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Clinical Trial Results:
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AND/OR FOLLOWING CHEMOTHERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED EPITHELIAL OVARIAN CANCER

Summary
EudraCT number	2015-003239-36
Trial protocol	SK NL BG HU EE IE GB LV DE PL HR IT
Global end of trial date	16 May 2019

Results information
Results version number	v1(current)
This version publication date	29 May 2020
First version publication date	29 May 2020
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

B9991010

ISRCTN number

US NCT number

NCT02718417

WHO universal trial number (UTN)

Other trial identifiers

Alias Study Number: JAVELIN OVARIAN 100

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 E 42nd 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 8007181021, 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

03 Apr 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

16 May 2019

Was the trial ended prematurely?

Main objective of the trial

To demonstrate that avelumab in combination with platinum-based chemotherapy followed by avelumab maintenance (Arm C) is superior to platinum-based chemotherapy alone followed by observation (Arm A) in prolonging progression free survival (PFS) in subjects with previously untreated epithelial ovarian cancer (EOC). Also, to demonstrate that platinum-based chemotherapy alone followed by avelumab maintenance (Arm B) is superior to platinum-based chemotherapy alone followed by observation (Arm A) in prolonging PFS in patients with previously untreated EOC.

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 Council for Harmonization (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 May 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 41

Country: Number of subjects enrolled

United States: 240

Country: Number of subjects enrolled

Hong Kong: 12

Country: Number of subjects enrolled

Japan: 100

Country: Number of subjects enrolled

Korea, Republic of: 88

Country: Number of subjects enrolled

Singapore: 13

Country: Number of subjects enrolled

Taiwan: 34

Country: Number of subjects enrolled

European Union: 103

Country: Number of subjects enrolled

Mexico: 8

Country: Number of subjects enrolled

Turkey: 27

Country: Number of subjects enrolled

Russian Federation: 101

Country: Number of subjects enrolled

Ukraine: 61

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Ireland: 10

Country: Number of subjects enrolled

Italy: 79

Country: Number of subjects enrolled

Netherlands: 9

Country: Number of subjects enrolled

Switzerland: 2

Country: Number of subjects enrolled

United Kingdom: 62

Worldwide total number of subjects

998

EEA total number of subjects

168

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)

687

From 65 to 84 years

310

85 years and over

Subject disposition

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Recruitment details

Screening details

The study was conducted at 25 countries between 19 May 2016 and 16 May 2019.

Period 1 title

Chemotherapy Phase (CP)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemotherapy followed by Avelumab

Arm description

In chemotherapy phase,based on investigator’s decision,subjects received either:paclitaxel 175 milligrams per square meter (mg/m2) intravenous (IV) infusion,followed by carboplatin dose at area under curve (AUC) 5 or 6,IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (glomerular filtration rate[GFR] mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6; or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15, along with carboplatin dose at AUC 5 or 6, IV infusion over 1 hour on Day 1 of Cycle 1 to 6.Each cycle was of 21 days.After completion of chemotherapy phase, subjects without evidence of disease progression, received avelumab 10 mg/kg, over 1 hour IV infusion,once every 2 weeks on Days 1, 15, and 29 of each cycle of 42 days in maintenance phase until confirmed progressive disease,unacceptable toxicity, or withdrawal of consent, or a maximum duration of 24 months. Safety evaluation followed up to Month 36.

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 milligrams per square meter (mg/m2) intravenous (IV) infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at area under curve (AUC) 5 or 6,IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (glomerular filtration rate[GFR] mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Avelumab 10 mg/kg, over 1 hour IV infusion, once every 2 weeks on Days 1, 15, and 29 of each cycle of 42 days in maintenance phase.

Chemotherapy + Avelumab followed by Avelumab

Arm description

In chemotherapy phase,based on investigator’s decision,subjects received either:paclitaxel 175 mg/m2,IV,followed by carboplatin dose at AUC 5 or 6,IV (carboplatin dose [milligrams](mg) = Target AUC (mg*min/mL) x GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6;or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15, along with carboplatin dose at AUC 5 or 6, IV infusion over 1 hour on Day 1 of Cycle 1 to 6 along with Avelumab 10 mg/kg administered as a 1-hour IV infusion once every 3 weeks for Cycle 1 to 6. Each cycle was of 21 days (3 weeks).After completion of chemotherapy phase, subjects without evidence of disease progression, received Avelumab IV, 10 mg/kg, once every 2 weeks on Days 1, 15, and 29 of each cycle of 42 days in maintenance phase until confirmed progressive disease (PD), unacceptable toxicity, or withdrawal of consent, or a maximum duration of 24 months. Safety evaluation followed up to Month 36.

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 mg/m2, IV infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Avelumab 10 mg/kg, over 1 hour IV infusion, once every 3 weeks on Day 1 for Cycle 1 to 6 in chemotherapy phase. Each cycle was of 21 days (3 weeks). After completion of chemotherapy phase, Avelumab IV, 10 mg/kg, once every 2 weeks on Days 1, 15, and 29 of each cycle of 42 days in maintenance phase.

Chemotherapy followed by Observation

Arm description

In chemotherapy phase, based on investigator’s decision, subjects received either: paclitaxel 175 mg/m2, IV infusion, followed by carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose [milligrams](mg) = Target AUC [milligrams*minute per milliliter] (mg*min/mL) x GFR mL/min + 25), and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6; or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15, along with carboplatin dose at AUC 5 or 6, IV infusion over 1 hour on Day 1 of Cycle 1 to 6. Each cycle was of 21 days (3 weeks). After completion of chemotherapy phase, subjects were followed every 12 weeks for survival status until death or until study completion, whichever was earlier or a maximum duration of 24 months in observation phase. Subjects were then followed up to Month 36 for safety evaluation (long-term follow up phase).

Arm type

Control

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 mg/m2, IV infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Number of subjects in period 1	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Started	332	331	335
Safety population	328	329	334
Completed	280	294	289
Not completed	52	37	46
Adverse event, serious fatal	5	4	1
Consent withdrawn by subject	13	8	15
Physician decision	5	-	4
Global deterioration of health status	3	2	1
Adverse event, non-fatal	9	14	13
No longer met eligibility criteria	4	2	1
Unspecified	2	-	1
Progressive disease	11	7	10

Period 2 title

Maintenance (MP), Observation Phase (OP)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemotherapy followed by Avelumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 milligrams per square meter (mg/m2) intravenous (IV) infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Avelumab 10 mg/kg, over 1 hour IV infusion, once every 2 weeks on Days 1, 15, and 29 of each cycle of 42 days in maintenance phase.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Chemotherapy + Avelumab followed by Avelumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 mg/m2, IV infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Chemotherapy followed by Observation

Arm description

Arm type

Control

Investigational medicinal product name

No investigational medicinal product assigned in this arm

Number of subjects in period 2 ^[1]	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Started	267	288	284
Completed	1	1	2
Not completed	266	287	282
Adverse event, serious fatal	1	1	2
Consent withdrawn by subject	17	20	34
Physician decision	6	7	9
Global deterioration of health status	5	3	1
Adverse event, non-fatal	21	26	1
No longer met eligibility criteria	-	1	-
Study terminated by sponsor	114	140	135
Unspecified	2	1	7
Progressive disease	100	88	92
Lost to follow-up	-	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Subjects not completing chemotherapy phase could also start this phase.

Period 3 title

Follow-up Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemotherapy followed by Avelumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 milligrams per square meter (mg/m2) intravenous (IV) infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Avelumab 10 mg/kg, over 1 hour IV infusion, once every 2 weeks on Days 1, 15, and 29 of each cycle of 42 days in maintenance phase.

Chemotherapy + Avelumab followed by Avelumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 mg/m2, IV infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Chemotherapy followed by Observation

Arm description

Arm type

Control

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 mg/m2, IV infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Number of subjects in period 3 ^[2]	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Started	1	1	1
Completed	103	91	20
Not completed	135	172	19
Adverse event, serious fatal	7	7	3
Consent withdrawn by subject	19	17	5
Adverse event, non-fatal	3	1	1
Study terminated by sponsor	100	138	6
Unspecified	4	6	4
Lost to follow-up	2	3	-
Joined	237	262	38
Not completing MP or OP who started	237	262	38

Notes
[2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Subjects not completing maintenance, observation phase could also start this phase.

Period 4 title

Long-term follow-up Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Chemotherapy followed by Avelumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 milligrams per square meter (mg/m2) intravenous (IV) infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Avelumab 10 mg/kg, over 1 hour IV infusion, once every 2 weeks on Days 1, 15, and 29 of each cycle of 42 days in maintenance phase.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Chemotherapy + Avelumab followed by Avelumab

Arm description

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 mg/m2, IV infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Avelumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Chemotherapy followed by Observation

Arm description

Arm type

Control

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel 175 mg/m2, IV infusion on Day 1 of Cycles 1 to 6 or Paclitaxel 80 mg/m2 IV infusion over 1 hour on Days 1, 8, and 15 of Cycles 1 to 6.

Investigational medicinal product name

Carboplatin

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Intravenous use

Dosage and administration details

Carboplatin dose at AUC 5 or 6, IV infusion (carboplatin dose (mg) = Target AUC (mg*min/mL) x (GFR mL/min + 25),and maximum carboplatin dose = target AUC x (150 mL/min) on Day 1 of Cycles 1 to 6.

Number of subjects in period 4 ^[3]	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Started	89	82	19
Completed	0	0	0
Not completed	139	112	135
Adverse event, serious fatal	20	17	11
Consent withdrawn by subject	6	9	9
Study terminated by sponsor	105	80	112
Unspecified	-	2	-
Lost to follow-up	8	4	3
Joined	50	30	116
Not completing follow-up phase who started	50	30	116

Notes
[3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Subjects not completing follow-up phase could also start this phase.

Baseline characteristics

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Reporting group title

Chemotherapy followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy + Avelumab followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy followed by Observation

Reporting group description

Reporting group values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation	Total
Number of subjects	332	331	335	998
Age categorical
Units: Subjects
Adults (18-64 years)	224	224	239	687
From 65-84 years	107	107	96	310
85 years and over	1	0	0	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	58.34 ± 11.00	58.16 ± 10.85	57.10 ± 11.27	-
Sex: Female, Male
Units: Subjects
Female	332	331	335	998
Male	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
Black or African American	2	4	1	7
American Indian or Alaska Native	1	0	0	1
Asian	86	82	95	263
White	236	238	236	710
Other	7	7	3	17

End points

Top of page

Reporting group title

Chemotherapy followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy + Avelumab followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy followed by Observation

Reporting group description

Reporting group title

Chemotherapy followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy + Avelumab followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy followed by Observation

Reporting group description

Reporting group title

Chemotherapy followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy + Avelumab followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy followed by Observation

Reporting group description

Reporting group title

Chemotherapy followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy + Avelumab followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy followed by Observation

Reporting group description

Subject analysis set title

PK: Chemotherapy followed by Avelumab

Subject analysis set type

Per protocol

Subject analysis set description

In chemotherapy phase, subjects received paclitaxel once every three weeks (Q3W) (or once weekly [QW] on Days 1, 8 and 15), followed by carboplatin Q3W on Day 1 of each 21 day cycle for 6 cycles. During the maintenance phase, subjects received avelumab once every 2 weeks (Q2W) on Days 1, 15 and 29 of each 42 day cycle.

Subject analysis set title

PK: Chemotherapy + Avelumab followed by Avelumab

Subject analysis set type

Per protocol

Subject analysis set description

In chemotherapy phase, subjects received paclitaxel Q3W (or QW on Days 1, 8 and 15), followed by carboplatin Q3W along with avelumab Q3W on Day 1 of each 21 day cycle for 6 cycles. During the maintenance phase, subjects received avelumab Q2W (on Days 1, 15 and 29 of each 42 day cycle).

Subject analysis set title

PK: Chemotherapy followed by Observation

Subject analysis set type

Per protocol

Subject analysis set description

In chemotherapy phase, subjects received paclitaxel Q3W (or QW on Day 1, 8 and 15), followed by carboplatin Q3W on Day 1 of each 21 day cycle for 6 cycles.

Subject analysis set title

PK: Chemotherapy followed by Avelumab

Subject analysis set type

Per protocol

Subject analysis set description

In chemotherapy phase, subjects received paclitaxel Q3W (or QW on Days 1, 8 and 15), followed by carboplatin Q3W on Day 1 of each 21 day cycle for 6 cycles. During the maintenance phase, subjects received avelumab Q2W on Days 1, 15 and 29 of each 42 day cycle.

Subject analysis set title

PK: Chemotherapy + Avelumab followed by Avelumab

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PK: Chemotherapy followed by Observation

Subject analysis set type

Per protocol

Subject analysis set description

In chemotherapy phase, subjects received paclitaxel Q3W (or QW on Day 1, 8 and 15), followed by carboplatin Q3W on Day 1 of each 21 day cycle for 6 cycles.

Subject analysis set title

PK: Chemotherapy followed by Avelumab

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PK: Chemotherapy followed by Observation

Subject analysis set type

Per protocol

Subject analysis set description

In chemotherapy phase, subjects received paclitaxel Q3W (or QW on Day 1, 8 and 15), followed by carboplatin Q3W on Day 1 of each 21 day cycle for 6 cycles.

Subject analysis set title

PK: Chemotherapy + Avelumab followed by Avelumab

Subject analysis set type

Per protocol

Subject analysis set description

Subject analysis set title

PK: Chemotherapy followed by Observation

Subject analysis set type

Per protocol

Subject analysis set description

In chemotherapy phase, subjects received paclitaxel Q3W (or QW on Day 1, 8 and 15), followed by carboplatin Q3W on Day 1 of each 21 day cycle for 6 cycles.

Primary: Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)

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End point title

Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)

End point description

BICR assessed PFS: Duration from randomization until disease progression or death. PFS data censored on date of last adequate tumor assessment for subjects who did not have an event (progression of disease or death),who started new anti-cancer therapy prior to an event or subjects with an event after 2 or more missing tumor assessments. Progression as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1:at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes the baseline sum if that is smallest on study). In addition to relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method. Median and upper limit of 95% CI was not estimable due to limited number of events and has been denoted by '99999'. Full analysis set: all randomized subjects

End point type

Primary

End point timeframe

Baseline to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	332	331	335
Units: months
median (confidence interval 95%)	16.8 (13.5 to 99999)	18.1 (14.8 to 99999)	99999 (18.2 to 99999)

Chemotherapy by Avelumab Vs. Chemo by Observation

Statistical analysis description

Analysis was performed using a Cox’s Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.

Comparison groups

Chemotherapy followed by Avelumab v Chemotherapy followed by Observation

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.989 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.43

Confidence interval

level

95%

sides

2-sided

lower limit

1.051

upper limit

1.946

Notes
[1] - One-sided log-rank test was used.

Chemo + Avel by Avel Vs. Chemo by Observation

Statistical analysis description

Analysis was performed using a Cox’s Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.

Comparison groups

Chemotherapy + Avelumab followed by Avelumab v Chemotherapy followed by Observation

Number of subjects included in analysis

666

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7935 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.832

upper limit

1.565

Notes
[2] - One-sided log-rank test was used.

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall survival was defined as the time (in months) from the date of randomization to the date of death due to any cause. Subjects last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method. Median and 95% CI were not estimable due to limited number of events and has been denoted by '99999'. The full analysis set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	332	331	335
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

Chemotherapy by Avelumab Vs. Chemo by Observation

Statistical analysis description

Analysis was performed using a Cox’s Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.

Comparison groups

Chemotherapy followed by Avelumab v Chemotherapy followed by Observation

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8848 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.53

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

3.08

Notes
[3] - One-sided log-rank test was used.

Chemo + Avel by Avel Vs. Chemo by Observation

Statistical analysis description

Analysis was performed using a Cox’s Proportional Hazard model stratified by the randomization strata and a stratified log-rank test.

Comparison groups

Chemotherapy + Avelumab followed by Avelumab v Chemotherapy followed by Observation

Number of subjects included in analysis

666

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8953 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.776

upper limit

3.111

Notes
[4] - One-sided log-rank test was used.

Secondary: Progression-Free Survival (PFS) as Assessed by Investigator

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End point title

Progression-Free Survival (PFS) as Assessed by Investigator

End point description

Investigator assessed PFS was defined as time (in months) from date of randomization to the first documentation of disease progression or death (due to any cause), whichever occurred first. Progression as per RECIST 1.1, was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using a Cox’s Proportional Hazard model stratified by the randomization strata and a stratified log-rank test. The full analysis set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	332	331	335
Units: months
median (confidence interval 95%)	13.8 (12.1 to 15.9)	16.1 (13.9 to 19.4)	15.0 (13.2 to 18.7)

Chemotherapy by Avelumab Vs. Chemo by Observation

Comparison groups

Chemotherapy followed by Avelumab v Chemotherapy followed by Observation

Number of subjects included in analysis

667

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.9278 ^[5]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.21

Confidence interval

level

95%

sides

2-sided

lower limit

0.935

upper limit

1.578

Notes
[5] - One-sided log-rank test was used.

Chemo + Avel by Avel Vs. Chemo by Observation

Comparison groups

Chemotherapy + Avelumab followed by Avelumab v Chemotherapy followed by Observation

Number of subjects included in analysis

666

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.2367 ^[6]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

0.688

upper limit

1.189

Notes
[6] - One-sided log-rank test was used.

Secondary: Percentage of Subjects With Objective Response as Assessed by Investigator

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End point title

Percentage of Subjects With Objective Response as Assessed by Investigator

End point description

Investigator assessed objective response according to RECIST version 1.1, was defined as subjects with confirmed best overall response of complete response (CR) or partial response (PR). CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. The full analysis set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	332	331	335
Units: percentage of subjects
number (confidence interval 95%)	25.9 (21.3 to 31.0)	31.1 (26.2 to 36.4)	27.8 (23.0 to 32.9)

No statistical analyses for this end point

Secondary: Percentage of Subjects With Objective Response as Assessed by Blinded Independent Central Review (BICR)

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End point title

Percentage of Subjects With Objective Response as Assessed by Blinded Independent Central Review (BICR)

End point description

BICR assessed objective response according to RECIST version 1.1, was defined as subjects with confirmed best overall response of CR or PR. CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. The full analysis set included all randomized subjects.

End point type

Secondary

End point timeframe

Baseline to progression of disease, start of new anti-cancer therapy or discontinuation from study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	332	331	335
Units: percentage of subjects
number (confidence interval 95%)	30.4 (25.5 to 35.7)	36.0 (30.8 to 41.4)	30.4 (25.6 to 35.7)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as Assessed by Investigator

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End point title

Duration of Response (DOR) as Assessed by Investigator

End point description

Investigator assessed DOR: time in months from first documentation of objective response to date of first documentation of PD or death due to any cause. RECIST version 1.1, CR:disappearance of all target and non-target lesions,sustained for at least 4 weeks. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD:at least 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (included baseline sum if that is smallest). In addition, sum must have an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method on subset of randomized subjects, who had objective response, as assessed by Investigator. Median and upper limit of 95% CI was not estimable due to limited number of events and denoted by '99999'

End point type

Secondary

End point timeframe

First response subsequently confirmed to progression of disease or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	86	103	93
Units: months
median (confidence interval 95%)	10.6 (8.3 to 20.2)	99999 (11.7 to 99999)	15.4 (8.3 to 18.4)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR)

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End point title

Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR)

End point description

BICR assessed DOR: time from first documentation of objective response to date of first documentation of PD or death due to any cause. RECIST version 1.1, CR:disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR:at least 30% decrease in sum of longest dimensions of target lesions taking as reference baseline sum longest dimensions. PD:at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that is smallest on study). In addition, sum must havean absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method on subset of randomized subjects, who had objective response, as assessed by BICR. Median and upper limit of 95% CI was not estimable due to limited number of events and denoted by '99999'.

End point type

Secondary

End point timeframe

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	101	119	102
Units: months
median (confidence interval 95%)	11.9 (8.9 to 99999)	14.5 (11.7 to 99999)	99999 (16.1 to 99999)

No statistical analyses for this end point

Secondary: Maintenance Progression-Free Survival as Assessed by Blinded Independent Central Review (BICR)

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End point title

Maintenance Progression-Free Survival as Assessed by Blinded Independent Central Review (BICR)

End point description

BICR assessed maintenance PFS: defined as time from Cycle 1 Day 1 of maintenance phase to date of first documentation of PD or death due to any cause, whichever occurs first. Defined, for subjects who proceeded to maintenance phase and who did not have disease progression by BICR during chemotherapy phase. RECIST version 1.1, PD: at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that is smallest on study). In addition, sum must have an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method. Analysis set: randomized subjects who proceeded to maintenance phase and who did not have PD by BICR assessment during chemotherapy phase. Median and upper limit of 95% CI was not estimable due to limited number of events and is denoted by '99999'.

End point type

Secondary

End point timeframe

From Day 1 of Cycle 1 (42 days) of maintenance phase to progression of disease or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	248	267	247
Units: months
median (confidence interval 95%)	13.6 (9.3 to 99999)	13.8 (11.1 to 99999)	99999 (13.8 to 99999)

No statistical analyses for this end point

Secondary: Maintenance Progression-Free Survival (PFS) as Assessed by Investigator

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End point title

Maintenance Progression-Free Survival (PFS) as Assessed by Investigator

End point description

Investigator assessed maintenance PFS: time from Cycle 1 Day 1 of maintenance phase to date of first documentation of PD or death due to any cause, whichever occurs first. Defined, for subjects who proceeded to maintenance phase and who did not have disease progression by investigator during chemotherapy phase.RECIST version 1.1, PD:at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this included baseline sum if that is smallest on study). In addition,sum must have also demonstrated an absolute increase of at least 5 mm. Appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method. Analysis set:randomized subjects who proceeded to maintenance phase and who did not have PD by investigator assessment during chemotherapy phase. Upper limit of 95% CI was not estimable due to limited number of events and denoted by '99999'.

End point type

Secondary

End point timeframe

From Day 1 of Cycle 1 (42 days) of maintenance phase to progression of disease or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	252	271	252
Units: months
median (confidence interval 95%)	10.4 (8.2 to 13.6)	11.6 (9.9 to 13.8)	12.7 (9.5 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Subjects with Pathological Complete Response (pCR)

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End point title

Percentage of Subjects with Pathological Complete Response (pCR)

End point description

pCR was defined (for neoadjuvant subjects who underwent interval debulking surgery [IDS]), as the chemotherapy response score 3 (CSR3), based on a study by Bohm et al, 2015. CSR3 was defined as complete or near-complete response with no residual tumor or minimal irregularly scattered tumor foci seen as individual cells, cell groups, or nodules up to 2 mm. Complete or near-complete response was defined as complete or near-complete microscopic disappearance of invasive tumor/ residual disease. Analysis was performed on a subset of randomized subjects which included neoadjuvant subjects who underwent IDS.

End point type

Secondary

End point timeframe

Baseline to progression of disease or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	108	115	116
Units: percentage of subjects
number (not applicable)	15.7	17.4	25.9

No statistical analyses for this end point

Secondary: Progression-Free Survival 2 (PFS2)

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End point title

Progression-Free Survival 2 (PFS2)

End point description

PFS2 was defined as time (in months) from the date of randomization to the start of second subsequent treatment after first documentation of PD, or death from any cause, whichever occurred first. Progression as per RECIST version 1.1, was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression. Analysis was performed using Kaplan-Meier method. The trial was terminated due to crossing of futility boundaries for both experimental arms as compared to the control arm at the pre-specified interim analysis for PFS based on BICR assessment. Subsequently, the data for this endpoint was not collected and analyzed.

End point type

Secondary

End point timeframe

Baseline up to start of second subsequent treatment after first PD or discontinuation from study or death, which ever occured first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	0 ^[7]	0 ^[8]	0 ^[9]
Units: months
median (confidence interval 95%)	( to )	( to )	( to )

Notes
[7] - The data for this endpoint was not collected and analyzed due to futility reasons.
[8] - The data for this endpoint was not collected and analyzed due to futility reasons.
[9] - The data for this endpoint was not collected and analyzed due to futility reasons.

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) as Assessed by Gynecological Cancer Intergroup (GCIG) Criteria

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End point title

Progression-Free Survival (PFS) as Assessed by Gynecological Cancer Intergroup (GCIG) Criteria

End point description

PFS by GCIG was assessed by both RECIST 1.1 and cancer antigen 125 (CA-125). Defined as time from randomization to first documentation of disease progression (PD) or death, whichever occurred first. PD defined as per RECIST 1.1. PD based on serum CA-125 was defined as (i) subjects with elevated CA-125 pretreatment and normalization of CA-125, (ii) CA-125 in reference range before treatment; (i) and (ii) must have showed CA-125 >= 2 times upper limit of reference range on 2 occasions >= 1 week apart, or (iii) elevated CA-125 before treatment, which never normalized, showed CA-125 >= 2 times the nadir value on 2 occasions >= 1 week apart. Censoring date for PFS by GCIG was latest of censoring dates for PFS by RECIST 1.1 and PFS by CA-125. Trial was terminated due to crossing of futility boundaries for both experimental arms as compared to the control arm at pre-specified interim analysis for PFS based on BICR assessment. Data for this endpoint was not collected and analyzed.

End point type

Secondary

End point timeframe

Baseline until disease progression by GCIG criteria or start of new anti-cancer therapy or discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	0 ^[10]	0 ^[11]	0 ^[12]
Units: months
median (confidence interval 95%)	( to )	( to )	( to )

Notes
[10] - The data for this endpoint was not collected and analyzed due to futility reasons.
[11] - The data for this endpoint was not collected and analyzed due to futility reasons.
[12] - The data for this endpoint was not collected and analyzed due to futility reasons.

No statistical analyses for this end point

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

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End point title

Number of Subjects With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

End point description

AE:any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship.NCI-CTCAE version 4.03,Grade 1:asymptomatic or mild symptoms,clinical or diagnostic observations only,intervention not indicated;Grade 2:moderate,minimal,local or noninvasive intervention indicated,limiting age-appropriate instrumental activities of daily life(ADL); Grade 3:severe or medically significant but not immediately life-threatening,hospitalization or prolongation of existing hospitalization indicated,disabling,limiting self-care ADL; Grade 4:life-threatening consequence,urgent intervention indicated; Grade 5:death related to AE. Treatment-emergent events: events between first dose of study drug and up to 36 months that were absent before treatment or worsened relative to pretreatment state. Safety analysis set:all subjects who had received at least one dose of study drug. Here,‘number of subjects analysed’=subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 36 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	323	328	321
Units: subjects
Grade 1	11	13	15
Grade 2	89	77	96
Grade 3	151	148	131
Grade 4	67	84	76
Grade 5	5	6	3

No statistical analyses for this end point

Secondary: Number of Subjects With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

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End point title

Number of Subjects With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

End point description

NCI-CTCAE v 4.03,Grade 3 and above criteria; Hematology [Anemia - Grade 3: hemoglobin <8.0 grams per deciliter (g/dL), <4.9 millimoles per liter (mmol/L),<80 grams per liter (g/L), transfusion indicated, Grade 4: life-threatening consequences, urgent intervention indicated, Grade 5:death; platelet count decreased- Grade 3:<50.0 to 25.0*10^9/Liters(L),Grade 4: <25.0*10^9/L;lymphocyte count decreased-Grade 3: <0.5-0.2*10^9/L, Grade 4: <0.2*10^9/L; neutrophil count decreased-Grade 3: <1.0 to 0.5*10^9 /L, Grade 4: <0.5*10^9/L]. Chemistry[creatinine increased-Grade 3: >3.0 to 6.0*upper limit of normal (ULN), Grade 4: >6.0*ULN; serum amylase increased, lipase increased-Grade 3: >2.0 - 5.0*ULN, Grade 4: >5.0*ULN]. Liver function [aspartate aminotransferase(AST) and alanine aminotransferase(ALT)-Grade 3: >5.0 to 20.0*ULN, Grade 4: >20.0*ULN]. Safety analysis set:all subjects who had received at least one dose of study drug. Here,‘n’ = Subjects evaluable for this end point at specified rows.

End point type

Secondary

End point timeframe

Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	328	329	334
Units: subjects
Anemia(n=326,326,328)	73	68	63
Platelet Count Decreased(n=326,326,328)	20	35	38
Lymphocyte Count Decreased(n=326,326,328)	35	63	29
Neutrophil Count Decreased(n=326,326,328)	144	159	156
Creatinine Increased(n=324,326,327)	2	7	0
Serum Amylase Increased(n=321,322,326)	5	9	10
Lipase Increased(n=323,323,325)	19	24	11
ALT or AST(n=324,326,327)	0	1	0

No statistical analyses for this end point

Secondary: Change from Baseline in Vital Signs - Blood Pressure at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

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End point title

Change from Baseline in Vital Signs - Blood Pressure at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

End point description

Vital signs included blood pressure and pulse rate. Blood pressure included sitting diastolic blood pressure (DBP) and sitting systolic blood pressure (SBP). Safety analysis set:all subjects who had received at least one dose of study drug. Here, ‘number of subjects analysed’ = subjects who were evaluable for this endpoint and ‘n’ = subjects evaluable for this end point at specified rows.

End point type

Secondary

End point timeframe

Baseline, first 3 months of Chemotherapy Phase (CP): Day 1 of Cycles 2, 3 and 4 (each cycle 21 days); Maintenance Phase (MP): Days 1, 15 and 29 of Cycles 1 and 2 (each cycle 42 days) and at end of treatment (up to 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	318	317	316
Units: millimeters of mercury
arithmetic mean (standard deviation)
CP:ChangeatDay1,Cycle2:SittingDBP(n=310,305,301)	0.00 ± 9.28	0.10 ± 9.86	0.70 ± 9.33
CP:ChangeatDay 1,Cycle 3:SittingDBP(n=305,299,295)	-0.50 ± 10.18	0.50 ± 10.84	1.00 ± 9.69
CP:ChangeatDay1,Cycle4:SittingDBP(n=287,291,289)	-0.10 ± 10.48	-0.50 ± 10.89	-0.40 ± 10.19
MP:ChangeatDay1,Cycle1:SittingDBP(n=253,266,253)	-2.20 ± 10.36	-1.30 ± 10.74	-0.90 ± 10.54
MP:ChangeatDay15,Cycle1:SittingDBP(n=241,249,3)	-2.10 ± 10.04	-1.80 ± 10.57	-9.70 ± 5.69
MP:ChangeatDay29,Cycle1:SittingDBP(n=233,249,3)	-1.70 ± 10.29	-1.80 ± 11.24	-8.30 ± 6.03
MP:ChangeatDay1,Cycle2:SittingDBP(n=229,247,226)	-2.30 ± 10.26	-1.70 ± 10.63	-0.70 ± 10.67
MP:ChangeatDay15,Cycle2:SittingDBP(n=219,236,0)	-2.00 ± 10.71	-2.40 ± 10.82	99999 ± 99999
MP:ChangeatDay29,Cycle2:SittingDBP(n=215,225,0)	-2.60 ± 10.86	-1.90 ± 10.16	99999 ± 99999
ChangeatEOT:SittingDBP(n=137,116,120)	-0.70 ± 11.36	0.00 ± 12.45	0.70 ± 10.00
CP:ChangeatDay1,Cycle2:SittingSBP(n=310,305,301)	2.30 ± 14.91	0.70 ± 15.32	1.00 ± 14.00
CP:ChangeatDay1,Cycle3:SittingSBP(n=305,299,295)	1.50 ± 14.00	-0.30 ± 15.48	1.70 ± 14.80
CP:ChangeatDay1,Cycle4:SittingSBP(n=287,291,289)	1.00 ± 14.60	0.10 ± 16.75	0.60 ± 15.61
MP:ChangeatDay1,Cycle1:SittingSBP(n=253,266,253)	-1.80 ± 15.12	-1.60 ± 16.64	0.00 ± 14.81
MP:ChangeatDay15,Cycle1:SittingSBP(n=241,249,3)	-1.10 ± 14.37	-3.20 ± 16.44	-4.70 ± 10.21
MP:ChangeatDay29,Cycle1:SittingSBP(n=233,249,3)	-2.20 ± 15.81	-2.80 ± 15.93	-9.30 ± 8.14
MP:Changeat Day1,Cycle2:SittingSBP(n=229,247,226)	-1.20 ± 15.16	-0.60 ± 15.46	-0.50 ± 14.43
MP:ChangeatDay15,Cycle 2:SittingSBP(n=219,236,0)	-2.10 ± 14.44	-3.90 ± 16.20	99999 ± 99999
MP:Changeat Day29,Cycle2:SittingSBP(n=215,225,0)	-2.70 ± 13.79	-2.90 ± 15.28	99999 ± 99999
Changeat EOT:Sitting SBP(n=137,116,120)	1.70 ± 16.96	-1.00 ± 17.56	2.90 ± 16.69

No statistical analyses for this end point

Secondary: Change from Baseline in Vital Signs - Pulse Rate at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

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End point title

Change from Baseline in Vital Signs - Pulse Rate at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

End point description

Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized. Safety analysis set:all subjects who had received at least one dose of study drug. Here, ‘number of subjects analysed’ = subjects who were evaluable for this endpoint and ‘n’ = subjects evaluable for this end point at specified rows.

End point type

Secondary

End point timeframe

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	318	317	316
Units: beats per minute
arithmetic mean (standard deviation)
CP:Change at Day 1, Cycle 2(n=310,304,301)	-0.5 ± 12.34	1.80 ± 12.04	-0.70 ± 11.42
CP: Change at Day 1, Cycle 3(n=305,298,295)	-0.20 ± 12.71	2.90 ± 13.64	-0.0 ± 12.29
CP: Change at Day 1, Cycle 4(n=287,290,289)	-0.30 ± 13.49	1.90 ± 13.86	-0.30 ± 14.02
MP: Change at Day 1, Cycle 1(n=253,266,253)	-1.90 ± 13.70	-0.10 ± 13.99	-0.70 ± 13.02
MP: Change at Day 15, Cycle 1(n=241,249,3)	-2.90 ± 12.94	-2.40 ± 13.57	-11.70 ± 15.14
MP: Change at Day 29, Cycle 1(n=233,249,3)	-3.10 ± 12.48	-3.60 ± 13.48	-4.00 ± 7.55
MP: Change at Day 1, Cycle 2(n=228,247,226)	-3.50 ± 13.71	-4.70 ± 13.09	-3.40 ± 13.11
MP: Change at Day 15, Cycle 2(n=219,236,0)	-5.10 ± 13.73	-4.90 ± 13.67	99999 ± 99999
MP: Change at Day 29, Cycle 2(n=215,225,0)	-5.60 ± 13.71	-5.20 ± 12.79	99999 ± 99999
Change at EOT(n=136,116,119)	-1.60 ± 14.47	-1.50 ± 15.22	-3.70 ± 15.03

No statistical analyses for this end point

Secondary: Number of Subjects With Electrocardiogram (ECG) Abnormalities

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End point title

Number of Subjects With Electrocardiogram (ECG) Abnormalities

End point description

ECG abnormalities included: 1) QT interval, QT interval corrected using Bazett’s formula (QTcB) and QT interval corrected using Fridericia’s formula (QTcF): increase from baseline greater than (>) 30 millisecond (ms) or 60 ms; absolute value > 450 ms, >480 ms and > 500 ms; 2) heart rate (HR) : absolute value <=50 bpm and decrease from baseline >=20 bpm; absolute value >=120 beats per minute (bpm) and increase from baseline >=20 bpm; 3) PR interval: absolute value >=220 ms and increase from baseline >=20 ms; 4) QRS interval: absolute value >= 120 ms. Safety analysis set:all subjects who had received at least one dose of study drug. Here, ‘number of subjects analysed’ = subjects who were evaluable for this endpoint and ‘n’ = subjects in safety analysis set who had at least one baseline and post-baseline ECG assessment.

End point type

Secondary

End point timeframe

Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 27 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	317	321	320
Units: subjects
QT increase from baseline >30 ms(n=314,314,314)	128	152	106
QT increase from baseline >60 ms(n=314,314,314)	31	60	35
QT >450 ms (n=317,321,320)	12	30	20
QT >480 ms (n=317,321,320)	2	10	7
QT >500 ms (n=317,321,320)	1	6	5
QTcB increase from baseline >30 ms (n=300,303,306)	107	137	116
QTcB increase from baseline >60 ms (n=300,303,306)	19	38	25
QTcB >450 ms (n=303,312,313)	135	185	165
QTcB >480 ms (n=303,312,313)	29	63	32
QTcB >500 ms (n=303,312,313)	16	29	17
QTcF increase from baseline >30 ms (n=300,303,306)	90	125	89
QTcF increase from baseline >60 ms (n=300,303,306)	14	34	17
QTcF >450 ms (n=303,312,313)	44	83	53
QTcF >480 ms (n=303,312,313)	10	25	15
QTcF >500 ms (n=303,312,313)	6	11	11
Heartrate<=50 bpm&decrease>= 20bpm(n=300,303,306)	1	1	3
Heartrate>=120bpm&increase>=20bpm(n=300,303,306)	7	10	6
PR>=220msincreasefrombaseline>=20ms(n=312,311,313)	7	6	6
QRS >=120 ms (n=317,321,320)	7	9	16

No statistical analyses for this end point

Secondary: Functional Assessment of Ovarian Symptom Index- 18 (FOSI-18) Score

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End point title

Functional Assessment of Ovarian Symptom Index- 18 (FOSI-18) Score

End point description

The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy (NCCN-FACT) Ovarian Symptom Index-18 (FOSI-18) is an 18-itemed questionnaire, completed by patients, designed to assess the impact of cancer therapy on ovarian cancer-related symptoms. It is based on numerical point scoring of symptoms. It includes three subscales: disease-related symptoms (10 items), treatment-related side effects (5 items) and general function/well-being (3 items). Subjects rated their level of symptoms for each of the 18 items using 5-point scale from 0 (not at all) to 4 (very much). For items that were negatively framed, scores were reversed for analysis so that higher scores equated to good quality of life. The total symptom index was calculated as the total of 18 scores, ranging from 0 ("severely symptomatic") to 72 ("asymptomatic"). Higher FOSI-18 scores indicated better functioning or lower symptom burden. The full analysis set included all randomized subjects.

End point type

Secondary

End point timeframe

CP: Pre-dose on Day 1 of Cycles 2 to 6 (1 cycle= 21 days); MP:Day 1 of Cycles 1 to 12 (1 cycle= 42 days), End of treatment (any time up to at Month 27)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	332	331	335
Units: units on a scale
arithmetic mean (confidence interval 95%)
CP: Day 1, Cycle 2	54.33 (53.5 to 55.2)	53.88 (53.0 to 54.7)	54.27 (53.4 to 55.1)
CP: Day 1, Cycle 3	54.61 (53.8 to 55.5)	54.10 (53.2 to 54.9)	54.51 (53.6 to 55.4)
CP: Day 1, Cycle 4	54.88 (54.0 to 55.7)	54.31 (53.5 to 55.1)	54.75 (53.9 to 55.6)
CP: Day 1, Cycle 5	55.16 (54.3 to 56.0)	54.53 (53.7 to 55.4)	54.99 (54.1 to 55.8)
CP: Day 1, Cycle 6	55.43 (54.6 to 56.3)	54.74 (53.9 to 55.6)	55.23 (54.4 to 56.1)
MP: Day 1, Cycle 1	55.70 (54.9 to 56.5)	54.96 (54.1 to 55.8)	55.47 (54.6 to 56.3)
MP: Day 1, Cycle 2	56.25 (55.4 to 57.1)	55.39 (54.6 to 56.2)	55.95 (55.1 to 56.8)
MP: Day 1, Cycle 3	56.80 (55.9 to 57.7)	55.82 (55.0 to 56.7)	56.43 (55.6 to 57.3)
MP: Day 1, Cycle 4	57.35 (56.5 to 58.2)	56.25 (55.4 to 57.1)	56.91 (56.0 to 57.8)
MP: Day 1, Cycle 5	57.90 (57.0 to 58.8)	56.69 (55.8 to 57.6)	57.39 (56.4 to 58.3)
MP: Day 1, Cycle 6	58.45 (57.5 to 59.4)	57.12 (56.1 to 58.1)	57.87 (56.9 to 58.9)
MP: Day 1, Cycle 7	59.00 (57.9 to 60.1)	57.55 (56.5 to 58.6)	58.36 (57.3 to 59.4)
MP: Day 1, Cycle 8	59.55 (58.4 to 60.7)	57.98 (56.9 to 59.1)	58.84 (57.7 to 60.0)
MP: Day 1, Cycle 9	60.09 (58.9 to 61.3)	58.41 (57.2 to 59.6)	59.32 (58.1 to 60.5)
MP: Day 1, Cycle 10	60.64 (59.4 to 61.9)	58.84 (57.6 to 60.1)	59.80 (58.5 to 61.1)
MP: Day 1, Cycle 11	61.19 (59.8 to 62.6)	59.28 (57.9 to 60.6)	60.28 (58.9 to 61.7)
MP: Day 1, Cycle 12	61.74 (60.3 to 63.2)	59.71 (58.3 to 61.1)	60.76 (59.3 to 62.2)
End of treatment	57.04 (56.2 to 57.9)	56.01 (55.1 to 56.9)	56.64 (55.8 to 57.5)

No statistical analyses for this end point

Secondary: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Score

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End point title

European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Score

End point description

EQ-5D-5L:standardized subject completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). In VAS, subjects rated their overall health status from 0 (worst imaginable) to 100 (best imaginable). EQ-5D health state profile has 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. 57 overall scores ranged from 0 to 1, with low scores representing a higher level of dysfunction. Trial was terminated due to crossing of futility boundaries for both experimental arms as compared to the control arm at the pre-specified interim analysis for PFS based on BICR assessment. Data for this outcome measure was not collected and analyzed.

End point type

Secondary

End point timeframe

Baseline to discontinuation from the study or death, whichever occurred first (maximum duration of 36 months)

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	0 ^[13]	0 ^[14]	0 ^[15]
Units: units on a scale
arithmetic mean (standard deviation)	±	±	±

Notes
[13] - Data for this outcome measure was not collected and analyzed due to futility reasons.
[14] - Data for this outcome measure was not collected and analyzed due to futility reasons.
[15] - Data for this outcome measure was not collected and analyzed due to futility reasons.

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once a Week [QW] Regimen)

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End point title

Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once a Week [QW] Regimen)

End point description

Cmax is maximum plasma concentration of paclitaxel. The LLQ of paclitaxel was 10.0 ng/mL. Paclitaxel PK parameter analysis set: all subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for paclitaxel. Here ‘number of subjects analysed’ signifies subjects who received Paclitaxel infusion on QW regimen and had data available for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2

End point values	PK: Chemotherapy followed by Avelumab	PK: Chemotherapy + Avelumab followed by Avelumab	PK: Chemotherapy followed by Observation
Number of subjects analysed	6	4	9
Units: ng/mL
geometric mean (geometric coefficient of variation)	2880 ± 44	2678 ± 22	2649 ± 35

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once Every Three Weeks [Q3W] Regimen)

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End point title

Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once Every Three Weeks [Q3W] Regimen)

End point description

Cmax is maximum plasma concentration of paclitaxel. The LLQ of paclitaxel was 10.0 ng/mL. Paclitaxel PK parameter analysis set: all subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for paclitaxel. Here ‘number of subjects analysed’ signifies subjects who received Paclitaxel infusion on Q3W regimen and had data available for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2

End point values	PK: Chemotherapy followed by Avelumab	PK: Chemotherapy + Avelumab followed by Avelumab	PK: Chemotherapy followed by Observation
Number of subjects analysed	7	5	9
Units: ng/mL
geometric mean (geometric coefficient of variation)	5646 ± 68	4775 ± 24	4694 ± 28

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Carboplatin (Total and Free)

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End point title

Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Carboplatin (Total and Free)

End point description

Cmax is maximum plasma concentration of carboplatin. The LLQ of carboplatin was 100.0 ng/mL. Carboplatin PK parameter analysis set included all subjects who had received at least one dose of study drug and who had at least one of the PK parameters of interest for carboplatin. Here ‘number of subjects analysed’ signifies subjects who had data available for this outcome measure.

End point type

Secondary

End point timeframe

Pre-dose and at 0.5, 1, 5, 6, 10, and 24 hours post carboplatin infusion on Day 1 of Cycle 2

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	11	7	13
Units: ng/mL
geometric mean (geometric coefficient of variation)
Total Carboplatin	23580 ± 34	18350 ± 44	18990 ± 31
Free Carboplatin	21740 ± 39	15350 ± 65	17090 ± 33

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (QW Regimen)

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End point title

Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (QW Regimen)

End point description

AUCinf is the plasma area under the plasma concentration-time profile from time 0 extrapolated to infinite time.Paclitaxel PK parameter analysis set: all subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for paclitaxel. Here ‘number of subjects analysed’ signifies subjects who received Paclitaxel infusion on QW regimen and had data available for this endpoint

End point type

Secondary

End point timeframe

Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2

End point values	PK: Chemotherapy + Avelumab followed by Avelumab	PK: Chemotherapy followed by Avelumab	PK: Chemotherapy followed by Observation
Number of subjects analysed	4	5	7
Units: nanogramhour per milliliter (nghr/mL)
geometric mean (geometric coefficient of variation)	4997 ± 15	5138 ± 39	4921 ± 18

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (Q3W Regimen)

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End point title

Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (Q3W Regimen)

End point description

AUCinf is the plasma area under the plasma concentration-time profile from time 0 extrapolated to infinite time. Paclitaxel PK parameter analysis set: all subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for paclitaxel. Here ‘number of subjects analysed’ signifies subjects who received Paclitaxel infusion on Q3W regimen and had data available for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose and at 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2

End point values	PK: Chemotherapy followed by Avelumab	PK: Chemotherapy + Avelumab followed by Avelumab	PK: Chemotherapy followed by Observation
Number of subjects analysed	7	4	8
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	18070 ± 58	16190 ± 25	17470 ± 26

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Carboplatin (Total and Free)

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End point title

Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Carboplatin (Total and Free)

End point description

AUCinf is the plasma area under the plasma concentration-time profile from time 0 extrapolated to infinite time. Carboplatin PK parameter analysis set included all subjects who had received at least one dose of study drug and who had at least one of the PK parameters of interest for carboplatin. Here, ‘n’ = Subjects evaluable for this end point at specified rows. For the chemotherapy followed by Avelumab group, the geometric coefficient of variation value cannot be calculated when there is only one subject and is denoted as "0" in this field.

End point type

Secondary

End point timeframe

Pre-dose and at 0.5, 1, 5, 6, 10, and 24 hours post carboplatin infusion on Day 1 of Cycle 2

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	15	9	18
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Total Carboplatin (n=1,5,5)	87600 ± 0	100500 ± 13	90430 ± 18
Free Carboplatin (n=11,6,13)	55840 ± 25	52000 ± 29	52300 ± 25

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (QW Regimen) When Given With Avelumab

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End point title

Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (QW Regimen) When Given With Avelumab

End point description

AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). Paclitaxel PK parameter analysis set: all subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for paclitaxel. Here ‘number of subjects analysed’ signifies subjects who received Paclitaxel infusion on QW regimen and had data available for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2

End point values	PK: Chemotherapy followed by Avelumab	PK: Chemotherapy + Avelumab followed by Avelumab	PK: Chemotherapy followed by Observation
Number of subjects analysed	6	4	9
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	4960 ± 38	4572 ± 16	4304 ± 24

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (Q3W Regimen) When Given With Avelumab

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End point title

Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (Q3W Regimen) When Given With Avelumab

End point description

AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose (0 to 24). Paclitaxel PK parameter analysis set: all subjects who received at least one dose of study drug and who had at least one of the PK parameters of interest for paclitaxel. Here ‘number of subjects analysed’ signifies subjects who received Paclitaxel infusion on Q3W regimen and had data available for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 1, 3, 4, 5, 6, 10, and 24 hours post paclitaxel infusion on Day 1 of Cycle 2

End point values	PK: Chemotherapy followed by Avelumab	PK: Chemotherapy + Avelumab followed by Avelumab	PK: Chemotherapy followed by Observation
Number of subjects analysed	7	5	9
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	17540 ± 60	15870 ± 21	16390 ± 26

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Carboplatin (Total and Free) When Given With Avelumab

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End point title

Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Carboplatin (Total and Free) When Given With Avelumab

End point description

AUC24 is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose. Carboplatin PK parameter analysis set included all subjects who had received at least one dose of study drug and who had at least one of the PK parameters of interest for carboplatin. Here ‘number of subjects analysed’ signifies subjects who had data available for this outcome measure.

End point type

Secondary

End point timeframe

Pre-dose (0 hour), 0.5, 1, 5, 6, 10, and 24 hours post carboplatin infusion on Day 1 of Cycle 2

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	11	7	13
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Total Carboplatin	84380 ± 22	84100 ± 12	80960 ± 17
Free Carboplatin	56880 ± 25	52100 ± 26	52590 ± 24

No statistical analyses for this end point

Secondary: Maintenance Phase: Predose Plasma Concentration (Ctrough) of Avelumab

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End point title

Maintenance Phase: Predose Plasma Concentration (Ctrough) of Avelumab ^[16]

End point description

Ctrough=concentration at the end of the dosing interval when avelumab was given as a Q2W regimen in the absence of carboplatin and paclitaxel following 1 cycle of avelumab dosing, i.e. before administration of drug on Day 1 of cycle 2. The LLQ of avelumab was 0.20 micro-gram per milliliter (mcg/mL). Data for this endpoint was not reported for reporting arms “Chemotherapy + Avelumab followed by Avelumab” (since data was not planned to be collected 1 cycle after the initiation of avelumab dosing ) and “Chemotherapy followed by Observation” (since avelumab was not administered in this arm and therefore data collection was not planned). Avelumab PK concentration analysis set:all subjects who had received at least one dose of study drug and who had at least one post-dose concentration measurement above the LLQ for avelumab. Here ‘number of subjects analysed’ signifies subjects who had data available for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose (0 hour) on Day 1 of Cycle 2

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: This endpoint was analyzed only for reporting arm: Chemotherapy followed by Avelumab

End point values	Chemotherapy followed by Avelumab
Number of subjects analysed	209
Units: mcg/mL
geometric mean (geometric coefficient of variation)	29.18 ± 57

No statistical analyses for this end point

Secondary: Maintenance Phase: Maximum Plasma Concentration (Cmax) of Avelumab

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End point title

Maintenance Phase: Maximum Plasma Concentration (Cmax) of Avelumab ^[17]

End point description

Cmax is the concentration at the end of a 1 hour infusion, corresponding to the maximum plasma concentration of avelumab. The LLQ of avelumab was 0.20 mcg/mL. Data for this endpoint was not reported for reporting arms “Chemotherapy + Avelumab followed by Avelumab” (since data was not planned to be collected 1 cycle after the initiation of avelumab dosing ) and “Chemotherapy followed by Observation” (since avelumab was not administered in this arm and therefore data collection was not planned). Avelumab PK concentration analysis set included all subjects who had received at least one dose of study drug and who had at least one post-dose concentration measurement above the LLQ for avelumab. Here ‘number of subjects analysed’ signifies subjects who had data available for this endpoint.

End point type

Secondary

End point timeframe

End of avelumab infusion on Day 1 of Cycle 2

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only for reporting arm: Chemotherapy followed by Avelumab

End point values	Chemotherapy followed by Avelumab
Number of subjects analysed	174
Units: mcg/mL
geometric mean (geometric coefficient of variation)	205.6 ± 50

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Avelumab When Given With Paclitaxel and Carboplatin

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End point title

Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Avelumab When Given With Paclitaxel and Carboplatin ^[18]

End point description

Cmax is the concentration at the end of a 1 hour infusion, corresponding to the maximum plasma concentration of avelumab. The LLQ of avelumab was 0.20 mcg/mL. Data for this endpoint was not reported for reporting arms "Chemotherapy followed by Avelumab" (data not available for this OM as avelumab was not given along with paclitaxel and carboplatin in this arm) and “Chemotherapy followed by Observation” (since avelumab was not administered in this arm and therefore data collection was not planned). PK concentration analysis set included all subjects who had received at least one dose of study drug and who had at least one post-dose concentration measurement above the LLQ for avelumab. Here ‘number of subjects analysed’ signifies subjects who had data available for this endpoint.

End point type

Secondary

End point timeframe

End of infusion on Day 1 of Cycle 2

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only for reporting arm: Chemotherapy + Avelumab followed by Avelumab

End point values	Chemotherapy + Avelumab followed by Avelumab
Number of subjects analysed	220
Units: mcg/mL
geometric mean (geometric coefficient of variation)	162.9 ± 139

No statistical analyses for this end point

Secondary: Chemotherapy Phase: Predose Plasma Concentration (Ctrough) of Avelumab When Given With Paclitaxel and Carboplatin

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End point title

Chemotherapy Phase: Predose Plasma Concentration (Ctrough) of Avelumab When Given With Paclitaxel and Carboplatin ^[19]

End point description

Ctrough is the concentration at the end of the dosing interval when avelumab was given as a Q2W regimen in the absence of carboplatin and paclitaxel following 1 cycle of avelumab dosing, i.e. before administration of drug on Day 1 of cycle 2. The LLQ of avelumab was 0.20 mcg/mL. Data for this endpoint was not reported for reporting arms "Chemotherapy followed by Avelumab" (data not available for this OM as avelumab was not given along with paclitaxel and carboplatin in this arm) and “Chemotherapy followed by Observation” (since avelumab was not administered in this arm and therefore data collection was not planned). Avelumab PK concentration analysis set included all subjects who had received at least one dose of study drug and who had at least one post-dose concentration measurement above the LLQ for avelumab. Here ‘number of subjects analysed’ signifies subjects who had data available for this endpoint.

End point type

Secondary

End point timeframe

Pre-dose (0 hour) on Day 1 of Cycle 2

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only for reporting arm: Chemotherapy + Avelumab followed by Avelumab

End point values	Chemotherapy + Avelumab followed by Avelumab
Number of subjects analysed	251
Units: mcg/mL
geometric mean (geometric coefficient of variation)	3.607 ± 113

No statistical analyses for this end point

Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

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End point title

Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status ^[20]

End point description

ADA against avelumab in serum samples was determined and reported separately for ADA never-positive and ADA ever-positive subjects. Subjects were considered ADA ever-positive if they had at least one positive (ADA titer greater than or equal to 60 with assay cut point of 1.12) ADA result at any time point and were otherwise considered negative. The immunogenicity analysis set included all subjects who had received at least one dose of study drug and who had at least one ADA sample collected for avelumab in the avelumab containing arms. Here ‘number of subjects analysed’ signifies subjects who had data available for this endpoint.

End point type

Secondary

End point timeframe

Up to 36 months

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was analyzed only for reporting arms: Chemotherapy followed by Avelumab and Chemotherapy + Avelumab followed by Avelumab

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab
Number of subjects analysed	272	328
Units: subjects
Never-positive	231	197
Ever-positve	41	131

No statistical analyses for this end point

Secondary: Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status

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End point title

Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status ^[21]

End point description

nAb against avelumab in serum samples was determined and reported separately for nAb never-positive and nAb ever-positive subjects. Subjects were considered nAb ever-positive if they had at least one positive nAb results (less than or equal to cut point of 0.710 in qualitative competitive ligand binding assay) at any time point. nAb never-positive subjects were those who had at least one negative nAb results (greater than cut point of 0.710 in qualitative competitive ligand binding assay) at any time point. The immunogenicity analysis set included all subjects who had received at least one dose of study drug and who had at least one nAb sample collected for avelumab in the avelumab containing arms. Here ‘number of subjects analysed’ signifies subjects who had data available for this endpoint.

End point type

Secondary

End point timeframe

Up to 36 months

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: This endpoint was analyzed only for reporting arms: Chemotherapy followed by Avelumab and Chemotherapy + Avelumab followed by Avelumab

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab
Number of subjects analysed	272	328
Units: subjects
Never-positive	256	282
Ever-positve	16	46

No statistical analyses for this end point

Secondary: Number of Subjects With Positive Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

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End point title

Number of Subjects With Positive Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

End point description

PD-L1 assessment was performed using immunohistochemistry. Subjects were considered positive if their pretreatment tumor tissue sample demonstrated cell surface PD-L1 expression on greater than or equal to (>=) 1 percentage (%) tumor cells or >= 5% immune cells and were otherwise considered negative. PD-L1 biomarker analysis set included all subjects who had received at least one dose of study drug and who had at least one screening biomarker assessment for PD-L1.

End point type

Secondary

End point timeframe

Up to 36 months

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	270	263	280
Units: subjects	158	160	169

No statistical analyses for this end point

Secondary: Number of Subjects With Positive Tumor-Infiltrating Cluster of Differentiation 8 (CD8+) T Lymphocytes Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

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End point title

Number of Subjects With Positive Tumor-Infiltrating Cluster of Differentiation 8 (CD8+) T Lymphocytes Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

End point description

CD8 assessment was performed using immunohistochemistry. Subjects were considered positive if their pretreatment tumor tissue sample demonstrated >= 1% CD8 positive cells and were otherwise considered negative. CD8 biomarker analysis set included all subjects who had received at least one dose of study drug and who had at least one screening biomarker assessment for CD8.

End point type

Secondary

End point timeframe

Up to 36 months

End point values	Chemotherapy followed by Avelumab	Chemotherapy + Avelumab followed by Avelumab	Chemotherapy followed by Observation
Number of subjects analysed	250	250	257
Units: subjects	107	107	118

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Baseline up to maximum duration of 36 months

Adverse event reporting additional description

Same event may appear as both an AE and SAE. However, what is presented are distinct events. 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. Analysis performed on safety set.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

22.1

Reporting group title

Chemotherapy followed by Avelumab

Reporting group description

Reporting group title

Chemotherapy followed by Observation

Reporting group description

Reporting group title

Chemotherapy + Avelumab followed by Avelumab

Reporting group description

Serious adverse events	Chemotherapy followed by Avelumab	Chemotherapy followed by Observation	Chemotherapy + Avelumab followed by Avelumab
Total subjects affected by serious adverse events
subjects affected / exposed	92 / 328 (28.05%)	64 / 334 (19.16%)	118 / 329 (35.87%)
number of deaths (all causes)	34	20	31
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer stage I
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Flushing
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphocele
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Phlebitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subclavian vein occlusion
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Essential hypertension
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	3 / 328 (0.91%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 3	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Disease progression
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperpyrexia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incarcerated hernia
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Non-cardiac chest pain
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perforation
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Pyrexia
subjects affected / exposed	6 / 328 (1.83%)	1 / 334 (0.30%)	10 / 329 (3.04%)
occurrences causally related to treatment / all	5 / 8	0 / 1	4 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic shock
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contrast media allergy
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sarcoidosis
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Female genital tract fistula
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Menorrhagia
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vaginal perforation
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	3 / 328 (0.91%)	1 / 334 (0.30%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	2 / 3	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	7 / 328 (2.13%)	3 / 334 (0.90%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	1 / 7	1 / 4	2 / 3
deaths causally related to treatment / all	0 / 2	0 / 1	0 / 0
Pulmonary infarction
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Depression suicidal
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Persistent depressive disorder
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphocyte count decreased
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutrophil count decreased
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anastomotic leak
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	4 / 329 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural intestinal perforation
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vaginal cuff dehiscence
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Myocardial infarction
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial nerve disorder
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lethargy
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral sensorimotor neuropathy
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 328 (1.83%)	6 / 334 (1.80%)	8 / 329 (2.43%)
occurrences causally related to treatment / all	6 / 7	5 / 6	9 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	10 / 328 (3.05%)	7 / 334 (2.10%)	8 / 329 (2.43%)
occurrences causally related to treatment / all	11 / 11	7 / 7	7 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 328 (0.61%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	2 / 328 (0.61%)	1 / 334 (0.30%)	5 / 329 (1.52%)
occurrences causally related to treatment / all	2 / 2	1 / 1	6 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	3 / 328 (0.91%)	4 / 334 (1.20%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	0 / 3	1 / 4	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	5 / 328 (1.52%)	1 / 334 (0.30%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	3 / 328 (0.91%)	3 / 334 (0.90%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 3	2 / 4	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diaphragmatic hernia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	4 / 328 (1.22%)	1 / 334 (0.30%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	4 / 4	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal obstruction
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	3 / 328 (0.91%)	9 / 334 (2.69%)	4 / 329 (1.22%)
occurrences causally related to treatment / all	0 / 3	1 / 12	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal dilatation
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	4 / 328 (1.22%)	6 / 334 (1.80%)	6 / 329 (1.82%)
occurrences causally related to treatment / all	0 / 8	1 / 8	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	4 / 328 (1.22%)	2 / 334 (0.60%)	5 / 329 (1.52%)
occurrences causally related to treatment / all	2 / 4	2 / 2	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritoneal adhesions
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	3 / 328 (0.91%)	1 / 334 (0.30%)	7 / 329 (2.13%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Subileus
subjects affected / exposed	0 / 328 (0.00%)	2 / 334 (0.60%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	6 / 328 (1.83%)	6 / 334 (1.80%)	7 / 329 (2.13%)
occurrences causally related to treatment / all	5 / 6	4 / 7	8 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune-mediated enterocolitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal mucosal disorder
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urogenital fistula
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
alternative dictionary used: MedDRA 22.1
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia of malignancy
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypopituitarism
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fistula
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polymyositis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Systemic lupus erythematosus
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Abdominal wall abscess
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected lymphocele
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymph gland infection
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic infection
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic inflammatory disease
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	3 / 328 (0.91%)	1 / 334 (0.30%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	1 / 3	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pseudomembranous colitis
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	2 / 329 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tooth infection
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	7 / 328 (2.13%)	2 / 334 (0.60%)	7 / 329 (2.13%)
occurrences causally related to treatment / all	3 / 7	0 / 2	3 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vulval abscess
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	1 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 328 (0.00%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	3 / 329 (0.91%)
occurrences causally related to treatment / all	2 / 2	1 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 328 (0.30%)	1 / 334 (0.30%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	1 / 1	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophagia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 328 (0.00%)	0 / 334 (0.00%)	1 / 329 (0.30%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 1 diabetes mellitus
subjects affected / exposed	2 / 328 (0.61%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 328 (0.30%)	0 / 334 (0.00%)	0 / 329 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Chemotherapy followed by Avelumab	Chemotherapy followed by Observation	Chemotherapy + Avelumab followed by Avelumab
Total subjects affected by non serious adverse events
subjects affected / exposed	320 / 328 (97.56%)	317 / 334 (94.91%)	325 / 329 (98.78%)
Vascular disorders
Hot flush
subjects affected / exposed	23 / 328 (7.01%)	16 / 334 (4.79%)	18 / 329 (5.47%)
occurrences all number	26	18	23
Hypertension
subjects affected / exposed	16 / 328 (4.88%)	13 / 334 (3.89%)	19 / 329 (5.78%)
occurrences all number	20	20	32
General disorders and administration site conditions
Asthenia
subjects affected / exposed	35 / 328 (10.67%)	22 / 334 (6.59%)	46 / 329 (13.98%)
occurrences all number	53	36	83
Fatigue
subjects affected / exposed	123 / 328 (37.50%)	110 / 334 (32.93%)	115 / 329 (34.95%)
occurrences all number	244	206	250
Malaise
subjects affected / exposed	22 / 328 (6.71%)	14 / 334 (4.19%)	17 / 329 (5.17%)
occurrences all number	29	19	17
Oedema peripheral
subjects affected / exposed	27 / 328 (8.23%)	23 / 334 (6.89%)	29 / 329 (8.81%)
occurrences all number	33	28	34
Pain
subjects affected / exposed	21 / 328 (6.40%)	14 / 334 (4.19%)	23 / 329 (6.99%)
occurrences all number	26	16	29
Pyrexia
subjects affected / exposed	33 / 328 (10.06%)	23 / 334 (6.89%)	42 / 329 (12.77%)
occurrences all number	48	25	60
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	36 / 328 (10.98%)	22 / 334 (6.59%)	55 / 329 (16.72%)
occurrences all number	51	27	68
Dyspnoea
subjects affected / exposed	38 / 328 (11.59%)	29 / 334 (8.68%)	47 / 329 (14.29%)
occurrences all number	51	37	69
Epistaxis
subjects affected / exposed	22 / 328 (6.71%)	12 / 334 (3.59%)	12 / 329 (3.65%)
occurrences all number	22	15	14
Psychiatric disorders
Anxiety
subjects affected / exposed	14 / 328 (4.27%)	15 / 334 (4.49%)	18 / 329 (5.47%)
occurrences all number	15	16	18
Insomnia
subjects affected / exposed	52 / 328 (15.85%)	32 / 334 (9.58%)	39 / 329 (11.85%)
occurrences all number	68	37	48
Investigations
Alanine aminotransferase increased
subjects affected / exposed	28 / 328 (8.54%)	20 / 334 (5.99%)	33 / 329 (10.03%)
occurrences all number	54	37	49
Aspartate aminotransferase increased
subjects affected / exposed	18 / 328 (5.49%)	21 / 334 (6.29%)	28 / 329 (8.51%)
occurrences all number	34	28	36
Neutrophil count decreased
subjects affected / exposed	60 / 328 (18.29%)	75 / 334 (22.46%)	54 / 329 (16.41%)
occurrences all number	267	255	223
Platelet count decreased
subjects affected / exposed	25 / 328 (7.62%)	44 / 334 (13.17%)	39 / 329 (11.85%)
occurrences all number	79	96	103
White blood cell count decreased
subjects affected / exposed	32 / 328 (9.76%)	34 / 334 (10.18%)	31 / 329 (9.42%)
occurrences all number	173	150	156
Weight decreased
subjects affected / exposed	15 / 328 (4.57%)	13 / 334 (3.89%)	17 / 329 (5.17%)
occurrences all number	19	18	20
Injury, poisoning and procedural complications
Infusion related reaction
subjects affected / exposed	26 / 328 (7.93%)	19 / 334 (5.69%)	30 / 329 (9.12%)
occurrences all number	35	27	48
Procedural pain
subjects affected / exposed	27 / 328 (8.23%)	12 / 334 (3.59%)	22 / 329 (6.69%)
occurrences all number	33	15	31
Nervous system disorders
Dizziness
subjects affected / exposed	45 / 328 (13.72%)	28 / 334 (8.38%)	38 / 329 (11.55%)
occurrences all number	61	33	49
Dysgeusia
subjects affected / exposed	22 / 328 (6.71%)	18 / 334 (5.39%)	20 / 329 (6.08%)
occurrences all number	25	21	21
Headache
subjects affected / exposed	55 / 328 (16.77%)	30 / 334 (8.98%)	51 / 329 (15.50%)
occurrences all number	72	34	88
Hypoaesthesia
subjects affected / exposed	12 / 328 (3.66%)	13 / 334 (3.89%)	21 / 329 (6.38%)
occurrences all number	13	19	27
Neuropathy peripheral
subjects affected / exposed	63 / 328 (19.21%)	65 / 334 (19.46%)	77 / 329 (23.40%)
occurrences all number	93	103	114
Paraesthesia
subjects affected / exposed	18 / 328 (5.49%)	10 / 334 (2.99%)	26 / 329 (7.90%)
occurrences all number	21	14	29
Peripheral sensory neuropathy
subjects affected / exposed	91 / 328 (27.74%)	82 / 334 (24.55%)	76 / 329 (23.10%)
occurrences all number	114	120	121
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	148 / 328 (45.12%)	140 / 334 (41.92%)	151 / 329 (45.90%)
occurrences all number	465	415	424
Leukopenia
subjects affected / exposed	27 / 328 (8.23%)	20 / 334 (5.99%)	28 / 329 (8.51%)
occurrences all number	53	50	73
Neutropenia
subjects affected / exposed	112 / 328 (34.15%)	113 / 334 (33.83%)	125 / 329 (37.99%)
occurrences all number	324	376	343
Thrombocytopenia
subjects affected / exposed	46 / 328 (14.02%)	59 / 334 (17.66%)	62 / 329 (18.84%)
occurrences all number	79	128	165
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	22 / 328 (6.71%)	18 / 334 (5.39%)	17 / 329 (5.17%)
occurrences all number	27	22	26
Abdominal pain
subjects affected / exposed	69 / 328 (21.04%)	58 / 334 (17.37%)	68 / 329 (20.67%)
occurrences all number	99	88	82
Abdominal pain upper
subjects affected / exposed	32 / 328 (9.76%)	24 / 334 (7.19%)	39 / 329 (11.85%)
occurrences all number	38	29	51
Constipation
subjects affected / exposed	113 / 328 (34.45%)	95 / 334 (28.44%)	100 / 329 (30.40%)
occurrences all number	164	135	141
Diarrhoea
subjects affected / exposed	84 / 328 (25.61%)	63 / 334 (18.86%)	101 / 329 (30.70%)
occurrences all number	142	92	158
Dyspepsia
subjects affected / exposed	31 / 328 (9.45%)	22 / 334 (6.59%)	24 / 329 (7.29%)
occurrences all number	38	27	29
Gastrooesophageal reflux disease
subjects affected / exposed	11 / 328 (3.35%)	11 / 334 (3.29%)	18 / 329 (5.47%)
occurrences all number	13	12	20
Nausea
subjects affected / exposed	153 / 328 (46.65%)	152 / 334 (45.51%)	149 / 329 (45.29%)
occurrences all number	288	308	318
Stomatitis
subjects affected / exposed	28 / 328 (8.54%)	20 / 334 (5.99%)	24 / 329 (7.29%)
occurrences all number	41	23	43
Vomiting
subjects affected / exposed	86 / 328 (26.22%)	66 / 334 (19.76%)	74 / 329 (22.49%)
occurrences all number	133	86	111
Dry mouth
subjects affected / exposed	17 / 328 (5.18%)	5 / 334 (1.50%)	10 / 329 (3.04%)
occurrences all number	18	5	12
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	167 / 328 (50.91%)	177 / 334 (52.99%)	169 / 329 (51.37%)
occurrences all number	220	220	215
Pruritus
subjects affected / exposed	38 / 328 (11.59%)	19 / 334 (5.69%)	37 / 329 (11.25%)
occurrences all number	53	20	60
Rash
subjects affected / exposed	59 / 328 (17.99%)	25 / 334 (7.49%)	66 / 329 (20.06%)
occurrences all number	107	36	104
Rash maculo-papular
subjects affected / exposed	13 / 328 (3.96%)	5 / 334 (1.50%)	21 / 329 (6.38%)
occurrences all number	23	6	43
Endocrine disorders
Hypothyroidism
subjects affected / exposed	34 / 328 (10.37%)	5 / 334 (1.50%)	33 / 329 (10.03%)
occurrences all number	43	5	36
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	76 / 328 (23.17%)	57 / 334 (17.07%)	85 / 329 (25.84%)
occurrences all number	102	76	136
Back pain
subjects affected / exposed	31 / 328 (9.45%)	31 / 334 (9.28%)	36 / 329 (10.94%)
occurrences all number	45	37	47
Musculoskeletal pain
subjects affected / exposed	20 / 328 (6.10%)	13 / 334 (3.89%)	15 / 329 (4.56%)
occurrences all number	28	19	17
Myalgia
subjects affected / exposed	67 / 328 (20.43%)	43 / 334 (12.87%)	53 / 329 (16.11%)
occurrences all number	112	81	89
Pain in extremity
subjects affected / exposed	30 / 328 (9.15%)	37 / 334 (11.08%)	32 / 329 (9.73%)
occurrences all number	50	62	46
Infections and infestations
Cystitis
subjects affected / exposed	19 / 328 (5.79%)	8 / 334 (2.40%)	7 / 329 (2.13%)
occurrences all number	32	8	9
Upper respiratory tract infection
subjects affected / exposed	27 / 328 (8.23%)	14 / 334 (4.19%)	28 / 329 (8.51%)
occurrences all number	32	18	34
Urinary tract infection
subjects affected / exposed	36 / 328 (10.98%)	28 / 334 (8.38%)	46 / 329 (13.98%)
occurrences all number	49	35	65
Nasopharyngitis
subjects affected / exposed	18 / 328 (5.49%)	10 / 334 (2.99%)	16 / 329 (4.86%)
occurrences all number	24	10	21
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	64 / 328 (19.51%)	37 / 334 (11.08%)	55 / 329 (16.72%)
occurrences all number	86	54	68
Hypokalaemia
subjects affected / exposed	22 / 328 (6.71%)	20 / 334 (5.99%)	27 / 329 (8.21%)
occurrences all number	32	27	62
Hypomagnesaemia
subjects affected / exposed	32 / 328 (9.76%)	27 / 334 (8.08%)	42 / 329 (12.77%)
occurrences all number	63	34	88

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Were there any global substantial amendments to the protocol? No

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 RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AND/OR FOLLOWING CHEMOTHERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED EPITHELIAL OVARIAN CANCER

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)

Primary: Progression-Free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR)

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Progression-Free Survival (PFS) as Assessed by Investigator

Secondary: Progression-Free Survival (PFS) as Assessed by Investigator

Secondary: Percentage of Subjects With Objective Response as Assessed by Investigator

Secondary: Percentage of Subjects With Objective Response as Assessed by Investigator

Secondary: Percentage of Subjects With Objective Response as Assessed by Blinded Independent Central Review (BICR)

Secondary: Percentage of Subjects With Objective Response as Assessed by Blinded Independent Central Review (BICR)

Secondary: Duration of Response (DOR) as Assessed by Investigator

Secondary: Duration of Response (DOR) as Assessed by Investigator

Secondary: Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR)

Secondary: Duration of Response (DOR) as Assessed by Blinded Independent Central Review (BICR)

Secondary: Maintenance Progression-Free Survival as Assessed by Blinded Independent Central Review (BICR)

Secondary: Maintenance Progression-Free Survival as Assessed by Blinded Independent Central Review (BICR)

Secondary: Maintenance Progression-Free Survival (PFS) as Assessed by Investigator

Secondary: Maintenance Progression-Free Survival (PFS) as Assessed by Investigator

Secondary: Percentage of Subjects with Pathological Complete Response (pCR)

Secondary: Percentage of Subjects with Pathological Complete Response (pCR)

Secondary: Progression-Free Survival 2 (PFS2)

Secondary: Progression-Free Survival 2 (PFS2)

Secondary: Progression-Free Survival (PFS) as Assessed by Gynecological Cancer Intergroup (GCIG) Criteria

Secondary: Progression-Free Survival (PFS) as Assessed by Gynecological Cancer Intergroup (GCIG) Criteria

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) Graded Based on, National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Number of Subjects With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Number of Subjects With Laboratory Abnormalities Greater Than or Equal to (>=) Grade 3, Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE), Version 4.03

Secondary: Change from Baseline in Vital Signs - Blood Pressure at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

Secondary: Change from Baseline in Vital Signs - Blood Pressure at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

Secondary: Change from Baseline in Vital Signs - Pulse Rate at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

Secondary: Change from Baseline in Vital Signs - Pulse Rate at Day 1 of Cycles 2, 3, 4 in Chemotherapy Phase; Days 1, 15 and 29 of Cycles 1 and 2 in Maintenance Phase and at End of Treatment

Secondary: Number of Subjects With Electrocardiogram (ECG) Abnormalities

Secondary: Number of Subjects With Electrocardiogram (ECG) Abnormalities

Secondary: Functional Assessment of Ovarian Symptom Index- 18 (FOSI-18) Score

Secondary: Functional Assessment of Ovarian Symptom Index- 18 (FOSI-18) Score

Secondary: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Score

Secondary: European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) Score

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once a Week [QW] Regimen)

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once a Week [QW] Regimen)

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once Every Three Weeks [Q3W] Regimen)

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Paclitaxel (Once Every Three Weeks [Q3W] Regimen)

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Carboplatin (Total and Free)

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Carboplatin (Total and Free)

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (QW Regimen)

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (QW Regimen)

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (Q3W Regimen)

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Paclitaxel (Q3W Regimen)

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Carboplatin (Total and Free)

Secondary: Chemotherapy Phase: Area Under the Plasma Concentration Time Curve From Time Zero to Infinite Time (AUCinf) of Carboplatin (Total and Free)

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (QW Regimen) When Given With Avelumab

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (QW Regimen) When Given With Avelumab

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (Q3W Regimen) When Given With Avelumab

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Paclitaxel (Q3W Regimen) When Given With Avelumab

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Carboplatin (Total and Free) When Given With Avelumab

Secondary: Chemotherapy Phase: Area Under the Concentration Time Curve From Time Zero to 24 Hours (AUC24) of Carboplatin (Total and Free) When Given With Avelumab

Secondary: Maintenance Phase: Predose Plasma Concentration (Ctrough) of Avelumab

Secondary: Maintenance Phase: Predose Plasma Concentration (Ctrough) of Avelumab

Secondary: Maintenance Phase: Maximum Plasma Concentration (Cmax) of Avelumab

Secondary: Maintenance Phase: Maximum Plasma Concentration (Cmax) of Avelumab

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Avelumab When Given With Paclitaxel and Carboplatin

Secondary: Chemotherapy Phase: Maximum Plasma Concentration (Cmax) of Avelumab When Given With Paclitaxel and Carboplatin

Secondary: Chemotherapy Phase: Predose Plasma Concentration (Ctrough) of Avelumab When Given With Paclitaxel and Carboplatin

Secondary: Chemotherapy Phase: Predose Plasma Concentration (Ctrough) of Avelumab When Given With Paclitaxel and Carboplatin

Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

Secondary: Number of Subjects With Anti-Drug Antibodies (ADA) Against Avelumab by Never and Ever Positive Status

Secondary: Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status

Secondary: Number of Subjects With Neutralizing Antibodies (nAb) Against Avelumab by Never and Ever Positive Status

Secondary: Number of Subjects With Positive Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

Secondary: Number of Subjects With Positive Programmed Death Receptor-1 Ligand-1 (PD-L1) Biomarker Expression in Tumor Tissue as Assessed by Immunohistochemistry (IHC)

Clinical Trial Results:
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH AND/OR FOLLOWING CHEMOTHERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED EPITHELIAL OVARIAN CANCER