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Clinical Trial Results:
A Phase 1b/2 Study to Evaluate Safety and Anti-Tumor Activity of Avelumab in Combination With the Poly (Adenosine Diphosphate [ADP]-Ribose)

Summary
EudraCT number	2017-001509-33
Trial protocol	BE HU DK GB
Global end of trial date	04 Jan 2023

Results information
Results version number	v1(current)
This version publication date	14 Sep 2023
First version publication date	14 Sep 2023
Other versions

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

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Trial information

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Sponsor protocol code

B9991025

ISRCTN number

US NCT number

NCT03330405

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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

22 Jun 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Jan 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

To assess the dose limiting toxicity (DLT) rate of avelumab in combination with talazoparib in subjects with locally advanced or metastatic solid tumors in order to select the recommended Phase 2 dose (RP2D) of talazoparib for the combination, and to assess objective response rate (ORR) of avelumab in combination with talazoparib, as assessed by the investigator, per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) in subjects with locally advanced or metastatic solid tumors and per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) in subjects with metastatic castration resistant prostate cancer (mCRPC).

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

19 Oct 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

62 Months

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 10

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

Denmark: 11

Country: Number of subjects enrolled

Hungary: 9

Country: Number of subjects enrolled

Korea, Republic of: 10

Country: Number of subjects enrolled

Russian Federation: 43

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

United States: 117

Worldwide total number of subjects

223

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)

108

From 65 to 84 years

112

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 2 phases: Phase 1b (talazoparib dose level cohorts) and Phase 2 (expansion phase). Phase 2 was conducted at the highest dose level of talazoparib which was determined safe for subjects in Phase 1b.

Screening details

Phase 1b: 12 subjects were enrolled and assigned to study treatment. Phase 2: 211 subjects were enrolled and assigned to study treatment.

Period 1 title

Overall Study (Treatment Phase) (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD

Arm description

Subjects with locally advanced or metastatic solid tumors were treated with talazoparib 1.0 mg orally once daily (QD) in combination with avelumab 800 mg intravenously (IV) every 2 weeks (Q2W) for a maximum of 246.3 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Phase 2: Cohort A1 (NSCLC)

Arm description

Subjects with locally advanced (primary or recurrent) or metastatic non-small cell lung cancer (NSCLC) were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 183.6 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort A2 (NSCLC DDR+)

Arm description

Subjects with locally advanced (primary or recurrent) or metastatic NSCLC with DNA damage repair positive (DDR+) were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 173.0 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort B1 (TNBC)

Arm description

Subjects with locally advanced (primary or recurrent) or triple-negative breast cancer (TNBC) were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 93.0 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort B2 (BC HR+ HER2- DDR+)

Arm description

Subjects with locally advanced (primary or recurrent) or metastatic hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) with DDR+ were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 180.0 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort C1 (OVC)

Arm description

Subjects with locally advanced (primary or recurrent) or metastatic ovarian cancer (OVC) were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 161.1 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort C2 (OVC BRCA-mutated)

Arm description

Subjects with locally advanced (primary or recurrent) or metastatic OVC with germline or somatic BRCA1 or BRCA2 gene defect were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 144.0 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort D (UC)

Arm description

Subjects with locally advanced (primary or recurrent) or metastatic urothelial cancer (UC) were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 164.0 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort E1 (mCRPC)

Arm description

Subjects with metastatic castration-resistant prostate cancer (mCRPC) were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 54.1 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort E2 (mCRPC DDR+)

Arm description

Subjects with mCRPC with DDR+ were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 74.0 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Phase 2: Cohort F (BRCA/ATM-mutated)

Arm description

Subjects with locally advanced (primary or recurrent) or metastatic solid tumors, independent of tissue of origin, with previously identified pathogenic, or likely pathogenic, germline or somatic defects in BRCA1, BRCA2, or ATM genes were treated with talazoparib 1 mg QD orally in combination with avelumab 800 mg IV Q2W for a maximum of 49.9 weeks. Safety follow-up was for 90 days after last dose of study treatment or until time of initiation of new anticancer treatment, whichever comes first.

Arm type

Experimental

Investigational medicinal product name

Talazoparib 1 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received talazoparib 1 mg orally QD.

Investigational medicinal product name

Avelumab 800 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects received avelumab 800 mg as an IV infusion over 1 hour every 2 weeks on Day 1 and Day 15 of each 28-day cycle.

Number of subjects in period 1	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Started	12	42	5	22	23	20	11	40	21	18	9
Completed	0	0	0	0	0	0	0	0	0	0	0
Not completed	12	42	5	22	23	20	11	40	21	18	9
Consent withdrawn by subject	1	4	-	1	1	1	-	2	2	1	1
Physician decision	-	-	-	-	-	-	-	1	-	-	-
Global deterioration of health status	2	3	-	2	3	3	-	2	8	4	1
Adverse event, non-fatal	-	1	-	1	1	1	3	4	2	2	2
Death	-	4	-	-	-	1	-	2	-	-	-
Unspecified	1	3	1	-	2	-	1	-	-	-	-
Progressive disease	8	27	4	18	16	14	7	29	9	11	5

Baseline characteristics

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Reporting group title

Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD

Reporting group description

Reporting group title

Phase 2: Cohort A1 (NSCLC)

Reporting group description

Reporting group title

Phase 2: Cohort A2 (NSCLC DDR+)

Reporting group description

Reporting group title

Phase 2: Cohort B1 (TNBC)

Reporting group description

Reporting group title

Phase 2: Cohort B2 (BC HR+ HER2- DDR+)

Reporting group description

Reporting group title

Phase 2: Cohort C1 (OVC)

Reporting group description

Reporting group title

Phase 2: Cohort C2 (OVC BRCA-mutated)

Reporting group description

Reporting group title

Phase 2: Cohort D (UC)

Reporting group description

Reporting group title

Phase 2: Cohort E1 (mCRPC)

Reporting group description

Reporting group title

Phase 2: Cohort E2 (mCRPC DDR+)

Reporting group description

Reporting group title

Phase 2: Cohort F (BRCA/ATM-mutated)

Reporting group description

Reporting group values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)	Total
Number of subjects	12	42	5	22	23	20	11	40	21	18	9	223
Age Categorical
Units: Subjects
<65 years	6	15	4	15	17	12	7	16	8	3	5	108
65 - <75 years	5	19	1	6	3	5	3	16	12	8	2	80
75 - <85 years	1	7	0	1	3	3	1	7	1	6	2	32
>= 85 years	0	1	0	0	0	0	0	1	0	1	0	3
Age Continuous
The reporting group of "Phase 2: All Cohorts Combined" was a combination of all Phase 2 subjects. No analysis of this combined group was planned, therefore "0" was added.
Units: years
arithmetic mean (standard deviation)	62.67 ( 9.49 )	67.00 ( 9.37 )	59.60 ( 7.40 )	56.18 ( 12.49 )	53.83 ( 14.08 )	62.65 ( 10.66 )	61.36 ( 9.24 )	65.73 ( 9.19 )	63.71 ( 7.40 )	71.56 ( 7.37 )	63.00 ( 10.91 )	-
Sex: Female, Male
Units: Subjects
Female	3	9	2	22	22	20	11	14	0	0	3	106
Male	9	33	3	0	1	0	0	26	21	18	6	117
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0	1	0	0	2	3	1	0	7
Not Hispanic or Latino	12	39	5	19	21	18	11	38	11	16	8	198
Not reported	0	3	0	3	1	2	0	0	7	1	1	18
Race/Ethnicity, Customized
Units: Subjects
Black or African American	3	1	0	0	0	0	2	1	5	2	0	14
American Indian or Alaska Native	0	0	0	0	1	0	0	0	0	0	0	1
Asian	0	5	0	1	1	0	3	2	1	2	0	15
Native Hawaiian or Other Pacific Islander	0	0	1	0	0	0	0	0	0	0	0	1
White	9	34	4	20	17	18	6	36	12	14	9	179
Not reported	0	2	0	1	4	2	0	1	3	0	0	13
Geographic Region
Units: Subjects
North America	12	9	3	14	15	10	7	15	20	11	8	124
Western Europe	0	10	2	0	1	2	1	5	1	4	1	27
Eastern Europe	0	19	0	6	4	5	1	16	0	1	0	52
Australasia	0	0	0	2	2	3	0	2	0	1	0	10
Asia	0	4	0	0	1	0	2	2	0	1	0	10
ECOG Performance Status
ECOG=Eastern Cooperative Oncology Group. Score 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light house work or office work.
Units: Subjects
ECOG Score = 0	4	5	1	12	12	9	8	16	4	6	1	78
ECOG Score = 1	8	37	4	10	11	11	3	24	17	12	8	145

End points

Top of page

Reporting group title

Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD

Reporting group description

Reporting group title

Phase 2: Cohort A1 (NSCLC)

Reporting group description

Reporting group title

Phase 2: Cohort A2 (NSCLC DDR+)

Reporting group description

Reporting group title

Phase 2: Cohort B1 (TNBC)

Reporting group description

Reporting group title

Phase 2: Cohort B2 (BC HR+ HER2- DDR+)

Reporting group description

Reporting group title

Phase 2: Cohort C1 (OVC)

Reporting group description

Reporting group title

Phase 2: Cohort C2 (OVC BRCA-mutated)

Reporting group description

Reporting group title

Phase 2: Cohort D (UC)

Reporting group description

Reporting group title

Phase 2: Cohort E1 (mCRPC)

Reporting group description

Reporting group title

Phase 2: Cohort E2 (mCRPC DDR+)

Reporting group description

Reporting group title

Phase 2: Cohort F (BRCA/ATM-mutated)

Reporting group description

Subject analysis set title

Avelumab PK Concentration Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects from Phaise 1b and Phase 2 combined (excluding site 1055). Treatment = Avelumab 800 mg IV Infusion Q2W coadministered with Talazoparib 1 mg QD. This analysis set is for PK analysis only, and not applicable for baseline characteristics.

Subject analysis set title

Talazoparib PK Concentration Analysis Set (1 mg QD)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects from Phase 1b and Phase 2 combined (excluding site 1055). Treatment = Avelumab 800 mg IV Infusion Q2W coadministered with Talazoparib 1 mg QD (subjects with normal renal function or mild renal impairment). This analysis set is for PK analysis only, and not applicable for baseline characteristics.

Subject analysis set title

Talazoparib PK Concentration Analysis Set (0.75 mg QD)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects from Phase 1b and Phase 2 combined (excluding site 1055). Treatment = Avelumab 800 mg IV Infusion Q2W coadministered with Talazoparib 0.75 mg QD (subjects with moderate renal impairment). This analysis set is for PK analysis only, and not applicable for baseline characteristics.

Subject analysis set title

Phase 2 All Cohorts Combined

Subject analysis set type

Sub-group analysis

Subject analysis set description

All subjects from Cohort A to Cohort F combined. Not applicable for baseline characteristics.

Primary: Phase 1b: Number of Subjects with Dose Limiting Toxicities (DLTs)

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End point title

Phase 1b: Number of Subjects with Dose Limiting Toxicities (DLTs) ^[1] ^[2]

End point description

DLTs=any of the following adverse events (AEs) due to any study treatment in Cycle 1:Hematologic: grade(G)4 neutropenia >5 days (absolute neutrophil count [ANC]<0.5*10^9/L);febrile neutropenia;neutropenic infection (ANC<1.0*10^9/L and G>3 infection); G>=3 thrombocytopenia (platelet count [PC] <50.0*10^9/L) with bleeding; G4 thrombocytopenia (PC<25.0*10^9/L); G4 anemia (life-threatening;urgent intervention indicated). Non-hematologic: G>=3 toxicities unless predefined in the protocol; potential Hy’s law cases. Non-adherence to treatment schedule: failure to deliver >=75% of the planned doses of talazoparib during Cycle 1 due to treatment-related toxicities;G3 non-hematologic toxicity that delayed either study drug for >=2 weeks. Dose reductions: any AE resulting in talazoparib dose reduction. The DLT analysis set included all eligible enrolled subjects in Phase 1b with >=1 dose of the combination who experienced DLT in Cycle 1 or completed the DLT observation period for Cycle 1.

End point type

Primary

End point timeframe

Cycle 1; 28 days

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned for this end point.
[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 endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD
Number of subjects analysed	12
Units: Subjects	3

No statistical analyses for this end point

Primary: Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment

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End point title

Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment ^[3] ^[4]

End point description

This outcome measure (OM) is reported for subjects with solid tumors except mCRPC; for those subjects, OR was defined as a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors (RECIST) version(v) 1.1 by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis <10 mm); all lesions must be assessed. PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-progressive disease (PD), where PD is unequivocal progression of pre-existing lesions. The full analysis set (FAS) included all enrolled subjects who received >=1 dose of study treatment. Data for this OM was not planned to be collected and analyzed for Phase 1b arm. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Primary

End point timeframe

From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)

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: No statistical analyses were planned for this end point.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	42	5	22	23	20	11	40	7
Units: Percentage of Subjects
number (confidence interval 95%)	16.7 (7.0 to 31.4)	20.0 (0.5 to 71.6)	18.2 (5.2 to 40.3)	34.8 (16.4 to 57.3)	20.0 (5.7 to 43.7)	63.6 (30.8 to 89.1)	15.0 (5.7 to 29.8)	0 (0.0 to 41.0)

No statistical analyses for this end point

Primary: Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) by Investigator Assessment

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End point title

Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) by Investigator Assessment ^[5] ^[6]

End point description

This OM is reported for subjects with mCRPC; for those subjects, OR was defined as the proportion of subjects with a best overall soft tissue response of CR or PR per RECIST v1.1 and with no evidence of confirmed bone disease progression per PCWG3 criteria by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis <10 mm); all lesions must be assessed. PR: >=30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-PD. The full analysis set (FAS) included all enrolled subjects who received >=1 dose of study treatment. Data for this OM was not planned to be collected and analyzed for Phase 1b arm. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Primary

End point timeframe

From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)

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: No statistical analyses were planned for this end point.
[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: The endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	21	18	2
Units: Percentage of Subjects
number (confidence interval 95%)	0 (0.0 to 16.1)	11.1 (1.4 to 34.7)	50.0 (1.3 to 98.7)

No statistical analyses for this end point

Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number of Subjects with Treatment-Emergent Adverse Events (TEAEs) ^[7]

End point description

Adverse event (AE) was any untoward medical occurrence in a subject who received any study drug without regard to possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs). The safety analysis set included all enrolled subjects who received >=1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
Subjects with all-causality TEAEs	12	207
Subjects with treatment-related TEAEs	11	197

No statistical analyses for this end point

Secondary: Number of Subjects with Serious TEAEs

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End point title

Number of Subjects with Serious TEAEs ^[8]

End point description

TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs). A serious TEAE was any untoward medical occurrence that at any dose resulted in any of following outcomes/considered to be an important medical event: death;life-threatening experience (immediate risk of death);required inpatient hospitalization or prolongation of existing hospitalization;persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions);congenital anomaly/birth defect. The safety analysis set included all enrolled subjects who received >=1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
Subjects with all-causality serious TEAEs	1	75
Subjects with treatment-related serious TEAEs	1	25

No statistical analyses for this end point

Secondary: Number of Subjects with TEAEs Leading to Discontinuation of Either Study Drug

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End point title

Number of Subjects with TEAEs Leading to Discontinuation of Either Study Drug ^[9]

End point description

Either study drug = avelumab only or talazoparib only. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related (TR) AEs were those related to any study drug (ie, at least one of the study drugs). AC=all-causality. No.=Number of subjects. d/c=discontinuation. The safety analysis set included all enrolled subjects who received at least 1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
No. with AC TEAEs leading to d/c of avelumab	0	5
No. with TR TEAEs leading to d/c of avelumab	0	4
No. with AC TEAEs leading to d/c of talazoparib	1	9
No. with TR TEAEs leading to d/c of talazoparib	1	8

No statistical analyses for this end point

Secondary: Number of Subjects with Grade >=3 TEAEs

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End point title

Number of Subjects with Grade >=3 TEAEs ^[10]

End point description

AE was any untoward medical occurrence in a subject who received any study drug regardless of possibility of causal relationship. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. TEAEs were graded by the investigator using National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) v4.03 as Grade(G) 1=mild; G2 =moderate; G3=severe; G4=life-threatening; G5=death. In this outcome measure, number of subjects with G3 or higher TEAEs were reported. Treatment-related AEs were those related to any study drug (ie, at least one of the study drugs). The safety analysis set included all enrolled subjects who received >=1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[10] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
Subjects with all-causality Grade >=3 TEAEs	9	156
Subjects with treatment-related Grade >=3 TEAEs	9	120

No statistical analyses for this end point

Secondary: Number of Subjects with TEAEs Leading to Death

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End point title

Number of Subjects with TEAEs Leading to Death ^[11]

End point description

TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. No.=Number of subjects. Either study drug = avelumab only or talazoparib only. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related (TR) AEs were those related to any study drug (ie, at least one of the study drugs). AC=all-causality. No.=Number of subjects. d/c=discontinuation. The safety analysis set included all enrolled subjects who received at least 1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[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: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
No. with all-causality TEAEs leading to death	0	21
No. with treatment-related TEAEs leading to death	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with TEAEs Leading to Discontinuation of All Study Drugs

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End point title

Number of Subjects with TEAEs Leading to Discontinuation of All Study Drugs ^[12]

End point description

All study drugs = all study drugs in the combination. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. Treatment-related (TR) AEs were those related to any study drug (ie, at least one of the study drugs). AC=all-causality. No.=Number of subjects. d/c=discontinuation. Either study drug = avelumab only or talazoparib only. The safety analysis set included all enrolled subjects who received at least 1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
No.with AC TEAEs leading to d/c of all study drugs	1	20
No.with TR TEAEs leading to d/c of all study drugs	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=3 During the On-Treatment Period

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End point title

Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=3 During the On-Treatment Period ^[13]

End point description

The number of subjects with newly occurring or worsening hematology abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. N=x, y in the following table represents the number of evaluable subjects in the reporting groups of Phase 1b and Phase 2. APTT=Activated partial thromboplastin time. The safety analysis set included all enrolled subjects who received at least 1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
APTT prolonged (N=11, 143)	0	1
Anemia (N=12, 208)	4	78
Lymphocyte count decreased (N=12, 208)	4	44
Neutrophil count decreased (N=12, 208)	5	27
Platelet count decreased (N=12, 208)	4	47
White blood cell decreased (N=12, 208)	3	20

No statistical analyses for this end point

Secondary: Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=1 During the On-Treatment Period

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End point title

Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=1 During the On-Treatment Period ^[14]

End point description

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
APTT prolonged (N=11, 143)	4	21
Anemia (N=12, 208)	8	161
Hemoglobin increased (N=12, 208)	0	1
Lymphocyte count decreased (N=12, 208)	9	145
Lymphocyte count increased (N=12, 208)	1	3
Neutrophil count decreased (N=12, 208)	8	100
Platelet count decreased (N=12, 208)	6	141
White blood cell decreased (N=12, 208)	10	139

No statistical analyses for this end point

Secondary: Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=1 During the On-Treatment Period

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End point title

Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=1 During the On-Treatment Period ^[15]

End point description

The number of subjects with newly occurring or worsening chemistry abnormalities during the on-treatment period were summarized by worst grade on-treatment. On-treatment period was defined as time from first dose of any study treatment and up to 30 days after last dose or start day of new anti-cancer drug therapy minus 1 day, whichever occurred first. NCI-CTCAE criteria version 4.03 is used. As per NCI CTCAE toxicity grading v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death. N=x, y in the following table represents the number of evaluable subjects in the reporting groups of Phase 1b and Phase 2. CPK=Creatinine phosphokinase. GGT=Gamma-glutamyl transferase. The safety analysis set included all enrolled subjects who received at least 1 dose of study drug. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
Alanine aminotransferase increased (N=12, 208)	1	41
Alkaline phosphatase increased (N=12, 208)	3	74
Aspartate aminotransferase increased (N=12, 208)	2	53
Blood bilirubin increased (N=12, 208)	0	24
CPK increased (N=12, 206)	2	37
Creatinine increased (N=12, 208)	9	147
GGT increased (N=12, 206)	2	69
Hypercalcemia (N=12, 208)	1	23
Hyperglycemia (N=12, 208)	0	48
Hyperkalemia (N=12, 208)	2	25
Hypermagnesemia (N=12, 207)	0	21
Hypernatremia (N=12, 208)	0	9
Hypoalbuminemia (N=12, 208)	2	60
Hypocalcemia (N=12, 208)	1	45
Hypoglycemia (N=12, 208)	0	13
Hypokalemia (N=12, 208)	3	36
Hypomagnesemia (N=12, 207)	2	33
Hyponatremia (N=12, 208)	4	66
Hypophosphatemia (N=12, 206)	2	43
Lipase increased (N=12, 207)	4	36
Serum amylase increased (N=12, 207)	2	32

No statistical analyses for this end point

Secondary: Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=3 During the On-Treatment Period

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End point title

Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=3 During the On-Treatment Period ^[16]

End point description

End point type

Secondary

End point timeframe

From start of the treatment up to 30 days after last dose or start of new anticancer therapy minus 1 day, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[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: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
Alanine aminotransferase increased (N=12, 208)	0	2
Alkaline phosphatase increased (N=12, 208)	0	7
Aspartate aminotransferase increased (N=12, 208)	0	2
Blood bilirubin increased (N=12, 208)	0	3
CPK increased (N=12, 206)	0	4
Creatinine increased (N=12, 208)	0	2
GGT increased (N=12, 206)	0	11
Hyperglycemia (N=12, 208)	0	6
Hyperkalemia (N=12, 208)	0	1
Hypermagnesemia (N=12, 207)	0	5
Hypoalbuminemia (N=12, 208)	0	2
Hypocalcemia (N=12, 208)	0	4
Hypokalemia (N=12, 208)	0	1
Hyponatremia (N=12, 208)	0	12
Hypophosphatemia (N=12, 206)	1	6
Lipase increased (N=12, 207)	0	14
Serum amylase increased (N=12, 207)	0	7

No statistical analyses for this end point

Secondary: Trough concentrations (Ctrough)/Predose and maximum concentrations (Cmax) of Serum Avelumab Concentrations (μg/mL) by Visit (Excluding Site 1055)

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End point title

Trough concentrations (Ctrough)/Predose and maximum concentrations (Cmax) of Serum Avelumab Concentrations (μg/mL) by Visit (Excluding Site 1055)

End point description

Pharmacokinetics (PK) data analyses included descriptive summary statistics of the pre-dose/Ctrough concentrations for both investigational products and post-dose (for talazoparib) or Cmax concentrations (for avelumab) for each cycle. N=x represents the number of evaluable subjects in each analysis set. "99999"=not available/applicable; for Cycle 1 Day 1, the result was not available as no observations were above the avelumab lower limit of quantitation (LLQ) of 0.2 μg/mL; for Cycle 24 results, only 1 subject was evaluable for the timepoints, so coefficient of variation is not applicable. The PK concentration analysis sets (1 unique set for each study drug used in the combination) were subsets of the safety analysis set including subjects who had >= 1 post-dose concentration measurement above the LLQ for avelumab or talazoparib. Cohorts were combined as pre-specified in reporting and analysis plan. Site 1055 was excluded as samples were not meeting the protocol requirements.

End point type

Secondary

End point timeframe

Predose/0 Hour (H) and 1 H on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2-4, and additionally on Day 1 of Cycles 6, 9, 12, 18, and 24

End point values	Avelumab PK Concentration Analysis Set
Number of subjects analysed	194
Units: μg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 / Day 1 (0 Hour [H]) (N=194)	99999 ( 99999 )
Cycle 1 / Day 1 (1 H) (N=178)	221.0 ( 41 )
Cycle 1 / Day 15 (0 H) (N=183)	21.20 ( 72 )
Cycle 1 / Day 15 (1 H) (N=164)	206.6 ( 86 )
Cycle 2 / Day 1 (0 H) (N=168)	26.41 ( 68 )
Cycle 2 / Day 1 (1 H) (N=156)	199.6 ( 110 )
Cycle 3 / Day 1 (0 H) (N=120)	31.45 ( 80 )
Cycle 3 / Day 1 (1 H) (N=126)	188.8 ( 105 )
Cycle 4 / Day 1 (0 H) (N=106)	34.59 ( 81 )
Cycle 4 / Day 1 (1 H) (N=114)	190.6 ( 99 )
Cycle 6 / Day 1 (0 H) (N=78)	37.40 ( 73 )
Cycle 6 / Day 1 (1 H) (N=81)	185.9 ( 98 )
Cycle 9 / Day 1 (0 H) (N=40)	39.97 ( 91 )
Cycle 9 / Day 1 (1 H) (N=44)	171.1 ( 145 )
Cycle 12 / Day 1 (0 H) (N=18)	47.10 ( 63 )
Cycle 12 / Day 1 (1 H) (N=18)	202.9 ( 88 )
Cycle 18 / Day 1 (0 H) (N=3)	53.94 ( 33 )
Cycle 18 / Day 1 (1 H) (N=3)	135.6 ( 354 )
Cycle 24 / Day 1 (0 H) (N=1)	76.40 ( 99999 )
Cycle 24 / Day 1 (1 H) (N=1)	378.0 ( 99999 )

No statistical analyses for this end point

Secondary: Predose and Postdose Plasma Talazoparib Concentrations (pg/mL) by Visit (Excluding Site 1055)

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End point title

Predose and Postdose Plasma Talazoparib Concentrations (pg/mL) by Visit (Excluding Site 1055)

End point description

PK data analyses included descriptive summary statistics of the pre-dose/Ctrough concentrations for both investigational products and post-dose (for talazoparib) or Cmax concentrations (for avelumab) for each cycle.Cmax/Ctrough =maximum/trough concentration.Subjects with moderate renal impairment were started at a lower, 0.75 mg QD, dose to compensate for decreased talazoparib clearance. N=x, y represents the number of evaluable subjects in each analysis set. "99999"=not available/applicable;for Cycle 1 Day 1, the result was not available as no observations were above the avelumab LLQ of 25 pg/mL. The PK concentration analysis sets (1 unique set for each study drug in the combination) were subsets of the safety analysis set including subjects who had >=1 post-dose concentration measurement above the LLQ for avelumab or talazoparib. Cohorts were combined as pre-specified in reporting and analysis plan. Site 1055 was excluded as samples were not meeting the protocol requirements.

End point type

Secondary

End point timeframe

Pre-dose and post-dose (at the end of the avelumab infusion) on Days 1 and 15 of Cycle 1 and on Day 1 of Cycles 2-4.

End point values	Talazoparib PK Concentration Analysis Set (1 mg QD)	Talazoparib PK Concentration Analysis Set (0.75 mg QD)
Number of subjects analysed	163	31
Units: pg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 / Day 1 (Predose) (N=163, 31)	99999 ( 99999 )	99999 ( 99999 )
Cycle 1 / Day 1 (Postdose) (N=46, 12)	2295 ( 137 )	2015 ( 112 )
Cycle 1 / Day 15 (Predose) (N=72, 10)	4672 ( 63 )	4657 ( 47 )
Cycle 1 / Day 15 (Postdose) (N=33, 3)	9055 ( 88 )	8257 ( 11 )
Cycle 2 / Day 1 (Predose) (N=66, 10)	4385 ( 53 )	5871 ( 53 )
Cycle 2 / Day 1 (Postdose) (N=21, 5)	8479 ( 73 )	9834 ( 62 )
Cycle 3 / Day 1 (Predose) (N=47, 6)	4212 ( 46 )	3874 ( 48 )
Cycle 3 / Day 1 (Postdose) (N=22, 3)	6765 ( 239 )	1236 ( 8074 )
Cycle 4 / Day 1 (Predose) (N=22, 3)	4713 ( 38 )	3826 ( 73 )
Cycle 4 / Day 1 (Postdose) (N=29, 6)	6506 ( 76 )	6735 ( 70 )

No statistical analyses for this end point

Secondary: Number of Subjects With at Least 1 Valid Anti-drug Antibody (ADA) Result at: Any Time Point (N0), Baseline (N1), Baseline and Post-Baseline (N2), and Post-Baseline and Without Positive Baseline ADA Result (N3)

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End point title

Number of Subjects With at Least 1 Valid Anti-drug Antibody (ADA) Result at: Any Time Point (N0), Baseline (N1), Baseline and Post-Baseline (N2), and Post-Baseline and Without Positive Baseline ADA Result (N3) ^[17]

End point description

Immunogenicity blood samples were assayed for ADA using a validated assay. The sample analysis followed a tiered approach of screening, confirmation, and titer determination. Samples tested positive for ADA were further analyzed for neutralizing antibodies (Nab) using a validated assay. Baseline was defined as the last assessment prior to the date/time of the first dose of avelumab. N0, N1, N2, and N3=Number of subjects with at least 1 valid ADA result at any time point, baseline (pre-dose on Day 1), baseline and post-baseline, and post-baseline, respectively. The immunogenicity analysis set was a subset of the safety analysis set and included subjects who had at least 1 ADA/Nab sample collected for avelumab. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

Pre-dose (within 2 hours of talazoparib dose) on Day 1 and Day 15 of Cycle 1, on Day 1 of Cycle 2-4 and then on Day 1 of Cycles 6, 9, 12, 18, 24, and at the end of treatment (EOT)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
N0	12	211
N1	12	209
N2	11	202
N3	11	200

No statistical analyses for this end point

Secondary: Number of Subjects by ADA Categories

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End point title

Number of Subjects by ADA Categories ^[18]

End point description

Immunogenicity blood samples were assayed for ADA using a validated assay. The sample analysis followed a tiered approach of screening, confirmation, and titer determination. Samples tested positive for ADA were further analyzed for neutralizing antibodies (Nab) using a validated assay. Baseline was defined as the last assessment prior to the date/time of the first dose of avelumab. N0, N1, N2, and N3=Number of subjects with at least 1 valid ADA result at any time point, baseline (pre-dose on Day 1), baseline and post-baseline, and post-baseline, respectively. n=number of subjects in each category. The immunogenicity analysis set was a subset of the safety analysis set and included subjects who had at least 1 ADA/Nab sample collected for avelumab. Cohorts in Phase 2 were combined as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

Pre-dose (within 2 hours of talazoparib dose) on Day 1 and Day 15 of Cycles 1, on Day 1 of Cycle 2-4 and then on Day 1 of Cycles 6, 9, 12, 18, 24, and at the end of treatment (EOT)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Phase 2 All Cohorts Combined
Number of subjects analysed	12	211
Units: Subjects
ADA never-positive (n/N0)	12	205
ADA ever-positive (n/N0)	0	6
ADA ever-positive (n/N1)	0	4
ADA ever-positive (n/N2)	0	0
ADA ever-positive (n/N3)	0	2

No statistical analyses for this end point

Secondary: Phase 2: TTR in Subjects with Confirmed CR or PR

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End point title

Phase 2: TTR in Subjects with Confirmed CR or PR ^[19]

End point description

For subjects with solid tumors except mCRPC, TTR was defined for subjects with confirmed OR (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For subjects with mCRPC, TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a best overall response (BOR) of CR or PR as assessed by Investigator using RECIST v1.1. The full analysis set (FAS) included all enrolled participants who received at least 1 dose of study treatment. Data for this OM was planned for Phase 2 only. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

From the first dose of study treatment to the first documentation of objective tumor response/the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression (<= 5.2 years approximately)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	7	1	4	8	4	7	6	2	1
Units: Months
median (full range (min-max))	3.7 (1.7 to 11.3)	1.8 (1.8 to 1.8)	1.8 (1.6 to 2.0)	1.9 (1.6 to 3.6)	3.6 (1.7 to 17.9)	1.7 (1.6 to 3.7)	2.1 (1.4 to 5.9)	5.5 (5.4 to 5.6)	1.8 (1.8 to 1.8)

No statistical analyses for this end point

Secondary: Phase 1b: Time to Response (TTR) in Subjects with Confirmed CR or PR

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End point title

Phase 1b: Time to Response (TTR) in Subjects with Confirmed CR or PR ^[20]

End point description

For subjects with solid tumors except mCRPC, TTR was defined for subjects with confirmed OR (CR or PR) as the time from the first dose of study treatment to the first documentation of objective tumor response. For subjects with mCRPC, TTR was defined as the time from the first dose of study treatment to the first objective evidence of soft tissue response with no evidence of confirmed bone disease progression on bone scan per PCWG3. Soft tissue response was defined as a best overall response (BOR) of CR or PR as assessed by Investigator using RECIST v1.1. The FAS included all enrolled participants who received at least 1 dose of study treatment. Data for this OM was planned for Phase 1b arm only. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD
Number of subjects analysed	2
Units: Months
median (full range (min-max))	1.8 (1.8 to 1.8)

No statistical analyses for this end point

Secondary: Phase 1b: Percentage of Subjects With Confirmed OR as per RECIST v1.1 and PCWG3 by Investigator Assessment

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End point title

Phase 1b: Percentage of Subjects With Confirmed OR as per RECIST v1.1 and PCWG3 by Investigator Assessment ^[21]

End point description

This OM is reported for subjects in Phase 1b; OR was defined as the proportion of subjects with a best overall soft tissue response of CR or PR per RECIST v1.1 and with no evidence of confirmed bone disease progression per Prostate Cancer Working Group 3 (PCWG3) criteria by investigator. CR: Complete disappearance of all target and non-target lesions with the exception of nodal disease; all target and non-target nodes must decrease to normal size (short axis <10 mm); all lesions must be assessed. PR: Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions; all target lesions must be assessed. Non-target PR lesions must be non-PD. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was planned for Phase 1b arm only.

End point type

Secondary

End point timeframe

From start of the treatment until disease progression or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[21] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD
Number of subjects analysed	12
Units: Percentage of Subjects
number (confidence interval 95%)	16.7 (2.1 to 48.4)

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DR) in Subjects with Confirmed CR or PR

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End point title

Phase 2: Duration of Response (DR) in Subjects with Confirmed CR or PR ^[22]

End point description

For subjects with solid tumors except mCRPC, DR was defined for subjects with confirmed OR (CR or PR) as the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. "99999"=Not applicable: Median and 95% CI were not estimated for <10 subjects. The full analysis set (FAS) included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was planned for Phase 2 only. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure; Cohorts without evaluable subjects for this outcome measure [i.e., Phase 2: Cohort A2 (NSCLC DDR+), Phase 2: Cohort E1 (mCRPC), Phase 2: Cohort E2 (mCRPC DDR+), Phase 2: Cohort F (BRCA/ATM-mutated)] are not presented.

End point type

Secondary

End point timeframe

From the first objective tumor response/soft tissue response to the first objective tumor progression/subsequent objective evidence of radiographic progression or death due to any cause, whichever occurred first (<=5.2 years approximately)

Notes
[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: The endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)
Number of subjects analysed	7	1	4	8	4	7	6
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1 and PCWG3)

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End point title

Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1 and PCWG3) ^[23]

End point description

This OM was reported for subjects with mCRPC; for these subjects, PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue as assessed by Investigator using RECIST v1.1, in bone as assessed by Investigator using PCWG3, or death, whichever occurred first. "99999"= Upper limit of 95% CI was not reached due to fewer number of subjects with event. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was planned for Phase 2 only. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

From the first dose of study treatment to the date of disease progression/radiographic progression in soft tissue or bone, or death due to any cause, whichever occurred first (maximum up to 5.2 years approximately)

Notes
[23] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	21	18	2
Units: Months
median (confidence interval 95%)	4.1 (1.9 to 99999)	4.6 (1.7 to 9.8)	8.4 (5.9 to 10.9)

No statistical analyses for this end point

Secondary: Phase 1b: Progression-Free Survival (PFS) in Subjects with Confirmed CR or PR

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End point title

Phase 1b: Progression-Free Survival (PFS) in Subjects with Confirmed CR or PR ^[24]

End point description

For subjects with solid tumors except mCRPC, PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. For subjects with mCRPC, PFS was defined as the time from the first dose of study treatment to documentation of radiographic progression in soft tissue as assessed by Investigator using RECIST v1.1, in bone as assessed by Investigator using PCWG3, or death, whichever occurred first. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was planned for Phase 1b only.

End point type

Secondary

End point timeframe

Notes
[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: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD
Number of subjects analysed	12
Units: Months
median (confidence interval 95%)	6.0 (1.8 to 11.5)

No statistical analyses for this end point

Secondary: Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1)

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End point title

Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1) ^[25]

End point description

This OM is reported for subjects with solid tumors except mCRPC; for those subjects, PFS was defined as the time from the first dose of study treatment to the date of disease progression by RECIST v1.1 or death due to any cause, whichever occurred first. "99999"= Upper limit of 95% CI was not reached due to fewer number of subjects with event. The full analysis set (FAS) included all enrolled participants who received at least 1 dose of study treatment. Data for this OM was planned for Phase 2 only. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Notes
[25] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	42	5	22	23	20	11	40	7
Units: Months
median (confidence interval 95%)	4.7 (3.7 to 7.4)	1.9 (1.8 to 99999)	3.6 (1.9 to 5.6)	5.3 (2.0 to 12.8)	7.2 (4.0 to 9.1)	16.8 (7.2 to 99999)	3.6 (1.9 to 5.4)	1.7 (1.4 to 3.3)

No statistical analyses for this end point

Secondary: Phase 1b: Overall Survival

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End point title

Phase 1b: Overall Survival ^[26]

End point description

Overall survival (OS) was defined as the time from the first dose of study treatment to the date of death. Subjects without an event (death) were censored at the date of last contact. "99999"= Upper limit of 95% CI was not reached due to fewer number of subjects with event. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was for Phase 1b only.

End point type

Secondary

End point timeframe

From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately)

Notes
[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: The endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD
Number of subjects analysed	12
Units: Months
median (confidence interval 95%)	18.5 (6.4 to 99999)

No statistical analyses for this end point

Secondary: Phase 2: Time to Prostate-Specific Antigen (PSA) Progression for Subjects with mCRPC

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End point title

Phase 2: Time to Prostate-Specific Antigen (PSA) Progression for Subjects with mCRPC ^[27]

End point description

Time to PSA progression for subjects with mCRPC was defined as the time from the first dose to the date that a >=25% increase in PSA with an absolute increase of >=2 μg/L (2 ng/mL) above the nadir (or baseline for subjects with no PSA decline) was documented, confirmed by a second consecutive PSA value obtained >=3 weeks (21 days) later. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was planned for Phase 2 only. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

From the first dose to the date that a >=25% increase in PSA with an absolute increase of >=2 μg/L (2 ng/mL) above the nadir (or baseline for subjects with no PSA decline) was documented (maximum up to 5.2 years approximately)

Notes
[27] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	21	18	2
Units: Months
median (confidence interval 95%)	1.0 (1.0 to 4.6)	2.8 (1.0 to 6.5)	3.1 (1.6 to 4.6)

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival

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End point title

Phase 2: Overall Survival ^[28]

End point description

OS was defined as the time from the first dose of study treatment to the date of death. Subjects without an event (death) were censored at the date of last contact. "99999"=Upper limit of 95% CI was not reached due to fewer number of subjects with event. The full analysis set (FAS) included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was for Phase 2 only.

End point type

Secondary

End point timeframe

From the first dose of study treatment to the date of death (maximum up to 5.2 years approximately)

Notes
[28] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	42	5	22	23	20	11	40	21	18	9
Units: Months
median (confidence interval 95%)	11.6 (8.4 to 14.9)	26.3 (3.5 to 43.3)	8.2 (5.8 to 13.0)	27.5 (12.6 to 40.2)	22.9 (7.8 to 99999)	38.8 (16.9 to 99999)	13.1 (8.5 to 19.2)	15.9 (9.6 to 20.7)	16.1 (10.8 to 23.4)	6.9 (1.4 to 27.4)

No statistical analyses for this end point

Secondary: Phase 2: Percentage of Subjects With PSA Response

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End point title

Phase 2: Percentage of Subjects With PSA Response ^[29]

End point description

PSA response was defined as the proportion of subjects with confirmed PSA decline >=50% compared to baseline. PSA response was calculated as a decline from baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%. A PSA response must be confirmed by a second consecutive value at least 3 weeks later. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was planned for Cohorts E1, E2, and F in Phase 2 only as pre-specified in reporting and analysis plan. Cohorts without evaluable subjects for this outcome measure [ie, Phase 2: Cohort F (BRCA/ATM-mutated)] are not presented.

End point type

Secondary

End point timeframe

From baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50% (maximum up to 5.2 years approximately)

Notes
[29] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)
Number of subjects analysed	21	18
Units: Percentage of Subjects
number (confidence interval 95%)	9.5 (1.2 to 30.4)	5.6 (0.1 to 27.3)

No statistical analyses for this end point

Secondary: Phase 1b: Percentage of Subjects With CA-125 Response

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End point title

Phase 1b: Percentage of Subjects With CA-125 Response ^[30]

End point description

Cancer Antigen 125 (CA-125) response is defined as at least a 50% reduction in CA-125 levels from baseline. The response must be confirmed and maintained for at least 28 days. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was for Phase 1b only. Here 'number of subjects analyzed' signifies subjects evaluable for this outcome measure.

End point type

Secondary

End point timeframe

From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately)

Notes
[30] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 1b: Avelumab 800 mg Q2W + Talazoparib 1 mg QD
Number of subjects analysed	1
Units: Percentage of Subjects
number (confidence interval 95%)	100 (2.5 to 100.0)

No statistical analyses for this end point

Secondary: Number of Subjects With Different Programmed Death-Ligand 1 (PD-L1) Status at Baseline

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End point title

Number of Subjects With Different Programmed Death-Ligand 1 (PD-L1) Status at Baseline ^[31]

End point description

PD-L1 expression on tumor and infiltrating immune cells were measured by immunohistochemistry (IHC). PD-L1 expression level corresponds to the percentage of positive cells. The PD-L1 Positive category does not apply to cohorts A1 and A2. The PD-L1 High/Low categories only apply to cohorts A1 and A2. Subjects were considered positive if their baseline tumor tissue sample demonstrated cell surface PD-L1 expression: 1) for Cohorts E1, E2, and F: >=1% tumor cells (TC) or >= 5% immune cells (IC); 2) for Cohort D: TC/IC>=25%; 3) for Cohorts B1, B2, C1, C2: IC>=5%; otherwise were considered negative. Categories based on PD-L1 expression level ≥50% and <50% were defined as High and Low, respectively. The full analysis set (FAS) included all enrolled subjects who received at least 1 dose of study treatment. Data for this outcome measure was presented for Phase 2 only as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

At baseline (the last available assessment prior to the start of study treatment was defined as ‘baseline’ value or ‘baseline’ assessment)

Notes
[31] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	42	5	22	23	20	11	40	21	18	9
Units: Subjects
High	3	1	0	0	0	0	0	0	0	0
Low	8	1	0	0	0	0	0	0	0	0
Positive (Not applicable for Cohorts A1 and A2)	0	0	8	3	5	5	13	1	2	0
Negative	22	2	6	16	13	4	19	13	12	3
Unknown	9	1	8	4	2	2	8	7	4	6

No statistical analyses for this end point

Secondary: Phase 2: Percentage of Subjects With CA-125 Response

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End point title

Phase 2: Percentage of Subjects With CA-125 Response ^[32]

End point description

CA-125 response is defined as at least a 50% reduction in CA-125 levels from baseline. The response must be confirmed and maintained for at least 28 days. The FAS included all enrolled subjects who received at least 1 dose of study treatment. Data for this OM was for Cohorts C1 and C2 in Phase 2 only as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

From baseline to at least a 50% reduction in CA-125 level (maximum up to 5.2 years approximately)

Notes
[32] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)
Number of subjects analysed	20	11
Units: Percentage of Subjects
number (confidence interval 95%)	45.0 (23.1 to 68.5)	63.6 (30.8 to 89.1)

No statistical analyses for this end point

Secondary: Number of Subjects With Different Tumor Mutational Burden (TMB) at Baseline

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End point title

Number of Subjects With Different Tumor Mutational Burden (TMB) at Baseline ^[33]

End point description

TMB was defined as the total number of mutations in the tumor genome, or number of mutations per megabase of DNA if derived from targeted sequencing. High: TMB score >=20 muts/mb (number of mutations per megabase of DNA); Medium: TMB score >=10 muts/mb and <20 muts/mb; Low: TMB score <10 muts/mb. The full analysis set (FAS) included all enrolled subjects who received at least 1 dose of study treatment. Data for this outcome measure was presented for Phase 2 only as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

At baseline (the last available assessment prior to the start of study treatment was defined as ‘baseline’ value or ‘baseline’ assessment)

Notes
[33] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	42	5	22	23	20	11	40	21	18	9
Units: Subjects
High	4	1	0	0	0	0	5	0	2	0
Medium	9	1	3	2	1	2	4	0	0	0
Low	13	3	12	20	12	6	22	11	13	8
Unknown	16	0	7	1	7	3	9	10	3	1

No statistical analyses for this end point

Secondary: Number of Subjects With Different DNA Damage Repair (DDR) Status at Baseline

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End point title

Number of Subjects With Different DNA Damage Repair (DDR) Status at Baseline ^[34]

End point description

DDR defect positive was determined by presence of one or more pathogenic or likely pathogenic mutations in tissue, DNA and/or blood samples. The full analysis set (FAS) included all enrolled subjects who received at least 1 dose of study treatment. Data for this outcome measure was presented for Phase 2 only as pre-specified in reporting and analysis plan.

End point type

Secondary

End point timeframe

At baseline

Notes
[34] - 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 endpoint is reporting statistics for the arms specified.

End point values	Phase 2: Cohort A1 (NSCLC)	Phase 2: Cohort A2 (NSCLC DDR+)	Phase 2: Cohort B1 (TNBC)	Phase 2: Cohort B2 (BC HR+ HER2- DDR+)	Phase 2: Cohort C1 (OVC)	Phase 2: Cohort C2 (OVC BRCA-mutated)	Phase 2: Cohort D (UC)	Phase 2: Cohort E1 (mCRPC)	Phase 2: Cohort E2 (mCRPC DDR+)	Phase 2: Cohort F (BRCA/ATM-mutated)
Number of subjects analysed	42	5	22	23	20	11	40	21	18	9
Units: Subjects
Positive	12	3	10	19	5	10	18	7	16	8
Negative	30	2	12	4	15	1	22	13	2	1
Unknown	0	0	0	0	0	0	0	1	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All-cause mortality:From start of the treatment (A) up to 90 days post last dose of study treatment (B), TEAEs and Serious TEAEs:From A up to 30 days post B or start of new anti-cancer drug therapy -1 day, whichever came first (<=about 5.2 years)

Adverse event reporting additional description

Same event may appear as both an AE and SAE. However, what is presented are distinct events. Safety set (all subjects who received at least 1 dose of study drug) was evaluated. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

Cohort A1 (NSCLC)

Reporting group description

Reporting group title

Avelumab 800 mg Q2W + Talazoparib 1 mg QD

Reporting group description

Reporting group title

Cohort B1 (TNBC)

Reporting group description

Reporting group title

Cohort A2 (NSCLC DDR+)

Reporting group description

Reporting group title

Cohort E1 (mCRPC)

Reporting group description

Reporting group title

Cohort E2 (mCRPC DDR+)

Reporting group description

Reporting group title

Cohort D (UC)

Reporting group description

Reporting group title

Cohort C2 (OVC BRCA-mutated)

Reporting group description

Reporting group title

Cohort F (BRCA/ATM-mutated)

Reporting group description

Reporting group title

Cohort B2 (BC HR+ HER2- DDR+)

Reporting group description

Reporting group title

Cohort C1 (OVC)

Reporting group description

Serious adverse events	Cohort A1 (NSCLC)	Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Cohort B1 (TNBC)	Cohort A2 (NSCLC DDR+)	Cohort E1 (mCRPC)	Cohort E2 (mCRPC DDR+)	Cohort D (UC)	Cohort C2 (OVC BRCA-mutated)	Cohort F (BRCA/ATM-mutated)	Cohort B2 (BC HR+ HER2- DDR+)	Cohort C1 (OVC)
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 42 (38.10%)	1 / 12 (8.33%)	7 / 22 (31.82%)	2 / 5 (40.00%)	5 / 21 (23.81%)	9 / 18 (50.00%)	16 / 40 (40.00%)	2 / 11 (18.18%)	4 / 9 (44.44%)	5 / 23 (21.74%)	9 / 20 (45.00%)
number of deaths (all causes)	33	6	16	3	16	14	26	6	7	16	11
number of deaths resulting from adverse events	3	0	1	0	1	1	3	1	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neoplasm progression
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Face oedema
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Disease progression
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	2 / 9 (22.22%)	1 / 23 (4.35%)	2 / 20 (10.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Suprapubic pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	2 / 40 (5.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Female genital tract fistula
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Testicular pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood bilirubin increased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	2 / 18 (11.11%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyphaema
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial thrombosis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Dizziness
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	3 / 22 (13.64%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	3 / 40 (7.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	2 / 23 (8.70%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 4	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune neutropenia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 8	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	2 / 9 (22.22%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Anuria
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	4 / 40 (10.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage urinary tract
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Glucocorticoid deficiency
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis of jaw
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coccydynia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	2 / 40 (5.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort A1 (NSCLC)	Avelumab 800 mg Q2W + Talazoparib 1 mg QD	Cohort B1 (TNBC)	Cohort A2 (NSCLC DDR+)	Cohort E1 (mCRPC)	Cohort E2 (mCRPC DDR+)	Cohort D (UC)	Cohort C2 (OVC BRCA-mutated)	Cohort F (BRCA/ATM-mutated)	Cohort B2 (BC HR+ HER2- DDR+)	Cohort C1 (OVC)
Total subjects affected by non serious adverse events
subjects affected / exposed	41 / 42 (97.62%)	12 / 12 (100.00%)	21 / 22 (95.45%)	5 / 5 (100.00%)	21 / 21 (100.00%)	16 / 18 (88.89%)	38 / 40 (95.00%)	10 / 11 (90.91%)	9 / 9 (100.00%)	22 / 23 (95.65%)	20 / 20 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	1	2	0	0	0	0	0	0
Squamous cell carcinoma
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Basal cell carcinoma
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0
Flushing
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0
Embolism
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	1	0	0
Deep vein thrombosis
subjects affected / exposed	1 / 42 (2.38%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0	0	0	0
Hot flush
subjects affected / exposed	1 / 42 (2.38%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	2 / 20 (10.00%)
occurrences all number	4	1	0	0	0	0	0	0	0	1	2
Hypertension
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	2	0	1	1	0	5	0	0	0
Hypotension
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	3 / 22 (13.64%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	2	0	3	0	1	0	1	0	1	1	1
Peripheral coldness
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Orthostatic hypotension
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Lymphoedema
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	3	0	0	0	2	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	8 / 42 (19.05%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	4 / 40 (10.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 23 (8.70%)	4 / 20 (20.00%)
occurrences all number	13	0	2	0	0	1	8	0	0	2	9
Chest pain
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 23 (8.70%)	0 / 20 (0.00%)
occurrences all number	3	0	0	1	0	0	0	1	0	3	0
Fatigue
subjects affected / exposed	17 / 42 (40.48%)	2 / 12 (16.67%)	8 / 22 (36.36%)	4 / 5 (80.00%)	10 / 21 (47.62%)	5 / 18 (27.78%)	14 / 40 (35.00%)	8 / 11 (72.73%)	6 / 9 (66.67%)	10 / 23 (43.48%)	11 / 20 (55.00%)
occurrences all number	34	2	11	5	16	8	28	16	9	12	13
Facial pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Chills
subjects affected / exposed	7 / 42 (16.67%)	5 / 12 (41.67%)	0 / 22 (0.00%)	0 / 5 (0.00%)	3 / 21 (14.29%)	2 / 18 (11.11%)	4 / 40 (10.00%)	2 / 11 (18.18%)	2 / 9 (22.22%)	4 / 23 (17.39%)	4 / 20 (20.00%)
occurrences all number	8	5	0	0	3	2	4	2	2	4	4
Influenza like illness
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	3 / 40 (7.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	1	3	0	1	2	1
Localised oedema
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Mucosal inflammation
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	2 / 40 (5.00%)	2 / 11 (18.18%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	2	0	1	0
Non-cardiac chest pain
subjects affected / exposed	5 / 42 (11.90%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	3 / 40 (7.50%)	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	8	0	3	0	0	0	3	2	0	0	0
Oedema peripheral
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	3 / 21 (14.29%)	2 / 18 (11.11%)	3 / 40 (7.50%)	2 / 11 (18.18%)	4 / 9 (44.44%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	2	0	1	0	3	3	3	2	6	0	2
Peripheral swelling
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	1	2
Pyrexia
subjects affected / exposed	7 / 42 (16.67%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	2 / 21 (9.52%)	4 / 18 (22.22%)	8 / 40 (20.00%)	3 / 11 (27.27%)	0 / 9 (0.00%)	4 / 23 (17.39%)	2 / 20 (10.00%)
occurrences all number	8	0	2	0	3	5	9	4	0	5	2
Immune system disorders
Seasonal allergy
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0	0	0	0
Vulvovaginal dryness
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0
Vulvovaginal pruritus
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	17 / 42 (40.48%)	0 / 12 (0.00%)	9 / 22 (40.91%)	1 / 5 (20.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	8 / 40 (20.00%)	3 / 11 (27.27%)	2 / 9 (22.22%)	2 / 23 (8.70%)	7 / 20 (35.00%)
occurrences all number	22	0	9	1	2	2	13	5	3	2	11
Dysphonia
subjects affected / exposed	4 / 42 (9.52%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	4	0	0	0	0	0	0	0	0	1	1
Cough
subjects affected / exposed	8 / 42 (19.05%)	1 / 12 (8.33%)	2 / 22 (9.09%)	0 / 5 (0.00%)	1 / 21 (4.76%)	4 / 18 (22.22%)	7 / 40 (17.50%)	3 / 11 (27.27%)	1 / 9 (11.11%)	2 / 23 (8.70%)	2 / 20 (10.00%)
occurrences all number	12	1	2	0	1	5	8	3	1	2	6
Nasal congestion
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 23 (8.70%)	1 / 20 (5.00%)
occurrences all number	2	0	1	0	0	0	1	1	0	2	1
Rhinorrhoea
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	2 / 11 (18.18%)	1 / 9 (11.11%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	3	1	1	0
Pulmonary haemorrhage
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	3 / 20 (15.00%)
occurrences all number	2	1	0	0	0	1	1	0	1	1	3
Pharyngeal erythema
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Productive cough
subjects affected / exposed	5 / 42 (11.90%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	2 / 11 (18.18%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	8	0	1	0	0	0	0	3	0	1	0
Pulmonary embolism
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	3	0	0	1	0	1	0	0	0	0	3
Sinus congestion
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	2 / 22 (9.09%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	3	1	0	0	1	1	0	0	2
Confusional state
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	4	0	0	0	0	0	1	0	1	0	0
Depressed mood
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	1	0	0	0	0	0	0
Depression
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 23 (8.70%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	2	0
Hallucination
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0
Restlessness
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Mood altered
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Insomnia
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	2 / 22 (9.09%)	1 / 5 (20.00%)	2 / 21 (9.52%)	1 / 18 (5.56%)	2 / 40 (5.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 23 (8.70%)	2 / 20 (10.00%)
occurrences all number	2	0	2	1	2	1	2	1	0	3	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	1 / 22 (4.55%)	1 / 5 (20.00%)	2 / 21 (9.52%)	0 / 18 (0.00%)	2 / 40 (5.00%)	2 / 11 (18.18%)	1 / 9 (11.11%)	2 / 23 (8.70%)	4 / 20 (20.00%)
occurrences all number	3	0	1	1	4	0	6	3	1	2	8
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	2	0	0
Amylase decreased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0
Amylase increased
subjects affected / exposed	3 / 42 (7.14%)	1 / 12 (8.33%)	1 / 22 (4.55%)	2 / 5 (40.00%)	3 / 21 (14.29%)	2 / 18 (11.11%)	1 / 40 (2.50%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 23 (4.35%)	3 / 20 (15.00%)
occurrences all number	4	3	1	3	8	16	4	1	2	1	3
Aspartate aminotransferase increased
subjects affected / exposed	1 / 42 (2.38%)	1 / 12 (8.33%)	1 / 22 (4.55%)	2 / 5 (40.00%)	3 / 21 (14.29%)	1 / 18 (5.56%)	1 / 40 (2.50%)	2 / 11 (18.18%)	1 / 9 (11.11%)	2 / 23 (8.70%)	3 / 20 (15.00%)
occurrences all number	1	1	1	2	8	1	2	2	2	3	5
Blood albumin decreased
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	3
Blood alkaline phosphatase increased
subjects affected / exposed	9 / 42 (21.43%)	1 / 12 (8.33%)	3 / 22 (13.64%)	1 / 5 (20.00%)	3 / 21 (14.29%)	2 / 18 (11.11%)	4 / 40 (10.00%)	1 / 11 (9.09%)	3 / 9 (33.33%)	2 / 23 (8.70%)	3 / 20 (15.00%)
occurrences all number	17	1	6	1	7	2	5	1	3	4	14
Blood bilirubin increased
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	0 / 40 (0.00%)	1 / 11 (9.09%)	2 / 9 (22.22%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	3	2	0	1	4	1	3
Blood calcium decreased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	1 / 22 (4.55%)	1 / 5 (20.00%)	2 / 21 (9.52%)	0 / 18 (0.00%)	1 / 40 (2.50%)	2 / 11 (18.18%)	0 / 9 (0.00%)	1 / 23 (4.35%)	3 / 20 (15.00%)
occurrences all number	2	0	1	4	4	0	2	5	0	3	7
Blood creatinine increased
subjects affected / exposed	1 / 42 (2.38%)	2 / 12 (16.67%)	2 / 22 (9.09%)	0 / 5 (0.00%)	4 / 21 (19.05%)	3 / 18 (16.67%)	7 / 40 (17.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	4 / 20 (20.00%)
occurrences all number	3	4	2	0	7	6	14	0	1	0	9
Blood lactate dehydrogenase increased
subjects affected / exposed	4 / 42 (9.52%)	0 / 12 (0.00%)	3 / 22 (13.64%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	4 / 20 (20.00%)
occurrences all number	4	0	6	0	0	0	1	0	0	0	8
Blood magnesium decreased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	4 / 20 (20.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	15
Blood urea increased
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	4	0	1	0	0	0	0	0	0	0	18
Blood uric acid increased
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	3 / 20 (15.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	17
Creatinine renal clearance decreased
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	5	0	5	0	0	0	0	0	0	0	4
Electrocardiogram QT prolonged
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	1	0	2	0	0	1
Neutrophil count decreased
subjects affected / exposed	2 / 42 (4.76%)	2 / 12 (16.67%)	1 / 22 (4.55%)	0 / 5 (0.00%)	3 / 21 (14.29%)	2 / 18 (11.11%)	5 / 40 (12.50%)	10 / 11 (90.91%)	1 / 9 (11.11%)	3 / 23 (13.04%)	5 / 20 (25.00%)
occurrences all number	9	9	1	0	5	3	24	75	1	20	21
Lymphocyte count decreased
subjects affected / exposed	1 / 42 (2.38%)	1 / 12 (8.33%)	2 / 22 (9.09%)	1 / 5 (20.00%)	4 / 21 (19.05%)	2 / 18 (11.11%)	3 / 40 (7.50%)	0 / 11 (0.00%)	2 / 9 (22.22%)	3 / 23 (13.04%)	3 / 20 (15.00%)
occurrences all number	5	1	6	3	7	8	3	0	16	10	18
Lipase increased
subjects affected / exposed	4 / 42 (9.52%)	1 / 12 (8.33%)	1 / 22 (4.55%)	1 / 5 (20.00%)	3 / 21 (14.29%)	1 / 18 (5.56%)	2 / 40 (5.00%)	1 / 11 (9.09%)	3 / 9 (33.33%)	1 / 23 (4.35%)	4 / 20 (20.00%)
occurrences all number	6	1	1	2	6	2	4	1	6	1	9
International normalised ratio increased
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	2	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	5 / 42 (11.90%)	0 / 12 (0.00%)	3 / 22 (13.64%)	1 / 5 (20.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	3 / 40 (7.50%)	1 / 11 (9.09%)	4 / 9 (44.44%)	0 / 23 (0.00%)	3 / 20 (15.00%)
occurrences all number	12	0	3	1	3	5	11	6	4	0	6
Platelet count decreased
subjects affected / exposed	3 / 42 (7.14%)	1 / 12 (8.33%)	4 / 22 (18.18%)	1 / 5 (20.00%)	8 / 21 (38.10%)	7 / 18 (38.89%)	7 / 40 (17.50%)	7 / 11 (63.64%)	2 / 9 (22.22%)	4 / 23 (17.39%)	5 / 20 (25.00%)
occurrences all number	7	3	17	1	12	12	24	38	3	11	19
SARS-CoV-2 test positive
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Weight decreased
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	1 / 22 (4.55%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	3	1	1	2	0	0	1	4	2	0	1
White blood cell count decreased
subjects affected / exposed	1 / 42 (2.38%)	4 / 12 (33.33%)	1 / 22 (4.55%)	0 / 5 (0.00%)	4 / 21 (19.05%)	5 / 18 (27.78%)	9 / 40 (22.50%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 23 (4.35%)	4 / 20 (20.00%)
occurrences all number	9	17	3	0	9	15	35	23	1	10	30
Weight increased
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	3	0	2	0	0	0	0	0	0	0	4
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	2 / 23 (8.70%)	3 / 20 (15.00%)
occurrences all number	0	0	1	0	0	0	2	0	1	2	3
Muscle injury
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Limb injury
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0
Infusion related reaction
subjects affected / exposed	4 / 42 (9.52%)	1 / 12 (8.33%)	1 / 22 (4.55%)	0 / 5 (0.00%)	4 / 21 (19.05%)	2 / 18 (11.11%)	6 / 40 (15.00%)	1 / 11 (9.09%)	2 / 9 (22.22%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	4	1	1	0	5	2	6	1	2	1	1
Fall
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	2 / 23 (8.70%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	1	1	0	0	2	2	0
Soft tissue injury
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Spinal fracture
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Congenital, familial and genetic disorders
Hypophosphatasia
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	1	0	3	0	0	0	1	0	0	0	2
Atrial fibrillation
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	3	0	0	0	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	8 / 42 (19.05%)	0 / 12 (0.00%)	1 / 22 (4.55%)	1 / 5 (20.00%)	2 / 21 (9.52%)	3 / 18 (16.67%)	3 / 40 (7.50%)	2 / 11 (18.18%)	1 / 9 (11.11%)	2 / 23 (8.70%)	4 / 20 (20.00%)
occurrences all number	9	0	1	1	3	3	4	2	1	2	9
Disturbance in attention
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Memory impairment
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	2	0	0	0	0	1	0	0	1	0	0
Headache
subjects affected / exposed	7 / 42 (16.67%)	0 / 12 (0.00%)	4 / 22 (18.18%)	0 / 5 (0.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	3 / 40 (7.50%)	4 / 11 (36.36%)	1 / 9 (11.11%)	4 / 23 (17.39%)	2 / 20 (10.00%)
occurrences all number	10	0	5	0	2	3	4	6	1	5	7
Dysgeusia
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	3 / 22 (13.64%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	2 / 40 (5.00%)	5 / 11 (45.45%)	0 / 9 (0.00%)	2 / 23 (8.70%)	0 / 20 (0.00%)
occurrences all number	2	0	5	0	0	0	3	5	0	2	0
Neuropathy peripheral
subjects affected / exposed	0 / 42 (0.00%)	2 / 12 (16.67%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	0 / 40 (0.00%)	2 / 11 (18.18%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	2	0	0	1	1	0	2	0	0	0
Somnolence
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	2	0	0
Spinal cord compression
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	0	1	0
Tremor
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	3
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	28 / 42 (66.67%)	8 / 12 (66.67%)	18 / 22 (81.82%)	4 / 5 (80.00%)	15 / 21 (71.43%)	10 / 18 (55.56%)	31 / 40 (77.50%)	7 / 11 (63.64%)	5 / 9 (55.56%)	10 / 23 (43.48%)	12 / 20 (60.00%)
occurrences all number	114	42	59	12	51	33	134	41	26	29	77
Leukopenia
subjects affected / exposed	7 / 42 (16.67%)	0 / 12 (0.00%)	3 / 22 (13.64%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	5 / 40 (12.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	4 / 20 (20.00%)
occurrences all number	21	0	16	0	2	0	9	0	0	1	13
Thrombocytopenia
subjects affected / exposed	15 / 42 (35.71%)	5 / 12 (41.67%)	9 / 22 (40.91%)	1 / 5 (20.00%)	6 / 21 (28.57%)	3 / 18 (16.67%)	16 / 40 (40.00%)	4 / 11 (36.36%)	2 / 9 (22.22%)	2 / 23 (8.70%)	9 / 20 (45.00%)
occurrences all number	66	40	30	3	19	4	50	8	9	7	39
Neutropenia
subjects affected / exposed	10 / 42 (23.81%)	7 / 12 (58.33%)	6 / 22 (27.27%)	2 / 5 (40.00%)	3 / 21 (14.29%)	0 / 18 (0.00%)	6 / 40 (15.00%)	2 / 11 (18.18%)	2 / 9 (22.22%)	4 / 23 (17.39%)	4 / 20 (20.00%)
occurrences all number	22	77	20	22	6	0	26	7	8	6	9
Lymphopenia
subjects affected / exposed	5 / 42 (11.90%)	0 / 12 (0.00%)	4 / 22 (18.18%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	4 / 40 (10.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	5 / 20 (25.00%)
occurrences all number	34	0	16	0	0	0	12	0	0	0	33
Lymphadenopathy
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Ear and labyrinth disorders
Ear congestion
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Vertigo
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	2	0	1	0	1	0	0	0	1
Eye disorders
Vision blurred
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	3	0	0	0	2	0	0	1	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0	0
Diplopia
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal pain lower
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	3 / 20 (15.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3
Abdominal pain upper
subjects affected / exposed	6 / 42 (14.29%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	2 / 20 (10.00%)
occurrences all number	8	0	1	0	0	0	0	0	0	1	2
Ascites
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Constipation
subjects affected / exposed	6 / 42 (14.29%)	1 / 12 (8.33%)	5 / 22 (22.73%)	3 / 5 (60.00%)	5 / 21 (23.81%)	2 / 18 (11.11%)	7 / 40 (17.50%)	4 / 11 (36.36%)	2 / 9 (22.22%)	4 / 23 (17.39%)	3 / 20 (15.00%)
occurrences all number	13	1	6	3	7	4	12	8	2	5	3
Diarrhoea
subjects affected / exposed	8 / 42 (19.05%)	0 / 12 (0.00%)	2 / 22 (9.09%)	1 / 5 (20.00%)	4 / 21 (19.05%)	4 / 18 (22.22%)	7 / 40 (17.50%)	3 / 11 (27.27%)	3 / 9 (33.33%)	5 / 23 (21.74%)	7 / 20 (35.00%)
occurrences all number	9	0	3	2	9	6	7	8	4	6	10
Abdominal discomfort
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Abdominal distension
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	1 / 11 (9.09%)	2 / 9 (22.22%)	1 / 23 (4.35%)	5 / 20 (25.00%)
occurrences all number	1	0	0	0	0	1	1	1	2	1	5
Abdominal pain
subjects affected / exposed	2 / 42 (4.76%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	3 / 11 (27.27%)	3 / 9 (33.33%)	2 / 23 (8.70%)	3 / 20 (15.00%)
occurrences all number	2	0	3	0	0	2	2	7	3	2	3
Dysphagia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0
Dyspepsia
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	3 / 11 (27.27%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	1	0	0	0	1	6	0	0	0
Dry mouth
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	2 / 40 (5.00%)	2 / 11 (18.18%)	1 / 9 (11.11%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	1	0	2	0	1	1	2	3	1	1	0
Flatulence
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0
Gastritis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1
Gastrointestinal pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	1
Gingival bleeding
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	1	0	1	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Lip swelling
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Lip dry
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Nausea
subjects affected / exposed	14 / 42 (33.33%)	0 / 12 (0.00%)	10 / 22 (45.45%)	0 / 5 (0.00%)	8 / 21 (38.10%)	6 / 18 (33.33%)	12 / 40 (30.00%)	6 / 11 (54.55%)	2 / 9 (22.22%)	11 / 23 (47.83%)	14 / 20 (70.00%)
occurrences all number	20	0	13	0	8	11	12	10	2	15	17
Proctalgia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0
Oral pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	1
Noninfective gingivitis
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Stomatitis
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	1 / 22 (4.55%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	2 / 11 (18.18%)	1 / 9 (11.11%)	3 / 23 (13.04%)	1 / 20 (5.00%)
occurrences all number	3	1	4	1	0	0	0	6	1	9	1
Subileus
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0
Tongue discolouration
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Tongue pigmentation
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Vomiting
subjects affected / exposed	4 / 42 (9.52%)	0 / 12 (0.00%)	4 / 22 (18.18%)	0 / 5 (0.00%)	6 / 21 (28.57%)	3 / 18 (16.67%)	2 / 40 (5.00%)	4 / 11 (36.36%)	2 / 9 (22.22%)	6 / 23 (26.09%)	4 / 20 (20.00%)
occurrences all number	6	0	5	0	7	4	3	8	2	6	7
Hepatobiliary disorders
Jaundice
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	3 / 22 (13.64%)	1 / 5 (20.00%)	0 / 21 (0.00%)	2 / 18 (11.11%)	1 / 40 (2.50%)	3 / 11 (27.27%)	0 / 9 (0.00%)	3 / 23 (13.04%)	3 / 20 (15.00%)
occurrences all number	3	1	3	1	0	2	3	3	0	3	3
Ecchymosis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	4	1	0
Night sweats
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	1	0	1	1	0	1	1
Petechiae
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Skin ulcer
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	2	0	0	1	0	0	0	0	0
Skin hyperpigmentation
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	3	0	0	0	0	0	0	1	1	0	1
Rash erythematous
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Rash
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	2 / 18 (11.11%)	3 / 40 (7.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	2	1	2	0	0	2	3	0	0	0	1
Pruritus
subjects affected / exposed	5 / 42 (11.90%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	3 / 18 (16.67%)	3 / 40 (7.50%)	2 / 11 (18.18%)	1 / 9 (11.11%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	8	0	0	0	0	5	5	2	1	0	2
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Acute kidney injury
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	3 / 40 (7.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0	0	0
Haematuria
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	6 / 40 (15.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	1	0	0	0	0	1	6	0	1	0	2
Hydronephrosis
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	3	0	0	0	0	1	1	0	1	0	0
Nocturia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Pollakiuria
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	1
Proteinuria
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	1	0	0
Urinary incontinence
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	0	0	1	1	1	1
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	3	0	0	1	0	0	0	0	0	1	1
Glucocorticoid deficiency
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Immune-mediated hypothyroidism
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	0 / 22 (0.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	3 / 23 (13.04%)	2 / 20 (10.00%)
occurrences all number	2	1	0	1	1	0	2	1	0	3	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 42 (14.29%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	2 / 21 (9.52%)	4 / 18 (22.22%)	8 / 40 (20.00%)	2 / 11 (18.18%)	1 / 9 (11.11%)	6 / 23 (26.09%)	2 / 20 (10.00%)
occurrences all number	12	0	3	0	3	5	9	4	1	6	2
Muscular weakness
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	4 / 21 (19.05%)	0 / 18 (0.00%)	0 / 40 (0.00%)	2 / 11 (18.18%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	5	0	0	2	1	0	0
Muscle spasms
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	1 / 40 (2.50%)	3 / 11 (27.27%)	1 / 9 (11.11%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	2	2	1	4	1	1	1
Groin pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	2 / 18 (11.11%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	2	1	0	0	0	1
Flank pain
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	2 / 23 (8.70%)	3 / 20 (15.00%)
occurrences all number	0	0	2	0	1	1	1	0	0	3	4
Bone pain
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	1 / 22 (4.55%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	0	1	1	0	1	0	1	0	0	1	1
Back pain
subjects affected / exposed	7 / 42 (16.67%)	0 / 12 (0.00%)	1 / 22 (4.55%)	1 / 5 (20.00%)	4 / 21 (19.05%)	2 / 18 (11.11%)	5 / 40 (12.50%)	2 / 11 (18.18%)	1 / 9 (11.11%)	8 / 23 (34.78%)	5 / 20 (25.00%)
occurrences all number	10	0	2	2	4	5	5	2	1	11	6
Musculoskeletal chest pain
subjects affected / exposed	1 / 42 (2.38%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	1	0	0	0	1	1	2	0	0	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0
Tendon disorder
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Pain in extremity
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	1 / 18 (5.56%)	3 / 40 (7.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 23 (8.70%)	4 / 20 (20.00%)
occurrences all number	5	0	0	0	5	2	3	1	0	2	5
Osteoporosis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Osteonecrosis of jaw
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	2 / 18 (11.11%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Myositis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1
Myalgia
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	2 / 18 (11.11%)	1 / 40 (2.50%)	3 / 11 (27.27%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	3	0	0	0	1	2	1	3	0	3	2
Infections and infestations
Candida infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	2	0	0	0
COVID-19
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0
Balanitis candida
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Cystitis
subjects affected / exposed	1 / 42 (2.38%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	1	0
Nasopharyngitis
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	4	0	0	0	0	0	0	1	0	1	1
Lower respiratory tract infection
subjects affected / exposed	3 / 42 (7.14%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	4	0	0	3	0	0	0	0	0	0	0
Localised infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0
Oral candidiasis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0	0
Pneumonia
subjects affected / exposed	5 / 42 (11.90%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	3 / 40 (7.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	5	0	2	0	0	0	5	0	0	0	1
Sinusitis
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	2	0	1	0	0	1	1	0	1
Vulvovaginal mycotic infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	0 / 9 (0.00%)	1 / 23 (4.35%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	2
Urinary tract infection
subjects affected / exposed	2 / 42 (4.76%)	1 / 12 (8.33%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	2 / 18 (11.11%)	6 / 40 (15.00%)	1 / 11 (9.09%)	2 / 9 (22.22%)	2 / 23 (8.70%)	1 / 20 (5.00%)
occurrences all number	5	1	1	0	0	4	9	4	2	2	1
Upper respiratory tract infection
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	2 / 5 (40.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	2	0	1	0	1	1	0	1
Skin infection
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	0 / 21 (0.00%)	1 / 18 (5.56%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	1	0	1	0	0	1	0	0	0	1	0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	3 / 42 (7.14%)	2 / 12 (16.67%)	1 / 22 (4.55%)	0 / 5 (0.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	4 / 40 (10.00%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 23 (0.00%)	4 / 20 (20.00%)
occurrences all number	5	3	1	0	3	6	4	0	5	0	6
Hypercalcaemia
subjects affected / exposed	1 / 42 (2.38%)	1 / 12 (8.33%)	0 / 22 (0.00%)	1 / 5 (20.00%)	1 / 21 (4.76%)	1 / 18 (5.56%)	1 / 40 (2.50%)	1 / 11 (9.09%)	1 / 9 (11.11%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	4	0	1	1	2	2	1	1	0	0
Dehydration
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	0 / 40 (0.00%)	1 / 11 (9.09%)	3 / 9 (33.33%)	0 / 23 (0.00%)	2 / 20 (10.00%)
occurrences all number	1	0	2	0	0	0	0	1	3	0	2
Decreased appetite
subjects affected / exposed	18 / 42 (42.86%)	1 / 12 (8.33%)	4 / 22 (18.18%)	2 / 5 (40.00%)	5 / 21 (23.81%)	6 / 18 (33.33%)	5 / 40 (12.50%)	1 / 11 (9.09%)	4 / 9 (44.44%)	3 / 23 (13.04%)	5 / 20 (25.00%)
occurrences all number	25	1	4	2	7	6	9	6	4	3	7
Hyperkalaemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	0 / 22 (0.00%)	0 / 5 (0.00%)	2 / 21 (9.52%)	0 / 18 (0.00%)	2 / 40 (5.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	4	0	5	0	0	0	1
Hypermagnesaemia
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	1 / 5 (20.00%)	2 / 21 (9.52%)	0 / 18 (0.00%)	0 / 40 (0.00%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	1	0	1	2	0	0	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	2 / 22 (9.09%)	0 / 5 (0.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	5 / 40 (12.50%)	0 / 11 (0.00%)	2 / 9 (22.22%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	3	0	3	3	7	0	4	0	1
Hypocalcaemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	0 / 5 (0.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	3 / 40 (7.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	0	4	2	5	0	0	0	1
Hypokalaemia
subjects affected / exposed	2 / 42 (4.76%)	2 / 12 (16.67%)	2 / 22 (9.09%)	2 / 5 (40.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	3 / 40 (7.50%)	1 / 11 (9.09%)	0 / 9 (0.00%)	2 / 23 (8.70%)	2 / 20 (10.00%)
occurrences all number	5	6	2	5	3	3	4	2	0	2	2
Hyperuricaemia
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	1 / 21 (4.76%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	4	0	0	1	0	1	0	0	0	1
Hypomagnesaemia
subjects affected / exposed	0 / 42 (0.00%)	1 / 12 (8.33%)	0 / 22 (0.00%)	0 / 5 (0.00%)	0 / 21 (0.00%)	3 / 18 (16.67%)	2 / 40 (5.00%)	3 / 11 (27.27%)	0 / 9 (0.00%)	0 / 23 (0.00%)	3 / 20 (15.00%)
occurrences all number	0	1	0	0	0	4	2	3	0	0	8
Hyponatraemia
subjects affected / exposed	0 / 42 (0.00%)	0 / 12 (0.00%)	1 / 22 (4.55%)	2 / 5 (40.00%)	1 / 21 (4.76%)	2 / 18 (11.11%)	4 / 40 (10.00%)	2 / 11 (18.18%)	2 / 9 (22.22%)	0 / 23 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	1	2	1	5	8	6	6	0	1
Hypophosphataemia
subjects affected / exposed	3 / 42 (7.14%)	2 / 12 (16.67%)	1 / 22 (4.55%)	1 / 5 (20.00%)	2 / 21 (9.52%)	2 / 18 (11.11%)	4 / 40 (10.00%)	0 / 11 (0.00%)	1 / 9 (11.11%)	1 / 23 (4.35%)	0 / 20 (0.00%)
occurrences all number	6	12	2	1	4	4	5	0	1	6	0
Vitamin D deficiency
subjects affected / exposed	1 / 42 (2.38%)	0 / 12 (0.00%)	0 / 22 (0.00%)	1 / 5 (20.00%)	0 / 21 (0.00%)	0 / 18 (0.00%)	1 / 40 (2.50%)	0 / 11 (0.00%)	0 / 9 (0.00%)	0 / 23 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	1	0	0	1	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Nov 2018

• Human epidermal growth factor receptor 2 negative requirement was added to inclusion criterion for hormone receptor positive breast cancer patients for clarity. • Flexibility in the target number of patients to be enrolled in the Phase 2 cohorts of the study was added to avoid a dedicated protocol amendment in case additional data are needed in a specific biomarker defined population. • The Schedule of Activities was updated to clarify procedures for patients who continue treatment beyond 2 years (Cycles >25) to lessen study participation burden for long term study participants. Serum/urine pregnancy test procedures are no longer required at Day 60 and Day 90 of Short Term Follow Up (only Day 30). • Physical exams are permitted to be performed 1 day prior to the scheduled visit to confirm any findings before dosing. • Permissible highly effective methods of contraception were updated as per current protocol standard, including the addition of sexual abstinence. • DDR defect status assessment procedures were revised to allow prospective and local (where applicable) testing of DDR defects. • Preliminary safety data from the Phase 1b portion of this study were added to Benefit/Risk Assessment. • In response to queries raised by the Ministry of Food and Drug Safety of South Korea for sites in South Korea only, specific eligibility criteria were restricted for Cohorts A1, B1, and D. • A DDR gene list has been added inclusion criteria for Cohorts A2, B2, and E2, to better define the DDR defect positive status required for eligibility. • Requirements for tumor assessments for progressive disease confirmation were removed. • A separate withdrawal of consent form is not applicable to this study and was removed from procedures. • Activated partial thromboplastin time assessment was permitted as an alternative to partial thromboplastin time. Prothrombin time was removed.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase 1b/2 Study to Evaluate Safety and Anti-Tumor Activity of Avelumab in Combination With the Poly (Adenosine Diphosphate [ADP]-Ribose)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1b: Number of Subjects with Dose Limiting Toxicities (DLTs)

Primary: Phase 1b: Number of Subjects with Dose Limiting Toxicities (DLTs)

Primary: Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment

Primary: Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 by Investigator Assessment

Primary: Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) by Investigator Assessment

Primary: Phase 2: Percentage of Subjects With Confirmed Objective Response (OR) as per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) by Investigator Assessment

Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects with Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Subjects with Serious TEAEs

Secondary: Number of Subjects with Serious TEAEs

Secondary: Number of Subjects with TEAEs Leading to Discontinuation of Either Study Drug

Secondary: Number of Subjects with TEAEs Leading to Discontinuation of Either Study Drug

Secondary: Number of Subjects with Grade >=3 TEAEs

Secondary: Number of Subjects with Grade >=3 TEAEs

Secondary: Number of Subjects with TEAEs Leading to Death

Secondary: Number of Subjects with TEAEs Leading to Death

Secondary: Number of Subjects with TEAEs Leading to Discontinuation of All Study Drugs

Secondary: Number of Subjects with TEAEs Leading to Discontinuation of All Study Drugs

Secondary: Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=3 During the On-Treatment Period

Secondary: Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=3 During the On-Treatment Period

Secondary: Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=1 During the On-Treatment Period

Secondary: Number of Subjects with New or Worsening Hematology Laboratory Test Results to Grade >=1 During the On-Treatment Period

Secondary: Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=1 During the On-Treatment Period

Secondary: Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=1 During the On-Treatment Period

Secondary: Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=3 During the On-Treatment Period

Secondary: Number of Subjects with New or Worsening Chemistry Laboratory Test Results to Grade >=3 During the On-Treatment Period

Secondary: Trough concentrations (Ctrough)/Predose and maximum concentrations (Cmax) of Serum Avelumab Concentrations (μg/mL) by Visit (Excluding Site 1055)

Secondary: Trough concentrations (Ctrough)/Predose and maximum concentrations (Cmax) of Serum Avelumab Concentrations (μg/mL) by Visit (Excluding Site 1055)

Secondary: Predose and Postdose Plasma Talazoparib Concentrations (pg/mL) by Visit (Excluding Site 1055)

Secondary: Predose and Postdose Plasma Talazoparib Concentrations (pg/mL) by Visit (Excluding Site 1055)

Secondary: Number of Subjects With at Least 1 Valid Anti-drug Antibody (ADA) Result at: Any Time Point (N0), Baseline (N1), Baseline and Post-Baseline (N2), and Post-Baseline and Without Positive Baseline ADA Result (N3)

Secondary: Number of Subjects With at Least 1 Valid Anti-drug Antibody (ADA) Result at: Any Time Point (N0), Baseline (N1), Baseline and Post-Baseline (N2), and Post-Baseline and Without Positive Baseline ADA Result (N3)

Secondary: Number of Subjects by ADA Categories

Secondary: Number of Subjects by ADA Categories

Secondary: Phase 2: TTR in Subjects with Confirmed CR or PR

Secondary: Phase 2: TTR in Subjects with Confirmed CR or PR

Secondary: Phase 1b: Time to Response (TTR) in Subjects with Confirmed CR or PR

Secondary: Phase 1b: Time to Response (TTR) in Subjects with Confirmed CR or PR

Secondary: Phase 1b: Percentage of Subjects With Confirmed OR as per RECIST v1.1 and PCWG3 by Investigator Assessment

Secondary: Phase 1b: Percentage of Subjects With Confirmed OR as per RECIST v1.1 and PCWG3 by Investigator Assessment

Secondary: Phase 2: Duration of Response (DR) in Subjects with Confirmed CR or PR

Secondary: Phase 2: Duration of Response (DR) in Subjects with Confirmed CR or PR

Secondary: Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1 and PCWG3)

Secondary: Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1 and PCWG3)

Secondary: Phase 1b: Progression-Free Survival (PFS) in Subjects with Confirmed CR or PR

Secondary: Phase 1b: Progression-Free Survival (PFS) in Subjects with Confirmed CR or PR

Secondary: Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1)

Secondary: Phase 2: PFS in Subjects with Confirmed CR or PR (RECIST v1.1)

Secondary: Phase 1b: Overall Survival

Secondary: Phase 1b: Overall Survival

Secondary: Phase 2: Time to Prostate-Specific Antigen (PSA) Progression for Subjects with mCRPC

Secondary: Phase 2: Time to Prostate-Specific Antigen (PSA) Progression for Subjects with mCRPC

Secondary: Phase 2: Overall Survival

Secondary: Phase 2: Overall Survival

Secondary: Phase 2: Percentage of Subjects With PSA Response

Secondary: Phase 2: Percentage of Subjects With PSA Response

Secondary: Phase 1b: Percentage of Subjects With CA-125 Response

Secondary: Phase 1b: Percentage of Subjects With CA-125 Response

Secondary: Number of Subjects With Different Programmed Death-Ligand 1 (PD-L1) Status at Baseline

Secondary: Number of Subjects With Different Programmed Death-Ligand 1 (PD-L1) Status at Baseline

Secondary: Phase 2: Percentage of Subjects With CA-125 Response

Secondary: Phase 2: Percentage of Subjects With CA-125 Response

Secondary: Number of Subjects With Different Tumor Mutational Burden (TMB) at Baseline

Secondary: Number of Subjects With Different Tumor Mutational Burden (TMB) at Baseline

Secondary: Number of Subjects With Different DNA Damage Repair (DDR) Status at Baseline

Secondary: Number of Subjects With Different DNA Damage Repair (DDR) Status at Baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
A Phase 1b/2 Study to Evaluate Safety and Anti-Tumor Activity of Avelumab in Combination With the Poly (Adenosine Diphosphate [ADP]-Ribose)