Conditions: Ovarian Cancer
Keywords: untreated epithelial ovarian cancer fallopian tube cancer primary peritoneal cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 79
Healthy volunteers: no

Brief summary:
JAVELIN Ovarian PARP 100 (B9991030) is an open-label, randomized study designed to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with talazoparib versus an active comparator in treatment-naïve patients with locally advanced or metastatic ovarian cancer (Stage III or Stage IV). On March 19, 2019, Sponsors alliance announced the discontinuation of the ongoing Phase III study, and the decision was based on several factors, including previous announced interim results from JAVELIN Ovarian 100 study (B9991010). Patients who remain in B9991030 study will continue receiving their randomized treatment assigned and will be monitored for appropriate safety assessments until treatment discontinuation.

Detailed description:
JAVELIN Ovarian PARP 100 (B9991030) is an open-label, international, multi-center, randomized study designed to evaluate the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with talazoparib versus an active comparator in treatment-naïve patients with locally advanced or metastatic ovarian cancer (Stage III or Stage IV). The primary endpoint is progression-free survival (PFS) as determined based on blinded independent central review (BICR) assessment per RECIST v1.1.

On March 19, 2019, Sponsors alliance announced the discontinuation of the ongoing Phase III JAVELIN Ovarian PARP 100 study. The alliance has notified health authorities and trial investigators of the decision to discontinue the trial. The decision was based on several emerging factors since the trial's initiation, including the previously announced interim results from JAVELIN Ovarian 100 study (B9991010), which was stopped due to futility of efficacy at a planned interim analysis on 21 December 2018. The alliance determined that the degree of benefit observed with avelumab in frontline ovarian cancer in that study does not support continuation of the JAVELIN Ovarian PARP 100 trial in an unselected patient population and emphasizes the need to better understand the role of immunotherapy in ovarian cancer. Additional factors include the rapidly changing treatment landscape and the approval of a PARP inhibitor in the frontline maintenance setting. The decision to discontinue the JAVELIN Ovarian PARP 100 trial was not made for safety reasons.

Patients who remain in the study will continue receiving investigational products according to their randomized treatment assignment and will be monitored for appropriate safety assessments until treatment discontinuation.

Arms:
arm 1: Platinum-based chemotherapy + avelumab followed by avelumab + talazoparib maintenance arm 2: Platinum-based chemotherapy followed by talazoparib maintenance arm 3: Platinum-based chemotherapy + bevacizumab followed by bevacizumab maintenance

Interventions: intervention 1: Chemotherapy + avelumab followed by avelumab + talazoparib intervention 2: Chemotherapy followed by talazoparib maintenance intervention 3: Chemotherapy + bevacizumab followed by bevacizumab
Intervention descriptions: intervention 1: Chemotherapy Period Paclitaxel Carboplatin Avelumab

Maintenance Period Avelumab Talazoparib intervention 2: Chemotherapy Period Paclitaxel Carboplatin

Maintenance Period Talazoparib intervention 3: Chemotherapy Period Paclitaxel Carboplatin Bevacizumab

Maintenance Period Bevacizumab

Protocol document:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB IN COMBINATION 
WITH CHEMOTHERAPY FOLLOWED BY MAINTENANCE THERAPY OF 
AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE DIPHOSPHATE
[ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN 
PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER
JAVELIN OVARIAN PARP 100 
Investigational Product Number:
MSB0010718C
MDV3800, BMN 673
Investigational Product Name:
Avelumab
Talazoparib
United States (US) Investigational New Drug 
(IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
EudraCT 2017-004456-30 
ClinicalTrials.gov Registry Number:
NCT03642132
Protocol Number:
B9991030
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Protocol 
Amendment 2
06 June 2019
The JAVELIN Ovarian 100 study (B9991010) was 
stopped due to futility of efficacy at a planned 
interim analysis, and therefore, the Sponsor decided 
to stop enrollment in the JAVELIN Ovarian PARP 
100 study (B9991030). 
On 19 March 2019, a Dear Investigatior Letter was 
issued to notify the investigational sites that no new 
patients could be screened or randomized.  
Patients who remain in the study will continue 
receiving investigational products according to 
their randomized treatment assignment and will be 
monitored for appropriate safety assessments until 
treatment discontinuation.
The purpose of protocol amendment 2 is to reduce 
study-specific procedure assessments (ie, efficacy, 
physical examination, electrocardiogram, ePROs 
and tumor assessments, PK and Biomarkers) for the 
ongoing patients. 
The original schedule of activities (SOA) has been 
replaced by a new SOA found in Appendix 6.  
The following sections were modified based on the 
above: 

Protocol Summary Section: Added enrollment 
termination rationale to the Protocol Summary 
section.

1.2.2.2. Safety of Avelumab Combined with 
Carboplatin and Paclitaxel in Ovarian Patients: 
Added that no new safety signals were 
identified from the B9991010 study relative to 
the known safety profile of avelumab or the 
other study medications.

1.2.3.2. Clinical Efficacy of Talazoparib in 
Patients with Advanced Breast Cancer and a 
Germline BRCA 1/2 Mutation): Added the 
approval of talazoparib in United States and 


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European Union.  

1.2.3.3 PARP Inhibitor in Ovarian Cancer: 
Added results from the Phase 3 SOLO-1 study 
that led to the approvals of olaparib.  

2. Study Objectives and Endpoints: The original 
study objectives and endpoints are no longer 
applicable and/or feasible.  

3.1.1 Study Treatment Plan: Removed wording 
related to BICR assessment per RECIST v1.1, 
new anti-cancer therapy and tumor assessments.  
No longer requiring BICR.  Patient can receive 
study treatment until progressive disease as 
assessed by the investigator according to 
institutional local guidelines.  

3.2 Safety Monitoring and 9.10 Data 
Monitoring Committee: Use of an External 
Data Monitoring Committee is no longer 
applicable.

5. Study Treatments and 5.5.1 Avelumab Plus 
Talazoparib: Removed wording related to BICR 
assessment.  Disease progression is to be 
confirmed based on investigator assessment.

Table 9. Modification Guidance for 
Hematologic Toxicity: Updated row 1 
DLT-PLT from Yes to No due to a 
typographical error.   

5.7 Treatment after Initial Evidence of 
Radiological Disease Progression: Removed 
wording related to BICR assessment.  Disease 
progression is to be confirmed based on 
investigator assessment.

5.10. Concomitant Treatment, Radiotherapy, 
and Surgery: Minor updates including 
concomitant medications and treatments will 
not be captured in the INFORM database unless 
they contribute or are associated with the 
treatment for an AE/SAE.  

5.10.2.1 Interval Debulking Surgery: May be 


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performed according to local guidelines or 
standard of care at the discretion of the 
investigator.  Removed wording related to 
BICR.

5.10.2.2 Other Surgery: Removed wording 
related to second debulking surgery and 
subsequent anti-cancer therapy.  No longer 
required to be reported on the eCRF.  

5.10.5 Corticosteriods & 5.10.6 Other 
Prohibited Concomitant Medicines and 
Therapies: Modified this section to allow for 
therapeutic and/or prophylactic corticosteroids 
to be used as needed per standard of care.

6. Study Procedures: The following was 
updated: 

Screening: Obsolete.

Treatment Period and End of Treatment: 
Removal of RECIST v1.1 and BICR 
wording as well as reference to PK 
specimens and genomic banked specimens 
as they are no longer being collected.  

Short-Term and Long-Term Follow-up: 
Removal of long-term and survival 
follow-up wording.  

7.1 Safety Assessments: Physical examination, 
ECOG and ECG are not required per protocol 
but may be performed as clinically necessary.  

7.1.4 Laboratory Assessments: Do not need to 
be recorded in the INFORM database, unless 
the findings support an AE/SAE.  Also, updated 
and removed certain previously required safety 
laboratory tests that are no longer required.
The following assessments will no longer be 
collected as outlined in Section 7: 

Pharmacokinetic (Avelumab and Talazoparib);


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
Immunogenicity;

Biomarker and Pharmacodynamic;

Tumor Tissue Sample;

Banked Biospecimens;

Tumor Response Assessments including scans;

Patient Reported Outcomes.
9. Data Analysis/Statistical Methods section was 
updated to reflect the following:
As of 19 March 2019, the Sponsor made the 
decision to stop enrollment/randomization in study 
B9991030.  Patients who were randomized can 
continue treatment and will be monitored for 
appropriate safety assessments until treatment 
discontinuation. As of 19 March 2019, 
approximately 11% of the patients originally 
planned to be randomized in the study had been 
randomized.  Therefore, the study endpoints are no 
longer applicable and/or feasible.  No formal 
statistical analyses will be conducted, but patient 
characteristics, duration of treatment and safety
data will be summarized by treatment arm. 
Only the Safety Analysis Set, Pharmacokinetic 
Analysis Set and Immunogenicity Analysis Set are 
applicable. 
All randomized patients received at least 1 dose of 
study drug in the study; therefore, the safety 
analysis set will also be used for patient 
characteristics.
The results of the pharmacokinetic analyses on 
samples collected prior to IRB/EC approval of 
protocol amendment 2 will not be included in the 
Clinical Study Report but will be retained by the 
Sponsor and may be pooled with data from other 
studies to further inform the development programs 
of avelumab and talazoparib, as appropriate.


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The interim analysis is no longer applicable. 
Marked the following Appendices as Obsolete:

3. Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1. Guidelines;

4. PFS by GCIG Criteria;

5. Patient Global Impression of Severity 
(PGI-S) and Patient Global Impression of 
Change (PGI-C).
Added Appendix 6. Revised Schedule of Activities.
Protocol 
Amendment 1
11 October 2018
1. Reduction of Talazoparib starting dose to lower 
the risk for treatment emerging adverse events that 
require dose modifications and improve long-term 
tolerability in the maintenance setting.  The 
following sections were modified:

1.0 (Introduction);

1.2 (Background and Rationale);

3.1.1 (Study Treatment Plan);

5.3.1.2 (Talazoparib);

5.5 (Administration of Bevacizumab Plus 
Chemotherapy);

5.6.1 (Dose Reductions for Talazoparib);

5.6.2 (Study Treatment Modifications for 
Drug-related Toxicity from Avelumab and 
Talazolparib).
2. Modifications to align with USPI for 
bevacizumab.  Changed maximum duration of 
bevacizumab treatment to 21 or 22 doses per local 
approval.  The following sections were modified:

3.1.1 (Study Treatment Plan);

6.2 (Treatment Period).


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3. Modifications to align with updated Investigator 
Brochure for Talazoparib dated August 2018.  
Extended duration of contraception and 
concomitant medication interactions, and updated 
with most recent PK data.  The following section 
were modified:

1.2.3.3 (Pharmacokinetics of Talazoparib in 
Humans); 

4.1 (Inclusion Criteria);

4.3 (Lifestyle Requirements);

5.6.3 (Overdose of Talazoparib);

5.10.6 (Other Prohibited Concomitant 
Medications and Therapies);

5.10.7 (Cautionary Use of Concomitant 
Medicines While on Treatment with 
Talazoparib;

7.1.2 (Contraception Check).
4. Modifications based on Health Authority request 
to collect temperature and ECG at the start and end 
of maintenance treatment and add Acute Myeloid 
Leukemia to Exclusion criteria #10.  The following 
sections were modified: 

Schedule of Activities (Table 1 & 2);

4.2 (Exclusion Criteria);

7.1.5 (Vitals Signs and Physical 
Examination);

7.1.6 (Electrocardiogram Assessments).
5. Clarified DDR+ definition to align with 
Foundation Medicine’s approved CDx.  The 
following section was modified: 

1.2.7 (Rationale for Biomarker 
Assessments).


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7. To be consistent and align with avelumab 
program the tumor assessment time point at End of 
Treatment/Withdrawal was updated to indicate 
tumor scans do not need to be repeated if 
performed within 6 weeks of EOT/Withdrawal 
visit. 
•
Table 1. & 2. SOA footnote #40: End of 
Treatment/Withdrawal was updated to 
remove 12 weeks and replaced with 
6 weeks. 
8. There are no scheduled visits requiring 
assessments on Days 8, 15, 29 and 36 in Arm C.  
Removed Days 8, 15, 29 and 36 from the Table 2.0 
SOA (Arm C). 
9. Added ClinicalTrials.gov Registry Number to 
title page.
10. Removed statement that tumor tissue must 
contain 40% or greater tumor nuclei per central 
laboratory assessment from inclusion criterion #4 to 
avoid non-compliance with source verification at 
time of screening.  This requirement is provided in 
protocol Section 7.4.1 Baseline Tumor Tissue and 
in the central laboratory manual. 
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11. Modifications were made for administrative 
changes, typographical corrections, and for clarity 
and consistency including but not limited to the 
following sections:

Table 1. SOA Footnote 6 corrected from 
Day 22 to Day 29 of each maintenance 
cycle for hematology and blood chemistry 
(PACL 12Jun2018);

Table 1. SOA Footnote 10 updated to 
specify serum/urine pregnancy test and 
clarify time point descriptions in SOA table 
to align with Section 7.1.1.  Pregnancy 
Testing (PACL 12Jun2018 and 11Jul2018);

Table 1. SOA Footnote 28: corrected blood 
volume from 3.5 to 3.0 mL for PK blood 
sample (PACL 12Jun2018);

Table 2. SOA added ECOG Performance 
Status collection at Day 1 of each 
chemotherapy cycle to align with protocol 
Section 7.1.5 Vital Signs and Physical 
Exam (PACL12Jun2018);

Table 2. SOA updated to reflect that 
pregnancy testing is not required during 
short-term follow-up (Day 30, 60, and 90), 
[PACL11Jul2018]);

Table 2. SOA footnotes 37 and 38 corrected 
to align with SOA table (PACL 11Jul2018);

Section 1.2.5.1 (Rationale for 
Investigational Product Doses - Avelumab) 
removed reference to Arm B given that 
avelumab is only administered in Arm A 
(PACL 11Jul2018);

Section 5.2 (Patient Compliance) clarified 
to state that time of dose for talazoparib is 
not collected (PACL 11Jul2018);

Table 7. Management of Immune-Related 
Adverse Events updated to align with 


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current IB v.8 for avelumab; 

10.4 Pharmacokinetic Analysis was updated 
to remove operational instructions for study 
team members about PK blinding;

10.4.1 PK Analysis for Avelumab and 
Talazoparib was updated to remove text that 
is not applicable to this study. 
Original 
Protocol
30 March 2018
Not applicable (N/A)


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................18
LIST OF FIGURES .................................................................................................................18
APPENDICES .........................................................................................................................19
PROTOCOL SUMMARY.......................................................................................................20
SCHEDULE OF ACTIVITIES (OBSOLETE) .......................................................................29
1. INTRODUCTION ...............................................................................................................39
1.1. Mechanism of Action/Indication.............................................................................39
1.1.1. Avelumab....................................................................................................39
1.1.2. Talazoparib .................................................................................................39
1.2. Background and Rationale ......................................................................................40
1.2.1. Ovarian Cancer ...........................................................................................41
1.2.2. Clinical Experience with Avelumab...........................................................42
1.2.2.1. Clinical Experience From Study EMR 100070-001 in 
Patients with Ovarian Cancer ............................................................45
1.2.2.2. Safety of Avelumab Combined with Carboplatin and 
Paclitaxel in Ovarian Cancer Patients ...............................................46
1.2.2.3. Pharmacokinetics of Avelumab in Humans..............................46
1.2.3. Clinical Experience with Talazoparib ........................................................47
1.2.3.1. Clinical Efficacy of Talazoparib in Patients with 
Advanced Solid Tumors....................................................................49
1.2.3.2. Clinical Efficiacy of Talazoparib in Patients with 
Advanced Breast Cancer and a Germline BRCA 1/2 Mutation........49
1.2.3.3. PARP Inhibitor in Ovarian Cancer............................................49
1.2.3.4. Pharmacokinetics of Talazoparib in Humans............................50
1.2.4. Study Design Rationale ..............................................................................52
1.2.4.1. Rationale for Tumor Type to be Evaluated...............................52
1.2.4.2. Rationale for Avelumab and Talazoparib Combination............52
1.2.4.3. Rationale for Avelumab in Combination with 
Chemotherapy....................................................................................53
1.2.5. Rationale for the Investigational Product Doses ........................................55
1.2.5.1. Avelumab ..................................................................................55
1.2.5.2. Talazoparib................................................................................56


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1.2.6. Rationale for Randomization Stratification................................................57
1.2.7. Rationale for Biomarker Assessments........................................................58
1.3. Summary of Benefit/Risk Assessment....................................................................60
2. STUDY OBJECTIVES AND ENDPOINTS (OBSOLETE)...............................................60
3. STUDY DESIGN.................................................................................................................62
3.1. Study Overview.......................................................................................................63
3.1.1. Study Treatment Plan .................................................................................64
3.1.1.1. Interval Debulking Surgery After Neoadjuvant Treatment.......66
3.2. Safety Monitoring ...................................................................................................66
4. PATIENT ELIGIBILITY CRITERIA.................................................................................66
4.1. Inclusion Criteria.....................................................................................................67
4.2. Exclusion Criteria....................................................................................................69
4.3. Lifestyle Requirements ...........................................................................................71
4.4. Sponsor’s Qualified Medical Personnel..................................................................72
5. STUDY TREATMENTS.....................................................................................................72
5.1. Allocation to Treatment ..........................................................................................74
5.2. Patient Compliance .................................................................................................75
5.2.1. Patient Compliance with Avelumab...........................................................75
5.2.2. Patient Compliance with Talazoparib.........................................................76
5.2.3. Patient Compliance with Bevacizumab......................................................76
5.3. Investigational Product Supplies.............................................................................77
5.3.1. Dosage Form(s) and Packaging..................................................................77
5.3.1.1. Avelumab ..................................................................................77
5.3.1.2. Talazoparib................................................................................77
5.3.1.3. Bevacizumab .............................................................................77
5.3.1.4. Chemotherapy (Paclitaxel and Carboplatin) .............................77
5.3.2. Preparation and Dispensing........................................................................78
5.3.2.1. Preparation of Avelumab ..........................................................78
5.3.2.2. Dispensing of Talazoparib ........................................................78
5.3.2.3. Preparation of Bevacizumab .....................................................79
5.4. Administration of Chemotherapy Regimens...........................................................79
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5.4.1. Paclitaxel and Carboplatin..........................................................................79
5.4.1.1. Premedication for Chemotherapy Administration ....................79
5.4.1.2. Chemotherapy Regimen and Starting Doses.............................80
5.4.2. Administration of Avelumab Plus Chemotherapy......................................80
5.4.3. Administration of Bevacizumab Plus Chemotherapy.................................81
5.5. Administration of Maintenance Therapies..............................................................81
5.5.1. Avelumab Plus Talazoparib........................................................................81
5.5.1.1. Administration of Talazoparib ..................................................82
5.5.1.2. Premedication for Avelumab ....................................................82
5.5.1.3. Administration of Avelumab.....................................................83
5.5.1.4. Food Requirements ...................................................................83
5.5.2. Administration of Bevacizumab.................................................................83
5.6. Recommended Dose Modifications and Toxicity Management.............................84
5.6.1. Dose Reductions for Talazoparib ...............................................................84
5.6.2. Study Treatment Modifications for Drug-related Toxicity from 
Avelumab and Talazoparib (Excluding Infusion-Related Reactions and 
Immune-Related Adverse Events)...................................................................85
5.6.3. Overdose of Talazoparib.............................................................................88
5.6.4. Treatment Modifications for Infusion-Related Reactions Associated 
with Avelumab.................................................................................................88
5.6.5. Immune-Related Adverse Events Toxicity Management...........................89
5.6.6. Guidelines for Toxicity Management Bevacizumab..................................96
5.6.7. Guidelines for Toxicity Management Chemotherapy ................................96
5.6.7.1. General Guidelines for Hematologic Toxicity..........................96
5.6.7.2. Modifications for Hematologic Toxicities ................................97
5.6.7.3. Dose Modifications and Delays of Chemotherapy: Other 
Non Hematologic Toxicities and Laboratory Abnormalities ............97
5.6.8. Dose Modifications for Chemotherapy Combinations...............................99
5.6.8.1. Dose Modifications for Avelumab in Combination with 
Chemotherapy (Arm A)...................................................................100
5.6.8.2. Dose Modifications for Bevacizumab in Combination 
with Chemotherapy (Arm C)...........................................................101
5.7. Treatment after Initial Evidence of Radiological Disease Progression (Only 
for Patients on Arm A in Maintenance Period).......................................................102


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5.8. Investigational Product Storage ............................................................................103
5.9. Investigational Product Accountability.................................................................104
5.9.1. Destruction of Investigational Product Supplies ......................................104
5.10. Concomitant Treatment(s)...................................................................................104
5.10.1. Concomitant Radiotherapy.....................................................................105
5.10.2. Concomitant Surgery..............................................................................105
5.10.2.1. Interval Debulking Surgery...................................................105
5.10.2.2. Other Surgery ........................................................................106
5.10.3. Hematopoietic Growth Factors...............................................................106
5.10.4. Bisphosphonates or Denosumab.............................................................106
5.10.5. Corticosteroids........................................................................................106
5.10.6. Other Prohibited Concomitant Medicines and Therapies.......................106
5.10.7. Cautionary Use of Concomitant Medicines While on Treatment 
with Talazoparib ............................................................................................107
5.11. Rescue Medication and Supportive Care ............................................................107
5.11.1. Supportive Care Guidelines....................................................................107
6. STUDY PROCEDURES ...................................................................................................108
6.1. Screening (Obsolete).............................................................................................108
6.2. Treatment Period...................................................................................................109
6.3. End of Treatment...................................................................................................110
6.4. Patient Withdrawal................................................................................................110
6.4.1. Withdrawal of Consent.............................................................................111
6.4.2. Lost to Follow-Up.....................................................................................111
6.5. Short-Term Follow-Up..........................................................................................112
7. ASSESSMENTS................................................................................................................112
7.1. Safety Assessments ...............................................................................................112
7.1.1. Pregnancy Testing ....................................................................................112
7.1.2. Contraception Check ................................................................................113
7.1.3. Adverse Events .........................................................................................113
7.1.4. Laboratory Safety Assessments................................................................113
7.1.5. Vital Signs and Physical Examination......................................................114
7.1.6. Electrocardiogram Assessments...............................................................115


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7.2. Pharmacokinetic Assessments (Obsolete).............................................................115
7.2.1. Blood for PK Analysis of Avelumab (Obsolete)......................................116
7.2.2. Blood for PK Analysis of Talazoparib (Obsolete) ...................................116
7.4. 
 Pharmacodynamic Assessments (Obsolete).................................117
7.4.1. Baseline Tumor Tissue Sample (Obsolete) ..............................................118
7.4.2. End of Treatment Tumor Tissue Sample (Obsolete)................................119
7.4.3. Peripheral Blood Samples (Obsolete).......................................................119
7.4.4. Additional Analyses (Obsolete)................................................................120
7.5.1. Additional Research..................................................................................121
7.6. Tumor Response Assessments ..............................................................................121
7.7. Patient Reported Outcomes Assessments (Obsolete)............................................123
7.7.1. NFOSI-18 (Obsolete)................................................................................123
7.7.2. PGI-S (Obsolete) ......................................................................................124
7.7.3. PGI-C (Obsolete)......................................................................................124
7.7.4. EuroQoL EQ-5D-5L (Obsolete)...............................................................124
8. ADVERSE EVENT REPORTING....................................................................................126
8.1. Requirements.........................................................................................................126
8.1.1. Additional Details on Recording Adverse Events on the CRF.................128
8.1.2. Eliciting Adverse Event Information........................................................128
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Patient Withdrawal Section) ..........................................................................128
8.1.4. Time Period for Collecting AE/SAE Information....................................128
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................128
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............129
8.1.5. Causality Assessment ...............................................................................129
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................129
8.2. Definitions.............................................................................................................130
8.2.1. Adverse Events.........................................................................................130
8.2.2. Abnormal Test Findings ...........................................................................131
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8.2.3. Serious Adverse Events ............................................................................131
8.2.4. Hospitalization..........................................................................................132
8.3. Severity Assessment..............................................................................................133
8.4. Special Situations ..................................................................................................133
8.4.1. Protocol-Specified Serious Adverse Events.............................................133
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................133
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................135
8.4.3.1. Exposure During Pregnancy....................................................135
8.4.3.2. Exposure During Breastfeeding ..............................................137
8.4.3.3. Occupational Exposure ...........................................................137
8.4.4. Medication Errors .....................................................................................137
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................138
9.1. Sample Size Determination (Obsolete).................................................................138
9.2. Analysis Populations.............................................................................................143
9.2.1. Full Analysis Set (Obsolete).....................................................................143
9.2.2. Per Protocol Analysis Set (Obsolete) .......................................................143
9.2.3. Safety Analysis Set...................................................................................143
9.2.4. Pharmacokinetic Analysis Set ..................................................................143
9.2.5. Immunogenicity Analysis Set...................................................................143
9.2.6. Biomarker Analysis Set (Obsolete) ..........................................................143
9.3. Efficacy Analysis (Obsolete) ................................................................................144
9.3.1. Analysis of the Primary Endpoint (Obsolete)...........................................144
9.3.2. Analysis of Secondary Endpoints (Obsolete)...........................................145
9.3.2.1. PFS Based on BICR Assessment in all Randomized 
Patients (Obsolete)...........................................................................145
9.3.2.2. OS in the DDR+ Population and in all Randomized 
Patients (Obsolete)...........................................................................146
9.3.2.3. PFS Based on Investigator Assessment (Obsolete).................146
9.3.2.4. PFS on Next-line Therapy (PFS2) Based on Investigator 
Assessment (Obsolete) ....................................................................147
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9.3.2.5. PFS per GCIG Criteria Based on Investigator Assessment 
(Obsolete) ........................................................................................147
9.4. Pharmacokinetic Analysis.....................................................................................147
9.4.1. PK Analysis for Avelumab and Talazoparib............................................148
9.4.2. Population Pharmacokinetic and Exposure Response Analysis...............148
9.4.3. Analysis of Immunogenicity Data of Avelumab......................................148
9.5. Biomarker Analysis for Secondary 
 Endpoints (Obsolete) .........148
9.6. Analysis of Patient Reported Outcomes (Obsolete)..............................................149
9.8. Safety Analysis......................................................................................................151
9.8.1. Adverse Events.........................................................................................151
9.8.2. Laboratory Abnormalities.........................................................................152
9.8.3. Electrocardiograms (Obsolete) .................................................................152
9.9. Interim Analysis (Obsolete) ..................................................................................152
9.10. Data Monitoring Committee (Obsolete) .............................................................154
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................154
11. DATA HANDLING AND RECORD KEEPING ...........................................................155
11.1. Case Report Forms/Electronic Data Record .......................................................155
11.2. Record Retention.................................................................................................156
12. ETHICS............................................................................................................................156
12.1. Institutional Review Board/Ethics Committee....................................................156
12.2. Ethical Conduct of the Study ..............................................................................157
12.3. Subject Information and Consent........................................................................157
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................158
13. DEFINITION OF END OF TRIAL.................................................................................158
13.1. End of Trial in All Participating Countries .........................................................158
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................158
15. PUBLICATION OF STUDY RESULTS........................................................................159
15.1. Communication of Results by Pfizer ..................................................................159
15.2. Publications by Investigators ..............................................................................159
16. REFERENCES ................................................................................................................161
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LIST OF TABLES
Table 1.
Schedule of Activities: Chemotherapy + Avelumab Followed by Avelumab 
+ Talazoparib (Arm A)/Chemotherapy Followed by Talazoparib Alone 
(Arm B)—Obsolete ..............................................................................................29
Table 2.
Schedule of Activities: Chemotherapy + Bevacizumab Followed by 
Bevacizumab (Arm C)—Obsolete........................................................................33
Table 3.
Confirmed Tumor Response Observed in Ovarian Cancer Expansion 
Cohort ...................................................................................................................46
Table 4.
Dose Levels for Dose Reductions of Talazoparib ................................................85
Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related AEs) .....86
Table 6.
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated With Avelumab..................................................................................89
Table 7.
Management of Immune-Related Adverse Events...............................................90
Table 8.
Bevacizumab Treatment Modifications for Drug-Related Toxicity.....................96
Table 9.
Modification Guidance for Hematologic Toxicity ...............................................97
Table 10.
Dose Modification Levels for Paclitaxel and Carboplatin ...................................99
Table 11.
Avelumab in Combination With Chemotherapy (Arm A) Toxicity 
Management .......................................................................................................100
Table 12.
Required Safety Laboratory Tests ......................................................................114
Table 13.
Operating Characteristics for PFS in the DDR+ Population (Arm B vs. 
Arm C)—Obsolete..............................................................................................142
Table 14.
PFS Based on BICR Assessment in the DDR+ Population (Arm A vs. 
Arm C) - Efficacy and Futility Boundaries (Obsolete) ......................................153
Table 15.
PFS Based on BICR Assessment in All Randomized Patients and OS in the 
DDR+ Population (Arm A vs. Arm C) - Efficacy Boundaries (Obsolete).........153
Table 16.
OS in All Randomized Patients (Arm A vs. Arm C) – Efficacy Boundaries 
(Obsolete) ...........................................................................................................154
LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................64
Figure 2.
Statistical Testing Strategy for Arm A vs Arm C Comparisons (Obsolete).......140


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APPENDICES
Appendix 1. Abbreviations....................................................................................................169
Appendix 2. ECOG Performance Status................................................................................174
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines (Obsolete) .....................................................................175
Appendix 4. PFS by GCIG Criteria (Obsolete) .....................................................................181
Appendix 5. Patient Global Impression of Severity (PGI-S) (Obsolete)...............................182
Appendix 6. Revised Schedule of Activities – Effective with Amendment 2.......................183


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PROTOCOL SUMMARY
Background and Rationale
Ovarian cancer is the leading cause of death from gynecologic cancer and the fifth most 
common cause of cancer mortality in women.  The incidence of ovarian cancer increases 
with age and is most prevalent in the eighth decade of life.  The median age at the time of 
diagnosis is 63 years, and 70% of patients present with advanced disease.27  Although 
expectations for long-term survival can be high if the cancer is identified and treated early, 
the 5-year survival rate for women diagnosed with advanced ovarian cancer is less than 
30% from statistics in the United States and less than 20% in the United Kingdom.28,29
Ovarian neoplasms consist of several histopathological entities.  Epithelial ovarian cancer 
(EOC) comprises the majority of malignant ovarian neoplasms (about 80%);30 however, 
other less common pathologic subtypes must be considered in treatment recommendations, 
eg, fallopian tube cancer (FTC) and primary peritoneal cancer (PPC) which are less common 
neoplasms, are managed in a similar manner to EOC.
Carboplatin in combination with paclitaxel is the current standard of care in the front-line 
EOC treatment setting.  Complete response is achieved in approximately 75% of patients, but 
the median progression-free survival (PFS) is approximately 18 months and most patients 
ultimately succumb to the disease.30  Therefore, there remains a high unmet need for newer 
agents with novel mechanisms of action and combination regimens able to modify the natural 
history of the disease.
Several studies have been conducted in the frontline treatment setting.  Due to long 
post-progression survival and the potential for post-treatment crossover to confound overall 
survival (OS) results interpretation, PFS is an accepted endpoint in this setting.31  
Bevacizumab (Avastin, Genentech, Inc.) in combination with chemotherapy followed by 
maintenance therapy (16 cycles or 48 weeks in Gynecologic Oncology Group (GOG)-218 
study, 12 cycles or 36 weeks in International Collaboration on Ovarian Neoplasms (ICON) 
7 study) demonstrated improvement in PFS in the front-line treatment setting32,33 but without 
statistically significant improvement on OS.35  Both trials focused on patients who were at 
high-risk for recurrence; ICON 7 allowed Stage I and II patients considered high risk for 
recurrence (high-grade), whereas GOG-218 included only patients with Stage III and IV 
disease.  In ICON 7, 31% of patients had Federation of Gynecology and Obstetrics (FIGO) 
Stage III or IV disease and >1 cm residual disease after debulking surgery and in 
GOG-218, 66% of patients had Stage III and >1 cm residual disease or Stage IV.  
Bevacizumab is currently approved in the frontline, platinum-sensitive recurrent setting, and 
platinum-resistant recurrent treatment settings in the European Union (EU)57 while in the 
United States (US), it is approved in the platinum-sensitive recurrent and platinum-resistant 
treatment setting.  Despite this lack of approval in the US, bevacizumab is routinely used 
both in the US and EU in the frontline setting.  Subsequent to the original protocol, on 
June 13, 2018, the Food and Drug Administration (FDA) approved bevacizumab for use in 
the frontline setting.58


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Neoadjuvant chemotherapy is also increasing in usage and is currently selected for 25% of 
patients with Stage II disease, 40% of patients with Stage III disease, and 50% of patients 
with Stage IV disease.36  A randomized study demonstrated non-inferiority of this approach 
with respect to overall survival compared to adjuvant therapy in high-risk patients.21  
Typically, 3 cycles of chemotherapy are administered before surgery and 3 cycles after 
surgery.  The same chemotherapy regimens are used in the neoadjuvant treatment setting as 
for the traditional post-surgical approach.31  A number of frontline studies have successfully 
enrolled patients undergoing either adjuvant or neoadjuvant therapies in the same trial 
(GOG-262 and ICON 8).  ICON 8 results comparing neoadjuvant and adjuvant treatment are 
pending.  The primary analysis of GOG-262 was published in 2016.32  In GOG-262, the 
primary research question was whether dose dense paclitaxel could improve outcome in 
incompletely resected Stage III or IV disease.  Both neoadjuvant and adjuvant were 
(pre-specified) treatment options, as well as the addition of bevacizumab.  The primary 
endpoint was not met.  Dose dense paclitaxel was not superior to the every 3 weeks (Q3W; 
standard) paclitaxel regimen.  A pre-specified subgroup analysis showed that in the absence 
of bevacizumab, there was a benefit for dose dense paclitaxel (median PFS [mPFS] 
14.2 months versus 10.3 months, hazard ratio 0.62, 95% confidence interval [CI]: 0.40, 0.95, 
p=0.03).  In the presence of bevacizumab, there was no difference in mPFS (14.9 versus 
14.7 months).
The current standard of care in the frontline maintenance treatment setting is 
region-dependent.  A significant number of patients, especially those with poor prognostic 
factors (incompletely resected Stage III and Stage IV), receive bevacizumab in combination 
with induction chemotherapy followed by bevacizumab maintenance therapy in regions 
where bevacizumab is available in this setting.  For others, especially those with fewer poor 
prognostic factors, a standard of care option includes platinum doublet chemotherapy 
followed by best supportive care/observation or participation in a clinical trial.
Avelumab and talazoparib have the potential to produce additive or synergistic anti-tumor 
activity, with talazoparib functioning to promote immune priming and tumor 
immunogenicity and avelumab functioning to overcome Programmed Death 
Ligand 1 (PD-L1) mediated inhibition of any resulting anti-tumor immune response.
Specifically, the activity of avelumab depends on generation of a productive immune 
response, composed of effective antigen presentation, T-cell priming, infiltration of tumors, 
and recognition and killing of tumor cells.21  Talazoparib, via its ability to promote increased 
DNA (deoxyribonucleic acid) damage, has the potential to promote several of these key 
stages of the immune response.
Ovarian cancer has been reported to a have high prevalence (~20%) of defects in the BRCA 
(BReast CAncer Gene) 1/2 genes, which have been reported to predict for sensitivity to 
PARP inhibitors,43 such as talazoparib.  Ovarian tumors harboring such defects have also 
been shown to present with increased PD-L1 expression and increased T-cell infiltration.44,46  
Increased T-cell infiltration has been associated with improved outcome in ovarian cancer,45
and both increased T-cell infiltration and PD-L1 expression have been associated with 
improved response to anti-PD-1)/PD-L1 treatment.46  Given these data, tumors harboring 


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these defects may respond more robustly to combination treatment with talazoparib and 
avelumab.
Ovarian cancer has been reported to have a high prevalence (35%) of genomic scarring.  
Tumors with a high level of genomic scarring have been shown to have increased clinical 
benefit from PARP inhibitors,48,49 and as such might also be expected to respond more 
robustly to the combination of talazoparib and avelumab.
Given the intrinsic links between DNA damage and immune priming outlined above, and the 
potential for PARP inhibition to promote DNA damage in the presence of DNA damage 
repair (DDR) defects, ovarian cancer, with its high prevalence of such defects, represents a 
tumor type in which the combination of talazoparib and avelumab may optimally mediate 
anti-tumor activity.
Considering the above described mechanism of action and the preliminary clinical activity 
observed for the investigational products or agents of the same class (see Section 1.1.1 and 
Section 1.1.2), the avelumab and talazoparib combination is proposed for evaluation in 
patients with advanced epithelial ovarian cancer.
On 21 December 2018, the Sponsor (Pfizer and Merck KGaA) announced that the Phase 3 
JAVELIN Ovarian 100 study (B9991010) was stopped due to futility of efficacy at a planned 
interim analysis in alignment with the recommendation of both the Independent Data 
Monitoring Committee and the Protocol Steering Committee.  There were no new safety 
signals identified from the B9991010 study relative to the known safety profile of avelumab 
or the other study medications. 
Detailed analyses of the data from study B9991010 have since been performed to determine 
the impact on the ongoing JAVELIN Ovarian PARP 100 study (B9991030).  Although the 
overall safety profile of avelumab remains unchanged, the lack of efficacy with avelumab in 
the treatment of frontline ovarian cancer observed in study B9991010 reduces the probability 
of technical success of study B9991030 and of regulatory success of any submission based 
on this study. 
In addition, the recent approvals in the United States and in the European Union of a 
PARPinhibitor in the front-line maintenance setting based on the practice-changing results 
from the SOLO-1 trial (National Clinical Trial # 01844986) provide a sound rationale for 
PARP inhibitor therapy instead of bevacizumab for patients with deleterious germline or 
somatic BRCA mutations.  This new treatment paradigm creates a recruitment challenge for 
enrolling BRCA+ patients into the B9991030 study along with a risk for high attrition of 
BRCA+ patients when randomized to the bevacizumab control arm.
Therefore, based on the totality of the information, the Sponsor made the decision to stop 
enrollment in the B9991030 study.  On 19 March 2019, a Dear Investigatior Letter was 
issued to notify the investigational sites that no new patients could be screened or 
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Patients who had been randomized prior to 19 March 2019 were able to remain in the study 
provided they sign the Informed Consent Addendum upon its approval by local institutional 
review board (IRB)/ethics committee (EC). Patients who remain in the study will continue 
receiving investigational products according to their randomized treatment assignment and 
will be monitored for appropriate safety assessments until treatment discontinuation.
Objectives and Endpoints (Obsolete)
The original study objectives and endpoints are no longer applicable and/or feasible.  
The purpose of protocol amendment 2 is to reduce study-specific procedure assessments 
(ie, remove efficacy, physical examination, electrocardiogram, ePROs, tumor assessments, 
pharmacokinetics (PK) and Biomarkers) for the ongoing patients. 
The schedule of activities (SOA) found in Appendix 6 is replacing the previous SOA and has 
been revised to decrease the frequency of study procedures while maintaining appropriate 
assessment of patient safety. The new SOA is effective with IRB/EC approval of 
amendment 2. 
Primary Objective(s):
Primary Endpoint(s):

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
PFS in patients with advanced ovarian cancer with 
defects in DNA damage repair (DDR+).

PFS as determined based on BICR assessment per 
RECIST v1.1 in patients with newly diagnosed 
advanced ovarian cancer with defects in DNA 
damage repair (DDR+).
Secondary Objectives:
Secondary Endpoints:

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
overall survival (OS) in patients with advanced 
ovarian cancer with defects in DNA damage repair 
(DDR+). 

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
PFS in patients with advanced ovarian cancer 
unselected for DDR status.

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
OS in patients with advanced ovarian cancer 
unselected for DDR status.

To evaluate the effect on PFS and OS of 
platinum-based chemotherapy followed by talazoparib 
maintenance versus platinum-based chemotherapy 

OS in patients with tumors that are DDR+ and in 
patients unselected for DDR status. 

PFS based on BICR assessment per RECIST v1.1 in 
patients unselected for DDR status. 

PFS based on investigator assessment per RECIST 
v1.1 in patients with tumors that are DDR+ and in 
patients unselected for DDR status.

PFS2 based on investigator assessment in patients 
with tumors that are DDR+ and in patients 
unselected for DDR status. 

PFS based on investigator assessment per 
Gynecological Cancer Intergroup (GCIG) criteria in 
patients with tumors that are DDR+ and in patients 
unselected for DDR status. 

AEs (as graded by NCI CTCAE v4.03); laboratory 
abnormalities (as graded by NCI CTCAE v4.03); 
vital signs (blood pressure, pulse rate); 
electrocardiograms (ECGs). 

PK parameters, including Ctrough and Cmax for 
avelumab and Ctrough for talazoparib.

Anti-drug antibodies (ADA) and neutralizing 


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plus bevacizumab followed by bevacizumab 
maintenance in patients with advanced ovarian cancer 
with DDR+ and unselected for DDR status.
•
To evaluate the anti-tumor activity in each treatment 
arm.
•
To evaluate the overall safety profile in each treatment 
arm. 
•
To evaluate the pharmacokinetics (PK) of avelumab 
in combination with platinum-based chemotherapy 
followed by avelumab plus talazoparib maintenance in 
Arm A as well as well as PK of talazoparib in 
combination with avelumab (Arm A) and as a single 
agent (Arm B).
•
To evaluate the immunogenicity of avelumab in 
Arm A (avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance). 
•
To evaluate the effect of avelumab in combination 
with platinum-based chemotherapy followed by 
avelumab plus talazoparib maintenance and 
platinum-based chemotherapy followed by talazoparib 
maintenance versus platinum-based chemotherapy 
plus bevacizumab followed by bevacizumab 
maintenance on patient reported outcome (PRO) 
including the assessments of disease-related 
symptoms, treatment side effects and health-related 
quality of life (HRQoL).
•
To assess the correlation of anti-tumor activity with 
PD-L1 expression, tumor mutational burden (TMB) 
and with potential biomarkers of PARP inhibitor 
sensitivity in baseline tumor tissue.
•
To assess the correlation of anti-tumor activity with 
TMB and potential biomarkers of PARP inhibitor 
sensitivity in baseline circulating tumor (ct) DNA. 
antibody (NAb) against avelumab. 
•
Disease related symptoms and treatment side effects 
as measured by the NCCN-FACT FOSI-18 and 
health-related quality of life (HRQOL) as measured 
by NCCN-FACT FOSI-18 and the EuroQol Group 
5-Dimension 5-Level (EQ-5D-5L). 
•
PD-L1 expression, TMB, genomic scarring and the 
presence of defects in select genes, considered 
critical to effective DDR, in baseline tumor tissue. 
•
Assessment of defects in a panel of key oncogenes, 
including several considered critical to effective 
DDR and TMB in ctDNA at baseline.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Design
This is a Phase 3, randomized, open-label, multicenter study to evaluate the efficacy and 
safety of avelumab in combination with chemotherapy followed by maintenance therapy of 
avelumab in combination with the PARP inhibitor talazoparib in patients with previously 
untreated advanced ovarian cancer.  Patients must meet full eligibility criteria as specified in 
Section 4.
The study design, including the number of patients to be randomized in each treatment arm, 
is illustrated in the study schematic figure below.
Approximately 720 patients (including 360 patients with tumors that are DDR+) who are 
candidates for frontline chemotherapy followed by maintenance were planned to be 
randomized in a 2.5:1:2.5 ratio stratified by germline BRCA 1/2 mutational status 
(gBRCA+ vs gBRCA-) and resection status (adjuvant with >1 mm and ≤1 cm residual 
disease vs adjuvant with >1 cm residual disease vs neoadjuvant) to one of the following 
treatment arms:
•
Arm A: platinum-based chemotherapy + avelumab followed by avelumab 
+ talazoparib maintenance;
•
Arm B: platinum-based chemotherapy followed by talazoparib maintenance; 
•
Arm C: platinum-based chemotherapy + bevacizumab followed by bevacizumab 
maintenance.
No new patients could be screened or randomized as of 19 March 2019.
Intravenous carboplatin and paclitaxel will be used as the chemotherapy backbone, consisting 
of Q3W carboplatin and paclitaxel. 
Patients may be enrolled either following primary debulking surgery, or prior to initiation of 
neoadjuvant chemotherapy.  The latter group will undergo interval debulking surgery after 
3 study cycles of chemotherapy to be followed, upon recovery from surgery, by the 
remaining 3 cycles of chemotherapy.
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Study Schematic
Chemotherapy
Maintenance
gBRCA = germline BReast CAncer gene; N = number of patients.
Study Treatments
The study period includes two treatment periods, the chemotherapy period and the 
maintenance period.  For the purpose of scheduling evaluations, providing clarity on 
assessments, and consistent on-treatment assessments across all three treatment arms, the 
definition of cycle length varies between the chemotherapy period and the maintenance 
period.  In the chemotherapy period, a cycle is defined as 3 weeks (21 days), and due to the 
biweekly schedule of avelumab and the Q3W schedule for bevacizumab, a cycle in the 
maintenance period is defined as 6 weeks (42 days).  See Section 1.2.5.1 for additional 
information.
For the chemotherapy period of the study, study drugs will be assigned and given as 
follows:
Arm A: 

Paclitaxel 175 mg/m2 intravenously (IV) over 3 hours followed by Carboplatin area 
under the curve (AUC) 5 or 6 IV over 15-60 minutes on Days 1 of each 3-week cycle 
for 6 cycles. 
Chemotherapy 
+
Avelumab 
Chemotherapy
Chemotherapy 
+ 
Bevacizumab
Bevacizumab
Talazoparib
Avelumab + 
Talazoparib
Treatment 
Until: 
Progressive 
Disease per 
RECIST v1.1
OR
Unacceptable 
Toxicity
OR
Patient 
Withdrawal
2.5:1:2.5
N = ~720
Randomization Stratification: 

germline BRCA 1/2 mutational status (gBRCA+ vs gBRCA-).

Adjuvant with >1 mm and ≤1 cm residual disease vs. 
Adjuvant with >1 cm residual disease vs.
Neoadjuvant.
Arm A 
(N=300)
Arm C 
(N=300)
Arm B 
(N=120)


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
Avelumab 800 mg administered intravenously on Day 1 of each 3-week cycle for 
6 cycles.
Arm B: 

Paclitaxel 175 mg/m2 IV over 3 hours followed by Carboplatin AUC 5 or 6 IV over 
15-60 minutes on Days 1 of each 3-week cycle for 6 cycles. 
Arm C: 

Paclitaxel 175 mg/m2 IV over 3 hours followed by Carboplatin AUC 5or 6 IV over 
15-60 minutes on Day 1 of each 3-week cycle for 6 cycles. 

Bevacizumab 15 mg/kg IV on Day 1 of each 3-week cycle beginning with Cycle 2 for 
adjuvant patients (may begin with Cycle 1 if surgery completed >4 weeks prior to 
randomization and no contraindications), and for neoadjuvant patients, bevacizumab 
will be given on Day 1 of each 3-week cycle for Cycles 1, 2, 5, and 6.
For patients who are enrolled to undergo neoadjuvant chemotherapy with interval debulking 
surgery, the first 3 cycles of chemotherapy will be administered prior to interval debulking 
surgery.  Patients will stay on study regardless of the surgery outcome (eg, extend of residual 
disease) and will receive the remaining 3 cycles of chemotherapy.
Patients who have to discontinue chemotherapy (carboplatin and paclitaxel) for unacceptable 
toxicities prior to the end of Cycle 6 may enter maintenance period, if deemed clinically 
acceptable by the investigator, and will receive avelumab and talazoparib (Arm A) or 
talazoparib (Arm B), or bevacizumab (Arm C).
Maintenance period should begin within 4 weeks of the last dose of chemotherapy.  The first 
visit of maintenance therapy will be designated maintenance Cycle 1 Day 1 even if the last 
chemotherapy cycle was not completed.
For the maintenance period of the study, study drugs will be assigned and given as follows. 
Arm A:

Avelumab 800 mg administered intravenously on Days 1, 15, and 29 of each 6-week 
cycle in combination with talazoparib 0.75 mg self-administered orally once per day.
Arm B: 

Talazoparib 0.75 mg self-administered orally once a day, every day of each 6-week 
cycle.


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Arm C:

Bevacizumab 15 mg/kg administered intravenously on Days 1 and 22 of each 6-week 
cycle.
Effective with IRB/EC approval of amendment 2, patients will receive study treatment until 
progressive disease (PD) as assessed by the investigator, unacceptable toxicity, or withdrawal 
of consent, whichever is earliest.  For avelumab and talazoparib, the maximum duration of 
maintenance treatment is 24 months.  For bevacizumab, the maximum duration of treatment 
is 21 or 22 doses, per local approval, including the chemotherapy period.  Patients who 
discontinue all study treatment and have PD based on investigator assessment will be 
followed for a 90-day Safety Follow-up Period.  
Statistical Methods
As of 19 March 2019, the study was stopped for enrollment. Approximately 11% of the 
patients originally planned to be randomized in the study had been randomized.  Therefore, 
no statistical hypotheses will be tested.  Patient characteristics, treatment duration and safety 
endpoints will be summarized by treatment arm.


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SCHEDULE OF ACTIVITIES (OBSOLETE)
Effective with IRB/EC approval of Amendment 2, the SOA below is no longer applicable.  Please refer to Appendix 6 for the 
revised SOA.  
The schedule of activities (SOA) tables below provide an overview of the protocol visits and procedures for each treatment arm.  
Refer to the STUDY PROCEDURES and ASSESSMENTS sections of the protocol for detailed information on each procedure and 
assessment required for compliance with the protocol.  Patients who are enrolled prior to neoadjuvant therapy will undergo interval 
debulking surgery during the chemotherapy period as described in Section 5.10.2.1 and will resume on the schedule of assessments 
upon recovery.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the patient.
Table 1.
Schedule of Activities: Chemotherapy + Avelumab Followed by Avelumab + Talazoparib (Arm A)/Chemotherapy 
Followed by Talazoparib Alone (Arm B)—Obsolete
Protocol Activities1
Screening
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period39
(1 cycle = 6 weeks = 42 days)
Within 28 
Days Prior 
to 
Randomiza
tion
Day 1 
(3 days)
Day 8 
(3 days)
Day 15 
(3 days)
Day 1 
(3 days)
Day 15 
(3 days)
Day 29
(3 days)
End of 
Treatment/
Withdrawal
40
Short-Term 
Follow-up 
(Day After 
Last Dose, 30, 
60, and 90 3 
days)41
Survival 
and 
Long-Term 
Follow- up
14 days42
Clinical Assessments
Informed consent
X
Medical/Oncological history2
X
Physical examination3
X
X
X
X
X
X
ECOG Performance Status3
X
X
X
X
X
X
Blood Pressure, 
Temperature, Pulse Rate4
X
X
X
X
X
X
Contraception Check5
X
X
X
X
X
X


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Table 1.
Schedule of Activities: Chemotherapy + Avelumab Followed by Avelumab + Talazoparib (Arm A)/Chemotherapy 
Followed by Talazoparib Alone (Arm B)—Obsolete
Protocol Activities1
Screening
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period39
(1 cycle = 6 weeks = 42 days)
Within 28 
Days Prior 
to 
Randomiza
tion
Day 1 
(3 days)
Day 8 
(3 days)
Day 15 
(3 days)
Day 1 
(3 days)
Day 15 
(3 days)
Day 29
(3 days)
End of 
Treatment/
Withdrawal
40
Short-Term 
Follow-up 
(Day After 
Last Dose, 30, 
60, and 90 3 
days)41
Survival 
and 
Long-Term 
Follow- up
14 days42
Laboratory Studies 
Hematology6
X
X
X
X
X
X
X (Day 30)
Blood chemistry6
X
X
X
X
X
X
X (Day 30)
Coagulation6
X
X
X
X
CA-1257
X
X
X
X
HBV and HCV8
X
Thyroid Function/ACTH9
X
C2D1, C4D1, and C6D1 only
C1D1, then every 12 weeks thereafter
X
Serum/Urine Pregnancy 
Test10
X
X
X
X
X
Urinalysis11
X
X
X
X
X
12-Lead Electrocardiogram 
(ECG)12
X
X
(C1 only)
X
Randomization/Study Treatment
Blood sample for germline 
BRCA1/2 testing13
X
Randomization14
X
Paclitaxel/Carboplatin 
Administration15
X
Talazoparib Administration16
QD
Avelumab Administration17
X
(Arm A only)
X
(Arm A 
only)
X
(Arm A only)
X
(Arm A only)
Disease Assessments
Tumor Assessments 
(including scans)19
X
At 9 and 18 weeks after date of randomization, then every 12 weeks thereafter until PD by BICR regardless of initiation of new 
anti-cancer therapy 


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Table 1.
Schedule of Activities: Chemotherapy + Avelumab Followed by Avelumab + Talazoparib (Arm A)/Chemotherapy 
Followed by Talazoparib Alone (Arm B)—Obsolete
Protocol Activities1
Screening
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period39
(1 cycle = 6 weeks = 42 days)
Within 28 
Days Prior 
to 
Randomiza
tion
Day 1 
(±3 days)
Day 8 
(±3 days)
Day 15 
(±3 days)
Day 1 
(±3 days)
Day 15 
(±3 days)
Day 29
(±3 days)
End of 
Treatment/
Withdrawal
40
Short-Term 
Follow-up 
(Day After 
Last Dose, 30, 
60, and 90 ±3 
days)41
Survival 
and 
Long-Term 
Follow- up
±14 days42
Other Clinical Assessments
Serious and non-serious 
adverse event monitoring20
X
Monitored and recorded throughout treatment
X
X 
Concomitant Treatment(s)21
X
Monitored and recorded throughout treatment
X
X
Patient-Reported Outcomes 
(NFOSI-18)22
Weekly in the first 3 cycles, and then Day 1 of 
every subsequent cycle
X
X
Every 6 weeks for 3 years 
from randomization
Patient Global Impression of 
Severity (PGI-S)23
Weekly in the first 3 cycles
X
Patient Global Impression of 
Change (PGI-C)24
Days 8 and 15 of Cycle 1, and then Days 1, 8, 
15 of Cycles 2 and 3
X
Patient-Reported Outcomes
(EQ-5D-5L)25
X
X
X
Every 6 weeks for 3 years 
from randomization
 
 
Other Samplings
Blood for Avelumab ADA 
(Immunogenicity) Testing27
X (C1-C4 
only, Arm A 
only)
X (C1, 2, 4, 
6, 10, Arm A 
only)
X (C1, Arm A 
only)
X
Blood sampling for 
Talazoparib 
Pharmacokinetics28
X (C1 only)
X (C1 only)
X (C1 only)
Blood Sampling for 
Avelumab 
Pharmacokinetics29
X (C1-C4 
only, Arm A 
only)
X (C1, 2, 4, 
6, 10, Arm A 
only)
X (C1, Arm A 
only)
X
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Table 1.
Schedule of Activities: Chemotherapy + Avelumab Followed by Avelumab + Talazoparib (Arm A)/Chemotherapy 
Followed by Talazoparib Alone (Arm B)—Obsolete
Protocol Activities1
Screening
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period39
(1 cycle = 6 weeks = 42 days)
Within 28 
Days Prior 
to 
Randomiza
tion
Day 1 
(±3 days)
Day 8 
(±3 days)
Day 15 
(±3 days)
Day 1 
(±3 days)
Day 15 
(±3 days)
Day 29
(±3 days)
End of 
Treatment/
Withdrawal
40
Short-Term 
Follow-up 
(Day After 
Last Dose, 30, 
60, and 90 ±3 
days)41
Survival 
and 
Long-Term 
Follow- up
±14 days42
Mandatory Archival FFPE 
Tumor Tissue Block or De 
Novo Tumor Biopsy30
X
Optional De Novo Tumor 
Biopsy31
X
Genomic banked 
biospecimens Prep D132
X (C1 only)
Blood Biospecimen for 
DNA33
X (C1 only)
Plasma for circulating tumor 
(ct)DNA analysis34
X
X (C1 and C2 
only)
X (C1 only)
X (C1 only)
X
Plasma for 
Biomarker/Proteomic/ 
Metabolomic Analysis35
X (C1 only)
X (C1 only)
X (C1 only)
X
Serum for 
Biomarker/Proteomic/ 
Metabolomic Analysis36
X (C1 only)
X (C1 only)
X (C1 only)
X
 
 
Blood Draw for RNA 
analysis38
X (C1 only)
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Table 2.
Schedule of Activities: Chemotherapy + Bevacizumab Followed by Bevacizumab (Arm C)—Obsolete
Protocol Activities1
Screening
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period39
(1 cycle = 6 weeks = 42 
days)
Within 28 Days 
Prior to 
Randomization
Day 1 
(3 days)
Day 8 
(3 days)
Day 15 
(3 days)
Day 1 
(3 days)
Day 22 
(3 days)
End of 
Treatment/
Withdrawal40
Short-Term 
Follow-up (Day After 
Last Dose 30, 60, and 
90 ±3 days)41
Survival and 
Long-Term 
Follow-up
±14 days42
Informed consent
X
Medical/Oncological history2
X
Physical examination3
X
X
X
X
X
ECOG Performance Status3
X
X
X
X
X
Blood Pressure, Temperature, 
Pulse Rate4
X
X
X
X
X
Contraception Check5
X
X
X
X
X
X
Laboratory Studies 
Hematology6
X
X
X
X
X
Blood chemistry6
X
X
X
X
X
Coagulation6
X
X
X
X
CA-1257
X
X
X
X
HBV and HCV8
X
Thyroid Function/ACTH9
X
C2D1, then every other cycle thereafter
C1D1, then every 
12 weeks thereafter
X
Serum/Urine Pregnancy Test10
X
X
X
X
X
Urinalysis11
X
X
X
X
X
12-Lead ECG12
X
X (C1 only)
X
Randomization/StudyTreatment
Blood sample for germline 
BRCA1/2 testing13
X
Randomization14
X
Paclitaxel/Carboplatin 
Administration15
X
Bevacizumab Administration18
X 
X
X


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Table 2.
Schedule of Activities: Chemotherapy + Bevacizumab Followed by Bevacizumab (Arm C)—Obsolete
Protocol Activities1
Screening
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period39
(1 cycle = 6 weeks = 42 
days)
Within 28 Days 
Prior to 
Randomization
Day 1 
(±3 days)
Day 8 
(±3 days)
Day 15 
(±3 days)
Day 1 
(±3 days)
Day 22 
(±3 days)
End of 
Treatment/
Withdrawal40
Short-Term 
Follow-up (Day After 
Last Dose 30, 60, and 
90 ±3 days)41
Survival and 
Long-Term 
Follow-up
±14 days42
Disease Assessments
Tumor Assessments (including 
scans)19
X
At 9 and 18 weeks after date of randomization, then every 12 weeks thereafter until PD by BICR regardless of initiation of new 
anti-cancer therapy
Other Clinical Assessments
Serious and non-serious 
adverse event monitoring20
X
Monitored and recorded throughout treatment
X
X 
Concomitant Treatment(s)21
X
Monitored and recorded throughout treatment
X
X
Patient-Reported Outcomes 
(NFOSI-18)22
Weekly in the first 3 cycles, and then Day 1 
of every subsequent cycle
X
X
Every 6 weeks for 3 years from 
randomization
Patient Global Impression of 
Severity (PGI-S)23
Weekly in the first 3 cycles
X
Patient Global Impression of 
Change (PGI-C)24
Days 8 and 15 of Cycle 1, and then Days 1, 8, 
15 of Cycles 2 and 3
X
Patient-Reported Outcomes
(EQ-5D-5L)25
X
X
X
Every 6 weeks for 3 years from 
randomization
 
 
 
Other Samplings
Mandatory Archival FFPE 
Tumor Tissue Block or De 
Novo Tumor Biopsy30
X
Optional De Novo Tumor 
Biopsy31
X
Genomic banked biospecimens 
Prep D132
X (C1 only)
Blood Biospecimen for DNA33
X (C1 only)
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Table 2.
Schedule of Activities: Chemotherapy + Bevacizumab Followed by Bevacizumab (Arm C)—Obsolete
Protocol Activities1
Screening
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period39
(1 cycle = 6 weeks = 42 
days)
Within 28 Days 
Prior to 
Randomization
Day 1 
(±3 days)
Day 8 
(±3 days)
Day 15 
(±3 days)
Day 1 
(±3 days)
Day 22 
(±3 days)
End of 
Treatment/
Withdrawal40
Short-Term 
Follow-up (Day After 
Last Dose 30, 60, and 
90 ±3 days)41
Survival and 
Long-Term 
Follow-up
±14 days42
Plasma for circulating tumor 
(ct)DNA analysis34
X
X (C1 and C2 
only)
X (C1 only) X (C1 only)
X
Plasma for 
Biomarker/Proteomic/ 
Metabolomic Analysis35
X (C1 only)
X (C1 only)
X
Serum for 
Biomarker/Proteomic/ 
Metabolomic Analysis36
X (C1 only)
X (C1 only)
X
 
 
Blood Draw for RNA analysis38
X (C1 only)
Footnotes for Schedule of Activities Tables
1.
Protocol Activities: All assessments should be performed prior to dosing with study medications unless otherwise indicated.  Acceptable time windows for performing each 
assessment are described in the column headers.  Day 1 windows do not apply to Cycle 1 of chemotherapy or maintenance periods.
2.
Medical/Oncological History: Both medical and oncological histories are to be collected within 28 days prior to first dose of study treatment.  Medical history should include 
history of other disease (active or resolved) as well as concomitant illnesses.  Oncological history should include information on surgery and radiation therapy. 
3.
Physical Examination: Includes an examination of major body systems, assessment of ECOG performance status, and weight (height included at screening only).  Weight 
will not be collected at End of Treatment.  See Section 7.1.5.
4.
Blood Pressure, Temperature, Pulse Rate: See Section 7.1.5.
5.
Contraception Check: Only for patients who are of child-bearing potential.  See Section 4.3 and Section 7.1.2.
6.
Hematology, Blood Chemistry, and Coagulation: Cycle 1 Day 1 tests do not need to be repeated if they have been conducted in the prior 3 days.  Laboratory tests may be 
performed up to 3 days prior to the scheduled clinic visit.  Required tests are listed in Section 7.1.4.  Hematology and Blood Chemistry must be performed at screening, 
Cycle 1 Day 1 (unless done in the prior 3 days), and on Day 1, Day 15 and Day 29 of each maintenance cycle, End of Treatment, and at Day 30 during the follow-up for 
patients in Arm A & B.  Hematology and Blood Chemistry must be performed at screening, Cycle 1 Day 1, and on Days 1, and 22 of each maintenance cycle, and end of 
treatment in Arm C.  Coagulation and hematology are required as noted in this table.  Any test may also be performed when clinically indicated.
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7.
CA-125: To be assessed locally.  No need to repeat on Day 1 of Cycle 1 if screening assessment performed within 7 days prior to that date.  Rising CA-125 levels alone will
not be considered evidence of progression.
8.
HBV and HCV Tests: HBV surface antigen and anti-HCV antibody will be performed at Screening.  HCV RNA will be performed if anti-HCV antibody test is positive 
(see Section 7.1.4 and Table 12).
9.
Thyroid Function Tests and ACTH: Baseline free T4, TSH, and ACTH will be performed.  Additional tests will be performed at every other cycle.  See Section 7.1.4.
10. Serum/Urine Pregnancy Test: For women of childbearing potential, a serum or urine pregnancy test must be performed at screening, on Day 1 of each chemotherapy cycle, 
on Day 1 and Day 29 (Arms A and B) and Day 1 and Day 22 (Arm C) of each maintenance cycle, and at the end of study treatment.  The pregnancy test should be repeated if 
1 menstrual cycle is missed or if the potential of pregnancy is otherwise suspected.  See Section 7.1.1. 
11. Urinalysis: See Section 7.1.4. 
12. 12 lead ECG: See Section 7.1.6 for details.  All patients require a single ECG measurement at screening (clinically significant abnormal findings in baseline ECGs will be 
recorded as medical history), and prior to start of treatment on Cycle 1 Day 1 and at end of treatment/withdrawal of the maintenance period (all arms).  Additional ECGs will 
be performed as clinically indicated.  Clinically significant findings seen on follow-up ECGs should be recorded as adverse events.
13. Blood Sample for Germline BRCA1/2 Testing (10 mL): Results are to be used for designation of BRCA1/2 defect status and subsequent stratification during the 
randomization process.  See Section 6.1.  For patients with an existing test result for germline BRCA 1/2 defect status, test result must have been obtained using a CLIA (or 
comparable local validation) approved assay.
14. Randomization: Patients meeting all entry criteria will be randomized using the Interactive Response Technology system.  See Section 5.1.  Study treatment must start within 
3 days after randomization.
15. Paclitaxel/Carboplatin Administration: Paclitaxel 175 mg/m2 IV, followed by carboplatin dose AUC 5 or AUC 6 IV on Day 1 of every chemotherapy cycle as described in 
Section 5.4.  Premedication will be administered as specified in Section 5.4.1.1.  On visits when chemotherapy is administered in combination with avelumab or bevacizumab 
(Day 1 of each 21-day cycle), chemotherapy will be infused before either avelumab or bevacizumab.  See Section 5.4.2 and Section 5.4.3. See Section 6.2 for guidance on 
treatment duration.
16. Study Treatment Talazoparib (Arms A and B, Maintenance Period Only): Talazoparib will be self-administered orally once per day at 0.75 mg and will continue through 
end of Maintenance treatment.  On Days 1, 15, and 29 of each Maintenance cycle, the daily dose of talazoparib should not be taken prior to the study visit and will be taken at 
the clinic after all procedures/assessments have been completed and for patients randomized to Arm A, before the avelumab infusion.  See Section 6.2 for guidance on 
treatment duration.
17. Study Treatment Avelumab (Arm A Only): Patients will receive avelumab 800 mg administered on Day 1 of each 3-week cycle intravenously after administration of 
paclitaxel and carboplatin during the chemotherapy period.  During the maintenance period patients will receive avelumab 800 mg administered once every 2 weeks after
dosing with talazoparib on Days 1, 15, and 29 of each 6-week maintenance cycle.  See Section 6.2 for guidance on treatment duration.
18. Study Treatment Bevacizumab (Arm C Only): Patients will receive bevacizumab 15mg/kg administered once every 3 weeks intravenously on Day 1 of Cycle 2, 3, 4, 5, 
and 6 of chemotherapy (may begin with cycle 1 if surgery completed >4 weeks prior to randomization and no contraindications) for adjuvant patients, and on Day 1 of 
Cycles 1, 2, 5, and 6 for neoadjuvant patients.  During Maintenance, bevacizumab will be administered once every 3 weeks intravenously on Days 1 and 22 of each cycle.  
See Section 6.2 for guidance on treatment duration.
19. Tumor Assessments: Tumor assessment must be performed at screening, at 9 and 18 weeks (±3 days) from date of randomization, and every 12 weeks thereafter until PD by 
BICR regardless of initiation of new anti-cancer therapy.  For patients who undergo interval debulking surgery (IDS), an additional tumor assessment should be performed 
after surgery.  All radiographic images will be collected and may be objectively verified by an independent third party core imaging laboratory as described in Imaging 
Manual.  See Section 7.6 for additional detailed information.
20. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v 4.03.  See Section 8.1.4 for guidance on the time period for collecting and reporting AE and SAEs. 


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21. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up to 90 days after 
the last dose of study treatment, the end of treatment/withdrawal visit or the end of the safety follow-up period, whichever is later.  See Section 5.10 for further details.
22. NFOSI-18: All patients will complete the self-administered questionnaire electronically on Day 1, 8 and 15 of the first 3 cycles and then Day 1 of subsequent cycles in the
chemotherapy period, on Day 1 of every cycle in the maintenance period, at the EOT/Withdrawal visit, and every 6 weeks during the post treatment and survival follow-up 
period for a total of 3 years from the date of patient randomization. 
23. PGI-S: Patients enrolled in the US who are fluent in English will complete this 1 item electronically at Days 1, 8 and 15 of cycles 1, 2, and 3 in the chemotherapy period and 
at EOT/Withdrawal visit. 
24. PGI-C: Patients enrolled in the US who are fluent in English will complete this 1 item electronically at Days 8 and 15 of Cycle 1 and Days 1, 8, and 15 of Cycles 2 and 3 in 
the chemotherapy period and at EOT/Withdrawal visit. 
25. EQ-5D-5L: All patients will complete the self-administered questionnaire electronically on Day 1 of every chemotherapy cycle, on Day 1 of every cycle in the maintenance 
period, at the EOT/Withdrawal visit, and every 6 weeks during the post treatment and survival follow-up period for a total of 3 years from the date of patient randomization. 
 
 
27. Blood for Avelumab Immunogenicity (Arm A only): Testing (anti-avelumab antibodies; anti-drug antibodies [ADAs], neutralizing anti-avelumab antibodies [NAbs]): All 
immunogenicity samples (3.5 mL whole blood) should be collected pre-dose and within 2 hours before the start of the avelumab infusion.
Chemotherapy Period: Immunogenicity sample (3.5 mL whole blood) will be collected predose on Day 1 of chemotherapy Cycles 1-4.
Maintenance Period: Immunogenicity samples (3.5 mL whole blood) will be collected predose on Days 1 and 29 of maintenance Cycle 1.  Thereafter, immunogenicity 
samples will be collected predose on Day 1 of maintenance cycles 2, 4, 6, 10 and at the end of treatment.  All samples that are positive for ADA will also undergo 
characterization for NAb.  See Section 7.3.
28. Blood sampling for Talazoparib Pharmacokinetics (Arms A and B): PK samples (3.0 mL whole blood) will be collected pre-dose on Days 1, 15, and 29 of Cycle 1 of 
maintenance treatment.
29. Blood Sampling for Avelumab Pharmacokinetics for all patients receiving avelumab (Arm A Only): 
Chemotherapy Period: PK samples (3.5 mL whole blood) for avelumab will be collected within 2 hours prior to and at the end of infusion (within 10 minutes after the 
avelumab infusion ends) on Day 1 of Cycles 1-4. 
Maintenance Period: Pre-dose PK samples (3.5 mL whole blood) for avelumab will be collected within 1 hour prior to taking talazoparib dose and the post-dose avelumab 
PK sample should be taken within 10 minutes after the avelumab infusion ends on Days 1 and 29 of the first maintenance cycle.  Thereafter, PK samples will be collected 
pre-dose within 1 hour prior to taking talazoparib dose and the post-dose avelumab PK samples should be taken within 10 minutes after the avelumab infusion ends on Day 1 
of maintenance Cycles 2, 4, 6, 10 and at the end of treatment.  Details are provided in Section 7.2.1. 
30. Mandatory FFPE Tumor Tissue: A mandatory formalin-fixed, paraffin-embedded (FFPE) tumor tissue block sufficient in size to allow for sectioning of a minimum of 
twenty-five (25) 5-micron tissue sections must be submitted during screening.  If no appropriate archive tissue is available, a de novo (ie, fresh) tumor sample must be 
obtained in accord with local institutional practice for tumor biopsies.  If an FFPE tumor tissue block cannot be provided, due to documented local/institutional regulations, 
sites should provide a minimum of 25 unstained slides as detailed in Section 7.4.1.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell 
pellet material), is not adequate and should not be submitted. 
31. Optional De Novo Tumor Biopsy: An optional de novo (ie, fresh) tumor core biopsy, to provide a FFPE tumor tissue block, is requested to be collected at End of Treatment.  
If an FFPE tumor tissue block cannot be provided, due to documented local/institutional regulations, sites are requested to provide at least fifteen (15) unstained slides each 
containing a 5-micron tissue section cut serially from the same FFPE block.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet 
material), is not adequate and should not be submitted.
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32. Genomic Banked Biospecimen Prep D1: A 4 mL blood sample will be collected on Day 1 of Cycle 1 of chemotherapy prior to dosing and retained in a biobank for possible 
pharmacogenomic assessments, unless prohibited by local regulations or by decision of the IRB or EC.  If not collected on the designated collection day, collect at the next 
available time point when biospecimens are being collected in conjunction with a patient visit.
33. Blood Draw for DNA Analysis: A 4 mL whole blood biospecimen will be collected prior to dosing on Day 1 of chemotherapy Cycle 1.
34. Plasma for ctDNA: A 20 mL blood specimen will be collected at screening and prior to dosing on Day 1 of chemotherapy Cycles 1 and 2 (all Arms), on Day 1 of 
maintenance cycle 1 (all arms), on day 15 (Arms A and B only) and day 22 (Arm C only) of maintenance Cycle 1, and at EOT of maintenance treatment.
35. Plasma for Biomarker/Proteomic/Metabolomic Analysis: A 4 mL blood biospecimen will be collected prior to dosing on Day 1 of Cycle 1 of chemotherapy and of 
maintenance treatments (all arms), Day 15 of Cycle 1 maintenance (Arms A and B) and at EOT.
36. Serum for Biomarker/Proteomic/Metabolomic Analysis: A 10 mL blood biospecimen will be collected prior to dosing on Day 1 of Cycle 1 of chemotherapy and of 
maintenance treatments (all arms), Day 15 of Cycle 1 maintenance (Arms A and B) and at EOT.
 
 
38. Blood Draw for RNA Analysis: Two 2.5 mL whole blood samples will be collected in designated tube to optimize sample for RNA analysis prior to dosing on Day 1 of 
Cycle 1 of chemotherapy treatment (all arms).
39. Maintenance Period: Maintenance period should begin within 4 weeks after the last dose of chemotherapy. 
40. End of Treatment/Withdrawal: Performed when criteria for treatment discontinuation are met.  Obtain these assessments if not completed within the prior week, except for 
tumor assessments which need not be repeated if performed within the prior 6 weeks.  See Section 6.4.
41. Short-Term Follow-up: All patients will be followed for safety every 30 days (±3 days) through 90 days after the last dose of study treatment or until the start of new 
anti-cancer treatment whichever occurs first.  See Section 6.5 for guidance on tumor assessment during follow-up.
42. Long-Term/Survival Follow up: Following completion of the initial 90-day short-term follow-up period, all patients will be followed for survival and subsequent anti-cancer 
treatments and for diagnosis of myelodysplastic syndrome or acute myeloid leukemia every 12 weeks (±14 days) until death, end of study, or patient withdrawal of consent, 
whichever occurs first.  See Section 6.5 for guidance on tumor assessment during follow-up.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
1.1.1. Avelumab
Avelumab is an immunoglobulin-G1 (IgG1) monoclonal antibody (mAb) directed against 
PD-L1.  Avelumab selectively binds to PD-L1 and competitively blocks the interaction 
between PD-L1 and its receptors PD-1 and B7.1.  This removes the suppressive effects of 
PD-L1 on cytotoxic CD8+ T-cells, resulting in the restoration of anti-tumor T-cell responses.  
For complete details of the in vitro and nonclinical studies, refer to the Investigator’s 
Brochure (IB) for avelumab.
Additional information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the IB for avelumab.1
1.1.2. Talazoparib
Talazoparib is a potent, orally bioavailable PARP inhibitor, which is cytotoxic to human 
cancer cell lines harboring gene mutations that compromise DNA repair, an effect referred to 
as synthetic lethality, by inhibiting PARP catalytic activity and trapping PARP protein on 
DNA, thereby preventing DNA repair, replication, and transcription.2,3,4
PARP inhibitors including talazoparib exert cytotoxic effects by 2 mechanisms:

In cell-free enzyme assays, talazoparib inhibited PARP1 and PARP2 catalytic activity 
with inhibitory constant (Ki) values of 1.2 nM and 0.87 nM, respectively.5  
Talazoparib was 3.4- to 8.3-fold more potent than other PARP inhibitors that are in 
clinical development, veliparib, rucaparib, and olaparib.6

In addition to inhibition of PARP catalytic activity, talazoparib also promotes cell 
toxicity by trapping PARP protein on DNA, which prevents DNA repair, replication, 
and transcription.2,3,4
Although other PARP inhibitors also possess both activities, in vitro studies demonstrated 
that talazoparib has more potent PARP trapping activity than other PARP inhibitors that have 
been approved and/or in clinical development.4,7
DNA damage promotes inflammation via the NF-κB pathway8 and the stimulator of 
interferon genes (STING) pathway,9,10 and has been shown to increase the intrinsic 
immunogenicity of tumor cells via up regulation of major histocompatibility complex 
(MHC), natural killer group 2 member D Ligand (NKG2DL), and inducible costimulator 
ligand (ICOSL).11,12  As such, increased DNA damage via PARP inhibition is expected to 
enhance effective recognition and infiltration of tumors by immune cells.  In keeping with 
this expectation, talazoparib has been shown to promote T-cell and natural killer (NK) cell 
infiltration and activation in a mouse model of ovarian cancer.13  Additionally, talazoparib 
treatment has been shown to lead to increased expression of PD-L1 by tumor cells,14
suggesting that this may represent a means by which tumors function to inhibit talazoparib 


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mediated anti-tumor immunity, and that the combination of talazoparib and anti PD-L1 may 
further enhance anti-tumor activity.  This hypothesis is supported by preclinical studies in a 
syngeneic model of breast cancer, which have demonstrated increased tumor growth 
inhibition for an alternative PARP inhibitor, olaparib, when used in combination with an 
anti-PD-L1 antibody.14
Additional information for talazoparib may be found in the SRSD, which for this study is the 
IB for talazoparib.15
The SRSD for the comparator agent, bevacizumab is the Summary of Product Characteristics 
(SmPC).16
1.2. Background and Rationale
On 21 December 2018, the Sponsor (Pfizer and Merck KGaA) announced that the Phase 3 
JAVELIN Ovarian 100 study (B9991010) was stopped due to futility of efficacy at a planned 
interim analysis in alignment with the recommendation of both the Independent Data 
Monitoring Committee and the Protocol Steering Committee.  There were no new safety 
signals identified from the B9991010 study relative to the known safety profile of avelumab 
or the other study medications. 
Detailed analyses of the data from study B9991010 have since been performed to determine 
the impact on the ongoing JAVELIN Ovarian PARP 100 study (B9991030).  Although the 
overall safety profile of avelumab remains unchanged, the lack of efficacy with avelumab in 
the treatment of frontline ovarian cancer observed in study B9991010 reduces the probability 
of technical success of study B9991030 and of regulatory success of any submission based 
on this study. 
In addition, the recent approvals in the United States and in the European Union of a 
PARPinhibitor in the front-line maintenance setting based on the practice-changing results 
from the SOLO-1 trial (National Clinical Trial # 01844986) provide a sound rationale for 
PARP inhibitor therapy instead of bevacizumab for patients with deleterious germline or 
somatic BRCA mutations.  This new treatment paradigm creates a recruitment challenge for 
enrolling BRCA+ patients into the B9991030 study along with a risk for high attrition of 
BRCA+ patients when randomized to the bevacizumab control arm.
Therefore, based on the totality of the information, the Sponsor made the decision to stop 
enrollment in the B9991030 study.  On 19 March 2019, a Dear Investigatior Letter was 
issued to notify the investigational sites that no new patients could be screened or 
randomized.  
Patients who had been randomized prior to 19 March 2019 were able to remain in the study 
provided they sign the Informed Consent Addendum upon its approval by local institutional 
review board (IRB)/ethics committee (EC). Patients who remain in the study will continue 
receiving investigational products according to their randomized treatment assignment and 
will be monitored for appropriate safety assessments until treatment discontinuation.


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1.2.1. Ovarian Cancer
Ovarian cancer is the leading cause of death from gynecologic cancer and the fifth most 
common cause of cancer mortality in women.  The incidence of ovarian cancer increases 
with age and is most prevalent in the eighth decade of life.  The median age at the time of 
diagnosis is 63 years, and 70% of patients present with advanced disease.27  Although 
expectations for long-term survival can be high if the cancer is identified and treated early, 
the 5-year survival rate for women diagnosed with advanced ovarian cancer is less than 
30% from statistics in the United States and less than 20% in the United Kingdom.28,29
Ovarian neoplasms consist of several histopathological entities.  Epithelial ovarian cancer 
(EOC) comprises the majority of malignant ovarian neoplasms (about 80%)30 however, other 
less common pathologic subtypes must be considered in treatment recommendations, 
eg, fallopian tube cancer (FTC) and primary peritoneal cancer (PPC) which are less common 
neoplasms, are managed in a similar manner to EOC.
Carboplatin in combination with paclitaxel is the current standard of care in the front-line 
EOC treatment setting.  Complete response is achieved in approximately 75% of patients, but 
the median progression-free survival (PFS) is approximately 18 months and most patients 
ultimately succumb to the disease.30  Therefore, there remains a high unmet need for newer 
agents with novel mechanisms of action and combination regimens able to modify the natural 
history of the disease.
Several studies have been conducted in the frontline treatment setting.  Due to long 
post-progression survival and the potential for post-treatment crossover to confound overall 
survival (OS) results interpretation, PFS is an accepted endpoint in this setting.31  
Bevacizumab (Avastin, Genentech, Inc.) in combination with chemotherapy followed by 
maintenance therapy (16 cycles or 48 weeks in GOG-218 study, 12 cycles or 36 weeks in 
ICON 7 study) demonstrated improvement in PFS in the front-line treatment setting32,33 but 
without statistically significant improvement on OS.35  Both trials focused on patients who 
were at high-risk for recurrence; ICON 7 allowed Stage I and II patients considered high risk 
for recurrence (high-grade), whereas GOG-218 included only patients with Stage III and IV 
disease.  In ICON 7, 31% of patients had Federation of Gynecology and Obstetrics (FIGO) 
Stage III or IV disease and >1 cm residual disease after debulking surgery and in 
GOG-218, 66% of patients had Stage III and >1 cm residual disease or Stage IV.  
Bevacizumab is currently approved in the frontline, platinum-sensitive recurrent setting, and 
platinum-resistant recurrent treatment settings in the European Union (EU)57 while in the 
United States (US), it is approved in the platinum-sensitive recurrent and platinum-resistant 
treatment setting.  Despite this lack of approval in the US, bevacizumab is routinely used 
both in the US and EU in the frontline setting.  Subsequent to the original protocol, on 
June 13, 2018, the FDA approved bevacizumab for use in the frontline setting.58
Neoadjuvant chemotherapy is also increasing in usage and is currently selected for 25% of 
patients with Stage II disease, 40% of patients with Stage III disease, and 50% of patients 
with Stage IV disease.36  A randomized study demonstrated non-inferiority of this approach 
with respect to overall survival compared to adjuvant therapy in high-risk patients.21  
Typically, 3 cycles of chemotherapy are administered before surgery and 3 cycles after 


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surgery.  The same chemotherapy regimens are used in the neoadjuvant treatment setting as 
for the traditional post-surgical approach.31  A number of frontline studies have successfully 
enrolled patients undergoing either adjuvant or neoadjuvant therapies in the same trial 
(GOG-262 and ICON 8).  ICON 8 results comparing neoadjuvant and adjuvant treatment are 
pending.  The primary analysis of GOG-262 was published in 2016.32  In GOG-262, the 
primary research question was whether dose dense paclitaxel could improve outcome in 
incompletely resected Stage III or IV disease.  Both neoadjuvant and adjuvant were 
(pre-specified) treatment options, as well as the addition of bevacizumab.  The primary 
endpoint was not met.  Dose dense paclitaxel was not superior to the every 3 weeks (Q3W; 
standard) paclitaxel regimen.  A pre-specified subgroup analysis showed that in the absence 
of bevacizumab, there was a benefit for dose dense paclitaxel (median PFS [mPFS] 
14.2 months versus 10.3 months, hazard ratio 0.62, 95% confidence interval [CI]: 0.40, 0.95, 
p=0.03).  In the presence of bevacizumab, there was no difference in mPFS (14.9 versus 
14.7 months).
The current standard of care in the frontline maintenance treatment setting is 
region-dependent.  A significant number of patients, especially those with poor prognostic 
factors (incompletely resected Stage III and Stage IV), receive bevacizumab in combination 
with induction chemotherapy followed by bevacizumab maintenance therapy in regions 
where bevacizumab is available in this setting.  For others, especially those with fewer poor 
prognostic factors, a standard of care option includes platinum doublet chemotherapy 
followed by best supportive care/observation or participation in a clinical trial.
For patients with Stage III and IV ovarian cancer, 80-85% will experience recurrent 
disease.37  Depending on the time to recurrence (more or less than 6 months after last 
treatment), treatment options include retreatment with platinum containing therapy if 
recurrence occurs after more than 6 months (‘platinum sensitive recurrent disease’), and a 
variety of chemotherapy agents (eg, pegylated liposomal doxorubicin (PLD, topotecan, 
gemcitabine, weekly paclitaxel) if the recurrence occurs within 6 months (‘platinum resistant 
recurrent disease’).  For patients who have not previously received bevacizumab, this agent 
can be added to the treatment.  Newer treatment options include the addition of PARP 
inhibitor.  Prognosis remains poor in the recurrent setting with approximately a median OS of 
2-2.5 years for platinum sensitive recurrent disease.  Prognosis for patient with platinum 
resistant disease is worse with a median OS of approximately 1 year.
1.2.2. Clinical Experience with Avelumab
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono and is 
indicated in the US for the treatment of adults and pediatric patients 12 years and older with 
metastatic Merkel cell carcinoma (MCC) and in adult patients having urothelial carcinoma 
(UC) with disease progression during or following platinum-containing chemotherapy, or 
within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.  Avelumab 
has been approved in the EU, Switzerland, Japan and Australia, and Israel for the treatment 
of MCC.  Avelumab also is being studied in a wide variety of cancers, including non-small 
cell lung cancer (NSCLC), gastric cancer, renal cell carcinoma (RCC), ovarian cancer, UC, 
Hodgkin lymphoma, squamous cell cancer of the head and neck (SCCHN), and relapsed or 
refractory diffuse B-cell lymphoma, as a single agent or in combination with chemotherapy, 


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tyrosine kinase inhibitors (TKIs), or other immune modulating agents.  The safety profile of 
avelumab administered intravenously as a single agent at a dose of 10 mg/kg every 2 weeks 
(Q2W) has been characterized primarily in 1738 adult patients from Studies 
EMR100070-001 in various solid tumors (N=1650) and EMR100070-003 Part A in MCC 
(N=88).  Study EMR100070-001 consists of 2 parts, a dose-escalation phase and a dose 
expansion phase, which is performed in selected tumor types.
As of 09 June 2016, 53 patients were treated in the dose escalation phase of the 
EMR100070-001 study, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3,
10, and 20 mg/kg Q2W, respectively.  None of the patients treated with doses up to 10 mg/kg 
experienced a dose limiting toxicity (DLT), and the 10 mg/kg dose of avelumab was thus 
considered a safe and well tolerated dose for further investigation in the dose expansion 
cohorts.  One DLT (a Grade 3 immune related adverse event characterized by increased 
creatine kinase, myositis, and myocarditis) was observed in 1 patient at the dose of 20 mg/kg.
The dose expansion phase of study EMR100070-001 included patients with NSCLC, gastric 
cancer, breast cancer, colorectal cancer, castration-resistant prostate cancer (CRPC), 
adrenocortical carcinoma, melanoma, mesothelioma, UC, ovarian cancer, RCC, and SCCHN.  
Study EMR100070-003 Part A was conducted in patients with MCC. 
A summary of pooled safety data from patients treated at 10 mg/kg Q2W in studies 
EMR100070-001 and EMR100070-003 (N=1738) is provided here.
Treatment emergent adverse events (TEAEs) were observed in 1697 (97.6%) patients, with 
the most frequent (10%) being fatigue (32.4%), nausea (25.1%), diarrhea (18.9%), 
constipation (18.4%), decreased appetite (18.4%), infusion related reaction (17.1%), weight 
decreased (16.6%), vomiting (16.2%), anemia (14.9%), abdominal pain (14.4%), cough 
(13.8%), pyrexia (13.6%), dyspnea (13.2%), edema peripheral (11.9%), back pain (11.8%), 
and arthralgia (10.4%). 
Treatment-related TEAEs were observed in 1164 (67.0%) patients, and the most frequent 
(5%) were fatigue (17.7%), infusion related reaction (17.0%), nausea (8.6%), diarrhea 
(7.1%), chills (6.7%), pyrexia (6.1%), decreased appetite (5.2%), and hypothyroidism 
(5.0%).
A total of 177 patients (10.2%) experienced Grade 3 treatment-related TEAEs, and the most 
frequent (0.5%) were fatigue (1.0%), lipase increased (1.0%), gamma-glutamyl transferase 
(GGT) increased (0.6%), infusion related reaction (0.6%), and aspartate aminotransferase 
(AST) increased (0.5%). 
A total of 777 (44.7%) patients had at least 1 serious TEAE.  Treatment-related serious 
TEAEs were reported in 108 (6.2%) patients, with the most frequent (0.2%) being infusion 
related reaction (0.9%), pneumonitis (0.6%), pyrexia (0.3%), adrenal insufficiency (0.3%), 
and hypothyroidism, diarrhea, vomiting, autoimmune disorder, autoimmune hepatitis, 
transaminases increased, dyspnea, and colitis (0.2% each).


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There were 911 deaths (52.4%) in the pooled safety data set.  The majority of deaths were 
due to progressive disease (744, 42.8%).  There were 59 deaths (3.4%) attributed to TEAEs 
not related to trial treatment, and 4 deaths (0.2%) attributed to a treatment-related TEAE by 
the Investigator and which occurred up to 30 days after the last dose of avelumab: 
pneumonitis (1 case), acute liver failure (1 case), respiratory distress (in the context of sepsis) 
(1 case), and autoimmune hepatitis with hepatic failure (1 case).  In addition, 1 patient died 
with acute respiratory failure (in the context of lung cancer progression) considered related to 
avelumab by the Investigator 37 days after the last dose of avelumab.  The cause of death 
was marked as “other” or “unknown” in 17 (1.0%) and 83 (4.8%) cases, respectively. 
A total of 244 patients (14.0%) permanently discontinued avelumab treatment due to TEAEs, 
including 107 patients (6.2%) discontinuing because of treatment-related TEAEs.  The most 
frequent treatment-related TEAEs leading to treatment discontinuation were infusion related 
reaction (1.8%), GGT increased (0.4%), and diarrhea, fatigue, autoimmune disorder, alanine 
aminotransferase (ALT) increased, blood creatine phosphokinase (CPK) increased, lipase 
increased, arthralgia, and pneumonitis (0.2% each).
Immune Related Adverse Events (irAEs): in the pooled safety data (N=1738), a total of 
247 patients (14.2%) experienced irAEs, defined as adverse events (AE) requiring use of 
corticosteroids (and/or hormonal therapy for endocrinopathies), and no clear alternate 
etiology.  The median time to first onset of an irAE was 11.7 weeks.  The most frequent 
irAEs were thyroid disorders including hypothyroidism (5.2%), hyperthyroidism (0.4%) and 
thyroiditis (0.2%), immune-related rash (5.2%), immune-related colitis (1.5%), 
immune-related pneumonitis (1.2%), immune-related hepatitis (0.9%), adrenal insufficiency 
(0.5%), and immune-related myositis (0.5%).  In addition, irAEs reported in 0.1% of patients 
in the pooled safety dataset included: type 1 diabetes mellitus, immune-related nephritis/renal 
dysfunction, hypopituitarism, uveitis, and Guillain-Barre Syndrome.  The majority of irAEs 
were Grade 1 or Grade 2 in severity, with 39 (2.2%) being of Grade 3 severity.  Fatal 
outcome was reported in 1 patient (0.1%) with immune-related pneumonitis, and 2 patients 
(0.1%) with immune-related hepatitis.  Other relevant irAEs reported with avelumab outside 
the pooled safety dataset included 1 case of fatal immune-related myocarditis in Study 
B9991002 (avelumab in combination with axitinib for RCC), 1 case of non-fatal immune 
related myocarditis in the 20 mg/kg cohort of the dose escalation phase of Study 
EMR100070-001, and 2 patients with non-fatal graft versus host disease (GVHD) in Study 
B9991007 (avelumab in patients with classical Hodgkin’s lymphoma).
Infusion Related Reactions (IRRs): a total of 439 patients (25.3%) experienced at least 1 IRR, 
defined as a TEAE coded under the preferred terms of infusion related reaction, drug 
hypersensitivity, hypersensitivity, anaphylactic reaction, type I hypersensitivity, chills, 
pyrexia, back pain, dyspnea, hypotension, flushing, and abdominal pain according to a 
predefined case definition.  The most common preferred terms that met the definition for an 
IRR included: infusion related reaction (17.0%), chills (5.4%), and pyrexia (3.6%).  Most of 
the events were of Grade 1 or Grade 2 severity.  Grade 3 IRRs occurred in 12 patients 
(0.7%) including 3 patients (0.2%) who experienced Grade 4 IRRs.  No Grade 5 IRRs were 
reported.  In most cases, the first occurrence of an IRR was related to the first infusion, with 
only 6 patients experiencing the first IRR at the fifth or later infusion.  All Grade 3 IRRs 


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occurred with the first (7 patients) or second (5 patients) infusion.  Overall, 21.6% of patients 
had 1 IRR, 2.6% of patients had 2 IRRs, 14 patients (0.8%) had 3 IRRs, and 3 patients had 
>3 IRRs.  IRR recurrence after the fourth infusion was rare (15 patients) and all recurrent 
IRRs were of Grade 1 or 2 severity.  In 35 patients (2.0%), treatment was permanently 
discontinued because of an IRR.
Immunogenicity of Avelumab in Humans: immunogenicity assessment included all patients 
from Studies EMR100070-001 and EMR100070-003 treated with 10 mg/kg of avelumab 
Q2W and who had at least one valid anti-drug antibody (ADA) result as of the data cut-off 
date of 09 June 2016.  Of the 1738 patients treated with avelumab, 1558 were evaluable for 
treatment-emergent ADAs and 64 (4.1%) tested positive.  Titers were generally low across 
ADA ever positive subjects, with no clear relationship between the duration of 
immunogenicity response and the maximum observed titer.  Current data suggest there is no 
clinically meaningful impact of ADA positivity on the pharmacokinetics (PK), efficacy, or 
safety of avelumab.
1.2.2.1. Clinical Experience From Study EMR 100070-001 in Patients with Ovarian 
Cancer
Study EMR 100070-001 evaluated avelumab in two cohorts of patients with ovarian cancer.  
The efficacy analysis of the ovarian cancer expansion cohort had a data cut-off of 
31 December 2016.  The ovarian cancer expansion cohort enrolled and treated a total of 
125 patients.  This cohort consisted of patients with recurrent or refractory ovarian cancer 
who had progression within 6 months of platinum-based therapy or progression after 
subsequent therapy in previously relapsed patients.  All patients had a minimum follow-up 
time of 15 months, and 5 patients (4.0%) were still on treatment at the time of the cut-off for 
the analysis.
Table 3 presents the best overall response (BOR) results of 125 patients in the ovarian cancer 
expansion cohort, together with the objective response rate (ORR) according to RECIST 1.1, 
defined as the proportion of patients with a BOR of confirmed partial response (PR) or 
complete response (CR).  The BOR for 9 patients (7.2%) were non-evaluable.  The reasons 
for non-evaluable tumor response results included data missing or not assessable.  The ORR 
based on confirmed responses for patients treated in the ovarian cancer expansion cohort, 
was 10.4% (13 of 125 patients).  In 6 of the 13 responders (46.2%), the responses were 
ongoing at the time of the data cut-off.  The onset of the response occurred at the time of the 
first assessment (~6 weeks) in 6 patients.
The median PFS for the ovarian cancer expansion cohort was 2.63 months 
(95% CI: 1.41, 2.76 months).


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Table 3.
Confirmed Tumor Response Observed in Ovarian Cancer Expansion 
Cohort
BOR by RECIST 1.1 (Confirmed)
Ovarian Cancer Expansion Cohort
(N=125)
Complete Response, n (%)
2 (1.6)
Partial Response, n (%)
11 (8.8)
Stable Disease, n (%)
53 (42.4)
Progressive Disease, n (%)
50 (40.0)
Non-Evaluable a, n (%)
9 (7.2)
ORR, n(%), (95% CI)
13 (10.4), (5.7, 17.1)
Source: Pfizer/Merck KGaA data on file, cut-off 31 December 2016.
BOR = best overall response; CI = confidence interval; CR = complete response; ORR = objective response 
rate; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors.
Objective response rate was defined as proportion of patients with BOR of CR or PR.
a. Non-evaluable includes ‘missing’ and ‘not assessable’.
1.2.2.2. Safety of Avelumab Combined with Carboplatin and Paclitaxel in Ovarian 
Cancer Patients
The induction regimen as proposed for Arm A is similar to the regimen in Arm C (concurrent 
avelumab-carboplatin-paclitaxel) in the ongoing study B9991010.  In study B9991010, 
998 patients were randomized and 991 received at least one dose of study treatment including 
329 patients who were treated in Arm C.  On 14 December 2018, the external Data 
Monitoring Committee (eDMC) made the recommendation to terminate the B9991010 study 
due to futility of efficacy at a pre-planned interim analysis. However, there were no new 
safety signals identified from the B9991010 study relative to the known safety profile of 
avelumab or the other study medications. 
1.2.2.3. Pharmacokinetics of Avelumab in Humans 
Available pharmacokinetic (PK) data from Study EMR100070-001 show that the 
concentration at the end of the dosing interval (Ctrough) increased more than proportionally to 
dose between 1 to 10 mg/kg, and proportionally to dose for doses above 10 mg/kg.  The 
terminal half-life (t1/2) also increased with dose; however, the geometric mean values for 
t1/2 were similar for the 10 mg/kg and 20 mg/kg dose levels, at 94.6 hours (3.96 days) and 
99.1 hours (4.1 days), respectively.  This PK characteristic suggests that target-mediated drug 
disposition is involved in the clearance of avelumab, and that high PD-L1 target receptor 
occupancy (TO) is likely achieved throughout the dosing interval at doses of 10 mg/kg and 
20 mg/kg given Q2W.
The 10 mg/kg dose Q2W achieved high TO (mean TO >90%) of PD-L1 in peripheral blood 
mononuclear cells (PBMC) during the entire dosing interval, as determined from ex vivo
studies.  Based on the in vitro TO data and the observed trough serum avelumab levels in the 
dose escalation cohorts of Study EMR100070-001, TO was predicted to reach or exceed 
95% throughout the entire dosing interval in more subjects in the 10 mg/kg dose group than 


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in the 3 mg/kg dose group.  For the purposes of the current study, a fixed dosing strategy will 
be used for avelumab as described below in Section 1.2.5.1.
Avelumab is eliminated by intracellular lysosomal proteolytic degradation throughout the 
entire body and therefore is not expected to be affected by small molecule drugs that are 
cytochrome P450 (CYP450) enzyme modulators or by transporter modulators.  Furthermore, 
avelumab itself is not expected to interfere with either absorption or elimination of small 
molecule drugs that are substrates of transporters, are metabolized via CYP450, hydrolysis or 
conjugation, and/or are renally excreted.  Therefore, on this study there is very low potential 
for a drug-drug interaction (DDI) between avelumab and talazoparib, which is a small 
molecule cleared primarily via excretion of unchanged parent drug and metabolized to a 
minor extent via oxidation and dehydrogenation.
Population PK analysis did not show any meaningful effects on clearance of avelumab from 
premedication with acetaminophen (paracetamol) or diphenhydramine, nor from concomitant 
medication with ibuprofen, acetylsalicylic acid, opioids, corticosteroids, and biological 
therapies evaluated to date.
1.2.3. Clinical Experience with Talazoparib
Talazoparib is a potent, orally bioavailable, small molecule PARP inhibitor in development 
for the treatment of a variety of human cancers.
As of 30 November 2016, approximately 439 patients have received talazoparib in company 
sponsored studies in hematologic malignancies and solid tumors.  Studies in solid tumors 
include a Phase 1 study (PRP-001) in advanced or recurrent solid tumors, a Phase 1 study in 
advanced malignancies (PRP-002), a Phase 2 study (673-201) in locally advanced and/or 
metastatic breast cancer patients with a germline BRCA defect, a Phase 3 study (673-301) in 
locally advanced or metastatic breast cancer with a germline BRCA defect, a Phase 1 hepatic 
impairment study (MDV3800-02), a Phase 1 absorption, distribution, metabolism and 
excretion (ADME) study (MDV3800-03) and a Phase 1 study on cardiac repolarization 
(MDV3800-14).
As of 30 November 2016, aggregate safety data from 3 company sponsored clinical studies 
evaluating talazoparib monotherapy at the proposed dose of 1 mg every day (QD) in patients 
with advanced malignancies (Phase 1 studies PRP-001 and MDV3800-14 and Phase 2 study 
673-201; 164 patients total) provide the basis for the most common TEAEs.  The most 
common TEAEs associated with talazoparib (>20%) occurring in patients who received 1 mg 
QD talazoparib were anemia (42.1%), fatigue (36.6%), nausea (29.3%), thrombocytopenia 
(25.6%), neutropenia (20.7%), and alopecia (20.1%).  The most common Grade 3 or higher 
drug-related TEAEs occurring in 5% of patients were anemia (28.0%), thrombocytopenia 
(16.5%), and neutropenia (12.2%).
Serious adverse events (SAEs) occurred in 52 of 164 patients (31.7%) who received 1 mg 
QD talazoparib.  Serious adverse events occurring in 2% of patients were pleural effusion 
(4.3%), anemia and dyspnea (3.7% each), and neoplasm progression and thrombocytopenia 
(2.4% each).  Fourteen patients had SAEs considered related to talazoparib, which included 


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anemia (3.0%); thrombocytopenia (2.4%); platelet count decreased (1.2%); and increased 
transaminases, neutropenic sepsis, and vomiting (0.6% each).
A total of 12 of 164 patients (18.8%) who received 1 mg QD talazoparib had a TEAE that led 
to death (6 associated with the underlying malignancy including 1 also associated with 
bronchopneumonia; 2 dyspnea; and 1 each disease progression, lung infection, hypoxia, and 
respiratory failure).  Of these events, none were assessed as related to talazoparib.
Among the 164 patients who received 1 mg QD talazoparib, 19.5% had a TEAE that led to 
dose reduction and 57.3% had a TEAE that led to dose interruption.  The most common 
TEAEs that led to dose reduction or interruption were associated with myelosuppression.
Five of 164 patients (3.0%) treated with talazoparib at a dose of 1 mg QD permanently 
discontinued talazoparib due to a TEAE.  The TEAEs that led to study drug discontinuation 
were anemia, increased ALT, increased AST, metastatic breast cancer, and dyspnea.
In the ongoing Phase 3, open-label, randomized, parallel-group study (protocol no. 
673-301 [EMBRACA]), talazoparib is being evaluated in patients with germline BRCA 
1/2 mutations who received no more than 3 prior chemotherapy regimens for locally 
advanced or metastatic breast cancer.  Patients were randomly assigned (2:1) to receive 
talazoparib at 1 mg/day or 1 of 4 protocol-specified, physician-choice therapies (PCT; 
capecitabine, eribulin, gemcitabine, or vinorelbine) determined before randomization.  A 
total of 287 patients were included in the talazoparib arm and 144 patients in the PCT arm.  
The most common AEs observed with talazoparib (>20%, all grades) were anemia (52.8%), 
fatigue (50.3%), nausea (48.6%), neutropenia (34.6%), headache (32.5%), thrombocytopenia 
(26.9%), alopecia (25.2%), vomiting (24.8%), diarrhea (22%), constipation (22%), decreased 
appetite (21.3%), and back pain (21%).  The incidence of SAEs was 31.8% in the talazoparib 
arm and 29.4% in the chemotherapy arm.  Discontinuations due to AEs occurred in 7.7% of 
patients in the talazoparib arm and 9.5% of patients in the chemotherapy arm.38  A serious 
TEAE of veno occlusive disease of the liver leading to death was assessed as related to 
talazoparib by the Investigator in a 34 year old female patient with advanced breast cancer 
metastatic to the axilla and bone who developed asymptomatic Grade 3 liver test 
abnormalities (increased ALT and AST with normal bilirubin levels) while receiving 
talazoparib at 0.75 mg once daily.  Ten days after talazoparib dosing was discontinued due to 
Grade 4 thrombocytopenia, the patient had acute hepatic failure attributed to veno occlusive 
disease of the liver by the Investigator.  However, based on the information provided, the 
Sponsor considered this to be an unlikely etiology, a consideration supported by 
2 independent hepatologists who reviewed the case.
The combination of avelumab with talazoparib is currently being studied in Pfizer Phase 1b/2 
study B9991025 (JAVELIN PARP Medley) in patients with advanced solid tumors including 
NSCLC, breast, ovarian, bladder, and prostate.  The Phase 1b part was designed to establish 
the safety of talazoparib 1 mg QD in combination with avelumab 800 mg Q2W based on 
Cycle 1 data from 12 DLT-evaluable patients using a modified toxicity probability interval 
(mTPI) method.  By May 18, 2018, 12 patients were enrolled in the Phase 1b portion.  
Overall, 3 of 12 patients (25%) experienced dose limiting toxicities during Cycle 1; 


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2 patients (16.7%) experienced Grade 3 thrombocytopenia, while 1 patient (8.3%) 
experienced a Grade 3 neutropenia.
As of 18 May 2018, the most commonly reported treatment-emergent adverse events 
(TEAEs) were Anemia (66.7%), Neutropenia (58.3%), and Chills and Thrombocytopenia 
(41.7%).  Furthermore 7 patients (58%) required dose interruption of avelumab and 
8 patients (66%) required dose interruption of talazoparib.  The most common TEAE leading 
to dose interruptions of both agents was thrombocytopenia (41.7%).  Notably there were no 
AEs leading to treatment discontinuation of any of the study drugs.
1.2.3.1. Clinical Efficacy of Talazoparib in Patients with Advanced Solid Tumors
Talazoparib, as a single-agent, has demonstrated efficacy, as well as an acceptable toxicity 
profile in patients with multiple types of solid tumors with DNA repair pathway 
abnormalities, particularly those associated with BRCA and phosphatase and tensin homolog 
gene (PTEN) dysfunction, including breast cancer, ovarian/peritoneal cancer, and pancreatic 
cancer in the Phase 1 Study PRP-001.  In patients with advanced breast cancer, 
ovarian/peritoneal cancer and pancreatic cancer, ORRs of 50.0% (7 of 14), 41.7% (5 of 12) 
and 20% (2 of 10) were observed, respectively.  More recently, talazoparib demonstrated a 
statistically significant improvement of PFS when compared to standard of care 
chemotherapy [HR = 0.54 (0.41-0.71), p<0.0001] in patients with Human Epidermal Growth 
Factor Receptor 2 (HER2)-negative breast cancer with germline BRCA mutation with no 
prior treatment in the advanced setting.38 In the ongoing Phase 3 EMBRACA study in 
patients with BRCA 1/2-positive locally advanced and/or metastatic breast cancer, 
single-agent talazoparib demonstrated superior PFS versus physician choice chemotherapy.  
Median PFS was 8.6 months (95% CI: 7.2, 9.3) for patients treated with talazoparib and 
5.6 months (95% CI: 4.2, 6.7) for those treated with chemotherapy [HR: 0.54 (95% CI: 0.41, 
0.71), p<0.0001].38
1.2.3.2. Clinical Efficiacy of Talazoparib in Patients with Advanced Breast Cancer and 
a Germline BRCA 1/2 Mutation
Talazoparib received approval in the US as a once-daily monotherapy for the treatment of 
adult patients with deleterious or suspected deleterious germline BRCA (gBRCA)-mutated, 
HER2-negative locally advanced or metastatic breast cancer in October 2018. Appropriate 
patients are selected for therapy based on an FDA-approved companion diagnostic. In April 
2019, the Committee for Medicinal Products for Human Use (CHMP) of the EMA issued a 
positive opinion recommending marketing authorization for talazoparib in the European 
Union for the treatment of adult patients with germline breast cancer susceptibility gene 
(gBRCA)1/2-mutations, who have human epidermal growth factor receptor 2-negative 
(HER2-) locally advanced or metastatic breast cancer.
1.2.3.3. PARP Inhibitor in Ovarian Cancer
The mechanism of action is validated in ovarian cancer with (United States Food and Drug 
Administration [US FDA]) approvals of the PARP inhibitors olaparib, niraparib, and 
rucaparib.  Olaparib is approved for maintenance treatment for platinum-sensitive recurrent 
disease and BRCA mutated ovarian cancer after 3 or more lines of prior treatment.40  


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Rucaparib is approved for patients after 2 or more prior lines of treatment and 
BRCA-mutated disease.41  Niraparib is approved for in the maintenance setting after 
platinum-based treatment for platinum sensitive recurrent disease.42
Olaparib was approved in EU on 16 December 2014.  For niraparib, a positive Committee for 
Medicinal Products for Humans Use (CHMP) opinion was issued on 14 September 2017 and 
the European Commission decision is pending.  Rucaparib is not approved in the EU.
A Phase 3 SOLO-1 study of patients with centrally confirmed germline (or somatic) 
BRCA1/2 mutation, showed that the use of maintenance therapy with olaparib provided a 
substantial benefit with regard to PFS (HR for disease progression or death = 0.30; 95% CI, 
0.23 - 0.41; P<0.001).90
1.2.3.4. Pharmacokinetics of Talazoparib in Humans
The PK of talazoparib as a single agent following multiple daily doses was evaluated in a 
total of 5 studies in patients with cancer (Studies PRP-001, PRP-002, 673-201, 673-301, and 
MDV3800-14).  Following repeated 1 mg once daily dosing to steady state, talazoparib was 
rapidly absorbed with a median Tmax ranging from approximately 1.0 to 2.0 hours across 
studies.  The talazoparib geometric mean Cmax values ranged from 11.4 to 19.1 ng/mL and 
the geometric mean area under the plasma concentration-time curve for a dosing interval 
(AUC) values ranged from 126 to 208 ng•hr/mL.  Talazoparib Cmax and AUCincreased 
dose proportionally across the dose range of 0.025 to 2 mg after administration of multiple 
doses.  The talazoparib geometric mean steady-state Ctrough values ranged from 2.99 to
4.95 ng/mL.
Talazoparib was eliminated slowly, with a geometric mean CL/F ranging from 4.80 to 
5.53 L/hr.  The mean terminal plasma t½ of talazoparib was 89.8 hours after a single 1 mg 
dose of talazoparib was administered to patients with advanced solid tumors 
(Study MDV3800-03).  After administration of multiple doses, the geometric mean CLr was 
3.34 L/hr and 3.32 L/hr in Studies PRP-001 and PRP-002, respectively, indicating that 
urinary excretion was a major route of elimination for talazoparib.
Following repeated oral dosing, the median talazoparib accumulation ratio (Rac) ranged from 
2.23 to 12.3 across the dose range of 0.025 to 2 mg (Studies PRP-001 and PRP-002).  Based 
on the multiple dosing data from Studies PRP-001 and PRP-002 and consistent with its 
observed t½ of 89.8 hours (Study MDV3800-03), talazoparib plasma concentrations reached 
steady state around 3 weeks after repeated daily dosing. 
Study 673-103 evaluated the effect of food on the talazoparib plasma PK following 
administration of a single 0.5 mg dose of talazoparib oral capsule formulation in 18 healthy 
subjects.  Food intake (a high-fat, high-calorie meal) had no impact on the AUC while 
reduced the Cmax by 46%.  Consistent with findings from the food effect study, population 
PK analysis using data from Studies 673-301, 673-201, PRP-001, and PRP-002 showed food 
intake decreased absorption rate but had no impact on the extent of the absorption.  The 
reduction in the rate of absorption with food is not expected to be clinically relevant as 


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efficacy is generally driven by total exposure.  Therefore, talazoparib can be taken without 
regard of food. 
Based on population PK analysis, the talazoparib mean apparent volume of distribution at 
steady state (Vss/F) was estimated to be 420 L, which is significantly greater than total body 
water (42 L), indicating that talazoparib extensively distributes to peripheral tissues.
In vitro experiments with human hepatocytes and liver microsomes indicated that talazoparib 
undergoes minimal hepatic metabolism. Following oral administration of a single 1 mg dose 
of 14C-talazoparib to humans, excretion of unchanged talazoparib in urine was the major route 
of elimination (Study MDV3800-03).  No major circulating metabolites were identified in 
plasma, and talazoparib was the only circulating drug-derived entity identified in plasma.  No 
metabolites that individually represented more than 10% of the administered dose were 
recovered in the urine or feces. 
Talazoparib is a substrate for P-gp.  Population PK analysis indicated that concomitant 
administration of strong P-gp inhibitors with talazoparib increased talazoparib exposure by 
44.7% relative to talazoparib administered alone. 
A population PK analysis for talazoparib was conducted to assess the impact of renal 
impairment on the CL/F using renal function as a categorical covariate defined by the 
baseline creatinine clearance (BCCL).  The results of this analysis indicated that talazoparib 
CL/F was reduced by 14.4% and 37.1% in patients with mild renal impairment (creatinine 
clearance [CLCR], 60-89 mL/min) and moderate renal impairment (30 mL/min CLCR
<60 mL/min), respectively, compared to that of patients with normal renal function (CLCR
90 mL/min).  Due to limited number of severe renal impairment patients (CLCR
<30 mL/min), the impact of severe renal impairment on CL/F cannot be concluded.  The 
talazoparib starting dose for patients who develop renal impairment while on study 
(ie, during chemotherapy period) is discussed in Section 5.6.1.  The effect of renal 
impairment on talazoparib PK is also being investigated in the ongoing study MDV3800-01.
Results of the population PK analysis indicated that there was no effect of mild hepatic 
impairment (total bilirubin upper limit of normal [ULN] and aspartate aminotransferase 
[AST] > ULN, or total bilirubin >1.0 to 1.5 ULN and any AST) on talazoparib exposure.  
No dose adjustment is necessary for patients with mild hepatic impairment.  Talazoparib has 
not been studied in patients with moderate (total bilirubin >1.5 to 3.0 × ULN and any AST) 
or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST).  The effect of 
hepatic impairment on talazoparib PK is being investigated in the ongoing study 
MDV3800-02.
The potential for talazoparib to affect the PK of other drugs was assessed through in vitro 
experiments and is described in the talazoparib IB.


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1.2.4. Study Design Rationale
1.2.4.1. Rationale for Tumor Type to be Evaluated
Ovarian cancer was selected based on the following:
a.
PARP inhibitors and agents targeting the PD-1/PD-L1 axis have shown clinical 
activity in this setting.
b. Ovarian cancer has been reported to have a high prevalence (~20%) of defects in the 
BRCA 1/2 genes, which have been reported to predict for sensitivity to PARP 
inhibitors,43 such as talazoparib.  Ovarian tumors harboring such defects have also 
been shown to present with increased PD-L1 expression and increased T-cell 
infiltration.44,46  Increased T-cell infiltration has been associated with improved 
outcome in ovarian cancer,45 and both increased T-cell infiltration and PD-L1 
expression have been associated with improved response to anti-PD-1/L1
treatment.46  Given this data, tumors harboring these defects may respond more 
robustly to combination treatment with talazoparib and avelumab.
c.
Ovarian cancer has been reported to have a high prevalence (35%) of genomic 
scarring.  Tumors with a high level of genomic scarring have been shown to have 
increased clinical benefit from PARP inhibitors,48,49 and as such might also be 
expected to respond more robustly to the combination of talazoparib and avelumab.
Given the intrinsic links between DNA damage and immune priming outlined below, and the 
potential for PARP inhibition to promote DNA damage in the presence of DDR defects, 
ovarian cancer, with its high prevalence of such defects, represents a tumor type in which the 
combination of talazoparib and avelumab may optimally mediate anti-tumor activity. 
1.2.4.2. Rationale for Avelumab and Talazoparib Combination
Based on the mechanisms of action discussed in Section 1.1.1 and Section 1.1.2, avelumab 
and talazoparib have the potential to produce additive or synergistic anti-tumor activity, with 
talazoparib functioning to promote immune priming and tumor immunogenicity and 
avelumab functioning to overcome PD-L1 mediated inhibition of any resulting anti-tumor 
immune response.
Specifically, the activity of avelumab depends on generation of a productive immune 
response, composed of effective antigen presentation, T-cell priming, infiltration of tumors, 
and recognition and killing of tumor cells.21  Talazoparib, via its ability to promote increased 
DNA damage, has the potential to promote several of these key stages of the immune 
response.
Firstly, talazoparib mediated cell death, via either PARP trapping or via increased DNA 
damage, has the potential to release antigens into the tumor microenvironment, promoting 
effective antigen presentation; this has been described for other therapies that lead to 
increased tumor cell death.50  Secondly, DNA damage promotes inflammation via two 
alternative pathways, the first being activation of the NF-κB pathway via ataxia 
telangiectasia mutated (ATM) mediated phosphorylation of the NF-κB essential modulator 


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(NEMO),8 and the second being activation of the STING pathway via generation and 
detection of cytosolic DNA.9  Activation of these pathways leads to increased pro 
inflammatory signaling that enhances effective recognition and infiltration of tumors by 
immune cells, and has recently been shown to be critical to the response to checkpoint 
inhibition in mice.5  Finally, DNA damage has been shown to lead to up regulation of MHC, 
NKG2DL, and ICOSL,11,12 which would be expected to increase the intrinsic 
immunogenicity of tumor cells and enhance their recognition and killing by T-cells and 
NK-cells.
In keeping with these critical links between DNA damage and immune priming, talazoparib 
has been shown to drive the activation of STING and downstream target genes in cultured 
cell lines and to promote T-cell and NK-cell infiltration and activation in a mouse model of 
ovarian cancer.13
However, treatment with talazoparib has also been shown to lead to 2-3 fold increased 
expression of PD-L1 by tumor cells,14 suggesting that this may represent a mechanism of 
resistance to possible talazoparib mediated anti-tumor immunity, and that the combination of 
talazoparib and anti-PD-L1 may further enhance anti-tumor activity.  This hypothesis is 
supported by preclinical studies in syngeneic mouse models of ovarian and colorectal cancer, 
which demonstrate a significant improvement in overall survival in mice treated with the 
combination of talazoparib and an anti-mouse PD-L1, but not in mice treated with either 
talazoparib or anti-mouse PD-L1 alone.  Studies of the PARP inhibitor olaparib in a 
syngeneic model of breast cancer have also shown increased tumor growth inhibition when 
used in combination with an anti-PD-L1 antibody.14
In conclusion, considering the above described mechanism of action and the preliminary 
clinical activity observed for the individual investigational products and agents of the same 
class (see Section 1.1.1, Section 1.1.2, and Section 1.2), the avelumab and talazoparib 
combination is proposed for evaluation in patients with advanced epithelial ovarian cancer.
1.2.4.3. Rationale for Avelumab in Combination with Chemotherapy 
There are emerging data supporting the rationale for combinations of immune checkpoint 
inhibitors with chemotherapy.16,18  Chemotherapy has been shown to have 
immunostimulatory properties by stimulating the release of neoantigens and adjuvants from 
dying cells, increasing susceptibility to immune attack, and preferentially reducing 
immunosuppressive cells such as T regulatory cells.19-22  Certain chemotherapy agents, 
including platinum-based agents, are mutagenic.23  Therefore, treatment with chemotherapy 
may create a pro-immunogenic, hypermutated state that may be optimal for activity of 
checkpoint inhibitors.  In preclinical studies, the combination of avelumab with 
chemotherapy (gemcitabine, oxaliplatin, 5-fluorouracil) showed improved anti-tumor activity 
over single agent chemotherapy.1
Clinical proof of concept for concurrent administration of chemotherapy and checkpoint 
inhibition, followed by single agent checkpoint inhibition maintenance therapy, was provided 
in the randomized Phase 2 trial ‘Keynote -21’ in which (anti-PD-1 agent) pembrolizumab 
was combined with platinum-based chemotherapy in (non-squamous) NSCLC.24  Both ORR


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and PFS were statistically significantly and clinically relevantly increased (ORR 59% vs 
29% and median PFS 13 months versus 8.9 months (Hazard Ratio 0.53 [95% CI: 0.31, 0.91; 
p=0.01]).  Recently, the results were updated25 and the HR for OS was 0.59, which did not 
reach statistical significance.  Phase 3 trials with pembrolizumab, nivolumab, and 
atezolizumab in combination with chemotherapy are ongoing or recently released 
preliminary results in NSCLC and various other solid tumors.  A recent press release from 
Merck Serono in January 2018 indicated that pembrolizumab in combination with 
chemotherapy for first line treatment of patients with metastatic NSCLC did in fact meet its 
dual primary endpoint of OS and PFS based on an interim analysis conducted by the 
independent Data Monitoring Committee and resulted in significantly longer OS and PFS 
than pemetrexed plus platinum chemotherapy alone.  The safety profile of pembrolizumab in 
this combination was consistent with that previously observed.  Additionally, preliminary 
results of the phase 3 IMpower 150 trial were presented at the European Society for Medical 
Oncology (ESMO) IO 2017 congress.  The PFS survival comparison indicated the 
combination of atezolizumab, bevacizumab and chemotherapy was superior to bevacizumab 
and chemotherapy alone with a median PFS of 8.3 versus 6.8 months (hazard ratio [HR] 
0.62; 95% confidence interval [CI] 0.52, 0.74; P <0.0001) in the intention-to-treat (ITT) wild 
type (WT) population.51  No new safety signals were observed with combination therapy.
Avelumab is being tested concurrently and sequentially with chemotherapy in frontline 
ovarian cancer (B9991010 with carboplatin and paclitaxel) and as a single agent or 
concurrently with chemotherapy in the platinum-resistant and platinum-refractory population 
(B9991009 with PLD).  In addition, avelumab is also being evaluated with chemotherapy and 
radiotherapy in B9991016, in locally advanced head and neck cancer, with azacitidine and 
bendamustine in two arms of B9991011 in diffuse large B-cell lymphoma (DLBCL) and with 
cisplatinum and pemetrexed in NSCLC and cisplatinum and gemcitabine in UC in 
B9991023.  Lastly, sequential/ maintenance treatment is tested in B9991001 in UC.  The 
clinical proof of concept for sequential treatment came from the PACIFIC trial.25  In this 
placebo controlled randomized Phase 3 trial, 713 stage III patients with NSCLC were treated 
with either anti-PD-L1 agent durvalumab or placebo after radiotherapy-chemotherapy 
(2:1 ratio).  The study met its co-primary end point of progression free survival with a large 
treatment effect: HR 0.52 (95% CI: 0.42-0.65).  The median PFS for durvalumab 
(16.8 [95% CI: 13.0 - 18.1] months) was almost triple that of placebo (5.6 [95% CI: 
4.6 – 7.8] months).  However, the optimal sequence of chemotherapy and immunotherapy 
(concurrent vs sequential) remains to be determined, and a strong rationale exists both for 
concurrent and sequential administration.
In summary, avelumab has the potential to improve the durability of response to 
platinum-based therapy in the frontline maintenance setting.


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1.2.5. Rationale for the Investigational Product Doses
1.2.5.1. Avelumab
To date, avelumab has been administered at the clinically active, safe, and tolerable dose of 
10 mg/kg Q2W to more than 1700 patients across multiple indications.  Furthermore, this 
10 mg/kg Q2W avelumab dosing regimen has been approved by the US FDA for MCC and 
UC, as well as for MCC in the European Medicines Agency (EMA), Switzerland, Japan, 
Australia, and Israel.  Avelumab was originally dosed on a mg/kg basis in order to reduce 
inter subject variability in drug exposure.  However, emerging data for mAbs, including the 
marketed PD-1 and PD-L1 immune checkpoint inhibitors nivolumab, pembrolizumab and 
atezolizumab, reveal that body weight based dosing regimens do not result in less variability 
in measures of exposure over fixed (ie, body weight independent) dosing regimens.52,53,54  
Additionally, fixed dosing offers the advantages of less potential for dispensing errors, 
shorter dose preparation times in a clinical setting, and greater ease of administration.
Population PK analysis was conducted based on the acquired data across 3 single agent 
avelumab studies in 1827 patients with 14 different types of cancer.  PK simulations suggest 
that exposures to avelumab across the available range of body weights are less variable with 
800 mg Q2W compared with 10 mg/kg Q2W; exposures were similar near the population 
median weight.  Low weight subjects tended towards marginally lower exposures relative to 
the rest of the population when weight based dosing was used, and marginally higher 
exposures when flat dosing was applied.  However, the implications of these exposure 
differences are not expected to be clinically meaningful at any weight across the whole 
population.  Furthermore, based on these simulations, the 800 mg Q2W dosing regimen is 
expected to result in Ctrough >1 g/mL required to maintain avelumab serum concentrations at 
>95% TO throughout the entire Q2W dosing interval in all weight categories. 
Therefore, in this clinical trial, a fixed dosing regimen of 800 mg administered as a 1-hour IV 
infusion Q2W will be utilized for avelumab during the maintenance period.
Furthermore, in Arm A, avelumab will be dosed every 3 weeks during the chemotherapy 
period in order to align with the dosing of chemotherapy, which will also be every three 
weeks.  In an effort to mitigate unexpected hematologic toxicity and considering that the 
tolerability of avelumab in patients with severe myelosuppression is currently not well 
characterized, a Q3W schedule was adopted for avelumab in this study in order to avoid 
dosing of avelumab during the expected hematologic nadir period for the selected 
chemotherapy regimens.  In order to align with the dosing of chemotherapy and to avoid 
dosing at the nadir, PK and PD data support the exploration of Q3W dosing posology.  The 
preliminary data from clinical studies suggest >90% TO is required for clinical benefit.  PK 
simulations show that, the 800 mg Q3W dosing regimen is expected to provide median 
plasma Ctrough greater than 1 g/mL at 21 days, yielding a mean TO >90% over the entire 
Q3W dosing interval (Pfizer, data on file), including when used in combination with 
chemotherapy or other anti-cancer immunotherapies.


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1.2.5.2. Talazoparib
The dose level of talazoparib to be evaluated in this study is supported by clinical studies in 
patients with advanced malignancies and breast cancer.  In a Phase 1 study PRP-001, patients 
with advanced or recurrent solid tumors were treated with escalating doses of talazoparib 
from 0.025 to 1.1 mg QD.  Data from 1 mg QD dose in that study demonstrated objective 
responses or clinical benefit (CR, PR, or stable disease 24 weeks) in patients with breast, 
ovarian/peritoneal, pancreatic cancer, small cell lung cancer (SCLC), and Ewing sarcoma.  
For the 17 patients with ovarian cancer treated at talazoparib doses <1 mg QD, 7 patients 
(3 at 0.9 mg, 2 at 0.6 mg and 1 each at 0.2 and 0.1 mg) had objective responses resulting in 
an overall response rate of 41.2%.  All patients with a response had a best overall response of 
PR except for 1 patient treated at 0.9 mg QD who had a best overall response of CR.  In 
addition, sustained pharmacodynamic inhibition of PARP activity measured in PBMNCs was 
observed at dose levels 0.6 mg QD. 
Furthermore, in the Phase 3 study 673-301 (EMBRACA), 286 patients with locally advanced 
or metastatic breast cancer were treated with the single-agent maximum tolerated dose of 
talazoparib at 1 mg QD established in the dose escalation phase of study PRP-001.  In 
EMBRACA, the median treatment duration was 6.1 months; however, 52% of the patients 
required at least 1 dose reduction and 28% required >1 dose reduction.  Anemia (38.1%), 
neutropenia (19.2%) and thrombocytopenia (10.5%) were the most common TEAEs leading 
to dose modifications in this study. 
The safety of avelumab in combination with talazoparib is currently being evaluated in 
Study B9991025, a Phase 1b/2 study in adult patients with locally advanced (primary or 
recurrent) or metastatic solid tumors.  The Phase 1b part was completed on 18 May 2018 and 
the recommended Phase 2 dose for talazoparib administered orally in combination with 
avelumab 800 mg IV Q2W was 1 mg QD.  Preliminary evaluation of safety data from 
patients receiving the 1 mg QD talazoparib dose in combination with avelumab showed that 
8 patients (66.7%) experienced AEs that led to talazoparib dose interruption.  The 3 DLT’s 
observed, consisting of thrombocytopenia (n=2) and neutropenia (n=1), represent early 
hematopoietic toxicity.  Anemia has emerged as the most common TEAE (66.7%) and 
25% of these patients required transfusions.
As the duration of maintenance treatment in this study with talazoparib both in combination 
with avelumab (Arm A) and as a single-agent (Arm B) will be for up to 24 months, 
administration of a talazoparib dose that provides improved long-term tolerability, including 
a reduced frequency of TEAE leading to dose interruption and reduction is desired.  
Exposure-response analysis of data from talazoparib clinical studies showed that higher 
talazoparib exposure is associated with longer progression-free-survival (PFS) and also with 
a higher risk for Grade 3 or higher anemia and thrombocytopenia.  Therefore, dose reduction 
is an effective way to lower the probability of experiencing the AEs.  Given that objective 
responses were observed in study PRP-001 at talazoparib doses of 0.1 mg QD and that 
pharmacodynamic inhibition of PARP activity was similar at dose levels 0.6 mg QD, the 
B9991030 study will use a starting dose of 0.75 mg QD for talazoparib both Arms A and B 
for improved long-term tolerability while maintaining adequate PARP inhibition.  The 


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starting dose of talazoparib for patients with moderate renal impairment 
(CLCR=30-59 mL/min) will be 0.5 mg QD to account for the lower talazoparib clearance.  
Patients who already started at 1 mg QD talazoparib prior to Protocol amendment 1 must be 
informed and dose reduce to 0.75 mg QD at their subsequent study visit after protocol 
IRB/EC approval.
1.2.6. Rationale for Randomization Stratification
The combination of avelumab and talazoparib is predicated on the ability of talazoparib to 
promote DNA damage, which leads to increased inflammation, immune priming and tumor 
immunogenicity, and on the ability of avelumab to overcome PD-L1 mediated inhibition of 
any anti-tumor immune response resulting from this priming event.  Based on this 
mechanism of action, the combination of avelumab and talazoparib is expected to be 
differentially effective in patients that have greater sensitivity to talazoparib-mediated DNA 
damage.
Clinical studies have indicated that the greatest sensitivity to PARP inhibitors, such as 
talazoparib, is observed in tumors that have defects in the BRCA1 or BRCA2 genes.43  Such 
defects result in defective repair of double strand DNA breaks, such breaks accumulate 
following PARP inhibition, leading to cell death.
Given the potential for differential activity of talazoparib and avelumab as monotherapy, and 
in combination, in patients with and without defects in BRCA1 or 2, the randomization of 
patients in this study will be stratified by BRCA 1/2 status.
BRCA1/2 status at the time of randomization for patients will be determined based on 
pre-existing results obtained from a blood or saliva based test.  Where no such historic test 
result exists, a de novo blood test will be conducted during the screening period in order to 
establish BRCA1/2 status.  Patients will be defined as germline (g)BRCA positive (+) if they 
are shown to carry an expected or known pathogenic mutation in either the BRCA1 or 
BRCA2 genes.  All other patients will be defined as gBRCA negative (-).
The high-risk target population of B9991030 includes patients who are candidates for 
neoadjuvant chemotherapy followed by IDS and patients who receive adjuvant chemotherapy 
following incomplete primary debulking surgery.  A number of recent Phase 3 studies have 
successfully combined adjuvant and neoadjuvant patient populations (GOG-262, ICON 8, 
B9991010).  In addition, recent studies in women with Stage III and IV ovarian cancer 
comparing neoadjuvant chemotherapy to primary debulking surgery have demonstrated that 
survival with upfront chemotherapy is non-inferior to primary surgery (EORTC55971 and 
CHORUS).  However, considering the overall difference in the treatment regimen, the 
randomization of patients in this study will also be stratified by the chemotherapy approach: 
adjuvant vs. neoadjuvant. 
The extent of residual disease is an important prognostic factor for patients undergoing 
primary debulking surgery (PDS) followed by adjuvant chemotherapy.  The Gynaecologic 
Oncology Group (GOG) currently defines “optimal” outcome of cytoreductive surgery as 
having residual disease of 1 cm or less, with complete cytoreduction being the ideal surgical 


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outcome.  However, women with residual disease ≤1 cm (optimal surgical outcome) showed 
improved PFS and OS compared to women with suboptimal surgical outcome or residual 
disease >1 cm (Chan 2003; Winter 2008).55  Based on these data, randomization will also be 
stratified by resection status (residual disease >1 mm and ≤1 cm vs residual disease >1 cm) 
in this study.
1.2.7. Rationale for Biomarker Assessments
As mentioned above the combination of avelumab and talazoparib is expected to be 
differentially effective in patients that have greater sensitivity to talazoparib-mediated DNA 
damage.  While defects in BRCA1/2 represent one potential marker of such sensitivity, it is 
clear, from studies of both niraparib48 and rucaparib49 that patients whose tumors lack 
BRCA1/2 defects can also be sensitive to PARP inhibition.  In particular, those whose 
tumors showed markers of genomic scarring, such as loss of heterozygosity (LOH), which 
are suggestive of ongoing or historic DNA damage, show increased sensitivity.  These data 
indicate that PARP inhibitor activity is not limited to tumors deficient in BRCA but is also 
seen in tumors with other defects in DDR, sometimes referred to as being homologous 
recombination deficient or having a BRCAness phenotype.43  Tumors with defects in DDR 
genes have also been shown to present with a more inflamed tumor phenotype in a number of 
settings,55,44,59 and therefore, are also expected to respond better to avelumab treatment.
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
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To enable the above mentioned biomarker assessments, the provision of pre-treatment tumor 
specimens from an archive tumor tissue sample or de novo biopsy is mandatory for patients 
randomized to the study.
Given the limited ability to assess tumor tissue based biomarkers longitudinally, a number of 
biomarkers will also be measured in peripheral blood at a number of time point’s 
pre-treatment and post-treatment.  The primary aim of these measurements is to identify 
pharmacodynamic or mechanistic biomarkers for the combination of avelumab and 
talazoparib.  Such biomarkers may have value in predicting response or resistance to 
treatment.  Planned assessments include, but are not limited to, gene expression profiling, 
diversity of TCR sequences by DNA sequencing, and levels of circulating soluble factors 
such as cytokines and chemokines.
Optional de novo biopsy tissue is also requested, where not clinically contraindicated, at the 
End of Treatment visit or in the event of permanent treatment discontinuation due to disease 
progression, in order to support an understanding of emerging resistance mechanisms. 
Finally, circulating tumor (ct)DNA will be collected at baseline, once during induction 
chemotherapy, following induction prior to initiation of maintenance treatment, once during 
maintenance treatment and at End of Treatment in order to enable assessment of genomic 
biomarkers that may predict for response or drive resistance, 
.
 
 
 
 
 
 
 
 
 
 
 
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1.3. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The benefit risk relationship has been carefully considered in the planning of this trial.  
Avelumab demonstrated clinical activity in patients with advanced solid tumors, including 
NSCLC (first line and second line or higher), breast cancer, CRPC, UC and ovarian cancer in 
the expansion cohorts of the ongoing Phase 1 Study EMR 100070- 001, as described in 
Section 1.2.2.  The clinical safety data available to date with single agent avelumab in 
patients with advanced solid tumors suggest an acceptable safety profile, as described in 
Section 1.2.2.1.  Most of the observed adverse events were either in line with those expected 
in patients with advanced solid tumors or with similar class effects of mAbs blocking the 
PD-1/PD-L1 axis.  Infusion-related reactions, including hypersensitivity and 
irAEs/autoimmune disorders, have been identified as important risks for avelumab.  
Respective risk mitigation measures have been implemented in all ongoing clinical studies 
with avelumab, including this clinical trial protocol.  These measures include guidelines for 
treatment interruption and discontinuation in case of irAEs, as well as mandatory 
pre-treatment with an antihistamine and acetaminophen prior to the first 4 infusions of 
avelumab and as clinically indicated thereafter.
Talazoparib also has demonstrated single agent clinical activity in patients with advanced 
solid tumors with DNA repair pathway abnormalities, particularly those associated with 
BRCA and PTEN dysfunction, including breast cancer, ovarian/peritoneal cancer, and 
pancreatic cancer in the Phase 1 Study PRP-001, as described in Section 1.2.3.  The clinical 
safety profile of talazoparib supports its use as both a single agent and in combination with 
cancer therapies.  The most common TEAEs associated with single agent talazoparib 
administration (>20%) were myelosuppression (eg, anemia, thrombocytopenia, neutropenia), 
gastrointestinal toxicity (eg, nausea, diarrhea, vomiting), and fatigue with severe and serious 
adverse events mostly associated with myelosuppression.  These adverse events were 
primarily Grade 1 or 2 severities and typically resolved with temporary dose interruptions or 
reductions.
Based on the manageable safety profiles of avelumab and talazoparib administered as single 
agents, the lack of anticipated severe overlapping severe toxicities, and the anticipated 
enhanced anti-tumor activity, the projected benefit-risk relationship of avelumab given in 
combination with talazoparib is expected to be favorable for investigation in this population 
of patients with advanced ovarian cancer.
2. STUDY OBJECTIVES AND ENDPOINTS (OBSOLETE)
The original study objectives and endpoints are no longer applicable and/or feasible.  
The purpose of protocol amendment 2 is to reduce study-specific procedure assessments 
(ie, remove efficacy, physical examination, electrocardiogram, ePROs, tumor assessments, 
PK and Biomarkers) for the ongoing patients. 


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The schedule of activities (SOA) found in Appendix 6 is replacing the previous SOA and has 
been revised to decrease the frequency of study procedures while maintaining appropriate 
assessment of patient safety. The new SOA is effective with IRB/EC approval of 
amendment 2.
Primary Objective:
Primary Endpoint:

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
PFS in patients with advanced ovarian cancer with 
defects in DNA damage repair (DDR+).

PFS as determined based on BICR assessment per 
RECIST v1.1 in patients with newly diagnosed 
advanced ovarian cancer with defects in DNA 
damage repair (DDR+).
Secondary Objectives:
Secondary Endpoints:

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
overall survival (OS) in patients with advanced 
ovarian cancer with defects in DNA damage repair 
(DDR+). 

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
PFS in patients with advanced ovarian cancer 
unselected for DDR status.

To demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance is superior to 
platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance in prolonging 
OS in patients with advanced ovarian cancer 
unselected for DDR status.

To evaluate the effect on PFS and OS of 
platinum-based chemotherapy followed by talazoparib 
maintenance versus platinum-based chemotherapy 
plus bevacizumab followed by bevacizumab 
maintenance in patients with advanced ovarian cancer 
with DDR+ and unselected for DDR status.

To evaluate the anti-tumor activity in each treatment 
arm.

To evaluate the overall safety profile in each treatment 
arm. 

To evaluate the pharmacokinetics (PK) of avelumab 
in combination with platinum-based chemotherapy 
followed by avelumab plus talazoparib maintenance in 
Arm A as well as well as PK of talazoparib in 
combination with avelumab (Arm A) and as a single 
agent (Arm B).

To evaluate the immunogenicity of avelumab in 

OS in patients with tumors that are DDR+ and 
in patients unselected for DDR status. 

PFS based on BICR assessment per RECIST 
v1.1 in patients unselected for DDR status. 

PFS based on investigator assessment per 
RECIST v1.1 in patients with tumors that are 
DDR+ and in patients unselected for DDR 
status.

PFS2 based on investigator assessment in 
patients with tumors that are DDR+ and in 
patients unselected for DDR status. 

PFS based on investigator assessment per 
Gynecological Cancer Intergroup (GCIG) 
criteria in patients with tumors that are DDR+ 
and in patients unselected for DDR status. 

AEs (as graded by NCI CTCAE v4.03); laboratory 
abnormalities (as graded by NCI CTCAE v4.03); 
vital signs (blood pressure, pulse rate); 
electrocardiograms (ECGs). 

PK parameters, including Ctrough and Cmax for 
avelumab and Ctrough for talazoparib.

Anti-drug antibodies (ADA) and neutralizing 
antibody (NAb) against avelumab. 

Disease related symptoms and treatment side effects 
as measured by the NCCN-FACT FOSI-18 and 
health-related quality of life (HRQOL) as measured 
by NCCN-FACT FOSI-18 and the EuroQol Group 
5-Dimension 5-Level (EQ-5D-5L). 

PD-L1 expression, TMB, genomic scarring and the 
presence of defects in select genes, considered 
critical to effective DDR, in baseline tumor tissue. 

Assessment of defects in a panel of key oncogenes, 
including several considered critical to effective 
DDR and TMB in ctDNA at baseline.


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Arm A (avelumab in combination with 
platinum-based chemotherapy followed by avelumab 
plus talazoparib maintenance).
•
To evaluate the effect of avelumab in combination 
with platinum-based chemotherapy followed by 
avelumab plus talazoparib maintenance and 
platinum-based chemotherapy followed by talazoparib 
maintenance versus platinum-based chemotherapy 
plus bevacizumab followed by bevacizumab 
maintenance on patient reported outcome (PRO) 
including the assessments of disease-related 
symptoms, treatment side effects and health-related 
quality of life (HRQoL).
•
To assess the correlation of anti-tumor activity with 
PD-L1 expression, tumor mutational burden (TMB) 
and with potential biomarkers of PARP inhibitor 
sensitivity in baseline tumor tissue.
•
To assess the correlation of anti-tumor activity with 
TMB and potential biomarkers of PARP inhibitor 
sensitivity in baseline circulating tumor (ct) DNA. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. STUDY DESIGN
This is a Phase 3, randomized, open-label, multicenter study to evaluate the efficacy and 
safety of avelumab in combination with chemotherapy followed by maintenance therapy of 
avelumab in combination with the PARP inhibitor talazoparib in patients with previously 
untreated advanced ovarian cancer.  Patients must meet full eligibility criteria as specified in 
Section 4.
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The study design, including the number of patients to be randomized in each treatment arm, 
is illustrated in Figure 1.
3.1. Study Overview
Approximately 720 patients (including a minimum of 360 patients with tumors that are 
DDR+) who are candidates for frontline chemotherapy followed by maintenance were 
planned to be randomized in a 2.5:1:2.5 ratio stratified by germline BRCA 1/2 mutational 
status (gBRCA+ vs gBRCA-) and resection status (adjuvant with >1 mm and 1 cm residual 
disease vs adjuvant with >1 cm residual disease vs neoadjuvant) to one of the following 
treatment arms:

Arm A: platinum-based chemotherapy + avelumab followed by avelumab + 
talazoparib maintenance;

Arm B: platinum-based chemotherapy followed by talazoparib maintenance; 

Arm C: platinum-based chemotherapy + bevacizumab followed by bevacizumab 
maintenance.
As of 19 March 2019, no new patients could be screened or randomized.  
Intravenous carboplatin and paclitaxel will be used as the chemotherapy backbone, consisting 
of Q3W carboplatin and paclitaxel. 
Patients may be enrolled either following primary debulking surgery, or prior to initiation of 
neoadjuvant chemotherapy.  The latter group will undergo interval debulking surgery after 
3 study cycles of chemotherapy to be followed, upon recovery from surgery, by the 
remaining 3 cycles of chemotherapy. 


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Figure 1.
Study Schematic
        Chemotherapy
Maintenance
gBRCA = germline BReast CAncer gene; N = number of patients
3.1.1. Study Treatment Plan
The study period includes two treatment periods, the chemotherapy period and the 
maintenance period.  For the purpose of scheduling evaluations, providing clarity on 
assessments, and consistent on-treatment assessments across all three treatment arms, the 
definition of cycle length varies between the chemotherapy period and the maintenance 
period.  In the chemotherapy period, a cycle is defined as 3 weeks (21 days), and due to the 
biweekly schedule of avelumab and the Q3W schedule for bevacizumab, a cycle in the 
maintenance period is defined as 6 weeks (42 days).  See Section 1.2.5.1 for additional 
information. 
For the chemotherapy period of the study, study drugs will be assigned and given as 
follows:
Arm A: 

Paclitaxel 175 mg/m2 IV over 3 hours followed by Carboplatin AUC 5 or 6 IV over 
15-60 minutes on Days 1 of each 3-week cycle for 6 cycles. 

Avelumab 800 mg administered intravenously on Day 1 of each 3-week cycle for 
6 cycles.
Chemotherapy 
+
Avelumab 
Chemotherapy
Chemotherapy 
+ 
Bevacizumab
Bevacizumab
Talazoparib
Avelumab + 
Talazoparib
Treatment 
Until: 
Progressive 
Disease per 
RECIST v1.1
OR
Unacceptable 
Toxicity
OR
Patient 
Withdrawal
2.5:1:2.5
N = ~720
Randomization Stratification: 

germline BRCA 1/2 mutational status (gBRCA+ vs gBRCA-).

Adjuvant with >1 mm and ≤1 cm residual disease vs. 
Adjuvant with >1 cm residual disease vs.
Neoadjuvant.
Arm A 
(N=300)
Arm C 
(N=300)
Arm B 
(N=120)


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Arm B: 

Paclitaxel 175 mg/m2 IV over 3 hours followed by Carboplatin AUC 5 or 6 IV over 
15-60 minutes on Days 1 of each 3-week cycle for 6 cycles. 
Arm C: 

Paclitaxel 175mg/m2 IV over 3 hours followed by Carboplatin AUC 5or 6 IV over 
15-60 minutes on Day 1 of each 3-week cycle for 6 cycles. 

Bevacizumab 15mg/kg IV on Day 1 of each 3-week cycle beginning with Cycle 2 for 
adjuvant patients (may begin with cycle 1 if surgery completed >4 weeks prior to 
randomization and no contraindications), and for neoadjuvant patients, bevacizumab 
will be given on Day 1 of each 3-week cycle for Cycles 1, 2, 5, and 6.
For patients who are enrolled to undergo neoadjuvant chemotherapy with interval debulking 
surgery, the first 3 cycles of chemotherapy will be administered prior to interval debulking 
surgery.  Patients will stay on study regardless of the surgery outcome (eg, extend of residual 
disease) and will receive the remaining 3 cycles of chemotherapy.
Patients who have to discontinue both chemotherapy agents (carboplatin and paclitaxel) for 
unacceptable toxicities prior to the end of Cycle 6 may enter maintenance period, if deemed 
clinically acceptable by the investigator and will receive avelumab and talazoparib (Arm A) 
or talazoparib (Arm B), or bevacizumab (Arm C).
Maintenance period should begin within 4 weeks of the last dose of chemotherapy.  The first 
visit of maintenance therapy will be designated maintenance Cycle 1 Day 1 even if the last 
chemotherapy cycle was not completed.
For the maintenance period of the study, study drugs will be assigned and given as follows. 
Arm A:

Avelumab 800 mg administered intravenously on Days 1, 15, and 29 of each 6-week 
cycle in combination with talazoparib 0.75 mg self-administered orally once per day.
Arm B: 

Talazoparib 0.75 mg self-administered orally once a day, every day of each 6-week 
cycle.
Arm C:

Bevacizumab 15 mg/kg administered intravenously on Days 1 and 22 of each 6-week 
cycle.


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Effective with IRB/EC approval of amendment 2, patients will receive study treatment until 
progressive disease (PD) as assessed by the investigator, unacceptable toxicity, or withdrawal 
of consent, whichever is earliest.  For avelumab and talazoparib, the maximum duration of 
maintenance treatment is 24 months.  For bevacizumab, the maximum duration of treatment 
is 21 or 22 doses, per local approval, including the period of initial chemotherapy.  
Patients who discontinue all study treatment and have PD based on investigator assessment 
will be followed for a 90-day Safety Follow-up Period.   
3.1.1.1. Interval Debulking Surgery After Neoadjuvant Treatment
Patients who are enrolled prior to initiation of neoadjuvant therapy will complete 3 cycles of 
chemotherapy (with avelumab in Arm A or with bevacizumab in Arm C), then treatment will 
be held, and interval debulking surgery will be performed.  According to institutional 
practice, upon recovery from surgery, the remainder of chemotherapy (with avelumab in 
Arm A and with bevacizumab in Arm C) should be administered for a maximum of 6 cycles 
of chemotherapy.  See Sections 5 and 5.10.2.1 for further details.
3.2. Safety Monitoring
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the Schedule of Activities tables for each treatment 
arm.
An external data monitoring committee (E-DMC) was planned to have an initial review of 
safety data, without an enrollment hold, after approximately 30 patients in the study 
(approximately 12 patients in the avelumab plus talazoparib combination, Arm A) have been 
treated and followed for at least 4 weeks after the first dose in the maintenance period.  
As of 19 March 2019, the initial E-DMC meeting had not yet occurred.  This study will no 
longer use an E-DMC.  
4. PATIENT ELIGIBILITY CRITERIA
Enrollment was stopped, and patients can no longer be screened as of 19 March 2019.
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol. 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study. 


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4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histologically confirmed Stage III-IV epithelial ovarian, fallopian tube, or primary 
peritoneal cancer (according to American Joint Committee on Cancer (AJCC)/UICC 
TNM and International Federation of Gynecology and Obstetrics (FIGO) Staging 
System 2014 edition), including carcinosarcoma with high-grade serous component.
2. Patients must be candidates for bevacizumab in combination with platinum based 
chemotherapy and previously untreated.
3. Must have completed a primary surgical debulking procedure, or be candidates for 
neoadjuvant chemotherapy with planned interval debulking surgery. 
a.
Patients who completed primary debulking must have had incompletely resected 
disease that is macroscopically/grossly visible and at least with lesions >1 mm per 
operative records and be randomized at a maximum of 8 weeks after surgery.
b. For patients who are candidates for neoadjuvant chemotherapy, the diagnoses 
must have been confirmed by:

Core tissue (not fine-needle aspiration) biopsy is required for diagnosis.  The 
tissue must be consistent with inclusion criteria #1 above. 

Stage IIIC–IV documented via imaging or surgery (without attempt at 
cytoreduction).

Serum CA-125/CEA ratio >25.  If the serum CA-125/CEA ratio is <25, then 
workup should be negative for the presence of a primary gastrointestinal or 
breast malignancy (<6 weeks before start of neoadjuvant treatment).

Randomization must occur within 8 weeks after diagnosis.
4. Availability of an archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue 
block or a minimum of 25 slides, together with an accompanying original 
Hemotoxylin and Eosin (H&E) slide.  If archived FFPE tissue is not available, a de 
novo (ie, fresh) tumor sample must be obtained in accordance with local institutional 
practice for tumor biopsies. 

Sites may randomize/enroll patients who meet all other eligibility criteria 
while awaiting central confirmation of tissue acceptance, but must provide 
additional tumor samples in the event that the central lab review shows 
insufficient sample quality.
5. Eastern Cooperative Group (ECOG) performance status 0-1 (see Appendix 2).


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6. Age 18 years (or 20 years in Japan).
7. Adequate bone marrow function including: absolute neutrophil count (ANC) 
1,500/mm3 or 1.5 x 109/L; Platelets 100,000/mm3 or 100 x 109/L; hemoglobin 
9.0 g/dL (may have been transfused).
8. Adequate hepatic function defined by a total bilirubin level 1.5 x upper limit of 
normal range (ULN), an ALT/AST level 2.5 x ULN.
9. Adequate renal function by estimated creatinine clearance 60 mL/min as calculated 
using the Cockcroft-Gault method or by 24 hour urine collection for creatinine 
clearance or according to local institutional standard method. 
10. Adequate blood coagulation parameters: International normalized ratio (INR) 
1.5 and aPTT <1.2 times the upper limit of normal.
11. Ability to swallow oral study drugs. 
12. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative) has been informed of all pertinent 
aspects of the study. 
13. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
14. Patients of childbearing potential and at risk for pregnancy must agree to use 
2 methods of contraception (at least one of which is considered to be highly effective 
with low user dependency) as outlined in this protocol for the duration of the study 
and for at least 30 days after the last dose of avelumab, 7 months after the last 
talazoparib dose, and for 6 months after the last dose of bevacizumab.  Patients of 
non-childbearing potential must meet at least 1 of the following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular 
menses for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level confirming the post-menopausal 
state.
All other patients (including patients with tubal ligations) will be considered to be of 
childbearing potential.


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4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Non-epithelial tumors or ovarian tumors with low malignant potential (ie, borderline 
tumors) or mucinous tumors.
2. Patients for whom intraperitoneal cytotoxic chemotherapy is planned. 
3. Prior exposure to immunotherapy with interleukin (IL)-2, interferon alpha (IFN-), 
an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte 
associated antigen 4 (anti-CTLA4) antibody (including ipilimumab), or any other 
antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways, excluding therapeutic anticancer vaccines. 
4. Prior treatment with a PARP inhibitor.
5. Prior treatment with any anti-vascular endothelial growth factor (VEGF) drug, 
including bevacizumab.
6. Major surgery (other than debulking or exploratory surgery for ovarian cancer) for 
any reason within 4 weeks prior to randomization and/or incomplete recovery from 
surgery.
7. Prior radiotherapy to any portion of the abdominal cavity or pelvis.  Prior radiation 
for localized cancer of the breast, head and neck, or skin is permitted, provided that it 
was completed more than three years prior to registration, and the patient remains free 
of recurrent or metastatic disease.
8. Prior targeted therapy (including but not limited to vaccines, antibodies, tyrosine 
kinase inhibitors) or hormonal therapy for management of their ovarian, peritoneal 
primary or fallopian tube carcinoma.
9. Prior organ transplantation including allogenic stem cell transplantation.
10. Diagnosis of Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML).
11. Known symptomatic brain metastases requiring steroids.  Patients with previously 
diagnosed brain metastases are eligible if they have completed their treatment and 
have recovered from the acute effects of radiation therapy or surgery prior to study 
enrollment, have discontinued corticosteroid treatment for these metastases for at 
least 4 weeks and are neurologically stable.
12. Current or anticipated use within 7 days prior to the first dose of talazoparib or 
anticipated use during the study of a P-glycoprotein (P-gp) inhibitor, P-gp inducer, or 
breast cancer resistance protein (BCRP) inhibitor (See Section 5.10.6 for specific list 
of medications).


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13. Current use of immunosuppressive medication at the time of randomization, 
EXCEPT for the following: (a). intranasal, inhaled, topical steroids, or local steroid 
injection (eg, intra-articular injection); (b). Systemic corticosteroids at physiologic 
doses 10 mg/day of prednisone or equivalent; (c). Steroids as premedication for 
hypersensitivity reactions (eg, CT scan premedication). 
14. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agents.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or 
hyperthyroidism not requiring immunosuppressive treatment are eligible. 
15. Clinically significant (ie, active) cardiovascular disease: cerebrovascular 
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months 
prior to enrollment), unstable angina, congestive heart failure (greater than New York 
Heart Association Classification Class II), or serious cardiac arrhythmia requiring 
medication. 
16. Uncontrolled hypertension, defined as systolic >140 mm Hg or diastolic >90 mm Hg 
documented by 2 blood pressure readings taken at least 1 hour apart.  Use of 
antihypertensive medications to control blood pressure (BP) is allowed.
17. Patients with active bleeding or pathologic conditions that carry high risk of bleeding, 
such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
18. Active infection requiring systemic therapy.
19. Known history of testing positive for human immunodeficiency virus (HIV), or 
acquired immunodeficiency syndrome (AIDS).
20. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive).
21. Administration of a live vaccine within 30 days prior to study enrollment.
22. Known severe hypersensitivity reactions to investigational products or any 
component in their formulations or to monoclonal antibodies (NCI CTCAE 
v4.03 Grade 3).
23. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however 
alopecia, sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a 
safety risk based on investigator's judgment are acceptable.
24. Previous malignant disease other than the target malignancy to be investigated in this 
trial within the last 5 years with the exception of adequately treated basal or 
squamous cell carcinoma of the skin, cervical carcinoma in situ, lobular carcinoma 
in situ (LCIS), or ductal carcinoma in situ (DCIS) and in situ carcinoma of the 
bladder.


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25. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees, including their family members, 
directly involved in the conduct of the study.
26. Participation in other clinical studies involving investigational drug(s) within 4 weeks 
prior to study randomization and/or during study participation.
27. Known history of immune colitis, inflammatory bowel disease, immune pneumonitis, 
or pulmonary fibrosis.
28. Other acute or chronic medical conditions, psychiatric conditions, including recent 
(within the past year) or active suicidal ideation or behavior) or laboratory 
abnormalities that may increase the risk associated with study participation or study 
treatment administration or may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate for entry 
into this study.
29. Pregnant patients or breastfeeding patients.
4.3. Lifestyle Requirements 
In this study, patients will receive avelumab for which the teratogenic risk is currently 
unknown in combination with talazoparib, which has been associated with teratogenic risk.  
All fertile female patients who are of childbearing potential, who are, in the opinion of the 
investigator, sexually active and at risk for pregnancy with their partner(s) must agree to use 
2 methods of contraception (at least one of which is considered to be highly effective with 
low user dependency as defined below) throughout the study and continue for at least 
30 days after the last dose of avelumab, 7 months after the last dose of talazoparib, and for 
6 months after the last dose of bevacizumab.  The Investigator or his or her designee, in 
consultation with the patient, will confirm that the patient has selected 2 appropriate methods 
of contraception for the individual patient and her partner from the list of permitted 
contraception methods (see below) and will confirm that the patient has been instructed in 
their consistent and correct use.  At time points indicated in the schedule of activities, the 
investigator or designee will inform the patient of the need to use 2 methods of contraception 
at least one of which is considered to be highly effective with low user dependency as 
defined below) consistently and correctly and document the conversation, and the patient’s 
affirmation, in the patient’s chart.  In addition, the investigator or designee will instruct the 
patient to call immediately if 1 or both of the selected contraception methods is discontinued 
or if pregnancy is known or suspected in the patient. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:


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1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, inserted, injected, implanted), provided the patient plans to remain on 
the same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicide product (ie, foam, 
gel, film, cream, or suppository).  For countries where spermicide is not available or 
condom plus spermicide is not accepted as highly effective contraception, this option 
is not appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study portal.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33). 


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For this study, the investigational products are avelumab and talazoparib.  Bevacizumab will 
be considered investigational product only in countries where a treatment used in the 
standard therapy arm to be deemed an investigational product is required by law.
The study includes two treatment periods, the chemotherapy period and the maintenance 
period. 
For the chemotherapy period of the study, study drugs will be given as follows:
Arm A: 

Paclitaxel 175 mg/m2 IV over 3 hours followed by Carboplatin AUC 5 or 6 IV over 
15-60 minutes on Days 1 of each 3-week cycle for 6 cycles. 

Avelumab 800 mg administered intravenously on Day 1 of each 3-week cycle for 
6 cycles.
On dosing days when both chemotherapy and avelumab are infused (Day 1), avelumab will 
be infused after chemotherapy.
Premedication for chemotherapy is described in Section 5.4.1.1 and premedication for 
avelumab is described in Section 5.5.1.2. 
Arm B: 

Paclitaxel 175 mg/m2 IV over 3 hours followed by Carboplatin AUC 5 or 6 IV over 
15-60 minutes on Days 1 of each 3-week cycle for 6 cycles. 
Arm C: 

Paclitaxel 175 mg/m2 IV over 3 hours followed by Carboplatin AUC 5 or 6 IV over 
15-60 minutes on Day 1 of each 3-week cycle for 6 cycles. 

Bevacizumab 15 mg/kg IV Day 1 of each 3-week cycle beginning with Cycle 2 for 
adjuvant patients, and for neoadjuvant patients, bevacizumab will be given on 
Day 1 of each 3-week cycle for Cycles 1, 2, 5, and 6.
For patients who are enrolled prior to neoadjuvant therapy, the first 3 cycles will be 
administered prior to interval debulking surgery, and the remainder of chemotherapy will be 
administered after surgery. 
Patients who have to discontinue both chemotherapy agents (carboplatin and paclitaxel) for 
unacceptable toxicities prior to the end of Cycle 6 may enter maintenance period, if deemed 
clinically acceptable by the investigator and will receive avelumab and talazoparib (Arm A) 
or talazoparib (Arm B), or bevacizumab (Arm C).


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Maintenance period should begin within 4 weeks of the last dose of chemotherapy.  The first 
visit of maintenance therapy will be designated maintenance Cycle 1 Day 1 even if the last 
chemotherapy cycle was not completed.
For the maintenance period of the study, study drugs will be given as follows. 
Arm A:

Avelumab 800 mg administered intravenously on Days 1, 15 and 29 of each 6-week 
cycle in combination with talazoparib 0.75 mg self-administered orally once per day.
On dosing days when both investigational products are administered, talazoparib will be 
administered first. 
Arm B: 

Talazoparib 0.75 mg self-administered orally once a day, every day of each 6-week 
cycle.
Arm C:

Bevacizumab 15 mg/kg administered intravenously on Days 1 and 22 of each 6-week 
cycle.
Other treatments for progressive disease including chemotherapy and/or palliative 
radiotherapy will require the patient to be taken off treatment.  All investigational product 
administration details will be recorded on the case report form (CRF).
5.1. Allocation to Treatment
Enrollment was stopped, and patients can no longer be allocated to treatment as of 19 March 
2019.
Once the patient has provided a signed informed consent document (ICD) and has met all 
inclusion and none of the exclusion criteria, allocation of patients to treatment arms will 
proceed through the use of an interactive response technology (IRT) system. 
Allocation of patients will be stratified according to germline BRCA 1/2 mutational status 
(gBRCA+ vs gBRCA-) and resection status (adjuvant with >1 mm and 1 cm residual 
disease vs adjuvant with >1 cm residual disease vs neoadjuvant).  This stratified 
randomization will be centrally allocated across all centers via the IRT system.
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the patient number.  The site personnel will then be provided with a 
treatment assignment and dispensable unit (DU) or container number when drug is being 
supplied via the IRT system.  The IRT system will provide a confirmation report containing 


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the patient number and DU or container number assigned.  The confirmation report must be 
stored in the site’s files. 
There is a 24-hour-a-day, 365-days-a-year IRT helpdesk available for any questions or 
issues. The study-specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system. 
Note: The IRT is the source of the patient number. The IRT system will provide the patient 
number at the end of the first IRT patient transaction.
Qualified patients will be randomized in a 2.5:1:2.5 ratio as follows:
Chemotherapy Period
Maintenance Period
Arm A
Chemotherapy + Avelumab
Avelumab + Talazoparib
Arm B
Chemotherapy
Talazoparib 
Arm C
Chemotherapy + Bevacizumab
Bevacizumab 
5.2. Patient Compliance
The information related to each trial drug administration (ie, infusions), including the date, 
time (except for talazoparib), and dose of study drug, will be recorded in the CRF.  The 
Investigator will make sure that the information entered into the CRF regarding drug 
administration is accurate for each patient.  Any reason for noncompliance should be 
documented.
5.2.1. Patient Compliance with Avelumab
All doses of avelumab will be administered at the investigational site by well-trained medical 
staff.  The start and stop times of the avelumab infusion, along with the total volume 
administered, will be recorded in the patients’ medical records.  Additionally, the start and 
stop times of any interruptions to infusions and/or changes in rate of avelumab infusion will 
also need to be recorded in the patients’ medical records.  The vials of avelumab that are 
assigned and prepared for patients will be recorded in the pharmacy records.  These records 
will all be available for Sponsor representatives to verify compliance. 
The site will complete the required dosage Preparation Record located in the Investigational 
Product manual (IP manual) for avelumab.  The use of the supplied Preparation Record is 
preferred, but it does not preclude the use of an existing appropriate clinical site 
documentation system.  The existing clinical site's documentation system should capture all 
pertinent/required information on the preparation of the avelumab dose.  This may be used in 
place of the Preparation Record after approval from the Sponsor and/or designee.
Non-compliance is defined as a patient missing >1 infusion of avelumab for non-medical 
reasons.  If 1 infusion is missed and the interval between the subsequent infusion and the last 
administered treatment is longer than 6 weeks for non-medical reasons, then the patient 
would also be considered noncompliant.


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5.2.2. Patient Compliance with Talazoparib
Patients will be required to return all unused talazoparib capsules every cycle.  The number 
of capsules returned by the patient should be counted, documented, and recorded by site 
personnel in the patient’s medical record and reconciled with the patient’s dosing diary to 
support the talazoparib accountability process.  Study site personnel must make reasonable 
efforts to obtain study drug packaging and any unused capsules from patients who do not 
routinely return them at study site visits.  Unreturned capsules will be considered to have 
been taken unless reported otherwise by the patient.
Additionally, a patient dosing diary and dosing card will be provided to aid in patient 
compliance with the dosing instructions.  The diary will be completed by the patient to 
include taken, missed or changed talazoparib doses.  The total dose of talazoparib taken each 
day will be recorded in the dosing diary.  On days when the patient’s talazoparib dose is 
given at the clinic due to combination dosing with avelumab and/or scheduled PK sample 
collection, the time of talazoparib dose administration and the total dose of talazoparib taken 
will be recorded in the patient’s dosing records that are included in the medical chart.
Treatment compliance (reported as a percent) will be defined as the number of capsules taken 
during the study divided by the expected number of capsules, multiplied by 100.
5.2.3. Patient Compliance with Bevacizumab
All doses of bevacizumab will be administered at the investigational site by well-trained 
medical staff.  The start and stop times of the infusion, along with the total volume 
administered, will be recorded in the patients’ medical records.  Additionally, the start and 
stop times of any interruptions to infusions and/or changes in rate of infusion will also need 
to be recorded in the patients’ medical records.  The vials of bevacizumab that are assigned 
and prepared for patients will be recorded in the pharmacy records.  These records will all be 
available for Sponsor representatives to verify compliance.
The site will complete the required dosage Preparation Record located in the Investigational 
Product manual (IP manual) for bevacizumab.  The use of the supplied Preparation Record is 
preferred, but it does not preclude the use of an existing appropriate clinical site 
documentation system.  The existing clinical site's documentation system should capture all 
pertinent/required information on the preparation of the bevacizumab dose.  This may be 
used in place of the Preparation Record after approval from the Sponsor and/or designee.
Noncompliance is defined as a patient missing >1 infusion of bevacizumab for non-medical 
reasons.  If 1 infusion is missed and the interval between the subsequent infusion and the last 
administered treatment is longer than 6 weeks for non-medical reasons, then the patient 
would also be considered noncompliant.


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5.3. Investigational Product Supplies
Clinical Trial supplies will be shipped to the study sites by Pfizer Global Clinical Supply 
(GCS), Worldwide Research and Development (WRD), and will include a Drug Shipment 
and Proof of Receipt form.  This form will be completed, filed, and the shipment confirmed 
as directed on the bottom of the Drug Shipment and Proof of Receipt form.  The Investigator 
shall take responsibility for and take all steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations.
5.3.1. Dosage Form(s) and Packaging
Packaging and labeling for all study drugs will be in accordance with applicable local 
regulatory requirements and applicable Good Manufacturing Guidelines (GMP) guidelines.  
The information on each study drug will be in accordance with approved submission 
documents.
5.3.1.1. Avelumab
Avelumab is a sterile, clear, non-pyrogenic, and colorless solution intended for IV 
administration.  It is presented at a concentration of 20 mg/mL with a nominal volume of 
10 mL in glass vials closed with a rubber stopper and sealed with an aluminum 
polypropylene flip off seal.  Each vial is intended for a single use in a single patient only and 
the contents are free of bacteriostatic preservatives.
5.3.1.2. Talazoparib
Talazoparib will be provided as capsules for oral administration.  The 0.25 mg (Size 4 white) 
capsules will be supplied in bottles and labeled according to local regulatory requirements.  
Talazoparib is packaged in induction sealed, high density polyethylene bottles with child 
resistant caps of a single strength per bottle.
5.3.1.3. Bevacizumab
Bevacizumab is a sterile clear, colorless to pale brown solution for intravenous infusion.  
Each vial contains 400 mg of bevacizumab in 16 ml of solution and is intended for a single 
use in a single patient only. 
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines.
Pfizer GCS, WRD will provide either branded bevacizumab or biosimilar product.
5.3.1.4. Chemotherapy (Paclitaxel and Carboplatin)
Paclitaxel and carboplatin to be administered during this study will be branded or generic 
product available in the local region.  Note that nanoparticle protein bound paclitaxel 
(nab-paclitaxel, Abraxanemay NOT be substituted for the Cremophor formulation of 
paclitaxel.  Paclitaxel and carboplatin are commercially available, and are to be stored, 
prepared, and administered according to locally approved product labeling.


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5.3.2. Preparation and Dispensing
Investigational products must not be used for any purpose other than the trial.  The 
administration of study treatment to patients who have not been enrolled into the trial is not 
covered by the trial insurance.
5.3.2.1. Preparation of Avelumab
See the dosage and administration instructions in the Investigational Product (IP) Manual for 
instructions on how to prepare the investigational products for administration.  
Investigational products should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance, as well as 
trained in the procedures specified in this protocol.
Detailed information on infusion bags and medical devices to be used for the preparation of 
the dilutions and subsequent administration(s) for avelumab will be provided in the IP 
Manual. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
study agents.
Any unused portion of the avelumab solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and national standards of incineration.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
5.3.2.2. Dispensing of Talazoparib
Talazoparib should be dispensed on the Day 1 Visit of every cycle.  A qualified staff member 
will dispense the investigational product in the bottles provided, in quantities sufficient to 
support dosing.  The patient/caregiver should be instructed to maintain the product in the 
bottle provided throughout the course of dosing, keep the investigational product away from 
children, and return the bottle to the site on the Day 1 Visit of the subsequent cycle.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the dispensing, handling, and safe 
disposal of talazoparib.  Talazoparib is considered a cytotoxic and clastogenic agent; 
precautions regarding appropriate secure storage and handling must be used by healthcare 
professionals, including personal protective clothing, disposable gloves, and equipment.60  
Patients should be advised that oral anti-cancer agents are toxic substances and that other 
caregivers should always use gloves when handling the capsules.


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5.3.2.3. Preparation of Bevacizumab
Bevacizumab to be administered during this study will be branded or biosimilar product 
available in the local region.  Bevacizumab may be commercially available, and is to be 
stored, prepared, and administered according to locally approved product labeling or 
institutional guidelines.
See the dosage and administration instructions in the Investigational Product (IP) Manual for 
instructions on how to prepare the investigational products for administration.  
Investigational products should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance, as well as 
trained in the procedures specified in this protocol.
Detailed information on infusion bags and medical devices to be used for the preparation of 
the dilutions and subsequent administration(s) for bevacizumab will be provided in the IP 
Manual. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
study agents.
Any unused portion of the bevacizumab solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and national standards of incineration.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
5.4. Administration of Chemotherapy Regimens 
5.4.1. Paclitaxel and Carboplatin
5.4.1.1. Premedication for Chemotherapy Administration
Premedication to ameliorate the toxicities associated with the chemotherapy are to be 
administered according to the local product label or institutional guidelines.
5.4.1.1.1. Paclitaxel
Premedication regimens that are standard for the institution or region will be used.  
Premedication will be supplied by the site.  The effect of steroid premedication in Arm A 
chemotherapy period on the activity of avelumab is unknown (see Section 5.10.5).


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5.4.1.1.2. Carboplatin
Carboplatin can induce emesis, which can be more severe in patients previously receiving 
emetogenic therapy.  The incidence and intensity of emesis have been reduced by using 
premedication with anti emetics.  Because anti emetics are given as part of the paclitaxel 
regimen, extra doses as premedication are not necessary, although additional doses may be 
required if the patient develops emesis.  Premedication according to institutional guidelines 
should be used if paclitaxel has been discontinued.  No pre- or post-treatment hydration or 
forced diuresis is required.
5.4.1.2. Chemotherapy Regimen and Starting Doses
In the absence of progressive disease, patients will receive paclitaxel and carboplatin 
treatment for 6 cycles during the chemotherapy period of the study.  Dose modifications for 
toxicity are allowed.  All patients should be weighed within 3 days prior to dosing for every 
cycle to ensure they did not experience either a weight loss or gain of >10% from the weight 
used for the last dose calculation.  For weight change less than 10% the decision to 
recalculate the chemotherapy doses can be in accordance with institutional practice.  If the 
patient experienced either a weight loss or gain >10% compared to the weight used for the 
last dose calculation, the amount of study drug must be recalculated.
5.4.1.2.1. Paclitaxel
Following pre medication, paclitaxel is administered as the first drug when chemotherapy is 
administered.  For this study, paclitaxel will be administered at 175 mg/m2 IV over 3 hours 
on Day 1 of each 3-week cycle.
5.4.1.2.2. Carboplatin
Carboplatin AUC 5 or AUC 6 is administered over 15-60 minutes (as per locally approved 
product labeling or institutional guidelines) after completion of the paclitaxel infusion on 
Day 1 of each 3-week chemotherapy cycle.
5.4.2. Administration of Avelumab Plus Chemotherapy
Avelumab will be administered by IV infusion at the investigational site.  Avelumab will not 
be used for any purpose other than the trial.
For patients on Arm A, avelumab will be administered after chemotherapy as an 800 mg 
fixed dose via a 1-hour (-10/+20 minutes) IV infusion Q3W on Day 1 of each 3-week 
(21 day) chemotherapy cycle.  Patients should be instructed to report any delayed reactions to 
the Investigator immediately.
Avelumab premedication requirement is described in Section 5.5.1.2.


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If premedication was administered prior to chemotherapy), the decision whether to repeat 
premedication prior to avelumab) is at the discretion of the investigator depending on the 
elapsed time and the half-life of corresponding premedication agent.  The line should be 
flushed, according to local practice, between infusions, and a new administration set should 
be used for avelumab.
Sites should make every effort to target the timing of avelumab infusion to be as close to 
1 hour as possible.  However, given the variability of infusion pumps from site to site, time 
windows of minus 10 minutes and plus 20 minutes is permitted (ie, infusion time is 
50-80 minutes).  The exact duration of infusion should be recorded in both source documents 
and CRFs.  Possible modifications of the infusion rate for the management of infusion related 
reactions are described in Section 5.6.4 and Section 5.6.5.
5.4.3. Administration of Bevacizumab Plus Chemotherapy
For patients on Arm C, when both chemotherapy and bevacizumab are infused on Day 1 of 
each 3-week cycle during the chemotherapy period, bevacizumab will be infused after 
chemotherapy. 
Bevacizumab 15 mg/kg will be administered intravenously once every 3 weeks starting on 
Day 1 of Cycle 2 in the chemotherapy period for adjuvant patients (may begin with Cycle 1 
if surgery completed >4 weeks prior to randomization and no contraindications).  For 
neoadjuvant patients, bevacizumab will be given on Day 1 of each 3-week cycle for 
Cycles 1, 2, 5 and 6 of the chemotherapy period. 
5.5. Administration of Maintenance Therapies
Prior to starting treatment with talazoparib in the maintenance period and following the last 
dose of chemotherapy, patients must be re-evaluated for adequate renal function.  Patients 
with a CLCR>=60 mL/min will receive the starting dose of 0.75 mg talazoparib QD.  For 
patients with moderate renal impairment (CL CR=30-59 mL/min), the talazoparib starting 
dose should be reduced to 0.50 mg QD as per Section 5.6.1.  All patients receiving 
talozoparib maintenance therapy should undergo routine renal function testing as per 
Section 7.1.4. 
5.5.1. Avelumab Plus Talazoparib
During the maintenance period, on Days 1, 15, and 29 of each cycle, when both avelumab 
and talazoparib are administered at the investigative site, the following must occur in the 
order specified:
1. All required tests and assessments will be performed, as per the Schedule of 
Activities tables and blood will be drawn for PK and ADA assessments (when 
scheduled); 
2. Avelumab premedication, as described below in Section 5.5.1.2, and talazoparib will 
be administered to the patient in any order chosen by the qualified site personnel;
3. Avelumab infusion will start after dosing with talazoparib; 


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4. Blood will be drawn for PK assessments (when scheduled) at the end of the avelumab 
infusion.
Effective with IRB/EC approval of amendment 2, treatment with avelumab and talazoparib 
will continue until disease progression is confirmed based on investigator assessment (except 
where treatment is allowed beyond progression, as per Section 5.7), unacceptable toxicity, or 
withdrawal of consent, whichever occurs first.
The investigational products and the required premedications are discussed in the 
following subsections, in the order of their administration.
5.5.1.1. Administration of Talazoparib
Talazoparib will be taken QD at 0.75 mg starting on Maintenance Cycle 1 Day 1 with or 
without avelumab (Arms A or B) and treatment should continue until End of 
Treatment/withdrawal.  On Days 1, 15, and 29 of each maintenance cycle, when the patient 
returns to the clinic for avelumab administration, the daily dose of talazoparib should not be 
taken prior to the study visit and will be taken at the clinic after all procedures/assessments 
have been completed and, for patients randomized to Arm A, before the avelumab infusion.
Patients should self-administer talazoparib orally QD, with or without food.  The capsules 
should be swallowed whole with a glass of water without chewing, dissolving, or opening the 
capsules prior to swallowing.
Patients should be instructed to take talazoparib at approximately the same time each day and 
to not take more than the prescribed dose at any time.
If a patient misses a day of treatment or vomits any time after taking a dose, she must be 
instructed not to “make it up” but to resume subsequent doses the next day as prescribed.
Patients should complete the Dosing Diary after taking each dose.  If the patient misses a day 
of treatment or takes a dose different than was prescribed, the reason for the missed dose or 
different dose must be recorded in the Dosing Diary.  The Dosing Diary should be returned 
to the site at every cycle.
5.5.1.2. Premedication for Avelumab
In order to mitigate possible infusion related reactions from the administration of avelumab, 
patients have to be premedicated with an antihistamine and with acetaminophen 
(paracetamol) or according to local institutional clinical guidelines prior to the first 
4 infusions of avelumab.  Premedication should be administered for subsequent avelumab 
doses based upon clinical judgment and presence/severity of prior infusion reactions.
When avelumab and talazoparib are administered on the same day, premedications may be 
given either prior to talazoparib, at the same time as talazoparib, or after talazoparib.  
However, the avelumab infusion will not start until after talazoparib and after the avelumab 
premedication was administered.


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5.5.1.3. Administration of Avelumab
Avelumab will be administered by IV infusion at the investigational site.
Avelumab will be administered as an 800 mg fixed dose via a 1-hour (-10/+20 minutes) IV 
infusion Q2W on Day 1, Day 15, and Day 29 of each 42-day maintenance cycle (6 week 
cycle).  Patients should be instructed to report any delayed reactions to the Investigator 
immediately.
Any unused portion of the avelumab solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and national standards of incineration.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
5.5.1.3.1. Special Precautions for the Administration of Avelumab
As with all mAb therapies, there is a risk of allergic reactions, including anaphylactic shock. 
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, 
such as the ability to implement immediate resuscitation measures. 
If an allergic reaction occurs, the patient must be treated according to the best available 
medical practice.  Patients should be instructed to report any delayed reactions to the 
Investigator immediately. 
Symptoms of avelumab infusion related reactions include, but are not limited to, fever, chills, 
flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria.  
Management of avelumab infusion related reactions is described in Section 5.6.4. 
5.5.1.4. Food Requirements
Both investigational products may be administered without regard to food.
5.5.2. Administration of Bevacizumab
Bevacizumab to be administered during this study will be branded or biosimilar product 
available in the local region.  Bevacizumab may be commercially available, and is to be 
stored, prepared, and administered according to locally approved product labeling or 
institutional guidelines.
Bevacizumab 15 mg/kg will be administered intravenously on Days 1 and 22 of each 6-week 
maintenance cycle. The initial dose should be delivered over 90 minutes as an IV infusion.  
If the first infusion is well tolerated, the second infusion may be administered over 
60 minutes.  If the 60-minute infusion is well tolerated, all subsequent infusions may be 
administered over 30 minutes.


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Patient weight at screening will be used to determine the bevacizumab dose to be used for the 
duration of the study.  If a patient’s weight changes by 10% during the course of the study, 
then the bevacizumab dose will be recalculated.
5.6. Recommended Dose Modifications and Toxicity Management
Every effort should be made to administer each investigational product at the planned dose 
and schedule. 
In the event of significant toxicity, dosing may be interrupted, delayed, and/or reduced, only 
as described for each investigational product.  In the event of multiple toxicities, 
treatment/dose modifications should be based on the worst toxicity observed.  Patients are to 
be instructed to notify Investigators at the first occurrence of any adverse symptom.
Investigators determine if an AE is attributed to one or more IP in combination treatment and 
the treatment/dose modifications may occur independently for each investigational product in 
the combination based on the general guidance, as follows: 

Avelumab: No dose reductions are permitted in this study, but the next infusion may 
be omitted based on persisting toxicity.

Talazoparib: Dose modifications (dose interruptions or dose reductions) may be 
implemented to manage toxicities.

Bevacizumab: There will be no dose reduction for Bevacizumab.  Treatment should 
be interrupted or discontinued for certain adverse events.  Dose modification (dose 
delays or omissions) for bevacizumab due to adverse drug reactions (ADRs) should 
be made in accordance with the guidance provided below, product labeling and/or 
institutional guidelines.
See sections below for details regarding the specific protocol permitted modifications for 
each investigational product.
All dose modifications must be clearly documented in the patient's medical chart and in the 
CRF. 
In addition to dose modifications, Investigators are encouraged to employ best supportive 
care according to local institutional clinical practices.
5.6.1. Dose Reductions for Talazoparib
Following dosing interruption due to toxicity at any time in the study, the talazoparib dose 
may need to be reduced, based on the worst toxicity reported, when treatment is resumed.  
Dose reduction should be made in accordance with the guidance provided below in 
Section 5.6.2.  Dose reduction of talazoparib by 1 dose level at a time will be allowed 
depending on the starting dose and type and severity of toxicity encountered.  Patients unable 
to tolerate 0.25 mg QD, will be permanently discontinued from the talazoparib, but may 


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continue on single agent avelumab if on Arm A.  Available dose levels for dose reductions 
are listed in Table 4.
Table 4.
Dose Levels for Dose Reductions of Talazoparib
Dose Level
Talazoparib Dose (Oral)
Starting
0.75 mg QD
Dose level -1
0.50 mg QD
Dose Level -2
0.25 mg QD
Talazoparib dose de-escalation below 0.25 mg QD is not allowed.
D = dose; QD = every day
Once a dose has been reduced for a given patient, all subsequent cycles should be 
administered at that dose level, unless further dose reduction is required.  Intra patient dose re 
escalation is not allowed.
Recommended dose reductions for talazoparib are described in Section 5.6.2.
5.6.2. Study Treatment Modifications for Drug-related Toxicity from Avelumab and 
Talazoparib (Excluding Infusion-Related Reactions and Immune-Related Adverse 
Events)
Recommended treatment modifications avelumab and talazoparib in case of investigational 
product related toxicity are shown in Table 5.  The specific guidelines are applicable in cases 
which can be attributed to one of the investigational products.  The instructions should be 
followed in the column regarding the investigational product that toxicity is attributed to.  In 
cases where an AE is possibly related to both investigational products, the guidelines in both 
columns for both investigational products should be followed.  Patients who stop avelumab 
or talazoparib for unacceptable toxicity may continue treatment with the investigational 
product that is not considered to be responsible for the toxicity observed.
Avelumab infusion related reactions should be managed according to guidelines in 
Section 5.6.4.
For patients receiving avelumab in combination with talazoparib, any AE suspected to be 
immune related should be managed according to the guidance for management of irAEs in 
Section 5.6.5.


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Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related 
AEs)
Talazoparib
Avelumab
Hematologic toxicities
Grade 1 and Grade 2

No requirement for dose interruption 
or dose reduction.

Continue as per schedule.
Anemia Grade 3
(hemoglobin <8 g/dL)

Hold talazoparib and implement 
supportive care per local guidelines.  
Monitor weekly until until 
hemoglobin returns to 9 g/dL or 
better.  Then resume talazoparib at a 
reduced dose at the initiation of the 
next cycle. 

If anemia with hgb <8.0 g/dL recurs 
after dose reduction, hold talazoparib 
and implement supportive care per 
local guidelines. Monitor weekly 
until hemoglobin returns to 9.0 g/dL 
(Day 1), then resume talazoparib at a 
further reduced dose at the initiation 
of the next cycle.

If anemia persists for >4 weeks 
without recovery of hemoglobin to at 
least 9.0 g/dL despite supportive care 
measures at any dose level, 
discontinue talazoparib and consider 
referral to a hematologist.
Transfusions and other supportive 
measures are permitted to support 
management of hematological toxicities at 
any occurrence.

Hold avelumab.

Re-initiate avelumab once 
hemoglobin 8 g/dL or 
baseline.

Permanently discontinue 
avelumab if hemoglobin does 
not return to 8g/dL within 
12 weeks or if the same 
Grade 3 toxicity recurs (if 
talazoparib had already been 
discontinued and recurrent 
event occurs on avelumab 
only).
Neutropenia Grade 3
(ANC <1000/L)

Hold talazoparib and implement 
supportive care per local guidelines.  
Monitor weekly until ANC 
1500/L.  Then resume talazoparib 
at a reduced dose at the initiation of 
the next cycle. 

If neutropenia recurs after the dose 
reduction, hold talazoparib and 
implement supportive care per local 
guidelines. Monitor weekly until 
ANC 1500/µL, then resume 
talazoparib at a further reduced dose 
at the initiation of the next cycle.

If neutropenia persists for >4 weeks 
without recovery to 1500/μL at any 
dose level despite supportive care 
measures, discontinue talazoparib and 
consider a referral to a hematologist.
G-CSF and GM-CSF may be used at 
investigators discretion for the supportive 
treatment of neutropenia at any occurence.

Hold avelumab.

Re-initiate avelumab once 
toxicity Grade 1 (ANC 
1500/L) or baseline.

Permanently discontinue 
avelumab if toxicity does not 
resolve to Grade 1 or 
baseline within 12 weeks or if 
the same Grade 3 toxicity 
recurs (if talazoparib had 
already been discontinued and 
recurrent event occurs on 
avelumab only).


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Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related 
AEs)
Talazoparib
Avelumab
Thrombocytopenia Grade 3 
(platelets <50,000/L)

Hold talazoparib and implement 
supportive care per local 
guidelines. Monitor weekly until 
platelets ≥50,000/μL, then then 
resume talazoparib at a reduced dose 
at the initiation of the next cycle.

If thrombocytopenia (<50,000/μL) 
recurs after one dose reduction, hold 
talazoparib and implement supportive 
care per local guidelines. Monitor 
weekly until platelets 75,000/µL, 
then resume talazoparib a further 
reduced dose at the initiation of the 
next cycle.

If thrombocytopenia persists for 
>4 weeks without recovery to 
50,000/μL despite supportive care 
measures, discontinue talazoparib and 
consider a referral to a hematologist.
Thrombopoietin analogues and/or platelet 
transfusions may be used at investigators 
discretion for the supportive treatment of 
thrombocytopenia at any occurrence.

Hold avelumab.

Re-initiate avelumab once 
platelets 50,000/μL.

Permanently discontinue 
avelumab if toxicity does not 
resolve to 50,000/μL within 
12 weeks or if the same 
Grade 3 toxicity recurs (if 
talazoparib had already been 
discontinued and recurrent 
event occurs on avelumab 
only).
Non-hematologic toxicities
Grade 1 and Grade 2

No requirement for dose interruption 
or dose reduction. 

For suspected immune-related 
toxicities due to avelumab that 
require avelumab delay or 
discontinuation as per Section 5.6.5, 
talazoparib should also be placed on 
hold until toxicity is Grade 1 or 
baseline.

Continue as per schedule.

For suspected immune-related 
toxicities due to avelumab 
follow guidance in 
Section 5.6.5.
Grade 3 

Hold talazoparib.

Resume talazoparib reduced by 
1 dose level, per Section 5.6.1 if 
toxicity resolves to Grade 1 or 
baseline within 4 weeks.

Exceptions are:
Nausea, vomiting, or diarrhea 
lasting 72 hours; fatigue lasting 
<5 days; hypertension controlled 
with medical therapy; increase in 
indirect bilirubin indicative of 
Gilbert’s syndrome; serum lipase 
or amylase lasting 
7 consecutive days without 
clinical signs or symptoms of 
pancreatitis; endocrinopathies 
controlled with hormonal 
therapy; laboratory values that 

Hold avelumab.

Resume once toxicity is 
Grade 1 or baseline.

Permanently discontinue if 
toxicities does not resolve to 
Grade 1 or baseline within 
12 weeks or if the same 
Grade 3 toxicity recurs:

Exceptions are:
Laboratory values that do 
not have any clinical 
correlate.

For suspected immune-related 
toxicities follow guidance in 
Section 5.6.5.


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Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related 
AEs)
Talazoparib
Avelumab
do not have any clinical 
correlate.

If the same Grade 3 toxicity recurs, 
reduce by 1 dose level.

Permanently discontinue if toxicity 
does not improve to Grade 1 or 
baseline within 4 weeks.

Exceptions are:
Laboratory values that do not 
have any clinical correlate.

Permanently discontinue if Grade 3 
liver test abnormality.  Rechallenge 
may be considered once toxicity is 
Grade 1 or baseline, if an alternative 
cause for the abnormal liver tests 
(ALT, AST, total bilirubin) is 
identified. 

For suspected immune-related 
toxicities due to avelumab that 
require avelumab delay or 
discontinuation as per Section 5.6.5, 
talazoparib should also be placed on 
hold until toxicity is Grade 1 or 
baseline.
Grade 4

Permanently discontinue talazoparib:

Exceptions are:
Laboratory values that do not 
have any clinical correlate.

Permanently discontinue 
avelumab. 

Exceptions are:
Laboratory values that do 
not have any clinical 
correlate.

For suspected immune-related 
toxicities follow guidance in 
Section 5.6.5.
Abbreviations: AML=Acute Myeloid Leukemia; ANC=Absolute Neutrophil Count; MDS=Myelodysplastic Syndrome.
5.6.3. Overdose of Talazoparib
There is no specific treatment in the event of talazoparib overdose, and symptoms of 
overdose are not established.  In the event of overdose, treatment with talazoparib should be 
stopped, and physicians should consider gastric decontamination, follow supportive 
measures, and treat symptomatically.
5.6.4. Treatment Modifications for Infusion-Related Reactions Associated with 
Avelumab
Recommended treatment modifications in case of avelumab infusion related reactions are 
shown in Table 6.


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Table 6.
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated With Avelumab
NCI CTCAE Severity Grade
Treatment Modification
Grade 1 – mild

Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.

Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 – moderate

Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (for 
example, antihistamines, NSAIDs, narcotics, IV 
fluids; prophylactic medications indicated for 
24 hours.

Temporarily discontinue avelumab infusion.

Resume avelumab infusion at 50% of previous rate 
once infusion-related reaction has resolved or 
decreased to at least Grade 1 in severity, and monitor 
closely for any worsening.a

If a Grade 2 infusion related reaction does not 
improve or worsens following the decrease in infusion 
rate and appropriate symptomatic treatment the 
infusion should not be resumed for that day.
Grade 3 or Grade 4 – severe or life-threatening

Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization 
indicated for clinical sequelae.

Grade 4: Life-threatening consequences; urgent 
intervention indicated.

Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject.

Patients have to be withdrawn immediately from 
avelumab treatment and must not receive any further 
avelumab treatment.
a. If avelumab infusion rate has been decreased by 50% due to an infusion reaction, it must remain decreased for the 
next scheduled infusion.  If no infusion reaction is observed at the next scheduled infusion, the infusion rate may be 
returned to baseline at subsequent infusions.
Abbreviations: NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs=nonsteroidal anti-inflammatory drugs; IV=intravenous.
If, in the event of a Grade 2 infusion related reaction that does not improve or worsens after 
implementation of the modifications indicated above (including reducing the infusion rate by 
50%), the Investigator may consider treatment with corticosteroids, and the infusion should 
not be resumed.  At the next dose, the Investigator may consider the addition of H2 blocker 
antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofen to the mandatory 
premedication. 
5.6.5. Immune-Related Adverse Events Toxicity Management
For patients receiving avelumab in combination with talazoparib, any AE suspected to be 
immune-related (ie, an irAE) should be managed according to the guidance for management 
of irAEs (see Table 7) below. 
Treatment of irAEs is mainly dependent on severity (NCI CTCAE grade):

Grades 1 to 2: treat symptomatically or with moderate dose steroids, more frequent 
monitoring.

Grades 1 to 2 (persistent): manage similar to Grades 3 to 4 AE. 


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
Grades 3 to 4: treat with high dose corticosteroids; if suspected to be related to 
avelumab, talazoparib should be withhold until toxicity resolves to Grade 1 or 
baseline.
For Grade 3 immune related toxicities suspected to be related to avelumab, talazoparib 
should be withheld until toxicity resolves to Grade 1 or baseline.
Table 7.
Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1

Diarrhea: <4 stools/day 
over Baseline.

Colitis: asymptomatic.

Continue avelumab therapy.

Symptomatic treatment 
(eg, loperamide).

Close monitoring for 
worsening symptoms.

Educate subject to report 
worsening immediately.

If worsens, treat as 
Grade 2, 3 or 4. 
Grade 2 

Diarrhea: 4 to 6 stools per 
day over Baseline; IV fluids 
indicated <24 hours; not 
interfering with ADL.

Colitis: abdominal pain; 
blood in stool. 

Withhold avelumab therapy.

Symptomatic treatment.

If improves to Grade 1, 
resume avelumab therapy.

If persists >5-7 days or 
recurs, treat as Grade 3 or 
4.
Grade 3 to 4

Diarrhea (Grade 3):
7 stools per day over 
Baseline; incontinence; IV 
fluids 24 h; interfering 
with ADL.

Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, 
peritoneal signs.

Grade 4: life-threatening, 
perforation.

Withhold avelumab for Grade 3.

Permanently discontinue avelumab 
for Grade 4 or recurrent Grade 3.

1.0-2.0 mg/kg/day prednisone IV or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections. 

Consider lower endoscopy.

If improves, continue 
steroids until Grade 1, 
then taper over at least 
1 month; resume 
avelumab therapy 
following steroids taper 
(for initial Grade 3). 

If worsens, persists >3 to 
5 days, or recurs after 
improvement, add 
infliximab 5 mg/kg (if no 
contraindication).  Note: 
infliximab should not be 
used in cases of 
perforation or sepsis.


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Table 7.
Management of Immune-Related Adverse Events
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1 to 2
Covering 30% body surface 
area. 

Continue avelumab therapy. 

Symptomatic therapy (for example, 
antihistamines, topical steroids). 

If Grade 2 persists >1 to 2 
weeks or recurs, withhold 
avelumab therapy. 

Consider skin biopsy. 

Consider 
0.5-1.0 mg/kg/day 
prednisone or equivalent.  
Once improving, taper 
steroids over at least 
1 month, consider 
prophylactic antibiotics 
for opportunistic 
infections, and resume 
avelumab therapy 
following steroids taper.

If worsens, treat as 
Grade 3 to 4. 
Grade 3 to 4

Grade 3: Covering >30% 
body surface area. 

Grade 4: Life threatening 
consequences. 

Withhold avelumab for Grade 3.

Permanently discontinue for Grade 4 
or recurrent Grade 3. 

Consider skin biopsy. 

Dermatology consult. 

1.0-2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections. 

If improves to Grade 1, 
taper steroids over at least 
1 month; resume 
avelumab therapy 
following steroids taper 
(for initial Grade 3).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only. 

Consider withholding avelumab 
therapy. 

Monitor for symptoms every
2 -3 days. 

Consider Pulmonary and Infectious 
Disease consults. 

Re-assess at least every 
3 weeks.

If worsens, treat as 
Grade 2 or Grade 3 to 4. 
Grade 2
Mild to moderate new
symptoms. 

Withhold avelumab therapy.

Pulmonary and Infectious Disease 
consults.

Monitor symptoms daily; consider 
hospitalization.

1.0-2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 

Re-assess every 1 to 
3 days.

If improves: When 
symptoms return to 
Grade 1, taper steroids 
over at least 1 month, and 
then resume avelumab 
therapy following steroids 


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Table 7.
Management of Immune-Related Adverse Events
opportunistic infections. 

Consider bronchoscopy, lung biopsy. 
taper.

If not improving after 
2 weeks or worsening, 
treat as Grade 3 to 4.
Grade 3 to 4

Grade 3: Severe new 
symptoms; New/worsening 
hypoxia;

Grade 4:  Life-threatening.

Permanently discontinue avelumab 
therapy.

Hospitalize.

Pulmonary and Infectious Disease 
consults.

1.0-2.0 mg/kg/day prednisone or 
equivalent. 

Add prophylactic antibiotics for 
opportunistic infections. 

Consider bronchoscopy, lung biopsy. 
If improves to Grade 1, taper 
steroids over at least 1 month. 
If not improving after 48 hours 
or worsening, add additional 
immunosuppression (for 
example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or 
mycophenolate mofetil).
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1

Grade 1 AST or ALT 
>ULN to 3.0 x ULN; 

and/or Total bilirubin 
>ULN to 1.5 x ULN. 

Continue avelumab therapy.

Continue liver function 
monitoring 

If worsens, treat as 
Grade 2 or 3 to 4. 
Grade 2

AST or ALT >3.0 to 5 x 
ULN; 

and/or total bilirubin >1.5 
to 3 x ULN. 

Withhold avelumab therapy.

Increase frequency of monitoring to 
every 3 days.

If returns to Grade 1, 
resume routine 
monitoring; resume 
avelumab therapy.

If elevation persists >5 to 
7 days or worsens, treat as 
Grade 3 to 4.
Grade 3 to 4

AST or ALT >5 x ULN; 

and/or total bilirubin 
>3 x ULN. 

Permanently discontinue avelumab 
therapy. 

Increase frequency of monitoring to 
every 1 to 2 days. 

1.0-2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections. 

Consult gastroenterologist/ 
hepatologist.

Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted. 

If returns to Grade 1, 
taper steroids over at least 
1 month.

If does not improve in 
>3 to 5 days, worsens or 
rebounds, add 
mycophenolate mofetil 
1 gram (g) twice daily. 

If no response within an 
additional 3 to 5 days, 
consider other 
immunosuppressants per 
local guidelines.


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Table 7.
Management of Immune-Related Adverse Events
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1
Creatinine increased >ULN to 
1.5 x ULN.

Continue avelumab therapy.

Continue renal function 
monitoring.

If worsens, treat as Grade 2 
to 3 or 4.
Grade 2 to 3
Creatinine increased >1.5 and 
6 x ULN.

Withhold avelumab therapy.

Increase frequency of monitoring to 
every 3 days.

Add prophylactic antibiotics for 
opportunistic infections.

Consider renal biopsy.

1.0-2.0 mg/kg/day prednisone or 
equivalent.

If returns to Grade 1, taper 
steroids over at least 
1 month, and resume 
avelumab therapy following 
steroids taper.

If worsens, treat as Grade 4.
Grade 4
Creatinine increased >6 x ULN.

Permanently discontinue avelumab 
therapy.

Monitor creatinine daily.

1.0 to 2.0 mg/kg/day prednisone or
equivalent. 

Add prophylactic antibiotics for 
opportunistic infections.

Consider renal biopsy.

Nephrology consultation.

If returns to Grade 1, taper 
steroids over at least 
1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management

New onset of cardiac 
signs or symptoms.

and / or new laboratory 
cardiac biomarker 
elevations (eg, troponin, 
CK-MB, BNP).

or cardiac imaging 
abnormalities suggestive 
of myocarditis. 

Withhold avelumab therapy.

Hospitalize.

In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and arrhythmia 
management.

Cardiology consult to establish 
etiology and rule-out 
immune-mediated myocarditis. 

Guideline based supportive treatment 
as per cardiology consult.*

Consider myocardial biopsy if 
recommended per cardiology consult.

If symptoms improve and 
immune-mediated etiology 
is ruled out, re-start 
avelumab therapy.

If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, 
and immune-mediated 
etiology is suspected or 
confirmed following 
cardiology consult, 
manage as 
immune-mediated 
myocarditis.
Immune-mediated 
myocarditis

Permanently discontinue avelumab.

Guideline based supportive treatment 
as appropriate as per cardiology 
consult.*

1.0-2.0 mg/kg/day prednisone or 

Once improving, taper 
steroids over at least 
1 month.

If no improvement or 
worsening, consider 


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Table 7.
Management of Immune-Related Adverse Events
equivalent.

Add prophylactic antibiotics for 
opportunistic infections.
additional 
immunosuppressants 
(eg, azathioprine, 
cyclosporine A).
*Local guidelines, or eg, ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001.
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus)

Continue avelumab therapy.

Endocrinology consult if needed.

Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 

Rule-out secondary endocrinopathies 
(ie, hypopituitarism/hypophysitis).

Continue hormone 
replacement/suppression 
and monitoring of 
endocrine function as 
appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I 
diabetes mellitus)

Withhold avelumab therapy.

Consider hospitalization.

Endocrinology consult.

Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as appropriate. 

Rule-out secondary endocrinopathies 
(ie, hypopituitarism/hypophysitis).

Resume avelumab once 
symptoms and/or 
laboratory tests improve 
to Grade 1 (with or 
without hormone 
replacement/suppression).

Continue hormone 
replacement/suppression 
and monitoring of 
endocrine function as 
appropriate.
Hypopituitarism
Hypophysitis 
(secondary 
endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (ie, subnormal 
serum FT4 with inappropriately low TSH 
and/or low serum cortisol with 
inappropriately low ACTH):

Refer to endocrinologist for dynamic 
testing as indicated and measurement 
of other hormones (FSH, LH, 
GH/IGF-1, PRL, testosterone in men, 
estrogens in women). 

Hormone replacement/suppressive 
therapy as appropriate. 

Perform pituitary MRI and visual field 
examination as indicated.
If hypophysitis confirmed:

Continue avelumab if mild symptoms 
with normal MRI.  Repeat the MRI in 

Resume avelumab once 
symptoms and hormone 
tests improve to Grade 1 
(with or without hormone 
replacement).

In addition, for 
hypophysitis with 
abnormal MRI, resume 
avelumab only once 
shrinkage of the pituitary 
gland on MRI/CT scan is 
documented. 

Continue hormone 
replacement/suppression 
therapy as appropriate.


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1 month.

Withhold avelumab if moderate, severe 
or life-threatening symptoms of 
hypophysitis and/or abnormal MRI. 

Consider hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed by 
corticosteroids taper during at least 
1 month.

Add prophylactic antibiotics for 
opportunistic infections.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 2 or Grade 3 
clinical signs or symptoms 
suggestive of a potential 
irAE

Withhold avelumab therapy pending 
clinical investigation.

If irAE is ruled out, 
manage as appropriate 
according to the diagnosis 
and consider re-starting 
avelumab therapy.

If irAE is confirmed, treat 
as Grade 2 or 3 irAE.
Grade 2 irAE or first 
occurrence of Grade 3 
irAE

Withhold avelumab therapy.

1.0-2.0 mg/kg/day prednisone or 
equivalent. 

Add prophylactic antibiotics for 
opportunistic infections. 

Specialty consult as appropriate.

If improves to Grade 1, 
taper steroids over at least 
1 month and resume 
avelumab therapy 
following steroids taper.
Recurrence of same 
Grade 3 irAEs

Permanently discontinue avelumab 
therapy.

1.0-2.0 mg/kg/day prednisone or 
equivalent.

Add prophylactic antibiotics for 
opportunistic infections. 

Specialty consult as appropriate.

If improves to Grade 1, 
taper steroids over at least 
1 month.
Grade 4 

Permanently discontinue avelumab 
therapy.

1.0-2.0 mg/kg/day prednisone or 
equivalent and/or other 
immunosuppressant as needed.

Add prophylactic antibiotics for 
opportunistic infections. 

Specialty consult.

If improves to Grade 1, 
taper steroids over at least 
1 month.
Requirement for 10 mg 
per day or greater 
prednisone or equivalent 
for more than 12 weeks 
for reasons other than 
hormonal replacement for 
adrenal insufficiency.
Persistent Grade 2 or 3 
irAE lasting 12 weeks or 

Permanently discontinue avelumab 
therapy.

Specialty consult.


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Table 7.
Management of Immune-Related Adverse Events
longer.
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB; CT= computed 
tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; 
irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; 
NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events; 
PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.
5.6.6. Guidelines for Toxicity Management Bevacizumab
Dose modification (dose delays and omissions) for bevacizumab due to ADRs should be 
made in accordance with the guidance provided in Table 8, product labeling and/or 
institutional guidelines.
Table 8.
Bevacizumab Treatment Modifications for Drug-Related Toxicity
Permanently discontinue bevacizumab for:
Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the gastrointestinal tract, intra-abdominal 
abscess), fistula formation involving an internal organ.
Wound dehiscence and wound healing complications requiring medical intervention.
Serious hemorrhage (ie, requiring medical intervention).
Severe arterial thromboembolic events.
Life-threatening (Grade 4) venous thromboembolic events, including pulmonary embolism.
Hypertensive crisis or hypertensive encephalopathy.
Posterior Reversible Encephalopathy Syndrome (PRES).
Nephrotic syndrome.
Temporarily suspend bevacizumab for:
At least 4 weeks prior to elective surgery.
Severe hypertension not controlled with medical management.
Moderate to severe proteinuria.
Severe infusion reaction.
5.6.7. Guidelines for Toxicity Management Chemotherapy
Dose modification (dose delays and dose change) for carboplatin/paclitaxel due to ADRs 
should be made in accordance with the product labeling and institutional guidelines or with 
the guidance provided in the sections below.  There will be no substitutions for paclitaxel or 
carboplatin in the management of any toxicities.  Starting doses for carboplatin and paclitaxel 
and dose reduction levels are described in Table 10.
5.6.7.1. General Guidelines for Hematologic Toxicity
Treatment decisions will be based on the absolute neutrophil count (ANC) rather than the 
total white blood cell (WBC) count. 
Day 1 of each cycle of cytotoxic chemotherapy will not be administered until the ANC is 
1,000 cells/L and the platelet count is 75,000/L.  All treatment (including avelumab on 
Arm A) will be delayed until these levels are achieved.  Chemotherapy can be delayed for a 
maximum of 3 weeks.  Patients who fail to recover adequate ANC despite a 3 week delay 
will no longer receive chemotherapy. 


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5.6.7.2. Modifications for Hematologic Toxicities
There will be no paclitaxel dose reductions based on hematologic toxicity. 
Initial occurrence of dose limiting neutropenia or dose limiting thrombocytopenia will be 
managed according to Table 9.

Dose limiting neutropenia (DLT-ANC) is defined by the occurrence of febrile 
neutropenia (as defined within the CTCAE), prolonged Grade 4 neutropenia 
persisting 7 days, delay of treatment for more than 7 days because of neutropenia, or
ANC <1000 cells/l on Day 1.

Dose limiting thrombocytopenia (DLT-PLT) is defined by any occurrence of Grade 4 
thrombocytopenia (<25,000/l) or bleeding associated with Grade 3 
thrombocytopenia (25,000 to <50,000/l), delay of treatment on Day 1 of a cycle by 
more than 7 days because of thrombocytopenia, or platelet count of <75,000/l on 
Day 1.  There will be no modifications for uncomplicated Grade 3 thrombocytopenia.
Table 9.
Modification Guidance for Hematologic Toxicity
DLT-ANC
DLT-PLT
First Occurrence
Second 
Occurrence
Third Occurrence
Yes
No
Reduce carboplatin 
one AUC unit
Add G CSF and 
maintain all current 
drug doses
Discontinue 
chemotherapy
Yes
Yes
Reduce carboplatin 
one AUC unit
Add G CSF and 
maintain all current 
drug doses
Discontinue 
chemotherapy
No
Yes
Reduce carboplatin 
one AUC unit
Reduce carboplatin 
one AUC unit
Discontinue 
chemotherapy
5.6.7.3. Dose Modifications and Delays of Chemotherapy: Other Non Hematologic 
Toxicities and Laboratory Abnormalities
5.6.7.3.1. Renal Toxicity
The combination of carboplatin and paclitaxel with avelumab is not directly expected to 
cause renal toxicity.  There are, therefore, no specific dose modifications for renal toxicity. 
The administered dose of carboplatin must however be recalculated each cycle in any patient 
who develops renal insufficiency defined by serum creatinine greater than 1.5 times the 
ULN.
5.6.7.3.2. Hepatic Toxicity
Hepatic toxicity is not expected as a direct complication of chemotherapy; however, in the 
event of Grade 3 (or greater) elevation in AST, ALT, alkaline phosphatase, or total bilirubin, 
paclitaxel should be reduced by 1 dose level and chemotherapy should be delayed until 
recovered to Grade 1.  For patients receiving chemotherapy in combination with avelumab, 
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in Section 5.6.5 and Table 7 for avelumab irAEs.  In cases where use of corticosteroids or 
other immunosuppressants is required per guidance for management of avelumab irAEs, 
chemotherapy may also be placed on hold until the irAE resolves to Grade 1 based on 
investigator’s medical judgment and after discussion with the Sponsor.
5.6.7.3.3. Neuropathy
Grade 2 sensory or motor neuropathy requires paclitaxel treatment to be interrupted until 
neuropathy has resolved to a maximum of Grade 1.  Upon recovery, paclitaxel should be 
reduced by 1 dose level.  If this requires a delay of more than 3 weeks, then paclitaxel should 
be omitted from subsequent cycles and treatment continued with single agent carboplatin at 
the same AUC used in combination with paclitaxel.
Grade 3 sensory or motor neuropathy requires paclitaxel to be omitted from subsequent 
cycles, and treatment continued with single agent carboplatin at the same dose as previously 
used.
5.6.7.3.4. Mucositis
For Grade 3 mucositis, chemotherapy should be delayed until the mucositis has resolved to 
Grade 1.  Paclitaxel may be reduced by one dose level in subsequent cycles based on 
investigator’s medical judgment.
5.6.7.3.5. Hypersensitivity to Paclitaxel
A hypersensitivity reaction to paclitaxel is not a dose limiting toxicity.  The acute 
management should occur as per local practice, however, there will be no substitutions 
allowed.
If a hypersensitivity reaction occurs, then patients may be retreated with paclitaxel at full 
dose according to local protocols.  This is likely to include increased prophylactic 
medications and/or a slowing of the initial infusion rate with a gradual increase in rate in the 
absence of further hypersensitivity reactions.
Emergency resuscitation equipment and personnel should be available during the period of re 
challenge.
If the re challenge occurs within 72 hours of the original intended dose and a negligible 
quantity, ie, 50 mL, of the original dose was administered, then re administer the full dose.  
If a substantial proportion has been given then the balance of the full original dose should be 
administered.
If the re challenge is being considered more than 72 hours after the original intended dose 
then a full blood count should be taken to check suitability.
In the case of recurrent hypersensitivity reactions, despite adequate premedication, paclitaxel 
may be discontinued at the discretion of the treating physician, and the patient may continue 
on treatment with single agent carboplatin avelumab.


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5.6.7.3.6. Hypersensitivity to Carboplatin
If there is a hypersensitivity reaction to carboplatin, then this should be managed as per local 
institutional protocols, however, there will be no substitutions allowed.
In the case of recurrent hypersensitivity reactions, despite adequate premedication, 
carboplatin may be discontinued at the discretion of the treating physician, and the patient 
may continue on treatment with single agent paclitaxel avelumab.
5.6.7.3.7. Other Toxicities of Chemotherapy
There are no dose modifications planned for alopecia, nausea, diarrhea, or constipation.  
These side effects should be treated with supportive medical therapy.  Non-steroidal 
anti-inflammatory agents may be used prophylactically, or symptomatically, as per local 
practice for the treatment of paclitaxel induced arthromyalgia.
For any other adverse event of NCI CTCAE v4.03 Grade 4 severity considered at least 
possibly related to chemotherapy treatment, the patient should be discontinued from 
chemotherapy treatment.
For any other adverse event of NCI CTCAE v4.03 Grade 3 severity considered at least 
possibly related to chemotherapy treatment, treatment should be withheld until recovery to 
Grade 1 and subsequent treatment should be reduced by one dose level (see Table 10).
5.6.8. Dose Modifications for Chemotherapy Combinations
In the event of significant toxicity, dosing may be delayed and/or dose reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify Investigators at the first occurrence 
of any adverse symptom.  In addition to dose modifications, investigators are encouraged to 
employ best supportive care according to local institutional clinical practices and according 
to the guidance for selected adverse events provided below.
Table 10.
Dose Modification Levels for Paclitaxel and Carboplatin
Drug
Starting Dose 
Dose Level 1
Dose Level 2
Paclitaxel Q3W
175 mg/m2
135 mg/m2
110 mg/m2
Carboplatin
AUC 6
AUC 5
AUC 4
Carboplatin
AUC 5
AUC 4
AUC 3
In order to maintain the dose intensity and cumulative dose delivery of carboplatin and 
paclitaxel chemotherapy, reasonable efforts should be made to minimize dose reduction and 
treatment delays.  Patients whose treatment is delayed because of adverse events should be 
evaluated at weekly intervals (or less) until adequate recovery has occurred.  Intrapatient 
dose escalations are not permitted (including dose re-escalation after a dose reduction).
Dose levels should be adjusted independently for each drug.  Patients who do not tolerate two 
carboplatin and/or paclitaxel dose reductions should discontinue treatment with trial 
chemotherapy.


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5.6.8.1. Dose Modifications for Avelumab in Combination with Chemotherapy (Arm A)
For avelumab, no dose reductions are permitted in this study, but doses may be omitted based 
on persisting toxicity.
For patients on Arm A (avelumab in combination with chemotherapy), chemotherapy dose 
modifications as well as infusion omissions/delays for chemotherapy and/or avelumab may 
occur independently according to the guidance provided below and investigator’s medical 
judgment and will be reported in the CRF.
Toxicities of the carboplatin-paclitaxel combination and avelumab are generally 
non- overlapping.  For patients receiving avelumab in combination with chemotherapy, any 
adverse event suspected to be immune related should be managed according to the guidance 
for management of irAEs (see Table 7).  For Grade 3 potentially immune related toxicities 
or where use of corticosteroids or other immunosuppressant is required per guidance for 
management of avelumab irAEs, chemotherapy may also be placed on hold until the irAE 
resolves to Grade 1 based on investigator’s medical judgment and after discussion with the 
Sponsor. 
Refer to Table 11 for guidance on management of toxicities in the combination treatment arm 
(Arm A) during the chemotherapy period. 
For any other adverse event not covered in Table 11 below, see Section 5.6 for relevant 
avelumab toxicity management guidelines and refer to local product label and standard 
institutional guidelines or guidance provided in the protocol for chemotherapy toxicity 
management (Section 5.6.7). 
Table 11.
Avelumab in Combination With Chemotherapy (Arm A) Toxicity 
Management
Toxicity
Treatment Modification for 
Chemotherapy
Treatment Modification for 
Avelumab
Hematologic toxicity
See Section 5.6.7.2.
Delay until ANC is 
1,000 cells/L and the platelet 
count is 75,000/L.  
Adverse events with potential 
immune-related etiology (see 
Section 5.6.5) such as 
Colitis/diarrhea, Hepatic/Liver 
test abnormalities, Rash, 
Pneumonitis, Endocrinopathy, 
Nephritis/Renal dysfunction.
Continue chemotherapy for 
G1/G2 events.
Chemotherapy may be placed on 
hold for events Grade 3 or 
events requiring 
corticosteroids/immunosuppressa
nt, until the event resolves to 
Grade 1 based on investigator’s 
medical judgment and after 
discussion with the Sponsor.
See Section 5.6.5 and Table 7.


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Table 11.
Avelumab in Combination With Chemotherapy (Arm A) Toxicity 
Management
Toxicity
Treatment Modification for 
Chemotherapy
Treatment Modification for 
Avelumab
Neuropathy (sensory or motor)
Grade 2: Delay paclitaxel until 
event resolves to Grade 1 and 
then resume paclitaxel at 
1 reduced dose level.  If required 
delay >3 weeks, paclitaxel should 
be permanently discontinued and 
treatment continued with single 
agent carboplatin. 
Grade 3: Permanently 
discontinue paclitaxel and 
treatment continued with single 
agent carboplatin (see 
Section 5.6.7.3.3).
Continue avelumab therapy for 
G1/G2 events.
Avelumab may be placed on hold 
for events Grade 3, until the 
event resolves to Grade 1 based 
on investigator’s medical 
judgment and after discussion 
with the Sponsor.
Mucositis
Grade 3: Delay chemotherapy 
until event resolves to Grade 1. 
Paclitaxel may be reduced by one 
dose level in subsequent cycles 
based on investigator’s medical 
judgment.
See Section 5.6.7.3.4.
Continue avelumab therapy for 
G1/G2 events.
Avelumab may be placed on hold 
for events Grade 3, until the 
event resolves to Grade 1 based 
on investigator’s medical 
judgment and after discussion 
with the Sponsor.
Hypersensitivity
Managed according to the local 
guidelines.
In case of Grade 3 
hypersensitivity reaction to 
paclitaxel or carboplatin, 
avelumab treatment should be 
postponed until symptoms 
resolve.  If symptoms do not 
resolve within 72 hours, avelumab 
dose should be skipped.
See Section 5.6.7.3.5 and
Section 5.6.7.3.6.
See Section 5.6.2 and Table 7.
5.6.8.2. Dose Modifications for Bevacizumab in Combination with Chemotherapy 
(Arm C)
For Bevacizumab, no dose reductions are permitted in this study, but doses may be delayed 
or omitted based on persisting toxicity, as described for bevacizumab in Section 5.6.6 and for 
chemotherapy management in Section 5.6.7.


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In the event of significant toxicity during the chemotherapy induction period, all treatment 
will be delayed (including Bevacizumab) until recovery.  If dose modifications are required 
for patients to continue therapy, only the chemotherapy will be reduced as described in 
Section 5.6.8.  Patients who fail to recover within reasonable time (3 weeks) or despite two 
carboplatin and/or paclitaxel dose reductions will no longer receive protocol directed 
chemotherapy but bevacizumab can be continued, provided absence of any contraindication.
5.7. Treatment after Initial Evidence of Radiological Disease Progression (Only for 
Patients on Arm A in Maintenance Period)
Immunotherapeutic agents such as avelumab may produce antitumor effects by potentiating 
cancer-specific immune responses.  Following immunotherapy, a clinical response may occur 
later than would typically be expected following treatment with a cytotoxic agent.  In 
addition, this response may occur after an initial increase in tumor burden or even after the 
appearance of new lesions. 
If radiologic imaging shows disease progression, and if in Investigator’s clinical judgement 
the patient is still experiencing clinical benefit, the patient may be eligible for continued 
treatment with avelumab if the following criteria are met:  

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression; 

No decline in ECOG performance status; 

Absence of rapid progression of disease by radiographic imaging; 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.
Before continuation of treatment after PD, the patient must be re-consented via informed 
consent addendum and informed that, by continuing to receive the investigational products 
on study, the patient may be foregoing approved therapy with possible clinical benefit(s). 
If repeat imaging does not confirm PD, treatment with avelumab and talazoparib may be 
continued. 
If the repeat imaging confirms PD, patients should be considered for discontinuation from all 
investigational products.  However, according to the Investigator’s clinical judgment and 
after discussion between the Investigator and the Sponsor, if a patient with evidence of PD is 
still experiencing clinical benefit, the patient may be eligible for continued treatment with 
avelumab.  The Investigator’s judgment should be based on the overall benefit risk 
assessment and the patient’s clinical condition, including performance status, clinical 
symptoms, adverse events, and laboratory data. 


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Effective with IRB/EC approval of amendment 2, if the patient is subsequently found to have 
further disease progression as assessed by investigator, then treatment with all investigational 
products should be permanently discontinued.
5.8. Investigational Product Storage 
The investigator or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparator and/or marketed products, are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.  See the IP manual for storage conditions of the products.
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated, and/or room-temperature products).  This should 
be captured from the time of investigational product receipt throughout the study.  Even for 
continuous-monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. Specific details regarding information the site should report 
for each excursion will be provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the products are briefly out of the temperature range described in the labeling are not 
considered excursions.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products. 


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5.9. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.
Pfizer may supply drug accountability forms that must be used or may approve use of 
standard institution forms.  In either case, the forms must identify the investigational product, 
including batch or code numbers, and account for its disposition on a patient by patient basis, 
including specific dates and quantities. 
The prescribed dose must be recorded in the patient’s medical records.  Drug dispensing 
needs to be verified and documented by a second individual and the forms must be signed by 
both the individual who dispensed the drug and the second individual who verified the 
dispensing.  Copies must be provided to Pfizer. 
At the end of the trial, or at appropriate points during the trial, Pfizer will provide instructions 
as to disposition of any unused investigational product.  If Pfizer authorizes destruction at the 
trial site, the Investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.  Destruction must be adequately documented.  If drug destruction is not 
permitted locally, Pfizer should be contacted for further directions.
All unused talazoparib must be returned to the Investigator or designated investigative site 
personnel by each patient on Day 1 of every cycle and at the end of the trial in order to 
perform and document drug accountability.
5.9.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.10. Concomitant Treatment(s)
Medications or vaccinations specifically prohibited in the exclusion criteria are also not 
allowed during the active treatment period, except for administration of inactivated vaccines. 
For corticosteroids use see Section 5.10.5.
If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy or 
medication/vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician.  
Concomitant treatment considered necessary for the patient’s well-being may be given at the 
discretion of the treating physician.


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Effective with IRB/EC approval of protocol amendment 2, concomitant medications and 
treatments will not be captured in the INFORM database unless these medications contribute 
or are associated with the treatment for an AE/SAE.  However, this information should be 
recorded in the patient’s source documents.  
Concurrent anti-cancer therapy with agents other than study treatments is not allowed.  
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
Recommended medications to treat infusion related reactions, and hypersensitivity reactions, 
and immune related events are reported in Section 5.6.4, and Section 5.6.5, respectively.
5.10.1. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease  is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain, the sites of bone disease should be present at baseline; otherwise, bone 
pain requiring radiotherapy will be considered as a sign of disease progression. 
Study treatment should be withheld for the entire duration of palliative radiotherapy and can 
be restarted upon recovery from any radiotherapy-related toxicities, but no sooner than 
48 hours after radiotherapy completion.  Effective with IRB/EC approval of Amendment 2,
concomitant radiotherapy data will not be captured in the INFORM database.  This 
information should be recorded in the patient’s source documents.  
5.10.2. Concomitant Surgery
Effective with IRB/EC approval of Amendment 2, concomitant surgey data will not be 
captured in the INFORM database.  This information should be recorded in the patient’s
source documents.  
5.10.2.1. Interval Debulking Surgery
Effective with IRB/EC approval of Amendment 2, interval debulking surgery may be 
performed according to local guidelines or standard of care at the discretion of the 
investigator.  This information should be recorded in the patient’s source documents.  
Patients who are enrolled prior to initiation of neoadjuvant therapy will complete 3 cycles of 
chemotherapy, treatment will be held, and patients will proceed to have interval debulking 
surgery.  Upon recovery from surgery, the remaining duration of chemotherapy should be 
administered according to local institutional practice. 
For neoadjuvant patients in Arm C, bevacizumab treatment will not be administered with 
chemotherapy on cycles before (Cycle 3) and after (Cycle 4) IDS due to concerns about its
impact on potential wound healing complications.
Patients who cannot undergo planned interval debulking surgery at all are allowed to 
continue treatment per protocol provided no disease progression.


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5.10.2.2. Other Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  
There is no evidence suggesting that treatment with avelumab increases surgical risk. 
The appropriate interval of time between surgery and administration of investigational 
products required to minimize the risk of impaired wound healing and bleeding has not been 
determined.  In case of a surgical procedure, investigational products should be delayed.  
Postoperatively, the decision to reinitiate investigational products should be discussed with 
the Sponsor.
5.10.3. Hematopoietic Growth Factors
It is anticipated that myelosuppression may be a significant side effect of chemotherapy.  
These factors may be used at any time to treat emergent neutropenia as indicated by the 
current American Society of Clinical Oncology (ASCO) guidelines61 or as allowed per local 
guidance.  Patients may receive erythropoietin (EPO), iron supplements, and/or transfusions 
as clinically indicated for management of anemia. 
5.10.4. Bisphosphonates or Denosumab 
Bisphosphonate or denosumab treatment is allowed and it will be given as per local practice.  
The need to initiate treatment with bisphosphonate or denosumab or to increase the dose of 
these therapies while on study treatment (for patients who started bisphosphonate or 
denosumab therapy >2 weeks before study enrollment), may be considered as a symptom of 
disease progression that should be confirmed radiologically.
5.10.5. Corticosteroids
Data indicate that corticosteroids have an adverse effect on T-cell function and that they 
inhibit and damage lymphocytes.62,63  Furthermore, as with all immunotherapies intended to 
augment cell-mediated immunity, there is a risk that concomitant immunosuppressives, such 
as steroids, will counteract the intended benefit of avelumab.  However, studies with 
anti-CTLA-4 compounds indicate that short-term use of steroids can be employed without 
compromising clinical outcomes.64  Therapeutic and/or prophylactic corticosteroids may be 
used as needed per standard of care.  
5.10.6. Other Prohibited Concomitant Medicines and Therapies
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Any anti-cancer systemic chemotherapy or biological therapy, including vitamins that 
are used as anti-cancer treatments, other than avelumab and talazoparib.

Immunotherapy not specified in this protocol. 

Investigational agents other than avelumab, talazoparib, and bevacizumab where 
considered investigational. 


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
Radiation therapy (with the exception noted above in the Concomitant Radiotherapy 
Section 5.10.1).

Other experimental pharmaceutical products.

Any vaccine therapies for the prevention of infectious disease (eg, human papilloma 
virus vaccine) except for inactivated vaccines (eg, influenza vaccine).

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or those 
known to potentially interfere with major organ function (eg, hypericin).

The following strong P-gp inhibitors that result in 2-fold increase in the exposure of 
in vivo probe P-gp substrates according to the University of Washington Drug-Drug 
Interaction database89 are prohibited while on talazoparib treatment: amiodarone, 
carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, 
indinavir, itraconazole, ketoconazole,  lapatinib, lopinavir, propafenone, quinidine, 
ranolazine, ritonavir, saquinvir, telaprevir, tipranavir, valspodar, and verapamil.

P-gp inducers including, but not limited to avasimibe, carbamazepine, phenytoin, 
rifampin, and St. John’s Wort are prohibited while on talazoparib treatment.

BCRP inhibitors including, but not limited to curcumin, cyclosporine, elacridar 
[GF120918], and eltrombopag are prohibited while on talazoparib treatment.
There are no prohibited therapies during the 90-day Follow-Up period. 
5.10.7. Cautionary Use of Concomitant Medicines While on Treatment with 
Talazoparib
Caution and monitoring for potential increased adverse reactions should be used upon 
concomitant use of the following transporter inhibitors with talazoparib: atorvastatin, 
azithromycin, conivaptan, diltiazem, diosmin, eliglustat, felodipine, flibanserin, fluvoxamine, 
piperine, quercetin, and schisandra chinensis extract.
5.11. Rescue Medication and Supportive Care
5.11.1. Supportive Care Guidelines
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.


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
Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice, assuming there is no expected drug-drug interaction with study 
treatments (see Section 5.10.6 and Section 5.10.7).  Prophylactic administration 
should be considered for the cases outlined in Table 7.

Anti-inflammatory or narcotic analgesics may be offered as needed. 

Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed.
6. STUDY PROCEDURES
All patients must sign an informed consent prior to any study specific procedures.
6.1. Screening (Obsolete)
Enrollment was stopped, and patients can no longer be screened as of 19 March 2019. Please 
refer to the new SOA in Appendix 6. 
To allow for additional flexibility in scheduling patient visit and procedures, Screening and 
Cycle 1 Day 1 procedures (except for tumor scans) may be completed on the same day for all 
treatment arms.  However, screening assessments for eligibility MUST have already been 
completed before the patient is randomized.  No re-screening will be permitted in this study.
Following informed consent, patients who are screened for treatment, and who do not have 
an existing test result for gBRCA1/2 defect status must provide a 10 mL of blood sample for 
testing during screening to enable stratification of randomization based on germline 
BRCA1/2 mutational status.  For patients with an existing test result for germline 
BRCA1/2 defect status, test result must have been obtained using a CLIA (or comparable 
local validation) approved assay.
Once completion of screening assessments and eligibility is confirmed, patients will 
subsequently be randomized to 1 of the 3 treatment arms for the study.  Treatment must start 
within 3 days after randomization. 


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Patients will be asked about any baseline signs and symptoms experienced within the 28 days 
prior to randomization and any findings will be recorded on the Medical History CRF page.  
After randomization, any new or worsening conditions since baseline should be reported on 
the AE CRF. 
6.2. Treatment Period
The study period includes two treatment periods, the chemotherapy period and the 
maintenance period.  For the purpose of scheduling evaluations, providing clarity on 
assessments, and consistent on-treatment assessments across all three treatment arms, the 
definition of cycle length varies between the chemotherapy period and the maintenance 
period.  In the chemotherapy period, a cycle is defined as 3 weeks (21 days), and due to the 
biweekly schedule of avelumab and the Q3W schedule for bevacizumab, a cycle in the 
maintenance period is defined as 6 weeks (42 days).
To allow for patient and investigator schedules, holidays, and weather or other emergencies 
requiring clinical facilities to be closed, all patient visits can be performed 3 days of 
scheduled visits on all cycles, as feasible.  For treatment period procedures, please refer to 
the new SOA in Appendix 6.
During the chemotherapy period, patients on all arms will continue with the chemotherapy 
treatment for up to 6 cycles until objective progression of disease based on investigator 
assessment that the patient is no longer receiving clinical benefit, unacceptable toxicity, 
consent withdrawal, or death whichever comes first. 
Prior to treatment with talazoparib in the maintenance period, patients must be evaluated for 
adequate renal function, and those with moderate renal impairment (30-59 mL/min) will 
receive a reduced starting dose of 0.50 mg for talazoparib (see Section 5.5).
During the maintenance period of the study, patients receiving talazoparib with or without 
avelumab (Arms A or B) will continue treatment until progression of disease based on 
investigator assessment that the patient is no longer receiving clinical benefit, unacceptable 
toxicity, consent withdrawal, a maximum duration of 24 months (not including 
chemotherapy period), or death, whichever comes first.  Patients receiving bevacizumab 
(Arm C), will continue maintenance treatment until progression of disease based on 
investigator assessment that the patient is no longer receiving clinical benefit, unacceptable 
toxicity, consent withdrawal, a maximum duration of 21 or 22 doses, per local approval 
(including chemotherapy period), or death, whichever comes first. 
For patients randomized to Arms A or B, the daily dose of talazoparib should not be taken 
prior to the study visit and will be taken at the clinic after all procedures/assessments have 
been completed and, for patients randomized to Arm A, before the infusion of avelumab.


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6.3. End of Treatment 
For End of Treatment procedures, see the Appendix 6 tables and ASSESSMENTS sections.
Patients will receive study treatment until progressive disease based on investigator 
assessment, unacceptable toxicity, a determination that the patient is no longer receiving 
clinical benefit, withdrawal of consent, or death whichever comes first.  Patients continuing 
to experience treatment related toxicity following discontinuation of study treatment will 
continue to be followed at least every 4 weeks until resolution or determination, in the 
clinical judgment of the investigator, that no further improvement is expected.
6.4. Patient Withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Reasons for withdrawal from the study treatment may include:

Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to 
continue study treatment, provided that the treating physician has determined that the 
benefit/risk for doing so is favorable (see Section 5.7 for details and exceptions); 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to 1 of the 
investigational products, the Investigator may continue treatment with the other 
investigational product(s); 

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Refused further follow-up;

Study terminated by Sponsor;

Death.
Reasons for withdrawal from the study may include:

Study terminated by Sponsor;

Lost to follow-up;


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
Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request that the patient return all unused talazoparib, request 
that the patient return for a final visit, if applicable, and follow up with the patient regarding 
any unresolved AEs.
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.  See additional details in Section 6.4.1 below. 
6.4.1. Withdrawal of Consent
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
her or persons previously authorized by the patient to provide this information.  Patients 
should notify the investigator in writing of the decision to withdraw consent from future 
follow-up, whenever possible.  The withdrawal of consent should be explained in detail in 
the medical records by the investigator, as to whether the withdrawal is only from further 
receipt of investigational product (in which case the withdrawal of consent form is not 
applicable) or also from study procedures and/or posttreatment study follow-up (in which 
case a withdrawal of consent form should be provided and signed).  In the event that vital 
status (whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
6.4.2. Lost to Follow-Up
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the patient as noted above.  Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter.  The site staff and representative will consult publicly available sources, such as public 
health registries and databases, in order to obtain updated contact information.  If, after all 
attempts, the patient remains lost to follow-up, then the last-known-alive date as determined 
by the investigator should be reported and documented in the patient’s medical records.


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6.5. Short-Term Follow-Up
For follow-up procedures see the updated SOA in Appendix 6.
In short-term follow-up, patients should be evaluated for safety through 90 days (at 30 days, 
60 days, and 90 days) after last dose of investigational product(s).
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety Assessments
Effective with IRB/EC approval of Amendment 2, safety assessments will include collection 
of AEs, SAEs, vital signs, laboratory assessments, including pregnancy tests, and verification 
of concomitant treatments. Physical examination and electrocardiogram (ECG) are not 
required per protocol but may be performed as clinically necessary.  
Please see Appendix 6 for the updated SOA for safety requirements.  
7.1.1. Pregnancy Testing
For patients of childbearing potential, a serum or urine pregnancy test, with a sensitivity of at 
least 25 mIU/mL and assayed in a certified laboratory, will be performed on 2 occasions 
prior to starting study treatment, once at the start of screening and once at the baseline visit, 
immediately before study treatment administration.  Following a negative pregnancy test 
result at screening, appropriate contraception must be commenced and another negative 
pregnancy result will then be required at the baseline visit before the patient may receive the 
study treatment.  Pregnancy tests will also be routinely repeated at Day 1 of each 
chemotherapy cycles, Day 1 and Day 29 (Arms A and B) and Day 1 and Day 22 (Arm C) of 
maintence treatment, and at the end of study treatment, and additionally whenever 
1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional 
pregnancy tests may also be undertaken if requested by institutional review boards 
(IRBs)/ethics committees (ECs) or if required by local regulations.  In the case of a positive 
confirmed pregnancy, the patient will be withdrawn from administration of investigational 
product but may remain in the study.  See also Appendix 6 tables for each arm.


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7.1.2. Contraception Check
The Investigator or his or her desigee will discuss and confirm that any fertile female patients 
who are of childbearing potential, who are, in the opinion of the Investigator, sexually active 
and at risk for pregnancy with their partner(s), will need to affirm that they meet the criteria 
for correct use of 2 of the selected methods of contraception (See Section 4.3).  The 
Investigator or his or her designee will discuss with the patient the need to use 2 methods of 
contraception (at least one of which is considered to be highly effective with low user 
dependency) consistently and correctly throughout the study and document such conversation 
in the patient’s chart.  In addition, the Investigator or his or her designee will instruct the 
patient to call immediately if one or both selected contraception methods are discontinued, or 
if pregnancy is known or suspected in the patient.  Patients who are, in the opinion of the 
Investigator, sexually active and at risk for pregnancy with their partner(s) must agree to use 
2 methods of contraception (at least one of which is considered to be highly effective with 
low user dependency) throughout the study or for at least 30 days after the last dose of 
avelumab, 7 months after the last dose of talazoparib, and for 6 months after the last dose of 
bevacizumab, whichever is longer.  See also Appendix 6 tables for each arm.
7.1.3. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE 
v4.03), timing, seriousness, and relatedness.
Patients will be monitored closely for toxicity.  Any AE that is suspected to be a potential 
irAE is considered an AE of special interest (AESI).  Specific guidance for the management 
of irAEs is provided in Table 7 Avelumab Management of Immune Related Adverse Events.  
AESIs are reported according to the general AE reporting rules specified in Section 8.1.
7.1.4. Laboratory Safety Assessments
Effective with IRB/EC approval of Amendment 2, samples for all laboratory assessments 
will be drawn at the time points indicated in the updated SOA Appendix 6 for details on 
sample timings for each arm and when clinically indicated and do not need to be recorded in 
the INFORM database, unless the findings support an AE/SAE.  Repeat samples do not have 
to be drawn on Cycle 1 Day 1 if these samples were drawn in the prior 3 days.  Laboratory 
tests may be performed up to 3 days prior to the scheduled clinic visit.  Results from 
pregnancy tests, if taken, must be available for review prior to dosing.  Samples will be 
analysed at local laboratories. 
Hematology and blood chemistry must be drawn prior to the administration of study 
treatment dose at the time points described in the SOA Appendix 6 table for each arm and 
analyzed at local laboratories.  Hemoglobin, platelets, absolute neutrophil count, creatinine, 
AST and ALT results must be reviewed by the treating physician prior to infusion of 
chemotherapy and/or avelumab.  They may also be performed when clinically indicated.  The 
required laboratory tests are listed in Table 12. 


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Table 12.
Required Safety Laboratory Tests
Hematology
Chemistry Panel
Hemoglobin
ALT
Platelets
AST
WBC
Alkaline Phosphatase
Absolute Neutrophils
Sodium
Potassium
Total Bilirubin
Thyroid Function Tests
BUN or Urea
Free T4
Creatinine
TSH
Uric Acid (for leukemia and lymphomas)
Glucose (non-fasted)
Pregnancy Test
Albumin
For female patients of childbearing potential, serum or 
urine
Phosphorous or Phosphate
Creatine kinase
Gamma glutamyltransferase
Abbreviations: ALT=alanine aminotransferase, AST=aspartate aminotransferase, TSH=thyroid-stimulating 
hormone, WBC=white blood cell 
Effective with IRB/EC approval of Amendment 2, urinalysis is to be conducted for patients 
in Arm C on Day 1 of every treatment cycle, and Day 22 of every maintenance cycle, and 
end of treatment.  If the results of the dipstick urine protein indicate 2+ proteinuria, 
follow-up should be performed with a quantitative urine protein analysis according to local 
standard practices with data captured on the AE CRF if AE criteria are met.
Adequate renal function by estimated creatinine clearance as calculated using the Cockcroft 
Gault method or by 24 hour urine collection for creatinine clearance or according to local 
institutional standard method will be conducted on Day 1 of every treatment cycle.
7.1.5. Vital Signs and Physical Examination
Effective with IRB/EC approval of Amendment 2, vital signs including weight, height, blood 
pressure, temperature, and pulse rate are to be performed per SOA in Appendix 6.  These 
data do not need to be recorded in the INFORM database, unless the findings support an 
AE/SAE.  
Effective with IRB/EC approval of Amendment 2, physical examination and ECOG 
performance status are not required per protocol, but may be performed as clinically 
necessary. These data do not need to be recorded in the INFORM database, unless the 
findings support an AE/SAE.  Clinically significant findings must be reported as AEs.


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7.1.6. Electrocardiogram Assessments
Effective with IRB/EC approval of Amendment 2, ECG assessments are not required per 
protocol but may be performed as clinically necessary.  These data do not need to be 
recorded in the INFORM database, unless the findings support an AE/SAE.
The remainder of this section is obsolete.  
A standard 12 lead (with a 10 second rhythm strip) tracing will be used for all ECG 
assessments.
All patients require a single ECG measurement at screening, prior to the start of treatment 
(Cycle 1 Day 1) and at the end of treatment/withdrawal of the maintenance period.  
Additional on treatment ECGs will be performed as clinically indicated. 
Clinically significant findings seen on subsequent ECGs should be recorded as adverse 
events.  In case of QTc >500 msec, a subsequent ECG should be repeated to verify the result.  
If ECG is confirmed >500 msec, local guidelines (eg, Repeat ECGs, review by cardiologist) 
should be followed.
7.2. Pharmacokinetic Assessments (Obsolete)
Effective with IRB/EC approval of Amendment 2, PK assessments will no longer be 
collected.  
PK sampling schedule may be modified based on emerging PK data.  Blood for PK samples 
will be drawn from the arm contralateral to the drug infusion. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, with the exception of samples where nominal time coincides with end of 
infusion, samples obtained within 10% of the nominal time (eg, within 3 minutes of a 
30 minute sample) will not be captured as a protocol deviation, as long as the exact time of 
the sample collection is noted on the source document and data collection tool (eg, CRF).  
For samples where nominal time coincides with end of infusion, a sample collected within 
10 min post end of infusion will not be captured as a protocol deviation, as long as the exact 
time of the sample collection is noted on the source document and data collection tool 
(eg, CRF).  If the infusion of avelumab is interrupted due to AE, any PK samples scheduled 
during the time the AE is occurring are not required.  If a scheduled blood sample collection 
cannot be completed for any reason, the missed sample time may be re-scheduled with 
agreement of clinical investigators, patient and Sponsor.
PK samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures (SOPs).
Details regarding the collection, processing, storage and shipping of the PK blood samples 
will be provided to the investigator site prior to initiation of the trial.  The samples must be 
processed and shipped as indicated to maintain sample integrity.  Any deviations from the 
processing steps (eg, sample collection and processing steps, interim storage or shipping 


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conditions), including any actions taken, must be documented and reported to the Sponsor.  
On a case by case basis, the Sponsor may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample 
handling procedure resulted in compromised sample integrity, will be considered a protocol 
deviation.
 
 
7.2.1. Blood for PK Analysis of Avelumab (Obsolete)
Effective with IRB/EC approval of Amendment 2, blood samples for PK analysis of 
avelumab will no longer be collected.  
Blood samples (3.5 mL whole blood at each time point) will be collected for PK analysis of 
avelumab into an appropriately labeled serum separator tube (SST), as outlined in the 
Schedule of Activities table for Arm A.  Pre-dose avelumab PK samples will be collected 
within 1 hour prior to taking talazoparib dose and the post-dose avelumab PK samples should 
be taken within 10 minutes after the avelumab infusion ends.  Blood for PK samples will be 
drawn from the contralateral arm of the drug infusion.  Please refer to the Laboratory Manual 
for instructions for specific details on collection tubes, processing and shipping.
7.2.2. Blood for PK Analysis of Talazoparib (Obsolete)
Effective with IRB/EC approval of Amendment 2, blood samples for PK analysis of 
talazoparib will no longer be collected.
Blood samples (3 mL whole blood at each time point) will be collected for PK analysis of 
talazoparib into an appropriately labeled tube as outlined in Schedule of Activities table for 
Arms A and B.  Pre-dose talazoparib PK samples will be collected within 1 hour prior to 
taking talazoparib dose.  Please refer to the Laboratory Manual for instructions for specific 
details on collection tubes, processing and shipping.
 
 
 
 
 
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7.4.
Pharmacodynamic Assessments (Obsolete)
Effective with IRB/EC approval of Amendment 2, 
 and pharmacodynamic 
assessments will no longer be collected.
Given the potential for differential activity of talazoparib and avelumab, as monotherapy and 
in combination, 
 
 
 to support the primary endpoint of the 
study.
Secondary objectives are focused on investigation of candidate biomarkers in tissue (defects 
in DDR, PD-L1 expression and TMB) and ctDNA (TMB and defects in DDR), that have 
been shown to have predictive value in identifying those patients who are most likely to 
benefit from treatment with either anti-PD-L1 or PARP inhibitors. 
 
 
 
Candidate biomarkers to be investigated include, but may not be limited to:
•
PD-L1 expression on tumor and infiltrating immune cells measured by 
immunohistochemistry (IHC).
•
The presence/absence of tumor-infiltrating CD8+ T lymphocytes.
CCI
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7.4.1. Baseline Tumor Tissue Sample (Obsolete)
Baseline tumor tissue sample is no longer applicable as enrollment in this study was stopped 
on 19 March 2019.
All patients must provide tumor tissue in the form of an FFPE tumor tissue block sufficient to 
provide a minimum of 25 slides, together with an orginal H&E slide.
If suitable archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample must be 
obtained in accord with local institutional practice for tumor biopsies.  For all biopsies, a core 
biopsy, using a minimum 18 gauge needle should be performed, in order to maximize the 
quality and value of obtained tissue.  A minimum of 3 separate cores are requested for each 
biopsy procedure.
All tumor tissue sections provided should ideally measure 5×5 mm and must contain 40% or 
greater tumor nuclei per central laboratory assessment. 
If a block cannot be provided due to documented local/institutional regulations, sites are 
requested to provide an original H&E slide and at least 25 unstained slides, each containing a 
5-micron tissue section cut serially from the same FFPE block.  Positively-charged glass 
slides should be used, and slides should not be baked.
Archived or de novo tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material) is not adequate and should not be submitted. 
Sites may randomize/enroll patients who meet all other eligibility criteria while awaiting 
central confirmation of tissue acceptance, but must provide additional tumor samples in the 
event that the central lab review shows insufficient sample quality.
Discontinuation of enrollment from sites that consistently fail to submit tissue which is 
adequate for the planned primary analysis will be at the discretion of the Sponsor.
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7.4.2. End of Treatment Tumor Tissue Sample (Obsolete)
Effective with IRB/EC approval of Amendment 2, the end of treatment tumor tissue sample 
will no longer be collected. 
At end of treatment, optional de novo (ie, fresh) tumor core biopsies are requested to provide 
FFPE tumor tissue blocks.  If a block cannot be provided due to documented 
local/institutional regulations, sites are requested to provide at least 15 unstained slides each 
containing a 5-micron tissue section cut serially from the same FFPE block.
7.4.3. Peripheral Blood Samples (Obsolete)
Effective with IRB/EC approval of Amendment 2, peripheral blood samples will no longer 
be collected.  
As described in the Schedule of Activities tables for all treatment arms, the following blood 
samples and subsequent analyses will be conducted in order to assess potential biomarkers of 
response, pharmacodynamic activity and resistance:  

Blood samples (6 mL whole blood) will be collected to assess the frequency and 
diversity of TCR sequences prior to the start of chemotherapy and maintenance 
treatments, once during both treatment periods, and at the end of treatment.

Blood sample (20 mL for processing to plasma) will be collected at screening and 
prior to the start of chemotherapy and maintenance treatments, once during both 
treatment periods, and at the end of treatment for processing to circulating tumor 
DNA (ctDNA) and subsequent analysis of genetic biomarkers that may relate to 
response and resistance.

Blood samples (4 mL and 10 mL for processing to plasma and serum, respectively) 
will be collected prior to the start of chemotherapy and maintenance treatments, 
C1D15 of maintenance (Arms A and B) and at the end of treatment to assess 
proteomic, epigenetic and metabolomic factors and signatures.

Blood samples (2 x 2.5 mL whole blood) will be collected prior to chemotherapy 
treatment to generate RNA.  RNA will be used to assess the level of expression of 
genes in peripheral blood.

A single blood sample (4 mL whole blood) will be collected prior to chemotherapy 
treatment and processed to generate DNA.  DNA will be used to assess potential 
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7.4.4. Additional Analyses (Obsolete)
Effective with IRB/EC approval of Amendment 2, no additional analyses will be performed.  
Analyses in addition to those described above may be warranted based on emerging data.  
These analyses may include identification or characterization of cells, DNA, RNA, or protein 
biomarkers.  Such biomarkers may aid in the identification of those patients who might 
preferentially benefit from treatment with the combination of avelumab and talazoparib, may 
be of relevance to the mechanisms of action of the combination or to the development of 
resistance to the combination.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
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7.5.1. Additional Research
Unless prohibited by local regulations or IRB/EC decision, patients will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients.
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Patients may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
7.6. Tumor Response Assessments 
Effective with IRB/EC approval of Amendment 2, tumor response assessments will be 
performed per institutional guidelines and at the investigator’s discretion. These data will not 
be recorded in the INFORM database.  
Effective with IRB/EC approval of Amendment 2, CA-125 level testing is no longer required 
per protocol but may be performed as clinically indicated.  
The decision for body areas to be scanned will depend on the disease under study and the 
extent of disease.  Tumor assessments must include all known or suspected disease sites.  
The minimum recommended body areas to be scanned are detailed in the Imaging Manual.  
All radiographic images will be collected and -will be objectively verified by an independent 
third party core imaging laboratory as described in Imaging Manual.
Baseline scans must be performed within 28 days prior to randomization.
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
screening, at 9 and 18 weeks (±3 days) from the date of randomization and every 12 weeks 
thereafter until disease progression by BICR assessment per RECIST v1.1, regardless of start 
of initiation of subsequent anti-cancer therapies.  For patients who undergo interval 
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debulking surgery during chemotherapy period, an additional tumor assessment should be 
performed after surgery. 
In addition, radiological tumor assessments will also be conducted whenever disease 
progression is suspected (eg, symptomatic deterioration or rising CA-125 levels), or when 
clinically indicated.  
The schedule of tumor assessments should be fixed according to the calendar, starting with 
enrollment/randomization, regardless of treatment schedule or treatment dealy or interuptions 
due to toxicity.
Imaging may incude chest, abdomen and pelvis CT or magnetic resonance imaging (MRI) 
scans and other anatomy such as head or neck, as clinically indicated or protocol required.  
Brain CT or MRI scans are required at baseline for all patients with stable brain lesions and 
for those for whom central nervous system involvement is suspected.  If stable brain 
metasteses are presnt at baseline, brain imaging should be repeated at each tumor assessment.  
Otherwise, brain imaging will be conducted post-baseline only when clinically indicated.
Whole body bone imaging using bone scan (bone scintigraphy) or other methods considered 
standard of care locally such as 18-fluorodeoxyglucose positron emission tomography (18F 
FDG PET), 18-F-sodium fluoride-PET (18F NaF PET), PET/CT, or MRI is required only if 
new bone metastases are suspected.  Bone lesion(s) identified at baseline by bone 
scintigraphy, 18F-FDG-PET, 18F-NaF PET, or PET/CT will be further assessed at baseline by 
correlative imaging, such as diagnostic CT or MRI and subsequently re assessed by 
diagnostic CT or MRI as per the tumor assessment schedule.  Only for those patients with 
bone lesions present at baseline, whole body bone imaging should be repeated at every other 
tumor assessment visit and at the time of confirmation of CR.  For all patients, whole body 
bone imaging may be repeated during study as clinically indicated (ie, patient has new or 
worsening bone pain, increasing alkaline phosphatase level, or other signs and symptoms of 
new/progressing bone metastases). 
The CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons.  The same imaging technique used to characterize each identified and 
reported lesion at baseline will be employed in the following tumor assessments.
Assessment of response will be made using RECIST version 1.1 (Appendix 3) as assessed by 
BICR and investigator.  Measurable or evaluable lesions that have been previously irradiated 
will not be considered target lesions unless progression of such lesions has been observed 
following completion of radiation therapy.
See Section 5.7 for treatment after evidence of disease progression. 
CA-125 will be assessed in a local laboratory at screening, on Day 1 of each cycle and at end 
of treatment.  Rising CA-125 levels alone will not be considered evidence of progression.


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To mitigate the potential for bias in determining disease progression, expedited BICR will be 
performed for investigator-assessed disease progression.  Upon investigator-assessed disease 
progression, all radiographic images collected for a patient from baseline onwards will be 
submitted to the BICR for expedited review.  See the Study Manual for process details.  
Every effort should be made to keep the patient on study treatment until the BICR has 
completed their imaging review. 
7.7. Patient Reported Outcomes Assessments (Obsolete)
Effective with IRB/EC approval of Amendment 2, patient reported outcome assessments will 
no longer be collected.
The instruments proposed are the NCCN-FACT FOSI-18 (NFOSI-18) and the EQ-5D-5L to 
capture disease and treatment-related symptoms and health-related quality of life (HRQoL) 
as secondary endpoints.  The Patient Global Impression of Severity (PGI-S) and the Patient 
Global Impression of Change (PGI-C) items will be administered as anchors to establish the 
meaningful threshold for the disease related symptoms- physical (DRS-P) subscale of the 
NFOSI-18. 
 
 
 The PRO instruments selection and administration schedule have been 
considered with patient burden in mind.  All PRO assessments will be administered per the 
Schedule of Activities tables for each treatment arm. 
Once the patient is enrolled in the study, the electronic Patient Reported Outcomes (ePRO) 
device training should be provided to the patient and the site coordinator should make sure 
the patient understands the materials and is able to use the device.  Patients must complete 
the questionnaires using the ePRO device at the clinic prior to any study or medical 
procedure during Day 1 Cycle 1 of chemotherapy period, and take the device home for 
subsequent assessments. 
7.7.1. NFOSI-18 (Obsolete)
Effective with IRB/EC approval of Amendment 2, the NFOSI-18 will no longer be collected.  
The NFOSI-18 is an ovarian cancer-specific symptom index comprised of symptoms rated as 
highest priority by both oncology clinical experts and women with advanced ovarian 
cancer.65,66  The NFOSI-18 was developed to be part of the Functional Assessment of 
Chronic Illness Therapy (FACIT) system and was specifically created with the input from the 
US FDA, including the recommendation that the assessment of specific symptoms is an 
appropriate starting point for improved measurement of Quality of Life (QoL) domains.65  It 
is specifically designed to be a stand-alone instrument to measure disease-related symptoms, 
treatment side effects and function/well-being in patients with ovarian cancer.
The NFOSI-18 has several subscales.  The DRS-P subscale include 9 physical 
symptoms/concerns (energy, pain, ill, stomach cramps, fatigue, constipation, stomach 
swelling, bowel control and sleep) and the disease related symptoms-emotional (DRS-E) 
subscale include 1 emotional symptom/concern (worry condition will get worse). The 
treatment side effect (TSE) subscale includes 5 items (nausea, hair loss, bothered by side 
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effects, vomiting and skin problems).  The functional well-being (FWB) subscale includes 
3 items (able to get around, enjoy life, and content with QoL).  As with all FACIT 
questionnaires, a high score is good.  Therefore, a score of “0” is a severely symptomatic 
patient and the highest possible score is an asymptomatic patient. 
The amount of time for a patient to complete the questionnaire is estimated to be about 
3 minutes.
7.7.2. PGI-S (Obsolete)
Effective with IRB/EC approval of Amendment 2, the PGI-S will no longer be collected.
The different versions of the Patient Global Impression scale are based on the original 
Clinical Global Impression scale created by Guy, 1976.67  The PGI-S is a 1-item 
questionnaire that can be adapted to assess patient’s impression of disease or symptom 
severity.  The PGI-S will be adapted to assess disease-related physical symptoms for this 
study (See Appendix 5).  The severity of the physical symptoms will be assessed on a 5 point 
Likert scale (eg, 0=no symptoms, 1=mild symptoms, 2=moderate symptoms, 3=severe 
symptoms, 4=very severe symptoms).  The expected questionnaire completion time is less 
than 1 minute and only to be completed by patients enrolled in the US who are fluent in 
English.
7.7.3. PGI-C (Obsolete)
Effective with IRB/EC approval of Amendment 2, the PGI-C will no longer be collected.
The PGI-C is a 1 item questionnaire that can be adapted to assess the patient’s impression of 
the change in symptom or overall health status.67  The PGI-C will be adapted to assess 
disease-related physical symptoms for this study (See Appendix 5).  The change in physical 
symptoms is assessed on a 7 point Likert scale (eg, -3=very much worse, -2= moderately 
worse, -1= a little worse, but a meaningful change, 0=about the same, 1=a little better, but a 
meaningful change, 2=moderately better, 3=very much better).  The expected questionnaire 
completion time is less than 1 minute and only to be completed by patients enrolled in the US 
who are fluent in English.
7.7.4. EuroQoL EQ-5D-5L (Obsolete)
Effective with IRB/EC approval of Amendment 2, the EQ-5D-5L will no longer be collected.
The EuroQol EQ-5D-5L is a 6 item patient completed questionnaire designed to assess health 
status in terms of a single index value or utility score.68,69  There are 2 components to the 
EuroQol EQ-5D-5L: a Health State Profile which has individuals rate their level of problems 
(none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) in 
which patients rate their overall health status from 0 (worst imaginable) to 100 (best 
imaginable).  Published weights are available based on the health state profile items that 
allow for imputation of the index score.69  Overall index scores range from 0 to 1, with low 
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The amount of time for a patient to complete the questionnaire is estimated to be about 
2 minutes.
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) 
non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
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8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject/legally acceptable representative.  In addition, each study 
subject/legally acceptable representative will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Patient 
Withdrawal Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 90 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
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Follow up by the investigator continues throughout and after the active collection period and
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anticancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
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8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study subject administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.


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8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
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
Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
active collection period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the active collection period, then the event leading to death 
must be recorded as an AE on the CRF, and as an SAE with Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
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
Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 


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(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. 


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In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels. 
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).


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
A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 


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subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors 
Exposures to the investigational product under study may occur in clinical trial settings, such 
as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.


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Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.  In the event of a 
medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by Pfizer.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint and/or its analysis will also be 
reflected in a protocol amendment.
As of 19 March 2019, the Sponsor made the decision to stop enrollment/randomization in
study B9991030.  Patients who were randomized can continue treatment and will be 
monitored for appropriate safety assessments until treatment discontinuation. As of 
19 March 2019, approximately 11% of the patients originally planned to be randomized in 
the study had been randomized. Therefore, the study endpoints are no longer applicable 
and/or feasible.  No formal statistical analyses will be conducted, but patient characteristics, 
duration of treatment and safety data will be summarized by treatment arm. 
9.1. Sample Size Determination (Obsolete)
The primary objective of this study is to demonstrate that avelumab in combination with 
platinum-based chemotherapy followed by avelumab plus talazoparib maintenance (Arm A) 
is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab 
maintenance (Arm C) in prolonging PFS in patients with newly diagnosed advanced ovarian 
cancer with defects in DNA damage repair (DDR+) (referred to as “DDR+ population” in 
what follows).
The key secondary objectives of this study are: 

To demonstrate that avelumab in combination with platinum-based chemotherapy 
followed by avelumab plus talazoparib maintenance (Arm A) is superior to 
platinum-based chemotherapy plus bevacizumab followed by bevacizumab 
maintenance (Arm C) in prolonging OS in patients with newly diagnosed advanced 
ovarian cancer in the DDR+ population.


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
To demonstrate that avelumab in combination with platinum-based chemotherapy 
followed by avelumab plus talazoparib maintenance (Arm A) is superior to 
platinum-based chemotherapy plus bevacizumab followed by bevacizumab 
maintenance (Arm C) in prolonging PFS in patients with newly diagnosed advanced 
ovarian cancer unselected for DDR status (all randomized patients).

To demonstrate that avelumab in combination with platinum-based chemotherapy 
followed by avelumab plus talazoparib maintenance (Arm A) is superior to 
platinum-based chemotherapy followed by bevacizumab maintenance (Arm C) in 
prolonging OS in patients with newly diagnosed advanced ovarian cancer unselected 
for DDR status (all randomized patients).
The following statistical hypothesis will be tested to address the primary objective:
H01: HRPFS+ 1 vs. H11: HRPFS+ <1.
where HRPFS+ is the hazard ratio (Arm A vs. Arm C) of PFS based on BICR assessment in 
the DDR+ population.
In addition the following statistical hypotheses will be tested to address the key secondary 
objectives:
H02: HRPFS 1 vs. H12: HRPFS <1;
H03: HROS+ 1 vs. H13: HROS+ <1;
H04: HROS 1 vs. H14: HROS <1.
where HRPFS and HROS are the hazard ratios (Arm A vs. Arm C) of PFS based on BICR 
assessment and OS, respectively, in all randomized patients, and HROS+ is the hazard ratio 
(Arm A vs. Arm C) of OS in the DDR+ population.  A gatekeeping procedure as illustrated 
in Figure 2, will be used to maintain the overall type I-error in the study at or below 1-sided 
0.025.  The significance levels for each test also take into account the group sequential nature 
of the design (see Section 9.9).


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Figure 2.
Statistical Testing Strategy for Arm A vs Arm C Comparisons (Obsolete)
For the primary comparison of PFS between Arm A and Arm C in the DDR+ population, 
200 PFS events based on BICR assessment in Arms A and C combined will provide 
90% power to detect a HR of 0.63 using a 1-sided log rank test at a significance level of 
0.025, and a 2-look group sequential design with Lan-DeMets (O’Brien-Fleming) 
-spending function to determine the efficacy boundary and a Gamma Family 
(-9) -spending function to determine the non-binding futility boundary.
The study will randomize a total of approximately 720 patients in a 2.5:1:2.5 ratio to Arm A 
(N=300 including N=150 DDR+), Arm B (N=120 including N=60 DDR+), and Arm C 
(N=300 including N=150 DDR+).  Randomization will be stratified by germline 
BRCA 1/2 mutational status (gBRCA+ vs gBRCA-), and resection status (adjuvant with 
>1mm and 1 cm residual disease vs. adjuvant with residual disease >1 cm vs. neoadjuvant). 
The sample size for this study is determined based on the following assumptions:
1. The median PFS for patients in Arm C is 14.1 months,74 and the median PFS for 
patients in Arm A is 22.4 months for the DDR+ population and 20.1 months for all 
randomized patients; this corresponds to a hazard ratio (HR) of 0.63 in the 
DDR+ population and 0.70 in all randomized patients, respectively under the 
exponential model assumption;


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2. The median OS for patients in Arm C is 39.7 months,74 and the median OS for 
patients in Arm A is 56.7 months for the DDR+ population and 52.9 months for all 
randomized patients; this corresponds to a HR of 0.70 in the DDR+ population and 
0.75 in all randomized patients, respectively under the exponential model assumption;
3. PFS drop-out rate of approximately 15% and OS drop-out rate of approximately 
5% at the time of primary analysis of PFS and OS, respectively;
4. The DDR+ population includes 50% of the randomized patients;
5. Non-uniform patient accrual accomplished over an 18-month period.
The sample size of approximately 720 patients will also allow an assessment of OS in the 
DDR+ population, and PFS and OS in all randomized patients.
If H01 is rejected then PFS in all randomized patients and OS in the DDR+ population can be 
tested. 

For the PFS comparison between Arm A and Arm C in all randomized patients, 
411 PFS events based on BICR assessment will provide 80.5% power to detect a HR 
of 0.70 using a 1-sided log-rank test at a significance level of 0.003, and a 2-look 
group-sequential design with Lan-DeMets (O’Brien-Fleming) -spending function to 
determine the efficacy boundary. 

For the OS comparison between Arm A and Arm C in the DDR+ population,
207 deaths will provide 70.1% power to detect a HR of 0.70 or 80.1% power to detect 
a HR of 0.67 using a 1-sided log rank test at a significance level of 0.022, and a 
4-look group sequential design with Lan-DeMets (O’Brien-Fleming) -spending 
function to determine the efficacy boundary.
If either H02 or H03 are rejected, then OS in all randomized patients can be tested at the sum 
of the significance levels associated with the significant H02 and H03 tests (see Figure 2).  
With 421 deaths the power to detect a HR of 0.75 is 83.2% (if both H02 and H03 are rejected), 
57.6% (if H02 is rejected and H03 is not rejected) or 81.9% (if H02 is not rejected and H03 is 
rejected) using a 1-sided log rank test at a significance level of 0.025, 0.003 or 0.022, 
respectively, and a 4-look group sequential design with Lan-DeMets (O’Brien-Fleming) 
-spending function to determine the efficacy boundary.
The data cut-off for the primary PFS analysis will occur after the target number of PFS 
events (200) based on BICR assessment in Arms A and C combined in the DDR+ population 
has been reached and the last patient randomized in the DDR+ population has been followed 
for at least 12 months after randomization.
The data cut-off for the primary analysis of OS will occur after the target number of deaths 
(207) in Arms A and C combined in the DDR+ population has been reached.


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The study will be considered positive if the 1-sided stratified log-rank test for PFS based on 
BICR assessment for comparing Arm A to Arm C in the DDR+ population is significant at 
the pre-specified level.
To establish that platinum-based chemotherapy followed by talazoparib maintenance 
(Arm B) has proof of efficacy compared to platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance (Arm C), a HR target of 0.792 for Arm B vs. Arm C 
is deemed to be clinically important (corresponding to a minimum improvement of 
3.7 months in median PFS over Arm C under the exponential model assumption).  Proof of 
efficacy for Arm B compared to Arm C will have been demonstrated if both of the following 
criteria are met in the DDR+ population: 
1. Clinical relevance: Estimated HRPFS+ BvsC) 0.792.
2. Statistical significance: Probability (true HRPFS+(BvsC) <1 | data) 80%.
where HRPFS+(BvsC) is the HR of Arm B vs. Arm C of PFS based on BICR assessment in the 
DDR+ population.  The calculation of the statistical significance criterion assumes 
asymptotic normality of log (HRPFS+(BvsC)) and a non-informative prior.
Table 13 shows the probability for demonstrating proof of efficacy for Arm B compared to 
Arm C under different scenarios.  If the true HRPFS+(BvsC) is 1 (ie, no difference between the 
two arms) the probability of claiming proof of efficacy (false detection rate) for Arm B 
compared to Arm C is 0.099.  If the true HRPFS+(BvsC) is 0.68 and the true HRPFS+(AvsC) is 
0.63, then 149 PFS events based on BICR assessment would be observed in the DDR+ 
population for Arms B and C combined at the time of the primary analysis and the 
probability of declaring proof of efficacy (true detection rate) for Arm B compared to Arm C 
is 0.80. 
Table 13.
Operating Characteristics for PFS in the DDR+ Population (Arm B vs. 
Arm C)—Obsolete
True HRPFS+(BvsC)
Probability of demonstrating proof of efficacy* 
0.65
0.862
0.68
0.800
0.75
0.618
0.792
0.500
0.90
0.240
1.00
0.099
*Assuming 149 PFS events in the DDR+ population for Arms B and C combined at the time of the primary 
analysis for PFS.


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9.2. Analysis Populations
Effective with Amendment 2, only the Safety Analysis Set, Pharmacokinetic Analysis Set 
and Immunogenicity Analysis Set are applicable. 
9.2.1. Full Analysis Set (Obsolete)
The full analysis set will include all patients who are randomized.  Patients will be classified 
according to the treatment and stratum assigned at randomization.  The full analysis set will 
be the primary population for evaluating all efficacy endpoints and patient characteristics.
9.2.2. Per Protocol Analysis Set (Obsolete)
The Per Protocol Analysis Set is a subset of the Full Analysis Set and will include patients 
who receive at least 1 dose of study drug (avelumab, talazoparib, bevacizumab, carboplatin, 
or paclitaxel) post randomization and do not have major protocol deviations expected to 
impact the primary objective of the study.  Major protocol deviations will be pre-specified in 
the SAP.  The Per-Protocol Analysis Set will be used for sensitivity analyses for the primary 
efficacy endpoint.
9.2.3. Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of 
study drug (avelumab, talazoparib, bevacizumab, carboplatin, paclitaxel).  Patients will be 
classified according to the treatment assigned at randomization unless the incorrect 
treatment(s) are received throughout the dosing period in which case patients will be 
classified according to the first treatment received.  The safety analysis set will be used for 
all analyses other than pharmacokinetics or immunogenicity. 
9.2.4. Pharmacokinetic Analysis Set
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least 1 concentration above the below limit of quantitation (BLQ) of 
either avelumab or talazoparib.
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least 1 of the PK parameters of interest of either avelumab or talazoparib.
9.2.5. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients in Arm A only, who have at least 1 ADA sample collected.
9.2.6. Biomarker Analysis Set (Obsolete)
The biomarker analysis set is a subset of the safety analysis set and will include patients who 
have at least one baseline biomarker assessment.


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9.3. Efficacy Analysis (Obsolete)
Effective with IRB/EC approval of Amendment 2, no efficacy data will be reported in the 
CSR.
All efficacy analyses will be performed on the full analysis set unless otherwise specified. 
All analyses will be performed by using Statistical Analysis System (SAS)® Version 9.1.3 or 
higher. 
All primary and secondary endpoints based on radiological assessments of tumor burden will 
be derived using the local radiologist’s/investigator’s assessment.  Radiographic images and 
clinical information collected on study will also be reviewed by a BICR to verify investigator 
reported tumor assessments.  Review by a BICR will be used for the primary analyses.
The primary analyses will be repeated on the per protocol analysis set as a sensitivity 
analyses.  All planned sensitivity analyses will be described in the SAP.
9.3.1. Analysis of the Primary Endpoint (Obsolete)
The primary endpoint is PFS based on BICR assessment in the DDR+ population. 
In what follows, progressive disease (PD) is based on BICR assessment unless otherwise 
specified.
PFS is defined as the time from randomization to the date of the first documentation of 
objective PD or death due to any cause, whichever occurs first.
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start new anti-cancer treatment prior to 
an event, or for patients with an event after two or more missing tumor assessments.  Patients 
who do not have a baseline tumor assessment or who do not have any post-baseline tumor 
assessments will be censored on the day of randomization, with a duration of 1 day, unless 
death occurred on or before the time of the second planned tumor assessment in which case 
the death will be considered an event.
A stratified log-rank test (one-sided) stratified by randomization stratification factors will be 
used at the interim and/or final analyses at the significance level associated with the testing 
strategy outlined in Section 9.1 for the testing of H01 (Arm A vs Arm C) in the 
DDR+ population.
CCI


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The Cox proportional hazards model stratified by randomization stratification factors will be 
fitted to compute the HR (Arm A vs Arm C, Arm A vs Arm B and Arm B vs Arm C) and the 
corresponding 95% CIs for PFS in the DDR+ population.  In order to account for the group 
sequential design in this study, the repeated confidence interval (RCI) method75 will be used 
to construct the 2-sided RCIs for the HR (Arm A vs. Arm C) at the interim and the final 
analyses of PFS in the DDR+ population. 
If there are large departures from proportional hazards (PH), then PFS by BICR assessment 
in the DDR+ population will also be analyzed based on restricted mean survival time 
(RMST) differences.76
The RMST is a robust and clinically interpretable summary measure of the survival time 
distribution.  Unlike median survival time, it is estimable even under heavy censoring.  There 
is a considerable body of methodological research76,77,78 about the use of RMST to estimate 
treatment effects as an alternative to the hazard ratio approach. 
The RMST methodology is applicable independently of the PH assumption and can be used, 
at a minimum, as a sensitivity analysis to explore the robustness of the primary analysis 
results.  However, when large departures from the PH assumption are observed, the log-rank 
test is underpowered to detect differences between the survival distributions for the treatment 
arms, and a test of the difference between the RMST for the experimental arm and the 
control arm may be more appropriate to determine superiority of the experimental arm 
compared to the control arm with respect to the time-to-event endpoint.
The probability of the HR (Arm B vs. Arm C) in the DDR+ population (HRPFS+(BvsC)) being 
less than 1 will be calculated assuming asymptotic normality of log(HRPFS+(BvsC)) a 
non-informative prior.  Proof of efficacy for Arm B compared to Arm C will have been 
demonstrated if both of the following two criteria are satisfied: 

Clinical relevance: Estimated HRPFS+(BvsC) 0.792. 

Statistical significance: Probability (True HRPFS+(BvsC) <1 | data) 0.80.
In addition, for descriptive purposes, PFS time associated with each treatment arm (Arm A, 
Arm B, Arm C) will be summarized using the Kaplan-Meier method and displayed 
graphically where appropriate in the DDR+ population.  CIs for the 25th, 50th, and 75th
percentiles will be reported. 
9.3.2. Analysis of Secondary Endpoints (Obsolete)
9.3.2.1. PFS Based on BICR Assessment in all Randomized Patients (Obsolete)
The methodology described in Section 9.3.1 for PFS based on BICR assessment in the 
DDR+ population for the Arm A vs Arm C comparison will be followed for PFS based on 
BICR assessment in all randomized patients.  A stratified log-rank test (one-sided) stratified 
by randomization stratification factors will be used at the interim and/or final analyses at the 
significance level associated with the testing strategy outlined in Section 9.1 for the testing of 
H02 (Arm A vs Arm C) in all randomized patients. 


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In addition, for descriptive purposes, PFS time associated with each treatment arm (Arm A, 
Arm B, Arm C) will be summarized using the Kaplan-Meier method and displayed 
graphically where appropriate for all randomized patients.  CIs for the 25th, 50th, and 75th
percentiles will be reported.  The Cox proportional hazards model stratified by randomization 
stratification factors will be fitted to compute the HR (Arm A vs Arm C, Arm A vs Arm B 
and Arm B vs Arm C) and the corresponding 95% CIs for PFS in all randomized patients.  In 
order to account for the group sequential design in this study, the RCI method will be used to 
construct the 2-sided RCIs for the HR (Arm A vs. Arm C) at the interim and the final 
analyses of PFS in all randomized patients.
If there are large departures from PH, then PFS by BICR assessment in all randomized 
patients will also be analyzed based on RMST differences.
9.3.2.2. OS in the DDR+ Population and in all Randomized Patients (Obsolete)
OS is defined as the time from randomization to date of death due to any cause.  Patients last 
known to be alive will be censored at date of last contact.
A stratified log-rank test (one-sided) stratified by randomization stratification factors will be 
used at the interim and/or final analyses at the significance level associated with the 
testing strategy outlined in Section 9.1 for the testing of H03 (Arm A vs Arm C) in the
DDR+ population and for the testing of H04 (Arm A vs Arm C) in all randomized
patients. 
In addition, for descriptive purposes, OS time associated with each treatment arm (Arm A, 
Arm B, Arm C) will be summarized using the Kaplan-Meier method and displayed 
graphically where appropriate in the DDR+ population and in all randomized patients.  CIs 
for the 25th, 50th, and 75th percentiles will be reported.  The Cox proportional hazards model 
stratified by randomization stratification factors will be fitted to compute the HR (Arm A vs 
Arm C, Arm A vs Arm B and Arm B vs Arm C) and the corresponding 95% CIs for OS in 
the DDR+ population and in all randomized patients.  In order to account for the group 
sequential design in this study, the RCI method will be used to construct the 2-sided RCIs for 
the HR (Arm A vs. Arm C) at the interim and the final analyses of OS in the DDR+ 
population and in all randomized patients.
If there are large departures from PH, then OS in the DDR+ population and in all randomized 
patients will also be analyzed based on RMST differences.
9.3.2.3. PFS Based on Investigator Assessment (Obsolete)
Using investigator’s assessment, PFS time associated with each treatment arm (Arm A, 
Arm B, Arm C) will also be summarized using the Kaplan-Meier method and displayed 
graphically where appropriate in the DDR+ population and in all randomized patients.  CIs 
for the 25th, 50th, and 75th percentiles will be reported.  The Cox proportional hazards model 
stratified by randomization stratification factors will be fitted to compute the HR (Arm A vs 
Arm C, Arm A vs Arm B and Arm B vs Arm C) and the corresponding 95% CIs for PFS in 
the DDR+ population and in all randomized patients.


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9.3.2.4. PFS on Next-line Therapy (PFS2) Based on Investigator Assessment (Obsolete)
PFS2 is defined as time from randomization to the start of second subsequent treatment after 
first disease progression, or death from any cause, whichever occurs first.  If no date of 
second subsequent therapy is available, patients will be censored at date of last contact. 
PFS2 in the DDR+ population and in all randomized patients will be summarized by 
treatment arm using Kaplan-Meier methodology and displayed graphically, where 
appropriate.  The median PFS2 and 95% CI for the median will be provided for each 
treatment arm.
9.3.2.5. PFS per GCIG Criteria Based on Investigator Assessment (Obsolete)
PFS based on investigator assessment per GCIG criteria will be assessed incorporating both 
RECIST 1.1 and CA-125 (Appendix 4).
PFS based on investigator assessment per GCIG criteria will be censored if both PFS by 
RECIST 1.1 and PFS by CA-125 are censored, the date of censoring will be the latest of the 
two censoring dates.
CA-125 data will be censored on the date of the last CA-125 assessment for patients who 
start new anti-cancer treatment prior to an event, or for patients with an event after two or 
more missing CA-125 assessments.  Patients who do not have a baseline CA-125 assessment 
or who do not have any post-baseline CA-125 assessments will be censored on the day of 
randomization, with a duration of 1 day.
PFS based on investigator assessment per GCIG criteria in the DDR+ population and in all 
randomized patients will be summarized by treatment arm using Kaplan-Meier method and 
displayed graphically, where appropriate.  The median PFS and 95% CI for the median will 
be provided for each treatment arm.
9.4. Pharmacokinetic Analysis 
The results of the pharmacokinetic analyses on samples collected prior to IRB/EC approval 
of protocol amendment 2 will not be included in the CSR but will be retained by the Sponsor 
and may be pooled with data from other studies to further inform the development programs 
of avelumab and talazoparib, as appropriate.
Pharmacokinetic data analyses will include pre-dose and post-dose sampling for serum 
avelumab and predose plasma talazoparib as per the Schedule of Activities.  PK data 
analyses will include descriptive summary statistics of the pre dose/trough (Ctrough) 
concentrations for both investigational products and maximum (Cmax) concentrations (for 
avelumab) for each cycle.


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9.4.1. PK Analysis for Avelumab and Talazoparib 
Effective with IRB/EC approval of Amendment 2, the PK analysis for avelumab and 
talazoparib will be limited to samples collected.  
Avelumab and talazoparib concentrations will be summarized descriptively (n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) by Dose (talazoparib only), cycle, day and nominal time.  Individual patient 
and median profiles of the concentration time data will be plotted by dose, cycle and day 
using nominal times.  Individual and median profiles will be presented on both linear-linear 
and log-linear scales.
9.4.2. Population Pharmacokinetic and Exposure Response Analysis
Effective with IRB/EC approval of Amendment 2, no population PK and exposure response 
analysis will be performed on data from this study; however PK data may be pooled with 
data from other studies to further inform the development programs of avelumab and 
talazoparib, as appropriate.
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab and talazoparib exposure and biomarkers or significant safety 
endpoints.  The results of these analyses, if performed, may be reported separately.
9.4.3. Analysis of Immunogenicity Data of Avelumab 
Immunogenicity analysis will be limited to samples collected prior to IRB/EC approval of 
amendment 2 and will be perfomed as appropriate. 
ADA/NAb data will be listed and summarized for each dosing interval for avelumab. 
The percentage of patients with positive ADA and neutralizing antibodies each will be 
summarized by dose.  For patients with positive ADA, the magnitude (titer), time of onset, 
and duration of ADA response will also be described, if data permit.  The effect of ADA on 
avelumab concentrations will be evaluated.
9.5. Biomarker Analysis for Secondary 
 Endpoints (Obsolete)
Effective with IRB/EC approval of Amendment 2, no biomarker data will be reported in the 
CSR.  
All analyses of biomarkers will be performed based on the biomarker analysis set.
Biomarker data will include baseline, on treatment and end of treatment measurements of 
biomarkers as detailed in Section 7.4. 
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
provided for at baseline and on treatment/end of treatment time points, as appropriate.
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Appropriate change from baseline measurements will be provided.  For discrete measurement 
biomarkers, frequencies and percentages of categorical biomarker measures will be provided 
for baseline and on treatment/post treatment time points, as appropriate; shift tables may also 
be provided.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Fisher’s exact test, Wilcoxon signed rank test, Wilcoxon rank sum test, 
correlation/linear regression, Kaplan-Meier estimate, etc, as appropriate.  The statistical 
approaches will examine correlations of biomarker results with pharmacokinetic parameters 
and measures of efficacy, such as progression free survival.
9.6. Analysis of Patient Reported Outcomes (Obsolete)
Effective with IRB/EC approval of Amendment 2, no PRO data will be reported in the CSR.
The FAS will be used for the NFOSI-18 and EQ-5D-5L analyses.  The PRO analysis below 
will be conducted in the DDR+ subset and also in all randomized patients. 
The NFOSI-18 and EQ-5D-5L will be scored according to their respective scoring or user 
guides.79  For the EQ-5D-5L, the index scores will be calculated using the published weights 
(tariffs) for the United Kingdom.  Specific country weights may be applied for country 
specific analyses as needed.
The primary PRO analysis will include treatment comparison of Arm A vs. Arm C on the 
time to deterioration (TTD) of the DRS-P in the DDR+ population.  TTD is defined as the 
time from randomization to deterioration where deterioration is defined, respectively, as a 
3-point decrease, maintained for 2 consecutive assessments, on the DRS-P (9 items) for 
physical symptoms or concerns of disease.
The TTD cut-off point proposed above for DRS-P is based on the clinically important 
differences calculation given by Yost and Eton80 as a general guidance for the FACIT 
measurement system.  The TTD for DRS-P will be calculated as of the date of randomization 
and to the date of the first of the 2 consecutive assessments used to identify the event.  A 
decline in DRS-P score represents an increase in physical symptoms or concerns of the 
disease.  Patients who do not have a TTD event will be censored on the date when they last 
completed a PRO assessment.  TTD will be compared between treatment arms using a 
one-sided log-rank test stratified by randomization stratification factors.  No adjustment for 
multiplicity will be conducted.  The Cox proportional hazards model stratified by the 
randomization factors and will be fitted to compute the hazard ratio (HR) and corresponding 
95% CIs.  Kaplan-Meier estimates will be presented by treatment arm together with a 
summary of associated statistics including the median TTD time with 2-sided 95% CIs.  The 
TTD cut-off for the DRS-P will be also examined using an anchor-based method with the 
PGI-S and PGI-C items and the cumulative distribution function.81


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Additionally, summary statistics (mean and standard deviation [SD], median, range) of 
absolute scores over time will be reported for each of the total and subscales of the 
NFOSI-18, EQ-5D-5L index, and EQ-VAS.  The mean change of absolute scores from 
baseline (and 95% CI) over time will also be reported.  Line charts depicting the means and 
changes from baseline with with standard error (SE) over time will be provided for each 
treatment arm.  For the EQ-5D-5L health state profiles, the proportions of patients reporting 
having “none”, “slight”, “moderate”, “severe”, or “extreme/unable” problems at each time 
point will be reported.
Several secondary PRO analyses will be conducted.  The NFOSI-18 total scores, subscales, a 
single question within the TSE subscale (“I am bothered by side effects of treatment”), as 
well as the EQ-5D-5L index and VAS scores will be assessed for the comparisons among 
treatment arms using a mixed effects logitudinal model.  The main analysis will be applied 
using scheduled assessments from baseline up to EOT (not including EOT), and the 
secondary analysis will be based on all scheduled assessments from baseline including EOT 
and until 3 years from patient’s enrollment. 
Time from randomization to development of significant side effect bother (TTB) will be 
analyzed similarly to the analysis of TTD of DRS-P where a TTB event will be defined as 
the first report of a score of ≥2 for at least two consecutive assessments on the side effect 
bother item.  Patients will be censored at the last time when they completed a NFOSI-18 
assessment if they have not had a TTB event.  This analysis will be applied using scheduled 
assessments from baseline up to EOT (not including EOT) to assess the level of treatment 
side effect bother on patients during the treatment period, and also using all scheduled 
assessments from baseline including EOT and until 3 years from patient’ enrollment to also 
assess the level of treatment side effect bother on patients from the next line of therapy.  TTB 
will be compared between treatments using a one-sided log-rank test stratified by 
randomization stratification factors.  No adjustment for multiplicity will be conducted.  The 
treatment effect will be estimated using a Cox proportional hazards model stratified by the 
randomization factors and fitted to compute the hazard ratio (HR) and corresponding 
95% CIs.  Kaplan-Meier estimates will be presented by treatment arm together with a 
summary of associated statistics including the median TTB time with 2-sided 95% CIs.
 
 
   
 
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9.8. Safety Analysis
Descriptive statistics will be used to summarize all patient characteristics, duration of 
treatment , and AEs/SAEs.  Data will also be displayed graphically, where appropriate.
9.8.1. Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html). 
The frequency of patients experiencing treatment emergent adverse events corresponding to 
body systems and MedDRA preferred term will be reported.  Adverse events will be graded 
by worst NCI CTCAE v4.03 Grade. 
Emphasis in the analysis will be placed on AEs classified as treatment emergent.  Adverse 
events leading to death or discontinuation of study treatment, events classified as NCI 
CTCAE v4.03 Grade 3 or higher, trial drug-related events, and serious adverse events will be 
considered with special attention.  As appropriate, the difference in risk between treatment 
arms for AEs of clinical interest may be further assessed as described in the SAP.
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study treatment, action taken, and 
clinical outcome.
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9.8.2. Laboratory Abnormalities (Obsolete)
Effective with IRB/EC approval of Amendment 2, no summary of laboratory data will be 
reported in the CSR. Only listings of laboratory test data will be provided
The laboratory results will be graded according to the NCI CTCAE v4.03 severity grade.
The frequency of patients with laboratory test abnormalities will be summarized according to 
the worst grade for each laboratory test.
For laboratory tests without an NCI CTCAE grade definition, results will be categorized as 
normal (within normal ranges), abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory abnormalities.
9.8.3. Electrocardiograms (Obsolete)
Effective with IRB/EC approval of Amendment 2, no electrocardiograms data will be 
reported in the CSR.  
ECG measurements and changes from baseline will be summarized by treatment arm and 
visit.  Interval measurements from clinically indicated on treatment ECGs will be included in 
the outlier analysis (categorical analysis) as individual values obtained at unscheduled time 
points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study-specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, QTc.
9.9. Interim Analysis (Obsolete)
Effective with IRB/EC approval of Amendment 2, interim analysis is no longer applicable.  
The interim and the primary analyses for each efficacy endpoint will be performed after all 
patients have been randomized in the study and the target number of events has occurred in 
Arms A and C combined as described below.  A maximum of 4 distinct analyses cut-offs are 
planned in the study at the approximate calendar times described below:

At the time when 140 PFS events (70% of the expected 200 events) based on BICR 
assessment have occurred in the DDR+ population in Arms A and C combined;

At the time when 200 PFS events based on BICR assessment have occurred in the 
DDR+ population in Arms A and C combined;

At the time when 155 deaths (74.9% of the expected 207 deaths) have occurred in the 
DDR+ population in Arms A and C combined;

At the time when 207 deaths have occurred in the DDR+ population in Arms A and 
C combined.


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Table 14 displays the maximum number of analyses expected for the primary endpoint and 
the associated efficacy and futility boundaries.  The futility boundaries are non-binding but 
the study may be stopped for futility if at the time of the interim analysis the futility 
boundary is crossed.  If the efficacy boundary is crossed at the time of the interim analysis or 
at the time of the primary analysis then the primary objective of the study will have been 
demonstrated.
Table 14.
PFS Based on BICR Assessment in the DDR+ Population (Arm A vs. 
Arm C) - Efficacy and Futility Boundaries (Obsolete)
PFS in the DDR+ Population
Analysis
IA1
PA
Analysis cut-off trigger
140 PFS events in DDR+
200 PFS events in DDR+
Number of eventsa (Information 
fraction) 
140 (70.0%)
200 (100%)
p-value (z-value) for efficacy
<0.0074 (<-2.438)
<0.0228 (<-2.000)
p-value (z-value) for futilityb 
>0.3975 (>-0.260)
NA
a Number of events expected under H11 for PFS (assuming a HR of 0.63).
b Non-binding.
IA1=interim analysis 1, PA=primary analysis
Table 15 displays the analysis triggers for PFS in all randomized patients and the analysis 
triggers for OS in the DDR+ population, as well as the associated efficacy boundaries.  As 
described in Section 9.1, the significance level for the analyses of these endpoints is 
determined by the gatekeeping procedure.
Table 15.
PFS Based on BICR Assessment in All Randomized Patients and OS in the 
DDR+ Population (Arm A vs. Arm C) - Efficacy Boundaries (Obsolete)
Endpoints
PFS in all randomized 
patients
OS in the DDR+ Population
Analysis
IA1
PA
IA1
IA2
IA3
PA
Analysis cut-off 
trigger
140 PFS 
events in 
DDR+
200 PFS 
events in 
DDR+
140 PFS 
events in 
DDR+
200 PFS 
events in 
DDR+
155 deaths
in DDR+
207 
deaths in 
DDR+
Number of eventsa
(Information 
fraction)
289 (70.3%)
411 (100%)
66 (31.9%)
110 
(53.1%)
155 
(74.9%)
207 
(100%)
p-value (z-value) 
for efficacy
<0.0004  
(<-3.352)
<0.0029 
(<-2.762)
<0.00005 
(<-3.891)
<0.0017 
(<-2.936)
<0.0076 
(<-2.428)
<0.0194 
(<-2.065)
a Number of events expected under H12 for PFS (assuming a HR of 0.70) and H13 for OS (assuming a HR of 
0.70).
IA1=interim analysis 1, IA2=interim analysis 2, IA3=interim analysis 3, PA=primary analysis
Table 16 displays the analysis triggers for OS in all randomized patients, as well as the 
associated efficacy boundaries.  As described in Section 9.1, the significance level for the 
analyses of this endpoint is determined by the gatekeeping procedure.


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Table 16.
OS in All Randomized Patients (Arm A vs. Arm C) – Efficacy Boundaries 
(Obsolete)
OS in All Randomized Patients
Analysis
IA1
IA2
IA3
PA
Analysis cut-off trigger
140 PFS events 
in DDR+
200 PFS events 
in DDR+
155 deaths in 
DDR+
207 deaths in 
DDR+
Number of eventsa (Information 
fraction)
135 (32.1%)
225 (53.4%)
317 (75.3%)
421 (100%)
p-value (z-value) for efficacyb
<0.00008 
(<-3.789)
<0.0021 
(<-2.856)
<0.0091 
(<-2.361)
<0.0219 
(<-2.016)
a Number of events expected under H14 for OS (assuming a HR of 0.75).
b The p-values and z-values noted for OS are those associated with the scenario when both H02 and H03 are 
rejected.
IA1 = interim analysis 1, IA2 = interim analysis 2, IA3=interim analysis 3, PA = primary analysis
Since the observed number of events at the interim analysis may not be exactly equal to the 
planned number of events, the efficacy and futility boundaries will be updated based on the 
actual number of observed events using the pre-specified -and -spending functions.  
Therefore, the observed Z-test statistic at the interim analysis will be compared with the 
updated efficacy and futility boundaries.  If the study continues to final analysis, the p-value 
that will be used to declare statistical significance at the final analysis for each endpoint will 
be based on the actual number of events documented at the cut-off date for the final analysis 
and the α already spent at the interim analysis. 
9.10. Data Monitoring Committee (Obsolete)
As of 19 March 2019, the initial E-DMC meeting had not yet occurred.  This study will no 
longer use an external data monitoring committee (E-DMC). 
The E-DMC planned an initial review of safety data without holding of recruitment, after 
approximately 30 patients in the study (approximately 12 patients to the avelumab plus 
talazoparib combination, Arm A) have been treated and followed for at least 4 weeks after 
the first dose in the maintenance period.  The E-DMC assessment will be conducted based on 
the available safety data and on all the available safety data of other patients treated up to that 
data cut-off.  
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.


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During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject's medical records.  The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.  The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic and/or paper form and will 
be password protected or secured in a locked room to prevent access by unauthorized third 
parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician’s chart.  In these cases, 
data collected on the CRFs must match the data in those charts. 


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In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
retained.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal, and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data are compiled for transfer to Pfizer and other authorized 
parties, patient names will be removed and will be replaced by a single, specific numerical 
code based on a numbering system defined by Pfizer.  All other identifiable data transferred 
to Pfizer or other authorized parties will be identified by this single, subject-specific code.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each subject’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of subjects’ personal 
data consistent with the Clinical Study Agreement and applicable privacy laws.
The personal data will be stored at the study site in encrypted electronic and/or paper form 
and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access.  The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster.  In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, providing 
breach notifications as required by law.
The informed consent documents and any patient recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC 
before use, and available for inspection.
The investigator must ensure that each study patient, or her legally acceptable representative, 
is fully informed about the nature and objectives of the study the sharing of data relating to 
the study and possible risks associated with participation, including the risks associated with 
the processing of the subject’s personal data.  The investigator further must ensure that each 
study patient or her legally acceptable representative is fully informed about his or her right 
to access and correct his or her personal data and to withdraw consent for the processing of 
his or her personal data.


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Whenever consent is obtained from a subject’s legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the patient has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, then, 
as permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the subject’s assent was obtained or waived.  If assent is obtained verbally, 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the subject's legally acceptable representative before any 
study-specific activity is performed.  The investigator will retain the original of each subject's 
signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in All Participating Countries 
End of trial in all participating countries is defined as last patient last visit (LPLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab or talazoparib at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 1 month.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 


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publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12 months of completion or termination of the study at 
all participating sites, the investigator is free to publish separately, subject to the other 
requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ACTH
Adrenocorticotopic Hormone
ADA
Anti-Drug Antibody
ADME
absorption, distribution, metabolism and excretion 
AE
adverse event
ADR
adverse drug reactions
AESI
AE of special interest  
AIDS
acquired immunodeficiency syndrome 
AJCC
American Joint Committee on Cancer 
ANC
Absolute neutrophil count 
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
aPPT
activated partial thromboplastin time 
ATM
ataxia telangiectasia mutated 
AUC
area under the concentration (for carboplatin dosing)
AUC
area under the curve
BBS
Biospecimen Banking System
BCCL
baseline creatinine clearance
BCRP
breat cancer resistance protein 
BICR
Blinded Independent Central Review
BLQ
below limit of quantitation
BOR
best overall response
BP
blood pressure
BRCA
BReast CAncer Gene
CAG
clinical assay group (Pfizer)
CEA
carcinoembryonic antigen
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CK
creatine kinase
CLCR
creatinine clearance
CL/F
oral clearance
CPK
creatine phosphokinase
CR
complete response
CRF
case report form
CRPC
castration-resistant prostate cancer
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
Clinical trial


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Abbreviation
Term
CT
computed tomography 
CTA
clinical trial application
CTLA4
cytotoxic T-lymphocyte-associated antigen 4
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CV
coefficient of variation
CYP450
cytochrome P450
DCIS
ductal carcinoma in situ
DDI
drug-drug interaction
DDR
DNA damage repair
DILI
drug-induced liver injury
DLBCL
diffuse large B-cell lymphoma 
DLT
dose limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRS-E
disease related symptoms-emotional
DRS-P
disease related symptoms- physical
DU
dispensable unit
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EMA
European Medicines Agency
EOC
epithelial ovarian cancer
EORTC
European Organization for Research and Treatment of Cancer
EOT
end of treatment
EPO
erythropoietin
ePRO
electronic patient reported outcomes
ESMO
European Society for Medical Oncology
EQ-5D-5L
EuroQol EQ-5D-5L
EU
European Union
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness Therapy 
FDA
The Food and Drug Administration
18F FDG PET
18-fluorodeoxyglucose positron emission tomography 
FFPE
formalin fixed, paraffin embedded
FIGO
International Federation of Gynecology and Obstetrics
18F NaF PET
18-F-sodium fluoride-PET 
FSH
follicle-stimulating hormone
FTC
fallopian tube cancer
FWB
functional well-being 


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Abbreviation
Term
gBRCA
germline BReast CAncer Gene
GCIG
Gynecological Cancer Intergroup 
GCP
Good Clinical Practice
GCS
Global Clinical Supply 
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
GVHD
graft versus host disease 
GOG
Gynecologic Oncology Group
H&E
Hemotoxylin and Eosin 
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HER2
Human Epidermal Growth Factor Receptor 2 
HIV
human immunodeficiency virus
HR
hazard ratio
HRQoL
health-related quality of life
IB
Investigator’s Brochure
ICD
Informed consent document
ICH
International Conference on Harmonisation
ICON
International Collaboration on Ovarian Neoplasms
ICOSL
inducible costimulator ligand
ID
identification
IDS
interval debulking surgery
IFN-α
interferon alpha 
IgG1
immunoglobulin G1
IL
interleukin 
IND
investigational new drug application
IHC
immunohistochemistry
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
irAE
immune-related adverse event
IRR
infusion-related reaction
IRT
interactive response technology
ITT
intent to treat
IUD
intrauterine device
IV
intravenously
IWR
interactive web response
K2EDTA
dipotassium ethylenediaminetetraacetic acid
LCIS
lobular carcinoma in situ
LFT
liver function test
LOH
loss of heterozygosity 
LPLV
last patient last visit 


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Abbreviation
Term
mAb
monoclonal antibody
MCC
Merkel cell carcinoma
MDS
Myelodysplastic Syndrome 
MedDRA
Medical Dictionary for Regulatory Activities
MHC
major histocompatibility complex
mPFS
median progression free survival
MRI
magnetic resonance imaging
mTPI
modified toxicity probability interval
N/A
not applicable
NAb
neutralizing antibody 
NCI 
National Cancer Institute 
NCT
National Clinical Trial
NE
Not evaluable
NEMO
NF-κB essential modulator
NFOSI-18
NCCN-FACT FOSI-18 
NK
natural killer
NKG2DL
natural killer group 2 member D Ligand
NSCLC
Non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PARP
Poly (adenosine diphosphate [ADP]-Ribose) Polymerase
PBMC
peripheral blood mononuclear cells 
PCD
primary completion date
PCT
physician-choice therapies
PD
pharmacodynamics 
PD
progression of disease
PD-1
programmed death–1
PD-L1
programmed death ligand 1
PDS
primary debulking surgery 
PET
positron emission tomography
PFS
Progression free survival
PGI-S
Patient Global Impression scale
PGI-C
Patient Global Impression change
PH
proportional hazards
PI
principal investigator
PK
pharmacokinetic
PLD
pegylated liposomal doxorubicin
PPC
primary peritoneal cancer
PR
partial response
PRO
patient reported outcome
PT
prothrombin time
PTEN
phosphatase and tensin homolog gene 
Q2W
every 2 weeks


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Abbreviation
Term
Q3W
every 3 weeks
QD
every day
QoL
Quality of Life
QW
every week
RCC 
Renal cell carcinoma
RCI
repeated confidence interval
RECIST
Response Evaluation Criteria in Solid Tumors
RMST
restricted mean survival time
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System
SCCHN
squamous cell cancer of the head and neck
SCLC
small cell lung cancer
SE
standard error
SOA
schedule of activities
SmPC
Summary of Product  Characteristics
SOP
standard operating procedure
SRSD
single reference safety document
SST
serum separator tube
STING
stimulator of interferon genes 
TBili
total bilirubin
TCR
T-cell receptor
TEAE
treatment-emergent adverse event
TKI
Tyrosine kinase inhibitors
TMB
tumor mutational burden
TNM
Classification of Malignant Tumours
TO
target occupancy
TSE
treatment side effect
TTB
Time to development of significant side effect bother 
TTD
time to deterioration 
UC
urothelial carcinoma
UICC
Union for International Cancer Control
ULN
upper limit of normal
US
United States
US FDA
United States Food and Drug Administration
V/F
volume of distribution
VAS
Visual Analogue Scale
VEGF
vascular endothelial growth factor 
WBC 
White blood cell
WHO
World Health Organization
WRD
Worldwide Research and Development 
WT
wild type


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Appendix 2. ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead.
From: Oken MM, Creech RH, Tormey DC et al.  Toxicity and response criteria of the Eastern Cooperative 
Oncology Group.  Am J Clin Oncol. 1982; 5: 649–655.


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Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines (Obsolete)
Adapted from E.A. Eisenhauer, et al.  New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228-247.82
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions 

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non measurable disease 
Non measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non cystic lesions are also present, these are preferred as target 
lesions.


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease. 
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large target 
lesion splits, the sum of the parts is used.
Measurements for target lesions that become small should continue to be recorded.  If the 
lesion is considered to have disappeared, 0 mm should be recorded; otherwise if a lesion is 
determined to be present but too small to measure, the lesion status will indicate “too small to 
measure and judged to be less than 10 mm” and 5 mm will be used in the calculation of the 
sum of the diameters.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non target disease 
All non-measurable disease is non target.  All measurable lesions not identified as target 
lesions are also included as non target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE (ie, Not Evaluable), 
PRESENT/NOT INCREASED, INCREASED.  Multiple non target lesions in one organ may 
be recorded as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are not evaluable. 


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Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  All target lesions must be assessed. 

Stable Disease (SD): Does not qualify for CR, PR or Progression.  All target lesions 
must be assessed.  Stable can follow PR only in the rare case that the sum increases 
by less than 20% from the nadir, (smallest sum of diameters considers baseline and 
all assessments prior to the time point under evaluation) but enough that a previously 
documented 30% decrease no longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate.  Progression has not been documented, and 

One or more target measurable lesions have not been assessed; 
or

Assessment methods used were inconsistent with those used at baseline;
or

One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);
or

One or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Non-Target Disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non CR/Non PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 


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
Not evaluable (NE): Progression has not been determined and:

One or more non target sites were not assessed or

Assessment methods were inconsistent with those used at baseline, or

One or more non-target lesions cannot be assessed (eg, poorly visible or unclear 
images), or

One or more non-target lesions were excised or irradiated and have not 
reappeared or increased.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations

If CR determination depends on a residual lesion that decreased in size but did not 
disappear completely, it is recommended the residual lesion be investigated with 
biopsy or fine needle aspirate.  If no disease is identified, objective status is CR.

If progression determination depends on a lesion with an increase possibly due to 
necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify 
status. 
Objective/Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.
Determination of Tumor Response by RECIST
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  New lesions will also be recorded separately.  Determination of tumor response 
at each assessment based on target, non-target and new lesions is summarized in the 
following table:


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Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Objective Response Status at Each Assessment for Patients with Measurable 
Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD or not all evaluated
No
PR
PR
Non-PD* or not all evaluated
No
PR
SD
Non-PD* or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes**
PD
*Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal 
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Objective Response Status at each Evaluation for Patients with Non-Target Disease 
Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD


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Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest sum 
on study).  For CR and PR, the patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  CR and PR must be confirmed 
by 2 measurements at least 4 weeks apart.  In the case of SD, follow up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 weeks.


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Appendix 4. PFS by GCIG Criteria (Obsolete)
As described in published guidelines,88 progression by GCIG criteria will be defined as 
progression by RECIST 1.1 OR progression by CA-125.
Progression or recurrence based on serum CA-125 levels will be defined on the basis of a 
progressive serial elevation of serum CA-125 according to the following criteria:
1. Patients with elevated CA-125 pretreatment and normalization of CA-125 must show 
evidence of CA-125 greater than, or equal to, 2 times the upper limit of the reference 
range on 2 occasions at least 1 week apart, OR
2. Patients with elevated CA-125 before treatment, which never normalizes, must show 
evidence of CA-125 greater than, or equal to, 2 times the nadir value on 2 occasions 
at least 1 week apart, OR
3. Patients with CA-125 in the reference range before treatment must show evidence of 
CA-125 greater than, or equal to, 2 times the upper limit of the reference range on 
2 occasions at least 1 week apart.
CA-125 progression will be assigned the date of the first measurement that meets the criteria 
as noted.  Patients are not evaluable by CA-125 if there has been medical and/or surgical 
interference with their peritoneum or pleura (eg, paracentesis) during the previous 28 days.
A patient may be declared to have PD on the basis of either the objective RECIST 1.1 criteria 
or the CA-125 criteria.  The date of progression will be the date of the earlier of the 2 events 
if both are documented.


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Appendix 5. Patient Global Impression of Severity (PGI-S) (Obsolete)
Patient Global Impression of Severity (PGI-S)
Please choose the response below that best describes the severity of the physical symptoms 
you experienced from ovarian cancer in the past week. 

no symptoms

mild symptoms

moderate symptoms

severe symptoms

very severe symptoms
Patient Global Impression of Change (PGI-C)
Please choose the response below that best describes the overall change from the start of the 
study in the physical symptoms you experience from ovarian cancer.

very much better

moderately better

a little better, but a meaningful change

about the same

a little worse, but a meaningful change

moderately worse

very much worse


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Appendix 6. Revised Schedule of Activities – Effective with Amendment 2
The revised SOA below will be followed in place of the SOA in the Protocol Summary Section of the protocol.  The SOA provides an 
overview of the protocol visits and procedures for each treatment arm.  Refer to the STUDY PROCEDURES and ASSESSMENTS
sections of the protocol for detailed information on each procedure and assessment required for compliance with the protocol.  
Table 1.0. Schedule of Activities: Chemotherapy + Avelumab Followed by Avelumab + Talazoparib (Arm A)/Chemotherapy 
Followed by Talazoparib Alone (Arm B)
Protocol Activities
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period
(1 cycle = 6 weeks = 42 days)
Day 1 (3 days)
Day 1 
(3 days)
Day 15 
(3 days)
Day 29
(3 days)
End of 
Treatment/Withdrawal12 Short-Term Follow-up 
(Day 30, 60, and 90 3 
days)13
Required Clinical Assessments
Blood Pressure, Temperature, Pulse1
X
X
X
X
X
Contraception Check2
X
X
X
X
X
Hematology, Blood chemistry3
X
X
X
X
X
X (Day 30)
Serum/Urine Pregnancy Test4
X
X
X
X
Thyroid Function/ACTH
C2D1, C4D1, and C6D1 only
C1D1, then every 12 weeks thereafter
X
Paclitaxel/Carboplatin Administration5
X
Avelumab Administration6
X 
(Arm A only)
X 
(Arm A only)
X 
(Arm A only)
X 
(Arm A only)
Talazoparib7
Once daily 
Serious and Non-Serious Adverse Event 
Monitoring9
Monitored and recorded throughout treatment
X
X
Concomitant Treatment(s)10
Recorded subject’s source document’s.
X
X
Urinalysis
Not required per protocol, but may be performed as clinically indicated
CA-125
Not required per protocol, but may be performed as clinically indicated
Physical examination
Not required per protocol, but may be performed as clinically indicated
ECOG Performance Status
Not required per protocol, but may be performed as clinically indicated
12-Lead Electrocardiogram (ECG)
Not required per protocol, but may be performed as clinically indicated
Tumor Assessments (including scans) 11
Performed per institutional guidelines and at investigator’s discretion.


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Table 2.0
Schedule of Activities: Chemotherapy + Bevacizumab Followed by Bevacizumab (Arm C)
Protocol Activities
On -Treatment 
Post Treatment Period
Chemotherapy Period
(1 cycle = 3 weeks = 21 days)
Maintenance Period
(1 cycle = 6 weeks = 42 days)
Day 1 
(3 days)
Day 1 
(3 days)
Day 22 
(3 days)
End of
Treatment/Withdrawal12
Short-Term Follow-up 
(Day 30, 60, and 90 3 
days)13
Clinical Assessments (Required)
Blood Pressure, Temperature, Pulse1
X
X
X
X
Contraception Check2
X
X
X
X
X 
Hematology, Blood chemistry3
X
X
X
X
X (Day 30)
Serum/Urine Pregnancy Test4
X
X
X
X
Thyroid Function/ACTH
C2D1, C4D1, and C6D1 only
C1D1, then every 12 weeks thereafter
X
Paclitaxel/Carboplatin Administration5
X
Bevacizumab Administration8
X
X
X
Serious and non-serious adverse event 
monitoring9
Monitored and recorded throughout treatment
X
X
Concomitant Treatment(s)10
Recorded in subject’s source document’s
X
X
Urinalysis
X
X
X
X
CA-125
Not required per protocol, but may be performed as clinically indicated
Physical examination
Not required per protocol, but may be performed as clinically indicated
ECOG Performance Status
Not required per protocol, but may be performed as clinically indicated
12-Lead Electrocardiogram (ECG)
Not required per protocol, but may be performed as clinically indicated
Tumor Assessments (including scans)11
Performed per institutional guidelines and at investigator’s discretion. 
Footnotes for Schedule of Activities Tables
1.
Blood Pressure, Temperature, Pulse: Effective with Amendment 2, vital signs including weight, height, blood pressure, temperature, and pulse rate are to be performed per 
SOA above.  These data do not need to be recorded in the INFORM database, unless the findings support an AE/SAE.  
2.
Contraception Check: Only for patients who are of child-bearing potential.  
3.
Hematology, and Blood Chemistry: Hematology and Blood Chemistry must be collected at Day 1 of each chemotherapy Cycle (unless done in the prior 3 days), and on 
Day 1, Day 15 and Day 29 of each maintenance cycle, and End of Treatment/Withdrawal and at Day 30 during the follow-up in Arms A/B.  Hematology and Blood 
Chemistry must be performed at Day 1 of each chemotherapy cycle, and on Days 1, and 22 of each maintenance cycle, and end of treatment/withdrawal and at Day 30 during 
the follow-up in Arm C.  Any test may also be performed when clinically indicated.


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4.
Serum/Urine Pregnancy Test: For women of childbearing potential, a serum or urine pregnancy test must be performed on Day 1 of each chemotherapy cycle, on Day 1 and 
Day 29 (Arms A and B) and Day 1 and Day 22 (Arm C) of each maintenance cycle, and at the end of study treatment.  The pregnancy test should be repeated if 1 menstrual 
cycle is missed or if the potential of pregnancy is otherwise suspected.  
5.
Paclitaxel/Carboplatin Administration: Paclitaxel 175 mg/m2 IV, followed by carboplatin dose AUC 5 or AUC 6 IV on Day 1 of every chemotherapy cycle as described in 
Section 5.4.  Premedication will be administered as specified in Section 5.4.1.1.  On visits when chemotherapy is administered in combination with avelumab or bevacizumab 
(Day 1 of each 21-day cycle), chemotherapy will be infused before either avelumab or bevacizumab.  See Section 5.4.2 and Section 5.4.3. See Section 6.2 for guidance on 
treatment duration
6.
Study Treatment Avelumab (Arm A Only): Patients will receive avelumab 800 mg administered on Day 1 of each 3-week cycle intravenously after administration of 
paclitaxel and carboplatin during the chemotherapy period.  During the maintenance period patients will receive avelumab 800 mg administered once every 2 weeks after 
dosing with talazoparib on Days 1, 15, and 29 of each 6-week maintenance cycle.  See Section 6.2 for guidance on treatment duration.
7.
Study Treatment Talazoparib (Arms A and B, Maintenance Period Only): Talazoparib will be self-administered orally once per day at 0.75mg and will continue through end 
of Maintenance treatment.  On Days 1, 15, and 29 of each Maintenance cycle, the daily dose of talazoparib should not be taken prior to the study visit and will be taken at the 
clinic after all procedures/assessments have been completed and for patients randomized to Arm A, before the avelumab infusion.  See Section 6.2 for guidance on treatment 
duration.
8.
Study Treatment Bevacizumab (Arm C Only): Patients will receive bevacizumab 15mg/kg administered once every 3 weeks intravenously on Day 1 of Cycle 2, 3, 4, 5, and 
6 of chemotherapy (may begin with cycle 1 if surgery completed >4 weeks prior to randomization and no contraindications) for adjuvant patients, and on Day 1 of Cycles 1, 
2, 5, and 6 for neoadjuvant patients.  During Maintenance, bevacizumab will be administered once every 3 weeks intravenously on Days 1 and 22 of each cycle.  See 
Section 6.2 for guidance on treatment duration.
9.
Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v 4.03.  
10. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded in the patient’s source document.  However, these do not need to be captured 
in the INFORM database unless they contribute or are associated with the treatment for an AE.
11. Tumor Assessments: Tumor response assessments will be performed per institutional guidelines and investigator’s discretion.
12. End of Treatment/Withdrawal: Performed when criteria for treatment discontinuation are met.  Obtain these assessments if not completed within the prior week.
13. Short-Term Follow-up: All patients will be followed for safety every 30 days (3 days) through 90 days after the last dose of study treatment.

SAP_001.pdf: 
Avelumab 
B9991030 (MSB0010718C, MDV3800, BMN 673) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 1 
 
JAVELIN OVARIAN PARP 100  
A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB IN COMBINATION 
WITH CHEMOTHERAPY FOLLOWED BY MAINTENANCE THERAPY OF 
AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE DIPHOSPHATE 
[ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR TALAZOPARIB IN 
PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OVARIAN CANCER 
 
STATISTICAL ANALYSIS PLAN – B9991030 
 
Compounds:  
MSB0010718C 
MDV3800, BMN 673 
 
Compound Name: 
Avelumab 
Talazoparib 
Version: 
1.0 
Date: 
29-May-2018 
 
 
 
 
 
 
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by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
 
 


A vel u ma b 
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P FI Z E R C O N FI D E N TI A L 
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T A B L E O F C O N T E N T S 
LI S T O F T A B L E S ..................................................................................................................... 6  
LI S T O F FI G U R E S ................................................................................................................... 7  
A P P E N DI C E S ........................................................................................................................... 7  
1. V E R SI O N HI S T O R Y ............................................................................................................ 8  
2. I N T R O D U C TI O N ................................................................................................................. 8 
2. 1. S t u d y O bjecti ves ....................................................................................................... 8 
2. 2. S t u d y Desi g n ........................................................................................................... 1 0 
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI NI TI O N S A N D 
C O N V E N TI O N S ................................ ................................................................................ 1 1 
3. 1. P ri mar y E n d p oi nt .................................................................................................... 1 1 
3. 2. S ec o n dar y E n d p oi nts ............................................................................................... 1 1  
3. 2. 1. Safet y e n d p oi nts .......................................................................................... 1 1  
3. 2. 2. Ef ficac y e n d p oi nts ...................................................................................... 1 1 
3. 2. 3. P atie nt re p orte d o utc o mes ........................................................................... 1 2  
3. 2. 4. P har mac o ki netic e n d p oi nts ......................................................................... 1 2  
3. 2. 5. I m m u n o ge nicit y e n d p oi nts ......................................................................... 1 3 
3. 2. 6. B i o mar ker e n d p oi nts ................................................................................... 1 3 
 
3. 4. B aseli ne Varia bl es ................................................................................................... 1 5  
3. 4. 1. S t u d y dr u g, st u d y treat me nt, a n d baseli ne defi niti o ns ................................ 1 5 
3. 4. 2. B aseli ne c haracteristics ............................................................................... 1 6  
3. 5. S afet y E n d p oi nts ..................................................................................................... 1 7  
3. 5. 1. A d ve rse e ve nts ............................................................................................ 1 7 
4. A N A L Y SI S S E T S ............................................................................................................... 1 8  
4. 1. F ull A nal ysis Set ..................................................................................................... 1 8  
4. 2. S afet y A nal ysis Set ................................................................................................ ..1 8  
4. 3. Ot her A nal ysis Set ................................................................................................... 1 8  
4. 3. 1. Per- pr ot oc ol a n al ysis set ............................................................................. 1 8  
4. 3. 2. P K a nal ysis sets .......................................................................................... 2 0  
4. 3. 3. Bi o mar ker a nal ysis sets .............................................................................. 2 0  
4. 3. 4. I m m u n o ge nicit y a nal ysis set ....................................................................... 2 0 
 
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5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................20 
5.1. Hypotheses and Decision Rules ..............................................................................20 
5.1.1. Hypotheses and sample size determination ................................................21 
5.1.2. Decision rules .............................................................................................24 
5.2. General Methods .....................................................................................................29 
5.2.1. Data handling after the cut-off date ............................................................30 
5.2.2. Pooling of centers .......................................................................................30 
5.2.3. Presentation of continuous and qualitative variables ..................................30 
5.2.4. Definition of study day ...............................................................................30 
5.2.5. Definition of start of new anti-cancer drug therapy ....................................31 
5.2.6. Definition of start of new anti-cancer therapy ............................................31 
5.2.7. Definition of on-treatment period ...............................................................31 
5.2.8. Standard derivations and reporting conventions .........................................32 
5.2.9. Unscheduled visits ......................................................................................32 
5.2.10. Adequate baseline tumor assessment ........................................................32 
5.2.11. Adequate post-baseline tumor assessment................................................33 
5.3. Methods to Manage Missing Data ..........................................................................33 
5.3.1. Missing data ................................................................................................33 
5.3.1.1. Pharmacokinetic concentrations ................................................33 
5.3.2. Handling of incomplete dates .....................................................................34 
5.3.2.1. Disease history ..........................................................................34 
5.3.2.2. Adverse events ..........................................................................34 
5.3.2.3. Prior and concomitant medications ...........................................35 
5.3.2.4. Exposure ....................................................................................35 
5.3.3. Imputation rules for date of last contact and efficacy assessments ............36 
5.3.3.1. Date of last contact ....................................................................36 
5.3.3.2. Death date ..................................................................................36 
5.3.3.3. Tumor assessments ....................................................................36 
5.3.3.4. Date of start of new anti-cancer therapy ...................................37 
5.3.3.5. PRO data ...................................................................................39 
6. ANALYSES AND SUMMARIES ......................................................................................39 
6.1. Primary Endpoint ....................................................................................................39 


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6. 1. 1. Pr o gressi o n-free s ur vi val as assesse d b y BI C R per R E CI S T v 1. 1 i n 
t he D D R + p o p ulati o n ....................................................................................... 3 9  
6. 1. 1. 1. P ri mar y a nal ysis ........................................................................ 3 9 
6. 1. 1. 2. A nal ysis i n Ar m B vers us Ar m C .............................................. 4 2  
6. 2. S ec o n dar y E n d p oi nt(s) ............................................................................................ 4 2  
6. 2. 1. S afet y e n d p oi nts .......................................................................................... 4 2  
6. 2. 2. Ef ficac y e n d p oi nts ...................................................................................... 4 2 
6. 2. 2. 1. P r o gressi o n-free s ur vi val as assesse d b y BI C R per 
R E CI S T v 1. 1 i n patie nts u nselecte d f or D D R stat us ......................... 4 2  
6. 2. 2. 2. O ve rall s ur vi val i n t he D D R + p o p ulati o n a n d i n patie nts 
u nselecte d f or D D R stat us ................................................................ .4 3  
6. 2. 2. 3. Se nsiti vit y a n al yses f or pr o gressi o n-free s ur vi val..................... 4 4  
6. 2. 2. 4. S e nsiti vit y a n al yses f or o verall s ur vi val .................................... 4 8  
6. 2. 2. 5. P F S 2 .......................................................................................... 4 8  
6. 2. 2. 6. P F S b y G CI G criteria base d o n i n v esti gat or assess me nt .......... 5 0  
6. 2. 3. P har mac o ki netic e n d p oi nts ......................................................................... 5 1  
6. 2. 4. P o p ulati o n p har mac o ki netic e n d p oi nts ....................................................... 5 2  
6. 2. 5. B i o mar ker e n d p oi nts ................................................................................... 5 2 
6. 2. 6. E n d p oi nt s f or i m m u n o ge ni cit y d ata of a v el u ma b ....................................... 5 3 
6. 2. 6. 1. Ti m e t o a n d D urati o n of A D A a n d n A b res p o nse ..................... 5 5  
6. 2. 6. 2. A D A titer ................................................................................... 5 6  
6. 2. 6. 3. A na l ysis of P K, safet y a n d efficac y b y i m m u n o ge nicit y 
stat us .................................................................................................. 5 6 
6. 3. Ot he r E n d p oi nts ....................................................................................................... 5 9 
 
6. 3. 2. P R O e n d p oi nts ............................................................................................ 6 0  
6. 3. 2. 1. S c ori n g pr oce d ure ..................................................................... 6 0  
6. 3. 2. 2. I nstr u m e nt c o m pleti o n rates ...................................................... 6 1  
6. 3. 2. 3. Descri pti ve s u m maries o ver ti me .............................................. 6 1  
6. 3. 2. 4. Ti me- t o-e ve nt e n d p oi nts ...........................................................6 1  
6. 3. 2. 5. C o nti n u o us e n d p oi nts ................................................................ 6 3  
 
6. 4. S u bset A nal yses ....................................................................................................... 6 3  
6. 5. B aseli ne a n d Ot her S u m maries a n d A nal yses ......................................................... 6 6  
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6.5.1. Baseline summaries ....................................................................................66 
6.5.1.1. Demographic characteristics .....................................................66 
6.5.1.2. Medical history ..........................................................................67 
6.5.1.3. Disease characteristics ...............................................................67 
6.5.1.4. Prior anti-cancer surgery ...........................................................68 
6.5.2. Study conduct and patient disposition ........................................................68 
6.5.2.1. Patient disposition .....................................................................68 
6.5.2.2. Protocol deviations ....................................................................69 
6.5.3. Study treatment compliance and exposure .................................................69 
6.5.3.1. Exposure to avelumab ...............................................................71 
6.5.3.2. Exposure to paclitaxel ...............................................................73 
6.5.3.3. Exposure to carboplatin .............................................................73 
6.5.3.4. Exposure to bevacizumab ..........................................................74 
6.5.3.5. Exposure to talazoparib .............................................................76 
6.5.3.6. Dose reductions .........................................................................76 
6.5.3.7. Dose interruptions .....................................................................77 
6.5.3.8. Dose delays ...............................................................................77 
6.5.3.9. Infusion rate reductions .............................................................78 
6.5.3.10. Infusion interruptions ..............................................................78 
6.5.4. Concomitant medications and non-drug treatments ...................................78 
6.5.5. Subsequent anti-cancer therapies ................................................................79 
6.6. Safety Summaries and Analyses .............................................................................79 
6.6.1. Adverse events ............................................................................................80 
6.6.1.1. All adverse events .....................................................................81 
6.6.1.2. Adverse events leading to dose reduction .................................82 
6.6.1.3. Adverse events leading to interruption of study treatment .......83 
6.6.1.4. Adverse events leading to discontinuation of study 
treatment ............................................................................................84 
6.6.2. Deaths .........................................................................................................84 
6.6.3. Serious adverse events ................................................................................85 
6.6.4. Other significant adverse events .................................................................85 
6.6.5. Laboratory data ...........................................................................................88 
6.6.5.1. Hematology and chemistry parameters .....................................88 


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6.6.5.2. Other laboratory parameters ......................................................91 
6.6.6. Vital signs ...................................................................................................91 
6.6.7. Electrocardiogram .......................................................................................92 
6.6.8. Physical examination ..................................................................................92 
6.6.9. ECOG performance status ..........................................................................92 
7. INTERIM ANALYSES .......................................................................................................92 
7.1. Introduction .............................................................................................................92 
7.2. Interim Analyses and Summaries ............................................................................92 
7.2.1. Interim analysis for PFS in the DDR+ population......................................92 
7.2.2. Interim analysis for PFS in patients unselected for DDR status .................93 
7.2.3. Interim analysis for OS in the DDR+ population .......................................94 
7.2.4. Interim analysis for OS in patients unselected for DDR status ..................94 
8. REFERENCES ....................................................................................................................96 
9. APPENDICES .....................................................................................................................98 
 
LIST OF TABLES 
Table 1.  
Summary of Major Changes in SAP Amendments ................................................8 
Table 2.  
PK Parameters to be Determined for Avelumab and Talazoparib .......................13 
Table 3.  
Biomarker Definition and Determination .............................................................13 
Table 4.  
Statistical Analyses by Analysis Set .....................................................................18 
Table 5.  
Operating Characteristics for PFS in the DDR+ Population (Arm B vs Arm 
C) ..........................................................................................................................24 
Table 6.    PFS Based on BICR Assessment in the DDR+ Population (Arm A vs Arm 
C) - Efficacy and Futility Boundaries ...................................................................25 
Table 7.  
Simulated Cumulative Probabilities to Stop for Efficacy or Futility at the 
Interim or Final PFS Analysis in the DDR+ Population (Arm A vs Arm C) .......26 
Table 8.  
PFS Based on BICR Assessment in Patients Unselected for DDR status 
and OS in the DDR+ Population (Arm A vs Arm C) - Efficacy Boundaries .......27 
Table 9.  
Simulated Cumulative Probabilities to Stop for Efficacy at the Interim or 
Final PFS Analysis in Patients Unselected for DDR Status (Arm A vs 
Arm C) ..................................................................................................................27 
Table 10.   Simulated Cumulative Probabilities to Stop for Efficacy at the Interim or 
Final OS Analysis in the DDR+ Population (Arm A vs Arm C)..........................28 
Table 11.  OS in Patients Unselected for DDR Status (Arm A vs Arm C) – Efficacy 
Boundaries ............................................................................................................28 


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Ta ble 1 2.  Si m ulate d C u m ulati ve Pr o ba bilities t o St o p f or Efficac y at t he I nteri m or 
Fi nal O S A nal ysis i n Patie nts U nselecte d f or D D R Stat us, Ass u mi n g α 
Le v el of 0. 0 2 5 ( Ar m A vs Ar m C)  ....................................................................... 2 9 
Ta ble 1 3.  O utc o me a n d E ve nt D ates f or P F S A nal yses ....................................................... 4 0  
Ta ble 1 4.  P F S Ce ns ori n g Reas o ns a n d Hierarc h y ................................................................ 4 1  
Ta ble 1 5.  O S Ce ns ori n g Reas o ns a n d Hierarc h y .................................................................. 4 4  
Ta ble 1 6.  P ossi ble O utc o mes f or I n vesti gat or vs BI C R ....................................................... 4 6  
Ta ble 1 7.  O utc o me, E ve nt Dat es, Ce ns ori n g R eas o ns a n d Hi erarc h y f or P F S 2 
A na l ys es ................................................................................................................ 4 9 
Ta ble 1 8.  Ce ns ori n g Reas o ns a n d Hierarc h y f or P F S b y G CI G Criteria Base d o n 
I n v esti gat or Assess me nt ....................................................................................... 5 1 
Ta ble 1 9.  Patie nts C haracteriz e d Base d o n A nti- Dr u g A nti b o d y Res ults ( A D A 
Stat us) ................................................................................................................... 5 4  
Ta ble 2 0.   Patie nts C haracteriz e d Base d o n Ne utr alizi n g A nti b o d y Res ults ( n A b 
Stat us) ................................................................................................................... 5 5  
  
 
Ta ble 2 2.   Case Defi niti o n f or ir A Es ..................................................................................... 9 8  
Ta ble 2 3.  Case Defi niti o n f or I R Rs – I V St u d y Dr u gs A d mi nistere d Al o ne Or I n 
C o m bi nati o n Wit h N o n-I V St u d y Dr u gs ............................................................ 1 0 0  
Ta ble 2 4.  Case Defi niti o n f or I R Rs – I V St u d y Dr u gs A d mi nistere d i n C o m bi nati o n 
(eg, D o u blets or Tri plets) .................................................................................... 1 0 1  
 
L I S T O F FI G U R E S 
Fi g ure 1.  St u d y Desi g n Sc he ma ........................................................................................... 1 0  
F i g ure 2.   Statistical Testi n g Strate g y f or Ar m A vs Ar m C C o m paris o ns ........................... 2 1  
 
A P P E N DI C E S 
A p pe n di x 1. I m m u ne- Relate d A d verse E ve nts ........................................................................ 9 8  
A p pe n di x 2. I nf usi o n Rel ate d Reacti o ns ............................................................................... 1 0 0  
 
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1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study B9991030 is based on the protocol dated 
30MAR2018.   
Table 1.  
Summary of Major Changes in SAP Amendments 
Version Version Date 
Summary of Changes 
1 
29-May-2018 
Not applicable (N/A) 
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991030.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment. 
A separate SAP will cover the interim analyses for periodic safety review by the External 
Data Monitoring Committee (E-DMC). 
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie, 
pharmacokinetic (PK) concentration, anti-drug antibodies (ADA; neutralizing antibody 
[nAb]), supplemental biomarker data, and tumor assessment results by the Blinded 
Independent Central Review [BICR]). The primary analysis will include all data up to a cut-
off date which is determined by the number of events for progression-free survival (PFS) by 
BICR in patients with advanced ovarian cancer with defects in DNA damage repair (DDR+) 
and minimum follow-up of 12 months. The cut-off date is determined once a data extract 
(before database lock) is available which indicates that the required number of events for PFS 
by BICR in the DDR+ population and minimum follow-up of 12 months is expected to occur 
by the cut-off date.  
Due to cleaning activities, the final number of events might deviate from the planned 
number. The data cut-off date will not be adjusted retrospectively in this case.   
2.1. Study Objectives 
Primary Objective 
To demonstrate that avelumab in combination with platinum-based chemotherapy followed 
by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus 
bevacizumab followed by bevacizumab maintenance in prolonging PFS in patients with 
advanced ovarian cancer with defects in DNA damage repair (DDR+). 
Secondary Objectives 
 To demonstrate that avelumab in combination with platinum-based chemotherapy 
followed by avelumab plus talazoparib maintenance is superior to platinum-based 
chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging 
overall survival (OS) in patients with advanced ovarian cancer with defects in DNA 
damage repair (DDR+).  


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 T o de m o nstrate t hat a v el u ma b i n c o m bi nati o n wit h plati n u m- base d c he m ot hera p y 
f oll o we d b y a vel u ma b pl us talaz o pari b mai nte na n ce is s u peri or t o plati n u m- base d 
c he m ot hera p y pl us b e vaciz u ma b f oll o we d b y be v aciz u ma b mai nte na nce i n pr ol o n gi n g 
P F S i n patie nts wit h a d va nce d o vari a n ca n cer u nselecte d f or D D R stat us. 
 T o de m o nstrate t hat a v el u ma b i n c o m bi nati o n wit h plati n u m- base d c he m ot hera p y 
f oll o we d b y a vel u ma b pl us talaz o pari b mai nte na n ce is s u peri or t o plati n u m- base d 
c he m ot hera p y pl us b e vaciz u ma b f oll o we d b y be v aciz u ma b mai nte na nce i n pr ol o n gi n g 
O S i n patie nts wit h a d va nce d o vari a n ca n cer u nselecte d f or D D R stat us. 
 T o e val uate t he effect o n P F S a n d O S of plati n u m- base d c he m ot hera p y f oll o we d b y 
talaz o pari b mai nte na nce vers us plati n u m- base d c h e m ot hera p y pl us be v aciz u ma b 
f oll o we d b y be vaciz u ma b mai nte na nce i n p atie nts wit h a d va nce d o v aria n ca ncer wit h 
D D R + a n d u nsele cte d f or D D R stat us. 
 T o e val uate t he a nti-t u m or acti vit y i n eac h tr eat m e nt ar m. 
 T o e val uate t he o v erall s afet y pr ofile i n eac h tr eat me nt ar m.  
 T o e val uate t he P K of a v el u ma b i n c o m bi nati o n wit h plati n u m- base d c he m ot hera p y 
f oll o we d b y a vel u m a b pl us talaz o pari b mai nte na n ce i n Ar m A as well as w ell as P K of 
talaz o pari b i n c o m bi nati o n wit h a vel u ma b ( Ar m A) a n d as a si n gle a ge nt ( Ar m B). 
 T o e val uate t he i m m u n o ge ni cit y of a vel u ma b i n Ar m A (a v el u ma b i n c o m bi nati o n wit h 
plati n u m- base d c he m ot h era p y f oll o we d b y a vel u ma b pl us talaz o pari b mai nte na nce a n d 
avel u ma b i n c o m bi nati o n wit h plati n u m- base d c he m ot hera p y). 
 T o e val uate t he effect of a vel u ma b i n c o m bi nati o n wit h plati n u m- base d c he m ot hera p y 
f oll o we d b y a vel u ma b pl us talaz o pari b mai nte na n ce a n d plati n u m- bas e d c h e m ot hera py 
f oll o we d b y talaz o pari b mai nte na nce v ers us plati n u m- base d c h e m ot hera p y pl us 
be vaciz u ma b f oll o we d b y be v aciz u ma b mai nte na nce o n patie nt r e p orte d o utc o me ( P R O) 
i ncl u di n g t he ass ess me nts of disease-relate d s y m pt o ms, treat me nt si de effects a n d healt h-
relate d q ualit y of life ( H R Q o L). 
 T o a ssess t he c orrelati o n of a nti-t u m or acti vit y wit h P D- L 1 e x pressi o n, t u m or m utati o nal 
b ur de n ( T M B) a n d wit h p ote ntial bi o mar kers of P A R P i n hi bit or se nsiti vit y i n baseli ne 
t u m or tiss ue. 
 T o assess t he c orrelati o n of a nti-t u m or acti vit y wit h T M B a n d p ote ntial bi o mar kers of 
P A R P i n hi bit or se nsiti vit y i n baseli ne circ ul ati n g t u m or (ct) D N A. 
 
 
 
 
 
 
 
 
 
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2. 2.  St u d y Desi g n 
T his is a P hase 3, ra n d o mize d, o pe n-la bel, m ultice nter st u d y t o e val uat e t he effi cac y a n d 
safet y of a v el u ma b i n c o m bi nati o n wit h c he m ot hera p y f oll o we d b y mai nte na nce t hera p y of 
a vel u ma b i n c o m bi nati o n wit h t he P A R P i n hi bit or talaz o pari b i n patie nts wit h pre vi o usl y 
u ntre ate d a d v a nce d o vari a n ca n cer.   
T he st u d y d esi g n is ill ustrate d i n t he f oll o wi n g fi g ure.  
Fi g ure 1.  St u d y Desi g n Sc he m a 
 
C r oss o ver bet wee n treat me nt ar ms will n ot be per mitte d.  Ra n d o mizati o n will be stratifie d b y 
g er mli ne B R C A 1/ 2 m utati o nal stat us ( g B R C A + vs g B R C A-) a n d resecti o n stat us (a dj u va nt 
wit h > 1 m m a n d ≤1 c m r esi d ual disease vs a dj u v a nt wit h > 1 c m resi d ual disease vs 
ne oa dj u va nt). 
I ntr a ve n o us car b o plati n a n d paclita xel will be use d as t he c h e m ot hera p y bac k b o ne, c o nsisti n g 
of e ver y 3 wee k ( Q 3 W) car b o plati n a n d paclita xel. 
Patie nts ma y be e nr olle d eit her f oll o wi n g pri mar y de b ul ki n g s ur ger y ( P D S), or pri or t o 
i nitiati o n of ne oa dj u va nt c he m ot hera p y. T he latter gr o u p will u n der g o i nter val de b ul ki n g 
C
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B9991030 (MSB0010718C, MDV3800, BMN 673) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 11 
surgery (IDS) after 3 study cycles of chemotherapy (plus avelumab in Arm A, or plus 
bevacizumab in Arm C) to be followed, upon recovery from surgery, by the remainder of 
chemotherapy (plus avelumab in Arm A, or plus bevacizumab in Arm C). 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint 
 PFS as determined based on BICR assessment per RECIST v1.1 in patients with newly 
diagnosed advanced ovarian cancer with defects in DNA damage repair (DDR+). 
PFS is defined as the time from the date of randomization to the date of the first 
documentation of progressive disease (PD) or death due to any cause, whichever occurs 
first.   
3.2. Secondary Endpoints 
3.2.1. Safety endpoints 
 AEs (as graded by National Cancer Institute [NCI] Common Terminology Criteria for 
Adverse Events [CTCAE] v4.03); laboratory abnormalities (as graded by NCI CTCAE 
v4.03); vital signs (blood pressure, pulse rate); electrocardiograms (ECGs).  
AEs will be graded by the investigator according to CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
3.2.2. Efficacy endpoints 
 OS in patients with tumors that are DDR+ and in patients unselected for DDR status.  
OS is defined as the time from the date of randomization to the date of death due to any 
cause. 
 PFS based on BICR assessment per RECIST v1.1 in patients unselected for DDR status. 
 PFS based on investigator assessment per RECIST v1.1 in patients with tumors that are 
DDR+ and in patients unselected for DDR status. 
 PFS2 based on investigator assessment in patients with tumors that are DDR+ and in 
patients unselected for DDR status.  
PFS2 is defined as time from the date of randomization to the start of second subsequent 
treatment after first documentation of PD, or death from any cause, whichever occurs 
first. 
 PFS based on investigator assessment per Gynecological Cancer Intergroup (GCIG) 
criteria in patients with tumors that are DDR+ and in patients unselected for DDR status.  
PFS by GCIG criteria will be assessed in this study incorporating both RECIST v1.1 and 
CA-125 (Rustin, G et.al, 2011).  


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3.2.3. Patient reported outcomes  
 Disease related symptoms and treatment side effects as measured by the NCCN-FACT 
FOSI-18 and health-related quality of life (HRQOL) as measured by NCCN-FACT 
FOSI-18 and the EuroQol Group 5-Dimension 5-Level (EQ-5D-5L).  
NFOSI-18 (Jensen et al. 2011, Jensen et al. 2015) is an ovarian cancer-specific symptom 
index comprised of symptoms rated as highest priority by both oncology clinical experts 
and women with advanced ovarian cancer. The NFOSI-18 was developed to be part of 
the Functional Assessment of Chronic Illness Therapy (FACIT) system and was 
specifically created with the input from the Food and Drug Administration (FDA), 
including the recommendation that the assessment of specific symptoms is an appropriate 
starting point for improved measurement of QoL domains.  It is specifically designed to 
be a stand-alone instrument to measure disease-related symptoms, treatment side effects 
and function/well-being in patients with ovarian cancer. 
The disease-related symptoms subscale is composed of the disease related symptoms- 
physical (DRS-P) domain which included 9 physical symptoms/concerns (energy, pain, 
ill, stomach cramps, fatigue, constipation, stomach swelling, bowel control, and sleep) 
and the disease related symptoms-emotional (DRS-E) which included 1 emotional 
symptom/concern (worry condition will get worse).  The treatment side effect (TSE) 
subscale included 5 items (nausea, hair loss, bothered by side effects, vomiting, and skin 
problems).  The functional well-being (FWB) subscale included 3 items (able to get 
around, enjoy life, and content with QoL).  As with all FACIT questionnaires, a high 
score is good.  Therefore, a score of “0” is a severely symptomatic patient and the highest 
possible score is an asymptomatic patient.   
The EuroQol EQ-5D-5L (Herdman at al. 2011; Rabin and de Charro 2001) is a 6 item 
patient-completed questionnaire designed to assess health status in terms of a single index 
value or utility score.  There are 2 components to the EQ-5D-5L, a Health State Profile 
which has individuals rate their level of problems (none, slight, moderate, severe, 
extreme/unable) in 5 areas (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression), and a Visual Analogue Scale (VAS) in which patients rate their 
overall health status from 0 (worst imaginable) to 100 (best imaginable).  Published 
weights are available that allow for imputation of the index score.  Overall index scores 
range from 0 to 1, with low scores representing a higher level of dysfunction. 
3.2.4. Pharmacokinetic endpoints 
 PK parameters, including Ctrough and Cmax for avelumab and Ctrough for talazoparib. 
PK parameters [Cmax and Ctrough for avelumab (Arm A) and Ctrough for talazoparib (Arms 
A and B)] will be reported after single dose and at steady state.  For talazoparib, dose 
normalized Ctrough [Ctrough(dn)] will also be determined, as appropriate.  


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P FI Z E R C O N FI D E N TI A L 
P a ge 1 3  
T a ble 2.  
P K P ar a meters t o be Deter mi ne d f or A vel u m a b a n d T al az o p ari b  
P ar a meter  
Defi niti o n  
M et h o d of Deter mi n ati o n  
C ma x  
Ma xi m u m o bser ve d plas ma c o nce ntrati o n 
f or a vel u ma b 
O bser ve d directl y fr o m data  
C tr o u g h 
Pre d ose c o nce ntrati o n d uri n g m ulti ple 
d osi n g  
O bser ve d directl y fr o m data  
C tr o u g h( d n) 
D ose n or malize d C tr o u g h f or tal az o pari b 
C tr o u g h / D ose 
 
3. 2. 5.  I m m u n o ge nicit y e n d p oi nts 
 A nti - dr u g a nti b o dies ( A D A) a n d n e utralizi n g a nti b o d y ( nA b ) agai nst a v el u ma b. 
3. 2. 6.   Bi o m ar ker e n d p oi nts 
 P D -L 1 e x pressi o n, T M B, ge n o mic s carri n g a n d t h e prese n ce of defects i n select ge n es, 
c o nsi dere d critical t o effecti ve D D R, i n baseli ne t u m or tiss ue.   
 Asse ss me nt of defects i n a pa nel of k e y o nc o ge n es, i ncl u di n g se veral c o nsi d ere d critical 
t o effecti ve D D R a n d T M B i n ct D N A at baseli ne. 
T a ble 3 .  
Bi o m ar ker Defi niti o n a n d Deter mi n ati o n 
P ar a meter  
Defi niti o n  
M et h o d of Deter mi n ati o n  
P D -L 1 e x pressi o n  
T he n u m ber of P D -L 1 p ositi ve cells a n d/ or 
q ualitati ve assess me nt of  P D -L 1 stai ni n g o n 
t u m or a n d i nfla m mat or y cells i n re gi o ns of 
i nterest t hat are defi ne d b y t u m or cell 
m or p h ol o g y a n d t he prese nce or a bse nce of 
i nfla m mat or y cells 
P at h ol o gi st, assiste d b y i ma ge 
a nal ysis  
Ge n o mic scarri n g a n d  
t he P rese nce of defects 
i n select ge nes, 
c o nsi dere d critical t o  
effecti ve D D R, i n  
baseli ne t u m or tiss ue  
Q ua ntitati o n of ge n o mic scarri n g i n t he f or m  
of l oss of heter oz y g osit y;  
T he n u m ber of s o matic a n d ger mli ne 
m utati o ns prese nt i n a pa nel of ge nes 
ass ociate d wit h D D R  i n baseli ne t u m or 
deri ve d n ucleic aci d, i n ger mli ne n ucleic aci d 
a n d i n circ ulati n g t u m or D N A.  
Ne xt ge nerati o n se q ue nci n g  
f oll o we d b y c o m p utati o nal 
a nal ysis  
T M B  
Deter mi nati o n/esti mati o n of t he fre q ue nc y of 
m utati o ns (t otal a n d n o n -s y n o n y m o us) prese nt 
i n baseli ne t u m or deri ve d n ucl eic aci d 
sa m ples a n d i n baseli ne circ ul ati n g t u m or 
D N A.  
W h ole e x o me or ge n o me 
se q ue nci n g a n d/ or R N Ase q 
 
 
 
 
 
 
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P a ge 1 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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P a ge 1 5  
 
 
 
 
 
    
3. 4.  B aseli ne V ari a bles 
3. 4. 1.  St u d y dr u g, st u d y tre at me nt, a n d b aseli ne d efi niti o ns 
In t his st u d y, ‘ st u dy dr u g ’ refers t o a vel u ma b, p aclita xel, car b o plati n, be v aciz u ma b, or 
talaz o pari b a n d ‘st u d y tre at me nt’ ( or ‘tre at me nt ar m’) refers t o o ne of t h e f oll o wi n g: 
 Ar m A = plati n u m- base d c he m ot hera p y + a v el u ma b f oll o we d b y a v el u ma b + talaz o pari b 
mai nte na nce; 
 Ar m B = pl ati n u m- base d c he m ot hera p y f oll o we d b y talaz o pari b mai nte n a nce; 
 Ar m C = plati n u m- base d c he m ot hera p y + be v aciz u ma b f oll o we d b y be vaci z u ma b 
mai nte na nce. 
St art a n d e n d d ates of st u d y tre at me nt:   
T he date/ti me of first d os e of st u d y treat me nt i n a c o m bi nati o n ar m is t he earliest date/ti me of 
t he first n o n-zer o d ose date/ti me f or t he st u d y dr u gs i n t he c o m bi nati o n.  
T he  date/ti me of last d os e of st u d y treat me nt i n a c o m bi nati o n ar m is t he latest date/ti me of 
t he last n o n-zer o d ose dat e/ti me f or t he st u d y dr u gs i n t he c o m bi nati o n. 
De fi niti o n of b aseli ne:  
Defi niti o n of baseli ne f or effic ac y a n d P R O a n al ys es  
T he last meas ur e me nt pri or t o ra n d o mizati o n will ser ve as t he b aseli ne meas ure me nt f or 
effic ac y a n d P R O  a n al ys es. If s uc h a val ue is missi n g (si nce per pr ot oc ol t he first P R O 
assess me nt is pla n ne d t o occ ur pri or t o d osi n g o n C ycle 1 Da y 1), t he l ast meas ure me nt pri or 
t o t he first d ose of st u d y treat me nt will be use d as t he baseli ne meas ure me nt e x ce pt f or 
a nal ys es of t u m or ass ess me nts data w here t he bas eli ne assess me nt w o ul d b e c o nsi dere d as 
missi n g.   
Defi niti o n of baseli ne f or i m m u n o ge nicit y a nal yses 
T he last a vaila ble assess me nt pri or t o t he start of treat me nt wit h a vel u ma b is defi ne d as 
‘ baseli ne’ res ult or ‘ bas eli ne’ assess me nt.  If a n assess me nt is pla n ne d t o be perf or me d pri or 
t o t he first d ose of a vel u ma b i n t he pr ot oc ol a n d t he assess me nt is perf or m e d o n t he sa me da y 
as t he first d ose of a vel u ma b, it will be ass u me d t hat it was perf or me d pri or t o a vel u ma b 
a d mi nistrati o n, if assess me nt ti me p oi nt is n ot c ollecte d or is missi n g. 
C
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Definition of baseline for safety analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for safety analyses.  If an assessment is planned to be 
performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration. 
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection.  
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
Definition of baseline for biomarker analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for biomarker analyses. For biomarkers that are planned to be 
measured on Cycle 1 Day 1 (eg, soluble proteins), if the assessment time point is not 
collected or is missing, it will be assumed that the measurement was performed prior to first 
dose of study treatment. 
3.4.2. Baseline characteristics 
Randomization is stratified by the following, as recorded in the Interactive Response 
Technology (IRT): 
 Germline BRCA 1/2 mutational status (gBRCA+ vs gBRCA-)  
 Resection status (adjuvant with >1 mm and ≤1 cm residual disease vs adjuvant with >1 
cm residual disease vs neoadjuvant). 
The primary analyses of PFS in the DDR+ population, as well as secondary analyses of OS 
in the DDR+ population, and PFS and OS in patients unselected for DDR status will be 
stratified by these randomization stratification factors. 
Patients will be defined as having defective DDR (DDR+) or having intact DDR (DDR-) 
using an analytically validated, investigational use only (IUO)-labelled next generation 
sequencing-based assay developed by Foundation Medicine.  The test and its associated 
technology will be executed by Foundation Medicine at their design controlled facility as a 
single centralized site.  The assay will assess baseline formalin fixed paraffin embedded 
tumor tissue from each patient for defects in the BRCA1 and BRCA2 genes as well as for the 


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degree of loss of heterozygosity (LOH) present.  Patients’ tumors will be defined as DDR+ if 
they have a defect in either BRCA1 or BRCA2 or if they have an LOH score above a 
predefined and analytically validated cut-off.  All other patients’ tumors will be defined as 
DDR-. 
Other baseline characteristics (including demographics, physical measurements, disease 
history, and prior anti-cancer surgery) are described in Section 6.5.1.  These baseline 
characteristics are not planned to be included as stratification variables or covariates in 
statistical models unless otherwise specified in Section 5.3.3.5.   
3.5. Safety Endpoints 
3.5.1. Adverse events 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period.  
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy – 
1 day).  The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5. 
Adverse Events of Special Interest (AESIs) 
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendix 1 and 
Appendix 2, respectively. 
3-Tier Adverse Events 
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analyses are 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates these exploratory analyses. 
Adverse events and clusters of adverse events, of any causality and treatment-related, will 
also be summarized following a 3-tier approach.  Under this approach, AEs are classified into 
1 of 3 tiers.   
Tier-1 events: These are pre-specified events or clusters of events of clinical importance and 
will be described in the Safety Review Plan.   
Tier-2 events: These are events that are not Tier-1 but are “common”.  A MedDRA PT is 
defined as a Tier-2 event if it is reported by  


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a) at least 10% of patients with any grade in any treatment arm, or 
b) at least 5% of patients with Grade 3, 4 or 5 in any treatment arm.   
Tier-3 events: All other AEs that are classified neither as Tier-1 nor Tier-2. 
4. ANALYSIS SETS 
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures. 
Only patients who signed informed consent will be included in the analysis sets below. 
Table 4 summarizes the use of the analysis sets for efficacy, safety, baseline characteristics, 
and exposure.  
Table 4.  
Statistical Analyses by Analysis Set 
Endpoints 
Full Analysis Set 
Per Protocol Analysis Set 
Safety Analysis Set 
Baseline Characteristics 
 
 
 
Prior and Concomitant Therapies 
 
 
 
Exposure 
 
 
 
Efficacy: Primary  
 
 
 
Efficacy: Secondary  
 
(key secondary endpoints 
only*) 
 
Efficacy: Exploratory 
 
 
 
Safety 
 
 
 
* Key secondary endpoints are OS in the DDR+ population, and PFS based on BICR assessment per RECIST v1.1 and OS 
in patients unselected for DDR status. 
4.1. Full Analysis Set 
The full analysis set (FAS) will include all randomized patients.  Patients will be classified 
according to the study treatment assigned at randomization.  
4.2. Safety Analysis Set 
The safety analysis set will include all patients who receive at least one dose of study drug. 
Patients will be classified according to the study treatment assigned at randomization unless 
the incorrect treatment(s) was/were received throughout the dosing period in which case 
patients will be classified according to the first study treatment received.  
4.3. Other Analysis Set 
4.3.1. Per-protocol analysis set 
Per protocol (PP) analysis set is a subset of the FAS and will include patients who do not 
meet any of the following criteria that could impact the key objectives of the study.   


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Patients who meet any of the following criteria will be excluded from the PP analysis set 
for PFS by BICR.  
 Patient did not receive at least one dose of chemotherapy in the chemotherapy period 
 Patient randomized to Arm A who did not receive at least one dose of avelumab 
 Patient randomized to Arm C who did not receive at least one dose of bevacizumab 
 Patient received a study drug to which he/she was not assigned at randomization  
 Patient without a tumor assessment on or after Week 9 (Day 63) from randomization 
(unless PD by BICR or death is observed before that time in which case the patient will 
not be excluded from the PP analysis set)  
 ECOG status ≥ 2 on or prior to randomization date 
 Patients did not meet inclusion criteria 1, 2, or 3 
1. Histologically confirmed Stage III-IV epithelial ovarian, fallopian tube, or primary 
peritoneal cancer (according to American Joint Committee on Cancer (AJCC)/UICC 
TNM and International Federation of Gynecology and Obstetrics (FIGO) Staging 
System 2014 edition), including carcinosarcoma with high-grade serous component. 
2. Patients must be candidates for bevacizumab in combination with platinum based 
chemotherapy and previously untreated. 
3. Must have completed a primary surgical debulking procedure, or be candidates for 
neoadjuvant chemotherapy with planned interval debulking surgery.  
a. Patients who completed primary debulking must have had incompletely resected 
disease that is macroscopically/grossly visible and at least with lesions >1 mm 
and be randomized at a maximum of 8 weeks after surgery. 
b. For patients who are candidates for neoadjuvant chemotherapy, the diagnoses 
must have been confirmed by: 
 Core tissue (not fine-needle aspiration) biopsy is required for diagnosis.  The 
tissue must be consistent with inclusion criteria #1 above.  
 Stage IIIC–IV documented via imaging or surgery (without attempt at 
cytoreduction). 
 
Serum CA-125/CEA ratio >25.  If the serum CA-125/CEA ratio is <25, then 
workup should be negative for the presence of a primary gastrointestinal or 
breast malignancy (<6 weeks before start of neoadjuvant treatment). 
 
Randomization must occur within 8 weeks after diagnosis. 
Patients who meet any of the following criteria will be excluded from the PP analysis set for 
OS.  


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P a ge 2 0  
 P atie nts di d n ot recei ve at least o ne d ose of c h e m ot hera p y i n t he c h e m ot hera p y p eri o d 
 P atie nt ra n d o mize d t o Ar m A w h o di d n ot recei ve at least o ne d ose of a vel u ma b 
 P atie nts ra n d o mize d t o Ar m C w h o di d n ot recei ve at least o ne d ose of be vaciz u ma b 
 P atie nt recei ve d a st u d y dr u g t o w hi c h he/s he was n ot assi g ne d at ra n d o mizati o n  
 E C O G sta t us ≥ 2 o n or pri or t o ra n d o mizati o n date 
 
Patie nts di d n ot meet i ncl usi o n criteria 1, 2, or 3  
4. 3. 2.  P K a n al ysis sets 
T he P K c o nce ntrati o n a n al ysis set is a s u bset of t h e safet y a nal ysis set a n d will i ncl u de 
patie nts w h o ha ve at least o ne p ost- d ose c o nce ntrati o n meas ure me nt a b o v e t he l o wer li mit of 
q ua ntitati o n ( L L Q) f or a vel u ma b ( Ar m A) or talaz o pari b ( Ar ms A a n d B). O n t his st u d y t h e 
P K para meters are o bser vati o nal, a n d t heref ore t h e P K para met er a n al ysis set is i de ntical t o 
t he P K co nce ntrati o n a nal ysis set.   
4. 3. 3.  B i o m ar ker a n al ysis sets  
T he  bi o mar ker a nal ysis s et f or bi o mar kers t hat are meas ure d o nl y at scree ni n g is a s u bset of 
t he safet y a n al ysis set a n d will i ncl u de patie nts w h o ha ve at least o ne scree ni n g bi o mar ker 
assess me nt. 
T he bi o mar ker a nal ysis s et f or bi o mar kers t hat are meas ure d se q ue ntiall y is a s u bset of t he 
safet y a n al ysis set a n d will i ncl u de patie nts w h o ha ve at least o ne baseli ne a n d o ne o n-
treat me nt bi o mar ker assess me nt f or t he sa me mar ker. T he bi o mar ker a nal ysis s et is defi ne d 
separat el y f or eac h bi o m ar ker of i nterest. 
A nal ysis sets will be defi ne d se paratel y f or bl o o d- base d a n d t u m or tiss ue- b ase d bi o mar kers. 
4. 3. 4.  I m m u n o ge nicit y a n al ysis set 
T he i m m u n o ge nicit y a n al ysis set is a s u bset of t he safet y a n al ysis set a n d will i ncl u de 
pa tie nts w h o ha ve at least o ne A D A/ n A b sa m ple c ollecte d f or a vel u ma b i n t he a vel u ma b 
co ntai ni n g ar m ( Ar m A).   
 
 
. 
5.  G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S 
5. 1.  H y p ot heses a n d Decisi o n R ules 
All refere nces t o P F S i n t his secti o n pertai n t o P F S base d o n BI C R assess me nt e ve n w he n n ot 
s pecificall y state d. 
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5.1.1. Hypotheses and sample size determination 
The following statistical hypothesis will be tested to address the primary objective: 
H01: HRPFS+ ≥1 vs H11: HRPFS+ <1 
where HRPFS+ is the hazard ratio (Arm A vs Arm C) of PFS based on BICR assessment in the 
DDR+ population. 
In addition the following statistical hypotheses will be tested to address secondary objectives: 
H02: HRPFS ≥1 vs H12: HRPFS <1 
H03: HROS+ ≥1 vs H13: HROS+ <1 
H04: HROS ≥1 vs H14: HROS <1 
where HRPFS and HROS are the hazard ratios (Arm A vs Arm C) of PFS based on BICR 
assessment and OS, respectively, in patients unselected for DDR status, and HROS+ is the 
hazard ratio (Arm A vs Arm C) of OS in the DDR+ population.  A gatekeeping procedure as 
illustrated in Figure 2, will be used to maintain the overall type I-error in the study at or 
below 1-sided 0.025.  The significance levels for each test also take into account the group 
sequential nature of the design (see Section 5.1.2).  
Figure 2.   Statistical Testing Strategy for Arm A vs Arm C Comparisons 
 


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For the primary comparison of PFS between Arm A and Arm C in the DDR+ population, 
200 PFS events based on BICR assessment in Arms A and C combined will provide 90% 
power to detect a HR of 0.63 using a 1-sided log-rank test at a significance level of 
0.025, and a 2-look group sequential design with Lan-DeMets (O’Brien-Fleming) 
-spending function to determine the efficacy boundary and a Gamma Family 
(-9) -spending function to determine the non-binding futility boundary. 
The study will randomize a total of approximately 720 patients in a 2.5:1:2.5 ratio to Arm A 
(N=300 including N=150 DDR+), Arm B (N=120 including N=60 DDR+), and Arm C 
(N=300 including N=150 DDR+).  Randomization will be stratified by germline BRCA 1/2 
mutational status (gBRCA+ vs gBRCA-), and resection status (adjuvant with >1mm and ≤1 
cm residual disease vs adjuvant with residual disease >1cm vs neoadjuvant). 
The sample size for this study is determined based on the following assumptions: 
 The median PFS for patients in Arm C is 14.1 months (Burger at al. 2011), and the 
median PFS for patients in Arm A is 22.4 months for the DDR+ population and 
20.1 months for patients unselected for DDR status; this corresponds to a hazard ratio 
(HR) of 0.63 in the DDR+ population and 0.70 in patients unselected for DDR status 
under the exponential model assumption; 
 The median OS for patients in Arm C is 39.7 months (Burger at al. 2011),  and the 
median OS for patients in Arm A is 56.7 months for the DDR+ population and 52.9 
months for patients unselected for DDR status; this corresponds to a HR of 0.70 in the 
DDR+ population and 0.75 in patients unselected for DDR status under the exponential 
model assumption; 
 PFS drop-out rate of approximately 15% and OS drop-out rate of approximately 5% at 
the time of primary analysis of PFS and OS; 
 50% of the randomized patients are with tumors that are DDR+; 
 Non-uniform patient accrual accomplished over an 18-month period. 
The sample size of approximately 720 patients will also allow an assessment of OS in the 
DDR+ population, and of PFS and OS in patients unselected for DDR status. 
If H01 is rejected then PFS in patients unselected for DDR status and OS in the DDR+ 
population can be tested.   
 For the PFS comparison between Arm A and Arm C in patients unselected for DDR 
status, 411 PFS events based on BICR assessment will provide 80.5% power to detect a 
HR of 0.70 using a 1-sided log-rank test at a significance level of 0.003, and a 2-look 
group-sequential design with Lan-DeMets (O’Brien-Fleming) α -spending function to 
determine the efficacy boundary.   


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 For the OS comparison between Arm A and Arm C in the DDR+ population, 207 deaths 
will provide 70.1% power to detect a HR of 0.70 or 80.1% power to detect a HR of 0.67 
using a 1-sided log-rank test at a significance level of 0.022, and a 4-look group 
sequential design with Lan-DeMets (O’Brien-Fleming) α -spending function to determine 
the efficacy boundary. 
If either H02 or H03 are rejected, then OS in patients unselected for DDR status can be tested 
at the sum of the significance levels associated with the significant H02 and H03 tests (see 
Figure 2).  With 421 deaths, the power to detect a HR of 0.75 is 83.2% (if both H02 and H03 
are rejected), 57.6% (if H02 is rejected and H03 is not rejected), or 81.9% (if H02 is not 
rejected and H03 is rejected) using a 1-sided log-rank test at a significance level of 0.025, 
0.003, or 0.022, respectively, and a 4-look group sequential design with Lan-DeMets 
(O’Brien-Fleming) -spending function to determine the efficacy boundary. 
The data cut-off for the primary PFS analysis will occur after the target number of PFS 
events (200) based on BICR assessment in Arms A and C combined in the DDR+ population 
has been reached and the last patient with tumor that is DDR+ randomized in the study has 
been followed for at least 12 months after randomization. 
The data cut-off for the primary analysis of OS will occur after the target number of deaths 
(207) in Arms A and C combined in the DDR+ population has been reached. 
The study will be considered positive if the 1-sided stratified log-rank test for PFS based on 
BICR assessment for comparing Arm A to Arm C in the DDR+ population is significant at 
the pre-specified  level. 
Arm B is not included in formal hypothesis testing. The sample size for Arm B is determined 
as follows.  
To establish that platinum-based chemotherapy followed by talazoparib maintenance 
(Arm B) has proof of efficacy compared to platinum-based chemotherapy plus bevacizumab 
followed by bevacizumab maintenance (Arm C), a HR target of 0.792 for Arm B vs Arm C is 
deemed to be clinically important (corresponding to a minimum improvement of 3.7 months 
in median PFS over Arm C under the exponential model assumption).  Proof of efficacy for 
Arm B compared to Arm C will have been demonstrated if both of the following criteria are 
met in the DDR+ population:  
1. Clinical relevance: Estimated HRPFS+ BvsC) ≤0.792. 
2. Statistical significance: Probability (true HRPFS+(BvsC) <1 | data) ≥80%. 
where HRPFS+(BvsC) is the HR of Arm B vs Arm C of PFS based on BICR assessment in the 
DDR+ population.  The calculation of the statistical significance criterion assumes 
asymptotic normality of log (HRPFS+(BvsC)) and a non-informative prior. 
Table 5 shows the probability of demonstrating proof of efficacy for Arm B compared to 
Arm C under different scenarios.  If the true HRPFS+(BvsC) is 1 (ie, no difference between the 
two arms) the probability of claiming proof of efficacy (false detection rate) for Arm B 


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compared to Arm C is 0.099.  If the true HRPFS+(BvsC) is 0.68 and the true HRPFS+(AvsC) is 0.63, 
then 149 PFS events based on BICR assessment would be observed in the DDR+ population 
for Arms B and C combined at the time of the primary analysis and the probability of 
declaring proof of efficacy (true detection rate) for Arm B compared to Arm C is 0.80.   
Table 5.  
Operating Characteristics for PFS in the DDR+ Population (Arm B vs Arm 
C) 
True HRPFS+(BvsC) 
Probability of demonstrating proof of efficacy*  
0.65 
0.862 
0.68 
0.800 
0.75 
0.618 
0.792 
0.500 
0.90 
0.240 
1.00 
0.099 
*Assuming 149 PFS events in the DDR+ population for Arms B and C combined at the time of the primary analysis for 
PFS. 
 
5.1.2. Decision rules 
The interim and the primary analyses for each efficacy endpoint will be performed after all 
patients have been randomized in the study and the target number of events has occurred in 
Arms A and C combined as described below.  A maximum of 4 distinct analyses cut-offs are 
planned in the study at the approximate calendar times described below: 
 At the time when approximately 140 PFS events (70% of the expected 200 events) based 
on BICR assessment have occurred in the DDR+ population in Arms A and C combined, 
and all patients have been randomized in the study; 
 At the time when 200 PFS events based on BICR assessment have occurred in the DDR+ 
population in Arms A and C combined, and the last patient randomized in the DDR+ 
population has been followed for at least 12 months after randomization; 
 At the time when 155 deaths (74.9% of the expected 207 deaths) have occurred in the 
DDR+ population in Arms A and C combined; 
 At the time when 207 deaths have occurred in the DDR+ population in Arms A and C 
combined. 
A maximum of 2 analyses will be performed for PFS (in the DDR+ population and in 
patients unselected for DDR status): 
 An interim analysis after all patients have been randomized in the study and at least  140 
PFS events (70% of the expected 200 events) based on BICR assessment have occurred 
in the DDR+ population in Arms A and C combined; 
 The final analysis for PFS after all patients in the DDR+ population have been followed 
for 12 months and at least 200 PFS events based on BICR assessment have occurred in 
the DDR+ population in Arms A and C combined; 


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A maximum of 4 analyses will be performed for OS (in the DDR+ population and in patients 
unselected for DDR status): 
 An interim analysis at the time of interim analysis for PFS 
 An interim analysis at the time of the final analysis for PFS; 
 At the time when 155 deaths have occurred in the DDR+ population in Arms A and C 
combined; 
 At the time when 207 deaths have occurred in the DDR+ population in Arms A and C 
combined. 
To protect the integrity of the study and to preserve the type I error rate, a gatekeeping testing 
strategy is implemented and the significance levels for the interim and final efficacy analyses 
for each endpoint will be determined by using the Lan-DeMets procedure with an O’Brien-
Fleming stopping boundary as described in Section 5.1.1.  
Primary endpoint 
Table 6 displays the maximum number of analyses expected for the primary endpoint and the 
associated efficacy and futility boundaries if the analyses are performed at the planned 
number of events as shown in the table.  The futility boundaries are non-binding but the 
study may be stopped for futility if at the time of the interim analysis for PFS in the DDR+ 
population the associated futility boundary is crossed.  If the efficacy boundary for PFS in the 
DDR+ population is crossed at the time of the interim analysis or at the time of the primary 
analysis then the primary objective of the study will have been demonstrated. 
Table 6.    PFS Based on BICR Assessment in the DDR+ Population (Arm A vs Arm C) 
- Efficacy and Futility Boundaries 
 
PFS in the DDR+ Population 
Analysis 
IA 
PA 
Analysis cut-off trigger 
140 PFS events in DDR+ 
200 PFS events in DDR+ 
Number of events a (Information fraction)  
140 (70.0%) 
200 (100%) 
p-value (z-value) for efficacy 
<0.0074 (<-2.438) 
<0.0228 (<-2.000) 
p-value (z-value) for futility b  
>0.3975 (>-0.260) 
Not Applicable 
a Number of events expected under H11 for PFS (assuming a HR of 0.63). 
b Non-binding. 
IA=interim analysis , PA=primary analysis 
Since the observed number of events at the interim analysis may not be exactly equal to the 
planned 140 PFS events, the efficacy and futility boundaries will be updated based on the 
actual number of observed events using the pre-specified α-and β-spending functions. 
Therefore, the observed Z-test statistic at the interim analysis will be compared with the 
updated efficacy and futility boundaries.  


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If the study continues to final analysis, the p-value that will be used to declare statistical 
significance at the final analysis  will be based on the actual number of PFS events 
documented at the cut-off date for the final analysis and the α already spent at the interim 
analysis. Therefore, if the interim analysis occurs after 140 PFS events for Arms A and C 
combined, and the study continues until the final analysis, the observed p-value for the 
comparison will have to be < 0.0228 to declare statistical significance.  If the number of 
events in the final analysis deviates from the expected number of events, the final analysis 
criterion will be determined so that the overall significance level across all analyses and 
comparisons is maintained at 1-sided 0.025.  Further details are provided in Section 7. 
Based on the stopping boundaries defined above and the timing of the interim and final 
analyses as described above, the design has the following operating characteristics. 
Table 7.  
Simulated Cumulative Probabilities to Stop for Efficacy or Futility at the 
Interim or Final PFS Analysis in the DDR+ Population (Arm A vs 
Arm C) 
Scenario 
Look  
Number of 
PFS events 
Calendar Time 
(months) 
P(Reject H01) 
P(Reject H11) 
H01 is true (HR=1) 
Interim PFS 
140 
24 
0.0073 
0.6090 
 
Final PFS 
200 
35 
0.0251 
0.9749 
H11 is true (HR=0.63) 
Interim PFS 
140 
27 
0.6011 
0.0066 
 
Final PFS 
200 
41 
0.8990 
0.1010 
Simulations performed in EAST 6.4 with number of simulations = 10,000 and seed=4062018  
Secondary endpoints 
Two secondary endpoints, PFS in patients unselected for DDR status and OS in the DDR+ 
population, will be analyzed using a hierarchical testing procedure, provided the primary 
endpoint PFS in the DDR+ population is statistically significant favoring Arm A. Two 
separate α-spending functions according to Lan-DeMets (O’Brien-Fleming) independent of 
the one used for the primary endpoint PFS in DDR+ population will be used so that the 
overall 1-sided level of significance across all analyses is preserved at 0.025. The trial allows 
for the stopping of the study for a superior OS result, provided the primary PFS endpoint has 
already been shown to be statistically significant favoring Arm A. 
Table 8 displays the analysis triggers for PFS in patients unselected for DDR status and the 
analysis triggers for OS in the DDR+ population, as well as the associated efficacy 
boundaries.  As described in Section 5.1.1, the significance level for the analyses of these 
endpoints is determined by the gatekeeping procedure. 


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Table 8.  
PFS Based on BICR Assessment in Patients Unselected for DDR status 
and OS in the DDR+ Population (Arm A vs Arm C) - Efficacy Boundaries 
  
Endpoints 
PFS in patients 
unselected for DDR 
status 
 
OS in the DDR+ Population 
 
Analysis 
IA1 
PA 
IA1 
IA2 
IA3 
PA 
Analysis cut-off 
trigger 
140 PFS 
events in 
DDR+ 
200 PFS 
events in 
DDR+ 
140 PFS 
events in 
DDR+ 
200 PFS 
events in 
DDR+ 
155 deaths  in 
DDR+ 
207 deaths  in 
DDR+ 
Number of events a 
(Information 
fraction) 
289 
(70.3%) 
411 
(100%) 
66           
(31.9%) 
110        
(53.1%) 
155           
(74.9%) 
207           
(100%) 
p-value (z-value) 
for efficacy 
<0.0004 
(<-3.352) 
<0.0029     
(<-2.762) 
<0.00005  
(<-3.891) 
<0.0017     
(<-2.936) 
<0.0076      
(<-2.428) 
<0.0194     
(<-2.065) 
a Number of events expected under H12 for PFS (assuming a HR of 0.70) and H13 for OS (assuming a HR of 
0.70). 
IA1=interim analysis 1, IA2=interim analysis 2, IA3=interim analysis 3,  PA=primary analysis 
 
Separately for each secondary endpoint, PFS in patients unselected for DDR status and OS in 
the DDR+ population, the exact nominal p-values that will need to be observed to declare 
statistical significance at the time of these analyses will depend on the number of events that 
have been observed at the time of these analyses and the α already spent at the time of earlier 
analyses. 
If PFS in patients unselected for DDR status is tested alone, independent of the testing 
strategy for PFS in the DDR+ population, the design concerning PFS in patients unselected 
for DDR status will have the following operating characteristics. These calculations are 
unadjusted for the pre-testing of PFS in the DDR+ population.   
Table 9.  
Simulated Cumulative Probabilities to Stop for Efficacy at the Interim or 
Final PFS Analysis in Patients Unselected for DDR Status (Arm A vs 
Arm C) 
Scenario 
Look  
Number of PFS 
events 
Calendar Time 
(months) 
P(Reject H02) 
H02 is true (HR=1) 
Interim PFS 
324 
27 
0.0003 
 
Final PFS 
446 
41 
0.0027 
H12 is true (HR=0.70) 
Interim PFS 
288 
27 
0.3701 
 
Final PFS 
410 
41 
0.8016 
Simulations performed in EAST 6.4 with number of simulations = 10,000 and seed=50021028.   
Interim and final PFS analyses calendar time expected at 27 and 41 months, respectively, under H11 (HR for 
PFS in the DDR+ population =0.63). 
 
If OS in the DDR+ population is tested alone, independent of the testing strategy for PFS in 
the DDR+ population, the design concerning OS in the DDR+ population will have the 


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following operating characteristics. These calculations are unadjusted for the pre-testing of 
PFS in the DDR+ population. 
Table 10.   Simulated Cumulative Probabilities to Stop for Efficacy at the Interim or 
Final OS Analysis in the DDR+ Population (Arm A vs Arm C) 
Scenario 
Look  
Number 
of OS 
events 
Calendar 
Time 
(months) 
P(Reject H03) 
H03 is true (HR=1) 
Interim PFS 
 76 
27 
<0.0001 
 
Final PFS 
124 
41 
0.0017 
 
75% information fraction OS in DDR+ 
155 
53 
0.0092 
 
Final OS 
207 
79 
0.0225 
H13 is true (HR=0.70) 
Interim PFS 
66 
27 
0.0068 
 
Final PFS 
109 
41 
0.1434 
 
75% information fraction OS in DDR+ 
155 
61 
0.4229 
 
Final OS 
207 
93 
0.6960 
Simulations performed in EAST 6.4 with number of simulations = 10,000 and seed=4072018.   
Interim and final PFS analyses calendar time expected at 27 and 41 months, respectively, under H11 (HR for 
PFS in the DDR+ population =0.63). 
 
The secondary endpoint, OS in patients unselected for DDR status, will be analyzed using a 
hierarchical testing procedure, provided the primary endpoint PFS in the DDR+ population 
and at least one of the previously mentioned secondary endpoints (PFS in patients unselected 
for DDR status and OS in DDR+ population) are statistically significant favoring Arm A. A 
separate α-spending function according to Lan-DeMets (O’Brien-Fleming) independent of 
the ones used before (ie. the three separate α-spending functions used for PFS in the DDR+ 
population, PFS in patients unselected for DDR status, and OS in DDR+ population) will be 
used so that the overall 1-sided level of significance across all analyses is preserved at 0.025.  
Table 11 displays the analysis triggers for OS in patients unselected for DDR status, as well 
as the associated efficacy boundaries.  As described in Section 5.1.1, the significance level 
for the analyses of this endpoint is determined by the gatekeeping procedure. 
Table 11.  OS in Patients Unselected for DDR Status (Arm A vs Arm C) – Efficacy 
Boundaries 
 
OS in Patients unselected for DDR status 
Analysis 
IA1 
IA2 
IA3 
PA 
Analysis cut-off trigger 
140 PFS events 
in DDR+ 
200 PFS events 
in DDR+ 
155 deaths in 
DDR+ 
207 deaths 
in DDR+ 
Number of events a (Information 
fraction) 
135 (32.1%) 
225 (53.4%) 
317 (75.3%) 
421 (100%) 
p-value (z-value) for efficacy b 
<0.00008         
(<-3.789) 
<0.0021          
(<-2.856) 
<0.0091       
(<-2.361) 
<0.0219       
(<-2.016) 


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a Number of events expected under H14 for OS (assuming a HR of 0.75). 
b The p-values and z-values noted for OS are those associated with the scenario when both H02 and H03 are 
rejected. 
IA1 = interim analysis 1, IA2 = interim analysis 2, IA3=interim analysis 3, PA = primary analysis 
 
The exact nominal p-values that will need to be observed to declare statistical significance at 
the time of these analyses for OS in patients unselected for DDR status will depend on which 
one or both of H02 (PFS in patients unselected for DDR status) and H03 (OS in DDR+ 
population) are rejected, the number of events that have been observed at the time of these 
analyses, and the α already spent at the time of earlier analyses. 
If OS in patients unselected for DDR status is tested alone at 1-sided α level of 0.025, 
independent of the testing strategy for PFS in the DDR+ population, PFS in patients 
unselected for DDR status and OS in DDR+ population, the design concerning OS in patients 
unselected for DDR status will have the following operating characteristics. These 
calculations are unadjusted for any pre-testing. 
Table 12.  Simulated Cumulative Probabilities to Stop for Efficacy at the Interim or 
Final OS Analysis in Patients Unselected for DDR Status, Assuming α Level 
of 0.025 (Arm A vs Arm C) 
Scenario 
Look  
Number of 
OS events 
Calendar Time 
(months) 
P(Reject H04) 
H04 is true (HR=1) 
Interim PFS 
151 
27 
0.0001 
 
Final PFS 
248 
41 
0.0022 
 
75% information fraction OS in 
DDR+ 
347 
61 
0.0096 
 
Final OS 
450 
93 
0.0233 
H14 is true (HR=0.75) 
Interim PFS 
135 
27 
0.0160 
 
Final PFS 
223 
41 
0.2351 
 
75% information fraction OS in 
DDR+ 
317 
61 
0.5858 
 
Final OS 
421 
93 
0.8319 
Simulations performed in EAST 6.4 with number of simulations = 10,000 and seed=5022018.   
The first and second interim OS analyses calendar time expected at 27 and 41 months, respectively, under H11 (HR 
for PFS in the DDR+ population =0.63).  
The third interim and final OS calendar time expected at 61 and 93 months, respectively, under H13 (HR for OS in 
the DDR+ population =0.70).  
 
5.2. General Methods 
As described in Section 3.4, in this study ‘treatment arm’ refers to one of the following: 
 Arm A = platinum-based chemotherapy + avelumab followed by avelumab + talazoparib 
maintenance; 


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 Arm B = platinum-based chemotherapy followed by talazoparib maintenance; 
 Arm C = platinum-based chemotherapy + bevacizumab followed by bevacizumab 
maintenance. 
Endpoints will be summarized based on the analysis sets described in Table 4 by treatment 
arm, unless otherwise specified.  
5.2.1. Data handling after the cut-off date 
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations. 
5.2.2. Pooling of centers 
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients randomized at each center. 
5.2.3. Presentation of continuous and qualitative variables 
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum, and first and third quartile (Q1 and Q3).  
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified. 
5.2.4. Definition of study day 
Start day of study treatment is the day of the first dose of study treatment. 
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as: 
Study day = Date of the assessment/event - start of study treatment + 1.  
The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as: 
Study day = Date of the assessment/event - start of study treatment. 
The study day will be displayed in all relevant data listings. 


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5.2.5. Definition of start of new anti-cancer drug therapy 
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7). 
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages. 
5.2.6. Definition of start of new anti-cancer therapy 
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.1 and Section 6.2.2). 
The start date of new anti-cancer therapy is the earliest date after randomization amongst the 
following: 
 Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages 
 Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’  
 For neoadjuvant patients, ie, patients that answer ‘Yes’ to the question ‘Neoadjuvant 
patient’ in the ‘Planned Neoadjuvant Therapy’ eCRF page: Surgery date recorded in 
‘Follow-up Cancer Surgery’ eCRF pages when ‘Surgery Outcome’ = ‘Resected’ or 
‘Partially Resected’. For patients that are NOT neoadjuvant: Surgery date recorded in 
‘On-Study Cancer Surgery’, and ‘Follow-up Cancer Surgery’ eCRF pages when ‘Surgery 
Outcome’ = ‘Resected’ or ‘Partially Resected’.     
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied using ‘Follow-up Cancer Therapy’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘On-Study Cancer 
Surgery’, and ‘Follow-up Cancer Surgery’ eCRF pages. 
5.2.7. Definition of on-treatment period 
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy – 
1 day). 
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized. 


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5.2.8. Standard derivations and reporting conventions 
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Demographics and physical measurements: 
 Age [years]:  
- (date of given informed consent - date of birth + 1) / 365.25 
- In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth) 
- In case only year of birth is given: Age [years]: (year of given informed consent - 
year of birth) 
The integer part of the calculated age will be used for reporting purposes.  
 BMI (kg/m2) = weight (kg)/[height (m)]2 
 BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5 
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6. 
5.2.9. Unscheduled visits 
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits. 
5.2.10. Adequate baseline tumor assessment 
Adequate baseline is defined using the following criteria: 
 All baseline assessments must be within 28 days prior to and including the date of 
randomization. 
 For patients with evidence of disease at baseline, all documented lesions must have non-
missing assessments (ie, non-missing measurements for target lesions and non-missing 
lesions assessment status at baseline for non-target lesions). 


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5.2.11. Adequate post-baseline tumor assessment 
For patients who undergo IDS, the IDS date will be identified as follows: 
 ‘Neoadjuvant Patient’ question on ‘Planned Neoadjuvant Therapy’ eCRF page is 
answered ‘Yes’, and 
 IDS date is the first surgery date recorded on the ‘On-Study Cancer Surgery’ eCRF page, 
where treatment intent is ‘Curative Intent’ and surgery outcome is ‘Resected’ or ‘Partially 
Resected’. 
For patients who do not undergo IDS, an adequate post-baseline assessment is defined as an 
assessment where a response of CR, PR, SD, non-CR/non-PD, or PD can be determined.  
Time points where the response is not evaluable (NE) or no assessment was performed will 
not be used for determining the censoring date. 
For patients who undergo IDS, since assessments after IDS can only be NE or PD, all post-
IDS tumor assessments will be considered adequate. Time points where no assessment was 
performed will not be used for determining the censoring date. 
5.3. Methods to Manage Missing Data 
5.3.1. Missing data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used. 
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged. 
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’.  
5.3.1.1. Pharmacokinetic concentrations 
Concentrations Below the Limit of Quantification 
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures. 
Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true: 


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1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample); 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist. 
Summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data. 
5.3.2. Handling of incomplete dates 
5.3.2.1. Disease history 
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
 If the day is missing, it will be imputed to the 15th day of the month.  
 If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st. 
 If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st.  
 If the date is completely missing, no imputation will be performed. 
5.3.2.2. Adverse events 
Incomplete AE-related dates will be imputed as follows: 
 If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment. 
 If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015. 
 If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014. 
 In all other cases the missing onset day or missing onset month will be replaced by 1. 
 Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
 In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off outcome of AE is ongoing at cut-off.  


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5.3.2.3. Prior and concomitant medications 
Incomplete prior/concomitant medication dates will be imputed as follows: 
 If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment. 
 If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015.  
 If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014. 
 In all other cases the missing medication day or missing medication month will be 
replaced by 1. 
 Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
 In all other cases the incomplete medication stop date will not be imputed.  
5.3.2.4. Exposure 
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows: 
 If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date 
 If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date)  
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date) 
= min (EOT date, death date), for all other cases. 


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5.3.3. Imputation rules for date of last contact and efficacy assessments 
5.3.3.1. Date of last contact 
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following: 
 All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments) 
 Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation 
 AE start and end dates 
 Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’) 
 Study drug start and end dates 
 Randomization date 
 Withdrawal of consent date 
 Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up). 
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date. 
5.3.3.2. Death date 
Missing or partial death dates will be imputed based on the last contact date: 
 If the date is missing it will be imputed as the day after the date of last contact  
 If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following: 
- Missing day:  
 
1st day of the month and year of death 
- Missing day and month: 
January 1st of the year of death 
5.3.3.3. Tumor assessments 
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year. 
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 


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associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment. 
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates (eg, 
X-ray, CT-scan).   
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used.  
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment.  If both a previous and following assessments are not available, this 
assessment will not be used for any calculations. 
5.3.3.4. Date of start of new anti-cancer therapy 
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment. 
 The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is 
o completely missing then it will be ignored in the imputations below 
o partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy 
o partially missing with only month and year  available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy 
 For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below.  
 If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is derived as follows: 
o Start date of new anti-cancer therapy is completely missing 
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy] 
o Only year (YYYY) for start of anti-cancer therapy is available 
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY;  
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  


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THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = 01JANYYYY 
o Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available 
IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy],  AND 
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY ; 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy],  AND 
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]); 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy],  AND 
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = 01 MMM YYYY; 
ELSE IF 
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 


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THEN  
imputed start date = 01 MMM YYYY. 
5.3.3.5. PRO data 
The respective scoring or user guides for NFOSI-18 and EQ-5D-5L provide missing data 
handling rules (FACIT, 2008; EuroQoL Group 2015). In particular, the following will be 
implemented.  
If there are missing items on the NFOSI-18, subscale scores can be prorated.  This is done by 
multiplying the sum of the subscale by the number of items in the subscale, then dividing by 
the number of items actually answered, as follows: 
Prorated subscale score = [Sum of item scores] × [Number of items in subscale] ÷ [Number 
of items answered] 
When there are missing data, prorating by subscale in this way is acceptable if > 50% of the 
items were answered.  The total score is then calculated as the sum of the un-weighted 
subscale scores.  In addition, a total score should only be calculated if all of the component 
subscales have valid scores.  The EQ-5D-5L questions not answered will be considered 
missing items and will not be utilized.  For EQ-5D-5L, the entire utility score for that cycle is 
deemed missing if the answer to any one of the 5 dimensions is missing. 
6. ANALYSES AND SUMMARIES 
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.  
6.1. Primary Endpoint  
6.1.1. Progression-free survival as assessed by BICR per RECIST v1.1 in the DDR+ 
population 
6.1.1.1. Primary analysis 
The following analyses will be based on patients in the DDR+ population in the FAS using 
the strata assigned at randomization.  PD below refers to PD by BICR assessment.  
Progression-Free Survival (PFS) is defined as the time from the date of randomization to the 
date of the first documentation of PD or death due to any cause, whichever occurs first.    
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.   Patients who do not have an adequate baseline tumor assessment or who do 
not have an adequate post-baseline tumor assessment will be censored on the date of 
randomization unless death occurred on or before the time of the second planned tumor 
assessment (ie ≤ 18 weeks after the date of randomization) in which case the death will be 
considered an event.  


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In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening, at 9 and 18 weeks (±3 days) from the date of randomization and 
every 12 weeks thereafter until PD by BICR assessment per RECIST v1.1, regardless of 
initiation of subsequent anti-cancer therapies.  For patients who undergo IDS during the 
chemotherapy period, an additional tumor assessment should be performed after surgery.  
The censoring and event date options to be considered for the PFS analysis are presented in 
Table 13.   
 
PFS (months) = [date of event or censoring– date of randomization +1]/30.4375 
Table 13.  Outcome and Event Dates for PFS Analyses 
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment 
Date of randomization a 
Censored a 
PD or death  
- After at most one missing or 
inadequate post-baseline tumor 
assessment, OR 
- ≤ 18 weeks after the date of 
randomization 
Date of PD or death 
Event 
 
PD or death  
- After 2 or more missing or 
inadequate post-baseline tumor 
assessments 
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments  
Censored 
 
No PD and no death 
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments  
Censored 
 
Treatment discontinuation due to ‘Disease 
progression’ 
without 
documented 
progression 
Not applicable 
 
Information is ignored. 
Outcome is derived 
based on documented 
progression only. 
New anti-cancer therapy given  
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored 
 
a However if the patient dies ≤18 weeks after the date of randomization the death is an event with date on death 
date 
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of randomization; if the criteria were met the censoring will be on 
the date of randomization. 
 
The primary efficacy analysis will compare the PFS time based on BICR assessment between 
Arm A and Arm C in the DDR+ population, and will be performed using a 1-sided stratified 
log-rank test as described in Section 5.1.  


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The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by 
the randomization strata to calculate the hazard ratio. Each stratum will define a separate 
baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie for the i-
th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(x), where h(i,0;t) defines 
the baseline hazard function for the i-th stratum and x defines the treatment arm (0=control 
arm, 1= experimental arm) and  is the unknown regression parameter. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG). 
In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 2000), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of PFS.  In addition, the unadjusted 95% CIs 
for the hazard ratio will also be reported at the interim and the final analyses for PFS. 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS time with 2-sided 95% CIs.  
In particular, the PFS rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54, and 60 
months will be estimated with corresponding 2-sided 95% CIs.  The CIs for the median will 
be calculated according to Brookmeyer and Crowley (1982) and the CIs for the survival 
function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2011) (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.   
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to the categories in Table 14 following the hierarchy shown. 
Table 14.  PFS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment 
No adequate baseline assessment 
2 
Start of new anti-cancer therapy    
Start of new anti-cancer therapy 
3  
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization 
Event after 2 or more missing 
assessments a 
4 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Subject refused 
further follow-up]  
Withdrawal of consent 
5 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
6 
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment  
No adequate post-baseline tumor 
assessment 
7  
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
a 2 or more missing or inadequate post-baseline tumor assessments.     


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The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
Time of Follow-Up for PFS 
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment arm. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment arms reversing the PFS censoring and event 
indicators. Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
arm together with a summary of associated statistics including the median time of follow-up 
for PFS with 2-sided 95% CIs.  In particular, the rate at 9 and 18 weeks and at 8, 12, 18, 24, 
30, 36, 42, 48, 54, and 60 months will be estimated with corresponding 2-sided 95% CIs. 
6.1.1.2. Analysis in Arm B versus Arm C 
The analyses described in Section 6.1.1.1 will be repeated for the Arm B vs Arm C 
assessment; however this comparison is not part of the formal testing strategy for the study as 
described in Section 5.1 and, therefore, RCI will not be applicable and p-values reported will 
be purely descriptive.  
The probability of the HR (Arm B vs Arm C) in the DDR+ population (HRPFS+(BvsC)) being 
less than 1 will be calculated assuming asymptotic normality of log(HRPFS+(BvsC)) and a non-
informative prior.  Proof of efficacy for Arm B compared to Arm C will have been 
demonstrated if both of the following two criteria are satisfied:  
 Clinical relevance: Estimated HRPFS+(BvsC) ≤0.792.  
 Statistical significance: Probability (True HRPFS+(BvsC) <1 | data) ≥0.80. 
6.2. Secondary Endpoint(s) 
6.2.1. Safety endpoints 
Refer to Section 6.6. 
6.2.2. Efficacy endpoints 
The following analyses will be based on the FAS by treatment arm unless otherwise 
specified.      
PFS by investigator assessment will be analyzed as a secondary endpoint using the same 
methodology that is described in Section 6.1.1.1 now referring to PD by investigator 
assessment instead of PD by BICR assessment; RCI will not be calculated.  
6.2.2.1. Progression-free survival as assessed by BICR per RECIST v1.1 in patients 
unselected for DDR status 
The analyses described in Section 6.1.1.1 will be repeated for patients unselected for DDR 
status: 


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 Arm A vs Arm C comparison will use a 1-sided stratified log-rank test as described in 
Section 5.1, and  
 Arm B vs Arm C assessment will be performed; RCI will not be reported and p-values 
will be nominal. 
6.2.2.2. Overall survival in the DDR+ population and in patients unselected for DDR 
status 
The following analyses will be based on the FAS using the strata assigned at randomization.    
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death due to any cause.  Patients last known to be alive will be censored at date of last 
contact. 
 
OS (months) = [date of death or censoring– date of randomization +1]/30.4375 
The analysis of OS will compare the OS time between Arm A and Arm C for patients in the 
DDR+ population and for patients unselected for DDR status, and will be performed using a 
1-sided stratified log-rank test as described in Section 5.1.   OS time between Arm B and 
Arm C will also be assessed (p-values reported will be purely descriptive) for patients in the 
DDR+ population and for patients unselected for DDR status. 
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by 
the randomization strata to calculate the hazard ratio. Each stratum will define a separate 
baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie for the i-
th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(x), where h(i,0;t) defines 
the baseline hazard function for the i-th stratum and x defines the treatment arm (0=control 
arm, 1= experimental arm) and  is the unknown regression parameter. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG). 
In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 2000), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of OS.  In addition, the unadjusted 95% CIs 
for the hazard ratio will also be reported at the interim and the final analyses for OS. 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median OS time with 2-sided 95% CIs.  
In particular, the OS rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 78, 96, 
120, and 144 months will be estimated with corresponding 2-sided 95% CIs.  The CIs for the 
median will be calculated according to Brookmeyer and Crowley (1982) and the CIs for the 
survival function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2011) (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.   


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Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment arm.  Reasons for censoring will be summarized according to 
the categories in Table 15. 
Table 15.  OS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Subject refused 
further follow-up]  
Withdrawal of consent 
2 
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 14 weeks]  
Lost to follow-up 
3 
No event and none of the conditions in the prior hierarchy 
are met  
Alive 
 
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
Time of Follow-Up for OS 
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment arms reversing the OS censoring and event indicators.  Kaplan-Meier 
estimates (product-limit estimates) will be presented by treatment arm together with a 
summary of associated statistics including the median time of follow-up for OS with 2-sided 
95% CIs.  In particular, the rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 
78, 96, 120, and 144 months will be estimated with corresponding 2-sided 95% CIs. 
6.2.2.3. Sensitivity analyses for progression-free survival 
All sensitivity analyses described below will be performed for PFS based on BICR in the 
DDR+ population and separately for PFS based on BICR in patients unselected for DDR 
status. 
The following sensitivity analyses will be performed to explore the robustness of the primary 
analysis results.  These analyses are regarded as purely exploratory. The sensitivity analyses 
will repeat the primary analysis (p-value, HR and 95% CIs) described in Section 6.1.1.1 with 
the modifications below: 
 PFS based on BICR assessment and counting all PD and deaths as events regardless of  
missing assessments or timing of the event  
 PFS based on BICR assessment on the PP analysis set for PFS  
 PFS based on BICR assessment using an unstratified analysis 
 PFS based on BICR assessment using strata recorded on eCRF instead of those entered in 
IRT 


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 PFS based on BICR assessment stratified by resection status per eCRF and BRCA1/2 
mutational status as determined by foundation medicine 
 PFS based on BICR assessment modifying the censoring rules in Table 13 to consider all 
deaths as events 
 PFS based on BICR assessment modifying the censoring rules in Table 13 with initiation 
of subsequent anti-cancer therapies not used as a censoring reason.  
 
Methods for evaluating the validity of model assumptions 
The proportional hazards assumption will be checked visually by plotting log(-log(PFS)) 
versus log(time) within each randomization stratum. 
Schoenfeld residuals for the stratified Cox proportional regression model will be plotted to 
investigate graphically violations from the proportional hazards (PH) assumption; a non-zero 
slope is evidence of departure from PH.  The PH assumption will be formally tested using 
Schoenfeld’s residual test (Schoenfeld, 1980; Therneau & Grambsch, 2000).  Large 
departures from PH will be evidenced by a p-value <0.05. 
If these show large departures from proportional hazards, then PFS by BICR assessment will 
also be analyzed based on restricted mean survival time (RMST) differences (Zhang, 2013).  
Restricted Mean Survival Time (RMST) 
The hazard ratio estimate from the Cox proportional hazard model is routinely used to 
empirically quantify the between-arm difference under the assumption that the ratio of the 
two hazard functions is constant over time.  When this assumption is plausible, such a ratio 
estimate may capture the relative difference between two survival curves.  However, the 
clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the 
underlying PH assumption is violated (ie, the hazard ratio is not constant over time).  
The RMST is a robust and clinically interpretable summary measure of the survival time 
distribution.  Unlike median survival time, it is estimable even under heavy censoring.  There 
is a considerable body of methodological research (eg, Royston and Parmar, 2011; Uno et al., 
2014; Zhang, 2013) about the use of RMST to estimate treatment effects as an alternative to 
the hazard ratio approach.   
The RMST methodology is applicable independently of the PH assumption and can be used, 
at a minimum, as a sensitivity analysis to explore the robustness of the primary analysis 
results.  However, when large departures from the PH assumption are observed, the log-rank 
test is underpowered to detect differences between the survival distributions for the treatment 
arms, and a test of the difference between the RMST for the experimental arm and the 
control arm may be more appropriate to determine superiority of the experimental arm 
compared to the control arm with respect to the time-to-event endpoint. 


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In particular, as it pertains to the cut-off point (τ) to evaluate the RMST, it is noted that the 
cut-off point should not exceed the minimum of the largest observed time for both treatment 
arms so that the RMST of all treatment arms being evaluated can be adequately estimated 
and comparison between treatments is feasible; τ should be clinically meaningful and closer 
to the end of the study follow-up so that the majority of survival outcomes will be covered by 
the time interval.  The RMST up to time τ can then be interpreted as the expected survival 
time restricted to the common follow-up time τ among all patients.  The selection of τ should 
ensure that the RMST evaluation will not go beyond the maximum time point where the 
evaluation can be performed while also taking into account a large period of time that is 
expected to provide a meaningful assessment of treatment effect.   To avoid arbitrary 
selection of the common cut-off τ for both treatment arms, three sets of analyses will be 
performed: 
 τ1 = minimum of (largest observed PFS time for the experimental arm, largest observed 
PFS time for the control arm).   
 τ2 = minimum of (largest PFS event time for the experimental arm, largest PFS event 
time for the control arm). 
 τ3 = midpoint between τ1 and τ2. 
The treatment effect between the experimental arm and the control arm will be assessed 
based on the difference in RMST. The associated 95% CI for the difference in means and 1-
sided p-value will be generated.   
BICR vs Investigator Assessment 
A summary of the BICR assessment versus investigator assessment will be provided 
including numbers of concordant and discordant assessments as well as the number of cases 
where PFS event was assessed at different timepoints based on BICR and investigator 
assessments. 
Table 16 outlines the possible outcomes by investigator and BICR (Amit et al. 2011).  
Table 16.  Possible Outcomes for Investigator vs BICR 
 
BICR 
Investigator 
 
Event  
No Event 
Event 
a = a1 + a2 + a3 
b 
No Event 
c 
d 
a1: number of agreements on timing and occurrence of event;  
a2: number of times agreement on event but INV declares event later than BICR;  
a3: number of times agreement on event but INV declares event earlier than BICR;  
N= a+b+c+d.  
The timing agreement of event is defined as a window of ± 7 days.  
 


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The following measure of discordance will be calculated for each treatment arm: 
 Total Event Discrepancy Rate: (b+c) / N 
 Early Discrepancy Rate (EDR): (a3+b) / (a+b) 
 Late Discrepancy Rate (LDR): (a2+c) / (a2+a3+b+c) 
 Overall Discrepancy Rate: (a2+a3+b+c) / N 
The EDR represents the positive predictive value of investigator assessment and quantifies 
the frequency with which the investigator declares PFS event earlier than BICR within each 
treatment arm as a proportion of the total number of investigator assessed events. 
The LDR quantifies the frequency with which the investigator declares PFS event later than 
BICR as a proportion of the total number of discrepancies within the treatment arm.  
Discordance metrics are calculated for each treatment arm and, for each metric, the 
difference in discordance between the experimental and control arms is used to evaluate 
potential bias.  If the discordance is similar across the treatment arms then this suggests the 
absence of evaluation bias favoring a particular treatment arm. A negative differential 
discordance for EDR and/or a positive differential discordance for LDR may be indicative of 
investigator evaluation bias in favor of the experimental arm (Amit et al, 2011).  
Exploratory analyses to investigate the impact of potential prognostic or effect 
modifying (predictive) factors  
See subgroups as defined in Section 6.3.3. 
Multivariable Cox regression analysis will be carried out to assess and adjust the treatment 
effect for relevant baseline factors of potential prognostic impact. A stepwise selection 
procedure will serve to identify explanatory variables of potential prognostic values 
additional to the randomization strata which will be included in all models during the 
selection procedure. The Cox's Proportional Hazard model is defined as:  
h(t) = h(0;t) eXb 
where h(0;t) defines the baseline hazard function and X defines the vector of explanatory 
variables and b the unknown vector of regression parameters.  
In the stepwise selection procedure, variables are entered into and removed from the model 
in such a way that each forward selection step can be followed by one or more backward 
elimination steps. The stepwise selection process terminates if no further variable can be 
added to the model or if the variable just entered into the model is the only variable removed 
in the subsequent backward elimination. The level of significance for an explanatory variable 
to enter the model is set to 0.15 (p-value of Score test) and the significance level for 
removing it is set to 0.40 (p-value of Wald test). This analysis will be performed using the 
stepwise selection method in SAS (Proc PHREG). Once this procedure stops, the factor 
'treatment arm' will be added to the last selected model in order to evaluate the effect of 


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treatment on PFS time when adjusted for the selected explanatory variables. The hazard 
ratios of all selected explanatory variables and of treatment effects will be reported including 
2-sided 95% CIs. No interactions will be considered. Post-baseline factors will not be 
considered for the model. 
6.2.2.4. Sensitivity analyses for overall survival 
All sensitivity analyses described below will be performed for OS in the DDR+ population 
and separately for OS in patients unselected for DDR status. 
The following sensitivity analyses will be performed to explore the robustness of the primary 
analysis results for OS.  These analyses are regarded as purely exploratory. The sensitivity 
analyses will repeat the primary analysis (p-value, HR and 95% CIs) described in Section 
6.2.2.2 with the modifications below: 
 PP analysis set; 
 unstratified; 
 using strata recorded on eCRF instead of that entered in IRT 
 stratified by resection status per eCRF and BRCA1/2 mutational status as determined by 
foundation medicine 
Methods for evaluating the validity of model assumptions 
The same methodology described in Section 6.2.2.3 for PFS will be used for OS. 
Exploratory analyses to investigate the impact of potential prognostic or effect 
modifying (predictive) factors  
The same methodology described in Section 6.2.2.3 for PFS will be used for OS. 
6.2.2.5. PFS2 
The analysis of PFS2 will be performed for the DDR+ population and for patients unselected 
for DDR status based on FAS.  
PFS2 is defined as time from the date of randomization to the start of second subsequent 
treatment after first PD by Investigator assessment, or death from any cause, whichever 
occurs first.   
PFS2 (months) = [date of event or censoring – date of randomization +1]/30.4375 
A patient will be considered to have an event if 
1) the patient had objective PD on or prior to start of next-line anti-cancer treatment, AND 
started a second subsequent anti-cancer treatment 
OR 


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2) the patient died. 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS2 time with 2-sided 95% 
CIs.  In particular, the PFS2 rate at 12, 24, 36, 48, 60, and 80 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982) and the CIs for the survival function estimates at the time 
points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2011) (conftype=loglog default option in SAS Proc LIFETEST) 
with back transformation to a CI on the untransformed scale. The estimate of the standard 
error will be computed using Greenwood’s formula. 
The censoring and event date options to be considered for PFS2, each corresponding 
censoring reason and its hierarchy are presented in Table 17 . Frequency (number and 
percentage) of patients with an event (second subsequent anti-cancer treatment or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to Table 17 following the hierarchy shown.  
Table 17.  Outcome, Event Dates, Censoring Reasons and Hierarchy for PFS2 
Analyses  
Scenario 
Date of event/ censoring 
Outcome/ 
Censoring reason/ 
Censoring hierarchy 
(No PDa) and (no death) 
 
Date of last adequate tumor 
assessmentb documenting no 
PD 
Censored/ 
No PD/ 
1 
(No PDa) and death  
Date of death 
Event (Death) 
 
(PDa date > NTX1c start date) and (no death) 
Start date of NTX1c 
Censored/ 
Start of new anti-cancer 
treatment before PD/ 
2 
(PDa date > NTX1c start date) and death 
Date of death 
Event (Death) 
(PDa date ≤ NTX1c start date) and (no death) 
 
 
 
If NTX2d start date is non-missing 
Start date of NTX2d 
Event 
(Start 
of 
second 
subsequent 
anti-cancer 
treatment) 
 
Else if [withdrawal of consent date ≥ 
date of randomization OR End of study 
(EOS) = Subject refused further follow-
up] 
(Withdrawal of consent date) 
or (EOS visit date where 
subject refusal of further 
follow-up is recorded)  
Censored/ 
Withdrawal of consent/ 
3 
 
Else if [lost to follow-up in any 
disposition page] 
Last contact date 
Censored/ 
Lost to follow-up/ 
4 
 
Else if no prior conditions are met 
Last contact date 
Censored/ 
Ongoing without PFS2 event/ 


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Scenario 
Date of event/ censoring 
Outcome/ 
Censoring reason/ 
Censoring hierarchy 
5 
(PDa and no NTX1c) and (no death) 
Last contact date 
Censored/ 
Ongoing without PFS2 event/ 
6 
 
(PDa date ≤ NTX1c start date) and death 
 
 
 
If NTX2d start date is non-missing 
Start date of NTX2d 
Event 
(Start 
of 
second 
subsequent 
anti-cancer 
treatment) 
 
Else if the prior condition is not met 
Date of death 
Event (Death) 
a PD is the first PD by investigator assessment per RECIST v1.1, without considering any censoring rules. 
b If there are no adequate post-baseline assessments, then the censoring date is the date of randomization. If patient has 
initiated next-line anti-cancer treatment, the last adequate post-baseline assessment on or prior to start date of next-line anti-
cancer treatment will be considered. 
c NTX1 is the first new anti-cancer treatment. 
d NTX2 is the second new anti-cancer treatment. 
 
The PFS2 time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
6.2.2.6. PFS by GCIG criteria based on investigator assessment 
The analysis of PFS by GCIG criteria will be performed for the DDR+ population and for 
patients unselected for DDR status based on FAS.  
PFS from the date of randomization by GCIG criteria will be assessed in this study 
incorporating both RECIST v1.1 and CA-125 (Rustin, G et.al.) (see Appendix 6 of the 
protocol) based on Investigator assessment.  
PFS by GCIG criteria will be censored if both PFS per RECIST v1.1 and PFS per CA-125 
are censored, the date of censoring will be the latest of the two censoring dates. 
CA-125 data will be censored on the date of the last CA-125 assessment for patients who 
start new anti-cancer therapy prior to an event, or for patients with an event after 2 or more 
missing CA-125 assessments. Patients who do not have an adequate baseline CA-125 
assessment or who do not have an adequate post-baseline CA-125 assessment will be 
censored on the day of randomization with a duration of 1 day.  
PFS by GCIG criteria (months) = [date of event or censoring – date of randomization 
+1]/30.4375 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS by GCIG criteria time with 
2-sided 95% CIs.  In particular, the PFS by GCIG criteria rate at 9 and 18 weeks and at 8, 12, 
24, 30, 36, 42, 48, 54 and 60 months will be estimated with corresponding 2-sided 95% CIs.  


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The CIs for the median will be calculated according to Brookmeyer and Crowley (1982) and 
the CIs for the survival function estimates at the time points defined above will be derived 
using the log-log transformation according to Kalbfleisch and Prentice (2011) 
(conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI 
on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula. 
Frequency (number and percentage) of patients with each event type (PD by Investigator 
assessment per RECIST v1.1 or PD by CA-125 or death) and censoring reasons will be 
presented by treatment arm. Reasons for censoring will be summarized according to the 
hierarchy shown in Table 18. 
Table 18.  Censoring Reasons and Hierarchy for PFS by GCIG Criteria Based on 
Investigator Assessment 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment per RECIST v1.1 and no 
adequate CA-125 baseline assessment 
No adequate baseline assessment 
2 
Start of new anti-cancer therapy  
Start of new anti-cancer therapy 
3  
Event by Investigator assessment per RECIST v1.1 after 2 
or more missing or inadequate post-baseline tumor 
assessments/date of randomization  
Event per RECIST v1.1 after 2 or 
more missing assessments a 
4 
Event per CA-125 after 2 or more (ie, > 12 weeks) missing 
post-baseline assessments  
Event per CA-125 after 2 or more 
missing assessments 
5 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Subject refused 
further follow-up]  
Withdrawal of consent 
6 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
7  
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment and no post-baseline CA-125 
assessment 
No adequate post-baseline tumor 
assessment and no adequate post-
baseline CA-125 assessment 
8 
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
a 2 or more missing or inadequate post-baseline tumor assessments 
 
The PFS by GCIG criteria time or censoring time and the reasons for censoring will also be 
presented in a patient listing. 
6.2.3. Pharmacokinetic endpoints 
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
arm for Arms A (avelumab and talazoparib) and B (talazoparib only).   
Ctrough and Cmax for avelumab and Ctrough for talazoparib will be reported.  Dose normalized 
Ctrough for talazoparib [Ctrough(dn)] will be reported as appropriate.  


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Pharmacokinetic parameters for avelumab and talazoparib will be taken from observed 
values as described in Section 3.2.4. 
Presentation of pharmacokinetic data will include: 
 One set of tables by analyte will be generated for plasma concentrations/PK parameters 
Ctrough and Cmax for avelumab and Ctrough and Ctrough(dn) (if needed) for talazoparib.  
 Parameters will be listed and summarized by treatment arm, cycle, day and nominal time 
using descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric 
mean and its associated %CV, and 95% CI). Data from patients who undergo intrapatient 
dose escalation or reduction for talazoparib or avelumab will be excluded from summary 
statistics for Ctrough and Cmax from the time the dose escalation or reduction occurs.  For 
talazoparib, Ctrough(dn) will be presented only if the patient undergoes intrapatient dose 
escalation or reduction. 
 Cmax and Ctrough for avelumab and Ctrough for talazoparib will be plotted for each treatment 
arm using a box-whisker plot by cycle and day within cycle in order to assess the 
attainment of steady-state. Data from patients who undergo intrapatient dose escalation or 
reduction will be excluded from the time the dose escalation or reduction occurs. 
Individual data points, the geometric mean and the median of the parameter for each 
analyte in each treatment arm will be overlaid on the box plots. If a treatment arm has 
limited evaluable PK data (n<4), matchstick plots showing changes in the parameter in 
individual patients will then be generated. The geometric mean of the parameter in each 
treatment will be overlaid in the plots.  
6.2.4. Population pharmacokinetic endpoints 
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab and talazoparib exposure and biomarkers or significant 
safety/efficacy endpoints. The results of these analyses, if performed, may be reported 
separately. 
6.2.5. Biomarker endpoints  
Secondary endpoints in the study are candidate predictive biomarkers in tumor tissue 
including PD-L1 expression, tumor mutational burden, genomic scarring and mutations in 
genes associated with DDR at baseline. 
Biomarker data will be analyzed based on the biomarker analysis sets as defined in Section 
4.3.3, by treatment arm. 
If a patient has more than one result at a visit for a specific biomarker analyte, then:  
 For continuous data, the duplicate results will be averaged, and the average used in 
the analysis; 


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P a ge 5 3  
 F or n o n - c o nti n u o us data (e g, i de ntifie d ge n es), t he st u d y tea m will select t he rec or d 
a p pr o priate f or a n al ysis. A fla g will be a d de d t o t h e data sets i n dicati n g w hi c h rec or d 
was select e d f or a nal ysis. 
F or P D- L 1 e x pressi o n, patie nts will be classifie d as p ositi ve a n d ne gati ve acc or di n g t o 
sc ori n g al g orit h ms a n d c ut- offs esta blis he d fr o m i nter nal or e xter nal s o ur ces. Patie nts w h ose 
stat us can n ot be deter mi ne d are n ot c o nsi dere d t o ha ve scree ni n g bi o mar ker assess me nt per 
t he bi o mar ker a nal ysis set defi niti o n, a n d t heref ore will be e x cl u de d. 
F or c o nti n u o us meas ure me nt bi o mar ker res ults, s u m mar y statistics (e g, t h e mea n, sta n dar d 
de viati o n, me dia n, perce nt of c oeffi cie nt of variati o n, a n d mi ni m u m/ ma xi m u m le vels) will be 
deter mi ne d at bas eli ne a n d o n-treat me nt/e n d of treat me nt ti me p oi nts, as a p pr o priate. 
C ha n ge fr o m bas eli ne meas ure m e nts will be pr o vi de d, as a p pr o priate. 
F or discrete meas ure me nt bi o mar ker res ults (e g, t u m or mar ker stat us), fre q ue ncies a n d 
perce nt a ges of cate g orical bi o mar ker meas ures will be deter mi ne d at b aseli ne a n d o n-
treat me nt/e n d of tr eat me nt ti m e p oi nts. S hift ta bles ma y als o b e pr o vi de d. 
Bi o mar ker s u b gr o u ps as defi ne d a b o v e will be use d t o perf or m s u b gr o u p a n al yses f or 
effic ac y e n d p oi nts ( P F S b y BI C R assess me nt, O S) usi n g t he met h o d ol o g y o utli ne d i n Secti o n 
6. 3. 3 .  I n a d diti o n, t he hazar d rati o f or t he bi o mar ker s u b gr o u p le vel c o m paris o ns a n d t he 
u na dj uste d 9 5 % CIs f or t he hazar d rati o will be re p orte d f or eac h tr eat me nt ar m.  
 
 
 
 
6. 2. 6.  E n d p oi nts f or i m m u n o g e nicit y d at a of a vel u m a b  
All a na l ys es descri be d bel o w are perf or m e d i n Ar m A o nl y. 
B l o o d sa m ples f or a vel u ma b i m m u n o ge nicit y testi n g will be c ollecte d pre d ose o n Da y 1 of 
che m ot hera p y C ycl es 1- 4 d uri n g t he c he m ot hera p y peri o d.  I n t he mai nte n a nce p eri o d, bl o o d 
sa m ples will be c ollecte d pre d ose o n Da ys 1 a n d 2 9 of mai nte na nce C ycle 1. T hereafter, 
i m m u n o ge nicit y sa m ples will be c ollecte d pre d ose o n Da y 1 of mai nte na n ce c ycles 2, 4, 6, 
1 0, a n d at t he e n d of treat me nt.  
S a m ples p ositi ve f or A D A will be a nal yz e d f or tit er a n d ma y b e a nal yze d f or n A b.  
Patie nts will be c haracteriz e d i nt o differe nt A D A cate g ories b ase d o n t he criteria defi n e d i n 
Ta ble 1 9 .   
C CI


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Table 19.  Patients Characterized Based on Anti-Drug Antibody Results (ADA Status) 
Category 
Definition 
Subjects at Risk (Denominator for 
Incidence) 
ADA never-positive  
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint) 
Number of patients with at least one 
valid ADA result at any time point 
ADA ever-positive  
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint) 
Number of patients with at least one 
valid ADA result at any time point 
Baseline ADA 
positive 
A positive ADA result at baseline 
Number of patients with valid baseline 
ADA result 
Treatment-boosted 
ADA 
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab 
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result 
Treatment-induced 
ADA 
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive past-baseline 
ADA result 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
Transient ADA 
response 
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive. 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
Persistent ADA 
response 
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR) 
ADA: anti-drug antibody, NR = not reportable. 
 
Patients will be characterized into different nAb categories based on the criteria in Table 20. 
For nAb, treatment-boosted is not applicable since no titer result is available. 


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Table 20.   Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) 
Category 
Definition 
Subjects at Risk (Denominator for 
Incidence) 
nAb never-positive  
No positive nAb results at any time point 
Number of patients with at least one 
valid ADA result at any time point 
nAb ever-positive  
At least one positive nAb result at any time 
point 
Number of patients with at least one 
valid ADA result at any time point 
Baseline nAb 
positive 
A positive nAb result at baseline 
Number of patients with valid baseline 
ADA result 
Treatment-induced 
nAb 
Patient is not nAb positive at baseline and  has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive past-
baseline ADA result 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR) 
Transient nAb 
response 
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive. 
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR) 
Persistent nAb 
response 
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR) 
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result. 
 
The number and percentage of patients in each ADA and nAb category will be summarized.  
 
6.2.6.1. Time to and Duration of ADA and nAb response  
The ADA and nAb analyses described below will include patients with treatment-induced 
ADA or nAb, respectively.   
Time (weeks) to ADA response is defined as: 
(Date of first positive ADA result – date of first dose of avelumab + 1)/7.  
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).   
Duration (weeks) of ADA response is defined as: 
(Date of last positive ADA result – date of first positive ADA result + 1)/7.  
Duration of ADA response will be censored if:  
 the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or 


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 the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (post-treatment 30-day follow-up) is after the cut-
off date. 
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result.  
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley 
(1982) and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2011) (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula. 
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided 
As data permit, the analyses described above will be repeated for patients with treatment-
induced nAb.  
6.2.6.2. ADA titer 
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated. The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory.  
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided. The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks. In this categorization, the censoring in duration of ADA response is ignored.  
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity status 
The following ADA and nAb status will be used for the analyses described below. 
ADA  
 ADA ever-positive versus ADA never-positive  
 ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive 


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nAb  
 nAb ever-positive versus nAb never-positive  
 nAb: treatment-induced nAb versus nAb never-positive or baseline nAb positive 
Data listings will include immunogenicity data together with relevant PK, safety and efficacy 
data. 
PK parameters and immunogenicity status 
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax.   
During the chemotherapy period, blood samples for avelumab PK will be collected within 2 
hours prior to and at the end of infusion (within 10 minutes after the avelumab infusion ends) 
on Day 1 of Chemotherapy Cycles 1-4.  During the maintenance period, PK samples will be 
collected within 1 hour prior to taking talazoparib dose and the post-dose avelumab PK 
sample should be taken within 10 minutes after the avelumab infusion ends on Days 1 and 29 
of the first maintenance cycle. Thereafter, PK samples will be collected predose within 1 
hour prior to taking talazoparib dose and the post-dose avelumab PK samples should be taken 
within 10 minutes after the avelumab infusion ends on Day 1 of maintenance cycles 2, 4, 6, 
10 and at the end of treatment. 
Ctrough and Cmax will be summarized descriptively (n, mean, SD, CV, median, minimum, 
maximum, geometric mean, its associated CV, and 95% CI) by nominal time and ADA 
status. Linear-linear plots of mean and median for Ctrough and Cmax over nominal time and by 
ADA status will be presented.  
Among patients with treatment-induced ADA, analyses will be conducted to assess whether 
there are any changes in Ctrough and/or Cmax after the first positive ADA assessment relative to 
before the first positive ADA assessment. To be included in this analysis, patients must have 
the same PK parameter available both before and after the first positive ADA assessment.  
Relative PK day will be calculated as: 
(PK assessment nominal day) – (first positive ADA assessment nominal day). 
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is 
collected on Day 1 of Cycle 2 in the chemotherapy period and the first positive ADA result is 
observed on Day 1 of Cycle 3 in the chemotherapy period, then the relative PK day for this 
Cycle 2 day 1 Ctrough is -21. Linear-linear plots of mean and median Ctrough and Cmax over 
relative PK day will be presented.  
As data permit, the analyses described above will be repeated for nAb. 


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Safety and immunogenicity status 
The following analyses will include patients in the immunogenicity analysis set. 
The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status. 
 TEAEs, by SOC and PT  
 TEAEs leading to dose reduction of avelumab, by SOC and PT 
 TEAEs leading to discontinuation of avelumab, by SOC and PT 
 TEAEs leading to discontinuation of study treatment by SOC and PT 
 Grade ≥ 3 TEAEs, by SOC and PT  
 SAEs, by SOC and PT 
 IRRs, by PT 
For patients who had at least one IRR and have treatment-induced ADA, time related to first 
onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4, or later) will be summarized 
taking into account whether the  IRR occurred on or after the first ADA positive assessment 
or whether the IRR occurred before the first ADA positive assessment.   
As data permit, the analyses described above will be repeated for nAb. 
Efficacy and immunogenicity status 
For the ADA ever-positive patients, a listing will be prepared with patient ID, start and stop 
of avelumab treatment, date of first positive ADA result, time to ADA response, duration of 
ADA response, date of last ADA positive result, PFS time or censoring time and reason for 
censoring, and OS time or censoring time and reason for censoring.   If applicable, date of 
first positive nAb result, time to nAb response, duration of nAb response, and date of last 
nAb positive result will also be presented.  PFS will be presented based on BICR assessment 
and based on Investigator assessment.  
For the ADA ever-positive patients, the percent change from baseline in target lesions as well 
as the first occurrence of a new lesion and patient off avelumab treatment will be displayed 
against time point (weeks) in a line plot. Additional symbols will indicate the first and last 
ADA positive result and, if applicable, the first and last nAb positive result. Plot will be 
presented separately based on BICR assessment and based on Investigator assessment. 


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6. 3. 2.  P R O e n d p oi nts 
All P R O a nal yses will be base d o n t he F A S, b y tr eat me nt ar m a n d will i ncl u de all t he 
assess me nts per sc h e d ule of assess me nt fr o m b aseli n e t o t he last P R O assess me nt, u nless 
ot her wise s pecifie d.  
T he pri mar y P R O a nal ysis is desi g ne d t o deter mi ne t he effect of Ar m A c o m pare d t o Ar m C 
o n t he ti me t o deteri orati o n ( T T D) of t h e D R S- P i n t he D D R + p o p ulati o n, fr o m 
ra n d o mizati o n u p t o E O T ( n ot i ncl u di n g E O T). T T D is defi ne d as t he ti me fr o m 
ran d o mizati o n t o deteri orati o n w here d eteri or ati o n is defi ne d as a ≥3- p oi nt decrease, 
mai ntai ne d f or 2 c o ns ec uti ve assess me nts, o n t he D R S- P ( 9 ite ms) f or p h ysical s y m pt o ms or 
c o ncer ns of diseas e. 
6. 3. 2. 1.  Sc ori n g pr oce d ure 
T he N F O SI- 1 8 a n d E Q- 5 D - 5 L will be sc ore d acc or di n g t o t heir res pecti ve sc ori n g or user 
g ui des ( F A CI T, 2 0 0 8; E ur o Q o L Gr o u p 2 0 1 5 ).  F or t he E Q - 5 D- 5 L, t h e i n de x sc ores will be 
C CI


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calculated using the published weights (tariffs) for the United Kingdom.  Specific country 
weights may be applied for country specific analyses as needed. 
6.3.2.2. Instrument completion rates 
For each treatment arm and at each time point, the number and percentage of patients who 
complete the NFOSI-18 and EQ-5D-5L will be summarized, as will the reasons for non-
completion of these measures. An instrument is considered complete if at least one item was 
answered by the patient. 
6.3.2.3. Descriptive summaries over time 
Absolute scores and change from baseline for the NFOSI-18 total scores, subscales and the 
single item “I am bothered by side effects of treatment”, as well as the EQ-5D-5L index and 
EQ-VAS will be summarized (as described in Section 5.2.3) at each time point by treatment 
arm. Line charts depicting the means and mean changes from baseline along with SE error 
bars over time will be provided for each scale by treatment arm. 
For the EQ-5D-5L health status, the proportions of patients reported having “none”, “slight”, 
“moderate”, “severe”, or “extreme/unable” problems at each time point will be presented by 
treatment arm. 
6.3.2.4. Time-to-event endpoints 
Time to deterioration (TTD) of DRS-P 
The TTD for DRS-P will be calculated from the date of randomization to the date of the first 
report of a score of ≥3-point decrease of the 2 consecutive assessments used to identify the 
event. A decline in DRS-P score represents an increase in physical symptoms or concerns of 
the disease. Patients who do not have a TTD event will be censored on the last date when 
they have a DRS-P score.  
The primary TTD analysis will include all assessments from baseline up to EOT (not 
including EOT) to assess the level of treatment side effect bother on patients during the 
treatment period. The sensitivity TTD analysis will include all assessments from baseline, 
post-baseline, EOT and until 3 years from patient’ enrollment to assess the level of treatment 
side effect bother on patients from the next line of therapy.  
Three additional sensitivity analyses for TTD will be conducted: based on a ≥2-point, 4-point 
and 5-point decrease from randomization in the DRS-P, maintained for 2 consecutive for up 
to EOT (not including EOT).  
TTD will be compared between treatment arms using a 1-sided log-rank test stratified by 
randomization stratification factors. No adjustment for multiplicity will be conducted.  
The treatment effect, as measured by the hazard ratio, will be estimated using a Cox’s 
Proportional Hazard model stratified by the randomization strata. Each stratum will define a 
separate baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie, 
for the i-th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 


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(0=reference  arm, 1= non-reference arm) and β is the unknown regression parameter. Ties 
will be handled by replacing the proportional hazards model by the discrete logistic model 
(Ties=Discrete option in SAS PROC PHREG).  The unadjusted 95% CIs for the hazard ratio 
will be reported. 
Kaplan-Meier estimates will be presented by treatment arm together with a summary of 
associated statistics including the median TTD time with 2-sided 95% CIs. In particular, the 
TTD rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months will be 
estimated with corresponding 2-sided 95% CIs. The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982) and the CIs for the survival function estimates 
at the time points defined above will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (2011) (conftype=loglog default option in SAS Proc LIFETEST) 
with back transformation to a CI on the untransformed scale. The estimate of the standard 
error will be computed using Greenwood’s formula. 
The TTD cut-off for the DRS-P will be also examined using an anchor-based method with 
the PGI-S and PGI-C items and the cumulative distribution function as part of a supplemental 
analysis, and reported separately from the clinical study report.  
Time to development of significant side effect bother 
TTB is defined as the time from the randomization date to the first report of a score of ≥2 for 
at least two consecutive assessments on the side effect bother item.  Patients will be censored 
at the last time when they completed the side effect bother item if they have not had a TTB 
event.  
The primary TTB analysis will include all assessments from baseline up to EOT (not 
including EOT) to assess the level of treatment side effect bother on patients during the 
treatment period. The sensitivity TTB analysis will include all assessments from baseline, 
post-baseline, EOT and until 3 years from patient’ enrollment to assess the level of treatment 
side effect bother on patients from the next line of therapy.  
TTB will be compared between treatment arms using a 1-sided log-rank test stratified by 
randomization strata. No adjustment for multiplicity will be conducted.  
The treatment effect, as measured by the hazard ratio, will be estimated using a Cox’s 
Proportional Hazard model stratified by the randomization strata. Each stratum will define a 
separate baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie, 
for the i-th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 
(0=reference  arm, 1= non-reference arm) and β is the unknown regression parameter. Ties 
will be handled by replacing the proportional hazards model by the discrete logistic model 
(Ties=Discrete option in SAS PROC PHREG).  The unadjusted 95% CIs for the hazard ratio 
will be reported. 
Kaplan-Meier estimates will be presented by treatment arm together with a summary of 
associated statistics including the median TTB time with 2-sided 95% CIs. In particular, the 
TTB rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months will be 


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esti mate d wit h c orres p o n di n g 2-si de d 9 5 % CIs. T he CIs f or t he me dia n will be calc ulate d 
acc or di n g t o Br o o k me yer a n d Cr o wle y ( 1 9 8 2)  an d t he CIs f or t he s ur vi val f u ncti o n esti mates 
at t he ti me p oi nts defi ne d a b o ve will be deri v e d usi n g t he l o g-l o g tra nsf or m ati o n acc or di n g t o 
Kal bfleisc h a n d Pre ntice ( 2 0 1 1)  (c o nft y p e =l o gl o g defa ult o pti o n i n S A S Pr oc LI F E T E S T) 
wit h bac k tra nsf or mati o n t o a CI o n t he u ntra nsf or me d scale. T he esti mate of t he sta n dar d 
err or will be c o m p ute d usi n g Gree n w o o d’s f or m ula. 
6. 3. 2. 5.  C o nti n u o us e n d p oi nts 
Mi x e d-effects l o n git u di nal m o deli n g will be carri e d o ut f or t he N F O SI- 1 8 t otal sc ores, 
s u bscales, a si n gle q uesti o n wit hi n t he T S E s u bscale (“I a m b ot here d b y si d e effects of 
treat me nt”), as well as t h e E Q- 5 D- 5 L a n d E Q - V A S sc ores f or t he c o m paris o ns a m o n g 
treat me nt ar ms usi n g P R O C MI X E D. O utc o mes are P R O p ost- baseli ne sc ores a n d t he 
pr e dict ors are t he c orres p o n di n g bas eli ne P R O sc ore, treat me nt, ra n d o mizati o n strat u m, ti me 
(treate d as a c o nti n u o us v aria ble), a n d treat me nt-b y -ti me i nteracti o n. I nterce pt a n d ti me are 
c o nsi dere d as ra n d o m effects partic ular t o eac h patie nt. All para meter esti mates s h o ul d be 
o btai ne d usi n g restricte d ma xi m u m li keli h o o d. T he u nstr uct ure d c o vari a nce str uct ure s h o ul d 
be use d t o defi ne c o vari a nce bet w ee n ra n d o m effects ( usi n g o pti o n “ T y p e = U N” as a part of 
t he R A N D O M state me nt i n P R O C MI X E D). F or t he de grees- of-free d o m calc ulati o ns t he 
Ke n war d a n d R o ger al g orit h m s h o ul d be use d ( usi n g o pti o n “ d df m = kr” as a part of t he 
M O D E L state me nt i n P R O C MI X E D). T he m ai n a nal ysis will be a p plie d usi n g sc he d ul e d 
assess me nts fr o m baseli n e u p t o E O T ( n ot i ncl u di n g E O T), a n d t he s e nsiti vit y a nal ysis will 
be  base d o n all sc he d ule d assess me nts fr o m b aseli ne i ncl u di n g E O T a n d u ntil 3 years fr o m 
patie nt’s e nr oll me nt.  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
6. 4.  S u bset A n al yses 
S u bset a nal ys es will be perf or me d f or t he D D R + p o p ulati o n a n d f or patie nts u nselecte d f or 
D D R stat us base d o n t he F A S. 
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Subset analyses will be performed for PFS per BICR assessment and OS for the subgroups 
defined below.  
The following subgroups will be defined and used for analyses: 
 Randomization stratification factor as per IRTs  
- Germline BRCA 1/2 mutational status (gBRCA+ vs gBRCA-)   
- Resection status (adjuvant with >1 mm and ≤1 cm residual disease vs adjuvant with 
>1 cm residual disease vs neoadjuvant). 
 BRCA 1/2 mutational status as determined by Foundation Medicine 
- Positive (Reference) 
- Negative 
- Unknown 
 DDR status 
- 
DDR+ 
- DDR- 
 Age  
- Age < 65 years (Reference) 
- Age ≥ 65 years  
 Race 
- Caucasian / White (Reference) 
- Asian 
- Black/African American 
- Other 
 Ethnicity 
- Hispanic/Latino  
- Non-Hispanic/Latino (Reference) 
 Pooled Geographical Region  
- North America  
- Europe (Reference) 
- Asia 
- Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional subgroups if including > 10% of the overall randomized 
population) 
 Stage 


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- III (Reference) 
- IV 
 ECOG Performance Status on or prior to randomization date 
- 0 (Reference) 
- ≥ 1 
 CA-125 at baseline 
- ≤2×ULN (Reference) 
- >2×ULN 
 Tumor mutation burden 
- Low (reference) 
- High  
The cut-off will be pre-specified using external data before the analysis.   
 PD-L1 status at baseline 
- Positive (Reference) 
- Negative 
The cut-off will be pre-specified using external data before the analysis.   
Subset analyses for PFS and OS will use the primary censoring rules described in Sections 
6.1.1.1 and 6.2.2.2. All the subgroup analyses are exploratory. Treatment arms will be 
compared for PFS and OS using a 2-sided unstratified log-rank test for each subgroup level 
and the unstratified HR and its corresponding 95% CI will be computed per subgroup level.  
All the subgroup analyses will be exploratory; no adjustment for multiplicity will be 
performed.  In the case of a low number of patients within a category (<5% of the 
randomized population), the categories will be pooled. 
To assess the heterogeneity of treatment effects for PFS and OS across the subgroup levels, 
two Cox regression model will be fitted with PFS or OS, respectively, as the dependent 
variable and  subgroup, treatment, and with and without the treatment-by-subgroup 
interaction as explanatory variables.  
 Model 1: factors + treatment + subgroup 
 Model 2: factors + treatment + subgroup + treatment×subgroup-variable  
A p-value for the interaction test (Likelihood Ratio test) will be provided together with the 
HR and corresponding 95% CI for the interaction model parameter.  
The HR for PFS and OS and corresponding 95% CIs for all subgroups will also be presented 
in a forest plot. 


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6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline summaries 
The following analyses will be performed for the DDR+ population and for patients 
unselected for DDR status and will be based on the FAS overall and separately by treatment 
arm. 
6.5.1.1. Demographic characteristics 
Demographic characteristics and physical measurements will be summarized by treatment 
arm using the following information from the ‘Screening/Baseline Visit’ eCRF pages. 
 Demographic characteristics  
- Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Unknown 
- Ethnic origin: Hispanic/Latino (Yes/No) 
- Age (years): summary statistics  
- Age categories:  
 < 65 years, ≥ 65 years  
 < 65, 65-<75, 75-<85, ≥ 85 years 
- Pooled Geographical Region (as applicable):  
 North America  
 Europe 
 Asia 
 Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the 
overall randomized population) 
- Geographic Region (as applicable): 
 North America 
 Latin America 
 Western Europe 
 Eastern Europe 
 Middle East 
 Australasia 
 Asia 


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 Africa 
- Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4  
 Physical measurements 
- Height (cm) 
- Weight (kg) 
- Body Mass Index (BMI) (kg/m2) 
- Body Surface Area (BSA) (m2) 
Center codes will be used for the determination of the patient’s geographic region. 
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment arm, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), BSA (m2), and ECOG performance status. 
6.5.1.2.  Medical history 
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Significant Medical 
History’ eCRF page. Medical history will be summarized as the numbers and percentages of 
patients by MedDRA preferred term (PT) as event category and MedDRA primary system 
organ class (SOC) as summary category. Each patient will be counted only once within each 
PT or SOC. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order. 
6.5.1.3.  Disease characteristics 
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Use’ and 
RECIST eCRF pages will be summarized overall and by treatment arm. Summary statistics 
will be presented for the following. 
From the ‘Primary Diagnosis’ eCRF page: 
 Site of primary tumor 
 Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page) 
 Time since initial diagnosis to date of randomization (months), defined as (date of 
randomization – date of initial diagnosis)/30.4375 
 Time since histopathological diagnosis (months), defined as (date of randomization – 
date of histopathological diagnosis)/30.4375 


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Separately from the RECIST eCRF page based on Investigator assessment and based on 
BICR assessment: 
 Measurable disease (lesions) at baseline (Yes, No, No disease) 
 Involved tumor sites at baseline 
From the ‘Substance Use’ eCRF page: 
 Smoking history: Never smoker vs current vs former smoker  
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ and ‘Substance Use’ eCRF pages) and derived variables as above. 
6.5.1.4.  Prior anti-cancer surgery 
The prior anti-cancer surgeries are collected under the ‘Prior Anti-Cancer Surgery’ eCRF 
page. 
The number and percentage of patients with at least one prior anti-cancer surgery will be 
tabulated.  Treatment intent and surgery outcome will also be summarized.   
Prior anti-cancer surgeries will be included in the listing of anti-cancer surgeries with a flag 
to identify prior surgeries. These will include the patient identification number, and all the 
relevant collected data-fields on the eCRF page. 
 
6.5.2. Study conduct and patient disposition 
The following analyses will be performed based on the FAS overall and separately by 
treatment arm. 
6.5.2.1. Patient disposition 
The percentages below will be calculated based on the number of patients in the FAS. 
 Total number of patients screened overall 
 Number of patients who discontinued from the study prior to randomization overall and 
by the main reason for discontinuation 
 Number and percentage of randomized patients in each of the analysis sets defined in 
Section 4 
 Number and percentage of randomized patients with study drug ongoing (separately for 
each study drug when administered in combination) 
 Number and percentage of randomized patients who discontinued study drug overall and 
by the main reason for discontinuation of study drug (separately for each study drug 
when administered in combination) 
 Number and percentage of patients who entered follow-up 


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 Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation 
In addition, a summary of patients who have discontinued all study drugs will be provided.  
The results of the randomization algorithm (according to IRT) will be summarized as 
follows: 
 Number and percentage of randomized patients overall, by region (Europe, EEA 
(required by EudraCT), North America, Latin America, Middle East, Asia, Australasia, 
Africa), by country within region  
 Number and percentage of randomized patients by center 
 Number and percentage of randomized patients by randomization strata (IRT) 
 Number and percentage of randomized patients by randomization strata (eCRF) 
 Cross tabulation: stratum by IRT vs stratum by eCRF 
 Cross tabulation: patients randomized (Arm A/Arm B/Arm C) vs patients treated (Arm 
A/Arm B/Arm C/none)  
6.5.2.2. Protocol deviations 
All protocol violations that impact the safety of the patients and/or the conduct of a study 
and/or its evaluation will be reported. These include: 
 Patients who are dosed on the study despite not satisfying the inclusion criteria 
 Patients who develop withdrawal criteria whilst on the study but are not withdrawn 
 Patients who receive the wrong treatment or an incorrect dose 
 Patients who receive an excluded concomitant medication 
 Deviations from GCP. 
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol. 
6.5.3. Study treatment compliance and exposure 
The following analyses will be based on the safety analysis set by treatment arm. 
All dosing calculations and summaries will be based on ‘Parenteral – Drug avelumab’ 
‘Parenteral – Drug paclitaxel’, ‘Parenteral – Drug carboplatin’, ‘Parenteral – Drug 
bevacizumab’, and ‘Oral – talazoparib’ eCRFs pages. A listing of study drug administration 
will be created with the information collected on these eCRF pages.  


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Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.   
For Cycle X, actual cycle start date for each patient is 
 the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the 
patient received study treatment on that visit (ie, any study drug with dose>0 at that visit) 
 the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit. 
Actual cycle end date for each patient is,  
 for all cycles X except the last cycle, actual cycle end date =  actual cycle (X+1) start date 
– 1 day; 
 for the last cycle,  
o actual cycle end date = actual cycle start date + 21 days – 1 day if the last cycle 
occurred in the chemotherapy period; 
o actual cycle end date = actual cycle start date + 42 days – 1 day if the last cycle 
occurred in the maintenance period; 
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7  
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.  
Exposure may be summarized (per cycle and overall within a study period) as dose received 
(cumulative dose, actual dose intensity) and as dose received relative to intended dose 
(relative dose intensity [RDI]).   
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical, oral daily).  The formulae below should be applied to each study drug 
separately even when study drugs are administered in combination. 
The derivations below are provided for the following. 
During the chemotherapy period 
 Avelumab administered as a 1-hour intravenous (IV) infusion at a dose of 800 mg on Day 
1 of each 3-week cycle for 6 cycles 


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 Paclitaxel administered as 175 mg/m2 IV over 3 hours on Day 1 of each 3-week cycle for 
6 cycles 
 Carboplatin dose AUC 5 or AUC 6 IV over 1 hour on Day 1 of each 3-week cycle for 
6 cycles 
 Bevacizumab administered as an IV infusion at a dose of 15 mg/kg on Day 1 of each 3-
week cycle beginning with cycle 2 for adjuvant patients (may begin with cycle 1 if 
surgery completed >4 weeks prior to randomization), and for neoadjuvant patients, 
bevacizumab will be given on Day 1 of each 3-week cycle in cycles 1, 2, 5 and 6 for 6 
cycles. 
During the maintenance period 
 Avelumab administered as a 1-hour IV infusion at a dose of 800 mg on Days 1, 15 and 29 
of each 6-week cycle for a maximum of 24 months.  
 Talazoparib 1 mg administered orally once a day, every day of each 6-week cycle for a 
maximum of 24 months 
 Bevacizumab administered as an IV infusion at a dose of 15 mg/kg on Days 1 and 22 of 
each 6-week cycle.  The maximum duration of treatment is 21 doses total, including the 
period of initial chemotherapy. 
Maintenance period should begin within 4 weeks of the last dose of platinum. The first visit 
of maintenance therapy will be designated maintenance Cycle 1 Day 1 even if the last 
chemotherapy cycle was not completed. 
Analysis of exposure will be based on the calculated actual dose levels: 
 Avelumab - total dose   
 Paclitaxel – total dose/m2 
 Carboplatin – AUC 
 Bevacizumab – total dose/weight 
 Talazoparib – total dose. 
6.5.3.1. Exposure to avelumab  
The dose level for avelumab is calculated as actual dose administered (mg).  
Chemotherapy period 
Intended duration of treatment with avelumab (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle in chemotherapy period with non-zero dose of study 
drug + 21 – 1 


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Duration of exposure to avelumab (weeks) =  
(last dose date of avelumab in chemotherapy period – first dose date of avelumab + 
21)/7   
Cumulative dose in a cycle or overall is the sum of the actual doses of avelumab received in 
a cycle or overall (in the chemotherapy period), respectively.   
Actual Dose Intensity (DI)  
 By cycle actual DI (mg/3-week cycle) = [cumulative dose in the cycle (mg)]/[cycle 
duration (weeks)/3] 
 Overall actual DI (mg/3-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/3].   
Relative Dose Intensity (RDI)   
 Intended DI (mg/ 3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [800 (mg)] / [1 (3-week cycle)]  = 800 (mg /3-week 
cycle) 
 By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [800 (mg/3-week cycle)]   
 Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [800 (mg/3-week cycle)]  
Maintenance period 
Intended duration of treatment with avelumab (weeks) =  
(end date–date of first dose of study drug in maintenance period +1)/7,  
where end date = start date of last cycle in maintenance period with non-zero dose of study 
drug + 42 – 1 
Duration of exposure to avelumab (weeks) =  
(last dose date of avelumab in maintenance period – first dose date of avelumab in 
maintenance period + 14)/7 
Cumulative dose in a cycle or overall is the sum of the actual doses of avelumab received in a 
cycle or overall (in the maintenance period), respectively  
Actual Dose Intensity (DI)  
 
By cycle actual DI (mg /6-week cycle) = [cumulative dose in the cycle (mg)]/[cycle 
duration (weeks)/6] 
 
Overall actual DI (mg/ 6-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/6]. 


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Relative Dose Intensity (RDI)   
 Intended DI (mg/ 6-week cycle) = 2400 (mg/ 6-week cycle) 
 By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [2400  (mg/ 6-week cycle)]   
 Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [2400 (mg/ 6-week cycle)] 
6.5.3.2. Exposure to paclitaxel  
The dose level for paclitaxel is calculated as actual dose administered/ m2 (mg/m2). The last 
available weight of the patient on or prior to the day of dosing will be used. 
Intended duration of treatment with paclitaxel (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle in chemotherapy period with non-zero dose of study 
drug + 21 – 1 
Duration of exposure to paclitaxel (weeks) =  
(last dose date of paclitaxel – first dose date of paclitaxel + 21)/7   
Cumulative dose in a cycle or overall is the sum of the actual doses of paclitaxel received in 
a cycle or overall (in chemotherapy period), respectively.   
Actual Dose Intensity (DI)  
 By cycle actual DI (mg/m2/3-week cycle) = [cumulative dose in the cycle 
(mg/m2)]/[cycle duration (weeks)/3] 
 Overall actual DI (mg/m2/3-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with paclitaxel (weeks)/3].   
Relative Dose Intensity (RDI)   
 Intended DI (mg/m2/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [175 (mg/m2)] / [1 (3-week cycle)]  = 175 (mg/m2/3-
week cycle) 
 By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [175 (mg/m2/3-week cycle)]   
 Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [175 (mg/m2/3-week cycle)] 
6.5.3.3. Exposure to carboplatin 
The dose level for carboplatin is calculated as actual AUC administered.  The carboplatin 
dose will be calculated based on the Calvert formula using the actual dose (mg) administered.  


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Intended duration of treatment with carboplatin (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle in the chemotherapy period with non-zero dose of 
study drug + 21 – 1 
Duration of exposure to carboplatin (weeks) =  
(last dose date of carboplatin– first dose date of carboplatin+ 21)/7   
Cumulative dose in a cycle or overall is the sum of the actual doses of carboplatin received 
in a cycle or overall (in chemotherapy period), respectively.   
Actual Dose Intensity (DI)  
 By cycle actual DI (AUC/3-week cycle) = [cumulative dose in the cycle (AUC)]/[cycle 
duration (weeks)/3] 
 Overall actual DI (AUC /3-week cycle) = [overall cumulative dose (AUC)] / [intended 
duration of treatment with carboplatin (weeks)/3].   
Relative Dose Intensity (RDI)   
 Intended DI (AUC/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [d (AUC)] / [1 (3-week cycle)]  = d (AUC/3-week cycle) 
 By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [d (AUC/3-week cycle)]   
 Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [d AUC /3-week cycle)]  
where d= 5 or 6  depending on the glomerular filtration rate (GFR) method used for the 
Cycle 1 Day 1 carboplatin dose. 
6.5.3.4. Exposure to bevacizumab  
The dose level for bevacizumab is calculated as actual dose administered/weight (mg/kg). 
The last available weight of the patient on or prior to the day of dosing will be used. 
Chemotherapy period 
Intended duration of treatment with bevacizumab (weeks) =  
(end date–date of first dose of bevacizumab +1)/7,  
where end date = start date of last cycle in chemotherapy period with non-zero dose of study 
drug + 21 – 1 
Duration of exposure to bevacizumab (weeks) =  
(last dose date of bevacizumab in the chemotherapy period – first dose date of 
bevacizumab + 21)/7   


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Cumulative dose in a cycle or overall is the sum of the actual doses of bevacizumab 
received in a cycle or overall (in chemotherapy period), respectively.   
Actual Dose Intensity (DI)  
 By cycle actual DI (mg/kg/3-week cycle) = [cumulative dose in the cycle (mg/kg)]/[cycle 
duration (weeks)/3] 
 Overall actual DI (mg/kg/3-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with bevacizumab (weeks)/3].   
Relative Dose Intensity (RDI)   
 Intended DI (mg/kg/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [d (mg/kg / 3-week cycle]   
where d=15 for adjuvant patients and d=10 for neoadjuvant patients. 
 By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [d (mg/kg/3-week cycle)]   
 Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [d (mg/kg/3-week cycle)] 
Maintenance period 
Intended duration of treatment with bevacizumab (weeks) =  
(end date–date of first dose of bevacizumab in maintenance period +1)/7,  
where end date = start date of last cycle in maintenance period with non-zero dose of study 
drug + 42 – 1 
Duration of exposure to bevacizumab (weeks) =  
(last dose date of bevacizumab in maintenance period – first dose date of 
bevacizumab in maintenance period + 21)/7   
Cumulative dose in a cycle or overall is the sum of the actual doses of bevacizumab 
received in a cycle or overall (in maintenance period), respectively.   
Actual Dose Intensity (DI)  
 By cycle actual DI (mg/kg/6-week cycle) = [cumulative dose in the cycle (mg/kg)]/[cycle 
duration (weeks)/6] 
 Overall actual DI (mg/kg/6-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with Drug D (weeks)/6].   


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Relative Dose Intensity (RDI)   
 Intended DI (mg/kg/6-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 6-weeks in a cycle] = [2 x 15 (mg/kg)] / [1 (6-week cycle)]  = 30 (mg/kg/6-
week cycle) 
 By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [30 (mg/kg/6-week cycle)]   
 Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [30 (mg/kg/6-week cycle)] 
6.5.3.5. Exposure to talazoparib  
The dose level is calculated as actual dose administered (mg/day).   
Intended duration of treatment with talazoparib (weeks) = (end date – date of first dose 
of talazoparib in maintenance period +1)/7,  
where end date = date of last dose of talazoparib. 
Duration of exposure to talazoparib (weeks) =  
(last dose date of talazoparib – first dose date of talazoparib + 1)/7   
Cumulative dose is the sum of the actual doses of talazoparib received in the study.   
Actual Dose Intensity (DI)  
 Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)]    
Relative Dose Intensity (RDI)   
 RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of talazoparib to last dose of talazoparib]  
 = 100 × [overall cumulative dose] / [7 × d × duration of exposure to talazoparib in 
weeks]  
where d is the dose for talazoparib. 
6.5.3.6. Dose reductions  
Applicable to avelumab, paclitaxel, carboplatin, and bevacizumab.  Dose reduction is defined 
as actual non-zero dose < 90% of the planned dose.  
Applicable to talazoparib.  Dose reduction is defined as a change to a non-zero dose level 
lower than that planned in the protocol. 
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized.  


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6.5.3.7. Dose interruptions 
Applicable to talazoparib only.   
An interruption is defined a 0 mg dose administered on one or more days for talazoparib. 
What follows defines how dose interruptions will be counted in the case of multiple dose 
interruptions. 
 If an interruption occurs consecutively for at least two days due to the same reason, then 
it will be counted only once (example: If the actual dose on days 1-3 is 1 mg and actual 
dose on days 4-5 is 0 mg and dose interruption on days 4-5 is due to AE, then the total 
number of dose interruptions is 1). 
 If an interruption occurs consecutively for at least two days due to different reasons, then 
it will be counted for each reason (example: If the actual dose on days 1-3 is 1 mg and 
actual dose on days 4-5 is 0 mg and dose interruption on day 4 is due to AE and dose 
interruption on day 5 is due to dosing error, then the total number of dose interruptions is 
2).  
 If an interruption occurs for more than one day due to the same reason, but the days are 
not consecutive, ie there is at least one dosing day in between, then each dose interruption 
will be counted as a different occurrence (example: If the actual dose on days 1, 3 and 5, 
is 1 mg and actual dose on days 2 and 4 is 0 mg, and dose interruptions on day 2 and 4 
are both due to dosing error, the total number of dose interruptions is 2).  
A dose interruption is not considered a dose reduction. 
The number and percentage of patients with dose interruptions and the corresponding reasons 
will be summarized. 
6.5.3.8. Dose delays  
Applicable to avelumab, paclitaxel, carboplatin, and bevacizumab.   
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses.  
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – Planned days between 
two consecutive doses, where planned days are:  
 21 for carboplatin,  
 21 for paclitaxel,  
 21 for bevacizumab in both chemotherapy and maintenance periods,  
 21 for avelumab in the chemotherapy period, 14 for avelumab in the maintenance period. 
For patients taking IDS, the interval encompassing the IDS date (ie Dose (x-1) Date < 
surgery < Dose x Date) will not be considered for dose delay assessment. 


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 Dose delays will be grouped into the following categories:  
 No delay  
 1-3 days delay  
 4-6 days delay 
 7 or more days delay 
For example, for avelumab administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16, 17, or 18, this is considered as 1-3 days delay.   
No delay and 1-3 days delay will also be summarized together.  
The number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized.   
6.5.3.9. Infusion rate reductions 
Applicable to avelumab, paclitaxel, carboplatin, and bevacizumab.    
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3, or ≥4 infusion rate reductions of ≥ 50% will be summarized. 
6.5.3.10. Infusion interruptions 
Applicable to avelumab, paclitaxel, carboplatin, and bevacizumab.    
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded). 
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized. 
6.5.4. Concomitant medications and non-drug treatments 
The following analyses will be based on the safety analysis set by treatment arm. 
Concomitant medications are medications, other than study medications, which started 
prior to first dose date of study treatment and continued on on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study medications and pre-medications for study drug, which are started before the first dose 
of study treatment.  
Prior and concomitant medications will be summarized from the ‘General Concomitant 
Medications’ eCRF page. Pre-medications for study drug will also be summarized separately 
from the ‘Pre-Medication Treatment’ eCRF page. 


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Summary of prior medications, summary of concomitant medications and summary of pre-
medications will include the number and percentage of patients by Anatomical Therapeutic 
Chemical (ATC) Classification level 2 and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. If any prior or concomitant medication is classified into 
multiple ATC classes, the medication will be summarized separately under each of these 
ATC classes. The summary tables will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. In case any 
specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category.  
A listing of prior medications and a listing of concomitant medications will be created with 
the relevant information collected on the ‘General Concomitant Medications’ eCRF page.  A 
listing of pre-medications will be created with the relevant information collected on the ‘Pre-
Medication Treatment’ eCRF page. 
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’.  
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page. 
6.5.5. Subsequent anti-cancer therapies 
The following analyses will be based on the FAS by treatment arm. 
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘On-
Study Cancer Surgery’, and ‘Follow-up Cancer Surgery’ eCRF pages.  
 Listing of anti-cancer drug therapies  
 Listing of anti-cancer radiotherapy  
 Listing of anti-cancer surgeries 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Cancer Surgery’ eCRF 
pages.  
6.6. Safety Summaries and Analyses 
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of 
AEs and other safety parameters will be based on the safety analysis set by treatment arm.  


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6.6.1. Adverse events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period as defined in Section 3.5.1. 
All analyses described will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings. 
 Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (ie, no answer to the question 
‘Relationship with study treatment’).  Related AEs are those related to any study drug (ie, 
at least one of the study drugs).  
 Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes). 
 Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction 
of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
= Dose reduced). 
 Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).   IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.  
 Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn). 
 Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5). 
 Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs 
documented in the Safety Review Plan and finalized for analysis of the current studies 
data prior to DB lock) 
 Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
Safety Review Plan and finalized for analysis of the current studies data prior to DB 
lock). 
 Complications Related to Surgery (CRS): CRS as collected on dedicated AE page 


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Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment arm, primary SOC 
and PT in decreasing frequency based on the frequencies observed for Arm A.  
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity. 
6.6.1.1. All adverse events 
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the  latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category.  
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed.  
The following tables will be created:  
 The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment arm: 
- TEAEs 
- TEAEs, Grade ≥ 3 
- Related TEAEs 
- Related TEAEs, Grade ≥ 3 
- TEAEs leading to dose reduction of avelumab  
- TEAEs leading to dose reduction of paclitaxel 
- TEAEs leading to dose reduction of carboplatin 
- TEAEs leading to dose reduction of bevacizumab 
- TEAEs leading to dose reduction of talazoparib  
- TEAEs leading to interruption of avelumab 
- TEAES leading to interruption of paclitaxel 
- TEAEs leading to interruption of carboplatin 
- TEAEs leading to interruption of bevacizumab 
- TEAEs leading to interruption of talazoparib  
- TEAEs leading to discontinuation of avelumab 
- TEAEs leading to discontinuation of paclitaxel 
- TEAEs leading to discontinuation of carboplatin 


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- TEAEs leading to discontinuation of bevacizumab 
- TEAEs leading to discontinuation of talazoparib  
- TEAEs leading to discontinuation of any study drug 
- TEAEs leading to discontinuation of all study drugs 
- Related TEAEs leading to discontinuation of avelumab 
- Related TEAEs leading to discontinuation of paclitaxel 
- Related TEAEs leading to discontinuation of carboplatin 
- Related TEAEs leading to discontinuation of bevacizumab 
- Related TEAEs leading to discontinuation of talazoparib  
- Related TEAEs leading to discontinuation of any study drug 
- Related TEAEs leading to discontinuation of all study drugs 
- Serious TEAEs 
- Related Serious TEAEs  
- TEAEs leading to death 
- Related TEAEs leading to death 
- irAEs 
- IRRs  
 TEAEs by SOC and PT and worst grade 
 Related TEAEs by SOC and PT and worst grade  
 TEAEs leading to death by SOC and PT 
 Related TEAEs leading to death by SOC and PT 
 TEAEs Excluding SAEs, with frequency ≥ 5% in any treatment arm by SOC and PT 
6.6.1.2. Adverse events leading to dose reduction 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment arm: 
 TEAEs leading to dose reduction of avelumab by SOC and PT 
 TEAEs leading to dose reduction of paclitaxel by SOC and PT 
 TEAEs leading to dose reduction of carboplatin by SOC and PT 
 TEAEs leading to dose reduction of bevacizumab by SOC and PT 


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 TEAEs leading to dose reduction of talazoparib by SOC and PT 
The listing of all AEs leading to dose reduction will also be provided with the relevant 
information.  
6.6.1.3. Adverse events leading to interruption of study treatment 
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).   IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay).  
As such, for parenteral drugs, AEs leading to interruption will be defined as AEs identified in 
the AE eCRF page with an action taken with study treatment of ‘drug interrupted’ excluding  
 IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.8). These IRRs will be considered as IRRs leading to 
interruption of infusion. 
 IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.8). 
For talazoparib, AEs leading to interruption will be defined as all AEs identified in the AE 
eCRF page with an action taken with study treatment of ‘drug interrupted’. 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment arm: 
 TEAEs leading to interruption of avelumab by SOC and PT 
 TEAEs leading to interruption of paclitaxel by SOC and PT  
 TEAEs leading to interruption of carboplatin by SOC and PT 
 TEAEs leading to interruption of bevacizumab by SOC and PT 
 TEAEs leading to interruption of talazoparib by SOC and PT 
The listing of all AEs leading to interruption of study treatment will also be provided with the 
relevant information. 
In addition, the frequency (number and percentage) of patients with each of the following 
will be presented for TEAEs leading to interruption of each study drug by treatment arm: 
 TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT 
 TEAEs leading to both interruption and dose reduction of paclitaxel by SOC and PT 
 TEAEs leading to both interruption and dose reduction of carboplatin by SOC and PT 


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 TEAEs leading to both interruption and dose reduction of bevacizumab by SOC and PT 
 TEAEs leading both interruption and dose reduction of talazoparib by SOC and PT 
This summary will take into account PTs with both actions as defined in Section 6.6.1, even 
though the actions may be captured for different PT records (ie, different onset for the PT 
with action “drug interrupted” and the PT with action “dose reduced”.  
6.6.1.4. Adverse events leading to discontinuation of study treatment 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment, by treatment arm: 
 TEAEs leading to discontinuation of avelumab by SOC and PT 
 Related TEAEs leading to discontinuation of avelumab by SOC and PT 
 TEAEs leading to discontinuation of paclitaxel by SOC and PT 
 Related TEAEs leading to discontinuation of paclitaxel by SOC and PT 
 TEAEs leading to discontinuation of carboplatin by SOC and PT 
 Related TEAEs leading to discontinuation of carboplatin by SOC and PT 
 TEAEs leading to discontinuation of bevacizumab by SOC and PT 
 Related TEAEs leading to discontinuation of bevacizumab by SOC and PT 
 TEAEs leading to discontinuation of talazoparib by SOC and PT 
 Related TEAEs leading to discontinuation of talazoparib by SOC and PT 
 TEAEs leading to discontinuation of any study drug by SOC and PT 
 Related TEAEs leading to discontinuation of any study drug by SOC and PT 
 TEAEs leading to discontinuation of all study drugs by SOC and PT 
 Related TEAEs leading to discontinuation of all study drugs by SOC and PT 
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information.  
6.6.2. Deaths 
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’ 
eCRFs, by treatment arm.   
 All deaths  


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 Deaths within 30 days after last dose of study treatment 
 Reason for Death  
- Disease progression 
- Study treatment toxicity 
- AE not related to study treatment 
- Unknown 
- Other. 
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information: 
 AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5),  
 Flag for death within 30 days of last dose of study treatment.  
6.6.3. Serious adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment arm: 
 SAEs by SOC and PT 
 Related SAEs by SOC and PT 
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period. 
6.6.4. Other significant adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment arm: 
 irAEs leading to death, by Cluster and PT  
 irAEs, by Cluster and PT 
 irAEs, Grade ≥ 3, by Cluster and PT 
 irAEs leading to discontinuation of avelumab, by Cluster and PT  
 irAEs leading to discontinuation of paclitaxel, by Cluster and PT  
 irAEs leading to discontinuation of carboplatin, by Cluster and PT  
 irAEs leading to discontinuation of bevacizumab, by Cluster and PT  


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 irAEs leading to discontinuation of talazoparib, by Cluster and PT  
 irAEs leading to discontinuation of any study drug, by Cluster and PT 
 irAEs leading to discontinuation of all study drugs, by Cluster and PT 
 Serious irAEs, by Cluster and PT  
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period.  
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment arm: 
 IRRs leading to death, by PT  
 IRRs, by PT 
 IRRs, Grade ≥ 3, by PT 
 IRRs leading to discontinuation of avelumab, by PT  
 IRRs leading to discontinuation of paclitaxel, by PT  
 IRRs leading to discontinuation of carboplatin, by PT  
 IRRs leading to discontinuation of bevacizumab, by PT  
 IRRs leading to discontinuation of any study drug, by PT  
 IRRs leading to discontinuation of all study drugs, by PT 
 Serious IRRs, by PT 
 Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later). For IV study drugs administered in combination the infusion numbers are those 
associated with the regimen, rather than the individual study drugs. 
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent CRSs, by treatment arm: 
 CRSs leading to death, by PT 
 CRSs, by PT 
 CRSs, Grade ≥ 3, by PT 
 CRSs leading to discontinuation of avelumab, by PT 


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 CRSs leading to discontinuation of paclitaxel, by PT 
 CRSs leading to discontinuation of carboplatin, by PT 
 CRSs leading to discontinuation of bevacizumab, by PT 
 CRSs leading to discontinuation of talazoparib, by PT 
 CRSs leading to discontinuation of any study drug, by PT 
 CRSs leading to discontinuation of all study drugs, by PT 
 Serious CRSs, by PT 
The listing of all CRSs will also be provided with the relevant information with a flag for 
CRSs with onset outside of the on-treatment period. 
In addition, the following analyses will be presented for Tier-1 (irAEs and IRRs as defined in 
Appendices 1 and 2) and Tier-2 events separately.  P-values and CIs for risk difference will 
be calculated based on the unconditional exact method by Santner and Snell (1980).  No 
additional analyses will be presented for Tier-3 AEs.  
 Frequency (number and percentage) of patients with each of the following by treatment 
arm and PT or Clustered Term: 
- Tier-2 AEs 
- Tier-2 AEs Grade ≥ 3 
 Point estimate for risk difference and 95% CI for risk difference (experimental arm vs 
comparator arm) for each of the following by PT or Clustered Term: 
- irAEs 
- irAEs Grade ≥ 3 
- IRRs  
- IRRs Grade ≥ 3  
- Tier-2 AEs 
- Tier-2 AEs Grade ≥ 3 
 2-sided p-value associated with risk difference (experimental arm vs comparator arm) for 
each of the following by PT or Clustered Term: 
- irAEs 
- irAEs Grade ≥ 3 
- IRRs  


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- IRRs Grade ≥ 3  
 The p-values and CIs reported are not adjusted for multiplicity and should be used for 
screening purposes only.  The 95% CIs are provided to help gauge the precision of the 
estimates for the risk difference and should be used for estimation purposes only. 
6.6.5. Laboratory data 
6.6.5.1. Hematology and chemistry parameters 
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits, and above normal limit (according 
to the laboratory normal ranges).  
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9). End of Treatment visit laboratory results will be 
summarized separately. The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories (ie, 
Low, Normal, High).  
Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 will be 
described using the worst grade. For those parameters which are graded with two toxicities 
such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 0 
when the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), 
and vice versa.   
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows:  
Derived differential absolute count = (WBC count) × (Differential %value / 100) 
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows:  
 Lymphocyte count decreased:   
- derived absolute count does not meet Grade 2-4 criteria, and 
- % value < % LLN value, and 
- derived absolute count  ≥ 800/mm3 


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 Neutrophil count decreased  
- derived absolute count does not meet Grade 2-4 criteria, and 
- % value < % LLN value, and 
- derived absolute count  ≥ 1500/mm3 
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows 
  
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L]) 
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.    
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment arm: 
 ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
  AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
 (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN 
 TBILI ≥ 2×ULN 
 Concurrent  ALT ≥ 3×ULN and TBILI ≥ 2×ULN 
 Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN 
 Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN  
 Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN 
 Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or 
missing) 
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages.  
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment arms, by graphically displaying 


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 peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN.  
 peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at  
AST=3×ULN and total bilirubin=2×ULN.  
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided. 
Parameters with NCI-CTC grades available:  
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period.  The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie those 
patients for whom a Grade 0, 1, 2, 3, or 4 can be derived). 
 The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4, and any grade (Grades 1-4), 
laboratory abnormalities during the on-treatment period. 
 The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary.  
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie: 
 Hematology:  
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased). 
  Serum Chemistry: 
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased, Creatinine (creatinine increased), Creatine Kinase (CPK increased), Potassium 
(hypokalemia/ hyperkalemia), Sodium (hyponatremia/ hypernatremia), Magnesium 
(hypomagnesemia/hypermagnesemia), Calcium (hypocalcemia/ hypercalcemia), Glucose 
(hypoglycemia/hyperglycemia), Gamma Glutamyl Transferase (GGT) (GGT increased), 
Lipase (lipase increased), Phosphates (hypophosphatemia). 
Parameters with NCI-CTC grades not available: 
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with:  
 shifts from baseline normal to at least one result above normal during on-treatment period  


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 shifts from baseline normal to at least one result below normal during on-treatment 
period 
In this study, these apply to the following parameters:  
 Serum Chemistry: Chloride, Uric Acid,   
6.6.5.2. Other laboratory parameters 
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF.  
 Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT) or 
international normalized ratio (INR). 
 Thyroid function: TSH, free T4 
 Urinalysis: Protein, glucose, blood 
 Other parameters: ACTH, HBV, Anti-HCV antibody. If Anti-HCV antibody positive, 
then HCV RNA testing  
 Pregnancy test 
 
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests.  
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing.  
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided. 
6.6.6. Vital signs 
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle. Weight will not be collected at End of Treatment. Height will 
be measured at screening only. 
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing.  
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline.  


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6.6.7. Electrocardiogram 
All patients require a single ECG measurement at screening (clinically significant abnormal 
findings in baseline ECGs will be recorded as medical history). Additional ECGs will be 
performed as clinically indicated. Clinically significant findings seen on follow-up ECGs 
should be recorded as adverse events. All ECG assessments will be listed. 
6.6.8. Physical examination 
Patient physical assessments, scheduled and performed, will be listed.  
6.6.9. ECOG performance status 
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment arm. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing. 
7. INTERIM ANALYSES 
7.1. Introduction 
The goals of the interim analyses are to allow early stopping of treatment arm(s) for futility 
or efficacy.  The interim analysis of PFS and OS will be performed as described in Sections 
5.1.1 and 5.1.2 using the methodology described in Sections 6.1.1.1 and 6.2.2.1 for PFS and 
Section 6.2.2.2 for OS.   
At the time of the interim analysis for PFS in the DDR+ population, hierarchical testing of 
other secondary endpoints will also be carried out as outlined in Section 5.1.1, with the 
analyses being performed by an independent statistician.  Unblinded results from the interim 
analysis will not be communicated to the Sponsor’s clinical team or to any party involved in 
the study conduct (apart from the independent statistician and E-DMC members) until the E-
DMC has determined that either (i) PFS analysis in the DDR+ population has crossed the 
pre-specified boundary for efficacy or (ii) the study needs to be terminated due to any cause, 
including futility or safety reasons.  Further details will be described in the E-DMC charter. 
At the time of final analysis of PFS in the DDR+ population, the analyses of other secondary 
endpoints will be performed by the Sponsor’s clinical team. All patients will continue to be 
followed for OS until the final OS analysis (or earlier if OS reaches statistical significance at 
an interim analysis). 
7.2. Interim Analyses and Summaries 
At each analysis time point, the critical boundaries for the group sequential test will be 
derived from the predefined spending function(s) as described in Section 5.1. The 
calculations of boundaries will be performed using EAST. 
7.2.1. Interim analysis for PFS in the DDR+ population 
Throughout this section, references to PFS pertain to PFS based on BICR assessment in the 
DDR+ population. 


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Let u(t1) and u(tF) denote the upper critical boundaries based on the test statistics Z1 and ZF 
for efficacy at the interim and the final analysis, respectively, and let l(t1) and l(tF) denote the 
lower critical boundary for futility at the interim and final analysis, respectively.  For the 
final analysis, l(tF)=u(tF).  
The critical values u(t1) and l(t1) for the interim analysis of PFS are determined such as  
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



   and   
)
(
))
(
(
1
1
1
t
t
l
Z
Pa



 , 
where P0 and Pa denote the probabilities under the null hypothesis and the alternative 
hypothesis, respectively, and 
)
( 1t

 and
)
( 1t

 denote the α and β spent, respectively, based on 
the predefined spending functions at information fraction t1 (t1 is calculated as the ratio of the 
number of PFS events observed at the time of the cut-off for the interim analysis and the total 
number of PFS events targeted for the final analysis).  
The boundary for the final efficacy analysis will be calculated such that 
025
.0
)
),
(
(
)
(
1
1
0
1




F
F
u
Z
t
u
Z
P
t

 
As described in Section 5.1.2, if the number of PFS events in the final analysis deviates from 
the target number of PFS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analysis and the actual correlation between 
the two test statistics Z1 and ZF, so that the overall 1-sided significance level across all 
analyses and comparisons is preserved at 0.025.  
7.2.2. Interim analysis for PFS in patients unselected for DDR status 
Throughout this section, references to PFS pertain to PFS based on BICR assessment in 
patients unselected for DDR status. 
The interim analysis for PFS for patients unselected for DDR status will be performed if H01 is 
rejected. No futility analysis will be performed for PFS in patients unselected for DDR status. 
Let u(t1) and u(tF) denote the upper critical boundaries based on the test statistics Z1 and ZF 
for efficacy at the interim and the final analysis, respectively. 
The critical value u(t1) for the interim analysis of PFS are determined such as  
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



, 
where P0 denotes the probabilities under the null hypothesis, and 
)
( 1t

 denotes the α spent,  
based on the predefined spending functions at information fraction t1 (t1 is calculated as the 
ratio of the number of PFS events observed at the time of the cut-off for the interim analysis 
and the total number of PFS events targeted for the final analysis).  
The boundary for the final efficacy analysis will be calculated such that 
003
.0
)
),
(
(
)
(
1
1
0
1




F
F
u
Z
t
u
Z
P
t

 


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As described in Section 5.1.2, if the number of PFS events in the final analysis deviates from 
the target number of PFS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analysis and the actual correlation between 
the two test statistics Z1 and ZF, so that the overall 1-sided significance level across all 
analyses and comparisons is preserved at 0.003.  
7.2.3. Interim analysis for OS in the DDR+ population 
Throughout this section, references to OS pertain to OS in the DDR+ population. 
The interim analysis for OS in the DDR+ population will be performed if H01 is rejected. No 
futility analysis will be performed for OS in the DDR+ population. 
Let u(ti) and u(tF) denote the upper critical boundaries based on the test statistics Zi and ZF 
for efficacy at the ith interim and the final analysis, respectively, where i=1, 2, 3.  
In what follows P0 denotes the probability under the null hypothesis, and 
)
( it

 denotes the α 
spent based on the predefined α-spending function at information fraction ti (ti is calculated 
as the ratio of the number of OS events observed at the time of the cut-off for the ith interim 
analysis and the total number of OS events targeted for the final analysis. 
For each comparison, the critical value u(t1) for the 1st interim analysis of OS is determined 
such as  
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



. 
Critical boundaries for the additional interim analyses and the final analysis of OS are 
calculated recursively as follows for each comparison  
u(t2) is derived such that 
)
(
))
(
),
(
(
)
(
2
2
2
1
1
0
1
t
t
u
Z
t
u
Z
P
t






 , 
u(t3) is derived such that 
)
(
))
(
),
(
),
(
(
)
(
3
3
3
2
2
1
1
0
2
t
t
u
Z
t
u
Z
t
u
Z
P
t







  
The boundary for the final efficacy analysis is derived such that 
022
.0
)
),
(
),
(
),
(
(
)
(
3
3
2
2
1
1
0
3






F
F
u
Z
t
u
Z
t
u
Z
t
u
Z
P
t

  
As described in Section 5.1.2, if the number of OS events in the final analysis deviates from 
the target number of OS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analyses and the actual correlation between 
the four test statistics Zi (i=1, 2, 3) and ZF, so that the overall 1-sided significance level 
across all analyses and comparisons is preserved at 0.022.  
7.2.4. Interim analysis for OS in patients unselected for DDR status 
Throughout this section, references to OS pertain to OS in patients unselected for DDR 
status. 


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The interim analysis for OS for patients unselected for DDR status will be performed 
according to the testing strategy described in Section 5.1.1. No futility analysis will be 
performed for OS in patients unselected for DDR status. 
In what follows P0 denotes the probability under the null hypothesis, and 
)
( it

 denotes the α 
spent based on the predefined α-spending function at information fraction ti (ti is calculated 
as the ratio of the number of OS events observed at the time of the cut-off for the ith interim 
analysis and the total number of OS events targeted for the final analysis. 
For each comparison, the critical value u(t1) for the 1st interim analysis of OS is determined 
such as  
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



. 
Critical boundaries for the additional interim analyses and the final analysis of OS are 
calculated recursively as follows for each comparison  
u(t2) is derived such that 
)
(
))
(
),
(
(
)
(
2
2
2
1
1
0
1
t
t
u
Z
t
u
Z
P
t






 , 
u(t3) is derived such that 
)
(
))
(
),
(
),
(
(
)
(
3
3
3
2
2
1
1
0
2
t
t
u
Z
t
u
Z
t
u
Z
P
t







 , 
The boundary for the final efficacy analysis is derived such that 
'
3
3
2
2
1
1
0
3
)
),
(
),
(
),
(
(
)
(








F
F
u
Z
t
u
Z
t
u
Z
t
u
Z
P
t
 
Where α’ = 0.025 or 0.003 or 0.022 for the analysis of OS in patients unselected for DDR 
status as determined according to the testing strategy described in Section 5.1.1.   
As described in Section 5.1.2, if the number of OS events in the final analysis deviates from 
the target number of OS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analyses and the actual correlation between 
the four test statistics Zi (i=1, 2, 3) and ZF, so that the overall 1-sided significance level 
across all analyses and comparisons is preserved at α’.  
 


A vel u ma b 
B 9 9 9 1 0 3 0 ( M S B 0 0 1 0 7 1 8 C , M D V 3 8 0 0, B M N 6 7 3) Statisti cal A nal ysis Pla n 
 
P FI Z E R C O N FI D E N TI A L 
P a ge 9 6  
8.  R E F E R E N C E S 
1.  
A mit O, et al.  Bli n de d i n de pe n de nt ce ntral r e vie w of pr o gressi o n i n ca ncer cli nical 
trials: Res ults fr o m a meta-a nal ysis a n d rec o m me n dati o n fr o m a P h R M A w or ki n g 
gr o u p. E ur o pea n J o ur nal of Ca ncer 4 7: 1 7 7 2- 1 7 7 8, 2 0 1 1. 
2.  
B r o o k me yer R, Cr o wle y JJ. A c o nfi de nce i nter val f or t he me dia n s ur vi v al ti me. 
Bi o metrics. 3 8: 2 9- 4 1, 1 9 8 2. 
3.  
B ur ger R A, Bra d y M F, B o o k ma n M A et al. 2 0 1 1. I n c or p orati o n of be vaciz u ma b i n t he 
pri mar y treat me nt of o varia n ca n cer. N E n gl J Me d. 3 6 5( 2 6): 2 4 7 3- 8 3.  
4.  
Cl o p per CJ, Pears o n E S ( 1 9 3 4). T he use of c o nfi d e nce or fi d ucial li mits ill ustrate d i n 
t he case of t he bi n o mial.  Bi o metri ka; 2 6, 4 0 4- 4 1 3. 
5.  
E ur o Q o L Gr o u p. Pre pare d b y va n R ee ne n M a n d J a nsse n B. E Q- 5 D- 5 L User G ui de: 
Basic i nf or mati o n o n h o w t o use t he E Q- 5 D- 5 L i nstr u me nt. Versi o n 2. 1. A pril 2 0 1 5. 
6.  
F A CI T.  N C C N/ F A C T O varia n S y m pt o m I n d e x- 1 8 ( F O SI- 1 8) Sc ori n g G ui deli nes 
( Versi o n 2) 2 0 0 8. 
7.  
He r d ma n M, G u d e x C, Ll o y d A, J a nsse n M F, Ki n d P, Par ki n D, B o nsel G, Ba dia X. 
2 0 1 1. De vel o p me nt a n d preli mi nar y testi n g of t he ne w fi ve-l e vel versi o n of E Q- 5 D 
( E Q- 5 D- 5 L). Q ualit y of Lif e Researc h. 2 0: 1 7 2 7- 1 7 3 6. 
8.  
Je n nis o n C, T ur n b ull B W. I n: Gr o u p Se q ue ntial Met h o ds wit h A p plicati o ns t o Cli nical 
Trials. C ha p ma n & Hall/ C R C, B oca Rat o n, 2 0 0 0.  
9.  
J e nse n S E, R ose n bl o o m S K, Bea u m o nt J L, et al. A ne w i n de x of pri orit y s y m pt o ms i n 
a d va nce d o varia n ca n cer. G y n ec ol O nc ol 2 0 1 1; 1 2 0( 2): 2 1 4- 9. 
1 0.  J e nse n S E, Kaiser K, Lacs o n L, et al. C o nte nt vali dit y of t he N C C N- F A C T o varia n 
s y m pt o m i n de x- 1 8 ( N F O SI- 1 8). G y nec ol O nc ol 2 0 1 5; 1 3 6( 2): 3 1 7- 2 2. 
1 1.  Kal bfleisc h J D, Pre ntice, R L. Statistical A nal ysis of Fail ure Ti me Data, 2 n d E diti o n. 
H o b o ke n, Wile y I ntersci e nce. 2 0 1 1.  
 
 
 
  
1 3.  Ka pla n E L, Meier P. N o n para metri c esti mati o n fr o m i nc o m plete o bser vati o ns. J A m 
Stat Ass oc. 5 3: 4 5 7- 8 1, 1 9 5 8. 
1 4.  R a bi n R, de C harr o F.  E Q -5 D -5 L: a m eas ure of healt h stat us fr o m t he E ur o Q ol Gr o u p.  
A n n Me d. 2 0 0 1 J ul; 3 3 ( 5): 3 3 7 -4 3. Re vie w.  
C C
I


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15. Royston, P. and Parmar, M.K. The use of restricted mean survival time to estimate the 
treatment effect in randomized clinical trials when the proportional hazards assumption 
is in doubt. Statistics in medicine, 2011; 30(19), pp.2409-2421. 
16. Rustin, G et.al. Definitions for Response and Progression in Ovarian cancer Clinical 
Trials Incorporating RECIST 1.1 and CA-125 Agreed by the Gynecological Cancer 
Intergroup (GCIG)., Int J Gynecol Cancer. 2011 Feb;21(2):419-23 
17. Santner TJ, Snell MK. (1980). Small-sample confidence intervals for p1-p2 and p1/p2 
in 2 x 2 contingency tables. Journal of the American Statistical Association, 75:386–
394 
18. Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression 
model. Biometrika 1980; 67:145-53. 
19. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. 
Statistics for Biology and Health 2000. 
20. Uno H, et al. Moving Beyond the Hazard Ratio in Quantifying the Between-Group 
Difference in Survival Analysis. J Clin Oncol 2014; 32. 
21. Zhang X. Comparison of restricted mean survival times between treatments based on a 
stratified Cox model. DOI 10.1515/bams-2013-0101 Bio-Algorithms and Med-Systems 
2013; 9(4): 183–9. 
 
 


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9. APPENDICES 
Appendix 1. Immune-Related Adverse Events 
The MedDRA PTs and clusters for irAEs are defined in the Safety Review Plan (SRP) for 
avelumab. 
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 22.   
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step.   
 Table 22.   Case Definition for irAEs 
 Step 
Selection Criteria 
Additional Notes 
1 
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step 
 
2 
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment. 
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications 
3 
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’ 
 
4 
AE treated with corticosteroids or other 
immunosuppressant therapy.   
For endocrinopathies only: AE required 
hormone replacement 
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs if 
A) OR B) below are met then the AE is in for the 
next step 
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA,  L04AB,  
L04AC,   L04AD,  L04AX, A07EA) and AE PT 
is in any of the irAE clusters. 
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters  associated with 
“Immune-mediated endocrinopathies” 
C) conmed ATC code is A10A and AE PT is in the 
irAE cluster associated with “Immune-mediated 
endocrinopathies: Type I Diabetes Mellitus” 


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5 
A) No clear etiology (other than immune 
mediated etiology) 
 
 
 
 
 
 
 
B) Histopathology / biopsy consistent with 
immune-mediated event 
 
 
 
 
 
 
 
 
 
Event is in if  
[Answer to 5B1 and 5B2 is YES  (regardless 
of answer to 5A)] 
OR 
[Answer to 5B1 is YES AND answer to 5B2 
is NO AND answer to 5A is NO]  
OR 
[Answer to 5B1 is NO AND answer to 5A is 
NO] 
A) From the AE eCRF page. 
Is the AE clearly related to an etiology other than 
immune-mediated etiology?    Yes / No 
If answer is Yes, check all that apply: 
 Underlying malignancy / progressive disease. 
 Other medical conditions.  
 Prior or concomitant medications / procedures.   
 Other.  Specify. 
 
B) From the AE eCRF page. 
B1) Was there a pathology /histology evaluation 
performed to investigate the AE?  Y/N 
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N 
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text) 
 
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (eg, addition of cases that are not selected 
by the programmatic algorithm) will be the basis of the irAE analyses. 


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Appendix 2. Infusion Related Reactions 
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered.  
 All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or 
after infusion) and the event resolved with end date within 2 days after onset.  
 All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, 
will be considered potential IRRs when onset is on the day of study drug infusion 
(during or after the infusion) or the day after the study drug infusion (irrespective of  
resolution date). 
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab.  
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 23    
or Table 24 and will be identified for IV drugs only.      
Table 23.  Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs 
Condition Selection criterion 
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)]  then AE is classified as an IRR 
1 
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list  
2 
 AE onset date = date of infusion of study drug AND  
 AE timing related to study drug (‘DURING’, ‘AFTER’) AND  
 AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND  
 AE  end date – AE onset date <=2  
3 
PT is included in the ‘IRRs CORE’ list  
4A 
 AE onset date = date of infusion of study drug AND  
 AE timing related to study drug in (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion 
 


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Table 24.  Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets) 
 
Condition 
Selection criterion 
IRR can be associated with the first IV drug and/or subsequent IV drugs that are administered in combination.  
Without loss of generality assume triplet IV with D1 administered first then D2 then D3.  The IV study drug or 
drugs associated with the IRR need to be identified in the analysis data set to enable subsequent analysis. 
 
The following are not sequential and an AE can be classified as an IRR associated with multiple DJ  from one 
or more of  I, II, III, IV, V below: 
 
I - If the AE meets [1 AND 2A1] for a DJ then the AE is classified as an IRR associated with the DJ that 
meets the 2A1 criterion  
  
II - If the AE meets [1 AND 2A2] for a DJ then the AE is classified as an IRR associated with the DJ  and 
associated with DJ+1 that meets the 2A2 criterion  
 
III - If the AE meets [3 AND 4B] for any DJ then the AE is classified as an IRR associated with all DJ that 
meet the 4B criterion. 
 
IV- If the AE meets [3 AND 4A1] for a DJ then the AE is classified as an IRR associated with the DJ that 
meets the 4A1 criterion  
  
V- If the AE meets [3 AND 4A2] for a DJ then the AE is classified as an IRR associated with the DJ  and 
associated with DJ+1 that meets the 4A2 criterion  
 
1 
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list  
2A1 
 AE onset date = date of infusion of study drug DJ AND 
 AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
 [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion of 
study drug DJ+1]AND 
 AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND  
 AE  end date – AE onset date <=2  
2A2 
 AE onset date = date of infusion of study drug DJ AND 
 AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
 AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) AND 
 AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND  
 AE  end date – AE onset date <=2  
3 
PT is included in the ‘IRRs CORE’ list  
4A1 
 AE onset date = date of infusion of study drug DJ AND 
 AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
 [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion of 
study drug DJ+1] 


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4A2 
 AE onset date = date of infusion of study drug DJ AND 
 AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
 AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion of study drug D J