetic data collected in pediatric subjects who were administered tazemetostat in tablet form. - Removal of language allowing subjects who do not have clinical or radiographic disease progression and do not experience unacceptable toxicity to receive tazemetostat beyond cycle 1. Removal of language allowing subjects who have modest disease progression in the absence of clinical deterioration to remain on study. - Addition of the definition of adverse drug reaction to the overall definitions section. - Addition of the definition of a suspected unexpected serious adverse reaction (SUSAR) to the overall definitions section. - Addition of safety language to suggest that rapid communication of adverse events of special interest should be communicated to the Sponsor to allow the event to be understood and characterized in a timely manner. - Removal of dose escalation from interim analysis section of the statistical analysis plan, as this was added in error. - Change in the confidence interval from 90% to 95% when calculating overall survival, and from 80% to 95% when calculating objective response rate.

15 Mar 2019

Amendment v6.3 – Country-specific for Germany Key changes: - Removal of the option of tablet dosing as dose reduction, if needed, is not possible with the tablet formulations currently in use. - Removal of the requirement of Karnofsky Performance Status >50% for subjects ≥12 years of age as all subjects in Germany are <12 years of age upon enrollment, and the Lansky Performance Scale is used for subjects <12 years of age. - Removal of the requirement specific to French subjects, that they be affiliated with or a beneficiary or a social security category, as this protocol only applies to subjects in Germany. - Removal of the requirement of SMARCA4 loss from IHC or molecular confirmation of SMARCA4 loss as this gene is associated with SCCOHT tumors, which will not be studied in Germany. - Removal of the requirement for subjects enrolled in cohort 4 (not open in Germany) to be able to swallow tablets as tablet dosing options will no longer be permitted. - Removal of language stating that for subjects who have modest disease progression in the absence of clinical deterioration and are receiving clinical benefit in the opinion of the Investigator, the Investigator should contact the Medical Monitor to discuss keeping the subject on study as subjects must come off study in the event of disease progression.

20 Feb 2020

Amendment v8.0 – submitted to all sites. Key changes: - Updated the study period to reflect the first subject’s first visit and current projections for last subject last visit. - Updated the anticipated safety profile to align with the current IB. - Included T-LBL/T-ALL with other events that will trigger convening of safety committees and to clarify that consequences of an event of T-LBL/T-ALL will occur regardless of dose level. - Modified dose modification text to state that for MDS, AML or any myeloid malignancy like MPN, tazemetostat will be discontinued. - Removed dose modification sub-section for dose modifications due to MDS. - Adjusted and clarified dose modifications for subjects in dose expansion starting at 1200mg/m2 and for subjects starting at 520mg/m2. - Removed blood chemistry collection at Day 15 of Cycles 2 and beyond to reduce the amount of blood drawn for unnecessary testing. - Modified requirement for the timing of screening disease assessments to allow for assessments done more than 14 days before enrollment. - Updated contraception requirements to reflect current expectations and to align with approved labeling in the US. - Added genitourinary exam to comprehensive physical exam to ensure abnormalities and malignancies are not missed. - Specified that elevated bromide is considered an event of clinical interest, and that events of clinical interest are to be reported in the same manner as SAEs. - Corrected the confidence internal from 90% to 95% to be estimated in the case of sufficient number of deaths to trigger survival endpoint assessments by Brookneyer-Crowley.

03 Apr 2020

Amendment v8.2 – Country-specific for United Kingdom - All changed from v8.0 incorporated

03 Apr 2020

Amendment v8.3 – Country-specific for Germany - All changed from v8.0 incorporated

01 Jul 2020

Amendment v8.4 – Country-specific for Germany Key changes: - Clarification of the roles of existing safety committees. - Corrected an inaccuracy in wording that was made to clarify that if enrollment of new patients is suspended in the event of a new case of T-LBL/T-ALL, patients on study who continue to derive clinical benefit “may” (rather than “will”) be maintained on therapy.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
06 Apr 2018	On 06 April 2018, an event of T-LBL was observed in a pediatric subject on study EZH-102. The SUSAR of T-LBL resulted in the Sponsor initiating a temporary global halt in enrollment for the pediatric study EZH-102. In addition, this event led to a partial clinical hold (PCH) on new subject enrollment for tazemetostat by the U.S. (FDA), France (ANSM), and Germany (BfArM) across all studies of the Tazemetostat Development Program. Following this report, Epizyme conducted a comprehensive evaluation. Based on this evaluation, we continued to believe that tazemetostat is a clinically active drug and has the potential to benefit both adult and pediatric patients across different tumor types where there are unmet medical needs. We also concluded that the risk assessment identifies a possible direct association between tazemetostat and T-LBL/T-ALL. Epizyme considers the risk for T-LBL/T-ALL in tazemetostat clinical trials to be largely concentrated in pediatric patients based on 1) higher AUC0-24h exposures in pediatric patients, 2) increases over time in age-related thymic involution, and 3) the known epidemiology/pathophysiology of T-LBL/ALL. The risk of T-LBL/T-ALL in adults is not known, however the incidence of treatment-related T-LBL/T-ALL in adults is expected to be uncommon. Heightened surveillance was and continues to be conducted to monitor and identify early signs and symptoms (per local practice/standard of care) of T-LBL/T-ALL so that tazemetostat may be discontinued in the subject and treatment can be initiated for these malignancies. If a case of adult T-LBL/T-ALL occurs, enrollment will be suspended and the benefit-risk of the drug will be assessed by the Tazemetostat Safety Committee and will be communicated to all Health Authorities and Ethics Committees. To date, no adult T-LBL/T-ALL cases have occurred.	28 Sep 2018

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 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

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Primary: Dose limiting toxicities (DLTs)

Primary: Dose limiting toxicities (DLTs)

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Primary: Overall response rate (ORR)

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Secondary: Progression Free Survival (PFS)

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Secondary: Overall survival (OS)

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Clinical trials

Clinical Trial Results: A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Dose limiting toxicities (DLTs)

Primary: Dose limiting toxicities (DLTs)

Primary: Overall response rate (ORR)

Primary: Overall response rate (ORR)

Secondary: Overall response rate (ORR)

Secondary: Overall response rate (ORR)

Secondary: Progression Free Survival (PFS)

Secondary: Progression Free Survival (PFS)

Secondary: Overall survival (OS)

Secondary: Overall survival (OS)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects with Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma