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Clinical Trial Results:
A Phase 1 Study of the TRK Inhibitor Selitrectinib (BAY 2731954) in Adult and Pediatric Subjects with Previously Treated NTRK Fusion Cancers

Summary
EudraCT number	2017-004246-20
Trial protocol	DK FR DE ES GB IE IT BE
Global end of trial date	30 Jan 2023

Results information
Results version number	v1(current)
This version publication date	30 Jul 2023
First version publication date	30 Jul 2023
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

20810

ISRCTN number

US NCT number

NCT03215511

WHO universal trial number (UTN)

Sponsor organisation name

Bayer AG

Sponsor organisation address

Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368

Public contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com

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

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?

Yes

Analysis stage

Final

Date of interim/final analysis

30 Jan 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2023

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to determine the recommended dose for further study of oral selitrectinib in 2 patient groups with previously treated neurotrophic tyrosine receptor kinase (NTRK) fusion cancers defined as age 12 years and older and age <12 years. The secondary objectives of this study were: • To characterize the pharmacokinetic (PK) properties of selitrectinib. • To characterize the safety and tolerability of selitrectinib. • To assess objective response rate (ORR) according to best response by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as determined by investigator, in patients with a documented NTRK fusion cancer previously treated with a tropomyosin receptor kinase (TRK) inhibitor. • To assess ORR according to best response by Response Assessment in Neuro-Oncology (RANO), as determined by investigator, in patients with primary central nervous system (CNS) malignancies with NTRK fusion.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. Participating subjects and/or their legally authorized representative signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.

Background therapy

Evidence for comparator

Actual start date of recruitment

03 Jul 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Denmark: 7

Country: Number of subjects enrolled

Austria: 1

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Italy: 1

Country: Number of subjects enrolled

Singapore: 2

Country: Number of subjects enrolled

Spain: 7

Country: Number of subjects enrolled

United States: 58

Worldwide total number of subjects

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

This multinational study was conducted at 42 centers of 13 countries from 03-Jul-2017 (first patient first visit) to 30-Jan-2023 (last patient last visit)

Screening details

A total of 91 patients were enrolled in the study. Of these, there were 10 screen failures, and 81 patients received at least 1 dose of study drug.

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

Capsule Cohort 1

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg twice daily (BID), in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg, Twice daily (BID)

Capsule Cohort 2

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 150 mg twice daily (BID), in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

150 mg, Twice daily (BID)

Capsule Cohort 3

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg once daily (QD), in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg, Once daily (QD)

Capsule Cohort 4

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg once daily (QD), in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

50 mg, Once daily (QD)

Capsule Cohort 5a

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 75 mg BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

50 mg QD with escalation every 14 days to 75 mg BID (capsule)

Capsule Cohort 5b

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 150 mg QD, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

50 mg QD with escalation every 14 days to 150 mg QD

Suspension Cohort 6a

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

50mg BID (liquid suspension)

Suspension Cohort 6b

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 75mg BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

75 mg BID (liquid suspension)

Suspension Cohort 7a

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg QD with escalation after 7 days to 50mg BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

50mg QD with escalation after 7 days to 50mg BID

Suspension Cohort 7b

Arm description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg QD for 7 days, then 50mg BID for 7 days, then 75mg BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

50mg QD for 7 days, then 50mg BID, for 7 days, then 75mg BID

Pediatric Cohort 43 mg/m^2 BID

Arm description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 43 mg/m^2 BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

75 mg BID

Pediatric Cohort 58 mg/m^2 BID

Arm description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 58 mg/m^2 BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

100 mg BID

Pediatric Cohort 87 mg/m^2 BID

Arm description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 87 mg/m^2 BID, in continuous 28-day cycles.

Arm type

Experimental

Investigational medicinal product name

Selitrectinib

Investigational medicinal product code

BAY2731954

Other name

Pharmaceutical forms

Oral suspension

Routes of administration

Oral use

Dosage and administration details

150 mg BID

Number of subjects in period 1	Capsule Cohort 1	Capsule Cohort 2	Capsule Cohort 3	Capsule Cohort 4	Capsule Cohort 5a	Capsule Cohort 5b	Suspension Cohort 6a	Suspension Cohort 6b	Suspension Cohort 7a	Suspension Cohort 7b	Pediatric Cohort 43 mg/m^2 BID	Pediatric Cohort 58 mg/m^2 BID	Pediatric Cohort 87 mg/m^2 BID
Started	5	2	2	8	23	3	3	4	14	6	6	4	1
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	5	2	2	8	23	3	3	4	14	6	6	4	1
Adverse event, serious fatal	4	2	1	7	18	3	2	2	9	3	4	2	-
Consent withdrawn by subject	1	-	-	1	3	-	1	1	3	-	-	-	-
Other	-	-	1	-	2	-	-	-	2	3	2	2	-
Lost to follow-up	-	-	-	-	-	-	-	1	-	-	-	-	1

Baseline characteristics

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Reporting group title

Capsule Cohort 1

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg twice daily (BID), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 2

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 150 mg twice daily (BID), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 3

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg once daily (QD), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 4

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg once daily (QD), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 5a

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 75 mg BID, in continuous 28-day cycles.

Reporting group title

Capsule Cohort 5b

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 150 mg QD, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 6a

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 6b

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 75mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 7a

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg QD with escalation after 7 days to 50mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 7b

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg QD for 7 days, then 50mg BID for 7 days, then 75mg BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 43 mg/m^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 43 mg/m^2 BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 58 mg/m^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 58 mg/m^2 BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 87 mg/m^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 87 mg/m^2 BID, in continuous 28-day cycles.

Reporting group values	Capsule Cohort 1	Capsule Cohort 2	Capsule Cohort 3	Capsule Cohort 4	Capsule Cohort 5a	Capsule Cohort 5b	Suspension Cohort 6a	Suspension Cohort 6b	Suspension Cohort 7a	Suspension Cohort 7b	Pediatric Cohort 43 mg/m^2 BID	Pediatric Cohort 58 mg/m^2 BID	Pediatric Cohort 87 mg/m^2 BID	Total
Number of subjects	5	2	2	8	23	3	3	4	14	6	6	4	1	81
Age Categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age Continuous
Units: years
median (full range (min-max))	55.0 (47 to 64)	53.0 (48 to 58)	59.5 (48 to 71)	34.5 (13 to 58)	51.0 (18 to 76)	48.0 (14 to 51)	56.0 (53 to 58)	48.0 (29 to 69)	47.0 (17 to 75)	56.5 (38 to 73)	5.5 (1 to 9)	6.0 (5 to 10)	2.0 (2 to 2)	-
Gender Categorical
Units: Subjects
Female	2	1	2	7	9	2	1	1	7	2	2	2	0	38
Male	3	1	0	1	14	1	2	3	7	4	4	2	1	43

End points

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Reporting group title

Capsule Cohort 1

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg twice daily (BID), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 2

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 150 mg twice daily (BID), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 3

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg once daily (QD), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 4

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg once daily (QD), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 5a

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 75 mg BID, in continuous 28-day cycles.

Reporting group title

Capsule Cohort 5b

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 150 mg QD, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 6a

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 6b

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 75mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 7a

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg QD with escalation after 7 days to 50mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 7b

Reporting group description

Subjects aged ≥12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg QD for 7 days, then 50mg BID for 7 days, then 75mg BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 43 mg/m^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 43 mg/m^2 BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 58 mg/m^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 58 mg/m^2 BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 87 mg/m^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 87 mg/m^2 BID, in continuous 28-day cycles.

Subject analysis set title

DLT Analysis Set (subjects aged 12 years and older)

Subject analysis set type

Sub-group analysis

Subject analysis set description

The DLT Analysis Set (DLT) included all patients enrolled in the dose escalation part who experienced a DLT within the DLT period, and those without a DLT who had completed the safety assessments through the assigned DLT period and had received at least 75% of the planned total dose during Cycle 1.

Subject analysis set title

DLT Analysis Set (subjects aged less than 12 years)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Safety Analysis Set

Subject analysis set type

Safety analysis

Subject analysis set description

All enrolled participants who received 1 or more doses of selitrectinib were included in the Safety Analysis Set

Subject analysis set title

Participants with primary CNS tumors

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants with primary CNS tumors evaluated via RANO

Primary: Maximum tolerated dose (MTD) / recommended dose in patients age 12 years and older and age < 12 years

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End point title

Maximum tolerated dose (MTD) / recommended dose in patients age 12 years and older and age < 12 years ^[1]

End point description

The MTD for either age group was defined as the dose level immediately below that in which 2 or more patients experienced a DLT during the assigned DLT period. In table below, w stands for "week", f/b stands for "followed by"

End point type

Primary

End point timeframe

For patients age 12 years and older: dose-limiting toxicity (DLT) period was up to 42 days; For patients age less than 12 years old: DLT period was 28 days or completion of cycle 1.

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: The analysis for this endpoint is descriptive.

End point values	DLT Analysis Set (subjects aged 12 years and older)	DLT Analysis Set (subjects aged less than 12 years)
Number of subjects analysed	29 ^[2]	7 ^[3]
Units: mg QD
number (not applicable)	50	99999

Notes
[2] - MTD was either 50mg QD for 1 w, f/b 50mg BID for 1 w, f/b 75mg BID or 50mg BID for 1 w f/b 75mg BID
[3] - "99999" stands for not determined, as there were no DLTs in this age group.

No statistical analyses for this end point

Secondary: Number of participants with TEAE and their severity

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End point title

Number of participants with TEAE and their severity

End point description

Treatment emergent adverse events (TEAEs) was defined as AEs that start on or after the first administration of study drug. TEAE were collected up to 28 ± 7 days post last dose.

End point type

Secondary

End point timeframe

From start of the first administration of study drug, up to 28 ± 7 days post last dose

End point values	Capsule Cohort 1	Capsule Cohort 2	Capsule Cohort 3	Capsule Cohort 4	Capsule Cohort 5a	Capsule Cohort 5b	Suspension Cohort 6a	Suspension Cohort 6b	Suspension Cohort 7a	Suspension Cohort 7b	Pediatric Cohort 43 mg/m^2 BID	Pediatric Cohort 58 mg/m^2 BID	Pediatric Cohort 87 mg/m^2 BID
Number of subjects analysed	5	2	2	8	23	3	3	4	14	6	6	4	1
Units: subjects
Any TEAEs	5	2	2	8	23	3	3	4	14	6	6	4	1
Serious TEAEs	3	1	1	5	16	1	0	4	8	2	3	3	0
Maximum Severity Grade ≥3	3	2	2	6	18	1	1	4	12	2	4	3	0

No statistical analyses for this end point

Secondary: Number of participants with treatment related TEAE

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End point title

Number of participants with treatment related TEAE

End point description

The causal relationship between the occurrence of TEAE and study drug was judged by the Investigator, based on the conventions described in protocol

End point type

Secondary

End point timeframe

Treatment emergent adverse events (TEAEs) was defined as AEs that start on or after the first administration of study drug. TEAE were collected up to 28 ± 7 days post last dose.

End point values	Capsule Cohort 1	Capsule Cohort 2	Capsule Cohort 3	Capsule Cohort 4	Capsule Cohort 5a	Capsule Cohort 5b	Suspension Cohort 6a	Suspension Cohort 6b	Suspension Cohort 7a	Suspension Cohort 7b	Pediatric Cohort 43 mg/m^2 BID	Pediatric Cohort 58 mg/m^2 BID	Pediatric Cohort 87 mg/m^2 BID
Number of subjects analysed	5	2	2	8	23	3	3	4	14	6	6	4	1
Units: subjects
Any TEAEs	5	2	2	8	18	3	2	4	13	6	5	4	1
Serious TEAEs	0	0	0	0	0	0	0	2	1	0	1	1	0
Maximum Severity Grade ≥3	0	2	1	1	5	1	1	2	6	0	2	2	0

No statistical analyses for this end point

Secondary: Number of participants with hematology shifts from normal baseline value

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End point title

Number of participants with hematology shifts from normal baseline value

End point description

Directional shifts from baseline according to normal range are summarized for hematology parameters for the Safety Analysis Set. LLN: lower limit of normal; ULN = upper limit of normal

End point type

Secondary

End point timeframe

Up to 56 months

End point values	Safety Analysis Set
Number of subjects analysed	81 ^[4]
Units: subjects
Basophils Count below LLN	0
Basophils Count Above ULN	3
Eosinophils Count Below LLN	7
Eosinophils Count Above ULN	7
Monocytes Count Below LLN	9
Monocytes Count Above ULN	7
Hematocrit Below LLN	19
Hematocrit Above ULN	3
Red Blood Cell Count Below LLN	10
Red Blood Cell Count Above ULN	8

Notes
[4] - Only subjects with baseline assessment and at least one post-baseline assessment were included

No statistical analyses for this end point

Secondary: Number participants with chemistry shifts from baseline according to normal range

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End point title

Number participants with chemistry shifts from baseline according to normal range

End point description

Directional shifts from baseline according to normal range are summarized for chemistry parameters for the Safety Analysis Set. A baseline measurement and at least 1 laboratory or other safety-related measurement obtained after at least 1 dose of study drug was required for inclusion in the analysis of a specific parameter.

End point type

Secondary

End point timeframe

up to 56 months

End point values	Safety Analysis Set
Number of subjects analysed	81
Units: subjects
Blood Urea Nitrogen Below LLN	3
Blood Urea Nitrogen Above ULN	18
Lactate Dehydrogenase Below LLN	3
Lactate Dehydrogenase Above ULN	25
Total Protein Below LLN	17
Total Protein Above ULN	5
Chloride Below LLN	9
Chloride Above ULN	34
Calcium Below LLN	19
Calcium Above ULN	9

No statistical analyses for this end point

Secondary: Objective Response Rate as determined by the Investigator in participants with a documented NTRK fusion cancer previously treated with a TRK inhibitor

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End point title

Objective Response Rate as determined by the Investigator in participants with a documented NTRK fusion cancer previously treated with a TRK inhibitor

End point description

Objective Response Rate (ORR) was defined as the proportion of patients with a BOR of confirmed CR, or PR. Response was confirmed by a repeat assessment no less than 28 days later.

End point type

Secondary

End point timeframe

up to 56 months

Capsule Cohort 1

Capsule Cohort 2

Capsule Cohort 3

Capsule Cohort 4

Capsule Cohort 5a

Capsule Cohort 5b

Suspension Cohort 6a

Suspension Cohort 6b

Suspension Cohort 7a

Suspension Cohort 7b

Pediatric Cohort 43 mg/m^2 BID

Pediatric Cohort 58 mg/m^2 BID

Pediatric Cohort 87 mg/m^2 BID

Number of subjects analysed

Units: Percent (%)

number (confidence interval 95%)

20 (0.5 to 71.6)

0 (0.0 to 84.2)

50 (1.3 to 98.7)

37.5 (8.5 to 75.5)

13.0 (2.8 to 33.6)

33.3 (0.8 to 90.6)

0 (0.0 to 60.2)

14.3 (1.8 to 42.8)

50.0 (11.8 to 88.2)

33.3 (4.3 to 77.7)

25.0 (0.6 to 80.6)

0 (0.0 to 97.5)

No statistical analyses for this end point

Secondary: Objective Response Rate as determined by investigator in participants with primary CNS malignancies

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End point title

Objective Response Rate as determined by investigator in participants with primary CNS malignancies

End point description

primary CNS tumors were evaluated via Response Assessment in Neuro-Oncology (RANO)

End point type

Secondary

End point timeframe

Objective Response Rate (%) is defined as the proportion of patients with Best Overall Response of confirmed CR, or PR. Response was confirmed by a repeat assessment no less than 28 days.

End point values	Participants with primary CNS tumors
Number of subjects analysed	14
Units: percent (%)
number (confidence interval 95%)	28.6 (8.4 to 58.1)

No statistical analyses for this end point

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1

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End point title

Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1 ^[5]

End point description

"99999" in data entry fields stands for "Not Calculated"

End point type

Secondary

End point timeframe

Cycle 1 Day 1

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: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 1	Capsule Cohort 2	Suspension Cohort 6a	Suspension Cohort 6b	Pediatric Cohort 43 mg/m^2 BID	Pediatric Cohort 58 mg/m^2 BID	Pediatric Cohort 87 mg/m^2 BID
Number of subjects analysed	5	2	3	4	6	4	1 ^[6]
Units: ng/mL
geometric mean (geometric coefficient of variation)	182 ± 60.9	69.1 ± 87.8	145 ± 13.5	206 ± 74.0	228 ± 80.2	167 ± 72.9	181 ± 99999

Notes
[6] - "99999" in data entry fields stands for "Not Calculated"

No statistical analyses for this end point

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8

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End point title

Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8 ^[7]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 8

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: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 1	Suspension Cohort 7a	Suspension Cohort 7b	Pediatric Cohort 43 mg/m^2 BID	Pediatric Cohort 58 mg/m^2 BID
Number of subjects analysed	5	10	6	6	2
Units: ng/mL
geometric mean (geometric coefficient of variation)	150 ± 62.1	161 ± 58.3	136 ± 57.8	274 ± 41.8	229 ± 37.6

No statistical analyses for this end point

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15

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End point title

Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15 ^[8]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 5a	Capsule Cohort 5b	Suspension Cohort 6a	Suspension Cohort 6b	Suspension Cohort 7b	Pediatric Cohort 58 mg/m^2 BID
Number of subjects analysed	14	3	2	3	5	2
Units: ng/mL
geometric mean (geometric coefficient of variation)	159 ± 93.3	244 ± 46.7	119 ± 3.6	101 ± 41.6	198 ± 48.1	354 ± 41.6

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1

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End point title

Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1 ^[9]

End point description

"99999" in data entry fields stands for "Not Calculated"

End point type

Secondary

End point timeframe

Cycle 1 Day 1

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: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 1	Capsule Cohort 2	Suspension Cohort 6a	Suspension Cohort 6b	Pediatric Cohort 43 mg/m^2 BID	Pediatric Cohort 58 mg/m^2 BID	Pediatric Cohort 87 mg/m^2 BID
Number of subjects analysed	5	1 ^[10]	3	4	6	2	1 ^[11]
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
AUC(0-10)	527 ± 85.0	525 ± 99999	380 ± 15.3	459 ± 57.2	492 ± 60.5	243 ± 57.5	229 ± 99999
AUC(0-12)	537 ± 87.3	538 ± 99999	384 ± 15.6	464 ± 57.0	493 ± 60.5	243 ± 57.5	229 ± 99999

Notes
[10] - "99999" in data entry fields stands for "Not Calculated"
[11] - "99999" in data entry fields stands for "Not Calculated"

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8

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End point title

Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8 ^[12]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 8

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 1	Capsule Cohort 5a	Suspension Cohort 7a	Suspension Cohort 7b
Number of subjects analysed	5	19	10	6
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
AUC(0-10)	593 ± 120.4	459 ± 101.4	401 ± 48.2	389 ± 51.1
AUC(0-12)	638 ± 135.6	500 ± 100.7	406 ± 48.5	394 ± 51.6

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15

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End point title

Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15 ^[13]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 5a	Suspension Cohort 6a	Suspension Cohort 6b	Suspension Cohort 7b	Pediatric Cohort 58 mg/m^2 BID
Number of subjects analysed	14	2	3	5	2
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
AUC(0-10)	454 ± 89.7	320 ± 4.1	287 ± 49.5	558 ± 57.4	436 ± 171
AUC(0-12)	470 ± 91.4	338 ± 3.0	295 ± 50.3	575 ± 60.5	449 ± 177.8

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 1

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End point title

Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 1 ^[14]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 3	Capsule Cohort 4	Capsule Cohort 5a	Capsule Cohort 5b	Suspension Cohort 7a	Suspension Cohort 7b
Number of subjects analysed	2	6	20	2	9	6
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	470 ± 37.3	435 ± 173.5	385 ± 105.7	197 ± 27.6	318 ± 39.7	366 ± 42.3

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 8

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End point title

Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 8 ^[15]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 8

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 3	Capsule Cohort 4	Capsule Cohort 5a	Capsule Cohort 5b
Number of subjects analysed	1 ^[16]	7	19	3
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	543 ± 99999	801 ± 98.9	618 ± 99.5	514 ± 101.6

Notes
[16] - "99999" in data entry fields stands for "Not Calculated"

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 15

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End point title

Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 15 ^[17]

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15

Notes
[17] - 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: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 5b
Number of subjects analysed	3
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	907 ± 50.7

No statistical analyses for this end point

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1

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End point title

Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1 ^[18]

End point description

End point type

Secondary

End point timeframe

Cycle 2 Day 1

Notes
[18] - 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: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 5a
Number of subjects analysed	13
Units: ng/mL
geometric mean (geometric coefficient of variation)	169 ± 135.4

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1

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End point title

Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1 ^[19]

End point description

End point type

Secondary

End point timeframe

Cycle 2 Day 1

Notes
[19] - 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: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 5a
Number of subjects analysed	13
Units: h*ng/mL
geometric mean (geometric coefficient of variation)
AUC(0-10)	504 ± 123.5
AUC(0-12)	520 ± 124.5

No statistical analyses for this end point

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 2 Day 1

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End point title

Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 2 Day 1 ^[20]

End point description

End point type

Secondary

End point timeframe

Cycle 2 Day 1

Notes
[20] - 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: This endpoint is only reporting PK data of arms with certain dosage schedule on certain day.

End point values	Capsule Cohort 5b
Number of subjects analysed	2
Units: h*ng/mL
geometric mean (geometric coefficient of variation)	761 ± 59.0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

TEAEs was defined as AEs that start on or after the first administration of study drug, TEAEs were collected up to 28 +/- 7 days post last dose.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Capsule Cohort 2

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) capsule 150 mg twice daily (BID), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 1

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg twice daily (BID), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 3

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) capsule 100 mg once daily (QD), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 4

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg once daily (QD), in continuous 28-day cycles.

Reporting group title

Capsule Cohort 5a

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 75 mg BID, in continuous 28-day cycles.

Reporting group title

Capsule Cohort 5b

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) capsule 50 mg QD with escalation every 14 days to 150 mg QD, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 87 mg/mm^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 87 mg/m^2 BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 6b

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 75mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 7b

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50 mg BID for 7 days, then 75 mg BID for 7 days, then 100 mg BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort7a

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50 mg BID with escalation after 7 days to 75 mg BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 58 mg/mm^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 58 mg/m^2 BID, in continuous 28-day cycles.

Reporting group title

Pediatric Cohort 43 mg/mm^2 BID

Reporting group description

Subjects aged < 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 43 mg/m^2 BID, in continuous 28-day cycles.

Reporting group title

Suspension Cohort 6a

Reporting group description

Subjects aged >= 12 years in this group were administrated with selitrectinib (BAY2731954) liquid suspension 50mg BID, in continuous 28-day cycles.

Capsule Cohort 2

Capsule Cohort 1

Capsule Cohort 3

Capsule Cohort 4

Capsule Cohort 5a

Capsule Cohort 5b

Pediatric Cohort 87 mg/mm^2 BID

Suspension Cohort 6b

Suspension Cohort 7b

Suspension Cohort7a

Pediatric Cohort 58 mg/mm^2 BID

Pediatric Cohort 43 mg/mm^2 BID

Suspension Cohort 6a

Total subjects affected by serious adverse events

subjects affected / exposed

1 / 2 (50.00%)

3 / 5 (60.00%)

1 / 2 (50.00%)

5 / 8 (62.50%)

16 / 23 (69.57%)

1 / 3 (33.33%)

0 / 1 (0.00%)

4 / 4 (100.00%)

2 / 6 (33.33%)

8 / 14 (57.14%)

3 / 4 (75.00%)

3 / 6 (50.00%)

0 / 3 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Glioblastoma

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Tumour haemorrhage

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal stromal tumour

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Neuroendocrine carcinoma

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Metastases to central nervous system

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oesophageal squamous cell carcinoma

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

1 / 2 (50.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Hypotension

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Embolism

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Asthenia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cyst

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Death

subjects affected / exposed

1 / 2 (50.00%)

1 / 5 (20.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

3 / 23 (13.04%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Fatigue

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Influenza like illness

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Non-cardiac chest pain

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Systemic inflammatory response syndrome

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Disease progression

subjects affected / exposed

0 / 2 (0.00%)

1 / 5 (20.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pyrexia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

2 / 4 (50.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

2 / 23 (8.70%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

2 / 14 (14.29%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hypoxia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

2 / 23 (8.70%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Investigations

Blood glucose increased

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Overdose

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Femoral neck fracture

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tracheal obstruction

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skull fracture

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Procedural pain

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Cardiac arrest

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sinus bradycardia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Tachycardia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Facial paralysis

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysarthria

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Depressed level of consciousness

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Coma

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Generalised tonic-clonic seizure

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Headache

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hydrocephalus

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

1 / 4 (25.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Hepatic encephalopathy

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Haemorrhage intracranial

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Seizure

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

1 / 4 (25.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Brain oedema

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Facial paresis

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cognitive disorder

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Ascites

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastric haemorrhage

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

2 / 23 (8.70%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

2 / 23 (8.70%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Biliary obstruction

subjects affected / exposed

0 / 2 (0.00%)

1 / 5 (20.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

1 / 2 (50.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal colic

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Arthralgia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bursitis

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

1 / 14 (7.14%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal pain

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

1 / 3 (33.33%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Muscular weakness

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Cellulitis

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

2 / 14 (14.29%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Septic shock

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory tract infection viral

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Biliary tract infection

subjects affected / exposed

0 / 2 (0.00%)

1 / 5 (20.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rhinovirus infection

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Staphylococcal bacteraemia

subjects affected / exposed

1 / 2 (50.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 23 (4.35%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Metabolism and nutrition disorders

Hypoalbuminaemia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypernatraemia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypercalcaemia

subjects affected / exposed

0 / 2 (0.00%)

0 / 5 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 23 (0.00%)

0 / 3 (0.00%)

0 / 1 (0.00%)

1 / 4 (25.00%)

0 / 6 (0.00%)

0 / 14 (0.00%)

0 / 4 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Capsule Cohort 2	Capsule Cohort 1	Capsule Cohort 3	Capsule Cohort 4	Capsule Cohort 5a	Capsule Cohort 5b	Pediatric Cohort 87 mg/mm^2 BID	Suspension Cohort 6b	Suspension Cohort 7b	Suspension Cohort7a	Pediatric Cohort 58 mg/mm^2 BID	Pediatric Cohort 43 mg/mm^2 BID	Suspension Cohort 6a
Total subjects affected by non serious adverse events
subjects affected / exposed	2 / 2 (100.00%)	5 / 5 (100.00%)	2 / 2 (100.00%)	8 / 8 (100.00%)	22 / 23 (95.65%)	3 / 3 (100.00%)	1 / 1 (100.00%)	4 / 4 (100.00%)	6 / 6 (100.00%)	14 / 14 (100.00%)	4 / 4 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to meninges
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Tumour pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Skin papilloma
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Cancer pain
subjects affected / exposed	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Tumour exudation
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Vascular disorders
Lymphoedema
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Hypotension
subjects affected / exposed	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	2	0	0	2	0	1	0	1	0
Hypertension
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	2	0	2	0
Haematoma
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Embolism venous
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Flushing
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Deep vein thrombosis
subjects affected / exposed	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0	0
Orthostatic hypotension
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	2	0	0	0
Hot flush
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	3 / 23 (13.04%)	0 / 3 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	5	0	1	0	0	0	1	0	0
Chest discomfort
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	1	0
Chills
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	3	1	0	0	0	0	0	0	0	0
Drug withdrawal syndrome
subjects affected / exposed	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	2	0	0	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	1 / 2 (50.00%)	1 / 5 (20.00%)	1 / 2 (50.00%)	2 / 8 (25.00%)	5 / 23 (21.74%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	3 / 14 (21.43%)	1 / 4 (25.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)
occurrences all number	2	1	2	4	6	0	0	0	2	3	1	2	1
Gait disturbance
subjects affected / exposed	0 / 2 (0.00%)	2 / 5 (40.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	6 / 23 (26.09%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	3 / 14 (21.43%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	3	9	2	0	0	4	4	0	0	0
Oedema
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Malaise
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	1	0	0	0	0	1	0	1	0
Face oedema
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Energy increased
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	0
Localised oedema
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1	0
Oedema peripheral
subjects affected / exposed	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	3 / 23 (13.04%)	0 / 3 (0.00%)	0 / 1 (0.00%)	4 / 4 (100.00%)	2 / 6 (33.33%)	1 / 14 (7.14%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	5	0	0	5	2	1	0	1	0
Pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	2 / 23 (8.70%)	0 / 3 (0.00%)	0 / 1 (0.00%)	3 / 4 (75.00%)	0 / 6 (0.00%)	3 / 14 (21.43%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	2	0	0	3	0	3	2	0	0
Pyrexia
subjects affected / exposed	1 / 2 (50.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	2 / 8 (25.00%)	2 / 23 (8.70%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	1 / 4 (25.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	7	4	0	0	0	1	1	4	6	0
Swelling
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Thirst
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Dysmenorrhoea
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Pelvic pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Scrotal oedema
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Scrotal pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Penile oedema
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	5 / 23 (21.74%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 4 (50.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	1	0	1	7	0	0	0	0	1	5	1	1
Bronchospasm
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Dyspnoea
subjects affected / exposed	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	8 / 23 (34.78%)	0 / 3 (0.00%)	0 / 1 (0.00%)	4 / 4 (100.00%)	1 / 6 (16.67%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	13	0	0	4	1	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hypercapnia
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	1 / 1 (100.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Pneumothorax
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0
Epistaxis
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	0	0
Hypoxia
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	1	0	1	0
Haemoptysis
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	1	0	0	0	0	0	0	3	0
Productive cough
subjects affected / exposed	0 / 2 (0.00%)	1 / 5 (20.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0	0	1	1	1	0	0	0
Respiratory failure
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	2	0	0
Sneezing
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1	0
Lower respiratory tract inflammation
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Paranasal sinus discomfort
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 3 (33.33%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	2 / 4 (50.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	2	3	0
Wheezing
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0
Delirium
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Confusional state
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	3 / 23 (13.04%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	3	0	0	1	0	0	0	0	0
Anxiety
subjects affected / exposed	1 / 2 (50.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	1	4	0	0	0	0	1	0	0	0
Disorientation
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Derealisation
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Hallucination, auditory
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Hallucination
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Depression
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	1 / 4 (25.00%)	1 / 6 (16.67%)	2 / 14 (14.29%)	2 / 4 (50.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	2	2	0	0
Hallucination, visual
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	1 / 4 (25.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Restlessness
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	1 / 14 (7.14%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Sleep disorder
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Irritability
subjects affected / exposed	0 / 2 (0.00%)	0 / 5 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 3 (0.00%)	0 / 1 (0.00%)	0 / 4 (0.00%)	0 / 6 (0.00%)	0 / 14 (0.00%)	0 / 4 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number

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Clinical trials

Clinical Trial Results: A Phase 1 Study of the TRK Inhibitor Selitrectinib (BAY 2731954) in Adult and Pediatric Subjects with Previously Treated NTRK Fusion Cancers

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Maximum tolerated dose (MTD) / recommended dose in patients age 12 years and older and age < 12 years

Primary: Maximum tolerated dose (MTD) / recommended dose in patients age 12 years and older and age < 12 years

Secondary: Number of participants with TEAE and their severity

Secondary: Number of participants with TEAE and their severity

Secondary: Number of participants with treatment related TEAE

Secondary: Number of participants with treatment related TEAE

Secondary: Number of participants with hematology shifts from normal baseline value

Secondary: Number of participants with hematology shifts from normal baseline value

Secondary: Number participants with chemistry shifts from baseline according to normal range

Secondary: Number participants with chemistry shifts from baseline according to normal range

Secondary: Objective Response Rate as determined by the Investigator in participants with a documented NTRK fusion cancer previously treated with a TRK inhibitor

Secondary: Objective Response Rate as determined by the Investigator in participants with a documented NTRK fusion cancer previously treated with a TRK inhibitor

Secondary: Objective Response Rate as determined by investigator in participants with primary CNS malignancies

Secondary: Objective Response Rate as determined by investigator in participants with primary CNS malignancies

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 1

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 8

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 1 Day 15

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 1

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 1

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 8

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 8

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 15

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 1 Day 15

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1

Secondary: Maximum concentration (Cmax) of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1

Secondary: Area under the concentration versus time curve of BAY2731954 in plasma for BID dosing, Cycle 2 Day 1

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 2 Day 1

Secondary: Area under the concentration versus time curve AUC(0-24) of BAY2731954 in plasma for QD dosing, Cycle 2 Day 1

Adverse events

Clinical Trial Results:
A Phase 1 Study of the TRK Inhibitor Selitrectinib (BAY 2731954) in Adult and Pediatric Subjects with Previously Treated NTRK Fusion Cancers