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Clinical Trial Results:
An open-label, first-in-human, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and maximum tolerated dose and / or recommended Phase II dose of the ATR inhibitor BAY 1895344 in patients with advanced solid tumors and lymphomas.

Summary
EudraCT number	2016-004484-39
Trial protocol	GB FR
Global end of trial date	13 Sep 2023

Results information
Results version number	v1(current)
This version publication date	02 Jun 2024
First version publication date	02 Jun 2024
Other versions

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

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Trial information

Top of page

Sponsor protocol code

18594

ISRCTN number

US NCT number

NCT03188965

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, +49 30 300139003 , clinical-trials-contact@bayer.com

Scientific contact

Therapeutic Area Head, Bayer AG, +49 30 300139003 , 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?

Analysis stage

Final

Date of interim/final analysis

19 Oct 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Sep 2023

Was the trial ended prematurely?

Main objective of the trial

Determine the maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D), safety, tolerability, and pharmacokinetics (PK) of BAY 1895344 as single agent, in patients with advanced solid tumors and lymphomas.

Protection of trial subjects

The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects 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

06 Jul 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Singapore: 101

Country: Number of subjects enrolled

United Kingdom: 129

Country: Number of subjects enrolled

United States: 306

Country: Number of subjects enrolled

Switzerland: 137

Country: Number of subjects enrolled

Canada: 123

Country: Number of subjects enrolled

China: 24

Country: Number of subjects enrolled

Japan: 85

Worldwide total number of subjects

905

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)

577

From 65 to 84 years

324

85 years and over

Subject disposition

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Recruitment details

The study was conducted in in 5 countries in Part A, 6 countries in Part A.1, 7 countries in Part B, and 2 countries in Part B.1 between 06 July 2017 (first subject first visit) and 13 September 2023 (last subject last visit).

Screening details

54 of 65 (Part A, including 8 in J-arm), 32 of 87 (Part A1) and 143 of 753 (Part B) subjects who signed ICF were assigned to study intervention. Neither of the 2 subjects who signed ICF in Part B.1 were assigned to study intervention.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part A - 5mg BID

Arm description

Subjects received elimusertib 5 mg 2 times daily (BID) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 5 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Liquid service formulation; 5 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A - 10mg BID

Arm description

Subjects received elimusertib 10 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 10 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Liquid service formulation; 10 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A - 20mg BID Pooled

Arm description

Subjects received elimusertib 20 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 20 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Liquid service formulation;20 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A - 40mg BID MTD

Arm description

Subjects received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Liquid service formulation; 40 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 40 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A - 40mg BID Non-MTD

Arm description

Subjects, who were not included in the maximum tolerated dose (MTD) analysis, received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Part A - 60mg BID

Arm description

Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 60 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Liquid service formulation; 60 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A - 60mg BID 2w/1w

Arm description

Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with 2 weeks on/1 week off in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 60 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with 2 weeks on/1 week off, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Liquid service formulation; 60 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with 2 weeks on/1 week off, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A - 80mg BID

Arm description

Subjects received elimusertib 80 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 80 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Liquid service formulation; 80 mg BID (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A.1 - 60mg BID 3d/11d

Arm description

Subjects received elimusertib 60 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 60 mg (BID, every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A.1 - 80mg BID 3d/11d

Arm description

Subjects received elimusertib 80 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 80 mg (BID, every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A.1 - 100mg BID 3d/11d

Arm description

Subjects received elimusertib 100 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 100 mg (BID, every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part A.1 - 120mg BID 3d/11d

Arm description

Subjects received elimusertib 120 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablet; 120 mg (BID, every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles, until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Part B - Prostate

Arm description

Subjects with prostate cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B - Colorectal

Arm description

Subjects with colorectal cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B - Gynecological

Arm description

Subjects with gynecological cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B - Breast

Arm description

Subjects with breast cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Oral solution

Routes of administration

Oral use

Dosage and administration details

Part B - ATM loss

Arm description

Subjects with ATM loss regardless of cancer type received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Arm type

Experimental

Investigational medicinal product name

Elimusertib

Investigational medicinal product code

BAY1895344

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1 ^[1]	Part A - 5mg BID	Part A - 10mg BID	Part A - 20mg BID Pooled	Part A - 40mg BID MTD	Part A - 40mg BID Non-MTD	Part A - 60mg BID	Part A - 60mg BID 2w/1w	Part A - 80mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part B - Prostate	Part B - Colorectal	Part B - Gynecological	Part B - Breast	Part B - ATM loss
Started	1	2	6	6	24	8	4	3	6	11	6	9	19	24	45	19	36
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	1	2	6	6	24	8	4	3	6	11	6	9	19	24	45	19	36
Physician decision	-	-	1	-	1	-	-	-	-	-	-	-	-	-	1	-	-
Consent withdrawn by subject	-	-	-	-	-	-	-	-	-	-	-	1	1	1	1	1	4
Progressive disease - clinical progression	-	-	-	1	4	1	1	-	1	-	1	2	5	2	7	3	6
Other	-	-	-	-	-	-	-	-	-	-	-	-	-	1	-	-	-
Adverse event	-	-	-	-	3	1	-	1	-	-	-	2	1	2	8	3	5
Progressive disease	1	2	5	5	16	6	3	2	5	11	5	4	12	18	28	12	21

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Of the 65 (Part A), 87 (Part A.1) 751 (Part B) and 2 (Part B.1) enrolled subjects, only 54 (Part A), 32 (Part A.1), 143 (Part B) subjects completed general screening and were assigned to study intervention.

Baseline characteristics

Top of page

Reporting group title

Part A - 5mg BID

Reporting group description

Subjects received elimusertib 5 mg 2 times daily (BID) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 10mg BID

Reporting group description

Subjects received elimusertib 10 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 20mg BID Pooled

Reporting group description

Subjects received elimusertib 20 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 40mg BID MTD

Reporting group description

Subjects received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 40mg BID Non-MTD

Reporting group description

Reporting group title

Part A - 60mg BID

Reporting group description

Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 60mg BID 2w/1w

Reporting group description

Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with 2 weeks on/1 week off in Part A of the study.

Reporting group title

Part A - 80mg BID

Reporting group description

Subjects received elimusertib 80 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A.1 - 60mg BID 3d/11d

Reporting group description

Subjects received elimusertib 60 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 80mg BID 3d/11d

Reporting group description

Subjects received elimusertib 80 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 100mg BID 3d/11d

Reporting group description

Subjects received elimusertib 100 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 120mg BID 3d/11d

Reporting group description

Subjects received elimusertib 120 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part B - Prostate

Reporting group description

Subjects with prostate cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Colorectal

Reporting group description

Subjects with colorectal cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Gynecological

Reporting group description

Subjects with gynecological cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Breast

Reporting group description

Subjects with breast cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - ATM loss

Reporting group description

Subjects with ATM loss regardless of cancer type received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group values	Part A - 5mg BID	Part A - 10mg BID	Part A - 20mg BID Pooled	Part A - 40mg BID MTD	Part A - 40mg BID Non-MTD	Part A - 60mg BID	Part A - 60mg BID 2w/1w	Part A - 80mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part B - Prostate	Part B - Colorectal	Part B - Gynecological	Part B - Breast	Part B - ATM loss	Total
Number of subjects	1	2	6	6	24	8	4	3	6	11	6	9	19	24	45	19	36	229
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	73.0 ( 0 )	67.0 ( 4.2 )	65.5 ( 5.4 )	53.0 ( 16.5 )	62.8 ( 12.1 )	61.0 ( 7.1 )	58.5 ( 6.9 )	51.0 ( 8.7 )	57.7 ( 10.1 )	59.3 ( 14.3 )	58.2 ( 11.1 )	63.4 ( 12.1 )	69.1 ( 7.7 )	55.6 ( 12.5 )	56.4 ( 9.5 )	49.8 ( 8.2 )	57.6 ( 11.1 )	-
Gender categorical
Units: Subjects
Female	0	0	0	4	14	6	1	3	2	2	3	2	0	9	45	19	15	125
Male	1	2	6	2	10	2	3	0	4	9	3	7	19	15	0	0	21	104

End points

Top of page

Reporting group title

Part A - 5mg BID

Reporting group description

Subjects received elimusertib 5 mg 2 times daily (BID) for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 10mg BID

Reporting group description

Subjects received elimusertib 10 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 20mg BID Pooled

Reporting group description

Subjects received elimusertib 20 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 40mg BID MTD

Reporting group description

Subjects received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 40mg BID Non-MTD

Reporting group description

Reporting group title

Part A - 60mg BID

Reporting group description

Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 60mg BID 2w/1w

Reporting group description

Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with 2 weeks on/1 week off in Part A of the study.

Reporting group title

Part A - 80mg BID

Reporting group description

Subjects received elimusertib 80 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A.1 - 60mg BID 3d/11d

Reporting group description

Subjects received elimusertib 60 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 80mg BID 3d/11d

Reporting group description

Subjects received elimusertib 80 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 100mg BID 3d/11d

Reporting group description

Subjects received elimusertib 100 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 120mg BID 3d/11d

Reporting group description

Subjects received elimusertib 120 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part B - Prostate

Reporting group description

Subjects with prostate cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Colorectal

Reporting group description

Subjects with colorectal cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Gynecological

Reporting group description

Subjects with gynecological cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Breast

Reporting group description

Subjects with breast cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - ATM loss

Reporting group description

Subjects with ATM loss regardless of cancer type received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Subject analysis set title

MTD analysis set - Part A (non-Japanese)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Maximum tolerated dose (MTD) analysis set - Part A (non-Japanese) included all (non-Japanese) subjects used to determine the MTD in Part A. Subjects in Part A who started treatment when the MTD was already determined at 40 mg BID were excluded from the MTD analysis set.

Subject analysis set title

MTD analysis set - Part A (J-arm)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Maximum tolerated dose (MTD) analysis set - Part A (J-arm) included all Japanese subjects used to determine the MTD in Japanese patients in Part A.

Subject analysis set title

MTD analysis set - Part A.1

Subject analysis set type

Sub-group analysis

Subject analysis set description

Maximum tolerated dose (MTD) analysis set - Part A.1 included all patients used to determine the MTD in Part A.1.

Subject analysis set title

Part A - J-arm 20mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part A - J-arm 20mg BID included all Japanese subjects who received elimusertib 20 mg 2 times daily (BID) (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule (in a 21-day cycle) with no break between cycles.

Subject analysis set title

Part A - non-J 20mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part A - non-J 20mg BID included all non-Japanese subjects who received elimusertib 20 mg 2 times daily (BID) (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule (in a 21-day cycle) with no break between cycles.

Subject analysis set title

Part A - J-arm 40mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part A - J-arm 40mg BID included all Japanese subjects who received elimusertib 40 mg 2 times daily (BID) (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule (in a 21-day cycle) with no break between cycles.

Subject analysis set title

Part A - non-J 40mg BID

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part A - non-J 40mg BID included all non-Japanese subjects who received elimusertib 40 mg 2 times daily (BID) (every 12±1 hours, except on Cycle 1 Day 1 when elimusertib was administered once daily) for 3 days on/4 days off in a weekly schedule (in a 21-day cycle) with no break between cycles.

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All subjects who received at least 1 dose of elimusertib and had post treatment safety data available were included in the safety evaluation.

Subject analysis set title

Efficacy analysis set (EAS)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects who received at least 1 dose of elimusertib and who had postbaseline efficacy data available and no important protocol deviations affecting validity were included in the efficacy evaluation. This included subjects with death due to any cause or clinical disease progression before the first postbaseline response assessment.

Subject analysis set title

PK analysis set (PKS)

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects who had received at least 1 dose of elimusertib and with at least 1 valid concentration of elimusertib after first dosing and no important protocol deviations affecting the validity were included in the PK evaluation.

Subject analysis set title

Part B PKS

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects in Part B who had received at least 1 dose of elimusertib and with at least 1 valid concentration of elimusertib after first dosing and no important protocol deviations affecting the validity were included in the PK evaluation.

Primary: Number of subjects with dose-limiting toxicities (DLTs) during Cycle 1 in dose escalation cohorts

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End point title

Number of subjects with dose-limiting toxicities (DLTs) during Cycle 1 in dose escalation cohorts ^[1] ^[2]

End point description

A DLT was defined as any of those hematological, non-hematological or miscellaneous TEAEs that listed in the study protocol that were related to BAY 1895344 for Part A, J-arm of Part A, and Part A.1, and occurring during Cycle 1 of a dose level. SAF was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

21 days (Cycle 1) in Part A and 28 days (Cycle 1) in Part A.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: Due to the nature of this trial, only descriptive statistics were performed for DLTs. No inferential statistical analyses were pre-specified.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The analyses of DLTs were only planned for Part A and Part A.1 of the study.

End point values	Part A - 5mg BID	Part A - 10mg BID	Part A - 20mg BID Pooled	Part A - 40mg BID MTD	Part A - 40mg BID Non-MTD	Part A - 60mg BID	Part A - 60mg BID 2w/1w	Part A - 80mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part A - J-arm 20mg BID	Part A - non-J 20mg BID	Part A - J-arm 40mg BID	Part A - non-J 40mg BID
Number of subjects analysed	1	2	6	6	24	8	4	3	6	11	6	9	4	2	4	2
Units: Subject(s)	0	0	0	0	0	2	2	2	0	0	0	2	0	0	0	0

No statistical analyses for this end point

Primary: Maximum tolerated dose (MTD)

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End point title

Maximum tolerated dose (MTD) ^[3]

End point description

The MTD was defined as the maximum dose at which the incidence of dose-limiting toxicities (DLTs) during Cycle 1 was below 30%, or the maximum dose tested, whichever was achieved first during dose escalation. The MTD for the 3 days on/4 days off dosing schedule was to be determined in Part A non-Japanese subjects and the safety and tolerability of the established MTD was to be evaluated in Part A Japanese subjects (J-arm). The MTD for the 3 days on/11 days off dosing schedule was planned to be determined in Part A.1. MTD analysis set was used for the analysis of this endpoint. "99999" denotes that MTD could not be formally identified due to no DLTs that met protocol-specified criteria were observed.

End point type

Primary

End point timeframe

21 days (Cycle 1)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the nature of this trial, only descriptive statistics were performed for MTD. No inferential statistical analyses were pre-specified.

End point values	MTD analysis set - Part A (non-Japanese)	MTD analysis set - Part A (J-arm)	MTD analysis set - Part A.1
Number of subjects analysed	18	7	29
Units: milligram(s)
number (not applicable)
3 days on/4 days off	40	40	99999

No statistical analyses for this end point

Primary: Number of subjects with treatment-emergent adverse events

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End point title

Number of subjects with treatment-emergent adverse events ^[4]

End point description

An adverse event (AE) was any untoward medical occurrence in a subject, associated with the use of study intervention, whether or not considered related to the study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly/birth defect; another medical important serious event as judged by the investigator. AEs or SAEs were considered to be treatment emergent (TEAEs or TESAEs) if they started or worsened after first administration of study drug up to 30 days after the last dose of study drug. SAF was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

After first administration of study drug up to 30 days after the last dose of study drug

Notes
[4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the nature of this trial, only descriptive statistics were performed for TEAEs. No inferential statistical analyses were pre-specified.

End point values	Part A - 5mg BID	Part A - 10mg BID	Part A - 20mg BID Pooled	Part A - 40mg BID MTD	Part A - 40mg BID Non-MTD	Part A - 60mg BID	Part A - 60mg BID 2w/1w	Part A - 80mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part B - Prostate	Part B - Colorectal	Part B - Gynecological	Part B - Breast	Part B - ATM loss
Number of subjects analysed	1	2	6	6	24	8	4	3	6	11	6	9	19	24	45	19	36
Units: Subject(s)
Any TEAE	1	2	6	6	24	8	4	3	6	10	6	9	19	24	45	19	36
Any TESAE	0	1	1	1	7	5	2	2	3	4	3	5	4	14	21	5	14
Any elimusertib related TEAE	1	2	5	6	22	8	4	3	6	9	6	8	18	22	45	18	33
Any elimusertib related TESAE	0	1	0	0	1	1	0	1	0	0	1	1	0	2	6	1	0

No statistical analyses for this end point

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=3 or higher)

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End point title

Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=3 or higher) ^[5] ^[6]

End point description

Results of AUC(0-12) after single dose of the noncompartmental analysis are reported below. Geometric mean and coefficient of variation (CV%) are presented for reporting groups with at least 3 subjects analyzed (n=3). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 60mg BID	Part A - 80mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part A - J-arm 20mg BID	Part A - J-arm 40mg BID	Part B PKS
Number of subjects analysed	8	3	5	11	6	9	4	4	87
Units: μg·h/L
geometric mean (geometric coefficient of variation)	13400 ( 30.1 )	19600 ( 27.2 )	8990 ( 31.2 )	13500 ( 29.3 )	14300 ( 18.3 )	18700 ( 40.7 )	3870 ( 28.6 )	9110 ( 30.0 )	7350 ( 32.8 )

No statistical analyses for this end point

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=2)

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End point title

Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=2) ^[7]

End point description

Results of AUC(0-12) after single dose of the noncompartmental analysis are reported below. Median and range are presented for reporting groups with 2 subjects analyzed (n=2). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[7] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.

End point values	Part A - non-J 20mg BID	Part A - non-J 40mg BID
Number of subjects analysed	2	2
Units: µg·h/L
median (full range (min-max))	4350 (3340 to 5360)	8390 (7180 to 9610)

No statistical analyses for this end point

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=1)

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End point title

Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=1) ^[8] ^[9]

End point description

Results of AUC(0-12) after single dose of the noncompartmental analysis are reported below. Individual value is presented for reporting groups with only 1 subject analyzed (n=1). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[8] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[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: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 5mg BID	Part A - 10mg BID
Number of subjects analysed	1	1
Units: μg·h/L
number (not applicable)	934	1590

No statistical analyses for this end point

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=3 or higher)

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End point title

Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=3 or higher) ^[10] ^[11]

End point description

Results of Cmax after single dose of the noncompartmental analysis are reported below. Geometric mean and coefficient of variation (CV%) are presented for reporting groups with at least 3 subjects analyzed (n=3 or higher). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[10] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 60mg BID	Part A - 80mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part A - J-arm 20mg BID	Part A - J-arm 40mg BID	Part B PKS
Number of subjects analysed	8	3	5	11	6	9	4	4	87
Units: µg/L
geometric mean (geometric coefficient of variation)	2480 ( 33.4 )	3260 ( 26.3 )	1470 ( 28.2 )	2270 ( 41.8 )	1740 ( 13.9 )	2920 ( 31.0 )	667 ( 37.5 )	1780 ( 44.3 )	1230 ( 37.4 )

No statistical analyses for this end point

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=2)

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End point title

Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=2) ^[12]

End point description

Results of Cmax after single dose of the noncompartmental analysis are reported below. Median and range are presented for reporting groups with 2 subjects analyzed (n=2). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[12] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.

End point values	Part A - non-J 20mg BID	Part A - non-J 40mg BID
Number of subjects analysed	2	2
Units: µg/L
median (full range (min-max))	619 (383 to 855)	1840 (1820 to 1860)

No statistical analyses for this end point

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=1)

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End point title

Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=1) ^[13] ^[14]

End point description

Results of Cmax after single dose of the noncompartmental analysis are reported below. Individual value is presented for reporting groups with 1 subject analyzed (n=1). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[13] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[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: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 5mg BID	Part A - 10mg BID
Number of subjects analysed	1	1
Units: µg/L
number (not applicable)	178	258

No statistical analyses for this end point

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=3 or higher)

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End point title

Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=3 or higher) ^[15] ^[16]

End point description

Results of AUC(0-12) after the 5th dose of the noncompartmental analysis are reported below. Geometric mean and coefficient of variation (CV%) are presented for reporting groups with at least 3 subjects analyzed (n=3 or higher). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[15] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 60mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part A - J-arm 20mg BID	Part A - J-arm 40mg BID	Part B PKS
Number of subjects analysed	7	5	9	3	7	4	4	65
Units: µg·h/L
geometric mean (geometric coefficient of variation)	18800 ( 52.9 )	20900 ( 34.8 )	24700 ( 37.2 )	29100 ( 45.1 )	36700 ( 47.5 )	6910 ( 40.9 )	16400 ( 27.8 )	12300 ( 46.2 )

No statistical analyses for this end point

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=2)

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End point title

Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=2) ^[17] ^[18]

End point description

Results of AUC(0-12) after the 5th dose of the noncompartmental analysis are reported below. Median and range are presented for reporting groups with 2 subjects analyzed (n=2). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[17] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[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: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 80mg BID	Part A - non-J 40mg BID
Number of subjects analysed	2	2
Units: µg·h/L
median (full range (min-max))	39900 (19300 to 60500)	13400 (11400 to 15300)

No statistical analyses for this end point

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=1)

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End point title

Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=1) ^[19] ^[20]

End point description

Results of AUC(0-12) after the 5th dose of the noncompartmental analysis are reported below. Individual value is presented for reporting groups with 1 subject analyzed (n=1). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[19] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[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: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 5mg BID	Part A - 10mg BID	Part A - non-J 20mg BID
Number of subjects analysed	1	1	1
Units: µg·h/L
number (not applicable)	1600	2450	8050

No statistical analyses for this end point

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=3 or higher)

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End point title

Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=3 or higher) ^[21] ^[22]

End point description

Results of Cmax after the 5th dose of the noncompartmental analysis are reported below. Geometric mean and coefficient of variation (CV%) are presented for reporting groups with at least 3 subjects analyzed (n=3 or higher). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[21] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[22] - 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: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 60mg BID	Part A.1 - 60mg BID 3d/11d	Part A.1 - 80mg BID 3d/11d	Part A.1 - 100mg BID 3d/11d	Part A.1 - 120mg BID 3d/11d	Part A - J-arm 20mg BID	Part A - J-arm 40mg BID	Part B PKS
Number of subjects analysed	7	5	9	3	7	4	4	65
Units: µg/L
geometric mean (geometric coefficient of variation)	3280 ( 54.7 )	2110 ( 42.1 )	3280 ( 36.6 )	3540 ( 30.2 )	4490 ( 38.4 )	1020 ( 52.4 )	2640 ( 44.1 )	1750 ( 44.7 )

No statistical analyses for this end point

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=1)

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End point title

Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=1) ^[23] ^[24]

End point description

Results of Cmax after the 5th dose of the noncompartmental analysis are reported below. Individual value is presented for reporting groups with 1 subject analyzed (n=1). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[23] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[24] - 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: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 5mg BID	Part A - 10mg BID	Part A - non-J 20mg BID
Number of subjects analysed	1	1	1
Units: µg/L
number (not applicable)	263	420	1070

No statistical analyses for this end point

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=2)

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End point title

Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=2) ^[25] ^[26]

End point description

Results of Cmax after the 5th dose of the noncompartmental analysis are reported below. Median and range are presented for reporting groups with 2 subjects analyzed (n=2). PKS was used for the analysis of this endpoint.

End point type

Primary

End point timeframe

Pre-dose and up to 12 hours post-dose

Notes
[25] - 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: Due to the nature of this trial, only noncompartmental pharmacokinetic analyses were planned as part of the primary endpoint analyses of the study. Dose proportionality, relative bioavailability and food effect were only planned and performed as explorative analyses.
[26] - 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: Pharmacokinetic analyses are reported separately per number of subjects analyzed.

End point values	Part A - 80mg BID	Part A - non-J 40mg BID
Number of subjects analysed	2	2
Units: µg/L
median (full range (min-max))	5660 (3330 to 8000)	2280 (2200 to 2360)

No statistical analyses for this end point

Secondary: Objective response rate (ORR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

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End point title

Objective response rate (ORR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

End point description

ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) during the course of the study. Best overall responses were evaluated by the investigator as per the RECIST 1.1 (Eisenhauer et al. 2009). EAS was used for the analysis. CRPC: castration-resistant prostate cancer; RECIST: Response Evaluation Criteria in Solid Tumors

End point type

Secondary

End point timeframe

Part A: up to 1340 days; Part A.1: up to 597 days; Part B: 1361 days

Part A - 5mg BID

Part A - 10mg BID

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID Non-MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Gynecological

Part B - Breast

Part B - ATM loss

Number of subjects analysed

0 ^[27]

Units: Percentage

number (confidence interval 95%)

0 (0 to 97.5)

0 (0 to 52.2)

33.3 (4.3 to 77.7)

0 (0 to 16.8)

14.3 (0.4 to 47.9)

0 (0 to 84.2)

33.3 (0.8 to 90.6)

0 (0 to 60.2)

0 (0 to 30.8)

20.0 (0.5 to 71.6)

12.5 (0.3 to 52.7)

( to )

0 (0 to 14.8)

2.4 (0.1 to 12.6)

11.1 (1.4 to 34.7)

4.3 (0.1 to 21.9)

Notes
[27] - No evaluable subject

No statistical analyses for this end point

Secondary: Objective response rate (ORR) of CRPC tumor responses consistent with the recommendations of PCWG3

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End point title

Objective response rate (ORR) of CRPC tumor responses consistent with the recommendations of PCWG3

End point description

ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) or a PSA-based response during the course of the study. Best overall responses were evaluated by the investigator as per the RECIST 1.1 according to the recommendations of PCWG3 (Scher et al. 2016). EAS was used for the analysis. CRPC: castration-resistant prostate cancer; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; PCWG3: Prostate Cancer Working Group 3

End point type

Secondary

End point timeframe

Part A: up to 1340 days; Part A.1: up to 597 days; Part B: 1361 days

Part A - 5mg BID

Part A - 10mg BID

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID Non-MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Gynecological

Part B - Breast

Part B - ATM loss

Number of subjects analysed

0 ^[28]

0 ^[29]

0 ^[30]

0 ^[31]

0 ^[32]

0 ^[33]

0 ^[34]

Units: Percentage

number (confidence interval 95%)

( to )

0 (0 to 97.5)

( to )

0 (0 to 60.2)

0 (0 to 97.5)

0 (0 to 84.2)

( to )

0 (0 to 84.2)

0 (0 to 97.5)

0 (0 to 18.5)

( to )

20.0 (2.5 to 55.6)

Notes
[28] - No evaluable subject
[29] - No evaluable subject
[30] - No evaluable subject
[31] - No evaluable subject
[32] - No evaluable subject
[33] - No evaluable subject
[34] - No evaluable subject

No statistical analyses for this end point

Secondary: Objective response rate (ORR) of lymphoma responses consistent with Lugano Classification

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End point title

Objective response rate (ORR) of lymphoma responses consistent with Lugano Classification

End point description

ORR was defined as the percentage of participants with best overall response of complete response (CR) or partial response (PR) during the course of the study. Best overall responses were to be evaluated by the investigator as per the Lugano Classification (Cheson et al. 2014). EAS was planned to be used for the analysis.

End point type

Secondary

End point timeframe

0 day as no subject was evaluated as per Lugano Classification

Part A - 5mg BID

Part A - 10mg BID

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID Non-MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Gynecological

Part B - Breast

Part B - ATM loss

Number of subjects analysed

0 ^[35]

0 ^[36]

0 ^[37]

0 ^[38]

0 ^[39]

0 ^[40]

0 ^[41]

0 ^[42]

0 ^[43]

0 ^[44]

0 ^[45]

0 ^[46]

0 ^[47]

0 ^[48]

0 ^[49]

0 ^[50]

0 ^[51]

Units: Percentage

number (confidence interval 95%)

( to )

Notes
[35] - No evaluable subject
[36] - No evaluable subject
[37] - No evaluable subject
[38] - No evaluable subject
[39] - No evaluable subject
[40] - No evaluable subject
[41] - No evaluable subject
[42] - No evaluable subject
[43] - No evaluable subject
[44] - No evaluable subject
[45] - No evaluable subject
[46] - No evaluable subject
[47] - No evaluable subject
[48] - No evaluable subject
[49] - No evaluable subject
[50] - No evaluable subject
[51] - No evaluable subject

No statistical analyses for this end point

Secondary: Disease control rate (DCR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

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End point title

Disease control rate (DCR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

End point description

DCR was defined as the percentage of subjects with complete response (CR) or partial response (PR) as best overall response, or stable disease (SD) for at least 10 weeks during the course of the study. Best overall responses were evaluated by the investigator as per the RECIST 1.1 (Eisenhauer et al. 2009). EAS was used for the analysis. CRPC: castration-resistant prostate cancer; RECIST: Response Evaluation Criteria in Solid Tumors

End point type

Secondary

End point timeframe

Part A: up to 1340 days; Part A.1: up to 597 days; Part B: 1361 days

Part A - 5mg BID

Part A - 10mg BID

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID Non-MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Gynecological

Part B - Breast

Part B - ATM loss

Number of subjects analysed

0 ^[52]

Units: Percentage

number (confidence interval 95%)

0 (0 to 97.5)

60.0 (14.7 to 94.7)

50.0 (11.8 to 88.2)

45.0 (23.1 to 68.5)

28.6 (3.7 to 71.0)

0 (0 to 84.2)

66.7 (9.4 to 99.2)

50.0 (6.8 to 93.2)

50.0 (18.7 to 81.3)

40.0 (5.3 to 85.3)

25.0 (3.2 to 65.1)

( to )

47.8 (26.8 to 69.4)

59.5 (43.3 to 74.4)

44.4 (21.5 to 69.2)

52.2 (30.6 to 73.2)

Notes
[52] - No evaluable subject

No statistical analyses for this end point

Secondary: Disease control rate (DCR) of CRPC tumor responses consistent with the recommendations of PCWG3

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End point title

Disease control rate (DCR) of CRPC tumor responses consistent with the recommendations of PCWG3

End point description

DCR was defined as the percentage of subjects with complete response (CR) or partial response (PR) as best overall response, or stable disease (SD) for at least 10 weeks during the course of the study. Best overall responses were evaluated by the investigator as per the RECIST 1.1 according to the recommendations of PCWG3 (Scher et al. 2016). EAS was used for the analysis. CRPC: castration-resistant prostate cancer; PSA: prostate-specific antigen; RECIST: Response Evaluation Criteria in Solid Tumors; PCWG3: Prostate Cancer Working Group 3

End point type

Secondary

End point timeframe

Part A: up to 1340 days; Part A.1: up to 597 days; Part B: 1361 days

Part A - 5mg BID

Part A - 10mg BID

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID Non-MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Gynecological

Part B - Breast

Part B - ATM loss

Number of subjects analysed

0 ^[53]

0 ^[54]

0 ^[55]

0 ^[56]

0 ^[57]

0 ^[58]

0 ^[59]

Units: Percentage

number (confidence interval 95%)

( to )

0 (0 to 97.5)

( to )

50.0 (6.8 to 93.2)

0 (0 to 97.5)

50.0 (1.3 to 98.7)

( to )

0 (0 to 84.2)

0 (0 to 97.5)

100.0 (2.5 to 100.0)

0 (0 to 97.5)

22.2 (6.4 to 47.6)

( to )

60.0 (26.2 to 87.8)

Notes
[53] - No evaluable subject
[54] - No evaluable subject
[55] - No evaluable subject
[56] - No evaluable subject
[57] - No evaluable subject
[58] - No evaluable subject
[59] - No evaluable subject

No statistical analyses for this end point

Secondary: Disease control rate (DCR) of lymphoma responses consistent with Lugano Classification

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End point title

Disease control rate (DCR) of lymphoma responses consistent with Lugano Classification

End point description

End point type

Secondary

End point timeframe

0 day as no subject was evaluated as per Lugano Classification

Part A - 5mg BID

Part A - 10mg BID

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID Non-MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Gynecological

Part B - Breast

Part B - ATM loss

Number of subjects analysed

0 ^[60]

0 ^[61]

0 ^[62]

0 ^[63]

0 ^[64]

0 ^[65]

0 ^[66]

0 ^[67]

0 ^[68]

0 ^[69]

0 ^[70]

0 ^[71]

0 ^[72]

0 ^[73]

0 ^[74]

0 ^[75]

0 ^[76]

Units: Percentage

number (confidence interval 95%)

( to )

Notes
[60] - No evaluable subject
[61] - No evaluable subject
[62] - No evaluable subject
[63] - No evaluable subject
[64] - No evaluable subject
[65] - No evaluable subject
[66] - No evaluable subject
[67] - No evaluable subject
[68] - No evaluable subject
[69] - No evaluable subject
[70] - No evaluable subject
[71] - No evaluable subject
[72] - No evaluable subject
[73] - No evaluable subject
[74] - No evaluable subject
[75] - No evaluable subject
[76] - No evaluable subject

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

After first administration of study drug up to 30 days after the last dose of study drug. Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Part A - 5mg BID

Reporting group description

Subjects received elimusertib 5 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 10mg BID

Reporting group description

Description: Subjects received elimusertib 10 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part B - Gynecological

Reporting group description

Description: Subjects with gynecological cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part A - 20mg BID Pooled

Reporting group description

Description: Subjects received elimusertib 20 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 40mg BID MTD

Reporting group description

Description: Subjects received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 40mg BID non MTD

Reporting group description

Description: Subjects, who were not included in the maximum tolerated dose (MTD) analysis, received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 60mg BID

Reporting group description

Description: Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A - 60mg BID 2w/1w

Reporting group description

Description: Subjects received elimusertib 60 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with 2 weeks on/1 week off in Part A of the study.

Reporting group title

Part A - 80mg BID

Reporting group description

Description: Subjects received elimusertib 80 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part A of the study.

Reporting group title

Part A.1 - 60mg BID 3d/11d

Reporting group description

Description: Subjects received elimusertib 60 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 80mg BID 3d/11d

Reporting group description

Description: Subjects received elimusertib 80 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 100mg BID 3d/11d

Reporting group description

Description: Subjects received elimusertib 100 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part A.1 - 120mg BID 3d/11d

Reporting group description

Description: Subjects received elimusertib 120 mg BID in a 3 days on/11 days off schedule in a 28-day cycle with no break between cycles in Part A.1 of the study.

Reporting group title

Part B - Prostate

Reporting group description

Description: Subjects with prostate cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Colorectal

Reporting group description

Description: Subjects with colorectal cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - Breast

Reporting group description

Description: Subjects with breast cancer received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Reporting group title

Part B - ATM loss

Reporting group description

Description: Subjects with ATM loss regardless of cancer type received elimusertib 40 mg BID for 3 days on/4 days off in a weekly schedule in a 21-day cycle with no break between cycles in Part B of the study.

Part A - 5mg BID

Part A - 10mg BID

Part B - Gynecological

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID non MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Breast

Part B - ATM loss

Total subjects affected by serious adverse events

subjects affected / exposed

0 / 1 (0.00%)

1 / 2 (50.00%)

21 / 45 (46.67%)

1 / 6 (16.67%)

7 / 24 (29.17%)

5 / 8 (62.50%)

2 / 4 (50.00%)

2 / 3 (66.67%)

3 / 6 (50.00%)

4 / 11 (36.36%)

3 / 6 (50.00%)

5 / 9 (55.56%)

4 / 19 (21.05%)

14 / 24 (58.33%)

5 / 19 (26.32%)

14 / 36 (38.89%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

Neoplasm

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

1 / 19 (5.26%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tumour pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

1 / 19 (5.26%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Vascular disorders

Hypotension

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

1 / 19 (5.26%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Jugular vein thrombosis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Orthostatic hypotension

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (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 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Multiple organ dysfunction syndrome

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (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

General physical health deterioration

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

3 / 24 (12.50%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 3

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

Pyrexia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

1 / 24 (4.17%)

2 / 8 (25.00%)

0 / 4 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

1 / 19 (5.26%)

1 / 24 (4.17%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Fatigue

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (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, thoracic and mediastinal disorders

Cough

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

1 / 19 (5.26%)

2 / 36 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 3

deaths causally related to treatment / all

0 / 0

Pleural disorder

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemoptysis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

1 / 19 (5.26%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

1 / 6 (16.67%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

1 / 19 (5.26%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Wheezing

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

1 / 19 (5.26%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Delirium

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mental status changes

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Liver function test abnormal

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Alanine aminotransferase increased

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Humerus fracture

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Femur fracture

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Medication error

subjects affected / exposed

0 / 1 (0.00%)

1 / 2 (50.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Subdural haematoma

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

Cardiac disorders

Bradycardia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

1 / 19 (5.26%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac failure

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Hypoaesthesia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

1 / 4 (25.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (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

Syncope

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Spinal cord compression

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

1 / 19 (5.26%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Somnolence

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

1 / 6 (16.67%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (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 / 1 (0.00%)

0 / 2 (0.00%)

5 / 45 (11.11%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

2 / 24 (8.33%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

4 / 5

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

3 / 45 (6.67%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

4 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Febrile neutropenia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

0 / 24 (0.00%)

1 / 19 (5.26%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Vision blurred

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (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 / 1 (0.00%)

0 / 2 (0.00%)

2 / 45 (4.44%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

5 / 45 (11.11%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

2 / 24 (8.33%)

1 / 19 (5.26%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 7

0 / 0

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal distension

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

2 / 45 (4.44%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Duodenitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (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

Ileus

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

2 / 24 (8.33%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

1 / 6 (16.67%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

2 / 36 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

2 / 36 (5.56%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 2

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Intestinal perforation

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal obstruction

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

2 / 45 (4.44%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Small intestinal obstruction

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

3 / 45 (6.67%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Enterovesical fistula

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

1 / 6 (16.67%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Small intestinal haemorrhage

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

3 / 45 (6.67%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

2 / 36 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Hyperbilirubinaemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypertransaminasaemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Rash

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (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

Renal impairment

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

2 / 45 (4.44%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Acute kidney injury

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

1 / 6 (16.67%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 1 (0.00%)

1 / 2 (50.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

3 / 24 (12.50%)

0 / 19 (0.00%)

2 / 36 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 5

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Bone pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

1 / 19 (5.26%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Flank pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Groin pain

subjects affected / exposed

0 / 1 (0.00%)

1 / 2 (50.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain in extremity

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Infections and infestations

Herpes zoster

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enterococcal bacteraemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cystitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Sinusitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (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 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

2 / 36 (5.56%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Peritonitis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

1 / 36 (2.78%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Wound infection

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urosepsis

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Groin abscess

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection bacterial

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 11 (9.09%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Device related bacteraemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Soft tissue infection

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

1 / 24 (4.17%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Hypoalbuminaemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

1 / 45 (2.22%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

1 / 4 (25.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (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

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

Part A - 5mg BID

Part A - 10mg BID

Part B - Gynecological

Part A - 20mg BID Pooled

Part A - 40mg BID MTD

Part A - 40mg BID non MTD

Part A - 60mg BID

Part A - 60mg BID 2w/1w

Part A - 80mg BID

Part A.1 - 60mg BID 3d/11d

Part A.1 - 80mg BID 3d/11d

Part A.1 - 100mg BID 3d/11d

Part A.1 - 120mg BID 3d/11d

Part B - Prostate

Part B - Colorectal

Part B - Breast

Part B - ATM loss

Total subjects affected by non serious adverse events

subjects affected / exposed

1 / 1 (100.00%)

2 / 2 (100.00%)

45 / 45 (100.00%)

6 / 6 (100.00%)

24 / 24 (100.00%)

8 / 8 (100.00%)

4 / 4 (100.00%)

3 / 3 (100.00%)

6 / 6 (100.00%)

10 / 11 (90.91%)

6 / 6 (100.00%)

9 / 9 (100.00%)

19 / 19 (100.00%)

23 / 24 (95.83%)

19 / 19 (100.00%)

35 / 36 (97.22%)

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

Tumour pain

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

1 / 8 (12.50%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

1 / 19 (5.26%)

0 / 24 (0.00%)

0 / 19 (0.00%)

2 / 36 (5.56%)

occurrences all number

Skin papilloma

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

0 / 24 (0.00%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

1 / 9 (11.11%)

0 / 19 (0.00%)

0 / 24 (0.00%)

0 / 19 (0.00%)

0 / 36 (0.00%)

occurrences all number

Vascular disorders

Hypertension

subjects affected / exposed

0 / 1 (0.00%)

0 / 2 (0.00%)

0 / 45 (0.00%)

0 / 6 (0.00%)

1 / 24 (4.17%)

0 / 8 (0.00%)

0 / 4 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 11 (0.00%)

0 / 6 (0.00%)

0 / 9 (0.00%)

1 / 19 (5.26%)

1 / 24 (4.17%)

1 / 19 (5.26%)

4 / 36 (11.11%)

occurrences all number

Lymphoedema

subjects affected / exposed

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Clinical trials

Clinical Trial Results: An open-label, first-in-human, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and maximum tolerated dose and / or recommended Phase II dose of the ATR inhibitor BAY 1895344 in patients with advanced solid tumors and lymphomas.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with dose-limiting toxicities (DLTs) during Cycle 1 in dose escalation cohorts

Primary: Number of subjects with dose-limiting toxicities (DLTs) during Cycle 1 in dose escalation cohorts

Primary: Maximum tolerated dose (MTD)

Primary: Maximum tolerated dose (MTD)

Primary: Number of subjects with treatment-emergent adverse events

Primary: Number of subjects with treatment-emergent adverse events

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=3 or higher)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=3 or higher)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=2)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=2)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=1)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]) after single-dose administration (n=1)

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=3 or higher)

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=3 or higher)

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=2)

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=2)

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=1)

Primary: Maximum observed drug concentration in plasma after single-dose administration (Cmax) (n=1)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=3 or higher)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=3 or higher)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=2)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=2)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=1)

Primary: Area under the plasma concentration versus time curve from 0 to 12 hours (AUC[0-12]md) after multiple-dose administrations (n=1)

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=3 or higher)

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=3 or higher)

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=1)

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=1)

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=2)

Primary: Maximum observed drug concentration in plasma after multiple-dose administrations (Cmax,md) (n=2)

Secondary: Objective response rate (ORR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

Secondary: Objective response rate (ORR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

Secondary: Objective response rate (ORR) of CRPC tumor responses consistent with the recommendations of PCWG3

Secondary: Objective response rate (ORR) of CRPC tumor responses consistent with the recommendations of PCWG3

Secondary: Objective response rate (ORR) of lymphoma responses consistent with Lugano Classification

Secondary: Objective response rate (ORR) of lymphoma responses consistent with Lugano Classification

Secondary: Disease control rate (DCR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

Secondary: Disease control rate (DCR) of solid tumor responses (except CRPC) consistent with the RECIST 1.1

Secondary: Disease control rate (DCR) of CRPC tumor responses consistent with the recommendations of PCWG3

Secondary: Disease control rate (DCR) of CRPC tumor responses consistent with the recommendations of PCWG3

Secondary: Disease control rate (DCR) of lymphoma responses consistent with Lugano Classification

Secondary: Disease control rate (DCR) of lymphoma responses consistent with Lugano Classification

Adverse events

Clinical Trial Results:
An open-label, first-in-human, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and maximum tolerated dose and / or recommended Phase II dose of the ATR inhibitor BAY 1895344 in patients with advanced solid tumors and lymphomas.