Clinical trial NCT03330405
Conditions: Avelumab in Combination With Talazoparib Will be Investigated in Patients With Locally Advanced (Primary or Recurrent) or Metastatic Solid Tumors
Keywords: NSCLC, TNBC, hormone receptor positive (HR+) breast cancer, recurrent epithelial ovarian cancer, UC, and castration resistant prostate cancer (CRPC).
Sponsor: Pfizer
Start date: 2017-10-19; Completion date: 2023-01-04
Enrollment: 223 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).

Detailed description:
Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against programmed death ligand 1 (PD L1). Avelumab selectively binds to PD L1 and competitively blocks its interaction with programmed death receptor 1 (PD 1), thereby interfering with this key immune checkpoint inhibition pathway. Avelumab is currently being investigated as single agent and in combination with other anti cancer therapies in patients with locally advanced or metastatic solid tumors and various hematological malignancies.

Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate \[ADP\] ribose) polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, replication, and transcription.

Avelumab in combination with talazoparib will be investigated in patients with locally advanced (primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), hormone receptor positive (HR+) breast cancer, recurrent platinum sensitive ovarian cancer, urothelial cancer (UC), and castration resistant prostate cancer (CRPC).

Arms: arm 1: Drug: Avelumab

Drug: Talazoparib arm 2: Drug: Avelumab

Drug: Talazoparib arm 3: Drug: Avelumab

Drug: Talazoparib arm 4: Drug: Avelumab

Drug: Talazoparib arm 5: Drug: Avelumab

Drug: Talazoparib arm 6: Drug: Avelumab

Drug: Talazoparib arm 7: Drug: Avelumab

Drug: Talazoparib arm 8: Drug: Avelumab

Drug: Talazoparib arm 9: Drug: Avelumab

Drug: Talazoparib arm 10: Drug: Avelumab

Drug: Talazoparib arm 11: Drug: Avelumab

Drug: Talazoparib arm 12: Drug: Avelumab

Drug: Talazoparib arm 13: Drug: Avelumab

Drug: Talazoparib
Interventions: intervention 1: Avelumab Phase 1b intervention 2: Talazoparib Phase 1b intervention 3: Avelumab Phase 2 intervention 4: Talazoparib Phase 2
Intervention descriptions: intervention 1: Avelumab intervention 2: Talazoparib intervention 3: The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated. intervention 4: The dose will be determined after the overall available data (including safety and preliminary anti tumor activity) emerging from the Phase 1b portion of the study have been evaluated.

Protocol documents:
Prot_000.pdf: 
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A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND ANTI-TUMOR ACTIVITY 
OF AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE 
DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR 
TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC 
SOLID TUMORS
JAVELIN PARP MEDLEY
Investigational Product Number:
MSB0010718C
MDV3800, BMN 673
Investigational Product Name:
Avelumab (MSB0010718C) 
Talazoparib (MDV3800, BMN 673)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database
(EudraCT) Number:
2017-001509-33
Protocol Number:
B9991025
Phase:
1b/2a
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
Original 
protocol
14 June 2017
Not applicable (N/A)
Protocol 
Amendment 1
14 August 2017
The following changes to the original protocol were 
requested by the US FDA:

Inclusion criteria 1 in Section 4.1 was updated to 
modify the Phase 1b study population;

The DLT definition criteria in Section 3.2 were 
updated; 

The recommended dose modification for 
talazoparib following Grade 3 non-hematologic 
toxicities has been updated in Table 5 to require 
dose reduction.  Exceptions to the requirement for 
dose reductions are included.
In addition, the following changes were 
implemented:

The secondary endpoint for PK was updated to 
better indicate the parameters to be reported and 
analyzed;

The study design schema (protocol summary and 
Figure 3) was updated to correct the number of 
patients with ovarian cancer to be enrolled in 
C1 and C2.  Section 9.3.3 was also updated 
accordingly;

The information about talazoparib clinical 
experience in Section 1.2.2 was updated to report 
the updates included in the talazoparib July 
2017 IB;

Several administrative changes were included to 
improve readability.

Changes were made to study design schema 
(protocol summary and Figure 3), secondary 
endpoints, Schedule of Activities, inclusion 
criteria and Sections 1.2.4, 1.2.8, and 7.4 to 


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Document
Version Date
Summary of Changes and Rationale
reflect a change in the choice of assay for 
assessment of DDR defects.
Protocol 
Amendment 2
26 January 2018
The following changes were implemented:
•
Addition of Cohort F and rationale to include 
patients with advanced solid tumors with 
germline or somatic defects in BRCA1, 
BRCA2, or ATM genes who are not eligible 
for Cohorts A1, A2, B1, B2, C1, C2, D, E1, 
or E2.
•
Rationale for eligibility criteria for pancreatic 
cancer patients in Cohort F was added.
•
Cohort C1 size was reduced to up to 
approximately 20 patients.
•
Inclusion criteria for all cohorts, bone marrow 
function, renal function, and use of 
P-glycoprotein inhibitors were clarified.
•
Coagulation tests were clarified.
•
Contraception methods were revised.
•
Tumor mutational burden in baseline tumor 
tissue was added as a secondary endpoint.
•
The introduction was updated with additional 
preliminary data for talazoparib.
•
The eligibility worksheet was removed as it 
will not be applicable to Cohort F.
•
Prohibited concomitant medications and 
therapies and use of inhibitors of P-gp were 
revised.
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Version Date
Summary of Changes and Rationale
•
Administrative changes were included to 
improve readability.
Protocol 
Amendment 3
20 November
2018
The following changes were implemented:
•
Human epidermal growth factor receptor 2 
negative requirement was added to inclusion 
criterion for hormone receptor positive breast 
cancer patients for clarity.
•
Consistent with the Avelumab Investigator’s 
Brochure (version 8, 16 May 2018), the
protocol was revised to update relevant 
background information, and
recommendation for management of Grade 1 
to 2 immune-related rash was updated.
•
Consistent with changes implemented in the 
updated talazoparib Investigator’s Brochure 
(dated August 2018), the protocol was revised 
to increase the duration of contraception use 
and concomitant medication restrictions.
Relevant background pharmacokinetic 
information was also updated.
•
Sample size for Cohort A2 was reduced to 
20 patients as the patient population has 
changed and this cohort is now only 
exploratory.
•
Sample size for Cohort F was reduced to 
10 patients as the original intent was to bridge 
enrollment until study B9991032 was 
enrolling.  That study is now open and there is 
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no longer a need to enroll 40 patients in this 
cohort.

Flexibility in the target number of patients to 
be enrolled in the Phase 2 cohorts of the study 
was added to avoid a dedicated protocol 
amendment in case additional data are needed 
in a specific biomarker-defined population.

The Schedule of Activities was updated to 
clarify procedures for patients who continue 
treatment beyond 2 years (Cycles >25) to 
lessen study participation burden for long 
term study participants.  Serum/urine 
pregnancy test procedures are no longer 
required at Day 60 and Day 90 of Short-Term 
Follow-Up (only Day 30).

Prep D1 collection was clarified to only be 
collected on Day 1 of Cycle 1.  It will not be 
collected on Day 1 of subsequent cycles 
(optional) or at end of treatment.

Physical exams are permitted to be performed 
1 day prior to the scheduled visit to confirm 
any findings before dosing.

Permissible highly effective methods of 
contraception were updated as per current 
protocol standard, including the addition of 
sexual abstinence.

DDR defect status assessment procedures 
were revised to allow prospective and local 
(where applicable) testing of DDR defects. 

Preliminary safety data from the Phase 1b 
portion of this study were added to 
Benefit/Risk Assessment.

Inclusion criteria for Cohort A2 were revised 
to allow inclusion of patients who have
previously received anti-PD-1/L1 treatment.


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•
In response to queries raised by the Ministry 
of Food and Drug Safety of South Korea for 
sites in South Korea only, specific eligibility 
criteria were restricted for Cohorts A1, B1, 
and D.
•
A DDR gene list has been added inclusion 
criteria for Cohorts A2, B2, and E2, to better 
define the DDR defect positive status required 
for eligibility.
•
Language regarding talazoparib 
administration was revised to clarify 
procedures for any missed doses.
•
Requirements for tumor assessments for 
progressive disease confirmation were 
removed. 
•
A separate withdrawal of consent form is not 
applicable to this study and was removed 
from procedures.
•
Activated partial thromboplastin time 
assessment was permitted as an alternative to 
partial thromboplastin time.  Prothrombin 
time was removed.
•
Existing objectives for biomarker 
assessments were revised 
and re-ordered for clarity.
•
Tumor tissue sample procedures were revised
for clarity on prospective and/or local testing.
•
Editorial updates have been made for 
consistency and readability.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES .................................................................................................................14
APPENDICES .........................................................................................................................14
PROTOCOL SUMMARY.......................................................................................................15
SCHEDULE OF ACTIVITIES................................................................................................24
1. INTRODUCTION ...............................................................................................................33
1.1. Mechanism of Action/Indication.............................................................................33
1.1.1. Avelumab....................................................................................................33
1.1.2. Talazoparib .................................................................................................34
1.2. Background and Rationale ......................................................................................34
1.2.1. Avelumab Clinical Experience...................................................................34
1.2.1.1. Clinical Experience in Patients with NSCLC ...........................37
1.2.1.2. Clinical Experience in Patients with Locally Advanced or 
Metastatic UC....................................................................................38
1.2.1.3. Clinical Experience in Patients with Ovarian Cancer ...............38
1.2.1.4. Clinical Experience in Patients with Advanced Breast 
Cancer................................................................................................39
1.2.1.5. Clinical Experience in Patients with mCRPC...........................39
1.2.1.6. Pharmacokinetics of Avelumab in Humans..............................39
1.2.2. Talazoparib .................................................................................................40
1.2.2.1. Talazoparib Clinical Experience ...............................................40
1.2.2.2. Clinical Efficacy in Patients with Advanced Solid Tumors......41
1.2.2.3. Clinical Efficacy in Patients with Germline BRCA 
Mutations and Locally Advanced and/or Metastatic Breast 
Cancer................................................................................................42
1.2.2.4. Pharmacokinetics of Talazoparib in Humans............................42
1.2.3. Clinical Experience in Patients with mCRPC Treated with PARP 
Inhibitors as a Single Agent or in Combination with Immunotherapy............43
1.2.4. Study Rationale...........................................................................................44
1.2.5. Rationale for the Tumor Types to be Evaluated.........................................47
1.2.6. Rationale for the Investigational Product Doses ........................................48


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1.2.6.1. Avelumab ..................................................................................48
1.2.6.2. Talazoparib................................................................................48
1.2.7. Summary of Benefit/Risk Assessment .......................................................49
1.2.8. Rationale for Biomarker Assessments and Prospective Patient 
Selection...........................................................................................................50
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................52
2.1. Objectives................................................................................................................52
2.2. Endpoints.................................................................................................................53
3. STUDY DESIGN.................................................................................................................54
3.1. Study Overview.......................................................................................................54
3.1.1. Phase 1b......................................................................................................55
3.1.1.1. Rules for Dose De-Escalation/Escalation in Phase 1b..............56
3.1.2. Phase 2........................................................................................................57
3.2. Dose-Limiting Toxicity Definition .........................................................................58
3.3. Maximum Tolerated Dose Definition .....................................................................59
3.4. Maximum Administered Dose Definition...............................................................59
3.5. Recommended Phase 2 Dose (RP2D) Definition ...................................................59
4. PATIENT ELIGIBILITY CRITERIA.................................................................................60
4.1. Inclusion Criteria.....................................................................................................60
4.2. Exclusion Criteria....................................................................................................69
4.3. Lifestyle Requirements ...........................................................................................71
4.4. Sponsor’s Qualified Medical Personnel..................................................................72
5. STUDY TREATMENTS.....................................................................................................73
5.1. Allocation to Treatment ..........................................................................................73
5.2. Patient Compliance .................................................................................................74
5.2.1. Avelumab Patient Compliance ...................................................................74
5.2.2. Talazoparib Patient Compliance.................................................................74
5.3. Investigational Product Supplies.............................................................................75
5.3.1. Dosage Forms and Packaging.....................................................................75
5.3.1.1. Avelumab ..................................................................................75
5.3.1.2. Talazoparib................................................................................75
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5.3.2. Preparation and Dispensing........................................................................76
5.3.2.1. Avelumab ..................................................................................76
5.3.2.2. Talazoparib................................................................................76
5.4. Administration.........................................................................................................76
5.4.1. Combination Therapy Administration........................................................76
5.4.2. Talazoparib Administration........................................................................77
5.4.3. Avelumab Premedication............................................................................78
5.4.4. Avelumab Administration ..........................................................................78
5.4.4.1. Special Precautions for Avelumab Administration...................78
5.4.5. Food Requirements.....................................................................................79
5.4.6. Recommended Dose Modifications............................................................79
5.4.6.1. Dosing Interruptions..................................................................79
5.4.6.2. Dose Reductions of Talazoparib ...............................................80
5.4.6.3. Study Treatment Modifications for Avelumab and 
Talazoparib Drug-Related Toxicity (excluding infusion-related 
reactions and immune-related adverse events)..................................80
5.4.6.4. Treatment Modifications for Infusion-Related Reactions 
Associated with Avelumab................................................................83
5.4.6.5. Immune-Related Adverse Events Toxicity Management .........84
5.4.7. Treatment After Initial Evidence of Radiological Disease 
Progression.......................................................................................................91
5.5. Investigational Product Storage ..............................................................................92
5.5.1. Avelumab Storage ......................................................................................93
5.5.2. Talazoparib Storage....................................................................................93
5.6. Investigational Product Accountability...................................................................93
5.6.1. Destruction of Investigational Product Supplies ........................................93
5.7. Concomitant Treatment...........................................................................................93
5.7.1. Supportive Care ..........................................................................................94
5.7.2. Hematopoietic Growth Factors...................................................................94
5.7.3. Anti-Diarrheal, Anti-Emetic Therapy.........................................................94
5.7.4. Anti-Inflammatory Therapy........................................................................94
5.7.5. Corticosteroids............................................................................................94
5.7.6. Bisphosphonates or Denosumab.................................................................95


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5.7.7. Androgen Deprivation Therapy for Patients with mCRPC........................95
5.7.8. Concomitant Surgery..................................................................................95
5.7.9. Concomitant Radiotherapy.........................................................................95
5.7.10. Prohibited Concomitant Medications and Therapies................................96
6. STUDY PROCEDURES .....................................................................................................97
6.1. Screening.................................................................................................................97
6.2. Treatment Period.....................................................................................................97
6.3. Patient Withdrawal/EOT.........................................................................................98
6.3.1. Withdrawal of Consent...............................................................................98
6.3.2. Lost to Follow-up .......................................................................................99
6.4. Short Term Follow-up Visits...................................................................................99
6.5. Long Term Follow-up Visits.................................................................................100
7. ASSESSMENTS................................................................................................................100
7.1. Safety Assessments ...............................................................................................100
7.1.1. Pregnancy Testing ....................................................................................100
7.1.2. Contraception Check ................................................................................101
7.1.3. Adverse Events .........................................................................................101
7.1.4. Laboratory Safety Assessments................................................................101
7.1.5. Physical Examinations and Vital Signs....................................................103
7.1.6. (12-Lead) Electrocardiograms..................................................................103
7.2. Pharmacokinetics Assessments.............................................................................103
7.2.1. Blood for PK Analysis of Avelumab........................................................104
7.2.2. Blood for PK Analysis of Talazoparib .....................................................104
7.3. Immunogenicity Assessments...............................................................................104
7.4. Biomarker and Pharmacodynamic Assessments...................................................105
7.4.1. Tumor Tissue Samples .............................................................................106
7.4.1.1. DDR Defect Sample................................................................106
7.4.1.2. Baseline Tumor Tissue Samples .............................................106
7.4.1.3. On Treatment and End of Treatment Tumor Tissue 
Samples............................................................................................107
7.4.1.4. Archival Tumor Tissue Samples.............................................107
7.4.2. Peripheral Blood Samples.........................................................................107


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7.4.3. Additional Analyses..................................................................................108
7.5. Banked Biospecimens ...........................................................................................108
7.5.1. Additional Research..................................................................................109
7.6. Tumor Response Assessment................................................................................109
7.6.1. mCRPC Tumor Response Assessments ...................................................110
7.7. Blood Tests for Tumor Markers............................................................................111
7.7.1. CA-125 for Patients with Ovarian Cancer................................................111
7.7.2. Prostate-Specific Antigen for Patients with mCRPC ...............................111
8. ADVERSE EVENT REPORTING....................................................................................111
8.1. Requirements.........................................................................................................111
8.1.1. Additional Details On Recording Adverse Events on the CRF................113
8.1.2. Eliciting Adverse Event Information........................................................113
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal/EOT section)..................................................................113
8.1.4. Time Period for Collecting AE/SAE Information....................................113
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................113
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF...............114
8.1.5. Causality Assessment ...............................................................................114
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................114
8.2. Definitions.............................................................................................................114
8.2.1. Adverse Events.........................................................................................114
8.2.2. Abnormal Test Findings ...........................................................................115
8.2.3. Serious Adverse Events ............................................................................116
8.2.4. Hospitalization..........................................................................................116
8.3. Severity Assessment..............................................................................................118
8.4. Special Situations ..................................................................................................118
8.4.1. Potential Cases of Drug-Induced Liver Injury..........................................118
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................120
8.4.2.1. Exposure During Pregnancy....................................................120
8.4.2.2. Exposure During Breastfeeding ..............................................121
8.4.2.3. Occupational Exposure ...........................................................121
8.4.3. Medication Errors .....................................................................................122


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9. DATA ANALYSIS/STATISTICAL METHODS.............................................................122
9.1. Analysis Sets .........................................................................................................123
9.1.1. Full Analysis Set.......................................................................................123
9.1.2. Safety Analysis Set...................................................................................123
9.1.3. Evaluable for DLT Analysis Set...............................................................123
9.1.4. Pharmacokinetics/Immunogenicity Analysis Set .....................................123
9.1.4.1. Pharmacokinetics Analysis Set ...............................................123
9.1.4.2. Immunogenicity Analysis Set .................................................123
9.1.4.3. Biomarker Analysis Set...........................................................123
9.2. Statistical Methods and Properties ........................................................................124
9.2.1. Phase 1b....................................................................................................124
9.3. Sample Size Determination...................................................................................125
9.3.1. Cohorts A1 and A2...................................................................................126
9.3.2. Cohorts B1 and B2....................................................................................126
9.3.3. Cohorts C1 and C2....................................................................................126
9.3.4. Cohort D ...................................................................................................126
9.3.5. Cohorts E1 and E2....................................................................................126
9.3.6. Cohort F....................................................................................................127
9.4. Efficacy Analysis ..................................................................................................127
9.4.1. Analysis of the Primary Endpoint.............................................................127
9.4.2. Analysis of the Secondary Endpoints.......................................................128
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................129
9.5.1. Analysis of Pharmacokinetics of Investigational Products ......................129
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/Pharmacodynamic) Modeling......130
9.5.3. Analysis of Biomarker Secondary
 Endpoints................130
9.5.4. Analysis of Immunogenicity Data of Avelumab......................................131
9.6. Safety Analysis......................................................................................................131
9.6.1. Analysis of the Primary Endpoint in Phase 1b .........................................131
9.6.2. Adverse Events.........................................................................................131
9.6.3. Laboratory Test Abnormalities.................................................................131
9.6.4. Electrocardiogram.....................................................................................132
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9.7. Analysis of Other Endpoints .................................................................................132
9.8. Interim Analysis ....................................................................................................132
9.9. Data Monitoring Committee .................................................................................133
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................133
11. DATA HANDLING AND RECORD KEEPING ...........................................................133
11.1. Case Report Forms/Electronic Data Record .......................................................133
11.2. Record Retention.................................................................................................134
12. ETHICS............................................................................................................................134
12.1. Institutional Review Board/Ethics Committee....................................................134
12.2. Ethical Conduct of the Study ..............................................................................135
12.3. Patient Information and Consent.........................................................................135
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................135
13. DEFINITION OF END OF TRIAL.................................................................................136
13.1. End of Trial in a Member State...........................................................................136
13.2. End of Trial in All Other Participating Countries...............................................136
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................136
15. PUBLICATION OF STUDY RESULTS........................................................................136
15.1. Communication of Results by Pfizer ..................................................................136
15.2. Publications by Investigators ..............................................................................137
16. REFERENCES ................................................................................................................139
LIST OF TABLES
Table 1.
Schedule of Activities: Safety and Efficacy Assessments (Phases 1b and 2) ......25
Table 2.
Schedule of Activities: Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic Assessments (Phases 1b and 2)..............................................30
Table 3.
Talazoparib and Avelumab Dose Levels..............................................................56
Table 4.
Dose Levels for Dose Reductions of Talazoparib ................................................80
Table 5.
Talazoparib and Avelumab Treatment Modifications for Drug-Related 
Toxicity (Excluding Infusion-Related Reactions and Immune-Related AEs) .....81
Table 6.
Treatment Modification for Symptoms of Infusion-related Reactions 
Associated with Avelumab...................................................................................84
Table 7.
Management of Immune-Related Adverse Events...............................................85


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Table 8.
Required Safety Laboratory Tests ......................................................................102
Table 9.
Sample Size and Exact 90% Confidence Intervals for ORR..............................125
LIST OF FIGURES
Figure 2.
Combination of Talazoparib (BMN 673) and Anti-mouse PD-L1 Treatment 
Significantly Prolongs Survival in an Ovarian Cancer Model .............................46
Figure 3.
Phase 1b and Phase 2 Study Design Schema........................................................55
APPENDICES
Appendix 1. Abbreviations and Definitions of Terms...........................................................143
Appendix 2. ECOG Performance Status................................................................................148
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines .......................................................................................149
Appendix 4. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design.................154
Appendix 5. Assessment of Radiographic Response and Progression in Patients with 
mCRPC...............................................................................................................157
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PROTOCOL SUMMARY 
Mechanism of Action/Indication:
Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against
programmed death-ligand 1 (PD-L1).  Avelumab selectively binds to PD-L1 and 
competitively blocks its interaction with programmed death receptor 1 (PD-1), thereby 
interfering with this key immune checkpoint inhibition pathway.  In March 2017, avelumab 
received accelerated approval by the United States (US) Food and Drug Administration 
(FDA) as the first treatment for metastatic Merkel cell carcinoma (MCC).  In May 2017, 
avelumab received accelerated approval by the US FDA for the treatment of patients with 
locally advanced or metastatic urothelial cancer (UC) with disease progression during or 
following platinum-containing chemotherapy, or within 12 months of neoadjuvant or 
adjuvant platinum-containing chemotherapy.  
Talazoparib is a potent, orally bioavailable poly (adenosine diphosphate [ADP]-ribose)
polymerase (PARP) inhibitor, which is cytotoxic to human cancer cell lines harboring gene 
mutations that compromise deoxyribonucleic acid (DNA) repair, an effect referred to as 
synthetic lethality, and by trapping PARP protein on DNA thereby preventing DNA repair, 
replication, and transcription. Talazoparib was approved by the FDA on 16 October 2018 for 
the treatment of adult patients with deleterious or suspected deleterious germline Breast 
Cancer susceptibility gene (BRCA)-mutated human epidermal growth factor receptor 
2-negative (HER2-) locally advanced or metastatic breast cancer.
The combination of avelumab and talazoparib is expected to produce additive or synergistic 
anti-tumor activity, relative to each drug used as a single agent.  Avelumab in combination 
with talazoparib will be investigated in patients with locally advanced (primary or recurrent) 
or metastatic solid tumors, including non-small cell lung cancer (NSCLC), triple-negative 
breast cancer (TNBC), hormone receptor-positive (HR+)/human epidermal growth factor 
receptor 2-negative (HER2-) breast cancer, recurrent platinum-sensitive ovarian cancer, UC, 
metastatic castration-resistant prostate cancer (mCRPC), and locally advanced (primary or 
recurrent) or metastatic solid tumors harboring pathogenic, or likely pathogenic (as classified 
by the American College of Medical Genetics and Genomics and the Association for 
Molecular Pathology),1 germline or somatic defects in -BRCA1, BRCA2, or 
ataxia-telangiectasia mutated (ATM) genes.
Background:
Avelumab, as a single agent, has demonstrated efficacy, as well as an acceptable toxicity 
profile in patients with multiple types of solid tumors, including NSCLC, breast cancer, 
mCRPC, UC, and ovarian cancer in Study EMR100070-001.  In patients with first-line 
advanced NSCLC, a confirmed and unconfirmed objective response rate (ORR) of 
22.4% (95% confidence interval [CI]: 16.2, 29.8) was observed, while 14.1% (95% CI: 9.4, 
20.0) of second-line NSCLC patients had confirmed or unconfirmed responses 
(39% responded by the first assessment at 6 weeks and 73% had responded by 12 weeks).  In 
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patients with locally advanced or metastatic UC, who were either cisplatin ineligible or had 
progressive disease (PD) after at least 1 line of platinum-based therapy, the confirmed ORR 
was 17.6% (95% CI: 10.9, 22.5).  In 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, the ORR, based on confirmed and unconfirmed 
responses, was 9.7% (95% CI: 5.1, 16.3).  In patients with metastatic breast cancer refractory 
to or progressing after standard-of-care therapy the unconfirmed ORR was 
4.8% (95% CI: 2.1, 9.2); stable disease was observed in 55.6% of the patients with mCRPC.
While subsets of patients in a growing number of tumor types respond to treatment with a 
single-agent PD-1 or PD-L1 inhibitor, most patients with advanced disease either do not 
respond to single-agent therapy or experience only a partial response.  Further, the majority 
of those patients who do respond will ultimately progress.  These findings of somewhat 
limited responses are observed regardless of either the PD-1 or PD-L1 inhibitor that is being 
tested or the tumor type in which the immune checkpoint inhibitor is being evaluated. 
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, an ORR of 
44.4% (8 of 18; 95% CI: 21.5, 69.2) was observed.  In patients with advanced 
ovarian/peritoneal cancer, an ORR of 48.0% (12 of 25; 95% CI: 27.8, 68.7) was observed.  
Only 1 patient with prostate cancer was treated in this study and that patient did not have an 
objective response. In a Phase 3 trial in patients with BRCA 1/2 positive locally advanced 
and/or metastatic breast cancer (protocol no. 673-301 [EMBRACA]), single-agent 
talazoparib demonstrated superior progression-free survival (PFS) versus physician choice 
chemotherapy.1
Talazoparib is proposed for evaluation in combination with avelumab in patients with locally 
advanced (primary or recurrent) or metastatic solid tumors based on the acceptable safety and 
pharmacokinetic (PK) profiles observed for each of the investigational products when 
administered as single agents.  Preliminary clinical activity has been observed for these 
investigational products, or an agent of the same class, in the tumor types to be evaluated.  
Furthermore, the proposed complementary mechanisms of action of avelumab and 
talazoparib may lead to increased anti-tumor activity.  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.  
Talazoparib, via its ability to promote increased DNA damage, has the potential to promote 
several of these key stages of the immune response.  Specifically, DNA damage via 
talazoparib is expected to promote inflammation and prime an immune response by 
enhancing effective recognition and infiltration of tumors by immune cells.  Additionally, 
talazoparib treatment has been shown to lead to two to three fold increased expression of 
PD-L1 by tumor cells, suggesting that this may represent a means by which tumors function 
to inhibit talazoparib-mediated anti-tumor immunity.  This expectation is further supported 
by preclinical studies in syngeneic mouse models of ovarian and colorectal cancer, which 


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demonstrate a significant improvement in overall survival (OS) 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.
The primary purpose of this study is to assess the safety and early signs of efficacy of the 
avelumab and talazoparib combination in patients with locally advanced (primary or 
recurrent) or metastatic solid tumors, including NSCLC, TNBC, HR+/HER2- breast cancer, 
recurrent platinum-sensitive ovarian cancer, UC, mCRPC, and locally advanced (primary or 
recurrent) or metastatic solid tumors harboring pathogenic, or likely pathogenic, germline or 
somatic defects in BRCA1, BRCA2, or ATM genes.  These tumor types were selected on the 
basis that one of the investigational products, or an agent of the same class, has shown 
preliminary clinical activity in the tumor type of interest or because the tumor types are 
expected to have a high prevalence (35%) of biomarkers indicating increased sensitivity to 
talazoparib-mediated DNA damage. In the setting of NSCLC, early signs of efficacy will be 
assessed in anti-PD-1/L1 naïve patients and also in a cohort of patients who have previously 
received anti-PD-1/L1 treatment, in order to assess the ability of the combination to 
overcome resistance to anti-PD-L1 treatment in this setting.  It is anticipated that patients 
with an increased sensitivity to talazoparib will be most likely to respond to the combination 
treatment, independent of their tumor type.  In order to test this hypothesis, two potential 
biomarkers of talazoparib sensitivity (genomic scarring measured via a loss of heterozygosity 
[LOH] and presence of defects in a panel of DNA damage repair [DDR] genes) will be 
evaluated prospectively or retrospectively using the Foundation One assay in all cohorts. 
The BRCA1, BRCA2, and ATM genes represent some of the DDR genes with the greatest 
amount of data supporting their ability to confer sensitivity to PARP inhibitors.3 Given the 
greater confidence in these 3 DDR genes as predictive biomarkers, they will be assessed in 
prospectively selected cohorts of patients.  Cohort C2, will constitute patients with ovarian 
cancer who have previously identified pathogenic, or likely pathogenic, germline or somatic 
defects in either BRCA1 or BRCA2 genes.  Cohort F will constitute patients with locally 
advanced (primary or recurrent) or metastatic solid tumors, independent of tissue of origin, 
with previously identified pathogenic, or likely pathogenic, germline or somatic defects in 
BRCA1, BRCA2, or ATM genes.
Study Objectives and Endpoints:
Primary Objectives

Phase 1b: To assess the Dose-Limiting Toxicity (DLT) rate of avelumab in 
combination with talazoparib in patients with locally advanced or metastatic solid 
tumors in order to select the recommended Phase 2 dose (RP2D) of talazoparib for 
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•
Phase 2: To assess ORR of avelumab in combination with talazoparib, as assessed by 
the Investigator, per Response Evaluation Criteria in Solid Tumors, 
version 1.1 (RECIST v1.1) in patients with locally advanced or metastatic solid 
tumors and per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) in 
patients with mCRPC.
Secondary Objectives
•
To assess the overall safety and tolerability of avelumab in combination with 
talazoparib.
•
To characterize the PK of avelumab and talazoparib when given in combination.
•
To evaluate the immunogenicity of avelumab when given in combination with 
talazoparib.
•
To assess the anti-tumor activity of avelumab in combination with talazoparib.
•
To assess the correlation of anti-tumor activity of avelumab in combination with 
talazoparib with PD-L1 expression, tumor mutational burden (TMB; defined as the 
total number of mutations in the tumor genome, or number of mutations per 
megabase of DNA if derived from targeted sequencing),4 and potential biomarkers of 
PARP inhibitor sensitivity in baseline tumor tissue.
 
 
 
Primary Endpoints
•
Phase 1b: DLT during the DLT evaluation period (Cycle 1).
•
Phase 2: Confirmed objective response (OR), as assessed by the Investigator using 
RECIST v1.1 in patients with locally advanced or metastatic solid tumors 
(see Appendix 3) and RECIST v1.1 and PCWG3 in patients with mCRPC 
(see Appendix 5).
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Secondary Endpoints
•
Adverse events (AEs) as characterized by type, severity (as graded by National 
Cancer Institute Common Terminology Criteria for AEs [NCI CTCAE] v.4.03), 
timing, seriousness, and relationship to study therapy.
•
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v.4.03) and timing.
•
PK parameters for avelumab and talazoparib including: pre-dose/trough 
concentrations (Ctrough) and post-dose concentrations (for talazoparib) or maximum 
concentrations (Cmax) for avelumab.
•
Avelumab anti-drug antibody (ADA) levels and neutralizing antibodies (Nab) against 
avelumab.
•
Phase 1b: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in 
patients with locally advanced or metastatic solid tumors and RECIST v1.1 and 
PCWG3 in patients with mCRPC. 
•
Phase 1b and Phase 2: Time-to-event endpoints including time to tumor response 
(TTR), duration of response (DR), and progression-free survival (PFS) as assessed by 
the Investigator using RECIST v1.1 for patients with solid tumors and using 
RECIST v1.1 and PCWG3 for patients with mCRPC, time to prostate-specific 
antigen (PSA) progression for patients with mCRPC, and OS.
•
PSA response ≥50% for patients with mCRPC.
•
Cancer antigen (CA)-125 response for patients with ovarian cancer.
•
PD-L1 expression level in baseline tumor tissue.
•
TMB in baseline tumor tissue.
•
Genomic scarring and the presence of defects in select genes, considered critical to 
effective DDR, in baseline tumor tissue. 
 
 
 
 
 
 
 
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Study Design:
The study design and specific expansion cohorts, including the number of patients to be 
enrolled into each cohort, are shown below.  Approximately 242 patients in total will be 
enrolled into the study.
ATM= ataxia telangiectasia mutated; BC= breast cancer; BRCA=BReast CAncer susceptibility gene; 
mCRPC= metastatic castration-resistant prostate cancer; D=Dose; HER2-=human epidermal growth factor 
receptor 2 negative; HR+=hormone receptor positive; DDR=DNA damage repair; DDR Defect +=DDR defect 
positive as determined by the Foundation One assay or validated local assay result; IV=intravenous; 
NSCLC=non-small cell lung cancer; PD-L1= Programmed Death-Ligand 1; PO= orally; Q2W=every 2 weeks; 
QD=every day; TNBC= triple-negative breast cancer; TPS= tumor proportion score.
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Phase 1b
During the Phase 1b portion of this study, patients with locally advanced or metastatic solid 
tumors, who meet eligibility criteria, will be treated with one of up to 3 different doses of 
talazoparib (0.5 mg, 0.75 mg, or 1.0 mg) administered orally every day (QD) in combination 
with a fixed dose of avelumab 800 mg intravenous (IV) every 2 weeks (Q2W), and will be 
evaluated for DLTs.  The modified toxicity probability interval (mTPI) method will be used 
to identify the RP2D for talazoparib (see Appendix 4).  The avelumab and talazoparib 
combination will be administered in 28-day cycles.  The DLT evaluation period will be 
28 days (ie, Cycle 1). The target enrollment cohort size is 3-6 patients.
The starting dose level will be 1.0 mg talazoparib QD plus 800 mg avelumab Q2W.  For 
patients with moderate renal impairment (CrCl 30-59 mL/min), the 1 mg QD talazoparib 
starting dose should be reduced to 0.75 mg QD (Section 1.2.6.2).  The dose levels of the 
combination to be evaluated are included in the table below.
Dose Level
Talazoparib Dose
(Oral)
Avelumab Dose
(IV)
D0
1 mg QD
800 mg Q2W
D-1
0.75 mg QD
800 mg Q2W
D-2
0.5 mg QD
800 mg Q2W
D=dose; QD=once daily; Q2W=every 2 weeks
Starting with dose level D0, 3 patients will be enrolled, treated, and monitored during the 
28-day DLT evaluation period.  The mTPI method recommends the dose level for the next 
enrollment cohort of patients based on the number of DLT-evaluable patients treated at the 
current dose level that have reported DLTs.  See Section 3.1.1.1 and Appendix 4 for Detailed 
Dose Escalation/De-Escalation Scheme. 
When all the DLT-evaluable patients treated in a given enrollment cohort have been 
evaluated for DLTs during the DLT observation period (28 days; Cycle 1) or experienced a 
DLT, whichever comes first, the patients in the next enrollment cohort will receive the dose 
level of the combination as assigned by the mTPI design.  As an example, if the total number 
of DLT-evaluable patients (cumulative in Phase 1b from prior and current cohorts) treated at 
the current dose combination is 3, the dose escalation/de-escalation rules are described 
below:

0 DLT in 3 DLT-evaluable patients escalate, if a higher dose level is available;

1 DLT in 3 DLT-evaluable patients remain at the same dose level;

2 DLTs in 3 DLT-evaluable patients de-escalate, if a lower dose level is available 
and allow for possible re-escalation; 

3 DLTs in 3 DLT-evaluable patients de-escalate, if a lower dose level is available 
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In Phase 1b, patients without DLTs who withdraw from study treatment before receiving at 
least 75% of the planned dose of the investigational products in Cycle 1 for reasons other 
than treatment-related toxicity are not evaluable for DLT.  Additional patients will be 
enrolled in the specific cohort to replace patients who are not considered DLT-evaluable.
Phase 1b portion is completed when at least 12 DLT-evaluable patients have been treated at 
the highest dose associated with DLT rate <0.33 (see Section 9.2).  Early completion of 
Phase 1b can be reached when 9 or more DLT-evaluable patients have been treated at the 
same dose level with no occurrence of DLT, as the DLT rate of <0.33 will be met.
Once the Phase 1b portion is completed and the RP2D of the combination is determined, the 
Phase 2 portion will be initiated.
Approximately 12-36 patients are expected to be enrolled in Phase 1b using the mTPI 
method.
If dose level D-2 is not tolerable, the study will be stopped and no dose combination will be 
further evaluated.
Phase 1b was completed in May 2018 with 12 patients enrolled.
Phase 2
The overall available data (including safety and preliminary anti-tumor activity) emerging 
from Phase 1b portion of the study will be evaluated before starting enrollment of patients in 
the Phase 2 portion of the study.  The Phase 2 portion of this study will further assess the 
safety and preliminary anti-tumor activity of the avelumab and talazoparib combination at the 
RP2D.  Phase 2 expansion cohorts will include patients with locally advanced (primary or 
recurrent) or metastatic NSCLC, TNBC, HR+/HER2- breast cancer, recurrent 
platinum-sensitive ovarian cancer, UC, mCRPC, and locally advanced (primary or recurrent) 
or metastatic solid tumors harboring pathogenic, or likely pathogenic, germline or somatic 
defects in BRCA1, BRCA2, or ATM genes.
Approximately 230 patients are expected to be enrolled in Phase 2.
A given cohort size may be expanded by a limited number of additional patients 
(approximately 10) per Sponsor’s discretion subsequent to the identification of any early 
signal of clinical activity that may emerge from the generated data in a biomarker-defined 
population.
Study Treatments:
All patients enrolled will receive avelumab and talazoparib. 
Avelumab will be administered as a 1-hour IV infusion Q2W on Days 1 and 15 of each 
28-day cycle at a dose of 800 mg in both Phase 1b and Phase 2. 


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Talazoparib will be self-administered orally once daily at 0.5 mg, 0.75 mg, or 1 mg during 
Phase 1b, where DLTs will be assessed during Cycle 1 and dose escalation/de-escalation will 
follow the mTPI design.  Once the RP2D is determined in Phase 1b, the Phase 2 expansion 
cohorts will start enrolling at the RP2D dose of talazoparib in combination with avelumab 
800 mg IV Q2W (as specified above).
In May 2018, the RP2D for talazoparib administered orally in combination with avelumab 
800 mg IV Q2W was confirmed to be 1 mg QD. The talazoparib starting dose for patients 
with moderate renal impairment (CrCl 30-59 mL/min) will be reduced to 0.75 mg QD as 
discussed in the talazoparib IB.12
Avelumab will be administered at the investigational site on an outpatient basis.  On days 
when both drugs are administered, talazoparib will be administered first, followed by 
initiation of the avelumab infusion 800 mg as a 1-hour IV infusion starting 30-60 minutes 
after the mandatory premedication is administered.
Statistical Methods:
The primary endpoint for Phase 2 is confirmed OR using RECIST v1.1 in patients with 
locally advanced or metastatic solid tumors and using RECIST v1.1 and PCWG3 in patients 
with mCRPC.  OR is defined as a complete response (CR) or partial response (PR) per 
RECIST v1.1 by Investigator from the first dose of study treatment until disease progression 
or death due to any cause.  Both CR and PR must be confirmed by repeat assessments 
performed no less than 4 weeks after the criteria for response are first met.  ORR is defined 
as the proportion of treated patients with confirmed CR or PR per Investigator’s assessment 
according to RECIST v1.1. 
In patients with mCRPC, OR is defined as the proportion of patients with a best overall soft 
tissue response of CR or PR per RECIST v1.1 by Investigator from the first dose of study 
treatment until disease progression or death due to any cause.  Soft tissue responses will be 
confirmed by a follow-up radiographic assessment at least 4 weeks later repeated computed 
tomography (CT) or magnetic resonance imaging (MRI) with no evidence of confirmed bone 
disease progression per PCWG3 criteria by Investigator.
It is expected that 12-36 patients will need to be enrolled in Phase 1b using the mTPI design.  
Phase 2 expansion cohorts may each enroll up to approximately 20 or 40 patients, depending 
on the tumor type, as shown in the study design figure above. 
In cohorts with 10, 20, and 40 treated patients, ORR can be estimated with a standard error 
not exceeding 0.158, 0.112, and 0.079, respectively.  Within each cohort, ORR will be 
estimated and the 2-sided exact 90% and 95% CIs will be calculated.


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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  
Refer to the ASSESSMENTS section of the protocol for detailed information on each 
assessment required for compliance with the protocol.
The Investigator may schedule visits (unplanned visits) in addition to those listed in the 
schedule of activities table in order to conduct evaluations or assessments required to protect 
the well-being of the patient.
This schedule of activities will be followed for the entire study, including Phase 1b and 
Phase 2 portions.  Further details can be found in Sections 5, 6 and 7.


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Table 1.
Schedule of Activities: Safety and Efficacy Assessments (Phases 1b and 2)
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
28 Days 
Prior to
Enrollment
Cycle 1
Cycle 2
Cycles 3
Cycles ≥25
End of 
Treatment[26]
Short-Term 
Follow-Up[29]
Long-Term 
Follow-Up 
(Every 
12 weeks)[30]
Day 
1
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Day
1
Day
15
Day 30 
after 
last 
dose
Days 60 and 
90 after last 
dose
Visit Window (Days)
2
2
2
2
2
3
3
+7
±3
±3
±14
Informed Consent[1]
X
Tumor History[2]
X
Medical History[3]
X
Baseline Signs and Symptoms[4]
X
Height
X
Weight
X
X
X
X
X
Contraception Check[5]
X
X
X
X
X
X
X
X
Laboratory and Safety Assessments – Must be performed pre-dose during the Treatment Period
Physical Examination[6]
X
X
X
X
As 
clinically 
indicated
X
X
As clinically 
indicated
Vital Signs[7]
X
X
X
X
X
X
X
X
X
X
X
As clinically 
indicated
ECOG Performance Status[8]
X
X
X
X
X
X
X
X
As clinically 
indicated
Hematology[9]
X
X[24]
X
X
X
X
X
X
X
X
X
As clinically 
indicated
Blood Chemistry[9]
X
X[24]
X
X
X
X
X
X
X
X
X
As clinically 
indicated
Coagulation[9]
X
X[24]
As clinically indicated
X
X
As clinically 
indicated
Urinalysis[10]
X
X[24]
As clinically indicated
X
Serum/Urine Pregnancy Test (for women of 
childbearing potential only)[11]
X
X
X 
X
X
X
X
Hepatitis B and Hepatitis C Virus tests[12]
X


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Table 1.
Schedule of Activities: Safety and Efficacy Assessments (Phases 1b and 2)
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
28 Days 
Prior to
Enrollment
Cycle 1
Cycle 2
Cycles 3
Cycles ≥25
End of 
Treatment[26]
Short-Term 
Follow-Up[29]
Long-Term 
Follow-Up 
(Every 
12 weeks)[30]
Day 
1
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Day
1
Day
15
Day 30 
after 
last 
dose
Days 60 and 
90 after last 
dose
Visit Window (Days)
2
2
2
2
2
3
3
+7
±3
±3
±14
ACTH and Thyroid Function Tests[9]
X
Every 
3 cycles 
(Cycles 
3, 6, 9, 
etc) 
X
X
X
Testosterone (for mCRPC patients only)
X 
Results 
required for 
eligibility 
criteria prior 
to enrollment
Triplicate 12-Lead ECG[13]
X
X[25]
Cycle 
3 only[25]
X
As clinically 
indicated
Enrollment and Treatment
Enrollment[14]
X
Talazoparib Administration[15]
QD 
Premedication for Avelumab[16]
X
X
X 
X Optional Administration, at PI 
discretion, based on 
presence/severity of prior 
infusion reactions
Avelumab Administration[17]
X
X
X
X
X
X
X
X
Tumor Assessments (for all tumor types 
except mCRPC)[18]
X
Every 8 weeks (7 days) after C1D1. 
After 1 year from C1D1, every 16 weeks (7 days) until 
progressive disease.
X[27]
Every 8 weeks (7 days) after C1D1. 
After 1 year from C1D1, every 
16 weeks (7 days) until progressive 
disease.
Tumor Assessments for mCRPC patients 
ONLY[19]
X
Every 8 weeks (7 days) after C1D1. 
After 24 weeks from C1D1, every 12 weeks (7 days) until 
progressive disease.
X[27]
Every 8 weeks (7 days) after C1D1. 
After 24 weeks from C1D1, every 
12 weeks (7 days) until progressive 
disease.


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Table 1.
Schedule of Activities: Safety and Efficacy Assessments (Phases 1b and 2)
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
28 Days 
Prior to
Enrollment
Cycle 1
Cycle 2
Cycles 3
Cycles ≥25
End of 
Treatment[26]
Short-Term 
Follow-Up[29]
Long-Term 
Follow-Up 
(Every 
12 weeks)[30]
Day 
1
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Day
1
Day
15
Day 30 
after 
last 
dose
Days 60 and 
90 after last 
dose
Visit Window (Days)
2
2
2
2
2
3
3
+7
±3
±3
±14
CA-125 Tumor Marker Blood Test (for 
ovarian cancer patients ONLY)
X
X[24]
X
X
X
PSA Tumor Marker Blood Test (for mCRPC 
patients ONLY)
X
X[24]
X
X
X
Other Clinical Assessments
Serious and Non-Serious Adverse Event 
Monitoring[20]
X
Monitored and recorded continually
X
X[28]
X[28]
Concomitant Treatments[21]
X
Monitored and recorded continually
X
X
X
Subsequent Anti-Cancer Treatment[22]
X
X
X
Survival[23]
X
ACTH=adrenocorticotropic hormone, C=Cycle; C1D1=Cycle 1 Day 1; CA-125=Cancer antigen 125; mCRPC=metastatic castration-resistant prostate cancer; 
CT=computed tomography; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group performance status; FFPE=formalin-fixed 
paraffin-embedded; PI=Principal Investigator; PSA=prostate-specific antigen; QD=once daily.
Footnotes for Safety and Efficacy Assessments (Phases 1b and 2) Schedule of Activities:
1.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure and may be obtained >28 days prior to enrollment.
2.
Tumor History: Includes oncology history, information on prior regimens (duration of administration, best overall response [BOR] observed, and recurrence date), surgery, 
and radiation therapy. 
3.
Medical History: Includes history of diseases or injuries (active or resolved) and concomitant illnesses that are not considered to be the disease under study. 
4.
Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days prior to enrollment and record on the Medical History 
case report form (CRF) page. 
5.
Contraception Check: Investigator to confirm correct use of highly effective contraception, as applicable and for the duration as detailed in Sections 4.3 and 7.1.2.
6.
Physical Examination: Physical exam may be performed up to 1 day prior to visit.
7.
Vital Signs: Record blood pressure (BP), pulse heart rate (HR), and temperature.
8.
ECOG Performance Status: See Appendix 2 for the criteria to assign the ECOG Performance Status at each time point.
9.
Hematology, Coagulation, Blood Chemistry, ACTH, and Thyroid Function Tests: Hematology and blood chemistry tests may be performed up to 3 days prior to visits on 
Days 1 and 15 of each cycle.  See Section 7.1.4 for the list of required Laboratory Tests and Section 5.4.6 for requirements to perform additional laboratory tests to monitor 
toxicity related to either investigational product.


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10. Urinalysis: Dipstick is acceptable.  Perform microscopic analyses if dipstick is positive for blood or protein.  See Section7.1.4.
11. Serum/Urine Pregnancy Test (for women of childbearing potential only): See Section 4.1 for criteria defining women of childbearing potential, as those patients require 
pregnancy testing.  Serum or urine pregnancy tests must have sensitivity of at least 25 mIU/mL. Additionally perform pregnancy tests whenever one menstrual cycle is 
missed or when potential pregnancy is otherwise suspected.  See Section 7.1.1 for additional pregnancy testing details.
12. Hepatitis B and Hepatitis C Virus tests: Includes HBV surface antigen and anti-HCV antibody tests.  If anti-HCV antibody test is positive, HCV RNA test must be to be 
performed.
13. Triplicate 12-Lead ECG: See Section 7.1.6 for details regarding ECGs and the procedure to follow if mean QTc is prolonged (>500 msec).  If the patient experiences any 
cardiac AE or syncope, dizziness, seizures, or stroke, triplicate ECGs should be obtained at the time of the event. 
14. Enrollment: Managed by an Interactive Response Technology (IRT) system operated by Pfizer Inc.  See Section 5.1 for information regarding the IRT system.  
Investigational product administration must begin within 3 days after enrollment. 
15. Talazoparib Administration: See Section 5.4.2 for details on talazoparib administration.  On Day 1 and Day 15 of each 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 before the avelumab infusion.
16. Premedication for Avelumab: An antihistamine and paracetamol (acetaminophen) must be administered approximately 30-60 minutes prior to the first 4 avelumab infusions 
(for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent).  See Section 5.4.3 for further details on the premedication and 
Section 5.4.1 on the administration of the study combination treatment. 
17. Avelumab Administration:  After the patient has taken talazoparib and the premedication was administered, avelumab 800 mg IV as a 1-hour infusion must start 
30-60 minutes after the premedication.  See Section 5.4.4.1 for special precautions for avelumab administration. 
18. Tumor Assessments (for all tumor types except mCRPC): See Section 7.6 for details on tumor assessments, including tumor assessments to confirm CR or PR using 
RECIST version 1.1 (See Appendix 3).  Brain and bone imaging are mandatory at baseline.  Baseline scans are to be performed within 28 days prior to the first dose of study 
treatment.  Imaging should be performed with contrast agents unless contraindicated for medical reasons.  Timing of disease assessment should follow calendar days and 
should not be adjusted for delays in cycle starts.  Tumor assessments should also be performed whenever disease progression is suspected.  If bone metastases are present at 
baseline (Screening), then repeat bone imaging is required every 16 weeks during the first year of study treatment and every 24 weeks thereafter). 
19. Tumor Assessments for mCRPC patients ONLY: See Section 7.6.1 for details on mCRPC tumor assessments, including timing of tumor assessments to confirm CR or PR 
using RECIST v1.1 (See Appendix 3) or to confirm PD using PCWG3 (See Appendix 5) and the documentation required for the determination of radiographic progression.  
Brain imaging is mandatory at baseline.  Baseline scans are to be performed within 28 days prior to the first dose of study treatment.  Imaging should be performed with 
contrast agents unless contraindicated for medical reasons.  Timing of disease assessment should follow calendar days and should not be adjusted for delays in cycle starts.  
Tumor assessments should also be performed whenever disease progression is suspected.  Bone imaging is required every 8 weeks during the first 24 weeks of study 
treatment and every 12 weeks thereafter. 
20. Serious and Non-Serious Adverse Event Monitoring: AEs should be documented and recorded at each visit using the National Cancer Institute Common Terminology 
Criteria for AEs (NCI CTCAE) v.4.03.  The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each patient begins from the time 
the patient provides informed consent through and including a minimum of 90 calendar days after the last investigational product administration.  If the patient begins a new 
anti-cancer therapy, the period for recording non-serious AEs on the CRF ends at the time the new treatment is started.  However, any SAEs occurring during the active 
collection period must still be reported to Pfizer Safety and recorded on the CRF, irrespective of any intervening treatment.
21. Concomitant Treatments: Includes all medications and non-drug supportive interventions (eg, transfusions) from 28 days prior to the start of study treatment and up to 
90 days after the last dose of investigational products.  If a patient begins a new anti-cancer therapy, reporting of concomitant medications should end at the time the new 
treatment is started.  See Section 5.7 for additional details, and Section 5.7.10 for prohibited medications, which should be discussed with the patient and appropriately 
managed. 
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23. Survival: Contact patients via telephone or at the clinic for survival status independently of time of disease progression until for at least 2 years after enrollment of the last 
patient until death, lost-to-follow-up, patient withdrawal of consent, or study discontinued by the Sponsor, whichever comes first.  For those patients without evidence of 
disease progression at the time of treatment discontinuation who continue to be followed with tumor assessments at Long-Term Follow-Up, survival status will be collected at 
the time of the scheduled tumor assessments.
24. Hematology, Coagulation, Blood Chemistry, Urinalysis, PSA, and CA125: It is not necessary to repeat on Cycle 1 Day 1 (C1D1) if performed within 7 days prior to 
C1D1 as part of Screening.
25. Triplicate 12-Lead ECG (Day 1 Cycle 1 and Cycle 3): Triplicate ECGs will be performed before administration of talazoparib and at the end of avelumab infusion.
26. End of Treatment: Perform tests/procedures if not completed during the previous 7 days.
27. End of Treatment Tumor Assessments: Tumor assessments should be repeated at the End of Treatment (EOT) visit if not done in the previous 4 weeks and the prior 
response is other than confirmed PD. 
28. Short-term Follow-up Serious and Non-Serious Adverse Event Monitoring: Patients continuing to experience toxicity following discontinuation of investigational 
products 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.
29. Short-Term Follow-up: All patients will be followed for safety Day 30 after last dose (3 days) through 90 days (Day 30 via a site visit, Day 60 and Day 90 via a site visit or 
via phone call) after the last dose of study treatment or until the start of new anti-cancer treatment whichever occurs first.  A subsequent site visit may be requested if any 
concerns are noted during a phone call visit.  If the patient has withdrawn from study treatment for a reason other than disease progression, the patient should continue to 
undergo tumor assessments during the Short Term Follow-Up period as if they were still on therapy, regardless if they start on a new anti-cancer therapy.  Laboratory 
assessments may be performed as clinically indicated. 
30. Long-Term Follow-up: Follow-Up to continue until death unless lost to follow-up, consent withdrawal, or study discontinued by the Sponsor.  If the patient has withdrawn 
from study treatment for a reason other than disease progression, the patient should continue to undergo tumor assessments during the Long Term Follow-Up period as if the 
patient was still on therapy, regardless if the patient starts a new anti-cancer therapy.


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Table 2.
Schedule of Activities: Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Assessments (Phases 1b and 2)
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
≤28 Days Prior to
Enrollment
Cycle 1
Cycle 2
Cycles ≥3
End of 
Treatment
Short-Term Follow-Up   
(Day 30, Day 60 and 
Day 90 after last dose)
Long-Term 
Follow-Up 
(Every 3 months)
Day 
1
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Visit Window (Days)
±2
±2
±2
±2
±2
+7
±3
±14
-DDR Defect Status (for NSCLC 
Cohort A2, Breast Cancer 
Cohort B2 and Prostate Cancer 
Cohort E2 ONLY)[1]
X
Results required 
for eligibility 
criteria prior to 
enrollment
BRCA Status (for ovarian 
cancer Cohort C2 ONLY)[2]
X
Results required 
for eligibility 
criteria prior to 
enrollment
ATM or BRCA Status (for Solid 
Tumor Cohort F)[3]
X
Results required 
for eligibility 
criteria prior to 
enrollment
DDR Defect sample on FFPE 
tissue for all patients[4]
X
Blood Draw for Talazoparib 
PK[6]
X
X
X
Cycles 3-4 only 
Blood Draw for Avelumab PK[7]
X
X
X
Cycles 3-4, 6, 
9, 12, 18, and 
24 only 
Blood Draw for Immunogenicity 
(ADA) Testing[8]
X
X
X
Cycles 3-4, 6, 
9, 12, 18, and 
24 only 
X
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Table 2.
Schedule of Activities: Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Assessments (Phases 1b and 2)
Protocol Activities
Screening
Treatment Period (1 Cycle =28 Days)
Post Treatment
≤28 Days Prior to
Enrollment
Cycle 1
Cycle 2
Cycles ≥3
End of 
Treatment
Short-Term Follow-Up   
(Day 30, Day 60 and 
Day 90 after last dose)
Long-Term 
Follow-Up 
(Every 3 months)
Day 
1
Day 
15
Day 
1
Day 
15
Day 
1
Day 
15
Visit Window (Days)
±2
±2
±2
±2
±2
+7
±3
±14
Tumor Biopsy/Tissue
X[15]
ADA=anti-drug antibodies; ATM=ataxia-telangiectasia mutated; BRCA=BReast CAncer susceptibility gene; C=Cycle; C1D1=Cycle 1 Day 1; 
ctDNA=circulating tumor DNA; DNA=deoxyribonucleic acid; FFPE=formalin-fixed paraffin-embedded; DDR=DNA damage repair; NSCLC=non-small cell 
lung cancer; PD-L1=Programmed Death-Ligand 1; PI=Principal Investigator; PK=pharmacokinetics; PSA=prostate-specific antigen; RECIST v1.1=Response 
Evaluation Criteria in Solid Tumors, version 1.1;  RNA=ribonucleic acid; 
; TPS=tumor proportion score.
Footnotes for Pharmacokinetic, Pharmacodynamic, and Pharmacogenomic Assessments (Phases 1b and 2) Schedule of Activities:
Please refer to Laboratory Manual for instructions on sample collection, processing and shipment for all Pharmacokinetic, Pharmacodynamic, and 
Pharmacogenomic tests listed in Table 2.
1.
Known DDR Defect Status (for NSCLC Cohort A2, HR+/HER2- Breast Cancer Cohort B2, and mCRPC Cohort E2 ONLY): For patients being screened for enrollment 
into cohorts A2, B2 or E2, a defect in one of 34 DDR genes, as described in Section 4.1, must have been previously documented through local laboratory testing using a tissue 
based next generation sequencing test performed in a CAP/CLIAcertified (or comparable local or regional certification) laboratory or using one of the approved germline 
tests, as described in Section 4.1.  If DDR status has not been previously determined then tissue, as described in Section 7.4.1.1, must be sent for prospective DDR testing at 
the Foundation Medicine central laboratory no more than 45 days prior to enrollment.
2.
BRCA Status (for ovarian cancer Cohort C2 ONLY): For patients to be eligible for enrollment into the ovarian cohort for tumors with a BRCA defect (Cohort C2), patients 
must have a previous BRCA test result demonstrating that the patient has a germline or somatic BRCA1 or BRCA2 gene defect.  The test result must have been obtained by 
one of the approved tests.  See Section 4.1.
3.
ATM or BRCA Status (for solid tumor Cohort F ONLY): For patients to be eligible for enrollment into the solid tumor cohort for tumors with an ATM, BRCA1, or 
BRCA2 defect (Cohort F), patients must have a previous ATM, BRCA1, or BRCA2 test result demonstrating that the patient has a germline or somatic ATM, BRCA1, or 
BRCA2 defect, respectively.  The test result must have been obtained by one of the approved tests.  See Section 4.1.
4.
DDR Defect sample on FFPE tissue: All patients in all cohorts must submit FFPE tumor tissue to the Foundation Medicine central laboratory for testing using the
Foundation One assay-, as described in Section 7.4.1.1.
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6.
Blood Draw for Talazoparib PK: Blood samples (3-mL whole blood) will be collected at pre-dose (within 1 hour prior to taking talazoparib dose); and at the end of the 
avelumab infusion (within 10 minutes after the avelumab infusion ends) on Day 1 and Day 15 of Cycle 1, and then on Day 1 of Cycles 2-4.  See Section 7.2.2.
7.
Blood Draw for Avelumab PK: Blood samples (3.5-mL whole blood) will be collected at pre-dose (within 1 hour prior to taking talazoparib dose) and at the end of infusion 
(within 10 minutes after the avelumab infusion ends) on Day 1 and Day 15 of Cycle 1, on Day 1 of Cycles 2-4,  6, 9,12, 18, and 24.  See Section 7.2.1.
8.
Blood Draw for Avelumab Immunogenicity (ADA) Testing: Blood samples (3.5-mL whole blood) for avelumab immunogenicity testing will be collected pre-dose (within 
2 hours of talazoparib dose) on Day 1 and Day 15 of Cycles 1, on Day 1 of Cycle 2-4 and then on Day 1 of Cycles 6, 9, 12, 18, 24, and at the EOT. See Section 7.3.
15. Tumor Biopsy/Tissue: All patients must submit FFPE tumor tissue as described in Section 7.4.1.
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1. INTRODUCTION
This is a Phase 1b/2 study to evaluate safety and anti-tumor activity of avelumab 
(MSB0010718C), a programmed death-ligand 1 (PD-L1) specific monoclonal antibody 
(mAb), in combination with talazoparib (MDV3800, BMN 673), a poly (adenosine 
diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, in patients with locally advanced 
(primary or recurrent) or metastatic solid tumors, including non-small cell lung cancer 
(NSCLC), triple-negative breast cancer (TNBC), hormone receptor-positive (HR+)/human 
epidermal growth factor receptor 2 negative (HER2-) breast cancer, recurrent 
platinum-sensitive ovarian cancer, urothelial cancer (UC), metastatic castration-resistant 
prostate cancer (mCRPC), and locally advanced (primary or recurrent) or metastatic solid 
tumors harboring pathogenic, or likely pathogenic (as classified by the American College of 
Medical Genetics and Genomics and the Association for Molecular Pathology),1 germline or 
somatic defects in BReast CAncer susceptibility gene (BRCA)-1, BRCA2, or 
ataxia-telangiectasia mutated (ATM) genes.
1.1. Mechanism of Action/Indication
1.1.1. Avelumab
Avelumab is a human immunoglobulin (Ig)G1 mAb directed against PD-L1.  Avelumab 
selectively binds to PD-L1 and competitively blocks its interaction with programmed death 
receptor 1 (PD-1).  Compared with anti-PD-1 antibodies that target T cells, avelumab targets 
tumor cells, and therefore is expected to have fewer side effects, including a lower risk of 
autoimmune-related safety issues, as blockade of PD-L1 leaves the programmed death 
ligand 2 (PD-L2)/PD-1 pathway intact to promote peripheral self-tolerance.5,6 For complete 
details of the in vitro and nonclinical studies, refer to the avelumab Investigator’s Brochure 
(IB).7
In March 2017, avelumab received accelerated approval by the United States (US) Food and 
Drug Administration (FDA) as the first treatment for metastatic Merkel cell carcinoma 
(MCC) followed by approvals in Japan, Australia, European Union, Switzerland, and Israel.  
In May 2017, avelumab received accelerated approval by the US FDA for the treatment of 
patients with locally advanced or metastatic UC with disease progression during or following 
platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant 
platinum-containing chemotherapy.  In January 2018, avelumab was approved for the same 
indication in Israel. 
Avelumab is currently being investigated as single agent and in combination with other 
anti-cancer therapies in patients with locally advanced or metastatic solid tumors and various 
hematological malignancies.
Additional information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab IB.7


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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.8,9,10 Although other 
PARP inhibitors also possess both activities, in vitro studies demonstrated that talazoparib 
has more potent PARP trapping activity than other PARP inhibitors in clinical 
development.9,11
DNA damage promotes inflammation via the NF-κB pathway13 and the stimulation of 
interferon genes (STING) pathway,14,15 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).16,17 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.18 Additionally, talazoparib 
treatment has been shown to lead to increased expression of PD-L1 by tumor 
cells,19 suggesting that this may represent a means by which tumors function to inhibit 
talazoparib-mediated anti-tumor immunity.
Talazoparib was approved by the FDA on 16 October 2018 for the treatment of adult patients 
with deleterious or suspected deleterious germline BRCA-mutated human epidermal growth 
factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer.
Additional information for talazoparib may be found in the SRSD, which for this study is the 
talazoparib IB.12
1.2. Background and Rationale
1.2.1. Avelumab Clinical Experience
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono and is 
indicated for the treatment of adults and pediatric patients 12 years and older with metastatic 
MCC and in adult patients having UC with disease progression during or following 
platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant 
platinum-containing chemotherapy. 
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The safety profile of avelumab administered intravenously (IV) as 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, in total, 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, mCRPC, adrenocortical carcinoma, melanoma, 
mesothelioma, UC, ovarian cancer, RCC, and squamous cell cancer of the head and neck.  
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 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 (AEs) 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 subjects 
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.
1.2.1.1. Clinical Experience in Patients with NSCLC
1.2.1.1.1. First-Line NSCLC Patients
Study EMR 100070-001 evaluated avelumab in first-line NSCLC patients in a tumor-specific 
expansion cohort.  As of 19 February 2016, 156 patients with advanced NSCLC not 
previously treated systemically for metastatic or recurrent disease, without an activating 
epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) 
rearrangement, and not preselected for PD-L1 expression, were enrolled in this cohort.  The 
majority of subjects were Eastern Cooperative Oncology Group (ECOG) performance status 
1 (69.2%), and tumor histology was adenocarcinoma (66.0%) or squamous (28.8%) in most 
subjects.
The objective response rate (ORR) based on confirmed and unconfirmed responses was 
22.4% (95% CI: 16.2, 29.8; 35 [2 complete responses (CRs) and 33 partial responses (PRs)] 
of 156 patients).  Responses were confirmed in 26 subjects (16.7%) at the time of data 
cut-off.  In 24 of 35 responders (68.6%), the responses were ongoing at the time of the data 
cutoff.  The onset of the response was rapid, with 28 of 35 responders (80%) having their 
first documented response by the first or second tumor assessments (Weeks 6 and 12, 
respectively).  An additional 67 patients (42.9%) had a best overall response (BOR) of stable 
disease (SD).  The ORR in patients with squamous cell carcinoma and adenocarcinoma was 
24.4% (95% CI: 12.9, 39.5) and 22.3% (95% CI: 14.7, 31.6), respectively.  An objective 
response was observed in 19 of 88 patients (21.6%; 95% CI: 13.5, 31.6) who had at least 
1% PD-L1 positive tumor cells compared with 2 of 23 patients (8.7%; 95% CI: 1.1, 28.0) 
who had less than 1% PD-L1 positive tumor cells. 
The median progression-free survival (PFS) as per the Response Evaluation Criteria in Solid 
Tumors (RECIST) version (v)1.1 was 17.6 weeks (95% CI: 11.6, 23.6). The Kaplan-Meier 
PFS rate at 24 weeks was 37.2% (95% CI: 28.6, 45.7). 


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1.2.1.1.2. Second-Line or Higher NSCLC Patients
Study EMR 100070-001 evaluated avelumab in second-line NSCLC patients in a 
tumor-specific expansion cohort.  As of 15 January 2015, 184 patients with advanced 
NSCLC were in this group of patients who had progressed after at least 1 line of 
platinum-containing doublet chemotherapy for metastatic or locally advanced disease. 
Of 184 patients, 22 had a confirmed objective response, including one CR and 21 PRs, 
resulting in a confirmed ORR of 12.0% (95% CI: 7.6, 17.5).  The ORR based on confirmed 
and unconfirmed responses was 14.1% (95% CI: 9.4, 20.0), including 1 CR and 25 PRs.  
Based on confirmed or unconfirmed responses, 10 of 26 responding patients (39%) had 
responded by the first assessment at 6 weeks, and 19 of 26 (73%) had responded by 
12 weeks.  The median PFS was 11.6 weeks (95% CI: 8.4, 13.7), and Kaplan-Meier PFS 
rates at 24 weeks and 48 weeks were 26% (95% CI: 20, 33) and 18% (95% CI: 12, 26), 
respectively.
1.2.1.2. Clinical Experience in Patients with Locally Advanced or Metastatic UC
Study EMR 100070-001 evaluated avelumab in patients with locally advanced or metastatic 
UC who were either cisplatin ineligible or had progressive disease (PD) after at least 1 line of 
platinum-based therapy in 2 different cohorts.  As of 19 March 2016, a combined 
241 patients had been treated in the 2 UC cohorts, of whom 153 had at least 6 months of 
follow-up. 
In the pooled group of 153 patients, the confirmed ORR by Independent Endpoint Review 
Committee (IERC) was 17.6% (95% CI: 10.9, 22.5) including 9 CRs and 18 PRs.  Onset of 
response was documented by the first or second tumor assessment for 21 of the 27 confirmed 
responders (77.8%).  The median PFS by IERC was 6.43 weeks (95% CI: 6.14, 11.43).  The 
PFS rate at 24 weeks was 22.6% (95% CI: 16.0, 29.9).
1.2.1.3. Clinical Experience in Patients with Ovarian Cancer
Study EMR 100070-001 evaluated avelumab in 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.  As of 23 October 2015, a total of 
124 patients were enrolled with a median follow-up of 12.4 months (range, 2.5 to 
23.2 months). 
The ORR, based on confirmed and unconfirmed responses, was 9.7% (95% CI: 5.1, 16.3; 
12 of 124 patients).  In 6 of the 12 responders (50.0%), the responses were ongoing at the 
time of the data cutoff.  In 6 patients, the onset of the response was at approximately 
6 weeks.  The onset of response for the other 6 responders occurred between Weeks 10 and 
18.  The median PFS was 11.3 weeks (95% CI: 6.1, 12.0 weeks).  The Kaplan-Meier PFS 
rates were 16.1% (95% CI: 9.2, 24.7) and 5.5% (95% CI: 1.3, 14.2) at 24 and 48 weeks, 
respectively.  Among the patients with baseline and at least on-treatment assessment of 
cancer antigen-125 (CA-125) (n=72), 13 patients (10.5%) showed a decrease in 
CA-125 anytime during treatment. 


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1.2.1.4. Clinical Experience in Patients with Advanced Breast Cancer
Study EMR 100070-001 evaluated avelumab in patients with metastatic breast cancer 
refractory to or progressing after standard-of-care therapy. As of 27 February 2015, 
168 patients were enrolled; 72 patients (42.9%) were human epidermal growth factor 
receptor 2 (HER2)-negative and estrogen receptor (ER)-positive or progesterone 
receptor-positive, 58 patients (34.5%) were TNBC, 26 patients (15.5%) were HER2-positive, 
and 12 patients (7.1%) had unknown biomarker status.  At the time of the data cutoff, 
9 patients (5.4%) remained on avelumab treatment.  Unconfirmed ORR per Investigator 
assessment was 4.8% (95% CI: 2.1, 9.2), with 1 CR and 7 PRs across 
HER2/ER/progesterone receptor status.  The median PFS was 5.86 weeks (95% CI: 5.86 to 
6.00 weeks).  The Kaplan-Meier PFS rates were 18.4% (95% CI: 12.9, 24.8), 10.1% 
(95% CI: 5.9, 15.5), and 5.6% (95% CI: 2.5, 10.7) at 12, 24, and 48 weeks, respectively.
1.2.1.5. Clinical Experience in Patients with mCRPC
Study EMR 100070-001 evaluated avelumab in patients with mCRPC.  As of 31 December 
2016, all 18 patients enrolled had permanently discontinued avelumab treatment.  No patient 
had responses (confirmed or unconfirmed) and 10 patients (55.6%) achieved SD according to 
RECIST v.1.1 per investigator assessment.  The median PFS was 5.4 months (95% CI: 1.4, 
5.5 months).  The Kaplan-Meier PFS rates at 3 and 6 months were 51.3% (95% CI: 24.0, 
73.2) and 20.5% (95% CI: 3.5, 47.3) respectively.
1.2.1.6. Pharmacokinetics of Avelumab in Humans
Available pharmacokinetic 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 (PBMCs) 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 
in the 3 mg/kg dose group.
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 


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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.
1.2.2. Talazoparib
1.2.2.1. Talazoparib Clinical Experience
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 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 AEs (SAEs) occurred in 52 of 164 patients (31.7%) who received 1 mg QD 
talazoparib.  SAEs 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 anemia (3.0%); 
thrombocytopenia (2.4%); platelet count decreased (1.2%); and increased transaminases, 
neutropenic sepsis, and vomiting (0.6% each).


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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 study 673-301, 308 patients with locally advanced or metastatic 
breast cancer were treated as of the cutoff date.  An estimated 206 patients were receiving 
talazoparib and 102 were receiving another single-agent chemotherapy of physician’s choice, 
based on the 2:1 randomization scheme.  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 (ALT and AST with normal 
bilirubin) while receiving talazoparib at 0.75 mg.  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.  The Sponsor considered 
veno-occlusive disease of the liver an unlikely etiology, a consideration supported by 
2 independent hepatologists who reviewed the case.
1.2.2.2. Clinical Efficacy in Patients with Advanced Solid Tumors
A total of 110 patients with advanced tumors with DNA repair pathway abnormalities, 
particularly those associated with BRCA and phosphatase tensin homolog (PTEN) 
dysfunction, were enrolled in the Phase 1 study PRP-001, which was completed in March 
2015.  The maximum tolerated dose (MTD) of talazoparib was defined as 1 mg QD and it 
was used in the expansion phase of the study in patients with breast, ovarian/primary 
peritoneal, and pancreatic cancer with deleterious germline mutations; small cell lung cancer 
(SCLC); and Ewing sarcoma.  As of 13 February 2015, the proportion of patients with breast, 
ovarian/primary peritoneal, and pancreatic cancers with BRCA mutations who were treated 
with talazoparib at 1 mg QD and had objective responses according to RECIST v1.1 was 
50% (7 of 14; 95% CI: 23.0, 77.0), 41.7% (5 of 12; 95% CI: 15.2, 72.3), and 20.0% (2 of 10), 
respectively.  Cancer patients harboring BRCA mutations who are resistant to 
platinum-based chemotherapy display decreased sensitivity to PARP inhibitors.20 Given the 
exploratory nature of Cohort F, pancreatic cancer patients in this cohort will not include 
patients who progressed within 6 months of starting previous platinum-based chemotherapy.  
This is aligned with the approach followed for other indications in this study.  Responses 
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1.2.2.3. Clinical Efficacy in Patients with Germline BRCA Mutations and Locally 
Advanced and/or Metastatic Breast Cancer
The ongoing Phase 2, open-label, 2-stage, 2-cohort study, 673-201, is evaluating talazoparib 
in patients with locally advanced or metastatic breast cancer with deleterious germline BRCA 
mutations.  Enrolled patients included those who were platinum-sensitive (Cohort 1) and 
patients who received at least 3 prior chemotherapy regimens and no prior platinum therapy 
(Cohort 2).  As of 1 September 2016, the data cut-off for the primary analysis, 83 patients 
with locally advanced or metastatic breast cancer with deleterious germline BRCA mutations 
were tumor evaluable (48 patients in Cohort 1; 35 patients in Cohort 2), and 9 patients were 
continuing on treatment.  Efficacy analyses were conducted by independent central radiology 
assessment.  The ORR was 20.8% (95% CI: 10.47, 34.99) in Cohort 1, 37.1% 
(95% CI: 21.47, 55.08) in Cohort 2 and 27.7% (95% CI: 18.45, 38.62) overall.  This response 
rate, which included 2 CRs and 8 PRs in Cohort 1 and 13 PRs in Cohort 2, is considered 
clinically meaningful as these populations have a poor prognosis.
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 [hazard ratio: 0.54 (95% CI: 0.41, 0.71), p<0.0001].1  Talazoparib was 
approved by the FDA on 16 October 2018 for the treatment of adult patients with deleterious 
or suspected deleterious germline BRCA-mutated (gBRCAm) HER2- negative locally 
advanced or metastatic breast cancer.
1.2.2.4. Pharmacokinetics of Talazoparib in Humans
Talazoparib plasma exposure was dose proportional in the dose range of 0.025 mg to 2 mg 
QD suggesting linear PK.  Talazoparib absolute bioavailability is at least 54.6%. After 
administration of a single 1 mg dose of talazoparib to cancer patients, the median time to 
maximum plasma concentration (Tmax) ranged from 0.5 to 2.0 hours across studies.  
Administration of talazoparib with food (a high-fat, high-calorie meal) had no impact on the 
area under the plasma concentration-time curve (AUC) while reduced the maximum plasma 
concentratioin (Cmax) by 46%. The reduction in the rate of absorption with food is not 
expected to be clinically relevant as efficacy is driven by total exposure.  Therefore, 
talazoparib can be taken without regard of food.
Mean talazoparib binding to human plasma proteins is 74%.  Population PK analysis showed 
that talazoparib apparent steady-state volume of distribution (Vss/F) was 420 L, which is 
greater than total body water (42 L), indicating that talazoparib extensively distributes to 
peripheral tissues.
Talazoparib undergoes minimal hepatic metabolism.  Based on population PK analysis, there 
was no effect of mild hepatic impairment (total bilirubin ≤upper limit of normal [ULN] and 
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.  The effect of hepatic 
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Talazoparib was eliminated slowly with a mean terminal plasma half-life (t½) of 89.8 hours.  
Talazoparib accumulated after -1 mg QD dosing with a median accumulation ratio ranging 
from 2.33 to 5.15, consistent with its t½.  Population PK analysis showed that talazoparib 
apparent oral clearance (CL/F) was 6.45 L/hr.  Excretion of unchanged talazoparib in urine 
was the major route of elimination accounting for 54.6% of the administered dose.  
Population PK analysis showed that talazoparib CL/F was reduced by 14.4% and 37.1% in 
patients with mild renal impairment (creatinine clearance [CrCl], 60--89 mL/min) and 
moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), respectively, compared to that 
of patients with normal renal function (CrCl >90 mL/min).  No dose adjustment is 
recommended for patients with mild renal impairment. The talazoparib starting dose for 
patients with moderate renal impairment is discussed in Section 1.2.6.2.  The effect of renal 
impairment on talazoparib PK is also being investigated in the ongoing study MDV3800-01.
In vitro studies showed that talazoparib is a substrate for the efflux transporters 
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).  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. Guidelines for 
concomitant use of talazoparib with P-gp inhibitors or inducers and BCRP inhibitors are 
provided in Section 5.7.10.
1.2.3. Clinical Experience in Patients with mCRPC Treated with PARP Inhibitors as a 
Single Agent or in Combination with Immunotherapy 
The PARP inhibitor olaparib given as single agent was evaluated in a Phase 2 study in 
50 patients with previously treated mCRPC.25 Of the 50 patients, all patients had received 
prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 
29 (58%) had received cabazitaxel.  Of the 49 patients evaluable for response (defined either 
as an objective response according to RECIST v1.1, or as a reduction of at least 50% in the 
prostate-specific antigen (PSA) level or a confirmed reduction in the circulating tumor-cell 
count from 5 or more cells per 7.5 mL of blood to less than 5 cells per 7.5 mL), 16 patients 
achieved a response (33%; 95% CI: 20.0, 48.0).  Homozygous deletions, deleterious 
mutations, or both were identified in DNA-repair genes in 16 patients (33%) and 14 of these 
patients (88%) achieved a response.
The combination of olaparib with durvalumab was evaluated in a Phase 1/2 study in 
10 patients with mCRPC.  Overall, 8 out of 10 patients had a reduction in PSA level, 
including 5 patients who had declines in PSA level 50% from baseline.  PSA level 
reductions were observed in patients with bone-only disease, in those who had bone disease 
and soft-tissue or visceral metastases, and in patients with or without mutations in DNA 
repair pathways.26
Veliparib given as a single agent was investigated in a Phase 1 dose-finding study in patients 
with advanced solid tumors; overall, 98 patients were enrolled, of whom 78 had disease with 
a germline BRCA defect.27 Three patients with BRCA2 germline mutated mCRPC were 
enrolled at the recommended Phase 2 dose (RP2D) and were evaluable for response.  In these 
patients, the ORR was 2/3 (66%) and all patients had a PSA reduction >50% with respect to 
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A Phase 1 study evaluated niraparib given as a single agent in 100 patients with advanced 
solid tumors.28 A total of 23 mCRPC patients were enrolled and 21 of these received 
niraparib at 290 mg QD or 300 mg QD.  No mCRPC patient achieved an objective response 
but 9 patients had an SD with a median duration of 254 days (range: 124–375 days) and 
1 patient had a >50% decrease in the concentration of PSA and had remained on study for 
306 days. 
1.2.4. Study Rationale
Based on the mechanisms of action discussed in Sections 1.1.1 and 1.1.2, talazoparib and 
avelumab 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.29 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.30 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 (NEMO),13 and the second being activation of the STING pathway via generation 
and detection of cytosolic DNA.14,15 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.31 Finally, DNA damage has been shown to lead to up-regulation of MHC, 
NKG2DL, and ICOSL,16,17 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.18
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However, talazoparib treatment has also been shown to lead to 2-3 fold increased expression 
of PD-L1 by tumor cells,19 suggesting that this may represent a mechanism of resistance to 
possible talazoparib-mediated anti-tumor immunity, and suggesting 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 (Figure 2) and 
colorectal cancer, which demonstrate a significant improvement in overall survival (OS) 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.
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Figure 2.
Combination of Talazoparib (BMN 673) and Anti-mouse PD-L1 Treatment 
Significantly Prolongs Survival in an Ovarian Cancer Model
1st
2nd
3rd
*
*
*
Survival curves from 3 independent experiments comparing the combination of BMN 673 (0.33 mg/kg daily by oral gavage) 
and anti-PD-L1 (200 g/mouse every 3 days) to talazoparib alone, anti-PD-L1 alone, or IgG control.  In the left and middle 
panels, mice were treated for 3 weeks and treatment was stopped to monitor survival of the mice.  In the right panel, mice 
were treated continuously until the mice met criteria for euthanasia and survival was monitored.  Statistical analysis was 
conducted by log rank test.  The combination treatment significantly improved mouse survival compared to IgG control in 
three experiments (p <0.01).
Given the proposed mechanism of the avelumab and talazoparib combination, one subgroup 
of patients likely to benefit from the combination will be those whose tumors are most 
sensitive to talazoparib.  A number of biomarkers have the potential to identify patients with 
increased sensitivity to talazoparib,21 and two of these biomarkers will be evaluated 
prospectively or retrospectively in the context of this study, as follows: 

Assessment of genomic scarring as measured via loss of heterozygosity (LOH).

Presence of defects in a panel of DNA damage repair (DDR) genes. 
Tumors with defects in DDR genes have also been shown to present with a more inflamed 
tumor phenotype in a number of settings,22,23,24 and therefore, are also expected to respond 
better to avelumab treatment.
In conclusion, considering the above described mechanism of action and the preliminary 
clinical activity observed for the investigational products or one agent of the same class (see 
Sections 1.2.1.1, 1.2.1.2, 1.2.1.3, 1.2.2, 1.2.3, and 1.2.5), the avelumab and talazoparib 
combination is proposed for evaluation in patients with locally advanced or metastatic solid 
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1.2.5. Rationale for the Tumor Types to be Evaluated
Tumor types in the anti-PD-1/L1 naïve setting were selected based on one or more of the 
following, in settings of unmet medical need:
a.
One of the investigational products, or an agent of the same class, has shown 
preliminary clinical activity in the tumor type of interest.
b. The tumor type has been reported, or is predicted, to have a high prevalence (30%) 
of defects in genes critical to DDR (eg, BRCA1/2, ATM, ataxia-telangiectasia and 
Rad3-related [ATR], the Fanconi anemia complementation [FANC] genes, and 
others).  Defects in such genes have been reported to predict for sensitivity to PARP 
inhibitors,21 such as talazoparib, and have also been shown to present with a more 
inflamed tumor phenotype, expected to lead to improved avelumab activity in a 
number of settings.22,23,24 As such, tumors harboring these defects may respond more 
robustly to combination treatment with talazoparib and avelumab.
c.
The tumor type has been reported, or is predicted, to have a high prevalence (35%) 
of genomic scarring, as defined by the homologous recombination deficiency (HRD) 
score.32 Tumors with a high HRD score have been shown to have increased clinical 
benefit from PARP inhibitors,33,34 As such, tumors with a high HRD might be 
expected to respond more robustly to the combination of talazoparib and avelumab.
NSCLC that has progressed on previous anti-PD-1/L1 treatment was selected as an area of 
high unmet medical need, in which the combination of avelumab and talazoparib could 
provide benefit.  Re-challenge of patients, who have progressed during anti-PD-1/L1 therapy, 
with subsequent monotherapy anti-PD-1/L1 has met with only limited anecdotal success.35
Resistance to anti-PD-1/L1 therapy is thought to occur via a number of potential 
mechanisms,36 several of which rely on tumor cell extrinsic, immunosuppression of the 
antitumor immune response. Examples of such tumor cell extrinsic suppression mechanisms 
include increases in immunosuppressive cytokines and cell sub-sets (such as MDSCs and 
macrophages), reduced infiltration and activation of dendritic cells and a reduction in antigen 
presentation. Talazoparib is expected to reprogram the local immune microenvironment, 
overcoming these immunosuppressive pathways via the immune priming mechanisms 
outlined above, and as such the addition of talazoparib to anti-PD-L1, in anti-PD-1/L1 
resistant patients, is hypothesized to overcome resistance and provide benefit to these 
patients.
PARP inhibition may have additional therapeutic benefit when combined with the 
anti-PD-L1 antibody avelumab.  Talazoparib, via its ability to promote increased DNA 
damage, may promote key stages of tumor immune response following PD-L1 blockade.  
DNA damage has the potential to release tumor antigens into the tumor microenvironment 
that may promote an antitumor immune response and increase in the infiltration of 
tumor-specific immune cells.37
Additional solid tumors may be incorporated into this protocol via an amendment, based on 
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1.2.6. Rationale for the Investigational Product Doses
1.2.6.1. 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 FDA as the first 
treatment for MCC.  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.38,39,40
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, 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. Preliminary PK data for avelumab from 
patients enrolled in Phase 1b of this study confirm that in all 12 patients (weight range 
55.9 kg to 105.1 kg) avelumab Ctrough was considerably >1 µg/mL following 800 mg Q2W 
dose.
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. Flat dosing for avelumab of 800 mg Q2W 
has recently been approved in the US for the MCC and UC indications (avelumab United 
States Product Insert, 19 October 2018).
1.2.6.2. Talazoparib
The dose levels of talazoparib to be evaluated in this study are supported by clinical studies 
in patients with advanced malignancies.  In the PRP-001 Phase 1 study in patients with 
advanced or recurrent solid tumors, talazoparib was escalated from 0.025 to 1.1 mg QD and 
the recommended dose for further development was determined to be 1 mg QD.  Data from 
that study at 1 mg/day demonstrated objective responses or clinical benefit (CR, PR, or SD 
24 weeks) in patients with breast, ovarian/peritoneal, pancreatic cancer, SCLC, and Ewing 
sarcoma.  The dose level of 1 mg QD is currently being used in the ongoing randomized 
Phase 3 study 673-301 in patients with locally advanced or metastatic breast cancer.


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Based on preliminary population PK analysis from patients in Studies PRP-001 and 
PRP-002, the talazoparib CL/F was decreased by 44% from normal in patients with moderate 
renal impairment (CrCl 30-59 mL/min), and therefore in those patients the 1 mg QD 
talazoparib starting dose should be reduced to 0.75 mg QD, as discussed in the talazoparib 
IB.12 In the Phase 1b portion of this study, only patients with a CrCl of ≥60 mL/min (as 
estimated using the Cockcroft-Gault formula) will be eligible for enrollment. 
Since avelumab is an immunoglobulin (Ig)G1 mAb eliminated by intracellular lysosomal 
proteolytic degradation throughout the entire body while talazoparib is a small molecule 
cleared primarily via excretion of unchanged parent drug and metabolized to a minor extent 
via oxidation and dehydrogenation, no PK DDI is anticipated between avelumab and 
talazoparib when given in combination. Nevertheless, concentration-time data will be 
measured on this study for both avelumab and talazoparib following coadministration at 
single dose and at steady state, and will be compared with historical PK data for avelumab 
and talazoparib as single agents. Preliminary PK data from the 12 patients in the Phase 1b 
cohort of this study support absence of a PK DDI between the 2 agents, with avelumab and 
talazoparib concentrations following co-administration similar to those observed when each 
is administered as monotherapy.
1.2.7. 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, mCRPC, UC and ovarian cancer
in the expansion cohorts of the ongoing Phase 1 Study EMR 100070-001, as described in 
Sections 1.2.1.1, 1.2.1.2, 1.2.1.3, and 1.2.1.6.  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 1.2.1.  Most of the observed AEs 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 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 avelumab infusions (Cycles 1-2) and as 
clinically indicated thereafter.
Talazoparib has also 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 1.2.2.2.  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), 


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gastrointestinal toxicity (eg, nausea, diarrhea, vomiting), and fatigue with severe and SAEs 
mostly associated with myelosuppression.  These AEs were primarily Grade 1 or 2 severity 
and typically resolved with temporary dose interruptions or reductions.
Based on the manageable safety profiles of avelumab and talazoparib administered as single 
agents, the expected low incidence of 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 solid tumors.
The Phase 1b portion of this study has been completed, following evaluation of the first 
12 enrolled patients. All patients had completed their first cycle with treatment of avelumab 
at 800 mg IV Q2W in combination with talazoparib 1 mg orally QD and were evaluable for 
DLT. The most frequently reported TEAEs were anemia (8 patients, 66.7%), neutropenia 
(7 patients, 58.3%), and chills and thrombocytopenia (both 5 patients, 41.7%). The most 
frequently reported Grade 3 TEAEs were thrombocytopenia (4 patients, 33.3%), anemia 
(3 patients 25.0%), and neutropenia (2 patients, 16.7%). A DLT rate of 0.25 was observed, 
with a total of 3 DLTs that warranted dose interruption and reduction (2 cases of Grade 3 
thrombocytopenia and one case of Grade 3 neutropenia).
1.2.8. Rationale for Biomarker Assessments and Prospective Patient Selection
This study intends to characterize the activity of avelumab in combination with talazoparib, 
with the aim of increasing the clinical benefit seen historically with either single agent.  The 
success of the combination will likely be contingent on identifying the specific tumor types 
and/or patients most likely to respond to the combination.  A key mechanistic hypothesis 
underpinning the combination is that increased DNA damage and cell death mediated by 
talazoparib will lead to enhanced immune priming and tumor immunogenicity, enabling a 
more effective anti-tumor immune response to be promoted by avelumab.  Given this 
hypothesis, one subgroup of patients likely to benefit from the combination will be those 
whose tumors are most sensitive to talazoparib-mediated cell death and DNA damage.  
A number of biomarkers have the potential to identify patients with such increased sensitivity 
to talazoparib,21 and two of these will be employed in the context of this study 
(ie, assessment of genomic scarring, as measured by LOH, and presence of defects in a panel 
of DDR genes).  In cohorts for NSCLC (Cohort A1), TNBC (Cohort B1), ovarian cancer 
(Cohort C1), and UC (Cohort D), these 2 biomarkers are expected to occur at a prevalence 
sufficient to allow for meaningful retrospective analysis of an unselected group of patients, 
given the selected sample sizes.  In cohorts for NSCLC (Cohort A2), HR+/HER2- breast 
cancer (Cohort B2) and mCRPC (Cohort E2), the prevalence of both biomarkers, or cohort 
size, is low enough that a prospective selection is considered necessary in order to enable 
recruitment of a sufficient number of patients to support meaningful analysis.  With respect 
to prospective patient selection, patients will be considered DDR+, and eligible for entry into 
cohorts A2, B2 and E2, if they have a previously documented defect in a predefined panel of 
DDR genes, or if they test positive for defects in a predefined panel of DDR genes or if they 
have a LOH score above a cutoff defined by the assay specifications.


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In addition to the 2 biomarkers described above, defects in BRCA1, BRCA2, and ATM have 
been extensively explored and validated as biomarkers of sensitivity to PARP 
inhibition,3 particularly in ovarian cancer.41 Given this context, 2 additional cohorts will 
prospectively select patients who test positive for defects in these genes.  The first, 
Cohort C2, will prospectively select for ovarian cancer patients with germline or somatic 
defects in BRCA1 or BRCA2.  The second, Cohort F, will prospectively select for patients 
with locally advanced (primary or recurrent) or metastatic solid tumors harboring pathogenic, 
or likely pathogenic, germline or somatic defects in BRCA1, BRCA2, or ATM genes.
Complementing the DDR biomarkers described above, a number of assessments will be 
undertaken to understand the immune context of patient tumors, which will likely also be a 
key contributing factor in response to the combination of talazoparib and avelumab.  These 
assessments may include,
 assessment of PD-L1 expression by tumor 
and/or immune cell types in the tumor using immunohistochemistry, assessment of 
infiltrating immune cell number and phenotype by immunohistochemistry or 
immunofluorescence, relative expression of genes representative of immune activation versus 
suppression by gene expression profiling,
 and assessment of mutational or neoantigen load within 
tumors. 
To enable the above mentioned biomarker assessments, the collection of pre-treatment tumor 
specimens, including 1) a tumor tissue sample from a biopsy performed during, or within 
1 year (5 years for mCRPC patients with no biopsable lesion outside of bone at screening) of, 
the screening period and 2) an archival tissue sample where available, is mandatory.
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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objectives
•
Phase 1b: To assess the DLT rate of avelumab in combination with talazoparib in 
patients with locally advanced or metastatic solid tumors in order to select the RP2D 
of talazoparib for the combination.
•
Phase 2: To assess ORR of avelumab in combination with talazoparib, as assessed by 
the Investigator, per RECIST v1.1 in patients with locally advanced or metastatic 
solid tumors and per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) 
in patients with mCRPC.
Secondary Objectives
•
To assess the overall safety and tolerability of avelumab in combination with 
talazoparib.
•
To characterize the PK of avelumab and talazoparib when given in combination.
•
To evaluate the immunogenicity of avelumab when given in combination with 
talazoparib.
•
To assess the anti-tumor activity of avelumab in combination with talazoparib.
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•
To assess the correlation of anti-tumor activity of avelumab in combination with 
talazoparib with PD-L1 expression, tumor mutational burden (TMB; defined as the 
total number of mutations in the tumor genome, or number of mutations per 
megabase of DNA if derived from targeted sequencing),4 and potential biomarkers of 
PARP inhibitor sensitivity in baseline tumor tissue.
2.2. Endpoints
Primary Endpoint
•
Phase 1b: DLT during the DLT evaluation period (Cycle 1). 
•
Phase 2: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in 
patients with locally advanced or metastatic solid tumors (see Appendix 3) and 
RECIST v1.1 and PCWG3 in patients with mCRPC (see Appendix 5). 
Secondary Endpoints
•
AEs as characterized by type, severity (as graded by National Cancer Institute 
Common Terminology Criteria for AEs [NCI CTCAE] v.4.03), timing, seriousness, 
and relationship to study therapy.
•
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v.4.03) and timing.
•
PK parameters for avelumab and talazoparib including: pre-dose/trough 
concentrations (Ctrough) and post-dose concentrations (for talazoparib) or maximum 
concentrations (Cmax) for avelumab.
•
Avelumab anti-drug antibody (ADA) levels and neutralizing antibodies (Nab) against 
avelumab.
•
Phase 1b: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in 
patients with locally advanced or metastatic solid tumors and RECIST v1.1 and 
PCWG3 in patients with mCRPC. 
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•
Phase 1b and Phase 2: Time-to-event endpoints including time to tumor response 
(TTR), duration of response (DR), and PFS as assessed by the Investigator using 
RECIST v1.1 for patients with solid tumors and using RECIST v1.1 and PCWG3 for 
patients with mCRPC, time to PSA progression for patients with mCRPC, and OS.
•
PSA response ≥50% for patients with mCRPC.
•
CA-125 response for patients with ovarian cancer.
•
PD-L1 expression level in baseline tumor tissue.
•
TMB in baseline tumor tissue.
•
Genomic scarring and the presence of defects in select genes, considered critical to 
effective DDR, in baseline tumor tissue.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b/2, open label, multi-center, study of avelumab in combination with 
talazoparib in adult patients with locally advanced (primary or recurrent) or metastatic solid 
tumors including NSCLC, TNBC, HR+/HER2- breast cancer, recurrent platinum-sensitive 
ovarian cancer, UC, mCRPC, and locally advanced (primary or recurrent) or metastatic solid 
tumors harboring pathogenic or likely pathogenic germline or somatic defects in BRCA1, 
BRCA2, or ATM genes.  Approximately 242 patients in total will be enrolled into the study.  
A given cohort size may be expanded by a limited number of additional patients 
(approximately 10) per Sponsor’s discretion subsequent to the identification of any early 
signal of clinical activity that may emerge from the generated data in a biomarker-defined 
population.
The study design and tumor-specific expansion cohorts, including the number of patients to 
be enrolled into each cohort, are shown in Figure 3.
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Figure 3.
Phase 1b and Phase 2 Study Design Schema
ATM= ataxia telangiectasia mutated; BC= breast cancer; BRCA=BReast CAncer susceptibility gene; mCRPC= metastatic 
castration-resistant prostate cancer; D=Dose; HER2-=human epidermal growth factor receptor 2 negative; HR+=hormone 
receptor positive; DDR=DNA damage repair; DDR Defect +=DDR defect positive, as determined by the Foundation One 
assay or validated local assay result; IV=intravenous; NSCLC=non-small cell lung cancer; PD-L1= Programmed 
Death-Ligand 1; PO=orally; Q2W=every 2 weeks; QD=every day; TNBC= triple-negative breast cancer; TPS= tumor 
proportion score.
3.1.1. Phase 1b
During the Phase 1b portion of this study, patients with locally advanced or metastatic solid 
tumors, who meet eligibility criteria, will be treated with one of up to 3 different doses of 
talazoparib (0.5 mg, 0.75 mg or 1.0 mg) administered orally QD in combination with a fixed 
dose of avelumab 800 mg IV Q2W, and will be evaluated for DLTs.  The modified toxicity 
probability interval (mTPI) method will be used to identify the RP2D for talazoparib 
(see Appendix 4).  The avelumab and talazoparib combination will be administered in 28-day 
cycles.  The DLT evaluation period will be 28 days (ie, Cycle 1).  The target enrollment 
cohort size is 3-6 patients.


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The starting dose level will be 1.0 mg talazoparib QD plus 800 mg avelumab Q2W.  For 
patients with moderate renal impairment (CrCl 30-59 mL/min), the 1 mg QD talazoparib 
starting dose should be reduced to 0.75 mg QD (Section 1.2.6.2).  The dose levels of the 
combination to be evaluated are included in Table 3. 
Table 3.
Talazoparib and Avelumab Dose Levels
Dose Level
Talazoparib Dose
(Oral)
Avelumab Dose
(IV)
D0
1 mg QD
800 mg Q2W
D-1
0.75 mg QD
800 mg Q2W
D-2
0.5 mg QD
800 mg Q2W
D=dose; QD=once daily; Q2W=every 2 weeks
In Phase 1b, patients without DLTs who withdraw from study treatment before receiving at 
least 75% of the planned dose of the investigational products in Cycle 1 for reasons other 
than treatment-related toxicity are not evaluable for DLT.  Additional patients will be 
enrolled in the specific enrollment cohort to replace patients who are not considered 
DLT-evaluable.
The Phase 1b portion is completed when at least 12 DLT-evaluable patients have been 
treated at the highest dose associated with DLT rate <0.33 (see Section 9.2).  Early 
completion of the Phase 1b portion can be reached when 9 or more DLT-evaluable patients 
have been treated at the same dose level with no occurrence of DLT, as the DLT rate of 
<0.33 will be met.
Once the Phase 1b portion is completed and the RP2D of the combination is determined, the 
Phase 2 portion will be initiated.
Approximately 12-36 patients are expected to be enrolled in Phase 1b using the mTPI 
method.
If dose level D-2 is not tolerable, the study will be stopped and no dose combination will be 
further evaluated. 
Phase 1b was completed in May 2018 with 12 patients enrolled.
In May 2018, the RP2D for talazoparib administered orally in combination with avelumab 
800 mg IV Q2W was confirmed to be 1 mg QD. The talazoparib starting dose for patients 
with moderate renal impairment (CrCl 30-59 mL/min) will be reduced to 0.75 mg/day as 
discussed in the talazoparib IB.12
3.1.1.1. Rules for Dose De-Escalation/Escalation in Phase 1b
Starting with dose level D0, 3 patients will be enrolled, treated, and monitored during the 
28-day DLT evaluation period. 


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The dose escalation/de-escalation rules for talazoparib administered in combination with 
avelumab will follow the mTPI method (overview provided here and described in greater 
detail in Section 9.2).  The mTPI method recommends the dose level for the next enrollment 
cohort of patients based on the number of DLT-evaluable patients treated at the current dose 
level that have reported DLTs.  Briefly, the mTPI method relies upon a statistical probability 
algorithm, calculated using all patients treated in prior and current enrollment cohorts at the 
same dose level to determine where future enrollment cohorts should involve dose 
re-escalation, no change in dose, or dose de-escalation.  The detailed dose 
escalation/de-escalation rules based on the mTPI method are illustrated in Appendix 4.
When all DLT-evaluable patients treated in a given enrollment cohort have completed the 
DLT observation period (28 days; Cycle 1) or experienced a DLT, whichever occurs first, the 
patients in the next cohort will receive the dose level of the combination as assigned by the 
mTPI design.  As an example, if the total number of DLT-evaluable patients (cumulative in 
the Phase 1b from prior and current cohorts) treated at the current dose combination is 3, the 
dose escalation/de-escalation rules are described below:

0 DLT in 3 DLT-evaluable patients escalate, if a higher dose level is available;

1 DLT in 3 DLT-evaluable patients remain at the same dose level;

2 DLTs in 3 DLT-evaluable patients de-escalate, if a lower dose level is available 
and allow for possible re-escalation; 

3 DLTs in 3 DLT-evaluable patients de-escalate, if a lower dose level is available 
and consider current dose as intolerable.
3.1.2. Phase 2
The overall available data (including safety and preliminary anti-tumor activity) emerging 
from the Phase 1b portion of the study will be evaluated before starting enrollment of 
patients in the Phase 2 portion of the study.  The Phase 2 portion of this study will further 
assess the safety and preliminary anti-tumor activity of the avelumab and talazoparib 
combination at the RP2D.  Phase 2 expansion cohorts will include patients with locally 
advanced (primary or recurrent) or metastatic NSCLC, TNBC, HR+/HER2- breast cancer, 
recurrent platinum-sensitive ovarian cancer, UC, mCRPC, and locally advanced (primary or 
recurrent) or metastatic solid tumors harboring pathogenic, or likely pathogenic, germline or 
somatic defects in BRCA1, BRCA2, or ATM genes.
As of May 2018, the RP2D for talazoparib administered orally in combination with avelumab 
800 mg IV Q2W was confirmed to be 1 mg orally QD.  The safety profile of the combination 
at the tested dose level is generally consistent with the safety profiles from the individual 
components and is generally manageable. 
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A given cohort size may be expanded by a limited number of additional patients 
(approximately 10) per Sponsor’s discretion subsequent to the identification of any early 
signal of clinical activity that may emerge from the generated data in a biomarker-defined 
population.
3.2. Dose-Limiting Toxicity Definition
Severity of AEs will be graded according to NCI CTCAE v4.03.  In the Phase 1b portion of 
the study, any of the following AEs occurring during the DLT observation period (Cycle 1; a 
cycle will be 28 days in duration), which are attributable to one or both of the investigational 
products will be classified as DLTs:
Hematologic:

Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 × 109/L) 
lasting >5 days;

Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of 
>38.3C (>101F) or a sustained temperature of 38C (100.4F) for more than 
1 hour;

Neutropenic infection (ANC <1,000/mm3 or <1.0 × 109/L, and Grade >3 infection);

Grade 3 thrombocytopenia (platelet count <50,000 mm3 or <50.0 × 109/L) with 
bleeding;

Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 × 109/L);

Grade 4 anemia (life-threatening consequences; urgent intervention indicated).
Non-Hematologic:

Grade 3 toxicities of any duration except:

Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea in the 
absence of maximal medical therapy that resolves in 72 hours;

Grade 3 fatigue lasting <5 days;

Grade 3 hypertension that can be controlled with medical therapy;

An increase of indirect (unconjugated) bilirubin indicative of 
Meulengracht/Gilbert’s syndrome;

Grade 3 serum lipase and/or serum amylase 7 consecutive days without clinical 
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
Grade ≥3 laboratory abnormalities without a clinical correlate and that do not 
require medical intervention;

Grade ≥3 laboratory abnormalities that do not represent a clinically relevant shift 
from baseline;

Grade 3 endocrinopathies controlled with hormonal therapy.

Potential Hy’s Law cases defined as: ALT or AST >3 × ULN if normal at baseline 
OR >3 × ULN and doubling the baseline (if >ULN at baseline) associated with total 
bilirubin >2 × ULN and an alkaline phosphatase <2 × ULN.
Non-Adherence to Treatment Schedule:

Failure to deliver at least 75% of the planned doses of talazoparib during the first 
cycle of treatment due to treatment-related toxicities;

Grade 3 non-hematologic toxicity that delays administration of either study drug for 
more than 2 weeks.
Dose Reductions:

Any AE that results in a dose reduction of talazoparib, as per 
Section 5.4.6.2 and 5.4.6.3. 
While the rules for adjudicating DLTs in the context of the Phase 1b portion of the study are 
specified above, an AE not listed above, or an AE meeting the DLT criteria above but 
occurring outside of the DLT observation period may be defined as a DLT after consultation 
between the Sponsor and Investigator, based on the emerging safety profile for the 
combination.
3.3. Maximum Tolerated Dose Definition
The MTD estimate is the highest dose level of the combination that is associated with a DLT 
rate <0.33 among the DLT-evaluable patients treated at that dose level. 
3.4. Maximum Administered Dose Definition
The maximum administered dose (MAD) is the highest dose level of the combination 
administered.  In this clinical study, the MAD is also the starting dose of the combination in 
Phase 1b, which is talazoparib 1 mg QD in combination with avelumab 800 mg IV Q2W.
3.5. Recommended Phase 2 Dose (RP2D) Definition
The RP2D is the dose level of the combination that will be chosen for further clinical 
development and for evaluation in the Phase 2 portion of the study.


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4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid 
tumors that are not amenable for treatment with curative intent, as follows:
a.
NSCLC: Phase 1b and Phase 2 Cohort A1

Have received 0-2 prior- chemotherapy regimens for locally advanced or 
metastatic NSCLC.  If previously treated with platinum-based chemotherapy, the 
patient must not have progressed while on treatment; disease progression after 
discontinuation of the platinum-based chemotherapy is allowed.
Applicable to South Korean Investigator Sites Only: have received 1 but no more 
than 2 prior chemotherapy regimens for locally advanced or metastatic NSCLC, 
unless the patient is not a candidate for such therapy or does not tolerate such 
therapy.  If previously treated with platinum based chemotherapy, the patient 
must not have progressed while on treatment; disease progression after 
discontinuation of the platinum based chemotherapy is allowed.

Previous neo-adjuvant/adjuvant treatment counts as 1 line of prior chemotherapy 
if disease progression occurred while on treatment or within 6 months after the 
last treatment dose. 

Patients with known B-Raf proto-oncogene (BRAF)V600 mutations or ALK and 
c-Ros oncogene 1 (ROS1) translocations/rearrangements must have received the 
appropriate targeted therapy if available.  Patients with activating EGFR 
mutations are not eligible; non-squamous cell histologies require testing if EGFR 
status is unknown.
Phase 2 Cohort A2

Have received 1 prior systemic treatment regimens for locally advanced or 
metastatic NSCLC.  This includes 1 but no more than 1 prior regimen of 
anti-PD-1/L1 therapy in the metastatic (Stage IV) setting, either as single agent or 
in combination with a platinum containing chemotherapy regimen, as their most 
recent treatment regimen.  Patients must not have progressed for at least 6 months 
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•
Patients with known BRAFV600 mutations or ALK and ROS1
translocations/rearrangements must have received the appropriate targeted therapy
if available. Patients with activating EGFR mutations are not eligible; 
non-squamous cell histologies require testing if EGFR status is unknown.
•
Disease is DDR defect positive, as determined by the presence of a previously 
documented -known or likely deleterious/pathogenic defect in one of the 
following 34 DDR genes: ATM; ATR; BRCA1; BRCA2; BRIP1; CDK12; 
CHEK1; CHEK2; ERCC4; FANCA; FANCC; FANCG; FANCL; MLH1; 
MRE11A; MSH2; MSH6; MUTYH; NBN; PALB2; PARP1; PARP2; PARP3; 
PMS2; POLD1; POLE; RAD51; RAD51B; RAD51C; RAD51D; RAD52; 
RAD54L; XRCC2; XRCC3.
Presence of such a defect must have been established via a tissue based next 
generation sequencing test, performed --in a CAP/CLIAcertified (or comparable 
local or regional certification) laboratory, or via a germline test from one of the 
following approved providers: Myriad Genetics; Invitae; Ambry; Quest; Color 
Genomics; MSKCC-IMPACT; GeneDx; Foundation Medicine.
Where the presence of a qualifying defect in one of the listed genes has not been
determined, the mandatory DDR Defect sample must be sent to the Foundation 
Medicine central laboratory, no more than 45 days prior to enrollment, for 
prospective testing to confirm eligibility.  See Schedule of Activities for tissue 
requirements for the Foundation One test.
b. Breast Cancer:
Phase 1b: Triple-Negative Breast Cancer (TNBC) defined as ER- and PgR-negative 
(immunohistochemistry [IHC] nuclear staining <1%) and HER-2 negative (IHC 0, 
1+ or 2+ and/or ISH non-amplified with ratio less than 2.0).
•
Have received at least 1 prior chemotherapy regimen for locally advanced or 
metastatic breast cancer.  If previously treated with a platinum-based 
chemotherapy in the advanced/metastatic setting, the patient must not have 
progressed while on treatment with the most recent platinum-based 
chemotherapy.
•
Previous neoadjuvant/adjuvant treatment counts as 1 line of prior chemotherapy if 
disease progression occurred while on treatment or within 6 months after the last 
treatment dose.  If previously treated with neoadjuvant/adjuvant platinum-based 
chemotherapy, the patient must not have progressed while on treatment or within 
6 months after stopping the platinum-based chemotherapy.


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
There is no limit on the number of prior hormonal therapies or targeted 
anti-cancer therapies such as mammalian target of rapamycin (mTOR) or 
cyclin-dependent kinase (CDK)4/6 inhibitors, or vascular endothelial growth 
factor (VEGF).
Phase 2 (Cohort B1): -TNBC:

Have received 0-2 prior chemotherapy regimens for locally advanced or 
metastatic breast cancer.  If previously treated with a platinum-based 
chemotherapy in the advanced/metastatic setting, the patient must not have 
progressed while on treatment with the most recent platinum-based 
chemotherapy.
Applicable to South Korean Investigator Sites Only: have received 1 but no more 
than 2 prior chemotherapy regimens for locally advanced or metastatic TNBC, 
unless the patient is not a candidate for such therapy or does not tolerate such 
therapy.  If previously treated with platinum based chemotherapy, the patient 
must not have progressed while on treatment; disease progression after 
discontinuation of the platinum based chemotherapy is allowed.

Previous neoadjuvant/adjuvant treatment counts as 1 line of prior chemotherapy if 
disease progression occurred while on treatment or within 6 months after the last 
treatment dose.  If previously treated with neoadjuvant/adjuvant platinum-based
chemotherapy, the patient must not have progressed while on treatment or within 
6 months after the last dose of platinum-based chemotherapy.

There is no limit on the number of prior hormonal therapies or targeted 
anti-cancer therapies such as mammalian target of rapamycin (mTOR) or 
cyclin-dependent kinase (CDK)4/6 inhibitors, or vascular endothelial growth 
factor (VEGF).
Phase 2 only (Cohort B2): --HR+/HER2- Breast Cancer:

Cohort B2 only: Disease is DDR defect-positive, as determined by the presence of 
a previously documented known or likely deleterious/pathogenic defect in one of 
the following 34 DDR genes: ATM; ATR; BRCA1; BRCA2; BRIP1; CDK12; 
CHEK1; CHEK2; ERCC4; FANCA; FANCC; FANCG; FANCL; MLH1; 
MRE11A; MSH2; MSH6; MUTYH; NBN; PALB2; PARP1; PARP2; PARP3; 
PMS2; POLD1; POLE; RAD51; RAD51B; RAD51C; RAD51D; RAD52; 
RAD54L; XRCC2; XRCC3.


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•
Presence of such a defect must have been established via a tissue based next 
generation sequencing test, performed in a CAP/CLIAcertified (or comparable 
local or regional certification) laboratory, or via a germline test from one of the 
following approved providers: Myriad Genetics; Invitae; Ambry; Quest; Color 
Genomics; MSKCC-IMPACT; GeneDx; Foundation Medicine.
•
Where the presence of a qualifying defect in one of the listed genes has not -been 
determined, the mandatory DDR Defect sample must be sent to the Foundation 
Medicine central laboratory, no more than 45 days prior to enrollment, for 
prospective testing to confirm eligibility.  See Schedule of Activities for tissue 
requirements for the Foundation One test.
•
Have received 0-2 prior chemotherapy regimens for locally advanced or 
metastatic breast cancer following standard hormone therapy.  If previously 
treated with a platinum-based chemotherapy in the advanced setting, the patient 
must not have progressed while on treatment with the most recent platinum-based 
chemotherapy.
•
There is no limit on prior hormonal therapies or targeted anti-cancer therapies 
such as mTOR or CDK4/6 inhibitors, or VEGF.
•
Previous neoadjuvant/adjuvant treatment counts as 1 line of prior chemotherapy if 
disease progression occurred while on treatment or within 6 months after the last 
treatment dose.  If previously treated with neoadjuvant/adjuvant platinum-based 
chemotherapy, the patient must not have progressed while on treatment or within 
6 months after the last dose of platinum-based chemotherapy.
a.
Recurrent Epithelial Ovarian Cancer:
Phase 1b:
•
Have been previously treated with at least 1 prior platinum-based chemotherapy 
regimen.
•
No disease progression while on treatment; disease progression within 6 months 
after stopping the last platinum-based chemotherapy is required, also termed 
“platinum resistant recurrent disease”.
Phase 2: Cohorts C1 and C2:
•
Have been previously treated with 1-2 prior platinum-based chemotherapy 
regimens for locally advanced or metastatic ovarian cancer and received 
platinum-based chemotherapy as their last treatment.


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
No disease progression while on treatment or within 6 months after stopping the 
last platinum-based chemotherapy, also termed “platinum sensitive recurrent 
disease”.

Cohort C2 only: Patients must have a germline or somatic BRCA1 or 
BRCA2 gene defect based on a previous test result.  The result must have been 
obtained from one of the following test providers: Myriad Genetics, Invitae, 
Ambry, Quest, Color Genomics, MSKCC-IMPACT (germline), Foundation 
Medicine (tissue or ctDNA based), Guardant, or other Clinical Laboratory 
Improvement Amendments (CLIA) approved tissue based next generation 
sequencing-based assay.
b. Transitional Cell Carcinoma of the Urothelium (UC) including Bladder, Urethra, 
Ureters, or Renal Pelvis:
Phase 1b:

Have received at least 1 prior systemic platinum-based chemotherapy regimen for 
locally advanced or metastatic UC unless deemed ineligible for platinum-based 
chemotherapy.  If disease progression occurred while on treatment or within 
12 months after the last treatment dose, neoadjuvant/adjuvant chemotherapy or 
chemotherapy as part of a chemotherapy-radiotherapy regimen is counted as 
1 prior treatment regimen towards the allowed limit of prior treatment regimens.

If previously treated with platinum-based chemotherapy, the patient must not 
have progressed while on treatment; disease progression after discontinuation of 
the platinum-based chemotherapy is required.
Phase 2: Cohort D:

Have received 0-2 prior systemic platinum-based chemotherapy regimens for 
locally advanced or metastatic UC.  If disease progression occurred while on 
treatment or within 12 months after the last treatment dose, neoadjuvant/adjuvant 
chemotherapy or chemotherapy as part of a chemotherapy-radiotherapy regimen 
is counted as 1 prior treatment regimen towards the allowed limit of prior 
treatment regimens.
Applicable to South Korean Investigator Sites Only: have received 1 but no more 
than 2 prior chemotherapy regimens for locally advanced or metastatic UC, unless 
the patient is not a candidate for such therapy or does not tolerate such therapy.  If 
previously treated with platinum-based chemotherapy, the patient must not have 
progressed while on treatment; disease progression after discontinuation of the 
platinum based chemotherapy is allowed.


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
If previously treated with platinum-based chemotherapy, the patient must not 
have progressed while on treatment; disease progression after discontinuation of 
the platinum-based chemotherapy is allowed.
c.
Metastatic CRPC without small cell features (Phase 1b, Phase 2: Cohorts E1 and E2):

Patients with disease spread limited to regional pelvic lymph nodes (below the 
aortic bifurcation) are not eligible unless bone metastasis is present on bone scan.

Have received at least 1 but no more than 2 prior chemotherapy regimens for 
mCRPC, or were deemed unsuitable, declined, or did not have access to these 
therapies.  Patients may have received radium-223, which does not count for a 
line of prior chemotherapy regimen.

Progressed on at least 1 line of second-generation anti-androgen therapy 
(enzalutamide and/or abiraterone acetate/prednisone) for treatment of mCRPC.

Serum testosterone 1.73 nmol/L (50 ng/dL).

Bilateral orchiectomy or ongoing androgen deprivation therapy with a 
gonadotropin-releasing hormone (GnRH) agonist/antagonist (surgical or medical 
castration).

Progressive disease at enrollment defined as 1 or more of the following 3 criteria:

A minimum of 3 consecutive rising PSA values with an interval of at least 
1 week between determinations.  The screening PSA value must be 2 g/L 
(2 ng/mL) if qualifying solely by PSA progression.

Soft tissue disease progression as defined by RECIST v1.1.

Bone disease progression defined by PCWG3 (see Appendix 5) with 2 or 
more new metastatic lesions on bone scan (confirm ambiguous results by 
other imaging modalities).

Cohort E2 only: Disease is DDR defect-- positive, as determined by the presence 
of a previously documented known or likely deleterious/pathogenic defect in one 
of the following 34 DDR genes: ATM; ATR; BRCA1; BRCA2; BRIP1; CDK12; 
CHEK1; CHEK2; ERCC4; FANCA; FANCC; FANCG; FANCL; MLH1; 
MRE11A; MSH2; MSH6; MUTYH; NBN; PALB2; PARP1; PARP2; PARP3; 
PMS2; POLD1; POLE; RAD51; RAD51B; RAD51C; RAD51D; RAD52; 
RAD54L; XRCC2; XRCC3.


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Presence of such a defect must have been established via a tissue based next 
generation sequencing test, performed in a CAP/CLIAcertified (or comparable 
local or regional certification) laboratory, or via a germline test from one of the 
following approved providers: Myriad Genetics; Invitae; Ambry; Quest; Color 
Genomics; MSKCC-IMPACT; GeneDx; Foundation Medicine.
Where the presence of a qualifying defect in one of the listed genes has not been 
determined, the mandatory DDR Defect sample must be sent to the Foundation 
Medicine central laboratory, no more than 45 days prior to enrollment, for 
prospective testing to confirm eligibility.  See Schedule of Activities for tissue 
requirements for the Foundation One test.
d. Advanced solid tumor with a germline or somatic BRCA1, BRCA2 or ATM gene 
defect (Phase 2 Cohort F) not eligible for Phase 2 Cohorts A1, A2, B1, B2, C1, C2, 
D, E1, or E2:
•
Patients must have a germline or somatic BRCA1, BRCA2 or ATM gene defect 
based on a previous test result.  The result must have been obtained from one of 
the following test providers: Myriad Genetics, Invitae, Ambry, Quest, Color 
Genomics, MSKCC-IMPACT (germline), Foundation Medicine (tissue or ctDNA 
based), Guardant, or other CLIA approved tissue based next generation 
sequencing-based assay.
•
Recurrent Epithelial Ovarian Cancer:
•
Patients must have received at least 1 but no more than 6 total prior cytotoxic 
chemotherapy regimens, including at least 1 course of platinum-based 
therapy.  Maintenance therapies begun with cytotoxic chemotherapy and 
continued following best response will count as a single line of therapy.
•
Patients must not have progressed during or within 1 month after stopping the 
most recent platinum-based chemotherapy.
•
Platinum sensitivity requirements:
•
If previously treated with ≤2 prior cytotoxic chemotherapy regimens, 
patients must have progressed within 6 months after stopping the 
platinum-based chemotherapy, also termed “platinum resistant recurrent 
disease”.
•
If previously treated with >2 prior cytotoxic chemotherapy regimens, 
platinum sensitive recurrent disease is allowed.


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
Metastatic pancreatic ductal adenocarcinoma (mPDAC):

Have been previously treated with at least 1 but no more than 2 prior cytotoxic 
chemotherapy regimens (including at least one of the following: 
FOLFIRINOX [oxaliplatin, irinotecan, fluorouracil, and leucovorin] or a 
gemcitabine-containing regimen) OR were deemed unsuitable, or declined 
these therapies.

If previously treated with FOLFIRINOX or other platinum-containing 
chemotherapy, the patient must not have progressed within 6 months of 
initiation of oxaliplatin treatment.

Any other advanced solid tumor:

Have received at least one prior standard of care regimen, if it exists, as 
appropriate for the respective tumor type unless deemed intolerable, 
unsuitable, or declined these therapies.

If previously treated with neoadjuvant/adjuvant platinum-based 
chemotherapy, the patient must not have progressed while on treatment or 
within 6 months after stopping the platinum-based chemotherapy.

If previously treated with platinum-based chemotherapy in the 
advanced/metastatic setting, the patient must not have progressed within 
6 months of initiation of platinum-based chemotherapy.
2. Measurable disease by RECIST v1.1 with at least 1 measurable lesion; This criterion is 
not required for patients with mCRPC.
3. Mandatory primary or metastatic tumor biopsy to be performed within 28 days (45 days 
for patients requiring prospective biomarker testing for eligibility evaluation) prior to 
study enrollment to allow FFPE tissue be submitted for protocol-required testing.  Core 
needle or excision biopsies are required, as fine needle aspirations will not yield enough 
tissue for protocol-specified testing.  If archival tumor tissue is available from a 
biopsy/surgery that was performed within 1 year prior to study enrollment and the patient 
did not receive any subsequent systemic anti-cancer treatment, the tumor tissue may be 
submitted without repeating a tumor biopsy during the screening period.  For mCRPC 
patients with no biopsable lesion outside of bone, archival tumor tissue from a 
biopsy/surgery performed within 5 years prior to study enrollment must be submitted 
without repeating a tumor biopsy during the screening period.
4. Age 18 years (except in Japan, where patients must be 20 years).
5. ECOG Performance Status 0 or 1.
6. Adequate Bone Marrow Function (without hematopoietic growth factor or transfusion 
support within 14 days prior to study enrollment), including:


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a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 × 109/L;
b. Platelets 100,000/mm3 or 100 × 109/L;
c.
Hemoglobin 9 g/dL (5.6 mmol/L).
7. Adequate renal function, defined by an estimated CrCl of 60 mL/min for patients 
enrolled in Phase 1b portion of the study and 30 mL/min for patients enrolled in Phase 
2 portion of the study.  CrCl should be estimated according to the Cockcroft-Gault 
formula as: 

CrCl={[(140–age) × weight)]/(72 x SCR)} × 0.85 (if female), where CrCl (creatinine 
clearance) is measured in mL/min, age is expressed in years, weight in kilograms 
(kg), and SCR (serum creatinine) in mg/dL.
NOTE: Patients enrolled in Phase 2 portion of the study with moderate renal impairment 
(30-59 mL/min) will receive a reduced starting dose for talazoparib of 0.75 mg QD.
8. Adequate Liver Function, including:
a.
Total serum bilirubin 1.5 × ULN;
b. AST and ALT 2.5 × ULN.
9. Female patients of childbearing potential must have negative serum pregnancy or urine 
pregnancy test at screening (see Section 7.1.1 for criteria to be considered not of 
childbearing potential).
Female patients of nonchildbearing potential must meet at least 1 of the following 
criteria:

Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological cause 
and have a serum follicle-stimulating hormone (FSH) level confirming the 
postmenopausal state;

Have undergone a documented hysterectomy and/or bilateral oophorectomy; 

Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are considered to 
be of childbearing potential.
10. Evidence of a personally signed and dated informed consent document indicating that the 
patient has been informed of all pertinent aspects of the study.


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11. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other procedures.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior treatment with a PARP inhibitor.
2. Prior immunotherapy with IL-2, IFN--, or an anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, OX-40, GITR, LAG-3, IDO, TDO, TIM-3, CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune 
checkpoint pathways.  Prior treatment with Sipuleucel-T for patients with mCRPC is 
allowed.
EXCEPTION for Cohort A2 only: Prior treatment with anti-PD-1/L1 therapy in the 
metastatic setting (Stage IV only) as described in Inclusion Criterion 1 is allowed. 
3. Prior anti-cancer therapy within 2 weeks prior to study enrollment.  Prior radiation 
therapy within 2 weeks prior to enrollment.  Prior palliative radiotherapy to metastatic 
lesion(s) is permitted, provided it has been completed 2 days prior to study enrollment 
and no clinically significant toxicities are expected (eg, mucositis, esophagitis).
4. Major surgery within 4 weeks prior to study enrollment.
5. Current use of immunosuppressive medication at the time of study enrollment, 
EXCEPT for the following permitted steroids (see Section 5.7.5).
a.
Intranasal, inhaled, topical steroids, eye drops 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).
6. Known prior severe hypersensitivity to investigational products or any component in 
their formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCI CTCAE v4.03 Grade 3).
7. Known history of immune-mediated colitis, inflammatory bowel disease, 
pneumonitis, pulmonary fibrosis.
8. Active or prior autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or 
hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible.


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9. Prior organ transplantation including allogenic stem-cell transplantation.
10. Vaccination within 4 weeks of study enrollment and while on trials is prohibited 
except for administration of inactivated vaccines.
11. Diagnosis of Myelodysplastic Syndrome (MDS).
12. 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.
13. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study enrollment and/or during study participation.
14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however 
alopecia and sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a 
safety risk, based on Investigator's judgment, are acceptable. 
15. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS).
16. 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 positive).
17. Active infection requiring systemic therapy.
18. Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months 
prior to enrollment), unstable angina, congestive heart failure (New York Heart 
Association Classification Class II) or a serious cardiac arrhythmia requiring 
medication.
19. Current or anticipated use within 7 days prior to first dose of study drug, or 
anticipated use during the study of a strong P-gp inhibitor (See Section 5.7.10 for 
specific list of medications).
20. Inability to swallow capsules, known intolerance to talazoparib or its excipients, 
known malabsorption syndrome, or other condition that may impair absorption of 
talazoparib.
21. Bisphosphonate or denosumab dosage that was not stable (ie, not the same) for at 
least 2 weeks before study enrollment for patients receiving these therapies.
22. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 


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increase the risk associated with study participation or investigational product 
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.
23. Diagnosis of any other malignancy within 5 years prior to study enrollment, except 
for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of 
the breast, bladder or of the cervix.  For patients not enrolled in Cohorts E1 and E2: 
low-grade (Gleason 6 or below) prostate cancer on surveillance with no plans for 
treatment intervention (eg, surgery, radiation, or castration) or prostate cancer that has 
been adequately treated with prostatectomy or radiotherapy and currently with no 
evidence of disease or symptoms is allowed.
24. Pregnant female patients; breastfeeding female patients; female patients of 
childbearing potential who are unwilling or unable to use highly effective 
contraception as outlined in this protocol during treatment and for at least 30 days 
after the last dose of avelumab and for at least 7 months after the last dose of 
talazoparib: fertile male patients with female partners of reproductive potential or 
pregnant partners, unwilling to use a condom (even after vasectomy) during treatment 
and for at least 4 months after the last dose of talazoparib. 
25. Investigator 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.
4.3. Lifestyle Requirements
In this study, all patients will receive avelumab for which the teratogenic risk is currently 
unknown in combination with talazoparib, which has been associated with genotoxic and 
teratogenic risk. 
All female patients of childbearing potential, who are, in the opinion of the investigator, 
sexually active and at risk for pregnancy must agree to use highly effective contraception 
preferably with low user dependency, during treatment and for at least 30 days after the last 
dose of avelumab and at least 7 months after the last dose of talazoparib.
Fertile male patients with female partners of reproductive potential or pregnant partners, 
must agree to use a condom (even after vasectomy) during treatment and for at least 
4 months after the last dose of talazoparib. 
Female partners of reproductive potential should use an additional highly effective 
contraceptive method for a least 4 months after the patient's last dose of talazoparib. 
The investigator or his or her designee, in consultation with the patient, will confirm that the 
patient has selected an appropriate method of contraception for the individual patient from 
the list of permitted contraception methods (see below) and will confirm that the patient has 


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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 highly 
effective contraception consistently and correctly and document the conversation, and the 
patient’s affirmation, in the patient’s chart (patients need to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the 
investigator or designee will instruct the patient to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the patient or 
partner. 
Highly Effective Methods That Have Low User Dependency:
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS)
4. Bilateral tubal occlusion.
5. Vasectomized partner.
Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of child-bearing potential (WOCBP) 
and the absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used. 
Highly Effective Methods That Are User Dependent:
1. Combined (estrogen and progestogencontaining) hormonal contraception 
associated with inhibition of ovulation: oral, intravaginal, transdermal, injectable.
2. Progestogenonly hormone contraception associated with inhibition of ovulation: 
oral, injectable.
3. Sexual abstinence:
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant.
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.


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To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains,
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigational 
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 investigational 
site and the study team are not available.  It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational 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 patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for 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).
For this study, the investigational products are avelumab and talazoparib.
5.1. Allocation to Treatment
All patients will be assigned to receive a fixed dose of avelumab 800 mg Q2W IV in 
combination with talazoparib 0.5 mg, 0.75 mg, or 1.0 mg orally QD.
Assignment of patient number, patient enrollment, and allocation of study treatment by dose 
level (Phase 1b) and cohorts at the RP2D (Phase 2) will be managed by an Interactive 
Response Technology (IRT) system.  At the time that a patient has signed informed consent 
and entered screening, the site should contact the IRT system to obtain the patient 
identification number.  Once a patient has met all eligibility criteria, the site then contacts the 
IRT system to enroll the patient and to obtain the study treatment allocation information.  
Study treatment must be initiated preferably on the day of enrollment, but no later than 
3 days after enrollment.
At the time of enrollment, site personnel (study coordinator or specified designee) will be 
required to enter into or select information from the IRT system including but not limited to 
the user’s identification (ID) and password, the protocol number, the patient number, and the 
date of birth of the patient.  The IRT system will then provide a treatment assignment and 
dispensable unit (DU) or vial number.  The IRT system will also provide a confirmation 
report containing the patient number and DU or vial number assigned.  The confirmation 
report must be stored in the site’s files. 


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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.
5.2. Patient Compliance
The information related to each trial drug administration, including the date, time, and dose 
of study drug will be recorded.  The Investigator will make sure that the information entered 
into the case report form (CRF) regarding drug administration is accurate for each patient.  
Any reason for noncompliance should be documented.
5.2.1. Avelumab Patient Compliance
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 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 and administration of the avelumab dose, including date of 
infusion, total dose administered, start and stop times of the infusion, and any reasons that a 
dose other than the protocol-specified dose or dosing schedule was administered.  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 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 4 weeks for non-medical reasons, then the patient 
would also be considered noncompliant.
5.2.2. Talazoparib Patient Compliance
Patients will be required to return all unused talazoparib capsules every cycle.  The number 
of capsules returned by the patient will 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.
Additionally, a patient dosing diary will be provided to the patients to aid in patient 
compliance with the dosing instructions.  The diary will be maintained by the patient to 
include missed or changed talazoparib doses.  The time of talazoparib dose administration 


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and the total dose of talazoparib taken each day will be recorded in the dosing diary.  Patients 
will be required to return the completed patient dosing diary for talazoparib on Day 1 of 
every cycle for timely review by site personnel and discussion of missed doses and/or 
compliance issues to ensure accurate data entry for the Dosing CRF.  On days when the 
patient’s talazoparib dose is given at the clinic due to 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 diary and dosing records that are included in the medical 
chart.
Patients will be considered out of compliance if ≥20% of the expected doses of each 
treatment are missed within a given cycle. 
5.3. Investigational Product Supplies 
Avelumab and talazoparib will both be supplied for the study by Pfizer Global Clinical 
Supply, Worldwide Research and Development.  Drug supplies will be shipped to the study 
sites with 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 shall take all steps to 
maintain appropriate records and ensure appropriate supply, storage, handling, distribution, 
and usage of investigational products in accordance with the protocol and any applicable 
laws and regulations.
5.3.1. Dosage Forms and Packaging
Packaging and labeling for all study drugs will be in accordance with applicable local 
regulatory requirements and applicable Good Manufacturing Practice 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, and colorless solution intended for IV administration.  It is 
presented at a concentration of 20 mg/mL in 10-mL glass vials closed with a rubber stopper 
and sealed with an aluminum polypropylene flip-off seal.  Each vial is intended for single use 
only. 
Avelumab will be packed in boxes each containing 1 vial. 
Avelumab will be shipped under refrigerated conditions (2C to 8C) that are monitored with 
temperature control monitoring devices.
5.3.1.2. Talazoparib
Talazoparib will be provided as capsules for oral administration.  The 0.25 mg (opaque 
white, size 4) and 1.0 mg (opaque pale-pink, size 4) capsules will be supplied in separate 
bottles and labeled according to local regulatory requirements.  Talazoparib is packaged in 
induction sealed, high-density polyethylene bottles with child-resistant caps with 30 capsules 
of a single strength per bottle.


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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. Avelumab
See the IP manual for instructions on how to prepare avelumab 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.
For administration in this trial, 4 vials of avelumab drug product must be diluted with 
0.9% saline solution (sodium chloride).  Detailed information on infusion bags and medical 
devices to be used for the preparation of the dilutions and subsequent administration will be 
provided in the Investigational Product Manual.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
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.
5.3.2.2. 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 of 30 capsules 
per bottle.  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 every 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.44
Patients should be advised that oral anti-cancer agents are toxic substances and that other 
caregivers should always use gloves when handling the capsules.
5.4. Administration
5.4.1. Combination Therapy Administration
On Days 1 and 15 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 and blood will be drawn for PK and ADA assessments (when scheduled);


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2. Avelumab premedication, as described below in Section 5.4.3, and talazoparib will be 
administered to the patient in any order chosen by the qualified site personnel;
3. Avelumab infusion will start within 30-60 minutes after the avelumab premedication 
was administered and after dosing with talazoparib;
4. Blood will be drawn for PK assessments (when scheduled) immediately at the end of 
the avelumab infusion and the patient will remain in the clinic for observation for at 
least 30 minutes after the avelumab infusion.
Treatment with avelumab and talazoparib will continue until disease progression is 
confirmed by the Investigator (except where treatment is allowed beyond progression, as per 
Section 5.4.7), patient refusal, unacceptable toxicity, or until the study is terminated by the 
Sponsor, whichever occurs first. 
The investigational products and the required premedications are discussed in the following 
subsections, in the order of their administration.
5.4.2. Talazoparib Administration
Talazoparib will be taken QD at 0.5 mg, 0.75 mg, or 1 mg starting on Cycle 1 Day 1 (C1D1) 
and treatment should continue until EOT.  On Days 1 and 15 of each 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 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 
them 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 forgets his/her daily dose of talazoparib at the time typically taken, but 
remembers this on the same day, within 12 hours of the usual dose time, the dose may be 
taken at that time. Any dose that is missed (not taken within 12 hours of the intended time) 
should be skipped and should not be replaced or made up on a subsequent day.  Patients 
should not make up vomited doses; dosing should resume on the next calendar day unless 
otherwise.
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.


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5.4.3. Avelumab Premedication
In order to mitigate infusion-related reactions, premedication with an antihistamine and with 
paracetamol (acetaminophen) approximately 30-60 minutes prior to the first 4 infusions of 
avelumab (ie, Cycles 1-2) is mandatory (eg, 25-50 mg diphenhydramine and 500-650 mg 
paracetamol [acetaminophen] IV or oral equivalent).  Premedication should be administered 
for subsequent avelumab doses (ie, Cycle 3) based on clinical judgment and 
presence/severity of prior infusion reactions.  The premedication regimen may be modified 
based on local treatment standards and guidelines, as appropriate.  Prophylactic 
corticosteroids are not permitted.
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 at least 30 minutes 
after the avelumab premedication was administered.
5.4.4. Avelumab Administration
Avelumab will be administered at 800 mg as a 1-hour IV infusion starting 30-60 minutes 
after the mandatory premedication was administered, as per Section 5.4.3, at the 
investigational site on an outpatient basis on Day 1 and Day 15 of each 28-day cycle.  
Investigational sites should make every effort to target the timing of the avelumab infusion to 
be as close to 1 hour as possible.  The exact duration of infusion should be recorded in both 
the source documents and the CRFs.  Additionally, the start and stop times of any 
interruptions to infusion and/or changes in rate of avelumab infusion will also need to be 
recorded in source documents. 
After Cycle 1, avelumab may be administered up to 2 days before or after the scheduled 
treatment day of each cycle for administrative reasons.
5.4.4.1. Special Precautions for Avelumab Administration
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.  Steroids (dexamethasone 
10 mg), epinephrine (1:1,000 dilution), allergy medications (IV antihistamines), 
bronchodilators, or equivalents, and oxygen should be available for immediate access.  If a 
hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice.  In order to mitigate avelumab infusion-related reactions, patients have to 
be premedicated, according to guidance in Section 5.4.3. 
Following the infusions of avelumab, patients must be observed for at least 30 minutes 
post-infusion for potential infusion-related reactions. 
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 Table 6.  Patients should 


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be instructed to immediately report to the Investigator any delayed reactions that may occur 
after they leave the clinic.
5.4.5. Food Requirements
Both investigational products may be administered without regard to food.
5.4.6. Recommended Dose Modifications
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.
Treatment/dose modifications may occur independently for each investigational product in 
the combination based on the observed toxicity and 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.
See Section 5.4.6.3 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.
5.4.6.1. Dosing Interruptions 
Guidelines for study treatment modifications for patients experiencing AEs are provided in 
Sections 5.4.6.3, 5.4.6.4, and 5.4.6.5.
Doses of either investigational product that were omitted for toxicity are not replaced within 
the same cycle.  The need for a dose reduction for talazoparib at the time of treatment 
resumption should be based on the criteria defined in Section 5.4.6.3. 
Appropriate follow-up assessments should be done until adequate recovery occurs as 
assessed by the Investigator. 


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In the event of a treatment interruption for reasons other than treatment-related toxicity 
(eg, elective surgery) for >7 consecutive days, treatment resumption will be decided in 
consultation with the Sponsor.
5.4.6.2. Dose Reductions of 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 in Section 5.4.6.3.  
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.
Doses less than 0.5 mg are not permitted.  Patients unable to tolerate 0.5 mg QD, will be 
permanently discontinued from the talazoparib, but may continue on single agent avelumab.  
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)
D0
1 mg QD
D-1
0.75 mg QD
D-2
0.5 mg QD a
a Talazoparib dose de-escalation below 0.5 mg QD is not allowed.
D = dose; QD = once daily
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.
If a dose reduction is required, the patient may need to return to the clinic to receive new 
drug supply prior to the next scheduled visit since dosage strengths of the capsules may be 
different.  Site personnel must ensure the patients are instructed how to take the reduced dose 
and that the patients have the correct dosage strength for the reduced dose. 
Recommended dose reductions for talazoparib are described in Section 5.4.6.3.
5.4.6.3. Study Treatment Modifications for Avelumab and Talazoparib Drug-Related 
Toxicity (excluding infusion-related reactions and immune-related adverse events)
Recommended avelumab and talazoparib treatment modifications 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.


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Avelumab infusion-related reactions should be managed according to guidelines in 
Section 5.4.6.4. 
For patients receiving avelumab, either as a single agent or in combination with talazoparib, 
any AE suspected to be immune-related should be managed according to the guidance for 
management of irAEs in Section 5.4.6.5.
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 monitor 
weekly until resolve to Grade ≤1 
(hemoglobin ≥10 g/dL) or 
baseline. 

Talazoparib may be reduced by 
1 dose level, per Section 5.4.6.2. 

Permanently discontinue if 
persists for >4 weeks without 
recovery to baseline.  Refer to 
hematologist for evaluation 
including assessment of possible 
MDS/AML.

Hold avelumab.

Re-initiate avelumab once 
toxicity Grade 1 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).

Neutropenia Grade 3
(ANC <1000/L)

Hold talazoparib and monitor 
weekly until ANC 1500/L.

Resume talazoparib based on the 
following recovery times:

1 week: No change.

>1 week: Talazoparib may be 
reduced by 1 dose level, per 
Section 5.4.6.2.

Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery to 
ANC 1500/L.  Refer to 
hematologist for evaluation 
including assessment of possible 
MDS/AML.

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).

Thrombocytopenia Grade 
3 (platelets <50,000/L)

Hold talazoparib and monitor 
weekly until platelets 
75,000/L.

Resume talazoparib based on the 
following recovery times:

1 week: No change

Hold avelumab.

Re-initiate avelumab once 
toxicity Grade 1 or 
baseline.

Permanently discontinue 
avelumab if toxicity does not 


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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

>1 week: Talazoparib may be 
reduced by 1 dose level, per 
Section 5.4.6.2.

Permanently discontinue 
talazoparib if persists for 
>4 weeks without recovery to 
platelets 75,000/L.  Refer to 
hematologist for evaluation 
including assessment of possible 
MDS/AML.
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).
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 5.4.6.5, 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 5.4.6.5.
Grade 3

Hold talazoparib.

Resume talazoparib reduced by 
1 dose level, per Section 5.4.6.2 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 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 

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 5.4.6.5.


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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
4 weeks.

Exceptions are:
Laboratory values that do not 
have any clinical correlate.

Permanenlty 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 5.4.6.5, 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 5.4.6.5.
Abbreviations: AML=Acute Myeloid Leukemia; ANC=Absolute Neutrophil Count; MDS=Myelodysplastic 
Syndrome.
5.4.6.4. 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
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.

Subjects 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.  Prophylactic corticosteroids are not permitted.
5.4.6.5. Immune-Related Adverse Events Toxicity Management
For patients receiving avelumab, either as a single agent or 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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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 

Re-assess every 1 to 
3 days;

When symptoms return to 
Grade 1, taper steroids 


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hospitalization;

1.0 - 2.0 mg/kg/day prednisone or 
equivalent;

Add prophylactic antibiotics for 
opportunistic infections;

Consider bronchoscopy, lung biopsy.
over at least 1 month, and 
then resume avelumab 
therapy following steroids 
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 × ULN;

and/or Total bilirubin 
>ULN to 1.5 × 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 × ULN;

and/or total bilirubin 
>1.5 to 3 × 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 × ULN;

and/or total bilirubin 
>3 × 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 

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 


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clinically warranted. 
local guidelines.
Renal irAEs
Grade of Creatinine 
Increased (NCI-CTCAE 
v4.03)
Initial Management
Follow-up Management
Grade 1
Creatinine increased >ULN to 
1.5 × 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 × 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 × ULN.

Permanently discontinue avelumab 
therapy;

Monitor creatinine daily;

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;

Once improving, taper 


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
Guideline based supportive treatment 
as appropriate as per cardiology 
consult*;

1.0-2.0 mg/kg/day prednisone or 
equivalent;

Add prophylactic antibiotics for 
opportunistic infections.
steroids over at least 
1 month;

If no improvement or 
worsening, consider 
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;

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;


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
Perform pituitary MRI and visual field 
examination as indicated.
If hypophysitis confirmed:

Continue avelumab if mild symptoms 
with normal MRI.  Repeat the MRI in 
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.

Continue hormone 
replacement/suppression 
therapy as appropriate.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
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.


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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 
longer

Permanently discontinue avelumab 
therapy;

Specialty consult.
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.
5.4.7. Treatment After Initial Evidence of Radiological Disease Progression
Immunotherapeutic agents such as avelumab, may produce anti-tumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiologic imaging shows disease progression after discussion between the Sponsor and 
Investigator, patients may continue to receive investigational products, at the Investigator’s 
discretion 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.


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Before continuation of treatment, the patient must be re-consented via informed consent 
addendum and informed that, by continuing to receive the investigational products, the 
patient may be foregoing approved or investigational therapies with possible clinical 
benefit(s).
If the patient is subsequently found to have further disease progression at a subsequent tumor 
assessment, either radiologically according to RECIST v1.1 or clinically, then treatment with 
investigational products should be permanently discontinued.
5.5. Investigational Product Storage
The Investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational 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.  Any storage conditions stated in the SRSD, which is the IB, will be superseded by 
the storage conditions stated on the product labels.  Reference Investigational Product 
Manual for storage and administration instructions.
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 nonworking 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 it is 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 as 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. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the investigational products are briefly out of the temperature range described in the labeling 
are not considered excursions.


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Specific details regarding information the site should report for each excursion will be 
provided to the site in the Investigational Product Manual.
5.5.1. Avelumab Storage
Avelumab must be stored in the refrigerator at 2C–8C (36F–46F).  Do not freeze.  
Protect from light.  Do not shake vigorously.  See the Investigational Product Manual for 
storage conditions of avelumab once diluted.
5.5.2. Talazoparib Storage
Talazoparib is stored at room temperature (15C–30C; 59F–86F) or per approved local 
label. 
Site staff will instruct patients on the proper storage requirements for take home 
investigational product, as talazoparib will be self-administered at home by patients.
5.6. Investigational Product Accountability 
The investigative 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. 
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.
5.6.1. 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 study 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.
5.7. Concomitant Treatment
Concomitant treatment considered necessary for the patient’s well-being (ie, antiemetics, 
analgesics, megestrol acetate for anorexia) may be given at discretion of the treating 
physician.
All concomitant medications and treatments, including herbal supplements, supportive care 
drugs (eg, antiemetic treatment and prophylaxis), drugs used to treat AEs or chronic diseases, 
blood products, and nondrug interventions (eg, paracentesis) will be recorded from 28 days 
prior to the start of study treatment (ie, the screening period) and up to 90 days after the last 
dose of investigational product (ie, the Short Term Follow-Up Day 90 Visit).  If a patient 
begins a new anti-cancer therapy, reporting of concomitant medications should end at the 
time the new treatment is started. 


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5.7.1. Supportive Care
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines and as deemed necessary by the treating Investigator.
5.7.2. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the DLT observation period (eg, Cycle 1), but they may be used to treat treatment-emergent 
neutropenia as indicated by the current ASCO guidelines.45
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  Erythropoietin or darbepoetin may be used at 
the Investigator’s discretion for the supportive treatment of anemia.
Patients who enter the study on stable doses of erythropoietin or darbepoetin may continue 
this treatment, and patients may start either drug during the study at the discretion of the 
treating physician.
5.7.3. Anti-Diarrheal, Anti-Emetic Therapy
Primary prophylaxis of diarrhea, nausea and vomiting is permitted at the investigator’s 
discretion.  The choice of the prophylactic drug, as well as the duration of treatment, is up to 
the investigator and assuming the drug is not included in the Prohibited Concomitant 
Medications and Treatment(s) section.

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.

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. 
5.7.4. Anti-Inflammatory Therapy
Anti-inflammatory or narcotic analgesic may be offered, as needed, assuming the drug is not 
included in the Prohibited Concomitant Medications and Treatments section (Section 5.7.10). 
5.7.5. Corticosteroids
Data indicate that corticosteroids have an adverse effect on T-cell function and that they 
inhibit and damage lymphocytes.46 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-CTLA4 compounds indicate that short-term use of steroids can be employed without 
compromising clinical outcomes.48 Therefore, the use of steroids during this trial is restricted 
as follows while on avelumab treatment:  


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
Treatment of infusion-related reactions and irAEs, according to the modalities 
indicated in Section 5.4.6.4 and Section 5.4.6.5.

Steroid replacement for adrenal insufficiency at physiologic doses equivalent to 
10 mg prednisone daily is acceptable.

Prophylactic use prior to CT or magnetic resonance imaging (MRI). 

Intranasal, inhaled topical steroids, eye drops, or local steroid injection 
(eg, intra-articular injection) are allowed.
See Section 5.7.10 Prohibited Concomitant Medications for information detailing specific 
prohibited uses of corticosteroids.
5.7.6. 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.
5.7.7. Androgen Deprivation Therapy for Patients with mCRPC
Patients with mCRPC must receive androgen deprivation therapy with a GnRH 
agonist/antagonist or bilateral orchiectomy (medical or surgical castration).
5.7.8. Concomitant Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  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.  Stopping investigational products temporarily is recommended in case of a 
surgical procedure.  Postoperatively, the decision to reinitiate treatment with investigational 
products should be based on a clinical assessment of satisfactory wound healing and recovery 
from surgery.
5.7.9. Concomitant Radiotherapy
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions and 
other sites of disease if considered medically necessary by the treating physician, provided 
that the bony lesions and/or other sites of disease to be irradiated were present at the time of 
the screening tumor assessments and the investigator clearly indicates that the need for 
palliative radiotherapy is not indicative of disease progression.  All attempts should be made 
to rule out disease progression in the event of increased localized pain. 
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.


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5.7.10. Prohibited Concomitant Medications 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. 

Radiation therapy (with the exception noted above in Section 5.7.8).

Any investigational agents other than avelumab and talazoparib.

Any vaccination for the prevention of infectious disease while on avelumab 
treatment, except for administration of inactivated vaccines. 

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin).

Prophylactic use of corticosteroids to prevent acute infusion-related reactions. 

Immunosuppressive drugs (ie, systemic corticosteroids) while on avelumab treatment, 
unless otherwise indicated for the treatment of irAEs or listed as an exception in 
Section 5.7.5.

Strong P--gp inhibitors that result in ≥2-fold increase in the exposure of an in vivo 
probe P-gp substrate according to the University of Washington Drug-Drug 
Interaction database (https://www.druginteractioninfo.org/) are prohibited: 
amiodarone, carvedilol, clarithromycin, cobicistat, dronedarone, erythromycin, 
indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, 
ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and verapamil.


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
Caution and monitoring for potential increased adverse reactions should be used upon 
concomitant use of the following transporter inhibitors with talazoparib: atorvastatin, 
azithromycin, conivaptan, curcumin, cyclosporine, diltiazem, diosmin, eliglustat, 
elacridar [GF120918], eltrombopag, felodipine, flibanserin, fluvoxamine, piperine, 
quercetin, and schisandra chinensis extract.
The list of strong P-gp inhibitors and transporter inhibitors to be used with caution will be 
updated annually and reflected in the talazoaprib IB.12
If there is a clinical indication for one of the medications or vaccinations specifically 
prohibited during the trial, discontinuation from study treatment may be required.  The 
Investigator should consult with the Sponsor about individual cases.
There are no prohibited therapies during the Short-Term and Long-Term Follow-up Phases.
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see the Schedule of Activities and Section 7.
All screening activities must take place within 28 days prior to enrollment into the study, 
unless otherwise noted.
6.2. Treatment Period
For the treatment period procedures, see the Schedule of Activities and Section 7.  For the 
treatment period, where multiple procedures are scheduled at the same nominal time point(s) 
relative to dosing, the following prioritization of events should be adhered to, where possible:

Pharmacokinetic blood specimens – obtain at the scheduled time.

Electrocardiograms (ECGs) – obtain as close as possible to the scheduled time 
(See Section 7.1.6).

Blood pressure/pulse rate – may be obtained prior to or after ECG collection but must 
be obtained prior to blood specimen collection.

Clinical safety laboratory tests – must be performed pre-dose.

Other procedures – All other procedures should be performed as close as possible to 
the scheduled time, but may be obtained before or after blood specimen collection, 
unless sampling is determined by the study personnel to potentially impact the results.


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6.3. Patient Withdrawal/EOT
For the EOT Visit procedures, see the Schedule of Activities and Section 7.
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the Investigator or Sponsor for safety (see also Section 8.1.3) 
or behavioral reasons, or the inability of the patient to comply with the protocol-required 
schedule of study visits or procedures at a given study site. 
Reasons for withdrawal of 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 5.4.7 for details and exceptions); 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to one of the two 
investigational products, the Investigator may continue treatment with the other 
investigational product;

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by Sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Study terminated by Sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
6.3.1. Withdrawal of Consent
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific 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.  Subjects should notify the investigator in 
writing of the decision to withdraw consent from future follow-up, whenever possible.  The 


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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 or also from study procedures and/or post treatment study follow-up.  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.
6.3.2. Lost to Follow-up
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient and report their ongoing status.  This includes follow-up with persons authorized by 
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. 
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.  If it is determined that the patient has died, the site will use locally 
permissible methods to obtain the date and cause of death.  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.
6.4. Short Term Follow-up Visits
For Short Term Follow-Up procedures, see the Schedule of Activities and Section 7.  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. 
Patients with ongoing treatment-related toxicity following discontinuation of study treatment 
will be followed at least every 4 weeks until resolution or determination, in the clinical 
judgment of the investigator, that no further improvement is expected.
If the patient has withdrawn from study treatment for a reason other than disease progression, 
the patient should continue to undergo tumor assessments during the Short-Term Follow-Up 
period as if they were still on therapy, regardless if they start on a new anti-cancer therapy.  
See the Schedule of Activities for the frequency of tumor assessments during Short-Term 
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6.5. Long Term Follow-up Visits 
After patients complete the Short Term Follow-Up period (90 days after the last dose of 
investigational product), patients will be followed for survival, independently of time of 
disease progression, and subsequent anti-cancer therapies every 12 weeks (14 days) until 
death, lost to follow-up, patient withdrawal of consent, or study discontinued by the Sponsor, 
whichever comes first.  For Long Term Follow-Up procedures, see the Schedule of 
Activities.  These visits may be conducted in-clinic or by remote contact (eg, telephone).
If the patient has withdrawn from study treatment for a reason other than disease progression, 
the patient should continue to undergo tumor assessments during the Long Term Follow-Up 
period as if they were still on therapy, regardless if they start on a new anti-cancer therapy.  
In these cases,  survival status will be collected at the time of the scheduled tumor 
assessments, which may be more or less frequent than the Long-Term Follow-Up visits (See 
Schedule of Activities for timing of tumor assessments in Long-Term Follow-Up Visits).
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, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study.
7.1. Safety Assessments
Safety assessments will include, but are not limited to, collection of AEs, SAEs, vital signs, 
physical examination, 12-lead ECG, and laboratory assessments, including pregnancy tests, 
and verification of concomitant treatments.  See the following sections regarding the specific 
safety assessments.
7.1.1. Pregnancy Testing
All pregnancy tests used in this study, either urine or serum, must have a sensitivity of at 
least 25 mIU/mL human chorionic gonadotropin and must be performed by a certified 
laboratory.  For female patients of childbearing potential, 2 negative pregnancy tests are 
required before receiving study treatment (1 negative pregnancy test at screening and one at 
the baseline (Cycle 1 Day 1) visit immediately before study treatment administration).


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Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and the second negative pregnancy result will then be required at the baseline 
(Cycle 1 Day 1) visit before the patient may receive the study treatment.  Pregnancy tests 
(serum or urine) will also be repeated on Day 1 of every cycle prior to dosing of either study 
drug during the active treatment period, at the EOT visit, at the Day 30 Short Term 
Follow-Up Visit to confirm that the patient has not become pregnant during the study.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed and when potential 
pregnancy is otherwise suspected, and may be repeated if requested by institutional review 
boards (IRBs)/ECs or if required by local regulations.  In the case of a positive confirmed 
pregnancy, the patient will be withdrawn from administration of investigational products but 
may remain in the study only for Short-Term Follow-up and Long-Term Follow-up (see 
Sections 8.4.2 and 8.4.2.1 for required pregnancy follow-up and safety reporting 
requirements and the Schedule of Activities for Short-Term and Long-Term Follow-Up 
procedures).
7.1.2. Contraception Check
Fertile male patients with female partners of reproductive potential or pregnant partners and 
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 the selected method of highly effective contraception.  The 
investigator or his or her designee will discuss with the patient the need to use highly 
effective contraception preferably with low user dependence consistently and correctly 
during treatment and for the required period after the last dose of each study drug 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 or the 
patient’s partner.
7.1.3. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by NCI CTCAE v4.03), 
timing, seriousness, and relatedness. 
7.1.4. Laboratory Safety Assessments
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at local laboratories.  Required safety laboratory tests including at 
a minimum: hematology (hemoglobin, platelets, and white blood cells), chemistry (ALT, 
AST, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, sodium, 
potassium, and glucose), and pregnancy test (Day 1 only) results must be reviewed prior to 
study drug administration on Days 1 and 15 of each treatment cycle.  If pregnancy tests are 
administered whenever 1 menstrual cycle is missed and when potential pregnancy is 
otherwise suspected, or if requested by IRBs/ECs, or if required by local regulations 
(Section 7.1.1), then pregnancy test results must also be reviewed prior to study drug 
administration on Day 15 for that treatment cycle.
The required safety laboratory tests are listed in Table 8.


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Table 8.
Required Safety Laboratory Tests
Hematology
Chemistry 
Coagulation 
Urinalysis (Dispstick 
is acceptable) 
Pregnancy Test
Hemoglobin
ALT
INR 
Urine dipstick for urine 
protein: If positive 
collect a microscopic 
sample (Reflex Testing)
For female patients of 
childbearing potential, 
serum or urine with a 
sensitivity of at least 
25 mIU/mL.
Platelets
AST
PTT or aPTT
WBC
Alkaline 
Phosphatase
Absolute 
Neutrophils
Sodium
Absolute 
Lymphocytes
Potassium
Absolute 
Monocytes
Magnesium
Urine dipstick for urine 
blood: If positive 
collect a microscopic 
sample (Reflex Testing)
Absolute 
Eosinophils
Chloride
Absolute Basophils Total Calcium
Total Bilirubina
Thyroid Function 
Tests:
BUN or Urea
TSH, Free T4
Creatinine
Uric Acid
Glucose 
(non-fasted)
Other Tests:
Albumin
ACTH
Phosphorus or 
Phosphate
HBV surface 
antigen
Total Protein
Anti-HCV antibody Amylase
If Anti-HCV 
antibody test 
positive, then HCV 
RNA
Gamma Glutamyl 
Transferase (GGT)
Testosterone (at 
screening only for 
mCRPC patients)
Creatine Kinase
C-reactive Protein 
(CRP)
Lactate 
Dehydrogenase 
(LDH)
Lipase
Abbreviations used in the table: ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT=activated 
partial thromboplastin time; AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, 
mCRPC=metastatic castration-resistant prostate cancer, GGT=gamma-glutamyltransferase, HBV=hepatitis B virus, 
HCV=hepatitis C virus, INR=international normalized ratio, LDH=lactate dehydrogenase, PTT=partial thromboplastin 
time,  RNA=ribonucleic acid, TSH=thyroid-stimulating hormone, WBC=white blood cell.
a For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include albumin, creatine 
kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time (PT)/INR, alkaline 
phosphatase, total bile acids and acetaminophen drug and/or protein adduct levels.


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7.1.5. Physical Examinations and Vital Signs
Patients will have focused physical examinations to include major body systems, vital signs, 
assessment of ECOG performance status (see Appendix 2), weight and height (height will be 
measured at screening only) at the time points described in the Schedule of Activities. 
Vital signs, to include blood pressure, pulse rate and temperature will be also recorded at the 
time points described in the Schedule of Activities.  Vitals signs should be taken prior to 
administration of any investigational products at the visit.
7.1.6. (12-Lead) Electrocardiograms
Triplicate 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  At each time point (see the Schedule of Activities), 3 consecutive ECGs will 
be performed approximately 2 minutes apart to determine mean QTc interval.  When 
coinciding with PK blood sample draws, ECG assessment should be performed prior to blood 
sample collection, such that the blood sample is collected at the nominal time (ie, the timing 
of the PK collections overrides the timing of the ECG collections).  On-treatment triplicate 
ECGs will be performed on Day 1 of Cycles 1 and 3, prior to PK collection at pre-dose 
(within 1 hour before administration of talazoparib) and post-dose (within 10 minutes after 
the end of avelumab infusion), at the EOT Visit and Short Term Follow-Up Visits (up to 
90 days after the last dose of study treatment). 
If the mean QTc is prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs should be 
re-evaluated by a qualified person at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate.  If manual reading verifies a QTc 
of >500 msec, immediate correction for reversible causes (including electrolyte 
abnormalities, hypoxia and concomitant medications for drugs with the potential to prolong 
the QTc interval) should be performed.  In addition, repeat ECGs should be immediately 
performed hourly for at least 3 hours until the QTc interval falls below 500 msec.  If QTc 
interval reverts to less than 500 msec, and in the judgment of the investigator(s) and sponsor 
is determined to be due to cause(s) other than investigational products, treatment may be 
continued with regular ECG monitoring as clinically indicated.  If in that timeframe the QTc 
intervals rise above 500 msec the investigational product will be held until the QTc interval 
decreases to 500 msec.  Additional triplicate ECGs may be performed as clinically 
indicated. 
If patient experiences any cardiac AE or syncope, dizziness, seizures, or stroke, triplicate 
ECGs should be obtained at time of the event.
7.2. Pharmacokinetics Assessments
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, the exact time of the sample collection will always be noted on the CRF.  
Where noted in the Schedule of Activities, blood samples for avelumab and talazoparib 
concentrations will be collected immediately after triplicate 12-lead ECGs are performed.  If 
a scheduled blood sample collection cannot be completed for any reason, the missed sample 


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time may be re-scheduled with agreement of clinical investigators, patient and Sponsor.  PK 
sampling schedule may be modified based on emerging PK data.
PK samples will be analyzed using a validated analytical method in compliance with Pfizer 
standard operating procedures.
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 
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
Blood samples (3.5 mL whole blood at each time point) will be collected for PK analysis of 
avelumab, as outlined in the Schedule of Activities.  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
Blood samples (3 mL whole blood at each time point) will be collected for PK analysis of 
talazoparib as outlined in the Schedule of Activities.  Please refer to the Laboratory Manual 
for instructions for specific details on collection tubes, processing and shipping.
7.3. Immunogenicity Assessments
Blood samples (3.5 mL whole blood) will be collected for assessment of avelumab ADAs, as 
outlined in the Schedule of Activities.  Please refer to the Laboratory Manual for instructions 
for specific details on collection tubes, processing and shipping. 
For all patients, blood for ADA samples will be drawn from the contralateral arm of the 
avelumab infusion.
Immunogenicity blood samples will be assayed for ADA using a validated assay in 
compliance with Pfizer standard operating procedures.  The sample analysis will follow a 
tiered approach of screening, confirmation, and titer determination.  Samples tested positive 
for ADA will be further analyzed for Nab using a validated assay in compliance with Pfizer 
standard operating procedures.  Additional details regarding the collection, processing, 
storage, and shipping of the blood samples will be provided in the Laboratory Manual to 
maintain sample integrity.  Any deviations from the processing steps (eg, sample collection 
and processing steps, interim storage or shipping conditions), including any actions taken, 
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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.
 
 
 
 
 
 
 
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7.4.1. Tumor Tissue Samples
7.4.1.1. DDR Defect Sample
All patients must provide a tumor tissue sample to the Foundation Medicine central 
laboratory for testing of DDR defects via the Foundation One assay or validated local assay 
result.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell 
pellet material) or from bone biopsies is not adequate and should not be submitted.
Tissue should be sent in the form of 15 unstained slides, positively charged and unbaked at 
4-5 microns thick, and one original (not recut) H&E slide.  The portion of the tumor used 
should optimally measure 5×5 mm and contain minimally 20% and optimally 40% or greater 
tumor nuclei. 
The slides should be taken from an FFPE tumor tissue sample, which was obtained from a 
biopsy or surgery that was performed within 2 years prior to study enrollment, during which 
time the patient should have received no more than one line of systemic anti-cancer therapy.
In instances where no such sample is available a biopsy from a locally recurrent or metastatic 
tumor site that is not the only RECIST v1.1 target lesion must be performed during 
screening. For mCRPC patients with no lesion that can be biopsied outside of bone at 
screening, tumor tissue from a biopsy/surgery performed within 5 years prior to study
enrollment must be submitted without repeating a tumor biopsy during the screening period.  
For patients who require prospective biomarker testing as part of the eligibility criteria, 
including NSCLC Cohort A2, HR+/HER2- breast cancer Cohort B2, and mCRPC Cohort E2, 
the biopsy may be performed within 45 days prior to enrollment. 
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 from the same biopsy site for each biopsy procedure.
7.4.1.2. Baseline Tumor Tissue Samples
In additionto the 15 slides described above in Section 7.4.1.1, all patients must submit an 
FFPE tumor tissue block to support the biomarker analyses outlined above.  This tissue block 
must be obtained from a biopsy or surgery that was performed within 2 years prior to study 
enrollment, during which time the patient should have received no more than one line of 
systemic anti-cancer therapy.  In instances where no such sample is available a biopsy must 
be performed during screening, as described above in Section 7.4.1.1.  For mCRPC patients 
with no lesion that can be biopsied outside of bone at screening, tumor tissue from a 
biopsy/surgery performed within 5 years prior to study must be provided.
Where documented local or institutional regulations prevent the submission of tissue blocks, 
then a minimum of 10 slides must be submitted.


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7.4.1.4. Archival Tumor Tissue Samples
For patients who have an older archive tissue sample, obtained from a surgery or biopsy 
performed greater than 2 years prior to enrollment, an FFPE tumor tissue block, or 
5-10 unstained slides, from this tissue sample must be submitted if available.
See the Laboratory Manual for additional details on the handling of all tissue samples 
including processing, storage, and shipment.
 
 
 
 
 
 
 
 
 
 
 
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7.6. Tumor Response Assessment
Tumor response assessments are dependent upon the patient’s tumor type.  All patients with 
the specified tumor types, except mCRPC, will undergo tumor assessments, as per the 
requirements described in this section.  For tumor response assessments that are unique for 
patients with mCRPC, see Section 7.6.1.
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen and pelvis CT or MRI scans.  Baseline Brain CT or MRI scan is required for 
all patients at baseline (Screening); patients with stable brain metastases present at baseline 
(Screening) will continue to have brain CT or MRI scans performed at each tumor 
assessment.  Otherwise, brain CT or MRI imaging is required only when clinically indicated 
if new brain metastases are suspected. 
Bone scans (preferred method) or 18-fluorodeoxyglucose positron emission tomography 
(18F- FDG-PET)/CT or MRI is required for all patients at baseline (Screening).  If bone 
metastases are present at baseline (Screening), then repeat bone imaging is required every 
16 weeks for the first year of study treatment and every 24 weeks thereafter.  Otherwise, 
bone imaging is required only if new bone metastases are suspected.  Bone imaging is also 
required at the time of confirmation of CR for patients who have bone metastases. 
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 (Screening) will be employed in the following tumor assessments. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline (Screening), during treatment every 8 weeks for 1 year from the start of the study 
treatment, and then every 16 weeks thereafter until disease progression regardless of 
initiation of subsequent anti-cancer therapy, as specified in the Schedule of Activities, 
whenever disease progression is suspected (eg, symptomatic deterioration), and at the time of 
withdrawal from treatment (if not done in the previous 4 weeks and the prior response is 
other than confirmed PD).  Timing of disease assessment should follow calendar days and 
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should not be adjusted for delays in cycle starts.  In case CR or PR is observed according to 
RECIST v1.1, tumor assessments must be confirmed on repeated imaging at least 4 weeks 
after initial documentation.  The allowable time window for tumor assessments is 7 days.
Assessment of response will be made using RECIST v1.1 (see Appendix 3).  Details of 
treatment after initial evidence of radiological disease progression are provided in 
Section 5.4.7.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.  All radiographic images will be collected and stored by an 
independent third-party imaging laboratory, according to instructions provided in the 
Imaging Manual.
7.6.1. mCRPC Tumor Response Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging is categorized 
as soft tissue or bone.  Soft tissue imaging may include CT scans of the chest, abdomen and 
pelvis or MRIs of the abdomen and pelvis.  Bone imaging must be whole body radionuclide 
bone scan.  Bone scans and brain CT or MRI scans are required for all patients at baseline 
(Screening).  Patients with stable brain metastases present at baseline (Screening) will 
continue to have brain CT or MRI scans performed at each tumor assessment.  Otherwise, 
brain CT or MRI imaging is required only when clinically indicated if new brain metastases 
are suspected.  Bone scans must be performed at every tumor assessment.
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 (Screening) will be employed in the following tumor assessments. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline (Screening), during treatment every 8 weeks for 24 weeks from the start of the study 
treatment, and then every 12 weeks thereafter until disease progression regardless of 
initiation of subsequent anti-cancer therapy, as specified in the Schedule of Activities, 
whenever disease progression is suspected (eg, symptomatic deterioration), and at the time of 
withdrawal from treatment (if not done in the previous 4 weeks and the prior response is 
other than confirmed PD).  Timing of disease assessment should follow calendar days and 
should not be adjusted for delays in cycle starts. 
Assessment of response will be made using RECIST v1.1 (see Appendix 3).  The 
Investigator will assess response of soft tissue disease by RECIST v1.1.  Bone disease will 
not be considered as non-target lesions assessed by RECIST v1.1, but will be assessed for 
progressive disease by PCWG3.43 The documentation required for the determination of 
radiographic progression is shown in Appendix 5. 


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An objective response is defined as a best overall response of CR or PR per 
RECIST v1.1 and must be confirmed on repeated imaging at least 4 weeks after initial 
documentation.  Disease progression in bone disease must be confirmed at least 6 weeks 
later, as per PCWG3.  The allowable time window for tumor assessments is 7 days.  See 
Appendix 5 for the timing of confirmatory imaging requirements.
Details of treatment after initial evidence of radiological disease progression are provided in 
Section 5.4.7.
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.  All radiographic images will be collected and stored by an 
independent third-party imaging laboratory, according to instructions provided in the 
Imaging Manual.
7.7. Blood Tests for Tumor Markers
7.7.1. CA-125 for Patients with Ovarian Cancer
For patients with ovarian cancer, blood will be collected at the time points described in the 
Schedule of Activities and analyzed at local laboratories for cancer antigen 125 (CA-125) 
testing to monitor the patient’s disease.  Elevated CA-125 test results should trigger a 
radiological tumor assessment due to suspected disease progression.
7.7.2. Prostate-Specific Antigen for Patients with mCRPC
For patients with mCRPC, blood will be collected at the time points described in the 
Schedule of Activities and analyzed at local laboratories for prostate-specific antigen (PSA) 
to monitor the patient’s disease.  Elevated PSA test results should trigger a radiological 
tumor assessment due to suspected disease progression.
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) SAE Report Form to Pfizer Safety.  These 
requirements are delineated for 3 types of events: (1) SAEs; (2) non-serious 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 suspected causal relationship to the 
investigational product 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 
patient 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 
study.


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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 patient.  In addition, each study patient 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/EOT 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 patient 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 patient begins from the time the patient provides informed consent, which 
is obtained before the patient’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 patients 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 patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient 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 
product must be reported to Pfizer Safety.
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.


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If a patient begins a new anti-cancer 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 anti-cancer 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 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient 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;


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
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.
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.


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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
An SAE 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 patient 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; 
or development of drug dependency or drug abuse.
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 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.


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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, patient 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 
cosmetic surgery);

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 patient;

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 
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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 patient'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. 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 patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 × ULN should be 
monitored more frequently to determine if they are an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or 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 patient’s 
individual baseline values and underlying conditions.  Patients 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:


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
Patients 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 patients 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 patient 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.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase, direct and indirect bilirubin, 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 liver function test (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 
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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.
8.4.2. 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.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an 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).

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 patient or patient’s partner becomes or is found to be pregnant during the patient’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 patient 
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).


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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 patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The Investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.2.2. 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.
8.4.2.3. 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 patient 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.


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8.4.3. Medication Errors
Other 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 patient, or at the wrong time, or at the wrong dosage strength.
Medication errors include:

Medication errors involving patient 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 patient.
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 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
This section describes the data analysis and statistical methods for each of the cohorts 
evaluated in this study and is further detailed in a statistical analysis plan (SAP), which will 
be maintained by the Sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.


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9.1. Analysis Sets 
9.1.1. Full Analysis Set
The full analysis set includes all enrolled patients who receive at least 1 dose of study 
treatment.  Patients will be classified according to the cohort assigned at enrollment.
9.1.2. Safety Analysis Set
The safety analysis set includes all enrolled patients who receive at least 1 dose of study 
treatment.  In this non-randomized study, the full analysis set and the safety analysis set are 
identical.
9.1.3. Evaluable for DLT Analysis Set
The DLT analysis set is a subset of the safety analysis set and includes all enrolled patients in 
the Phase 1b portion who are eligible for the study, receive at least one dose of the 
combination treatment, and either experience DLT during the first cycle (28 days) of 
treatment, or complete the DLT observation period for the first cycle of treatment. 
Patients without DLTs who withdraw from study treatment before receiving at least 75% of 
the planned dose of each of the investigational products in the combination in Cycle 1 for 
reasons other than toxicity which are attributable to the investigational products are not 
evaluable for DLT.  Additional patients will be enrolled in the specific cohort to replace 
patients who are not considered DLT evaluable.
9.1.4. Pharmacokinetics/Immunogenicity Analysis Set
9.1.4.1. Pharmacokinetics 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 lower limit of quantitation (LLQ) for 
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 for avelumab or talazoparib.
9.1.4.2. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/Nab sample collected for avelumab.
9.1.4.3. Biomarker Analysis Set
The biomarker analysis set includes all patients in the safety analysis set who have at least 
one screening biomarker assessment. CCI
CCI


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9.2. Statistical Methods and Properties
9.2.1. Phase 1b
Before expanding into Phase 2, the safety must be confirmed in the first 12 patients evaluable 
for DLT treated at the same dose level. 
A safe dose will be determined using the adaptive mTPI design.  The mTPI design is flexible 
and allows dose reduction to doses in between the planned doses.
The mTPI design uses a Bayesian statistics framework and a beta/binomial hierarchical 
model to compute the posterior probability of 3 dosing intervals that reflect the relative 
difference between the toxicity rate of each dose level to the target probability (pT) rate 
(pT=0.25).  If the toxicity rate of the currently used dose level is far smaller than pT, the 
mTPI will recommend escalating the dose level; if it is close to pT, the mTPI will 
recommend continuing at the current dose; if it is far greater than pT, the mTPI will 
recommend de-escalating the dose level.  These rules are conceptually similar to those used 
by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model.  As shown by Ji and Wang, 
mTPI design is more efficient and safer than the 3+3 design.49 They considered 42 scenarios 
to cover a wide range of practical dose-response shapes, and concluded that the 3+3 design 
was more likely to treat patients at toxic doses above the MTD and less likely to identify the 
true MTD than the mTPI design.  For example, the 3+3 design exhibited a lower overall 
toxicity percentage than the mTPI design in only 1 of 42 scenarios.
Being a model-based design, mTPI automatically and appropriately tailors dose re-escalation 
and de-escalation decisions for different studies with different toxicity parameters.  More 
importantly, all the dose re-escalation/de-escalation decisions for a given study can be 
pre-calculated under the mTPI design and presented in a 2-way table.  Thus, compared to 
other advanced model-based designs published in the literature, the mTPI design is 
logistically less complicated and easier to implement.
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and overdosing in terms of toxicity.  Specifically, the 
underdosing interval is defined as (0, pT-e1), the overdosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions.  Based on the 
safety profile of talazoparib and avelumab, e1 is selected as 0.09, and e2 is selected as 0.08.  
Therefore, the target interval for the DLT rate is (0.16, 0.33).
The 3 dosing intervals are associated with 3 different dose-escalation decisions (see
Section 3.1.1.1).  The underdosing interval corresponds to a dose re-escalation (E), 
overdosing corresponds to dose de-escalation (D), and proper dosing corresponds to staying 
at the current dose (S).  Given a dosing interval and a probability distribution, the UPM of 
that dosing interval is defined as the probability of a patient belonging to that dosing interval 
divided by the length of the dosing interval.  The mTPI design calculates the UPMs for the 
3 dosing intervals, and the one with the largest UPM informs the corresponding dose-finding 
decision, which is the dose level to be used for future patients.  For example, if the 


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underdosing interval has the largest UPM, the decision will be to escalate, and the next 
cohort of patients will be treated at the next higher dose level.  Simulations have 
demonstrated that the decision based on UPM is optimal in that it minimizes a posterior 
expected loss (ie, minimizes the chance of making a wrong dosing decision).
The Phase 1b evaluation is completed when 12 DLT-evaluable patients have been treated at 
the highest dose levels associated with a DLT rate <0.33 or if the combinations are deemed 
too toxic, as determined by the DLT rate and/or lower than expected doses of the study 
treatments.
Early completion of Phase 1b may occur if 9 or more DLT-evaluable patients have been 
treated at the same dose level with no occurrence of DLT, as the DLT rate of <0.33 will be 
met.
9.3. Sample Size Determination
Due to the dynamic nature of the Bayesian allocation procedure, the exact sample size of the 
“Up-and-Down” matrix design using the mTPI design cannot be determined in advance.  It is 
expected that 12-36 patients will need to be enrolled in Phase 1b using the mTPI design.
Phase 2 expansion cohorts will enroll up to approximately 10, 20 or 40 patients 
(cohort-specific as shown in Figure 3.
Table 9 provides the exact binomial 90% CIs for ORR based on different observed responses 
in a cohort.
Table 9.
Sample Size and Exact 90% Confidence Intervals for ORR
N per Cohort
Number of Responders
Observed ORR
90% CI for ORR
10
1
10%
(0.5% - 39.4%)
2
20%
(3.7% - 50.7%)
3
30%
(8.7% - 60.7%)
4
40%
(15.0% - 69.6%)
5
50%
(22.2% - 77.8%)
6
60%
(30.4% - 85.0%)
20
1
5%
(0.3% – 21.6%)
2
10%
(1.8% – 28.3%)
3
15%
(4.2% – 34.4%)
4
20%
(7.1% – 40.1%)
5
25%
(10.4% – 45.6%)
6
30%
(14.0% – 50.8%)
7
35%
(17.7% – 55.8%)
8
40%
(21.7% – 60.6%)
9
45%
(25.9% – 65.3%)
10
50%
(30.2% – 69.8%)
12
60%
(39.4% – 78.3%)
15
75%
(54.4% – 89.6%)
40
2
5%
(0.9% – 14.9%)
4
10%
(3.5% – 21.4%)
6
15%
(6.7% – 27.5%)
8
20%
(10.4% – 33.2%)


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Table 9.
Sample Size and Exact 90% Confidence Intervals for ORR
N per Cohort
Number of Responders
Observed ORR
90% CI for ORR
10
25%
(14.2% – 38.7%)
12
30%
(18.3% – 44.0%)
14
35%
(22.6% – 49.2%)
16
40%
(26.9% – 54.2%)
18
45%
(31.5% – 59.1%)
20
50%
(36.1% – 63.9%)
24
60%
(45.8% – 73.1%)
30
75%
(61.3% – 85.8%)
35
87.5%
(75.5% – 94.9%)
Abbreviations: CI=confidence interval; ORR=objective response rate
9.3.1. Cohorts A1 and A2
Cohorts A1 and A2 will enroll patients with NSCLC. 
Cohort A1: Up to approximately 40 patients will be enrolled. 
Cohort A2: Up to approximately 20 patients who are anti-PD-L1 resistant and DDR Defect 
+ will be enrolled. 
With approximately 40 patients in a cohort, ORR can be estimated with a maximum standard 
error of 0.079. 
9.3.2. Cohorts B1 and B2
Cohort B1 will enroll up to approximately 20 patients with TNBC and Cohort B2 will enroll 
up to approximately 20 patients with HR+/HER2- breast cancer and DDR Defect +.
With approximately 20 patients in a cohort, ORR can be estimated with a maximum standard 
error of 0.112. 
9.3.3. Cohorts C1 and C2
Cohorts C1 and C2 will enroll patients with platinum-sensitive recurrent ovarian cancer.  Up 
to approximately 20 patients with a BRCA defect will be enrolled.  With approximately 
20 patients, ORR can be estimated with a maximum standard error of 0.112. 
9.3.4. Cohort D
Up to approximately 40 patients with UC will be enrolled.  With approximately 40 patients, 
ORR can be estimated with a maximum standard error of 0.079.
9.3.5. Cohorts E1 and E2
Cohorts E1 and E2 will enroll patients with mCRPC.
Cohort E1: Up to approximately 20 patients will be enrolled. 


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Cohort E2: Up to approximately 20 patients with DDR Defect + will be enrolled. 
With approximately 20 patients in a cohort, ORR can be estimated with a maximum standard 
error of 0.112.
9.3.6. Cohort F
Up to approximately 10 patients will be enrolled in Cohort F.  With 10 patients, ORR can be 
estimated with a maximum standard error of 0.158.
9.4. Efficacy Analysis
All efficacy analyses will be performed based on the full analysis set, separately by dose 
level and for all dose levels combined in Phase 1b and by cohort in Phase 2.
In the definitions below, start date refers to the date of first dose of study treatment for all 
cohorts.
Summaries for efficacy endpoints in patients with mCRPC in Cohort F will be tabulated only 
if >3 patients with mCRPC in Cohort F receive study drug.
9.4.1. Analysis of the Primary Endpoint
The primary endpoint for Phase 2 is confirmed OR.  The definitions and analyses below 
apply to patients with locally advanced or metastatic solid tumors in Phase 1b.

For patients with solid tumors, except mCRPC (Cohorts A1, A2, B1, B2, C1, C2, D,
and F):
OR is defined as a CR or PR per RECIST v1.1 by Investigator from the first dose of study 
treatment until disease progression or death due to any cause.  Both CR and PR must be 
confirmed by repeat assessments performed no less than 4 weeks after the criteria for 
response are first met.  ORR is defined as the proportion of patients with a confirmed CR or 
PR per Investigator’s assessment according to RECIST v1.1.  Confirmed responses are those 
that persist on repeat tumor assessments for at least 4 weeks after initial documentation or 
response.  Otherwise, the patient will be counted as a non-responder in the assessment of 
ORR.  Additionally, patients with inadequate data for tumor assessment (eg, no baseline 
assessment or no follow-up assessments) will be considered as non-responders in the 
assessment of ORR.  The two-sided exact 90% and 95% CIs for ORR will be calculated.

For patients with mCRPC (Cohorts E1, E2, and F):
OR is defined as the proportion of patients with a best overall soft tissue response of CR or 
PR per RECIST v1.1 by Investigator from the first dose of study treatment until disease 
progression or death due to any cause.  Soft tissue responses will be confirmed by a 
follow-up radiographic assessment at least 4 weeks later with a repeated CT or MRI with no 
evidence of confirmed bone disease progression per PCWG3 criteria by Investigator.  The 
radiographic assessment of soft tissue disease will use RECIST v1.1 (see Appendix 3), and 
bone disease will be evaluated per PCWG3 (see Appendix 5).43


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9.4.2. Analysis of the Secondary Endpoints
For patients with solid tumors, except mCRPC (Cohorts A1, A2, B1, B2, C1, C2, D, and F):

TTR is defined for patients with confirmed objective response (CR or PR) as the time 
from the first dose of study treatment to the first documentation of objective tumor 
response.

DR is defined for patients with confirmed objective response (CR or PR) as the time 
from the first documentation of objective tumor response to the first documentation of 
objective tumor progression or to death due to any cause, whichever occurs first.  
Censoring for DR will follow that described below for PFS.

PFS is defined as the time from the first dose of study treatment to the date of disease 
progression by RECIST v1.1 or death due to any cause, whichever 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 2 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 start date 
unless death occurred on or before the time of the second planned tumor assessment 
in which case the death will be considered an event.

OS is defined as the time from the first dose of study treatment to the date of death.  
Patients without an event (death) will be censored at the date of last contact.

TTR will be summarized using simple descriptive statistics (eg, median and range).  
DR, PFS, and OS will be analyzed using Kaplan-Meier methods and descriptive 
statistics.  Point estimates will be presented with their 90% and 95% CIs. 
For patients with mCRPC (Cohorts E1, E2, and F):

TTR is defined as the time from the first dose of study treatment to the first objective 
evidence of soft tissue response with no evidence of confirmed bone disease 
progression on bone scan per PCWG3.  Soft tissue response is defined as a BOR of 
CR or PR as assessed by Investigator using RECIST v1.1.  The response must be 
confirmed at least 4 weeks later with a repeated CT/MRI. 

DR is defined for patients with confirmed objective response (CR or PR) as the time 
from the first objective evidence of soft tissue response (subsequently confirmed) as 
assessed by Investigator using RECIST v1.1 and no evidence of confirmed bone 
disease progression by PCWG3 to the first subsequent objective evidence of 
radiographic progression or death due to any cause, whichever occurs first.  
Radiographic progression is defined as soft tissue progression as assessed by 
Investigator using RECIST v1.1 or bone disease progression as assessed by 
Investigator using PCWG3 (see Appendix 5). 


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
PFS is defined as the time from the first dose of study treatment to documentation of 
radiographic progression in soft tissue as assessed by Investigator using 
RECIST v1.1, in bone as assessed by Investigator using PCWG3, or death, whichever 
occurs first (see Appendix 5).  Details associated with censoring will be presented in 
the SAP.

PSA response is defined as the proportion of patients with confirmed PSA decline 
50% compared to baseline.  PSA response will be calculated as a decline from 
baseline PSA (ng/mL) to the maximal PSA response with a threshold of 50%.  A PSA 
response must be confirmed by a second consecutive value at least 3 weeks later.  The 
proportion of patients with confirmed PSA decline 50% compared with baseline will 
be calculated along with the 90% and 95% CIs. 

Time to PSA progression for patients with mCRPC is defined as the time from the 
first dose to the date that a 25% increase in PSA with an absolute increase of 
2 g/L (2 ng/mL) above the nadir (or baseline for patients with no PSA decline) is 
documented, confirmed by a second consecutive PSA value obtained 3 weeks 
(21 days) later.  Details associated with censoring will be presented in the SAP.

OS is defined as the time from the first dose of study treatment to the date of death.  
Patients without an event (death) will be censored at the date of last contact.

TTR will be summarized using simple descriptive statistics (eg, median and range).  
DR, PFS, time to PSA progression and OS will be analyzed using Kaplan Meier 
methods and descriptive statistics.  Point estimates will be presented with their 
90% and 95% CIs. 
For patients with ovarian cancer (Cohorts C1 and C2):

CA-125 response is defined as at least a 50% reduction in CA-125 levels from 
baseline.  The response must be confirmed and maintained for at least 28 days. 
9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of Pharmacokinetics of Investigational Products
Pharmacokinetic data analyses will include pre-dose and post-dose sampling for serum 
avelumab and plasma talazoparib concentrations on Days 1 and 15 of Cycle 1 and on 
Day 1 of Cycles 2-4 for both talazoparib and avelumab, and additionally on Day 1 of 
Cycles 6, 9, 12, 18, and 24 for avelumab only.  PK data analyses will include descriptive 
summary statistics of the pre-dose/trough (Ctrough) concentrations for both investigational 
products and post-dose (for talazoparib) or maximum (Cmax) concentrations (for avelumab) 
for each cycle by dose level in Phase 1b and by cohort in Phase 2.  Other PK parameters may 
be determined if deemed appropriate.  Additional summary statistics will be presented for 
avelumab across all treatment groups by study phase as well as combined across both study 
phases.  For talazoparib, summary statistics will also be presented combined for all patients 
in Phase 2, as well as combined across all patients in Phase 2 with patients in the RP2D dose 


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level in Phase 1b.  The summary data will be compared with the historical data of avelumab 
and talazoparib as single agents to assess the effect of avelumab on the PK of talazoparib and 
the effect of talazoparib on the PK of avelumab. 
The pre-dose/trough and post-dose/Cmax concentrations for avelumab and talazoparib will be 
plotted using box whisker plots by cycle and day within cycle for the subsets of data 
corresponding to the summary statistics described above.
9.5.3. Analysis of Biomarker Secondary 
Endpoints
All analyses of biomarkers will be performed based on the biomarker analysis set, separately 
by dose level and for all dose levels combined in Phase 1b and by cohort in Phase 2.
Biomarker data will include baseline 
expression levels of protein markers 
associated with target and immune cell phenotypes of interest including,
PD-L1 expression in tumor tissue, presence of defects in DDR-related genes, presence of 
genomic scarring, and TMB.
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline
 For discrete measurement 
biomarkers, frequencies and percentages of categorical biomarker measures will be 
determined at baseline
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Wilcoxon signed-rank test, Wilcoxon rank-sum test, correlation/linear 
regression, box-and-whisker plots, etc.  The statistical approaches will examine correlations 
of biomarker results with pharmacokinetic parameters and measures of efficacy, such as 
tumor response and progression free survival.
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9.5.4. Analysis of Immunogenicity Data of Avelumab
ADA/Nab data for avelumab will be listed and summarized by cycle.
The percentage of patients with positive ADA and Nabs each will be summarized by cohort 
and, if deemed appropriate, combined across all cohorts.  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 and pharmacokinetics may be 
evaluated, if data permit.  A comparison of safety and efficacy endpoints between avelumab 
ADA and Nab positive vs. negative patients may be performed, if data permit. 
9.6. Safety Analysis
All safety analyses will be performed based on the safety analysis set, separately by dose 
level in Phase 1b and by cohort in Phase 2 and for all patients in the Phase 1b and 
Phase 2 combined.
9.6.1. Analysis of the Primary Endpoint in Phase 1b
DLT is the primary endpoint for Phase 1b. 
Analyses of DLT are based on the DLT-evaluable set.  The occurrence of DLTs and AEs 
constituting DLTs will be summarized and listed per cohort, overall and by dose level, for 
patients enrolled in Phase 1b.
9.6.2. Adverse Events
AEs will be graded by the Investigator according to the CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on TEAEs, those with initial onset or increasing in severity after the first dose of study 
treatment.  The number and percentage of patients who experienced any AE, SAE, 
treatment-related AE, and treatment-related SAE will be summarized according to worst 
toxicity grades.
9.6.3. Laboratory Test Abnormalities
The laboratory results will be graded according to the CTCAE v4.03 severity grade whenever 
applicable.  The number and percentage of patients who experienced laboratory test 
abnormalities will be summarized according to worst toxicity grade observed for each 
laboratory test.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory toxicities.


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9.6.4. Electrocardiogram
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data.  Baseline is defined as pre-dose triplicate ECG assessment 
obtained on Day 1 of Cycle 1.  ECG measurements (an average of the triplicate 
measurements) will be used for the statistical analysis and all data presentations.  Any data 
obtained from ECGs repeated for safety reasons after the nominal time points will not be 
averaged along with the preceding triplicates.  Interval measurements from repeated 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, and QTc.  
Individual QT (all evaluated corrections) intervals will be listed by cohort and timepoint.  
The most appropriate correction factor will be selected and used for the following analyses of 
central tendency and outliers, and used for the study conclusions.
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment by cohort and time point.  The maximum change from baseline will be 
calculated as well as the maximum post-baseline interval across time-points.  Categorical 
analysis will be conducted for the maximum change from baseline in corrected QT and the 
maximum post baseline corrected QT interval.
Shift tables will be provided for baseline versus worst on treatment corrected QT (one or 
more correction method will be used) using maximum CTCAE Grade.  Shift tables will also 
be provided for ECG abnormality at baseline versus on treatment (yes, no, not done: [n, %]).  
Patients experiencing clinically relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of talazoparib and avelumab drug concentrations on corrected QT change from 
baseline will be explored graphically.  Additional concentration-corrected QT analyses may 
be performed. 
9.7. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed 
graphically, where appropriate.
9.8. Interim Analysis
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label study, the Sponsor may conduct unblinded reviews of the data during the course 
of the study for the purpose of safety assessment, facilitating dose-finding decisions, 
 and/or to support clinical development.
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9.9. Data Monitoring Committee 
This study will not use a data monitoring committee.
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.
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 patient'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 patient.  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 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 


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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. 
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 patients 
(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 ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
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 to 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 patients.  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. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study patients. The investigator 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent document 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 document 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 is fully informed about the nature and 
objectives of the study and possible risks associated with participation.
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The Investigator 
will retain the original of each patient'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.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last subject last visit (LSLV).
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 and/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.
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.


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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 (CSR 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 
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.


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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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Strickland KC, Howitt BE, Shukla SA, et al. Association and prognostic significance of 
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Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic 
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Karzai FH, Madan RA, Owens H, et al. A phase II study of the anti-programmed death 
ligand-1 antibody durvalumab in combination with PARP inhibitor olaparib in 
metastatic castration-resistant prostate cancer (mCRPC). Poster presented at: 2017 
Genitourinary Cancers Symposium; Feb 16-18, 2017; Orlando, FL. Abstract 162.
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Pahuja S, Appleman LJ, Belani CP, et al. Preliminary activity of veliparib (V) in 
BRCA2-mutated metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 
33, 2015 (suppl 7; abstr 170).
28.
Sandhu SK, Schelman WR, Wilding G, et al. The poly (ADP-ribose) polymerase 
inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic 
cancer: a phase 1 dose-escalation trial. Lancet Oncol 2013; 14(9):882-92.
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Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. 
Immunity 2013; 39(1):1-10.
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Wang H, Hu S, Chen X, et al. cGAS is essential for the antitumor effect of immune 
checkpoint blockade. Proc Natl Acad Sci U S A 2017 Feb 14; 114(7):1637-1642.
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Timms KM, Abkevich V, Hughes E, et al. Association of BRCA1/2 defects with 
genomic scores predictive of DNA damage repair deficiency among breast cancer 
subtypes. Breast Cancer Res 2014 Dec 5; 16(6):475. 
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Lheureux S, Lai Z, Dougherty BA, et al. Long-term responders on olaparib maintenance 
in high-grade serous ovarian cancer: Clinical and molecular characterization. Clin 
Cancer Res 2017 Feb 21. pii: clincanres.2615.2016. doi: 
10.1158/1078-0432.CCR-16-2615. [Epub ahead of print].
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Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in 
platinum-sensitive, recurrent ovarian cancer. N Engl J Med 2016 Dec 1; 
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Saleh K, Khalifeh-Saleh N, Kourie HR. Is it possible to rechallenge with PD-1/PD-L1 
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Blockade.Am J Clin Dermatol 2018 Sep 26. [Epub ahead of print]
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monoclonal antibodies in adult clinical trials. J Clin Pharmacol 2009 Sep; 
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39.
Gangadhar TC, Mehnert J, Patnaik A, et al. Population pharmacokinetic (popPK) model 
of pembrolizumab (pembro; MK-3475) in patients (pts) treated in KEYNOTE-001 and 
KEYNOTE-002. J Clin Oncol 33, 2015 (suppl; abstr 3058).
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Zhao X, Suryawanshi S, Hruska M, et al. Assessment of nivolumab (Nivo) benefit-risk 
profile from a 240-mg flat dose versus a 3-mg/kg dosing regimen in patients (Pts) with 
solid tumors. Ann Oncol 2016;27(suppl_6):1098P.
41.
Ganguly B, Dolfi SC, Rodriguez-Rodriguez L, et al. Role of biomarkers in the 
development of PARP inhibitors. Biomark Cancer 2016; 8(Suppl 1):15-25.
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chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016; 
375(19):1823-1833.
43.
Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for 
castration-resistant prostate cancer: updated recommendations from the Prostate Cancer 
Clinical Trials Working Group 3. J Clin Oncol 2016 Apr 20; 34(12):1402-18.
44.
Goodin S, Griffith N, Chen B, et al. Safe handling of oral chemotherapeutic agents in 
clinical practice: recommendations from an international pharmacy panel. J Oncol Pract 
2011 Jan; 7(1):7-12.
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Recommendations for the use of WBC growth factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. J Clin Oncol 2015; 33(28): 3199-3212.
46.
Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T-cell-mediated cytotoxicity by 
anti-inflammatory steroids. J Immunol 1984; 132:266-71.
47.
Khan MM, Immunosuppressive Agents. In: Immunopharmacology. New York: 
Springer; 2008.
48.
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events 
and kinetics of response with ipilimumab. J Clin Oncol 2012 Jul 20; 30(21):2691-7.
49.
Ji Y and Wang S-J. Modified Toxicity Probability Interval Design: A Safer and More 
Reliable Method Than the 3 + 3 Design for Practical Phase I Trials. J Clin Oncol 2013; 
31(14):1785-1791.
50.
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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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J of Cancer 2009; 45(2):228-47.


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Appendix 1. Abbreviations and Definitions of Terms
The following is a list of abbreviations that are used in the protocol.
ACTH
Adrenocorticotropic Hormone
ADA
Anti-Drug Antibody
ADME
Absorption, Distribution, Metabolism, and Excretion
ADP
Adenosine Diphosphate
AE
Adverse Event
AIDS 
Acquired Immune Deficiency Syndrome
ALK
Anaplastic Lymphoma Kinase
ALT 
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
ATM
Ataxia-Telangiectasia Mutated
ATR
Ataxia-Telangiectasia and Rad3-Related
AUC
Area Under the Plasma Concentration-Time Curve
BBS
Biospecimen Banking System
BCRP
Breast Cancer Resistance Protein
BOR
Best Overall Response
BP
Blood Pressure
BRAF
B-Raf Proto-Oncogene, Serine/Threonine Kinase
BRCA
BReast CAncer Susceptibility Gene
BUN 
Blood Urea Nitrogen
C1D1
Cycle 1 Day 1
CA-125
Cancer Antigen 125
CDK
Cyclin-Dependent Kinase
CI
Confidence Interval
CrCl
Creatinine Clearance
CL/F
Apparent Oral Clearance
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum Plasma Concentration
Ctrough
Mean Plasma Trough Concentration 
CR
Complete Response
CRF
Case Report Form
CRP
C-Reactive Protein
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography
CTA
Clinical Trial Application
CTCAE 
Common Terminology Criteria for Adverse Events
ctDNA
Circulating Tumor DNA
CYP450
Cytochrome P450
D
Dose


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DDI
Drug-Drug Interaction
DDR
DNA Damage Repair
DILI
Drug-Induced Liver Injury
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
DU
Dispensable Unit
E
Escalation/ Re-Escalation
EC
Ethics Committee
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure During Pregnancy
EDTA
Ethylene Diamene Tetra-acetic Acid
EGFR
Epidermal Growth Factor Receptor
EOT
End of Treatment
ER
Estrogen Receptor
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FANC
Fanconi Anemia Complementation
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin-Fixed Paraffin-Embedded 
FSH
Follicle-Stimulating Hormone
GCP 
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GITR
Glucocorticoid Induced TNF Receptor
GnRH
Gonadotropin-Releasing Hormone
GVHD
Graft Versus Host Disease
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HER2
Human Epidermal Growth Factor Receptor 2
HIV 
Human Immunodeficiency Virus
HR+
Hormone Receptor Positive
HRD
Homologous Recombination Deficiency
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ICOSL
Inducible Costimulator Ligand
ID
Identification
IDO
Indoleamine 2,3-Dioxygenase
IERC
Independent Endpoint Review Committee
IFN
Interferon
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL-2
Interleukin-2
IND
Investigational New Drug
INR 
International Normalized Ratio


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IP
Investigational Product
irAE
Immune-Related Adverse Event
IRB 
Institutional Review Board
IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
IV
Intravenous
K2EDTA
Dipotassium Ethylenediaminetetraacetic Acid
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLQ
Lower Limit of Quantitation
LOH
Loss of Heterozygosity
LSLV
Last Subject Last Visit
mAb
Monoclonal Antibody
MAD
Maximum Administered Dose
MCC
Merkel Cell Carcinoma
mCRPC
Metastatic Castration-Resistant Prostate Cancer
M-CSF
Macrophage-Colony Stimulating Factor
MDS
Myelodysplastic Syndrome
MedDRA
Medical Dictionary for Regulatory Activities
MHC
Major Histocompatibility Compex
mPDAC
Metatstatic Pancreatic Ductal Adenocarcinoma
MRI 
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
mTOR
Mammalian Target of Rapamycin
mTPI
Modified Toxicity Probability Interval
NA
North America
N/A
Not Applicable
Nab
Neutralizing Antibody
NCI 
National Cancer Institute
NE
Not Estimable
NEMO
NF-κB essential modulator
NHL
Non-Hodgkin’s Lymphoma
NK
Natural Killer
NKG2DL
Natural Killer Group 2 Member D Ligand
NKT
Natural Killer T-cell
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PARP
Poly (ADP-Ribose) Polymerase
PBMC
Peripheral Blood Mononuclear Cell
PCD
Primary Completion Date
PCWG3
Prostate Cancer Working Group 3
PD
Progressive Disease 
PD-1
Programmed Death-1


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PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PET
Positron Emission Tomography
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PI
Principal Investigator
PK
Pharmacokinetics
PMAP
Pharmacometric analysis plan
PR
Partial Response
PSA
Prostate-Specific Antigen
PT
Prothrombin Time
PTEN
Phosphatase and Tensin Homolog Gene
PTT
Partial Thromboplastin Time
Q2W
Every 2 Weeks
QD
Once Daily
RCC
Renal Cell Carcinoma
RE
Re-escalation
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic Acid
ROS1
c-Ros Oncogene 1
RP2D
Recommended Phase 2 Dose
S
Stay (at current dose)
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCLC
Small Cell Lung Cancer
SD
Stable Disease
SRSD
Single Reference Safety Document
STING
Stimulation of Interferon Genes
t1/2
Terminal Half-Life
TBili
Total Bilirubin
TDO
Tryptophan 2,3-Dioxygenase
TEAE
Treatment Emergent Adverse Event
Tmax
Time to Maximum Plasma Concentration
TMB
Tumor mutational burden 
TNBC
Triple-Negative Breast Cancer
TO
Target Occupancy
TPS
Tumor Proportion Score
TSH
Thyroid Stimulating Hormone
TTR
Time-to-Tumor Response
UC
Urothelial Cancer
ULN 
Upper Limit of Normal
UPM
Unit Probability Mass
US
United States
VEGF
Vascular Endothelial Growth Factor
Vss/F
Apparent Steady-State Volume of Distribution
CCI
CCI


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V/F
Apparent Volume of Distribution
WBC 
White Blood Cell
WHO
World Health Organization


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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 selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  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: 649–655.50


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Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines
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) 228–247.51
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 <15 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 post-baseline. 

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’).


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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 
should be discussed with the radiologist and the Sponsor to determine if substitution is 
possible.  If not, subsequent objective statuses are not evaluable. 
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 consider 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. 

Not evaluable (NE): Progression has not been documented, and 

one or more target 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 
(if being followed).  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 (if 
being followed) above the normal limits.


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
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.

Not evaluable (NE): Progression has not been determined and one or more non-target 
lesion sites have not been assessed or assessment methods used 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. 
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 EOT CRF as off treatment due to Global Deterioration of Health Status.  
Every effort should be made to document PD even after discontinuation of study 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 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 
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 start of the treatment at a minimum interval of 
6 weeks.


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Appendix 4. Detailed Dose Escalation/De-Escalation Scheme for mTPI Design
E = Escalate to the next higher dose (if a higher dose level is available); otherwise remain at the current dose.
S = Stay at the current dose.
D = De-escalate to the next lower dose level (if a lower dose level is available).
U = The current dose is unacceptably toxic and it will not be tested further.
Target DLT rate at MTD = 0.25.
Escalation/De-escalation algorithms for total number of patients treated at the current 
dose level (current and previous cohorts):

With 3 patients treated at current dose level:

0 DLT escalate;

1 DLT remain at the same dose;

2 DLTs de-escalate ;

3 DLTs de-escalate and consider current dose as intolerable.

With 4 patients treated at current dose level:

0 DLT escalate;

1 DLTs remain at the same dose;


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
2 DLTs de-escalate;

3-4 DLTs de-escalate and consider current dose as intolerable.

With 5 patients treated at current dose level:

0 DLT escalate;

1-2 DLTs remain at the same dose;

3-5 DLTs de-escalate and consider current dose as intolerable.

With 6 patients treated at current dose level:

0 DLT escalate;

1-2 DLTs remain at the same dose;

3 DLTs de-escalate;

4-6 DLTs de-escalate and consider current dose as intolerable.

With 7 patients treated at current dose level:

0 DLT escalate;

1-3 DLTs remain at the same dose;

4-7 DLTs de-escalate and consider current dose as intolerable.

With 8 patients treated at current dose level:

0-1 DLT escalate;

2-3 DLTs remain at the same dose;

4-8 DLTs de-escalate and consider current dose as intolerable.

With 9 patients treated at current dose level:

0-1 DLT escalate;

2-3 DLTs remain at the same dose;

4 DLTs de-escalate;

5-9 DLTs de-escalate and consider current dose as intolerable.


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
With 10 patients treated at current dose level:

0-1 DLT escalate;

2-4 DLTs remain at the same dose;

5-10 DLTs de-escalate and consider current dose as intolerable.

With 11 patients treated at current dose level:

0-1 DLT escalate;

2-4 DLTs remain at the same dose;

5 DLTs de-escalate;

6-11 DLTs de-escalate and consider current dose as intolerable.

With 12 patients treated at current dose level:

0-1 DLTs escalate;

2-5 DLTs remain at the same dose;

6-12 DLTs de-escalate and consider current dose as intolerable.


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Appendix 5. Assessment of Radiographic Response and Progression in Patients with 
mCRPC
Radiographic imaging for patients with mCRPC is categorized as soft tissue or bone.  Soft 
tissue imaging may include CT scans of the chest, abdomen and pelvis or MRIs of the 
abdomen and pelvis).  Bone imaging must be whole body radionuclide bone scan.
The Investigator will assess response of soft tissue disease by RECIST v1.1 (see 
Appendix 3).  However, bone disease will not be considered as non-target lesions assessed by 
RECIST v1.1.  An objective response is defined as a best overall response of CR or PR per 
RECIST v1.1 and must be confirmed on repeated imaging at least 4 weeks after initial 
documentation. 
Bone disease will be assessed for progressive disease only by PCWG3.43 The documentation 
required for the determination of radiographic progression is shown in the table below.
Criteria for Evidence of Radiographic Progression
Date 
Progression 
Detecteda
Criteria for Progression
Criteria to Confirm 
Progression
Criteria to Document Disease 
Progression on Confirmatory 
Scan
Week 8
Bone lesions: 2 or more 
new lesions compared to 
screening bone scan by 
PCWG3
Timing: At least 6 weeks 
after progression identified 
or at Week 16 visitb  
2 or more new bone lesions on 
bone scan compared to 
Week 8 scan
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression
Week 16 or 
later
Bone lesions: 2 or more 
new lesions on bone scan 
compared to Week 8 bone 
scan
Timing: At least 6 weeks 
after progression identified 
or at next imaging time 
pointb
Persistent or increase in 
number of bone lesions on 
bone scan compared to prior 
scanc
Soft tissue lesions: 
Progressive disease on CT 
or MRI by RECIST v1.1
No confirmatory scan 
required for soft tissue 
disease progression
No confirmatory scan required 
for soft tissue disease 
progression 
a.
Progression detected by bone scan at an unscheduled visit either before Week 8 or between scheduled visits will 
require a confirmatory scan at least 6 weeks later and should follow confirmation criteria outlined in the table for the 
next scheduled scan. 
b.
Confirmation must occur at the next available scan. 
c.
For confirmation, at least 2 of the lesions first identified as new must be present at the next available scan 
(confirmation scan).  
Disease progression in bone disease must be confirmed at least 6 weeks later, as per PCWG3.  
See table below for the timing of confirmatory imaging requirements.


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Confirmatory Imaging Requirements for Patients with mCRPC Based on 
RECIST v1.1 and PCWG3
Disease Site
Response
Progressiona
Soft tissue
Must be confirmed at least 
4 weeks later 
No confirmation required 
Bone
Not applicable
Must be confirmed at least 6 weeks 
later 
a.
To inform permanent treatment discontinuation.
Radiographic PFS is defined as the time from enrollment to documentation of radiographic 
progression in soft tissue by Investigator’ assessment according to RECIST v1.1, in bone by 
Investigator’s assessment according to PCWG3, or death, whichever occurs first.

SAP_001.pdf: 
Avelumab
B9991025 (MSB0010718C, MDV3800) Statistical Analysis Plan    
PFIZER CONFIDENTIAL
Page 1
A PHASE 1B/2 STUDY TO EVALUATE SAFETY AND ANTI-TUMOR ACTIVITY 
OF AVELUMAB IN COMBINATION WITH THE POLY (ADENOSINE 
DIPHOSPHATE [ADP]-RIBOSE) POLYMERASE (PARP) INHIBITOR 
TALAZOPARIB IN PATIENTS WITH LOCALLY ADVANCED OR METASTATIC 
SOLID TUMORS
JAVELIN PARP MEDLEY
STATISTICAL ANALYSIS PLAN – B9991025
Compounds:
MSB0010718C
MDV3800, BMN 673
Compound Name:
Avelumab
Talazoparib
Version:
3.0
Date:
16-Dec-2021
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, 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.


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Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................6
APPENDICES ...........................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION ...............................................................................................................10
2.1. Study Objectives .....................................................................................................10
2.2. Study Design ...........................................................................................................11
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................13
3.1. Primary Endpoints...................................................................................................13
3.2. Secondary Endpoints...............................................................................................14
3.2.1. Safety endpoints..........................................................................................14
3.2.2. Efficacy endpoints ......................................................................................15
3.2.3. Pharmacokinetic endpoints.........................................................................15
3.2.4. Immunogenicity endpoints .........................................................................16
3.2.5. Biomarker endpoints...................................................................................16
3.4. Baseline Variables...................................................................................................17
3.4.1. Study drug, study treatment and baseline definitions.................................17
3.4.2. Baseline characteristics...............................................................................18
3.5. Safety Endpoints .....................................................................................................19
3.5.1. Adverse events............................................................................................19
4. ANALYSIS SETS ...............................................................................................................19
4.1. Full Analysis Set .....................................................................................................19
4.2. Safety Analysis Set..................................................................................................19
4.3. Other Analysis Set...................................................................................................19
4.3.1. DLT-evaluable set ......................................................................................19
4.3.2. PK analysis sets ..........................................................................................20
4.3.3. Biomarker analysis set................................................................................20
4.3.4. Immunogenicity analysis set.......................................................................20
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................20
5.1. Hypotheses and Decision Rules ..............................................................................20
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5.1.1. Hypotheses and sample size determination................................................20
5.1.2. Decision rules .............................................................................................21
5.2. General Methods .....................................................................................................23
5.2.1. Data handling after the cut-off date............................................................24
5.2.2. Pooling of centers .......................................................................................24
5.2.3. Presentation of continuous and qualitative variables..................................25
5.2.4. Definition of study day...............................................................................25
5.2.5. Definition of start of new anti-cancer drug therapy....................................25
5.2.6. Definition of start of new anti-cancer therapy............................................25
5.2.7. Definition of on-treatment period...............................................................26
5.2.8. Standard derivations and reporting conventions.........................................26
5.2.9. Unscheduled visits......................................................................................27
5.2.10. Adequate baseline tumor assessment........................................................27
5.2.11. Adequate post-baseline tumor assessment................................................27
5.3. Methods to Manage Missing Data ..........................................................................27
5.3.1. Missing data................................................................................................27
5.3.1.1. Pharmacokinetic concentrations................................................27
5.3.1.2. Pharmacokinetic parameters .....................................................28
5.3.2. Handling of incomplete dates .....................................................................28
5.3.2.1. Disease history ..........................................................................28
5.3.2.2. Adverse events ..........................................................................28
5.3.2.3. Prior and concomitant medications...........................................29
5.3.2.4. Exposure....................................................................................30
5.3.3. Imputation rules for date of last contact and efficacy assessments ............30
5.3.3.1. Date of last contact....................................................................30
5.3.3.2. Death date..................................................................................30
5.3.3.3. Tumor assessments....................................................................31
5.3.3.4. Date of start of new anti-cancer therapy ...................................31
6. ANALYSES AND SUMMARIES ......................................................................................33
6.1. Primary Endpoints...................................................................................................33
6.1.1. DLT for Phase 1b........................................................................................33
6.1.1.1. Primary analysis ........................................................................33
6.1.2. Objective response as assessed by the Investigator per RECIST v1.1.......33


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6.1.2.1. Primary analysis ........................................................................33
6.2. Secondary Endpoint(s) ............................................................................................36
6.2.1. Safety endpoints..........................................................................................36
6.2.2. Efficacy endpoints ......................................................................................36
6.2.2.1. Tumor shrinkage from baseline.................................................37
6.2.2.2. Duration of response .................................................................37
6.2.2.3. Time to response .......................................................................40
6.2.2.4. Progression-free survival...........................................................40
6.2.2.5. Overall Survival ........................................................................45
6.2.2.6. Time to PSA progression for patients with metastatic 
CRPC.................................................................................................45
6.2.2.7. PSA response for patients with metastatic CRPC.....................47
6.2.2.8. CA-125 response for patients with ovarian cancer ...................47
6.2.3. Pharmacokinetic endpoints.........................................................................48
6.2.4. Population pharmacokinetic endpoints.......................................................48
6.2.5. Biomarker endpoints...................................................................................49
6.2.6. Endpoints for immunogenicity data of avelumab and talazoparib.............50
6.4. Subset Analyses.......................................................................................................52
6.5. Baseline and Other Summaries and Analyses.........................................................52
6.5.1. Baseline summaries ....................................................................................52
6.5.1.1. Demographic characteristics .....................................................52
6.5.1.2. Medical history..........................................................................54
6.5.1.3. Disease characteristics...............................................................54
6.5.1.4. Prior anti-cancer therapies.........................................................54
6.5.2. Study conduct and patient disposition........................................................55
6.5.2.1. Patient disposition .....................................................................55
6.5.2.2. Protocol deviations....................................................................56
6.5.3. Study treatment compliance and exposure .................................................56
6.5.3.1. Exposure to avelumab ...............................................................57
6.5.3.2. Exposure to Talazoparib............................................................58
6.5.3.3. Dose reductions.........................................................................58
6.5.3.4. Dose interruptions .....................................................................58
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6.5.3.5. Dose delays ...............................................................................59
6.5.3.6. Infusion rate reductions.............................................................60
6.5.3.7. Infusion interruptions ................................................................60
6.5.4. Concomitant medications and non-drug treatments ...................................60
6.5.5. Subsequent anti-cancer therapies................................................................60
6.6. Safety Summaries and Analyses .............................................................................61
6.6.1. Adverse events............................................................................................61
6.6.1.1. All adverse events .....................................................................62
6.6.1.2. Adverse events leading to dose reduction.................................63
6.6.1.3. Adverse events leading to discontinuation of study 
treatment............................................................................................63
6.6.2. Deaths .........................................................................................................63
6.6.3. Serious adverse events................................................................................64
6.6.4. Other significant adverse events.................................................................64
6.6.5. Laboratory data...........................................................................................65
6.6.5.1. Hematology and chemistry parameters.....................................65
6.6.5.2. Other laboratory parameters......................................................67
6.6.6. Electrocardiogram.......................................................................................68
7. INTERIM ANALYSES.......................................................................................................69
7.1. Introduction .............................................................................................................69
7.2. Interim Analyses and Summaries............................................................................69
8. REFERENCES ....................................................................................................................70
9. APPENDICES .....................................................................................................................71
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................7
Table 2.
PK Parameters to be Determined for Avelumab and Talazoparib ...........16
Table 3.
Biomarker Definition and Determination.................................................16
Table 4.
Sample Size and Exact 90% Confidence Intervals for ORR in each 
Treatment Group.......................................................................................21
Table 5.
Study Summaries and Tabulations ...........................................................24
Table 6.
Outcome and Event Dates for DR Analyses for non-CRPC Patients.......38
Table 7.
Outcome and Event Dates for DR Analyses for CRPC Patients..............39


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Table 8. 
DR Censoring Reasons and Hierarchy .....................................................40
Table 9.
Outcome and Event Dates for PFS Analyses for non-CRPC Patiens.......42
Table 10.
PFS Censoring Reasons and Hierarchy....................................................43
Table 11.
Outcome and Event Dates for PFS Analyses for CRPC Patiens..............44
Table 12.
OS Censoring Reasons and Hierarchy......................................................45
Table 13.
Outcome and Event Dates for Time to PSA progression analysis ...........46
Table 14. 
Patients Characterized Based on Anti-Drug Antibody Results 
(ADA Status) ............................................................................................50
Table 15. 
Patients Characterized Based on Neutralizing Antibody Results 
(nAb Status)..............................................................................................51
Table 16.
Case Definition for irAEs .........................................................................71
Table 17.
Case Definition for IRRs – IV Study Drugs Administered Alone Or 
In Combination With Non-IV Study Drugs..............................................73
LIST OF FIGURES
Figure 1.
Phase 1b and Phase 2 Study Design Schema............................................12
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................71
Appendix 2. Infusion Related Reactions .................................................................................73
Appendix 3. Abbreviations and Definitions of Terms.............................................................74


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991025 is based on the protocol amendment 
03 dated 20NOV2018.  
Table 1.
Summary of Major Changes in SAP Amendments
Version
Version Date
Summary of Changes
3
16-Dec-2021
The following changes were implemented:
•
Section 2. “Introduction” – The definition of the primary analysis cutoff 
date was modified to allow longer patient follow-up.
•
Section 6.2.3. “Pharmacokinetic endpoints” – A criterion was added to 
clarify the exclusion from analyses of data for which time of collection 
cannot be confirmed.
•
Section 6.6.1.3. “Adverse events leading to interruption of study 
treatment” - The summary tables and listing of TEAEs leading to 
interruption of each study drug (avelumab, talazoparib) were deleted.
•
Section 6.6.1.1. “All adverse events” and Section 6.6.1.3. “Adverse 
events leading to discontinuation of study treatment” - The summary 
tables of TEAEs leading to permanent discontinuation of each study drug 
(avelumab, talazoparib) were deleted.
•
Section 6.6.4. “Other significant adverse events” - The summary tables 
of irAEs leading to discontinuation of each study drug (avelumab, 
talazoparib), any, and all drugs and the summary tables of IRRs leading 
to discontinuation of avelumab, and time related to first onset of an IRR 
were deleted.
•
Section 6.6.5.1. “Hematology and chemistry parameters” - The shift 
tables for the parameters with NCI-CTCAE grades available and the 
eDISH plot were deleted. The Hy’s Law criteria for the listing was 
corrected,
•
Section 6.6.6. “Vital signs” - The vital sign summaries by visit were 
deleted.
•
Section 6.6.6. “Electrocardiogram” – Pearson correlation was deleted.
2
22-Sep-2020
The following changes in the SAP were implemented in accordance to 
protocol amendment 3. 
• Section 2.1. “Study Objectives”,
analyses associated with irRECIST were deleted.
• Section 2.2. “Study Design”, Section 3.4.1. “Study drug, study treatment 
and baseline definitions”, Section 5.2. “General Methods” – Cohorts A2 
and B2 eligibility criteria was changed; cohort F was added. The target 
enrollment of Cohort A2 was reduced to up to approximately 20 as the 
patient population has changed and this cohort is now only exploratory, 
Cohort C1 size was reduced to up to approximately 20,
In addition, the following changes were implemented.
•
Section 3.2.3. “Pharmacokinetic endpoints” – ‘plasma’ was removed 
from Cmax definition as avelumab Cmax was measured in serum. Tmax 
will not be reported as Tmax is at the end of the avelumab IV infusion 
administration. The method of determining the actual time difference for 
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avelumab and talazoparib post-dose samples relative to dosing were 
clarified.

Section 3.4.2. “Baseline characteristics”, Section 5.2.8. “Standard 
derivations and reporting conventions”, Section 6.5.1.1. “Demographic 
characteristics” – the summary of physical measurements (BMI, height 
and weight) was deleted.

Section 3.5.1. “Adverse events – the definition of treatment-emergent 
adverse events was updated to include only adverse events that start 
during the on-treatment period.

Section 4.3.2. “PK analysis sets” – the definition of the PK parameter 
analysis set was clarified to be the same as the PK concentration analysis 
set..

Section 5.1.1. “Hypotheses and sample size determination” – sample size 
of 10 patients was added in Table 4 for Cohort F.

Section 5.1.1 “Hypotheses and sample size determination”, Section 6.2.3. 
“Pharmacokinetic endpoints” – since PK analysis will be run on all 
patients in Phase1b and Phase 2 combined, Table 5 was updated. 
Redundant explanations on the analyses were simplified. Analysis on 
patients who have undergone dose escalation was removed as it is not 
allowed per protocol. Drug-drug interactions will be analyzed using 
modeling approaches instead of comparison with the historical PK 
parameters with description moved to Section 6.2.4 “Population 
pharmacokinetic endpoints.

Section 5.1.1. “Hypotheses and sample size determination”, Section 
6.2.6. “Endpoints for immunogenicity data of avelumab and talazoparib” 
– immunogenicity analysis will be run on all patients in Phase 1b, in 
Phase 2 and in Phase1b and Phase 2 combined, Table 5 was updated.

Section 6.1.2. “Objective response as assessed by the Investigator per 
RECIST v1.1” – added "No evidence of disease at baseline" as a possible
reason for best overall response of NE as applicable to patients with 
mCRPC with no measurable disease and no non-target lesions at 
baseline.

Section 6.2.2.2. “Duration of response” – added details regarding 
censoring for duration of response since “no adequate baseline 
assessment” and “no adequate post-baseline assessment” which is used in 
censoring for PFS analyses is not applicable to analyses of duration of 
response for patients with objective response. The listing of duration of 
response time was removed.

Section 6.2.2.4. “Progression-free survival” - the summary of time of 
follow-up for PFS was simplified.

Section 6.2.2.5 “Overall survival” - the summary of time of follow-up for 
OS was simplified.

Section 6.2.2.7. “PSA response for patients with metastatic CRPC” – the 
plot of the percent change in PSA value from baseline and best 
percentage change in PSA value from baseline were added.

Section 6.2.3. “Pharmacokinetic endpoints” – redundant explanations on 
the analyses were simplified. Analysis on patients who have undergone 
dose escalation was removed as it is not allowed per protocol. Drug-drug 
interactions will be analyzed using modeling approaches instead of 
comparison with the historical PK parameters with description moved to 
Section 6.2.4 “Population pharmacokinetic endpoints.


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•
Section 6.2.5. “Biomarker endpoints”,
Table 5 – analysis on full analysis set was added 
to include the category of patients with unknown biomarker status.
•
Section 6.2.6. “Endpoints for immunogenicity data of avelumab and 
talazoparib” – ADA and nAb categories are described in Table 14 and 
Table 15. 
•
Section 6.5.1.3. “Disease characteristics” - the summary of substance use 
was removed.
•
Section 6.5.1.4. “Prior anti-cancer therapies”, Section 6.5.5. “Subsequent 
anti-cancer therapies” - the listings of anti-cancer radiation therapy and 
anti-cancer surgeries were removed.
•
Section 6.5.2.1. “Patient disposition” – a cross-tabulation of patient 
disposition was added.
•
Section 6.5.3.1. “Exposure to avelumab” - removed by-cycle summaries.
•
Section 6.5.3.4. “Dose interruptions” – the reason for dose interruption 
was removed from the analysis specifications.  
•
Section 6.5.4. “Concomitant medications and non-drug treatments” - the
summaries of prior medications and pre-medications and the listings of 
prior medications, concomitant medications, pre-medications and non-
drug treatments were removed.
•
Section 6.6.1 “Adverse events” and subsections – the following 
summaries were removed: adverse events leading to dose reduction of 
avelumab (avelumab dose reduction is not allowed per protocol),  
adverse events excluding serious adverse events, adverse events leading 
both dose reduction and interruption of avelumab or talazoparib, adverse 
events leading to both interruption and dose reduction.  
•
Section 6.6.1 “Other significant adverse events” – the related irAEs and 
related IRRs were removed.
•
Section 6.6.5.1. “Hematology and chemistry parameters” - the summary 
of laboratory parameters by CTCAE grade table was replaced by the 
summary of newly occurring or worsening laboratory abnormalities.
•
Section 6.6.6 “Electrocardiogram” – the summary of ECG parameters by 
timepoint  was removed. 
•
Section 6.6.8. “Physical Examination” was removed as no data were
collected in the eCRF.
•
Section 6.6.9. “ECOG performance status” - the ECOG shift table was 
removed.
•
Appendix 1 “Immune-Related Adverse Events” - steps 3 and 4 of the 
algorithm will be checked concurrently. 
•
Redundant listings or listings that do not provide meaningful information 
were removed. 
•
Throughout this document ‘start date’ was replaced by ‘date of first dose 
of study treatment’. 
•
Minor editorial and consistency changes throughout the document.
1
22-Aug-
2017
Not applicable (N/A)
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991025.  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.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie,
pharmacokinetics data [PK], immunogenicity data, biomarker data). The primary analysis 
will include all data up to a cut-off date corresponding to at least 18 months after the last 
patient is receives the first dose of study drug.  The final analysis of the data will 
be performed after last patient last visit (LPLV). 
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes.
2.1. Study Objectives
Primary Objectives
•
Phase 1b: To assess the Dose Limiting Toxicity (DLT) rate of avelumab in combination 
with talazoparib in patients with locally advanced or metastatic solid tumors in order to 
select the Recommended Phase 2 Dose (RP2D) of talazoparib for the combination;
•
Phase 2: To assess Objective Response Rate (ORR) of avelumab in combination with 
talazoparib, as assessed by the Investigator, per Response Evaluation Criteria in Solid 
Tumors (RECIST) version (v) 1.1 in patients with locally advanced or metastatic solid 
tumors and per RECIST v1.1 and Prostate Cancer Working Group 3 (PCWG3) in patients 
with metastatic Castration-Resistant Prostate Cancer (CRPC).
Secondary Objectives
•
To assess the overall safety and tolerability of avelumab in combination with talazoparib;
•
To characterize the pharmacokinetics (PK) of avelumab and talazoparib when given in 
combination;
•
To evaluate the immunogenicity of avelumab when given in combination with 
talazoparib;
•
To assess the anti-tumor activity of avelumab in combination with talazoparib;
•
To assess the correlation of anti-tumor activity of avelumab in combination with 
talazoparib with Programmed Death-Ligand 1 (PD-L1) expression and with potential 
biomarkers of poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor 
sensitivity in baseline tumor tissue.
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2.2. Study Design
This is a Phase 1b/2, open label, multi-center, study of avelumab in combination with 
talazoparib in adult patients with locally advanced (primary or recurrent) or metastatic solid 
tumors including non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), 
hormone receptor positive HER2 negative (HR+/HER2-) breast cancer, recurrent 
platinum-sensitive ovarian cancer, urothelial cancer (UC), mCRPC, and locally advanced 
(primary or recurrent) or metastatic solid tumors harboring pathogenic or likely pathogenic 
germline or somatic defects in BRCA1, BRCA2, or ATM genes.  
The study design, including the number of patients to be enrolled into each cohort, is shown 
in Figure 1.   
Phase 1b 
In Phase 1b, patients with locally advanced or metastatic solid tumors, who meet eligibility 
criteria, will be treated with one of up to 3 different doses of talazoparib (1.0 mg, 0.75 mg or 
0.5 mg) administered orally once daily (QD) in combination with a fixed dose of avelumab 
800 mg intravenous (IV) every 2 weeks (Q2W), and will be evaluated for DLTs.  The 
modified Toxicity Probability Interval (mTPI) method will be used to identify the RP2D for 
talazoparib.  The starting dose level will be 1.0 mg talazoparib QD plus 800 mg avelumab 
Q2W.  The dose levels of the combination to be evaluated are as follow:
•
D0:  talazoparib 1 mg PO QD in combination with avelumab 800 mg IV Q2W 
•
D-1:  talazoparib 0.75 mg PO QD in combination with avelumab 800 mg IV Q2W 
•
D-2:  talazoparib 0.5 mg PO QD in combination with avelumab 800 mg IV Q2W 
where IV=intravenously; PO=orally; QD=once daily; Q2W=every 2 weeks.
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Figure 1.
Phase 1b and Phase 2 Study Design Schema
ATM= ataxia telangiectasia mutated; BC= breast cancer; BRCA=BReast CAncer susceptibility gene; mCRPC= metastatic 
castration-resistant prostate cancer; D=Dose; HER2-=human epidermal growth factor receptor 2 negative; HR+=hormone 
receptor positive; DDR=DNA damage repair; DDR Defect +=DDR defect positive, as determined by the Foundation One 
assay or validated local assay result; IV=intravenous; NSCLC=non-small cell lung cancer; PD-L1= Programmed 
Death-Ligand 1; PO=orally; Q2W=every 2 weeks; QD=every day; TNBC= triple-negative breast cancer.
Approximately 12-36 patients are expected to be enrolled in Phase 1b using the mTPI 
method (see Section 5.1).
Phase 2 
All available data (including safety and preliminary anti-tumor activity) emerging from 
Phase 1b will be evaluated before starting enrollment of patients in Phase 2.  The Phase 2 
portion of this study will further assess the safety and preliminary anti-tumor activity of the 
avelumab in combination with talazoparib at the RP2D.  Cohorts in Phase 2 will include 
patients with locally advanced (primary or recurrent) or metastatic NSCLC, TNBC, 
HR+/HER2- breast cancer, recurrent platinum-sensitive ovarian cancer, UC, mCRPC, and 


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locally advanced (primary or recurrent) or metastatic solid tumors harboring pathogenic, or 
likely pathogenic, germline or somatic defects in BRCA1, BRCA2, or ATM genes. 
Up to approximately 230 patients are expected to be enrolled in Phase 2.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS
3.1. Primary Endpoints

Phase 1b: DLT during the DLT evaluation period (Cycle 1). 
Severity of adverse events (AEs) will be graded according to Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  In the Phase 1b, any of the following 
AEs occurring during the DLT observation period (Cycle 1; a cycle will be 28 days in 
duration), which are attributable to one or both of the study drugs will be classified as 
DLTs:
Hematologic:
-
Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 109/L) 
lasting > 5 days;
-
Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of 
>38.3C (>101F) or a sustained temperature of 38C (100.4F) for more than 
1 hour;
-
Neutropenic infection (ANC <1,000/mm3 or <1.0 × 109/L, and Grade >3 infection);
-
Grade 3 thrombocytopenia (platelet count <50,000 mm3 or <50.0 × 109/L) with 
bleeding;
-
Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 × 109/L);
-
Grade 4 anemia (life-threatening consequences; urgent intervention indicated).
Non-Hematologic:
-
Grade 3 toxicities of any duration except:

Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea in the 
absence of maximal medical therapy that resolves in 72 hours;

Grade 3 fatigue lasting < 5 days;

Grade 3 hypertension that can be controlled with medical therapy;

An increase of indirect (unconjugated) bilirubin indicative of 
Meulengracht/Gilbert’s syndrome;

Grade 3 serum lipase and/or serum amylase ≤7 consecutive days without 
clinical signs or symptoms of pancreatitis;


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
Grade ≥3 laboratory abnormalities without a clinical correlate and that do not 
require medical intervention;

Grade ≥3 laboratory abnormalities that do not represent a clinically relevant shift 
from baseline;

Grade 3 endocrinopathies controlled with hormonal therapy.
-
Potential Hy’s Law cases defined as: Alanine Aminotransferase (ALT) or Aspartate 
Aminotransferase (AST) >3×Upper Limit of Normal (ULN) if normal at baseline 
OR >3×ULN and doubling the baseline (if >ULN at baseline) associated with total 
bilirubin >2×ULN and an alkaline phosphatase (AP) <2×ULN.
Non-Adherence to Treatment Schedule:
-
Failure to deliver at least 75% of the planned doses of talazoparib during the first 
cycle of treatment due to treatment-related toxicities;
-
Grade 3 non-hematologic toxicity that delays administration of either study drug for 
more than 2 weeks.
Dose Reductions:
-
Any AE that results in a dose reduction of talazoparib. 
While the rules for adjudicating DLTs in the context of the Phase 1b portion of the study 
are specified above, an AE not listed above, or an AE meeting the DLT criteria above but 
occurring outside of the DLT observation period may be defined as a DLT after 
consultation between the Sponsor and Investigator, based on the emerging safety profile 
for the combination.

Phase 2: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients 
with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in 
patients with metastatic CRPC. 
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the date of first dose of study treatment until the date of the first documentation 
of progressive disease (PD). Both CR and PR must be confirmed by repeat assessments 
performed no less than 4 weeks after the criteria for response are first met.
3.2. Secondary Endpoints
3.2.1. Safety endpoints

AEs as characterized by type, severity (as graded by National Cancer Institute Common 
Terminology Criteria for AEs [NCI CTCAE] v.4.03), timing, seriousness, and 
relationship to study therapy.
AEs will be graded by the investigator according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA)


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
Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v.4.03) and timing.
3.2.2. Efficacy endpoints

Phase 1b: Confirmed OR, as assessed by the Investigator using RECIST v1.1 in patients 
with locally advanced or metastatic solid tumors and RECIST v1.1 and PCWG3 in 
patients with metastatic CRPC;

Phase 1b and Phase 2: Time-to-event endpoints including time to tumor response (TTR), 
duration of response (DR), and progression-free survival (PFS) as assessed by the 
Investigator using RECIST v1.1 for patients with solid tumors and using RECIST v1.1 
and PCWG3 for patients with metastatic CRPC, time to prostate-specific antigen (PSA) 
progression for patients with metastatic CRPC, and overall survival (OS);
DR is defined, for patients with OR, as the time from the first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.  
TTR is defined, for patients with an OR, as the time from the date of first dose of study 
treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
PFS is defined as the time from the date of first dose of study treatment to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.
Time to PSA progression for patients with metastatic CRPC is defined as the time from 
the date of first dose of study treatment to the date that a 25% increase in PSA with an 
absolute increase of 2 g/L (2 ng/mL) above the nadir (or baseline for patients with no 
PSA decline) is documented. PSA progression must be confirmed by a second, 
consecutive PSA assessment 3 weeks later. 
OS is defined as the time from the date of first dose of study treatment to the date of 
death due to any cause.

PSA response 50% for patients with metastatic CRPC.
PSA response is defined as PSA decline 50% compared to baseline. PSA response must 
be confirmed by a second, consecutive PSA assessment 3 weeks later.  

Cancer Antigen (CA)-125 response for patients with ovarian cancer.
CA-125 response is defined as ≥50% reduction in CA-125 levels from baseline.  CA-125 
response must be confirmed by a second, consecutive CA-125 value 4 weeks later.
3.2.3. Pharmacokinetic endpoints

PK parameters for avelumab and talazoparib including: pre-dose/trough concentrations 
(Ctrough) and post-dose concentrations for talazoparib and maximum concentrations (Cmax) 
for avelumab.


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Table 2.
PK Parameters to be Determined for Avelumab and Talazoparib
Parameter
Definition
Method of Determination
Cmax a
Maximum observed concentration (=End 
of Infusion (EOI) for avelumab)
Observed directly from data
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
a For avelumab only.
For avelumab, the actual time difference between avelumab infusion start time (for pre-
dose) and end time (for post-dose) will also be reported.
For talazoparib, the post-dose concentration, taken at the end of avelumab infusion, and 
its actual time relative to talazoparib dose will also be reported, when appropriate.
3.2.4. Immunogenicity endpoints
•
Avelumab Anti-drug antibody (ADA) levels and neutralizing antibodies (Nab) against 
avelumab.
3.2.5. Biomarker endpoints
•
PD-L1 expression level in baseline tumor tissue.
•
Genomic scarring and the presence of defects in select genes, considered critical to 
effective DDR, in baseline tumor tissue.
Table 3.
Biomarker Definition and Determination
Parameter
Definition
Method of Determination
PD-L1 expression level 
in baseline tumor 
tissue
The number of PD-L1 positive cells and/or 
qualitative assessment of  PD-L1 staining on 
tumor and inflammatory cells in regions of 
interest
Pathologist, assisted by 
image analysis.
Genomic scarring and 
the presence of defects 
in select genes, 
considered critical to 
effective DDR, in 
baseline tumor tissue 
Quantitation of genomic scarring in the form 
of genomic loss of heterozygosity;
The number of mutations present in a panel 
of genes associated with DDR.
Next generation sequencing 
followed by computational 
analysis.
 
 
 
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3.4. Baseline Variables
3.4.1. Study drug, study treatment and baseline definitions
In this study, ‘study drug’ refers to avelumab and to talazoparib and ‘study treatment’ (or 
‘treatment group’) refers to one of the following:
•
Dose level cohort D0 (Phase 1b): avelumab 800 mg IV Q2W plus talazoparib 1 mg QD 
PO;
•
Dose level cohort D-1 (Phase 1b): avelumab 800 mg IV Q2W plus talazoparib 0.75 mg 
QD PO;
•
Dose level cohort D-2 (Phase 1b): avelumab 800 mg IV Q2W plus talazoparib 0.5 mg 
QD PO;
•
Cohort A1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with NSCLC;
•
Cohort A2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with NSCLC and PD-1/L1 resistant and DDR Defect +;
•
Cohort B1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with TNBC;
•
Cohort B2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with HR+/HER2- breast cancer and DDR Defect + assay;
•
Cohort C1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with recurrent platinum-sensitive ovarian cancer;
•
Cohort C2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with recurrent platinum-sensitive ovarian cancer and BRCA defect;
•
Cohort D (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with UC;
•
Cohort E1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with CRPC;
•
Cohort E2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with CRPC and DDR defect+ assay;
•
Cohort F (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with advanced solid tumor with a germline or somatic BRCA1, BRCA2 or ATM gene 
defect.
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Start and end dates of study treatment:
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination. 
The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination.
Definition of baseline: 
Definition of baseline for efficacy analyses and for safety analyses
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety for safety and efficacy 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.
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
3.4.2. Baseline characteristics
Baseline characteristics (including demographics, disease history and prior anti-cancer 
therapies) 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 6.


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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. 
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.
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.
4.1. Full Analysis Set
The Full Analysis Set (FAS) will include all patients who receive at least one dose of study 
drug.  Patients will be classified according to the study treatment actually received.  If a 
patient receives more than one treatment the patient will be classified according to the first
study treatment received. 
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 actually received.  If a patient 
receives more than one study treatment, the patient will be classified according to the first
study treatment received. In this non-randomized study, the FAS and the safety analysis set 
are identical.
4.3. Other Analysis Set
4.3.1. DLT-evaluable set
The DLT analysis set is a subset of the safety analysis set and includes all enrolled patients in 
the Phase 1b who are eligible for the study, receive at least one dose of the combination 
treatment, and either experience DLT during the first cycle (28 days) of treatment, or 
complete the DLT observation period for the first cycle of treatment. 


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Patients without DLTs who withdraw from study treatment before receiving at least 75% of 
the planned dose of each of the study drugs in the combination in Cycle 1 for reasons other 
than toxicity which are attributable to the study drugs are not evaluable for DLT.  Additional 
patients will be enrolled to replace patients who are not considered DLT evaluable.
4.3.2. PK analysis sets
The PK concentration analysis sets (one unique set for each study drug used in the 
combination treatment) are subsets of the safety analysis set including patients who have at 
least one post-dose concentration measurement above the lower limit of quantitation (LLQ) 
for avelumab or talazoparib.
The PK parameter analysis sets (one unique set for each study drug used in the combination 
treatment) are the same as the concentration analysis sets, since the 2 reported PK parameters 
(Ctough and Cmax) are observational: i.e. taken directly from concentration data.                                                  
4.3.3. Biomarker analysis set 
The biomarker analysis set is a subset of the safety analysis set including patients who have 
at least one baseline biomarker assessment.  Analysis sets will be defined separately for 
blood-based and tumor tissue-based biomarkers.
4.3.4. Immunogenicity analysis set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/Nab sample collected for avelumab. 
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and sample size determination
Phase 1b 
There is no formal hypothesis testing in this phase. Due to the dynamic nature of the 
Bayesian allocation procedure, the exact sample size of the “Up-and-Down” matrix design 
using the mTPI approach cannot be determined in advance.  It is expected that 12-36 patients 
will need to be enrolled in Phase 1b using the mTPI design (see Section 5.1.2).  
Phase 2
In Phase 2, enrollment in each treatment group will be up to approximately 20 or up to 
approximately 40 patients in each treatment group (not including patients enrolled in Phase 
1b) as shown in Figure 1.  
With 20 patients in a treatment group, ORR can be estimated with a maximum standard error 
of 0.112.  With 40 patients in a treatment group, ORR can be estimated with a maximum 
standard error of 0.079.  Within each treatment group, ORR will be estimated and the 2-sided 
exact 90% confidence intervals (CIs) will be calculated. Table 4 provides the exact binomial 
90% CI for ORR based on different observed responses in a treatment group.


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Table 4.
Sample Size and Exact 90% Confidence Intervals for ORR in 
each Treatment Group 
N per treatment 
group
Number of 
responders
Observed ORR
90% CI for ORR
10
1
10%
(0.5% – 39.4%)
2
20%
(3.7% – 50.7%)
3
30%
(8.7% – 60.7%)
4
40%
(15.0% – 69.6%)
5
50%
(22.2% – 77.8%)
6
60%
(30.4% – 85.0%)
20
1
5%
(0.3% – 21.6%)
2
10%
(1.8% – 28.3%)
3
15%
(4.2% – 34.4%)
4
20%
(7.1% – 40.1%)
5
25%
(10.4% – 45.6%)
6
30%
(14.0% – 50.8%)
7
35%
(17.7% – 55.8%)
8
40%
(21.7% – 60.6%)
9
45%
(25.9% – 65.3%)
10
50%
(30.2% – 69.8%)
12
60%
(39.4% – 78.3%)
15
75%
(54.4% – 89.6%)
40
2
5%
(0.9% – 14.9%)
4
10%
(3.5% – 21.4%)
6
15%
(6.7% – 27.5%)
8
20%
(10.4% – 33.2%)
10
25%
(14.2% – 38.7%)
12
30%
(18.3% – 44.0%)
14
35%
(22.6% – 49.2%)
16
40%
(26.9% – 54.2%)
18
45%
(31.5% – 59.1%)
20
50%
(36.1% – 63.9%)
24
60%
(45.8% – 73.1%)
30
75%
(61.3% – 85.8%)
35
87.5%
(75.5% – 94.9%)
CI=confidence interval; ORR=objective response rate
  
5.1.2. Decision rules
Phase 1b 
Dose finding to identify a safe dose and RP2D of talazoparib to be used in combination with 
avelumab (all tumor types): 
A safe dose will be determined using the adaptive mTPI design. The mTPI method relies 
upon a statistical probability algorithm, calculated using data from all patients treated in prior 
and current patient groups at the same dose level to determine whether future patient groups 
should involve dose re-escalation, no change in dose, or dose de-escalation. The mTPI design 
is flexible and allows dose reduction to doses in between the planned doses. 


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The mTPI design uses a Bayesian statistics framework and a beta/binomial hierarchical 
model to compute the posterior probability of 3 dosing intervals that reflect the relative 
difference between the toxicity rate of each dose level to the target probability (pT) rate 
(pT=0.25). If the toxicity rate of the currently used dose level is far smaller than pT, the 
mTPI will recommend escalating the dose level; if it is close to pT, the mTPI will 
recommend continuing at the current dose; if it is far greater than pT, the mTPI will 
recommend de-escalating the dose level. These rules are conceptually similar to those used 
by the 3+3 design, except the decisions of an mTPI design are based on posterior 
probabilities calculated under a coherent probability model. As shown by Ji and Wang 
(2013)3, mTPI design is more efficient and safer than the 3+3 design. They considered 42 
scenarios to cover a wide range of practical dose-response shapes, and concluded that the 3 + 
3 design was more likely to treat patients at toxic doses above the Maximum Tolerated Dose
(MTD) and less likely to identify the true MTD than the mTPI design. For example, the 3 + 3 
design exhibited a lower overall toxicity percentage than the mTPI design in only one of 42 
scenarios. 
Being a model-based design, mTPI automatically and appropriately tailors dose re-escalation 
and de-escalation decisions for different studies with different toxicity parameters. More 
importantly, all the dose re-escalation/de-escalation decisions for a given study can be pre-
calculated under the mTPI design and presented in a 2-way table. Thus, compared to other 
advanced model-based designs published in the literature, the mTPI design is logistically less 
complicated and easier to implement. 
Decision rules are based on calculating unit probability mass (UPM) of 3 dosing intervals 
corresponding to under, proper, and overdosing in terms of toxicity. Specifically, the 
underdosing interval is defined as (0, pT-e1), the overdosing interval (pT+e2, 1), and the 
proper-dosing interval (pT- e1, pT+ e2), where e1 and e2 are small fractions. Based on the 
safety profile of talazoparib and avelumab, e1 is selected as 0.09, and e2 is selected as 0.08. 
Therefore, the target interval for the DLT rate is (0.16, 0.33). 
The 3 dosing intervals are associated with 3 different dose-escalation decisions. The 
underdosing interval corresponds to a dose re-escalation, overdosing corresponds to dose de-
escalation, and proper dosing corresponds to staying at the current dose. Given a dosing 
interval and a probability distribution, the UPM of that dosing interval is defined as the 
probability of a patient belonging to that dosing interval divided by the length of the dosing 
interval. The mTPI design calculates the UPMs for the 3 dosing intervals, and the one with 
the largest UPM informs the corresponding dose-finding decision, which is the dose level to 
be used for future patients. For example, if the underdosing interval has the largest UPM, the 
decision will be to escalate, and the next group of patients will be treated at the next higher 
dose level. Simulations have demonstrated that the decision based on UPM is optimal in that 
it minimizes a posterior expected loss (ie, minimizes the chance of making a wrong dosing 
decision). 
The Phase 1b dose finding evaluation of the trial is completed when 12 DLT-evaluable 
patients have been treated at the highest dose levels associated with a DLT rate <33% or if 
the combinations are deemed too toxic, as determined by the DLT rate and/or lower than


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expected doses of the study treatments. Early completion of Phase 1b can be reached when 9 
or more DLT-evaluable patients have been treated at the same dose level with no occurrence 
of DLT, as the DLT rate of <0.33 will be met. 
Phase 2
There are no formal decision rules in this phase of the study. 
5.2. General Methods
As described in Section 3.4, in this study ‘treatment group’ refers to one of the following:

Dose level cohort D0 (Phase 1b): avelumab 800 mg IV Q2W plus talazoparib 1 mg QD 
PO;

Dose level cohort D-1 (Phase 1b): avelumab 800 mg IV Q2W plus talazoparib 0.75 mg 
QD PO;

Dose level cohort D-2 (Phase 1b): avelumab 800 mg IV Q2W plus talazoparib 0.5 mg 
QD PO;

Cohort A1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with NSCLC;

Cohort A2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with NSCLC and PD-1/L1 resistant and DDR Defect +;

Cohort B1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with TNBC;

Cohort B2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with HR+/HER2- breast cancer and DDR Defect + assay;

Cohort C1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with recurrent platinum-sensitive ovarian cancer;

Cohort C2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with recurrent platinum-sensitive ovarian cancer and BRCA defect;

Cohort D (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with UC;

Cohort E1 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with CRPC;

Cohort E2 (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with CRPC and DDR defect+ assay;


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
Cohort F (Phase 2): avelumab 800 mg IV Q2W plus talazoparib at the RP2D in patients 
with advanced solid tumor with a germline or somatic BRCA1, BRCA2 or ATM gene 
defect.
Table 5 provides an overview of the summaries and the tabulations for this study.
Table 5.
Study Summaries and Tabulations
Summaries
Analysis 
Population
Phase 1b
Phase 2
Phase 1b and 
Phase 2 
combined
Baseline 
characteristics 
and disposition
FAS
- by treatment group
- for all treatment 
groups combined
by treatment group
For all patients 
treated with 
talazoparib at 
RP2D
DLTs
DLT-evaluable 
set
- by treatment group
- for all treatment 
groups combined
ND
ND
Efficacy data 
FAS
- by treatment group
- for all treatment 
groups combined
by treatment group
ND
Other safety data, 
exposure data, 
concomitant 
medications, non-
drug treatment
Safety analysis 
set
- by treatment group
- for all treatment 
groups combined
by treatment group
For all patients 
treated with 
talazoparib at 
RP2D
PK data for 
avelumab
PK analysis set
ND
ND
For all patients 
PK data for 
talazoparib
PK analysis set
ND
ND
For all patients 
treated with 
talazoparib at 
RP2D
Biomarker data
Full analysis set
ND
by treatment group
ND
Immunogenicity 
data
Immunogenicity 
analysis set
- for all treatment 
groups combined
- for all treatment 
group combined
For all patients 
ND = Not done
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 treated at each center.


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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.
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 6.1.2 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment amongst the following:

Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages


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
Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’ 

Surgery date recorded in ‘Concomitant Surgery’, and ‘Follow-up 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’, ‘Concomitant Surgery’, 
and ‘Follow-up 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.
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. 
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.


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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
(if such analyses are performed).
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 first 
dose of study treatment.

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).
5.2.11. Adequate post-baseline tumor assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, stable disease (SD), non-CR/non-PD, or progressive disease (PD) can be determined (see 
Section 6.1.2.1).  Time points where the response is not evaluable (NE) or 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.


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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:
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 fewer than 4 (n < 4) 
concentration values are available.  For analysis of pharmacokinetic concentrations, no 
values will be imputed for missing data.
5.3.1.2. Pharmacokinetic parameters
If a PK parameter cannot be derived from a patient’s concentration data, the parameter will 
be coded as NC (ie, not calculated).  NC values will not be generated beyond the day that a 
patient discontinues the associated study drug.
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if fewer than 4 (n < 4) concentration values 
are available.  For statistical analyses (ie, analysis of variance), PK parameters coded as NC 
will also be set to missing.
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level) in a given cycle, this will be footnoted in summary 
tables and will not be included in the calculation of summary statistics or statistical analyses
for this cycle.
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:


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
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. 
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. 


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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.
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

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 


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
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 
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. 


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
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] 
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] 


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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]
THEN 
imputed start date = 01 MMM YYYY.
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.
6.1. Primary Endpoints
6.1.1. DLT for Phase 1b
6.1.1.1. Primary analysis
The following analyses will be based on the DLT-evaluable set for patients in the Phase 1b.  
DLTs will be listed and summarized by treatment group and for all treatment groups 
combined, including data from Phase 1b only (Table 5).
6.1.2. Objective response as assessed by the Investigator per RECIST v1.1 
6.1.2.1. Primary analysis
The following analyses will be based on the FAS by treatment group using the data from 
Phase 2.   
Treatment groups A1, A2, B1, B2, C1, C2, D and F (non-CRPC patients)
Assessment of response will be made using RECIST v1.1.  Assessments below refer to 
investigator assessment.  
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the date of first dose of study treatment until the first 
documentation of PD, according to the following rules. Only tumor assessments performed 
on or before the start date of any further anti-cancer therapies will be considered in the 
assessment of BOR.  Clinical deterioration will not be considered as documentation of
disease progression.


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
CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD

PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart and before first documentation of PD (and not qualifying for a 
CR)

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of first dose of study treatment and before 
first documentation of PD (and not qualifying for CR or PR).

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the date of first dose 
of study treatment and before first documentation of PD (and not qualifying for CR or 
PR).

PD = first documentation of PD ≤ 12 weeks after the date of first dose of study treatment
(and not qualifying for CR, PR, SD or non-CR/non-PD).  

NE:  all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the 
rare case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met.
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set.
ORR by treatment group will also be calculated along with the 2-sided 90% CI using the 
Clopper-Pearson method 2 (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option). Two-sided 95% CIs will also be calculated and 
reported.
In addition, the frequency (number and percentage) of patients with a confirmed BOR of CR, 
PR, SD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), PD, and NE will be tabulated. Patients with confirmed BOR of NE will be 
summarized by reason for having NE status. The following reasons will be used:

No baseline assessment 

No post-baseline assessments due to death 


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
No post-baseline assessments due to other reasons

All post-baseline assessments have overall response NE

New anti-cancer therapy started before first post-baseline assessment

SD of insufficient duration (<6 weeks after the date of first dose of study treatment
without further evaluable tumor assessments)

PD too late (>12 weeks after the date of first dose of study treatment)
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD too early’ (ie, SD of insufficient duration).
Treatment groups E1, E2 and F (CRPC patients)
Assessment of response will be made using soft tissue assessment by RECIST v1.1 and bone 
lesion assessment by PCWG3.  Assessments below refer to investigator assessment.  
Best overall response (BOR) will be assessed based on reported overall soft tissue 
responses and PCWG3 bone scan assessment at different evaluation time points from the 
date of first dose of study treatment until documented disease progression, according to the 
following rules. Disease progression in bone disease must be confirmed at least 6 weeks 
later, as per PCWG3.  Only assessments performed before the start of any further anti-cancer 
therapies will be considered in the assessment of BOR.  Clinical deterioration will not be 
considered as documented disease progression.

CR = at least two determinations of CR in soft tissue per RECIST v1.1 at least 4 weeks 
apart and before first documentation of PD (in soft tissue per RECIST v1.1 or in bone by 
PCWG3).

PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) in soft tissue per RECIST v1.1 at least 4 weeks apart and before first documentation 
of PD (in soft tissue per RECIST v1.1 or in bone by PCWG3), and not qualifying for a 
CR.

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of first dose of study treatment and before 
first documentation of PD (in soft tissue per RECIST v1.1 or in bone by PCWG3), and 
not qualifying for CR or PR. 

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after date of first dose of 
study treatment and before first documentation of PD (in soft tissue per RECIST v1.1 or 
in bone by PCWG3), and not qualifying for CR or PR.

PD = progression ≤ 12 weeks after date of first dose of study treatment (and not 
qualifying for CR, PR, SD or non-CR/non-PD).  

NE:  all other cases.


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Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have any on-treatment radiographic assessment of soft tissue and bone 
lesion due to early progression, who receive anti-tumor therapies other than the study 
treatments prior to reaching a CR or PR, or who die, progress, or drop out for any reason 
prior to reaching a CR or PR will be counted as non-responders in the assessment of OR. 
Each patient will have an objective response status (0: no OR; 1: OR).  OR rate (ORR) is the 
proportion of patients with OR in the analysis set.
ORR by treatment group (E1 and E2) will also be calculated along with the 2-sided 90% CI 
using the Clopper-Pearson method (exact CI for a binomial proportion as computed by 
default by the FREQ procedure using the EXACT option). Two-sided 95% CIs will also be 
calculated and reported.
In addition, the frequency (number and percentage) of patients with a confirmed BOR of CR, 
PR, SD, PD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), and NE will be tabulated. Patients with confirmed BOR of NE will be summarized 
by reason for having NE status. The following reasons will be used:

No baseline assessment 

No evidence of disease at baseline

No post-baseline assessments due to death 

No post-baseline assessments due to other reasons

All post-baseline assessments have overall response NE

New anti-cancer therapy started before first post-baseline assessment

SD of insufficient duration  (<6 weeks after the date of first dose of study treatment 
without further evaluable tumor assessments)

PD too late (>12 weeks after the date of first dose of study treatment)
Special and rare cases where BOR is NE due to both early SD and late PD will be classified 
as ‘SD too early’ (ie, SD of insufficient duration).
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 group in Phase 2 and 
separately by treatment group and for all treatment groups combined in Phase 1b (Table 5). 
Assessment of response will be made using RECIST v1.1 for treatment groups from Phase 


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1b (non-CRPC patients) and for treatment groups A1, A2, B1, B2, C1, C2, D and F (non-
CRPC patients), and using RECIST v1.1 and PCWG3 for treatment groups from Phase 1b 
(CRPC patients) and for treatment groups E1, E2 and F (CRPC patients). Tumor-related 
endpoints will be analyzed based on investigator assessment.  
6.2.2.1. Tumor shrinkage from baseline
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:

((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment group. 
These plots will display the best percentage change from baseline in the sum of the diameters
of all target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment.
6.2.2.2. Duration of response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  
Phase 1b (non-CRPC patients) and Phase 2 treatment groups A1, A2, B1, B2, C1, C2, D
and F (non-CRPC patients): The documentation of PD is as assessed by Investigator using 
RECIST v1.1.
If a patient has not had an event (PD or death), DR is censored at the date of last adequate 
tumor assessment. The censoring rules for DR are described in Table 6.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375


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Table 6.
Outcome and Event Dates for DR Analyses for non-CRPC Patients
Scenario
Date of event/censoring
Outcome
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
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 a 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 a 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 a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a  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 first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment.
Phase 1b (CRPC patients) and Phase 2 treatment groups E1, E2 and F (CRPC 
patients): The documentation of PD is defined by either soft tissue progression as assessed 
by Investigator using RECIST v1.1 or by bone disease as assessed by Investigator using 
PCWG3. 
If a patient has not had an event (PD or death), DR is censored at the date of last adequate 
tumor assessment. The censoring rules for DR are described in Table 7.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375


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Table 7.
Outcome and Event Dates for DR Analyses for CRPC Patients
Scenario
Date of event/censoring
Outcome
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
Date of PD (if based on bone 
disease it should be the first 
documentation of bone disease PD 
that is subsequently confirmed b) or 
death
Event
PD or death 
-
After 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment a 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 a 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 a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a  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 first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment.
b For bone disease, PD must be subsequently confirmed to be counted as an event. The date of PD for bone 
disease is the date of first documentation of bone disease PD (that is subsequently confirmed)
Kaplan-Meier estimates5 (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with 2-sided 
95% CIs.  In particular, the DR rates at 3, 6 and 12 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)1 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 (2002)4 (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.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 8 following the hierarchy shown.


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Table 8. 
DR Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
Start of new anti-cancer therapy   
Start of new anti-cancer therapy
2 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization
Event after 2 or more missing 
assessments a
3
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up] 
Withdrawal of consent
4
No event and lost to follow-up in any disposition page 
Lost to follow-up
5
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
6 
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.   
6.2.2.3. Time to response
Time to response (TTR) is defined, for patients with OR, as the time from the date of first 
dose of study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
Phase 1b (non-CRPC patients) and Phase 2 treatment groups A1, A2, B1, B2, C1, C2, D
and F (non-CRPC patients): The first documentation of objective response (CR or PR) is as 
assessed by Investigator using RECIST v1.1.
Phase 1b (CRPC patients) and Phase 2 treatment groups E1, E2 and F (CRPC 
patients): The first documentation of objective response is the first objective evidence of soft 
tissue response as assessed by Investigator using RECIST v1.1 with no evidence of 
confirmed bone disease progression per PCWG3.    
TTR (in months) = [first date of OR 
                                             – date of first dose of study treatment +1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.4. Progression-free survival
Phase 1b (non-CRPC patients) and Phase 2 treatment groups A1, A2, B1, B2, C1, C2, D
and F (non-CRPC patients)
Progression-Free Survival (PFS) is defined as the time from the date of first dose of study 
treatment to the date of the first documentation of PD or death due to any cause, whichever 
occurs first.   


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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 first dose of 
study treatment unless death occurred on or before the time of the second planned tumor 
assessment (ie ≤ 16 weeks after the date of first dose of study treatment) in which case the 
death will be considered an event. 
In this study, antitumor activity will be assessed through radiological tumor assessments 
conducted at screening, every 8 weeks (± 7 days) for 1 year from start of study treatment, and 
then every 16 weeks (± 7 days) thereafter until disease progression regardless of initiation of 
subsequent anti-cancer therapy.  
The censoring and event date options to be considered for the PFS analysis are presented in 
Table 9.  
PFS (months) = [date of event or censoring
                                        – date of first dose of study treatment +1]/30.4375
Kaplan-Meier estimates5 (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided 
95% CIs.  In particular, the PFS rates at 3, 6, 9, 12 and 15 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982) 1 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 (2002)4 (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 group. Reasons for censoring will be 
summarized according to the categories in Table 10 following the hierarchy shown.
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.


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Table 9.
Outcome and Event Dates for PFS Analyses for non-CRPC Patiens
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of first dose of study 
treatment a
Censored a
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
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 ≤16 weeks after the date of first dose of study treatment 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 first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment


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Table 10.
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 first dose of study treatment
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = Patient
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.   
Phase 1b (CRPC patients) and Phase 2 treatment groups E1, E2 and F (CRPC patients)
Progression-Free Survival (PFS) is defined as the time from date of first dose of study 
treatment to the date of the first documentation of objective progression of disease (PD) or 
death due to any cause, whichever occurs first. 
The documentation of PD is defined by either soft tissue progression as assessed by 
Investigator using RECIST v1.1 or bone disease progression which is confirmed at least 6 
weeks later as assessed by Investigator using PCWG3.  
In this study, antitumor activity in patients with CRPC will be assessed through radiological 
tumor assessments conducted at screening, every 8 weeks (± 7 days) for 24 weeks from start 
of study treatment, and then every 12 weeks (± 7 days) thereafter until disease progression 
regardless of initiation of subsequent anti-cancer therapy.  
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 11.  
PFS (months) = [date of event or censoring
                                        – date of first dose of study treatment +1]/30.4375
Kaplan-Meier estimates5 (product-limit estimates) will be presented by treatment group using 
the data from the Phase 2 together with a summary of associated statistics including the 
median PFS time with 2-sided 90% and 95% CIs.  In particular, the PFS rate at 4, 6, 8, 10, 
12, 14 and 18 months will be estimated with corresponding 2-sided 90% and 95% CIs.  The 
CIs for the median will be calculated according to Brookmeyer and Crowley 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 (conftype=loglog default option in 


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SAS Proc LIFETEST). 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 group. Reasons for censoring will be 
summarized according to the categories in Table 10 following the hierarchy shown.
Table 11.
Outcome and Event Dates for PFS Analyses for CRPC Patiens
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of first dose of study treatment a
Censored a
PD (if based on bone disease, PD that 
is subsequently confirmed b) or death 
-
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR
-
≤ 16 weeks after date of first dose 
of study treatment
Date of PD (if based on bone disease it 
should be the first documentation of 
bone disease PD that is subsequently 
confirmed b) or death
Event
PD (if based on bone disease, PD that 
is subsequently confirmed b) or death 
after 2 or more missing or inadequate 
post-baseline tumor assessments 
Date of last adequate tumor 
assessment c documenting no PD b
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
No PD (or for bone disease PD that is 
not subsequently confirmed b) and no 
death
Date of last adequate tumor 
assessment c documenting no PD b
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 (prior to 
PD for soft tissue disease or confirmed 
PD for bone disease b)
Date of last adequate tumor 
assessment c documenting no PD b
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a However if the patient dies ≤16 weeks after date of first dose of study treatment the death is an event with date on 
death date
b For bone disease, PD must be subsequently confirmed to be counted as an event. The date of PD for bone disease 
is the date of first documentation of bone disease PD (that is subsequently confirmed)
c  If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment group. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment groups reversing the PFS censoring and event 
indicators. including the median time of follow-up for PFS with 2-sided 95% CIs.


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6.2.2.5. Overall Survival
Overall survival (OS) is defined as the time from the date of first dose of study treatment 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 first dose of study treatment +1]/30.4375
Kaplan-Meier estimates5 (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rates at 3, 6, 9, 12, 15, and 18 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982) 1 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 (2002)4 (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 an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 12 following the hierarchy shown.
Table 12.
OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = Patient
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 groups reversing the OS censoring and event indicators, including the 
median time of follow-up for OS with 2-sided 95% CIs.  
6.2.2.6. Time to PSA progression for patients with metastatic CRPC 
The following analyses will be based on the FAS for each of the treatment groups E1 and E2. 


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Time to PSA progression for patients with metastatic CRPC is defined as the time from the 
date of first dose of study treatment to the date that a 25% increase in PSA with an absolute 
increase of 2 g/L (2 ng/mL) above the nadir (or baseline for patients with no PSA decline) 
is documented. PSA progression must be confirmed by a second, consecutive PSA 
assessment 3 weeks later.
Time to PSA progression will be censored on the date of the last PSA assessment for patients 
who do not have an event (confirmed PSA progression), 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 PSA assessments. Patients who do not have a baseline PSA assessment or who 
do not have a post-baseline PSA assessment will be censored on the date of first dose of 
study treatment.
PSA assessments will be conducted at screening, every 4 weeks ± 2 days and at EOT.  The 
censoring and event date options to be considered for the time to PSA progression analysis 
are presented in Table 13.
Time to PSA progression (months) 
= [date of PSA progression or censoring
       – date of first dose of study treatment +1]/30.4375
Table 13.
Outcome and Event Dates for Time to PSA progression analysis 
Scenario
Date of event/censoring
Outcome
No PSA assessment at baseline
Date of first dose of study treatment
Censored 
PSA progression (subsequently 
confirmed), after at most one missing 
PSA assessment.
Date of first PSA progression 
Event
PSA progression (subsequently 
confirmed) after 2 or more missing 
PSA assessments 
Date of last PSA assessment 
documenting no PSA progression 
before new anti-cancer therapy is 
given or missed PSA assessments 
Censored
PSA progression not confirmed or no 
PSA progression
Date of last PSA assessment 
documenting no PSA progression 
before new anti-cancer therapy is 
given or missed PSA assessments
Censored
New anti-cancer therapy prior to 
confirmed PSA progression 
Date of last PSA assessment 
documenting no PSA progression 
before new anti-cancer therapy is 
given or missed PSA assessments
Censored
Kaplan-Meier estimates5 (product-limit estimates) will be presented by treatment group (E1 
and E2) together with a summary of associated statistics including the median time to PSA 
progression with 2-sided 90% and 95% CIs.  In particular, the PSA progression rate at 4, 6, 8, 
10, 12, 14, and 18 months will be estimated with corresponding 2-sided 90% and 95% CIs. 
The CIs for the median will be calculated according to Brookmeyer and Crowley 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 (conftype=loglog default option 


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in SAS Proc LIFETEST). The estimate of the standard error will be computed using 
Greenwood’s formula.  
Frequency (number and percentage) of patients with an event and patients censored will be 
presented by treatment group.  The time to PSA progression or censoring time will also be 
presented in a patient listing.
6.2.2.7. PSA response for patients with metastatic CRPC
The following analyses will be based on the FAS for each of the treatment groups E1 and E2. 
PSA response is defined as PSA decline 50% compared to baseline. PSA response must be 
confirmed by a second, consecutive PSA assessment 3 weeks later.  
PSA response will be assessed based on PSA assessments at different evaluation time points 
from the date of first dose of study treatment until PSA progression. Only PSA assessments 
performed before the start of any further anti-cancer therapies will be considered in the 
assessment of PSA response.  

PSA response = at least 2 assessments, at least 3 weeks apart with ≥50% reduction in 
PSA level from baseline.

No PSA response = all other cases.
Each patient will have a PSA response status (0: no PSA response; 1: PSA response).  PSA 
response rate is the proportion of patients with PSA response in the analysis set.
PSA response rate by treatment group (E1 and E2) will be calculated along with the 2-sided 
90% CI using the Clopper-Pearson method (exact CI for a binomial proportion as computed 
by default by the FREQ procedure using the EXACT option). Two-sided 95% CIs will also 
be calculated and reported.   
A spider plot of the percent change in PSA value from baseline per time point and a waterfall 
plot of the best percentage change in PSA value from baseline will be created. These plots
will display for each patient with a baseline assessment and at least one post-baseline 
assessment.
6.2.2.8. CA-125 response for patients with ovarian cancer 
The following analyses will be based on the FAS for each of the treatment groups C1 and C2. 
CA-125 response is defined as ≥50% reduction in CA-125 levels from baseline.  CA-125 
response must be confirmed by a second, consecutive CA-125 value 4 weeks later.  
CA-125 response will be assessed based on the CA-125 values (ng/mL) collected at baseline 
and at different time points from the date of first dose of study treatment until EOT, 
according to the following rule. Only CA-125 value collected before the start of any further 
anti-cancer therapies will be considered in the assessment of CA-125 response. 

CA-125 response = at least 2 consecutive assessments 4 weeks apart with ≥ 50% 
reduction in CA-125 level from baseline.


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
No CA-125 response = all other cases
Each patient will have a CA-125 response status (0: no CA-125 response; 1: CA-125
response).  CA-125 response rate is the proportion of patients with CA-125 response in the 
analysis set.
CA-125 response rate by treatment group (C1 and C2) will be calculated along with the 2-
sided 90% CI using the Clopper-Pearson method (exact CI for a binomial proportion as 
computed by default by the FREQ procedure using the EXACT option). Two-sided 95% CIs 
will also be calculated and reported.   
6.2.3. Pharmacokinetic endpoints
The following pharmacokinetic analyses will be based on the concentration and PK analyses 
sets, which on this study are identical for each analyte, given that PK parameters are 
observational and correspond to the two PK samples, pre-dose/0H/Ctrough and post-
dose/1H/EOI, as described in Section 3.2.3.  Data for which time of collection cannot be 
confirmed will be excluded. Data will be summarized as shown in Table 5.
Concentrations for talazoparib and avelumab will be listed by study phase (Phase1b and 
Phase 2), treatment group, starting dose (talazoparib only), cycle, day and nominal collection 
time, and will be summarized descriptively (n, mean, SD, CV, median, minimum, maximum,
geometric mean, its associated CV, and 95% CI) as shown in Table 5.
Presentation of pharmacokinetic data will include:

Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric 
mean, and its associated %CV and 95% CI will be presented in tabular form for 
avelumab and talazoparib concentrations as shown in Table 5. Concentrations with 
zero/BLQ values will be excluded from the calculation of geometric means and their 
associated %CV. Data from patients who have undergone intrapatient dose reduction will 
be excluded from the summary statistics beginning at the time of the dose reduction . 

In order to assess the attainment of steady-state, Ctrough and Cmax for avelumab and 
predose and postdose concentrations for talazoparib will be plotted using box-whisker 
plots by cycle and day within cycle for the sub-sets of data corresponding to the summary 
statistics described above. Individual data points, the geometric mean and the median of 
the parameter in each treatment will be overlaid on the box plots. If a treatment group has 
limited evaluable PK data (n<4), matchstick plots showing changes in Ctrough for each 
drug and Cmax for avelumab 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/or 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. 


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Additional exploratory PK analyses may be performed through the study to assess the drug-
drug interaction potential between avelumab and talazoparib exposures when administered in 
combination relative to when each agent is administered as monotherapy, and to monitor for 
consistency in each drug’s exposure among the patient cohorts.   
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, genomic scarring and mutations in genes associated with DDR 
at baseline.
Biomarker data will be analyzed based on the full analysis set. Data will be presented by 
treatment group including data from Phase 2 only. 
Biomarkers values at screening will be listed and summarized. 
Descriptive summary statistics (mean, SD, median, Q1, Q3, tertiles, coefficient of variation, 
minimum, and maximum) will be provided for each biomarker as follows:

PD-L1 expression level as percentage of positive tumor cells, immune cells and tumor 
and immune cells combined in a sample

Genomic scarring as measured by genomic loss of heterozygosity score

Total number of DDR gene mutations

Number of mutations present in each of the individual DDR genes
For PD-L1 expression level, patients may be classified as positive, negative, or some other 
category according to scoring algorithms and cut-offs established from external sources.  If 
no external standards exist, patients may be stratified using the median, quartiles and tertiles. 
For example, NSCLC patients of treatment group A1 may be categorized based on PD-L1 
expression level ≥ 50%, < 50% and >0, equal to 0 or Unknown. The number and percentage 
of patients by treatment group in each category will be tabulated. 
For genomic scarring, as measured by genomic loss of heterozygosity score, for the total 
number of DDR gene mutations and for the number of mutations in DDR genes, patients may 
be classified as positive, negative, or some other category according to scoring algorithms 
and cut-offs established from external sources.  If no external standards exist, patients may be 
stratified using the median, quartiles and tertiles. For example, patients will be classified as 
positive if they have a mutation in any one of the assessed DDR genes and will otherwise be 
classified as negative. The number and percentage of patients by treatment group in each 
category will be tabulated.
BOR will be summarized by treatment group and for each category following the 
methodology outlined in Section 6.1.2.1. The number of responders (patients with BOR of 


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CR or PR) will be tabulated relative to biomarker classifications using a contingency table 
and a Fisher’s exact test will be performed. 
DR, PFS and OS (if meaningful) will be summarized by treatment group and for each 
category following the methodology outlined in Sections 6.2.2.2, 6.2.2.4 and 6.2.2.5. The 
censoring rules for DR and PFS for treatment groups A1, A2, B1, B2, C1, C2, and D are as 
described in Table 6 and Table 9, and for treatment groups E1 and E2 are as described in 
Table 7 and Table 11.
6.2.6. Endpoints for immunogenicity data of avelumab and talazoparib
ADA and, if appropriate, nAb data for avelumab will be listed by study phase (1b or 2), 
treatment group and cycle. The percentage of patients with positive ADA and nAbswill be 
summarized separately for all patients in Phase 1b and for all patients in Phase 2, as well as 
combined across all available data from both study phases. For patients with positive ADA, 
the magnitude (titer), time of onset, and duration of ADA response will also be described, if 
data permit.
Table 14. Patients Characterized Based on Anti-Drug Antibody Results (ADA Status)
Category
Definition
Patients 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 post-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.


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The effect of ADA on avelumab concentrations/pharmacokinetics may be evaluated, if data 
permit. A comparison of safety and efficacy endpoints between avelumab ADA and Nab 
positive vs. negative patients may be performed, if data permit.
Blood samples for avelumab immunogenicity testing is collected pre-dose of  Cycle 1 Day 1 
and Day 15, and pre-dose in Day 1 of Cycles 2, 3, 4, 9, 12, 18, and 24. Samples collected 
pre-dose on the day of avelumab dosing will be included in the analysis. 
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb, if data 
permit.  
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 14.  
The number and percentage of patients in each ADA and nAb category will be summarized, 
if data permit.
If data are analyzed for nAb, patients will be characterized into different nAb categories 
based on the criteria in Table 15. For nAb, treatment-boosted is not applicable since no titer 
result is available.
Table 15. Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Patients 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 post-
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.


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.
6.4. Subset Analyses
OR and DR (if meaningful) will also be summarized for patients in the following subsets 
including data from Phase 2.
Within each treatment group: 
•
ECOG: 0, ≥1
•
Number of prior anti-cancer drug therapy regimens: 0, ≥1 
NSCLC patients pooled from treatment groups A1 and A2: 
•
Histology: Non-squamous, Squamous
•
Adenocarcinoma type: Yes, No
•
Received prior platinum treatment for locally advanced or metastatic disease: Yes, No 
Breast cancer (separately for treatment groups B1 and B2):
•
Received prior platinum treatment for locally advanced or metastatic disease: Yes, No
Ovarian cancer patients in treatment group C1:
•
BRCA status: BRCA defect, BRCA wild-type, Unknown
UC patients (treatment group D):
•
Visceral disease: Yes, No
•
Received prior platinum treatment for locally advanced or metastatic disease: Yes, No
CRPC patients pooled from treatment groups E1 and E2: 
•
Total Gleason score at diagnosis: ≤7, ≥8.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline summaries
The following analyses will be based on the FAS overall and separately by treatment group.
6.5.1.1. Demographic characteristics
Demographic characteristics will be summarized using the following information from the 
‘Screening/Baseline Visit’ eCRF pages.
CCI


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
Demographic characteristics 
-
Gender: Male, Female 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Not Reported
-
Ethnic origin: Hispanic/Latino (Yes/No/Not Reported)
-
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

Africa
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4 
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 group, age, sex, race, ethnicity and ECOG 
performance status.


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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 ‘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’ and RECIST eCRF 
pages will be summarized for the following.
From the ‘Primary Diagnosis’ eCRF page:

Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page)

Time since initial diagnosis to start date (months), defined as (start date – date of initial 
diagnosis)/30.4375
From the RECIST eCRF page:

Measurable disease (lesions) at baseline (Yes, No, No disease)

Involved tumor sites at baseline
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ eCRF page) and derived variables as above.
6.5.1.4. Prior anti-cancer therapies
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages.
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:

Patients with at least one type of prior anti-cancer therapy

Patients with at least one prior anti-cancer drug therapy

Patients with at least one prior anti-cancer radiotherapy

Patients with at least one prior anti-cancer surgery


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Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:

At least one prior anti-cancer drug therapy

Number of prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4

Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced – Metastatic
Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived from the 
last treatment regimen.
The prior anti-cancer drugs will also be summarized based on the number and percentage of 
patients by the drug class 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. The summary 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.
Prior anti-cancer drug therapies will be included in the listing that follow with a flag to 
identify prior therapies. These will include the patient identification number, and all the 
relevant collected data-fields on the corresponding eCRF pages.

Listing of anti-cancer drug therapies 
6.5.2. Study conduct and patient disposition
The following analyses will be performed based on the FAS overall and separately by
treatment group.
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 treatment with study drug 
overall and by the main reason for discontinuation

Number and percentage of treated patients in each of the analysis sets defined in Section 4

Number and percentage of patients with study drug ongoing (separately for each study drug 
administered in combination)

Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug administered in 
combination)

Number and percentage of patients who entered follow-up

Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation

Number and percentage of patients who entered long-term follow-up

Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation


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In addition, the following will be summarized:

Number and percentage of treated 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 treated patients by center
In addition, a cross tabulation of patients who have discontinued/are ongoing treatment with 
avelumab vs patients who have discontinued/are ongoing treatment with talazoparib will also 
be provided.
6.5.2.2. Protocol deviations
All protocol violations that impact the safety of the patients and/or the conduct of the 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 group as shown 
in Table 5.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  I.e., 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 (i.e., 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 (i.e., all study drugs had dose=0 at that visit).  Use earliest 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;


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
for the last cycle, actual cycle end date = actual cycle start date + 28 (in days) – 1 day
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/or overall) 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 (e.g., 
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 assuming 1 cycle = 4 weeks and for the following study 
drugs (administered alone or in combination):

Avelumab administered as a 1-hour IV infusion at a fixed dose of 800 mg once every 2 
weeks in 4-week cycles.

Talazoparib administered orally QD PO daily at dose of 1.0 mg, 0.75 mg or 0.5 mg.
6.5.3.1. Exposure to avelumab
The dose level for avelumab is calculated as actual dose administered (mg).
Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of avelumab +1)/7, 
where end date = start date of last cycle with non-zero dose of avelumab + 28 – 1
Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab – first dose date of avelumab + 14)/7  
Cumulative dose (mg) is the sum of the actual doses of avelumab received.  
Actual Dose Intensity (DI)

Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/4].  
Relative Dose Intensity (RDI)  

Intended DI (mg/4-week cycle) 
= [intended cumulative dose per cycle] / [intended number of 4-weeks in a cycle] 


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= [2 × 800 (mg)] / [1 (4-week cycle)]  
= 1600 (mg/4-week cycle)

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [1600 (mg/4-week cycle)] 
6.5.3.2. 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 +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  
Note: For talazoparib, the duration of exposure and the intended duration of treatment are the 
same.
Cumulative dose (mg) 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=1.0, 0.75 or 0.5.
6.5.3.3. Dose reductions
Applicable to talazoparib. Dose reduction is defined as a change to a non-zero dose level 
lower than the RP2D.
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) will be summarized.
6.5.3.4. Dose interruptions
Applicable to talazoparib.  


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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, then it will be counted only 
once (example: If the actual dose on days 1-3 is at the RP2D and actual dose on days 4-5 
is 0 mg, then the total number of dose interruptions is 1).

If an interruption occurs for more than one day, but the days are not consecutive, i.e. 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 at the RP2D and 
actual dose on days 2 and 4 is 0 mg, 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. A breakdown of the number of dose interruptions (1, 2, 3, ≥4) will be 
summarized.
6.5.3.5. Dose delays
Applicable to avelumab.
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. 
For Cycle 1:
Dose Delay (days) = day of the first day of study drug -1
After the first dose of Cycle 1:
Dose Delay for Dose x (days) 
= Date of Dose x – Date of Dose (x-1) – Planned days between two consecutive doses
= Date of dose x of study drug – Date of dose (x-1) of study drug – 15
Dose delays will be grouped into the following categories: 

No delay 

1-2 days delay

3-6 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 or 17, this is considered as 1-2 days delay.  
No delay and 1-2 days delay will be summarized together. 


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The number and percentage of patients with delayed study drug administration and maximum 
length of delay, i.e., the worst case of delay if patients have multiple dose delays will be 
summarized.
6.5.3.6. Infusion rate reductions
Applicable to avelumab.
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.
6.5.3.7. Infusion interruptions
Applicable to avelumab.
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (i.e., 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 group as shown 
in Table 5.
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study drugs and pre-medications for study drug, which are started before the first dose of 
study treatment. 
Concomitant medications will be summarized from the ‘General Concomitant Medications’ 
eCRF page. 
Summary of concomitant 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 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. 
6.5.5. Subsequent anti-cancer therapies
The following analyses will be based on the FAS by treatment group.


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Anti-cancer drug treatment will be provided in a data listing with data retrieved from 
‘Follow-up Cancer Therapy’ eCRF page. 
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 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 group as shown in Table 5.
Summaries described below by SOC and PT may further be presented by PT in decreasing 
frequency based on the frequencies observed in the overall group.  
6.6.1. Adverse events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
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).  


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
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 [SRP] and finalized for analysis of the current study
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 
SRP and finalized for analysis of the current study data prior to DB lock.
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 group, primary SOC 
and PT in decreasing frequency based on the frequencies observed for the group with all 
patients in the Phase 1b treated with talazoparib at the RP2D and in the Phase 2 combined. 
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:
-
TEAEs
-
TEAEs, Grade ≥ 3
-
Related TEAEs
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to discontinuation of any study drug
-
TEAEs leading to discontinuation of all study drugs
-
Related TEAEs leading to discontinuation of any study drug
-
Related TEAEs leading to discontinuation of all study drugs


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-
Serious TEAEs
-
Related Serious TEAEs 
-
TEAEs leading to death
-
Related TEAEs leading to death
-
irAEs
-
IRRs 

TEAEs by SOC and PT and worst grade

TEAEs related to any study drug by SOC and PT and worst grade

TEAEs leading to death by SOC and PT

Related TEAEs leading to death 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 talazoparib by SOC, PT and treatment 
group. 
6.6.1.3. 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 group:

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. 
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 group.  

All deaths 

Deaths within 30 days after last dose of study treatment

Reason for Death 
-
Disease progression


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-
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 group:

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 group:

irAEs leading to death, by Cluster and PT

irAEs, by Cluster and PT

irAEs, Grade ≥ 3, 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 group:

IRRs leading to death, by PT

IRRs, by PT

IRRs, Grade ≥ 3, by PT

Serious IRRs, by PT.


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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.
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). 
Abnormalities classified according to NCI-CTCAE toxicity grading v.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

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])


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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 group:

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. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with concurrent 
(ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing) and with an 
ALP ≤ 2×ULN or missing 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 number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)).
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie:

Hematology: 


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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), 
Triglycerides 
(hypertriglyceridemia).
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 

shifts from baseline normal to at least one result below normal during on-treatment period
In this study, these apply to the following parameters: 

Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils

Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH)
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) and prothrombin time (INR).
Urinalysis: all urinalysis parameters
Other parameters: hormone, and immunology parameters
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. 


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6.6.6. Electrocardiogram
QTcB and QTcF will be derived based on RR and QT (see below). The average of the 
replicate measurements should be determined after the derivation of the individual parameter 
at each time point.
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB 
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF 
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions. If QTcB and 
QTcF methods do not adequately correct for HR and there are a sufficient number of patients 
(eg >30) with baseline ECGs, an alternate correction to achieve the goal of getting 
uncorrelated QTc and RR is based on a linear regression method which yields, theoretically, 
uncorrelated QTc and RR.
Linear regression method:

Fit a model QT = a + b × RR to baseline data 

Use the estimated slope,  
^
b , to correct QT

Corrected QT for heart rate will be computed as follows:
QTcP = QT + 
^
b × (1- RR)
Data will be summarized using QTcF and QTcB. However, if these are not appropriate for 
the data set due to an observed large correlation between corrected QT and HR using the 
baseline assessments, the results will also be summarized using QTcP.  


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ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category.

Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:           
-
QT/QTc increase from baseline >30 ms, >60 ms
-
QT/QTc > 450 ms, > 480 ms, > 500 ms
-
HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm
-
HR ≥ 120 bpm and increase from baseline ≥ 20 bpm
-
PR ≥ 220 ms and increase from baseline ≥ 20 ms
-
QRS ≥ 120 ms 
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings.
7. INTERIM ANALYSES
There is no formal interim analysis planned for this study.
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Not applicable.


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8. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
2.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413, 1934.
3.
Ji Y, Wang S. Modified Toxicity Probability Interval Design: A Safer and More 
Reliable Method Than the 3+3 Design for Practical Phase I Trials. Journal of Clinical 
Oncology 31:1785-2792, 2013.
4.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience. 2002.  
5.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.


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9. APPENDICES
Appendix 1. Immune-Related Adverse Events
The MedDRA PTs and clusters for irAEs are defined in the SRP for avelumab.
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 16.  
Unless otherwise noted, this case definition is hierarchical, ie, each step is only checked for 
patients and events that have already met the prior step.  
Table 16.
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’
Steps 3 and 4 will be checked concurrently.  Step 5 
will be checked if the criteria in Step 4 is met, 
irrespective of whether the Criteria in Step 3 is met.
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) OR C) 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 17
and will be identified for IV drugs only.     
Table 17.
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs
Conditio
n
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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Appendix 3. Abbreviations and Definitions of Terms
The following is a list of abbreviations that may be used in the Statistical Analysis Plan.
ADA
Anti-Drug Antibody
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT 
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATM
Ataxia-Telangiectasia Mutated
BOR
Best Overall Response
BRCA
BReast CAncer Gene
CA-125
Cancer Antigen 125
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
Ctrough
Lowest (trough) Concentration 
CR
Complete Response
CRF
Case Report Form
CRPC
Castration Resistant Prostate Cancer
CSR
Clinical Study Report
CTC
Circulating Tumor Cell
CTCAE 
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DDR
DNA Damage Repair
DLT
Dose-Limiting Toxicity
DR
Duration of response
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
End of Treatment
HER2
Human Epidermal Growth Factor Receptor 2
HR+
Hormone Receptor Positive
irAE
Immune-Related Adverse Event
IV
Intravenous
mCRPC
metastatic Castration Resistant Prostate Cancer
MedDRA
Medical Dictionary for Regulatory Activities
N/A
Not Applicable
nAb
Neutralizing Antibody
NCI 
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PCWG3
Prostate Cancer Working Group 3
PD
Progressive Disease 
PD-1
Programmed Death 1
PD-L1
Programmed Death-Ligand 1
PFS
Progression-Free Survival


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PR
Partial Response
PSA
Prostate-Specific Antigen
Q2W
Every 2 Weeks
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
TBILI
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
Tmax
Time to Maximum Plasma Concentration
TTR
Time-to-Tumor Response
UC
Urothelial Cancer
ULN 
Upper Limit of Normal