Conditions: Squamous Cell Carcinoma of the Head and Neck (SCCHN) Metastatic Castration Resistant Prostate Cancer (mCRPC)
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 3
Healthy volunteers: no

Brief summary:
Evaluation of the combination of avelumab + bempegaldesleukin (NKTR-214 ) in locally advanced squamous cell carcinoma of the head and neck ( metastatic SCCHN) and avelumab + bempegaldesleukin (NKTR-214) + talazoparib or enzalutamide in metastatic castration resistant prostate cancer (mCRPC).

Detailed description:
Phase 1b/ Phase 2 Design

Phase 1b will be the sequential dose-finding study.

Once the Phase 1b component is completed, Phase 2 will be initiated to further evaluate the safety and anti-tumor activity across combinations of therapy.

Combination A will enroll participants with SCCHN.

Combination B and C will enroll participants with mCRPC

Arms:
arm 1: Avelumab + Bempegaldesleukin (NKTR-214) for treatment of locally recurrent (not amendable for treatment with curative intent) or metastatic squamous cell carcinoma of the head and neck arm 2: Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib for treatment of metastatic castration-resistant prostate cancer (mCRPC). Phase 2 will focus on enrolling participants with DDR defect positive mCRPC. arm 3: Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for Treatment of mCRPC

Interventions: intervention 1: avelumab intervention 2: Bempegaldesleukin intervention 3: talazoparib intervention 4: enzalutamide
Intervention descriptions: intervention 1: Investigational fully human anti-PD-L1 monoclonal antibody intervention 2: Investigational CD122-biased cytokine agonist intervention 3: poly (adenosine diphosphate \[ADP\] ribose) polymerase (PARP) inhibitor intervention 4: androgen receptor inhibitor

Protocol document:
Prot_000.pdf: 
Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 1
Title Page
Protocol Title: A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of 
Avelumab in Combination with Bempegaldesleukin (NKTR-214) with or without 
Talazoparib or Enzalutamide in Participants with Locally Advanced or Metastatic 
Solid Tumors 
Protocol Number: B9991040
Amendment Number:1
Compound Number: PF-06834635, NKTR-214, PF-04998299, and PF-06944076
Study Phase: Phase 1b/Phase 2
Short Title: JAVELIN IL-2 Medley
Acronym: not applicable
Sponsor Name: Pfizer, Inc
Legal Registered Address: 235 East 42nd Street, New York, NY 10017-5755, USA
Regulatory Agency Identifier Number(s)
Registry
ID
EudraCT
2019-001358-24
IND
142,664
Approval Date: 27 June 2019
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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 2
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Original Protocol
03-May-2019
Amendment 1
27-JUN-2019
Amendment 1 (27-JUN-2019)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment:
The overall rationale for the changes implemented in the protocol amendment are to expand 
the Dose Limiting Toxicity (DLT) criteria following the feedback received from the FDA
during the Investigational New Drug (IND) application review. 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
PFIZER CONFIDENTIAL
Page 3
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 4
TABLE OF CONTENTS
Protocol Amendment Summary of Changes Table..........................................................2
TABLE OF CONTENTS...........................................................................................................4
LIST OF TABLES...................................................................................................................12
LIST OF FIGURES .................................................................................................................13
1. PROTOCOL SUMMARY...................................................................................................14
1.1. Synopsis ..................................................................................................................14
1.2. Schema ....................................................................................................................30
1.3. Schedule of Activities (SoA)...................................................................................31
1.3.1. Table 4.  SoA for SCCHN Phase 1b and Phase 2 (Combination A): 
Screening, Cycle 1 and Cycle 2.......................................................................31
1.3.2. Table 5.  SoA for SCCHN Phase 1b and Phase 2 (Combination A): 
Cycle ı 3 and Post-Treatment........................................................................38
1.3.3. Table 6.  SoA for mCRPC Phase 1b and Phase 2 (Combinations B 
and C): Screening, Cycle 1, and Cycle 2 .........................................................44
1.3.4. Table 7.  SoA for mCRPC Phase 1b and Phase 2 (Combinations B 
and C): Cycle ı 3 and Post-treatment ............................................................53
2. INTRODUCTION ...............................................................................................................61
2.1. Study Rationale .......................................................................................................61
2.1.1. Rationale for Combination A (Avelumab + Bempegaldesleukin 
[NKTR-214]) for SCCHN ...............................................................................61
2.1.2. Rationale for Combination B (Avelumab + Bempegaldesleukin 
[NKTR-214] + Talazoparib) for mCRPC........................................................62
2.1.3. Rationale for Combination C (Avelumab + Bempegaldesleukin 
[NKTR-214] + Enzalutamide) for mCRPC.....................................................63
2.1.4. Rationale for Phase 1b Study Design: Bayesian Logistic Regression 
Model (BLRM) Design....................................................................................63
2.2. Background .............................................................................................................64
2.2.1. SCCHN.......................................................................................................64
2.2.2. Prostate Cancer ...........................................................................................65
2.2.3. Avelumab....................................................................................................66
2.2.3.1. Avelumab Mechanism of Action ..............................................66
2.2.3.2. Avelumab Clinical Experience..................................................66
2.2.4. Bempegaldesleukin (NKTR-214)...............................................................67
2.2.4.1. Bempegaldesleukin (NKTR-214) Mechanism of Action..........67


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 5
2.2.4.2. Bempegaldesleukin (NKTR-214) Clinical Experience.............68
2.2.4.3. Bempegaldesleukin (NKTR-214) plus Nivolumab Clinical 
Experience .........................................................................................68
2.2.5. Talazoparib .................................................................................................70
2.2.5.1. Talazoparib Mechanism of Action............................................70
2.2.5.2. Talazoparib Clinical Experience ...............................................71
2.2.6. Enzalutamide ..............................................................................................72
2.2.6.1. Enzalutamide Mechanism of Action.........................................72
2.2.6.2. Enzalutamide Clinical Experience ............................................73
2.3. Benefit/Risk Assessment.........................................................................................73
2.4. Drug-Drug Interactions ...........................................................................................76
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS ............................................................76
4. STUDY DESIGN.................................................................................................................81
4.1. Overall Design.........................................................................................................81
4.1.1. DLT Determination ....................................................................................85
4.2. Scientific Rationale for Study Design.....................................................................87
4.3. Justification for Dose ..............................................................................................87
4.3.1. Avelumab + Bempegaldesleukin (NKTR-214): Combination A...............87
4.3.2. Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib 
(Combination B); Avelumab + Bempegaldesleukin (NKTR-214) + 
Enzalutamide (Combination C) .......................................................................88
4.4. End of Study Definition ..........................................................................................88
5. STUDY POPULATION......................................................................................................89
5.1. Inclusion Criteria.....................................................................................................89
5.2. Exclusion Criteria....................................................................................................93
5.3. Lifestyle Considerations..........................................................................................96
5.4. Screen Failures ........................................................................................................97
6. STUDY INTERVENTION..................................................................................................97
6.1. Study Intervention(s) Administered........................................................................97
6.1.1. Avelumab Administration ..........................................................................97
6.1.1.1. Avelumab Dosage and Packaging.............................................97
6.1.1.2. Administration of Avelumab.....................................................98
6.1.1.3. Special Precautions for Administration of Avelumab...............99


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 6
6.1.2. Administration of Bempegaldesleukin (NKTR-214) .................................99
6.1.2.1. Special Precautions for Administration of 
Bempegaldesleukin (NKTR-214)....................................................100
6.1.3. Talazoparib Administration......................................................................101
6.1.3.1. Talazoparib Pre-medication ....................................................101
6.1.3.2. Administration of Talazoparib ................................................101
6.1.4. Enzalutamide Administration...................................................................101
6.1.4.1. Enzalutamide Pre-medication .................................................101
6.1.4.2. Administration of Enzalutamide .............................................101
6.2. Preparation/Handling/Storage/Accountability ......................................................102
6.3. Measures to Minimize Bias: Randomization and Blinding...................................103
6.4. Study Intervention Compliance.............................................................................103
6.5. Concomitant Therapy............................................................................................104
6.5.1. Permitted Concomitant Medications ........................................................105
6.5.2. Concomitant Radiotherapy.......................................................................106
6.5.3. Concomitant Surgery................................................................................106
6.5.4. Hematopoietic Growth Factors.................................................................106
6.5.5. Other Prohibited Concomitant Medicines and Therapies.........................107
6.5.6. Corticosteroids..........................................................................................108
6.5.7. Rescue Medication and Supportive Care..................................................109
6.5.7.1. Supportive Care Guidelines ....................................................109
6.5.7.2. Treatment after Initial Evidence of Radiological Disease 
Progression ......................................................................................109
6.6. Dose Modification.................................................................................................110
6.6.1. Recommended Dose Modifications..........................................................110
6.6.2. Study Treatment Modifications for Drug Related Toxicity (excluding 
infusion related reactions and immune related adverse events).....................113
6.6.2.1. Dose Modifications for Avelumab + Bempegaldesleukin 
(NKTR-214) Doublet (Combination A)..........................................113
6.6.2.2. Dose Modifications for Avelumab + Bempegaldesleukin 
(NKTR-214) + Talazoparib Triplet (Combination B).....................116
6.6.2.3. Dose Modifications for Avelumab + Bempegaldesleukin 
(NKTR-214) + Enzalutamide Triplet (Combination C)..................121
6.6.3. Immune-Related AEs................................................................................127


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 7
6.7. Intervention after the End of the Study.................................................................132
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.........................................................................132
7.1. Discontinuation of Study Intervention ..................................................................132
7.1.1. Abnormal Electrocardiograms (ECGs).....................................................133
7.2. Participant Discontinuation/Withdrawal from the Study......................................134
7.3. Lost to Follow up ..................................................................................................135
8. STUDY ASSESSMENTS AND PROCEDURES.............................................................136
8.1. Efficacy Assessments............................................................................................136
8.1.1. Tumor Efficacy Imaging Assessments .....................................................136
8.1.1.1. Tumor Related Endpoints and Definitions for 1L SCCHN 
(Combination A)..............................................................................136
8.1.1.2. Tumor Related Endpoints and Definitions for mCRPC 
(Combinations B and C)..................................................................137
8.1.2. Clinical Assessments ................................................................................138
8.1.2.1. Blood for Lymphocyte Count .................................................138
8.1.2.2. Circulating Tumor Cells (CTCs) for Participants with 
mCRPC (Combination C)................................................................138
8.1.2.3. PSA Antibody Testing for Participants with mCRPC 
(Combinations B and C)..................................................................138
8.1.2.4. Testosterone for Participants with mCRPC (Combinations 
B and C)...........................................................................................139
8.2. Safety Assessments ...............................................................................................139
8.2.1. Physical Examinations..............................................................................139
8.2.2. Vital Signs ................................................................................................140
8.2.3. Clinical Safety Laboratory Assessments ..................................................140
8.2.4. Pregnancy Testing ....................................................................................141
8.2.5. Electrocardiograms...................................................................................141
8.2.6. Echocardiogram/Multigated Acquisition Scan (ECHO/MUGA).............142
8.2.7. ECOG Performance Status .......................................................................142
8.3. Adverse Events and Serious Adverse Events........................................................142
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.....142
8.3.1.1. Reporting SAEs to Pfizer Safety.............................................143
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 8
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF ...............143
8.3.2. Method of Detecting AEs and SAEs ........................................................144
8.3.3. Follow-up of AEs and SAEs.....................................................................144
8.3.4. Regulatory Reporting Requirements for SAEs.........................................144
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ........................................................................................................145
8.3.5.1. Exposure During Pregnancy....................................................145
8.3.5.2. Exposure During Breastfeeding ..............................................145
8.3.5.3. Occupational Exposure ...........................................................145
8.3.6. Medication Errors .....................................................................................145
8.4. Treatment of Overdose..........................................................................................146
8.5. Pharmacokinetics ..................................................................................................147
8.5.1. Blood for PK Analysis of Avelumab........................................................148
8.5.2. Blood for PK Analysis of Bempegaldesleukin (NKTR-214) 
 
8.5.3. Blood for PK Analysis of Talazoparib .....................................................148
8.5.4. Blood for PK Analysis of Enzalutamide and N-Desmethyl-
Enzalutamide..................................................................................................148
8.6. Pharmacodynamics................................................................................................149
8.6.1. Tumor and other Biospecimens................................................................149
8.6.2. Collection of Samples for Pharmacodynamic Analysis ...........................149
8.7. Genetics.................................................................................................................149
8.7.1. Specified Genetics ....................................................................................149
8.8. Biomarkers ............................................................................................................150
8.8.1. Tumor Tissue Assessments.......................................................................150
8.8.1.1. Mandatory Tumor Tissue (1L SCCHN, Combination A).......150
8.8.1.2. Mandatory Tumor Tissue (mCRPC, Combinations B and 
C).....................................................................................................150
8.8.1.3. Mandatory Baseline Tumor Tissue for DDR Defect 
Assessment (Combination B – Phase 2 only)..................................151
8.8.1.4. On-Study Tumor Tissue (SCCHN, Combination A) ..............152
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 9
8.8.2. Other Biomarker Assessments..................................................................153
8.8.2.1. Saliva Sample for Germline Comparator................................153
8.8.2.2. Saliva sample for Targeted Germline DDR Assessment 
(Phase 2 Combination B only) ........................................................153
8.8.3. Immunogenicity Assessments ..................................................................154
8.8.3.1. Analysis of ADAs and NAbs for Avelumab...........................154
8.8.3.2. Analysis of ADAs and NAbs for Bempegaldesleukin 
(NKTR-214) ....................................................................................154
8.9. Health Economics ................................................................................................155
9. STATISTICAL CONSIDERATIONS ..............................................................................155
9.1. Estimands and Statistical Hypotheses...................................................................155
9.1.1. Estimands..................................................................................................155
9.1.2. Statistical Methods and Properties............................................................156
9.1.2.1. Statistical Methods for Dose Finding: BLRM ........................156
9.2. Sample Size Determination...................................................................................159
9.3. Populations for Analyses.......................................................................................161
9.4. Statistical Analyses ...............................................................................................162
9.4.1. Efficacy Analyses .....................................................................................163
9.4.2. Safety Analyses ........................................................................................166
9.4.3. Analysis of Pharmacokinetics, Pharmacodynamics, and Biomarkers......166
9.4.3.1. Analysis of Pharmacokinetics of Investigational Products.....167
9.4.3.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/Pharmacodynamic) 
Modeling..........................................................................................167
9.4.3.3. Analysis of Biomarker Endpoints ...........................................167
9.4.3.4. Analysis of Avelumab Immunogenicity Data.........................168
9.4.3.5. Analysis of Bempegaldesleukin Immunogenicity Data..........168
9.5. Interim Analyses ...................................................................................................168
9.5.1. Data Monitoring Committee (DMC)........................................................168
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 10
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................168
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............168
10.1.1. Regulatory and Ethical Considerations ..................................................168
10.1.2. Financial Disclosure ...............................................................................169
10.1.3. Informed Consent Process ......................................................................169
10.1.4. Data Protection .......................................................................................171
10.1.5. Dissemination of Clinical Study Data ....................................................171
10.1.6. Data Quality Assurance ..........................................................................172
10.1.7. Source Documents..................................................................................174
10.1.8. Study and Site Closure............................................................................174
10.1.9. Publication Policy...................................................................................174
10.1.10. Sponsor’s Qualified Medical Personnel ...............................................175
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................176
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................179
10.3.1. Definition of AE .....................................................................................179
10.3.2. Definition of SAE...................................................................................180
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE.......................181
10.3.4. Reporting of SAEs..................................................................................184
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..............................................................................................................185
10.5. Appendix 5: Genetics..........................................................................................189
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......190
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................192
10.8. Appendix 8: ECOG Performance Status.............................................................194
10.9. Appendix 9: Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines ............................................................................................195
10.10. Appendix 10: Assessment of Radiographic Response and Progression in 
Participants with mCRPC........................................................................................200
10.11. Appendix 11: BLRM Design for Avelumab and Bempegaldesleukin 
(NKTR-214) Doublet - Combination A ..................................................................202
10.12. Appendix 12: BLRM Design for Talazoparib Triplet - Combination B...........211
10.13. Appendix 13: BLRM Design for Enzalutamide Triplet – Combination C .......221


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 11
10.17. Appendix 17: Abbreviations .............................................................................238
11. REFERENCES   .............................................................................................................246
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 12
LIST OF TABLES
Table 1.
Phase 1b Combination A 1L SCCHN Avelumab + 
Bempegaldesleukin (NKTR-214) Dose Levels........................................23
Table 2.
Phase 1b Combination B mCRPC Avelumab, Bempegaldesleukin 
(NKTR-214), and Talazoparib Dose levels..............................................25
Table 3.
Phase 1b Combination C mCRPC Avelumab, Bempegaldesleukin 
(NKTR-214) and Enzalutamide Dose levels ............................................25
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): 
Screening, Cycle 1 and Cycle 2................................................................31
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ı
3 and Post-Treatment................................................................................38
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): 
Screening, Cycle 1 and Cycle 2................................................................44
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): 
Cycle ı 3 and Post-Treatment.................................................................53
Table 8.
Phase 1b Combination A 1L SCCHN Avelumab + 
Bempegaldesleukin (NKTR-214)  Dose Levels.......................................82
Table 9.
Phase 1b Combination B mCRPC Avelumab, Bempegaldesleukin 
(NKTR-214), and Talazoparib Dose levels..............................................82
Table 10.
Phase 1b Combination C mCRPC Avelumab, Bempegaldesleukin 
(NKTR-214), and Enzalutamide Dose levels ...........................................84
Table 11.
Treatment Modification for Symptoms of Infusion related 
Reactions Associated with Avelumab ....................................................111
Table 12.
Treatment Modification for Symptoms of Infusion related 
Reactions Associated with Bempegaldesleukin (NKTR-214) ...............112
Table 13.
Avelumab and Bempegaldesleukin (NKTR-214) Treatment 
Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)........................................114
Table 14.
Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib 
Triplet Treatment Modifications for Drug Related Toxicity 
(Excluding Infusion Related Reactions and Immune Related AEs).......118
Table 15.
Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide 
Triplet Treatment Modifications for Drug Related Toxicity 
(Excluding Infusion Related Reactions and Immune Related AEs).......123
Table 16.
Management of Immune Related Adverse Events for Avelumab and 
Bempegaldesleukin (NKTR-214)...........................................................127
Table 17.
B9991040 Sample Size and Exact 95% Confidence Interval for 
ORR/PSA Response Rate.......................................................................161


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 13
LIST OF FIGURES
Figure 1.
B9991040 Study Schematic......................................................................30


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 14
1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of 
Avelumab in Combination with Bempegaldesleukin (NKTR-214) with or without 
Talazoparib or Enzalutamide in Participants with Locally Advanced or Metastatic 
Solid Tumors 
Short Title: JAVELIN IL-2 Medley
Rationale:
Combination A: Avelumab + Bempegaldesleukin (NKTR-214) for treatment of locally 
recurrent (not amendable for treatment with curative intent) or metastatic squamous 
cell carcinoma of the head and neck (1L SCCHN)
Avelumab (MSB0010718C) is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) 
directed against programmed death receptor ligand 1 (PD-L1).  Avelumab selectively binds 
to PD-L1 and competitively blocks its interaction with the 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 approved 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 urothelial cancer (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.
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Currently, there are 2 ongoing Phase 3 studies investigating avelumab and 
chemoradiotherapy in locally advanced (LA) SCCHN, study B9991016 (NCT02952586) and 
the Randomized Trial of Avelumab-cetuximab-radiotherapy versus Standard of Cares 
(SOCs) in LA SCCHN (REACH) study (NCT02999087).  
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 15
Bempegaldesleukin (NKTR-214) is a CD122-biased cytokine agonist conjugated with 
multiple releasable chains of polyethylene glycol designed to provide sustained signaling 
through the heterodimeric interleukin-2 (IL-2) receptor pathway to preferentially activate and 
expand effector CD8+ T and natural killer (NK) cells over regulatory T-cells.2,3  
 
 
 
 
 
 
The combination of bempegaldesleukin (NKTR-214) with nivolumab in the PIVOT-02 study 
has showed preliminary evidence of improved clinical activity with the observed response 
rates comparing favorably when referencing to anti-PD-1/PD-L1 single agents data sets from 
phase 3 studies; clinical activity was observed also in patients with PD-L1 negative disease.5
Consistent with the mechanisms of actions of both agents, increased T-cell infiltration was 
observed in tumors and conversion of baseline PD-L1 negative disease to PD-L1 positive 
disease at week 3 of treatment was reported in serial biopsies from 7/10 patients in the 
PIVOT-02 study.6
Similar effect is expected when combining avelumab with bempegaldesleukin, and the 
combination may lead to increased PD-L1 expression and potentially improved anti-tumor 
activity over single-agent checkpoint inhibitors in locally recurrent (1L) SCCHN. Indeed, in 
the KEYNOTE-048 Phase 3 study (NCT02358031) of pembrolizumab or pembrolizumab + 
chemotherapy vs. EXTREME (platinum-based chemotherapy + 5-fluorouracil [5-FU]) as 
first-line systemic therapy for R/M SCCHN, the observed clinical benefit correlated with 
PD-L1 expression level.  The confirmed ORR was (pembrolizumab vs EXTREME) 23% vs 
36% for PD-L1 combined positive score (CPS) ≥20, 19% vs 35% for CPS ≥1, and 17% vs 
36% for the total population. Also, the observed overall survival benefit was dependent on 
the baseline PD-L1 expression level with a reported hazard ratio favoring pembrolizumab 
over EXTREME of 0.61 (95% confidence interval [CI] 0.45-0.83) and 0.78 (95% CI 0.64-
0.96) for the CPS ≥20 and CPS ≥1 populations, respectively.7
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 16
Based on current data, the avelumab + bempegaldesleukin (NKTR-214) combination is 
expected to enhance anti-tumor activity over single-agent checkpoint inhibitor in study 
participants with 1L SCCHN whose disease is positive or negative PD-L1 expression at 
baseline.
Combination B: Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib for 
treatment of DNA Damage Repair (DDR) + metastatic castration-resistant prostate 
cancer (mCRPC)
Single agent treatment with immune checkpoint blockers, including avelumab, delivers only 
modest clinical benefit in prostate cancer and correlative studies have demonstrated that the 
prostate tumor microenvironment is predisposed toward immunosuppression.8
As previously discussed, the combination of bempegaldesleukin (NKTR-214) with 
nivolumab in the PIVOT-02 study demonstrated preliminary signs of clinical activity 
referencing to anti-PD-1/PD-L1 single agents.5  Combination strategies aimed to enhance the 
immune recognition of the tumor create the potential for a therapeutically relevant treatment 
in prostate cancer.  One proposed treatment combination for evaluation in this study is the 
triplet of avelumab + bempegaldesleukin (NKTR-214) + talazoparib (Combination B).  
Talazoparib is a potent, small molecule poly (adenosine diphosphate [ADP]-ribose) 
polymerase inhibitor (PARPi) in development for the treatment of a variety of human 
cancers.  Talazoparib is a particularly potent PARP trapper, a property that is associated with 
cytotoxicity in preclinical models.9  Single agent treatment with talazoparib demonstrates 
potent antitumor effects in tissue culture studies, mouse tumor xenograft models, and in 
Phase 1 studies in patients with solid tumors.  Talazoparib has also been shown to enhance 
the cytotoxic effects of deoxyribose nucleic acid (DNA) damaging chemotherapy.  
Talazoparib was approved by the FDA on 16 October 2018 for the treatment of adults 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.10
Proof of concept of PARPi efficacy in metastatic castration-resistant prostate cancer 
(mCRPC) with DNA Damage Repair (DDR) deficiency was established in a Phase 2 study 
(TOPARP-A) with olaparib, which enrolled men heavily pre-treated with taxane based 
chemotherapy and novel hormonal therapy (NHT).  Of the 49 patients evaluable for response 
(defined either as an objective response according to Response Evaluation Criteria in Solid 
Tumors [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 [CTC] 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.11  These results were further confirmed with rucaparib in a similar 
therapeutic setting in the TRITON2 phase 2 study where the observed confirmed objective 
response rate (ORR) in mCRPC patients with BRCA1/2 defects was 45.5% (95% CI 
16.7-75.6).12  In addition, the combination of durvalumab and olaparib was evaluated in a 
Phase 2 study in 17 patients with mCRPC after progression on NHT and chemotherapy.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 17
Overall, 8 out of 17 patients had a reduction in PSA level ≥50% from baseline.  PSA level 
reductions were observed mainly in patients with mutations in DNA repair pathways, but 
also in some patients without alteration.13 In alignment with these findings, the combination 
of pembrolizumab and olaparib in the KEYNOTE-365 study showed early evidence of 
clinical activity in mCRPC patients whose disease was negative for homologous 
recombination defects (HRD) after treatment with taxane based chemotherapy and NHT with 
a reported ORR of 7% (95% CI 1-23), and disease control rate ≥6 months of 32% in patients 
with measurable disease.14
A key aim of the combination B in this study is to extend PARPi activity beyond BRCA 
deficiency to sustain and prolong responses to PARPi in mCRPC participants whose disease 
is positive for DDR defects (DDR+).  The proposed triple combination has the potential to 
activate several non-overlapping immune mechanisms to synergize and induce potent anti-
tumor immune response.  Talazoparib would induce the activation of proinflammatory 
dentritic cells (DCs) via stimulation of the interferon genes (STING) pathway to prime and 
differentiate tumor specific CD8 T-cells.15,16 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 
NK cell infiltration and activation in a mouse model of ovarian cancer.17 Bempegaldesleukin 
(NKTR-214) would allow the expansion of these CD8 T-cells as suggested by pre-clinical 
evidence that demonstrated improved anti-tumor activity for bempegaldesleukin 
(NKTR-214) + rucaparib in a BRCA-deficient and immuno-competent ovarian cancer 
model.2,3 Additionally, talazoparib treatment has been shown to lead to increased expression 
of PD-L1 by tumor cells18 suggesting that this may represent a mean by which tumors 
function to inhibit talazoparib-mediated anti-tumor immunity.  Addition of avelumab would 
release the checkpoint break by overcoming the PD-L1-mediated inhibition resulting in
anti-tumor immune response.
In summary, the proposed triple combination may produce enhanced anti-tumor activity with 
talazoparib, promoting immune priming and tumor immunogenicity and 
avelumab/bempegaldesleukin (NKTR-214) enhancing the anti-tumor immune response, so 
offering a therapeutic opportunity to patients with mCRPC after progression to taxane-based 
chemotherapy in the metastatic setting.
Combination C: Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide for 
Treatment of mCRPC
The second proposed treatment combination for mCRPC for this study is the triplet of 
avelumab + bempegaldesleukin (NKTR-214) + enzalutamide (Combination C).  Results from 
the PIVOT-02 study of bempegaldesleukin (NKTR-214) with nivolumab as discussed above 
also support the evaluation of avelumab plus bempegaldesleukin as the backbone of this 
triplet combination.
Enzalutamide is an androgen receptor inhibitor approved for treating patients with
non-metastatic castration-resistant prostate cancer (NM CRPC) as well as mCRPC.  
Preliminary results from the ARCHES study (NCT02677896) demonstrated that 
enzalutamide plus androgen deprivation therapy (ADT) also significantly improved 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 18
radiographic progression-free survival (rPFS) compared with ADT alone in patients with 
hormone-sensitive metastatic prostate cancer (mHSPC).  Enzalutamide acts by inhibiting the 
binding of androgens to the androgen receptor, androgen receptor nuclear translocation, and 
androgen receptor-mediated DNA binding and is currently being evaluated in combination 
with other anti-cancer therapies in Phase 3 studies, including atezolizumab (NCT03016312) 
and pembrolizumab (NCT03834493) in patients with mCRPC.  The combination of immune 
checkpoint blockers with androgen receptor blockers and CD8 T-cell stimulants may 
improve the therapeutic outcome of mCRPC patients.  In a study of biochemically recurrent 
prostate cancer, a preliminary analysis of 12 patients treated with a 3-month course of 
enzalutamide showed increases in NK cells and decreases in myeloid-derived suppressor 
cells (MDSC).19  In addition, patients who experienced progression during enzalutamide 
treatment showed increased PD-L1 expression on dendritic cells20 and encouraging evidence 
of clinical activity in patients were observed with pembrolizumab plus enzalutamide after 
progression on enzalutamide with PSA level reduction ≥50% reported in 5 out of 28 (18%) 
patients and radiographic response observed in 3 out of 12 patients (ORR=25%) with 
measurable disease at baseline.21  Moreover, the combination of pembrolizumab plus 
enzalutamide in mCRPC patients after abiraterone therapy failure induced PSA reduction 
≥50% in 18 out of 54 patients (33%) and radiographic response observed in 5 out of 25 
patients (ORR=20%) with measurable disease at baseline.22
Based on the above data, the proposed triplet combination could represent an effective 
treatment strategy by enzalutamide enhancing NK cells and lowering MDSC, 
bempegaldesleukin (NKTR-214) generating a robust CD-8 and NK cell level in the tumor 
tissue, and avelumab providing the release from the checkpoint blockade resulting from 
PD-L1-mediated inhibition of anti-tumor immune response. Therefore, Combination C may 
provide an innovative treatment option to mCRPC patients after disease progression on 
abiraterone treatment.
Objectives, Estimands and Endpoints
Primary Objectives
Primary Endpoints
Phase 1b: 

To assess the dose-limiting toxicity 
(DLT) rate of avelumab in combination 
with bempegaldesleukin (NKTR-214) 
(Combination A) and talazoparib 
(Combination B) or enzalutamide 
(Combination C) in order to determine 
the recommended Phase 2 dose (RP2D) 
for the combinations.
Phase 1b: 

DLT during the DLT evaluation period 
(Cycle 1)


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 19
Phase 2:

Combination A: To assess ORR of 
avelumab in combination with 
bempegaldesleukin (NKTR-214) in 
participants with locally recurrent or 
metastatic SCCHN.

Combination B: To assess soft tissue
ORR of avelumab in combination with 
bempegaldesleukin (NKTR-214) and 
talazoparib in participants with DDR 
defect positive mCRPC.

Combination C: To assess the PSA 
response rate of avelumab in combination 
with bempegaldesleukin (NKTR-214) 
and enzalutamide in participants with 
mCRPC after progression on abiraterone.
Phase 2:

Combination A: Confirmed objective 
response (OR) as determined by the 
investigator using RECIST v1.1 
(Appendix 9).

Combination B: Confirmed soft tissue 
OR as determined by the investigator 
using RECIST v 1.1 (Appendix 9) with 
no evidence of confirmed bone disease 
progression on repeat bone scan at least 6 
weeks later per PCWG3 criteria 
(Appendix 10).

Combination C: Confirmed prostate 
specific antigen (PSA) response decrease 
≥50% from baseline confirmed by a 
second consecutive assessment at least 3 
weeks later. 
Secondary Objectives
Secondary Endpoints

To assess the overall safety and 
tolerability of the combinations (A, B and 
C).

Adverse events (AEs) as characterized by 
type, severity (as graded by National 
Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI 
CTCAE] v4.03), timing, seriousness, and 
relationship to study therapy.

Laboratory abnormalities as characterized 
by type, severity (as graded by NCI 
CTCAE v4.03) and timing.

To assess other measures of antitumor 
activity.

Time-to-event endpoints as determined 
by the investigator, using RECIST v1.1 
(Combination A) and in participants with 
mCRPC (Combinations B and C), 
RECIST v1.1 (soft tissue disease) and 
PCWG3 (bone disease), including time to 
tumor response (TTR), duration of 
response (DR), progression free survival 
(PFS), and Overall Survival (OS).

Combination B: Confirmed PSA 
response ≥ 50% decrease from baseline 
confirmed by a second consecutive 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 20
assessment at least 3 weeks later.

Combination C: Confirmed soft tissue 
OR as determined by the investigator 
using RECIST v 1.1 (Appendix 9) with 
no evidence of confirmed bone disease 
progression on repeat bone scan at least 6 
weeks later per PCWG3 criteria 
(Appendix 10).

Combination C: Circulating tumor cells 
CTC count conversion (decrease in CTC 
count from ≥5 CTC per 7.5 mL of blood 
at baseline to < 5 CTC per 7.5 mL of 
blood at any assessment on treatment), 
and CTC0 (CTC0 is defined as a CTC 
count of ≥1 CTC per 7.5 mL of blood at 
baseline and 0 CTC per 7.5 mL of blood 
at any assessment on treatment).

Combinations B and C: Time to PSA 
progression (TTPSAP) defined according 
to the consensus guidelines of the 
Prostate Cancer Clinical Trials Working 
Group 3 (PCWG3) criteria.

To characterize the PK of avelumab, 
bempegaldesleukin (NKTR-214), and 
talazoparib or enzalutamide when given 
in combination.

PK parameters including trough 
concentrations (Ctrough) for avelumab, 
bempegaldesleukin (NKTR-214), 
talazoparib, enzalutamide, and N-
desmethyl-enzalutamide and maximum 
concentrations (Cmax) for avelumab and 
bempegaldesleukin (NKTR-214).

To assess the immunogenicity of 
avelumab and bempegaldesleukin when 
combined together and with talazoparib
or enzalutamide.

Anti-drug antibody (ADA) and 
neutralizing antibodies (NAb) against 
avelumab, bempegaldesleukin (NKTR-
214) and IL-2 when combined together 
and with talazoparib or enzalutamide. 

To assess the correlation of anti-tumor 
activity with PD-L1 expression level in 
baseline tumor tissue.

PD-L1 expression level in baseline tumor 
tissue.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 21

Combination A: To assess the 
correlation of anti-tumor activity with 
PD-L1 expression level in on-treatment 
tumor tissue.

Combination A: PD-L1 expression level 
in on-treatment tumor tissue.
Estimands
This section defines the estimands associated with the primary endpoints and the secondary 
efficacy endpoints of the study.
The populations associated with estimands for each combination are as follows:

Combination A - participants with 1L SCCHN.

Combination B Phase 1b - participants with mCRPC after progression on taxane-
based chemotherapy. Combination B Phase 2- participants with DDR defect 
positive mCRPC after progression on taxane-based chemotherapy.

Combination C - participants with mCRPC after progression on abiraterone
therapy.
The endpoint definitions, the observations that will be considered in the derivation of the 
endpoint and the associated analyses are described or referenced below.

Phase 1b: the primary endpoint (Combinations A, B and C) will be the occurrence 
of dose-limiting toxicity (DLT) during the primary DLT evaluation period (Cycle 
1).  DLTs are defined in Section 4.1 and the Synopsis.  DLTs will only be 
collected during Cycle 1 of Phase 1b and the DLT rate will be estimated for 
participants who are evaluable for DLTs.  DLT-evaluable participants are those 
enrolled in Phase 1b who 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 without 
DLT.  Participants without DLTs who withdraw from study treatment before 
receiving at least 2 doses of avelumab and bempegaldesleukin (NKTR-214; all 
Combinations) or 75% of the planned dose of talazoparib (Combination B) or 
enzalutamide (Combination C), in Cycle 1 for reasons other than treatment-
related toxicity are not evaluable for DLT.  All participants deemed non-evaluable 
for DLT may be replaced.

Phase 2 Objective Response (Combination A) or soft tissue Objective Response 
(Combination B): The primary estimand is the treatment effect of OR 
(Combination A) or soft tissue OR (Combination B) from the time of first dose 
until progression is met or subsequent anticancer therapy is administered.  Point 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 22
estimates and confidence intervals (following the methodology outlined in 
Section 9.4.1) will be calculated. 

Phase 2 PSA Response (Combination C): The primary estimand is the treatment 
effect of PSA response from the time of first dose until progression is met or 
subsequent anticancer therapy is administered.  Point estimates and confidence 
intervals (following the methodology outlined in Section 9.4.1) will be calculated. 

Phase 2 tumor-related endpoints (time to tumor response [TTR, Combinations A, 
B, and C], duration of response [DR, Combinations A, B and C], time to PSA 
progression [TTPSAP, Combinations B and C only], CTC count conversion and 
CTC0 [Combination C only]) are defined in Section 9.4.1.  This is a non-
randomized study and there will be no statistical comparisons between treatment 
groups; to address the objectives associated with tumor-related endpoints, point 
estimates and confidence intervals (following the methodology outlined in 
Section 9.4.1) will be calculated for each tumor-related endpoint including only 
assessments on or before start of new anti-cancer therapy and on or before 
progression.

Phase 2:  Overall survival (OS) is defined as the time from the first dose of study 
treatment to the date of death due to any cause. This is a non-randomized study 
and there will be no statistical comparisons between treatment groups; to address 
the OS objective,  point estimates and confidence intervals (following the 
methodology outlined in Section 9.4.1) will be calculated for OS including 
survival status for each participant at the time of the analysis; survival status is 
expected to be collected irrespective of study treatment discontinuation or 
participant’s request to discontinue study procedures.  All participants who have 
not withdrawn consent for further participation in the study should be followed 
for survival until at least 2 years after enrollment of the last participant in the 
study.
Overall Design:
This Phase 1b/2, open-label, multi-center study will include a dose-finding component of 
avelumab in combination with bempegaldesleukin (NKTR-214; Combination A), avelumab 
in combination with bempegaldesleukin (NKTR-214) and talazoparib (Combination B), and 
avelumab in combination with bempegaldesleukin (NKTR-214) and enzalutamide 
(Combination C). 
Phase 1b Design
Phase 1b will include 2 sequential dose-finding steps:
Step 1. Combination A will be evaluated in participants with 1L SCCHN to determine the 
recommended Phase 2 dose (RP2D).  Refer to Table 1 for the potential dose levels.  A 
minimum of 9 participants will be enrolled.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 23
Step 2.  Upon the determination of the RP2D for Combination A, the dose-finding for Phase 
1b for Combinations B and C in participants with mCRPC will commence and will be 
conducted in parallel with the Phase 2 Combination A portion of the study to determine the 
RP2D for Combinations B and C separately.  Refer to Table 2 and Table 3 for the potential 
dose levels for Combinations B and C, respectively.  A minimum of 9 participants will be 
enrolled in each combination.
Guidance for Phase 1b dosing (dose level to be evaluated in the next cohort) and enrollment 
(number of participants to be enrolled in the next cohort) decisions will be based on a 
Bayesian Logistic Regression Model (BLRM).   Refer to Appendix 11, Appendix 12, and
Appendix 13 for the BLRM designs for Combinations A, B, and C, respectively.  The BLRM 
incorporates single-agent and available combination DLT data (historical and prospectively 
across dose combinations) to estimate the posterior probability of under-dosing, target dosing 
and overdosing, thereby reducing participant risk and increasing efficiency and precision 
during dose finding with combination treatments.
Step 1. Dose-Finding for Combination A
The potential dose levels of avelumab and bempegaldesleukin (NKTR-214) for dose finding 
for Combination A are shown in Table 1.  The starting dose level is 800 mg avelumab 
intravenous (IV) every 2 weeks (Q2W) plus 0.006 mg/kg bempegaldesleukin Q2W, which 
satisfies the Escalation With Overdose Control (EWOC) criterion that the risk for excessive 
toxicity is less than 0.25.  For the starting dose level, the risk of excessive toxicity was 
estimated to be 13.7% based on information from prior single-agent Phase 1 studies and a 
pharmacokinetic (PK) assessment of no potential significant drug-drug interaction.  Dose 
reduction of bempegaldesleukin (NKTR-214) to 0.003 mg/kg Q2W will be triggered for 
future participants if higher than expected toxicity is observed at the higher dose (the risk of 
excessive toxicity ≥ 0.25).
Table 1.
Phase 1b Combination A 1L SCCHN Avelumab + Bempegaldesleukin
(NKTR-214) Dose Levels
Dose Level
Avelumab dose IV
(mg Q2W)
Bempegaldesleukin (NKTR-
214)  
(mg/kg Q2W)
D0
800
0.006
D-1
800
0.003
1L SCCHN= locally recurrent squamous cell carcinoma of the head and neck; D0= starting dose; D-1=reduced 
dose; IV= intravenous; mg= milligram; Q2W= every 2 weeks.
Step 2. Dose-Finding for Combinations B and C
The potential dose levels of avelumab, bempegaldesleukin (NKTR-214) and talazoparib for 
dose finding for Combination B are listed in Table 2.  The dose level for avelumab is fixed at 
800 mg Q2W. The starting dose level for bempegaldesleukin (NKTR-214) and talazoparib 
will be determined at the completion of the Phase 1b dose finding for Combination A based 
on available clinical data (including but not limited to safety and PK/pharmacodynamic


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 24
data).  The lowest allowed dose for bempegaldesleukin (NKTR-214) will be 0.003 mg/kg 
and the lowest allowed dose for talazoparib will be 0.5 mg once daily, in which case 
participants with moderate renal impairment cannot be enrolled.  The starting dose for 
talazoparib for participants with moderate renal impairment (creatinine clearance [CrCL] 30-
59 mL/min) will be reduced by 1 dose level unless the determined starting dose for 
talazoparib for participants with no or mild renal impairment is 0.5 mg once daily. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 25
Table 2.
Phase 1b Combination B mCRPC Avelumab, Bempegaldesleukin (NKTR-
214), and Talazoparib Dose levels
Dose Level
Avelumab Dose IV
(mg Q2W)
Bempegaldesleukin 
(NKTR-214) IV
(mg/kg Q2W)
Talazoparib Dose PO
(mg once daily)
D0-A*
800
0.006
1.0
D-1A
800
0.006
0.75
D-2A
800
0.006
0.5
D0-B*
800
0.003
1.0
D-1B
800
0.003
0.75
D-2B
800
0.003
0.5
D0= starting dose; D-1=reduced dose; D-2=second reduced dose; IV= intravenous; mCRPC= metastatic 
castration-resistant prostate cancer; mg= milligram; PO=orally; Q2W= every 2 weeks.  *Dose levels for 
Combination B designated with ‘A’ are applicable if the bempegaldesleukin (NKTR-214) dose is 0.006 mg/kg 
Q2W; dose levels for Combination B designated with ‘B’ are applicable if the bempegaldesleukin (NKTR-
214) dose is 0.003 mg/kg Q2W.
The potential dose levels of avelumab, bempegaldesleukin (NKTR-214) and enzalutamide 
for dose finding for Combination C are listed in Table 3.  The starting dose level for 
bempegaldesleukin (NKTR-214) and enzalutamide will be determined at the completion of 
the dose finding for Combination A based on available clinical data (including but not 
limited to safety and PK/pharmacodynamic data).  The approved label dose for enzalutamide 
is 160 mg once daily (QD).  The target starting enzalutamide dose to be used in Combination 
C is 160 mg QD unless unexpected safety issues require its lowering according to the BLRM 
recommendation.  In both the KEYNOTE-199 study (pembrolizumab + enzalutamide in 
mCRPC) and the IMbassador250 study (atezolizumab + enzalutamide in mCRPC), the full 
monotherapy dose of enzalutamide was used as the starting dose.  The lowest allowed dose 
for bempegaldesleukin (NKTR-214) will be 0.003 mg/kg and the lowest allowed dose for 
enzalutamide will be 80 mg once daily.
Table 3.
Phase 1b Combination C mCRPC Avelumab, Bempegaldesleukin (NKTR-
214) and Enzalutamide Dose levels
Dose Level
Avelumab Dose IV
(mg Q2W)
Bempegaldesleukin 
(NKTR-214) IV
(mg/kg Q2W)
Enzalutamide Dose PO
(mg once daily)
D0-A*
800
0.006
160
D-1A
800
0.006
120
D-2A
800
0.006
80
D0-B*
800
0.003
160
D-1B
800
0.003
120
D-2B
800
0.003
80
D0= starting dose; D-1=reduced dose; D-2=second reduced dose; IV= intravenous; mCRPC=metastatic 
castration-resistant prostate cancer; mg= milligram; PO=orally; Q2W= every 2 weeks.
*Dose levels for Combination C with ‘A’ are applicable if the bempegaldesleukin (NKTR-214) dose is 0.006 
mg/kg Q2W; dose levels for Combination C designated with ‘B’ are applicable if the bempegaldesleukin 
(NKTR-214) dose is 0.003 mg/kg Q2W.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 26
For each combination, beginning with the starting dose level, participants will be enrolled, 
treated, and monitored in increments of 3-6 during the 28-day dose-limiting toxicity (DLT)
evaluation period (Cycle 1) as follows:  

Participants who withdraw from study treatment in Cycle 1 before receiving at 
least 2 doses of bempegaldesleukin (NKTR-214) and avelumab and at least 75% 
of the planned dose of talazoparib (Combination B) or enzalutamide 
(Combination C) for reasons other than treatment-related toxicity are not 
evaluable for DLT.  All participants deemed non-evaluable for DLT may be 
replaced.

A minimum of 3 DLT-evaluable participants in each cohort will be required; 
additional participants will be enrolled in the specific enrollment cohort to replace 
participants who are not considered DLT-evaluable, where required. 

When all DLT-evaluable participants treated in a given enrollment cohort have 
completed the DLT observation period or experienced a DLT, whichever occurs 
first, the posterior distribution for the risk of DLT for new participants at different 
dose levels for the combination of interest will be evaluated. 

The posterior distributions will be summarized to provide the posterior probability 
that the risk of DLT lies within the intervals shown below: 

Underdosing: [0, 0.16)

Target toxicity: [0.16, 0.33)

Excessive toxicity or overdosing: [0.33, 1]
In addition to accumulating safety data and observed DLTs, decisions on further participant 
enrollment and dose level selection will be guided by the EWOC criterion.  A combination 
dose may only be used for newly enrolled participants if the risk of excessive toxicity at that 
combination dose is less than 0.25.
A dose level combination is a potential candidate for being the maximum tolerated dose 
(MTD) level when all the following criteria are met:

≥6 participants have been treated at that dose;

Probability of target dosing >0.50;

Probability of overdosing <0.25.
An RP2D below the MTD may be determined based on other safety, efficacy, PK, and 
pharmacodynamic data. Nine DLT-evaluable participants are needed to be treated at RP2D if 
no DLT is observed, and 12 evaluable participants if at least 1 DLT is observed.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 27
Phase 2 Design
Once the Phase 1b component is completed for each combination and the RP2Ds have been 
determined, Phase 2 will be initiated to further evaluate the safety and anti-tumor activity in 
Combinations A, B, and C.  

Combination A will enroll up to approximately 31 participants with 1L SCCHN.

Combination B will enroll up to approximately 20 participants with DDR+ mCRPC 
post taxane-based chemotherapy.

Combination C will enroll up to approximately 40 participants with mCRPC 
post-abiraterone therapy.
Combination A will proceed into Phase 2 once RP2D for Combination A has been 
determined in the Phase 1b dose finding component, in parallel with dose-finding for Phase 
1b for Combinations B and C.  
DLT Determination
The Combinations A, B, and C will be administered in 28-day cycles, and the DLT 
evaluation period will be limited to the first treatment cycle. The severity of adverse events 
(AEs) will be graded according to Common Terminology Criteria for Adverse Events
(CTCAE) v4.03.  For the purpose of dose finding, any of the following AEs occurring in the 
first cycle of treatment which are attributable to any or all agents in the combination will be 
classified as DLTs:
Hematologic:

Grade 4 anemia lasting >5 days (life-threatening consequences; urgent intervention 
indicated).

Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 109/L) 
lasting >5 days.

Grade ≥3 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.

Grade ≥3 neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 
infection).

Grade 3 thrombocytopenia (25,000/mm3 or 25.0 x 109/L to <50,000/ mm3 or <50.0 x 
109/L) with bleeding, or grade 4 thrombocytopenia (platelet count <25,000/mm3 or 
<25.0 x 109/L); 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 28
Non-Hematologic:

Potential Hy’s Law cases defined as: alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >3 x upper limit of normal (ULN) if normal at baseline 
OR >3 x ULN and doubling the baseline (if >ULN at baseline) associated with total 
bilirubin >2 x ULN and an alkaline phosphatase (AP) <2 x ULN. 

Grade 3 toxicities of any duration except:

Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea that 
resolves in 72 hours;

Grade 3 hypotension that occurs within 5 days post-dosing and resolves with 
adequate medical intervention; 

Grade 3 non-hematologic laboratory abnormalities without a clinical correlate.
Non-adherence to Treatment Schedule:

Delay of the subsequent cycle of two weeks or more due to toxicity occurring during 
the DLT observation period.

Failure to deliver at least 75% of the planned doses of all study interventions during 
the first cycle of treatment due to treatment related toxicities.
While the rules for adjudicating DLTs in the context of the Phase 1b 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 based on the emerging safety profile for 
the combination.
Disclosure Statement:
This is a Dose Finding Treatment study with 3 Arms that has No masking
Number of Participants:
Approximately 160 participants will be screened to achieve approximately 127 participants
assigned to study intervention based on eligibility, for an estimated total of 27-36
DLT-evaluable participants in Phase 1b and up to approximately 91 participants in Phase 2.  
A given combination size may be expanded in Phase 2 only by a limited number of 
additional participants (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. 
Intervention Groups and Duration:
Eligible participants will be centrally assigned via an interactive response technology (IRT)
to a study combination after providing informed consent and completing the screening 
procedures for their respective combination. Study drugs will be assigned and given as 
follows:


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 29
Combination A:

Bempegaldesleukin (NKTR-214) will be supplied as a sterile solution and will be 
administered as an approximately 30-minute intravenous (IV) infusion at a starting 
dose of 0.006 mg/kg Q2W on Days 1 and 15 of each 28-day cycle in Phase 1b.  The 
bempegaldesleukin (NKTR-214) dose level may be adjusted in Phase 2 if needed to 
the minimum dose of 0.003 mg/kg Q2W for this study.  Bempegaldesleukin 
(NKTR-214) will be administered before avelumab.  In order to mitigate hypotension, 
participants will receive IV fluids at each bempegaldesleukin (NKTR-214)
administration, as per Section 6.1.2.1.1.  In addition, participants may receive 
pre-medication to treat flu-like symptoms as per Section 6.1.2.1.2.

Avelumab will be supplied as a sterile solution (20 mg/mL) and will be administered 
as an approximately 1-hour IV infusion Q2W on Days 1 and 15 of each 28-day cycle 
at a fixed dose of 800 mg.  In order to mitigate infusion-related reactions (IRRs), 
participants will be pre-medicated with antihistamine and with paracetamol 
(acetaminophen) as per Section 6.1.1.3.1.
Combination B: 

Avelumab and bempegaldesleukin (NKTR-214) will be supplied and administered as 
in Combination A (bempegaldesleukin [NKTR-214] dose TBD), in addition to 
talazoparib (dose TBD) self-administered orally once a day, every day of each 28-day 
cycle.  Talazoparib may be taken before or after avelumab + bempegaldesleukin 
(NKTR-214) administration is complete and should be taken at approximately the 
same time each day.
Combination C:

Avelumab and bempegaldesleukin (NKTR-214) will be supplied and administered as 
in Combination A (bempegaldesleukin [NKTR-214] dose TBD), in addition to 
enzalutamide (dose TBD) self-administered orally once a day, every day of each 28-
day cycle.  Enzalutamide may be taken before or after avelumab + 
bempegaldesleukin (NKTR-214) administration is complete and should be taken at 
approximately the same time each day.

Participants will receive study treatment until progressive disease (PD) based on 
Investigator assessment per RECIST v1.1 (Appendix 9) for Combination A; RECIST 
v1.1 and PCWG3 (Appendix 9 and Appendix 10, respectively) for Combinations B 
and C; unacceptable toxicity, withdrawal of consent, or termination of study at 
sponsor discretion, whichever is earliest. 
Data Monitoring Committee: No


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 30
1.2. Schema
Figure 1.
B9991040 Study Schematic
Step 2: Phase 1b 
Combination B
Step 2: Phase 1b 
Combination C
Phase 2 
Combination C
mCRPC  (Combinations 
B and C)
Step 2:  Parallel dose-
finding Phase 1b for 
avelumab + talazoparib + 
bempegaldesleukin 
(NKTR-214) and 
avelumab + enzalutamide 
+ bempegaldesleukin 
(NKTR-214) 
BLRM to guide dose de-
escalation/escalation 
decisions
Avelumab (800 mg IV, Q2W)
Bempegaldesleukin (NKTR-
214); TBD, Q2W)
Talazoparib (TBD, QD)
Avelumab (800 mg IV, 
Q2W)
Bempegaldesleukin 
(NKTR-214; TBD, 
Q2W)
Talazoparib (TBD, QD)
Avelumab (800 mg IV, Q2W)
Bempegaldesleukin (NKTR-
214; TBD, Q2W)
Enzalutamide (TBD, QD)
Avelumab (800 mg IV,
Q2W)
Bempegaldesleukin 
(NKTR-214; TBD, Q2W)
Enzalutamide (TBD, QD)
DDR+
Abbreviations: 1L SCCHN== locally recurrent (not amendable 
for treatment with curative intent) or metastatic squamous cell 
carcinoma of the head and neck; BLRM= Bayesian Logistic 
Regression Model;  DDR=DNA damage repair; DDR+=positive 
for DNA damage repair defects; IV=intravenous; 
mCRPC=metastatic castration-resistant prostate cancer;  
Q2W=every two weeks; QD=once daily; TBD=to be determined.
Phase 2 
Combination B
1L SCCHN
Combination A
Step 1:  Dose finding 
Phase 1b for avelumab + 
bempegaldesleukin 
(NKTR-214)   
BLRM to guide dose 
de-escalation/escalation 
decisions
Avelumab (800 mg IV, 
Q2W)
Bempegaldesleukin 
(NKTR-214; TBD, 
Q2W)
Avelumab (800 mg IV, Q2W)
Bempegaldesleukin (NKTR-214; 
TBD, Q2W)
Note: Combination A Phase 2 will 
be conducted in parallel with the 
Phase 1b for Combinations B and C
Step 1: Phase 1b 
Combination A
Phase 2 Combination A


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 31
1.3. Schedule of Activities (SoA)
The SoA tables provide an overview of the protocol visits and procedures.  
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA tables in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
1.3.1. Table 4. SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Clinical Assessments
Informed consent
X
Refer to Section 10.1.3 in Appendix 1
Medical/Oncological 
History
X
Tumor Assessments 
(including scans)
X
Refer to Section 8.1.1.1 and Appendix 9.  Refer to Table 5 regarding 
continuing assessments for Cycle ≥3 and post-treatment.
Physical Examination
X
X
Complete physical examination at screening; brief physical exam at C1D1. 
Refer to Section 8.2.1 for details.  Refer to Table 5 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
Contraception Check
X
X
X
Must be performed D1 of each cycle. Refer to Appendix 4 and 
Section 5.3 for contraceptive guidance.  Refer to Table 5 regarding 
continuing assessments for Cycle ≥3 and post-treatment.
ECOG Performance Status
X
X
X
Refer to Section 8.2.7 and Appendix 8 for ECOG performance status 
criteria.  Refer to Table 5 regarding continuing assessments for Cycle ≥3 
and post-treatment.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 32
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Vital Signs
X
X
X*
X*
X*
X
X
X
Record blood pressure, heart rate, height, and weight at screening; *collect 
BP and HR only on C1 D3, D4 (72-96) hour window for D4 from D1, 
refer to PK assessments) and D8; collect BP and HR pre-dose at all other 
visits, and include weight pre-dose at D1 of each cycle.  Refer to 
Section 8.2.2.  Refer to Table 5 regarding continuing assessments for Cycle 
≥3 and post-treatment.
12-Lead ECG
X
X
X
Phase 1b:  12-lead ECGs should be performed at screening (singlet) and
on Day 1 of Cycles 1 and 2 (triplicate), prior to any pre-dose PK collection 
(within 2 hours) and prior to post-dose avelumab PK collection (within 10 
minutes after the end of avelumab infusion); then singlet 12-lead ECGs 
should be performed as clinically indicated.
Phase 2: Singlet 12-lead ECGs should be performed if clinically indicated. 
Refer to Section 8.2.5 for details.
ECHO/MUGA (LVEF 
determination)
X*
*Perform within six months prior to screening.  Refer to Section 8.2.6
Laboratory assessments (must be performed pre-dose during the treatment period).
Laboratory tests may be performed up to 3 days prior to the scheduled clinic visit so that results will be available for review before study treatment administration.  Unless 
otherwise noted, refer to Section 8.2.3 and Appendix 2 for additional information on Laboratory Assessments.  Refer to Table 5 regarding continuing assessments for Cycle ≥3 
and post-treatment.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 33
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Hematology/Blood for 
lymphocyte count
X
X
X
X*
X
X
X
X
Collect approximately 8-mL whole blood (*72-96 hour window from D1
for D4).  Refer to Section 8.1.2.1, Section 8.2.3 and Appendix 2 for further 
details.
Prior to study drug administration on Days 1 and 15 of each treatment 
cycle, hematology (ie, hemoglobin, platelets, and white blood cells) tests 
must be performed and results reviewed by the treating physician prior to 
study drug administration.  Refer to Table 5 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
Blood Chemistry
X
X
X
X
X
Collect approximately 4 mL whole blood prior to study drug administration 
on Days 1 and 15 of each treatment cycle.  Chemistry (ie, ALT, AST, 
alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, 
sodium, potassium, lipase, amylase, and glucose) tests must be performed 
and results reviewed by the treating physician prior to study drug 
administration.   Refer to Section 8.2.3, and also Table 5 regarding 
continuing assessments for Cycle ≥3 and post-treatment.
Coagulation
X
X*
X*
Collect approximately 4 mL whole blood.  Conduct at screening and then 
*at D1 for C1 and C2 for Phase 1b only.
Thyroid Function and 
ACTH Tests*
X
Collect approximately 4 mL whole blood. *Free T4, TSH, and ACTH must 
be performed at screening and at least every 8 weeks during study 
treatment (ie, every two cycles; D1 of C3, C5, C7, etc.).  Refer to Table 5
regarding continuing assessments for Cycle ≥ 3 and post-treatment.
Pregnancy Test
X
X*
X
Collect approximately 5 mL whole blood if using a serum-based pregnancy 
test.  Refer to Section 8.2.4 and Appendix 4 for details. *WOCBP must 
have a negative highly sensitive pregnancy test ([urine or serum] as 
required by local regulations) at C1D1. Results from pregnancy tests must 
be available for review prior to dosing.
Urinalysis
X
Conduct at screening and then additionally if clinically indicated.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 34
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Hepatitis B and C Virus 
tests
X
Collect approximately 5 mL whole blood for HBV surface antigen and 
anti-HCV antibody tests.  If anti-HCV antibody test is positive, participants 
must be tested for HCV RNA.
Enrollment, Study Treatment, and Safety
Enrollment/treatment 
assignment
X
Refer to Section 6.3 for details.
Pre-treatment for 
bempegaldesleukin 
(NKTR-214)  
X
X
X
X
Participants should receive at least one liter of IV fluids at each dosing of 
bempegaldesleukin (NKTR-214) to prevent hypotension as per 
Section 6.1.2.1.1 (particularly in Cycle 1 and Cycle 2).  Consider if anti-
hypertensive medications should be withheld.  Refer to Table 5 regarding 
continuing treatments for Cycle ≥3.
Study treatment 
(bempegaldesleukin 
[NKTR-214])
X
X
X
X
Refer to Section 6.1.2 for treatment details. Refer to Table 5 regarding 
continuing treatments for Cycle ≥3.
Participants should be carefully monitored for infusion reactions during 
administration. If an acute infusion reaction is noted, participants should be 
managed according to Table 12 in Section 6.6.1.
Pre-medication for 
avelumab
X
X
X
X
In order to mitigate IRRs, premedication with an antihistamine and with 
paracetamol (acetaminophen) 30 to 60 minutes prior to the first 4 infusions 
of avelumab is mandatory, as per Section 6.1.1.3.1. Refer to Table 5
regarding continuing treatments for Cycle ≥3.
Study treatment (avelumab)
X
X
X
X
Refer to Section 6.1.1 for treatment details. Refer to Table 5 regarding 
continuing treatments for Cycle ≥3.
Participants should be carefully monitored for infusion reactions during 
administration. If an acute infusion reaction is noted, participants should be 
managed according to Table 11 in Section 6.6.1.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 35
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Concomitant Therapy
X
→
→
→
→
→
→
→
→
Refer to Section 6.5 for details.  Refer to Table 5 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
Reporting of AEs and SAEs
X
→
→
→
→
→
→
→
→
Refer to Appendix 3 for details. Refer to Table 5 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
Tumor Biopsies
Mandatory Tumor Tissue
X
Refer to Section 8.8.1.1
On-Study Tumor Tissue
An on-treatment biopsy is 
required to be collected on 
Cycle 1 between Days 9 and 
14. When this is not feasible, 
a biopsy may be collected on 
Cycle 1 between Days 15 and 
21. These on-treatment 
biopsies are required except in 
instances where the procedure 
poses unacceptable risks per 
Investigator.
Refer to Section 8.8.1.4
Pharmacodynamic, Biomarker and Immunogenicity Assessments
Saliva sample for germline 
comparator
X
Collect pre-dose.  Refer to Section 8.8.2.1
 
 
 
 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 36
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
 
 
 
 
  
 
 
 
 
 
 
 
 
Immunogenicity for 
avelumab (ADA and NAb)
X
X
Collect approximately 3.5 mL whole blood.  Collections are pre-dose, 
within 2 hours prior to infusion.  Refer to Section 8.8.3.1 for details.  Refer 
to Table 5 regarding continuing assessments for Cycle ≥3 and post-
treatment.
Immunogenicity for 
bempegaldesleukin 
(NKTR-214; ADA and 
NAb)
X
X
Collect approximately 3.5 mL whole blood. Collections are pre-dose, 
within 2 hours prior to infusion. Refer to Section 8.8.3.2 for details. Refer 
to Table 5 regarding continuing assessments for Cycle ≥3 and post-
treatment.
Pharmacokinetic Assessments
PK for avelumab
X
X
X
X
Collect approximately 3.5 mL whole blood. All collections should occur 
within 2 hours prior to IV infusion and within 10 minutes after EOI.  Refer 
to Section 8.5.1 for details.  Refer to Table 5 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 37
Table 4.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
PK for Bempegaldesleukin 
(NKTR-214) 
X*
X
X†
X
X
X
Phase 1b: all participants.  Phase 2: a subset of approximately 20 
participants from Combination A receiving RP2D. 
 
 Collect 
approximately 3.5 mL whole blood.  *Collect a 3.5-mL whole blood 
sample at the following timepoints for C1D1: within 2 hours prior to IV 
infusion and within 10 minutes after, and 2 hours since the start of infusion 
(approximately 1.5 hours post-EOI).
For C2D1, collect within 2 hours prior to IV infusion and within 10 
minutes after EOI.
†72-96 hour window from C1D1 for C1D4 collection.
Refer to Section 8.5.2 for details.  Refer to Table 5 regarding continuing 
assessments for Cycle ≥3 and post-treatment.  
Abbreviations: ACTH=adrenocorticotropic hormone, ADA=anti-drug antibodies; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BP=blood pressure; C=Cycle; C1D1=Cycle 1 Day 1; CRF=case report form; 
 D=Day; ECG=electrocardiogram; 
ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOI=end of infusion; 
H&N=head and neck; HBV=hepatitis B virus; HCV=hepatitis C virus; HR=heart rate; IRR=infusion-related reaction; IV=intravenous; NAb=neutralizing antibodies; LVEF=left 
ventricular ejection fraction; MUGA=multigated acquisition; PD=progressive disease; PK=pharmacokinetic; QLQ=quality of life; RNA=ribonucleic acid; RP2D=recommended 
Phase 2 dose; SAE=serious adverse event; SCCHN=squamous cell carcinoma of the head and neck; 
; T4=thyroxine; 
 TSH=thyroid stimulating hormone; WOCBP=women of childbearing potential.
CCI
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 38
1.3.2. Table 5.  SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥ 3 and Post-Treatment
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Clinical Assessments
Tumor Assessments 
(including scans)
Every 8 weeks (7 days) after C1D1. 
After 52 weeks from C1D1, then every 16 weeks 
(7 days) until progressive disease, including during 
follow-up and long-term follow-up after end of treatment, 
for participants who discontinue treatment due to reasons 
other than PD.
Refer to Section 8.1.1.1 and Appendix 9 for details.  
Physical Examination
X
X
X (30 day visit only)
Brief physical exam. Refer to Section 8.2.1 for details.  
Contraception Check
X
X
X (30 day visit only)
Must be performed D1 of each cycle. Refer to Appendix 4 and Section 5.3 for 
contraceptive guidance.
ECOG Performance 
Status
X
X
X (30 day visit only)
Refer to Section 8.2.7 and Appendix 8 for ECOG performance status criteria.
Vital Signs*
X
X
X
X (30 day visit only)
*Collect BP and HR (pre-dose on D1 and D15 of all Cycles) at all visits, and include 
weight pre-dose at D1 of each cycle, EOT, and at the 30-day follow-up visit.  Refer 
to Section 8.2.2.  
12-Lead ECGs
Conduct a 12-lead singlet reading if clinically indicated.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 39
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
 
 
Laboratory Assessments (must be performed pre-dose during the treatment period).
Laboratory tests may be performed up to 3 days prior to the scheduled clinic visit so that results will be available for review before study treatment administration.  Unless 
otherwise stated, refer to Section 8.2.3 and Appendix 2 for additional information on Laboratory Assessments.
Hematology/Blood for 
lymphocyte count
X
X
X
X (30 Day Visit only)
Collect approximately 8 mL whole blood.  
Prior to study drug administration on Days 1 and 15 of each treatment cycle, hematology 
(ie, hemoglobin, platelets, and white blood cells) tests must be performed and results 
reviewed by the treating physician prior to study drug administration.  Refer to 
Section 8.1.2.1, Section 8.2.3, and Appendix 2 for details.
Blood Chemistry
X
X
X
X (30 Day Visit only)
Collect approximately 4 mL whole blood prior to study drug administration on Days 1 
and 15 of each treatment cycle.  Chemistry (ie, ALT, AST, alkaline phosphatase, total 
bilirubin, blood urea nitrogen, creatinine, sodium, potassium, lipase, amylase, and 
glucose) tests must be performed and results reviewed by the treating physician prior to 
study drug administration.   Refer to Section 8.2.3 and Appendix 2 for details.
Thyroid Function and 
ACTH Tests*
X
X
X (30 Day Visit only)
Collect approximately 4 mL whole blood.  *Free T4, TSH, and ACTH must be 
performed at least every 8 weeks during study treatment (ie, D1 of every two cycles; C3, 
C5, C7, etc.), at EOT, and at the 30-day short-term follow-up visit.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 40
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Pregnancy Test
X
X
X (30 Day Visit only)
Collect approximately 5 mL whole blood if using a serum-based pregnancy test.  Refer 
to Section 8.2.4 and Appendix 4 for details.  Results from pregnancy tests must be 
available for review prior to dosing.
Urinalysis
Conduct if clinically indicated.
Study Treatments and Safety
Pre-treatment for 
bempegaldesleukin 
(NKTR-214)  
X*
X*
Participants may or may not receive at least one liter of IV fluids at each dosing of 
bempegaldesleukin (NKTR-214) to prevent hypotension as per Section 6.1.2.1.1 *as per 
clinical judgement. Consider if anti-hypertensive medications should be withheld.  
Study treatment 
(bempegaldesleukin 
[NKTR-214])
X
X
Refer to Section 6.1.2 for treatment details.  Participants should be carefully monitored 
for infusion reactions during administration. If an acute infusion reaction is noted, 
participants should be managed according to Table 12 in Section 6.6.1.
Pre-medication for 
avelumab
Not mandatory for Cycles ≥3 (ie, beyond the first four infusions); premedication should 
be administered for subsequent avelumab doses based on clinical judgment and 
presence/severity of prior infusion reactions, as per Section 6.1.1.3.1. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 41
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Study treatment 
(avelumab)
X
X
Refer to Section 6.1.1 for treatment details.  Participants should be carefully monitored 
for infusion reactions during administration. If an acute infusion reaction is noted, 
participants should be managed according to Table 11 in Section 6.6.1.
Concomitant Therapy



X
Refer to Section 6.5 for details.
Reporting of AEs and 
SAEs



X
X
Refer to Appendix 3.
Tumor Biopsies
On-study tumor tissue
X
Refer to Section 8.8.1.4. An optional biopsy at End of Treatment is requested except in 
instances where the procedure poses unacceptable risks per Investigator documentation.  
The End of Treatment tumor biopsy should be performed before initiation of subsequent 
anti-cancer therapy and preferably no later than 7 days after the EOT visit.
Pharmacodynamic, Biomarker, and Immunogenicity Assessments


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 42
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
 
 
 
 
  
Immunogenicity for 
avelumab (ADA and 
NAb)
X*
X
Collect approximately 3.5 mL whole blood.  *Collections are within 2 hours prior to IV 
infusion on D1 for Cycles 3, 6, 9, and 12, and at EOT.  Refer to Section 8.8.3.1 for
details.
Immunogenicity for 
bempegaldesleukin 
(NKTR-214; ADA and 
NAb)
X*
X
Collect approximately 3.5 mL whole blood. *Collections are within 2 hours prior to IV 
infusion on D1 for Cycles 3, 6, 9, and 12, and at EOT.  Refer to Section 8.8.3.2 for 
details.
Pharmacokinetic Assessments
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 43
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
PK for avelumab
X*
Collect approximately 3.5 mL whole blood. *Collections are within 2 hours prior to IV 
infusion on D1 of Cycles 3, 6, 9, and 12.  Refer to Section 8.5.1 for details.
PK for 
bempegaldesleukin 
(NKTR-214)  
X*
Phase 1b: all participants.  Phase 2: a subset of approximately 20 participants from 
Combination A receiving RP2D.  Collect approximately 3.5 mL whole blood on *D1 
of Cycles 3, 6, 9, and 12.  Collections are within 2 hours prior to IV infusion and within
10 minutes after EOI.  Refer to Section 8.5.2 for details.  
Follow-up Assessments
Subsequent Cancer 
Treatment
X
X
Refer to Section 7.1 for details.
Survival Assessment
X
Refer to Section 7.1 for details.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 44
Table 5.
SoA for SCCHN Phase 1b and Phase 2 (Combination A): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Abbreviations: ACTH=adrenocorticotropic hormone, ADA=anti-drug antibodies; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BP=blood pressure; C=Cycle; C1D1=Cycle 1 Day 1; CRF=case report form; 
 D=Day; ECG=electrocardiogram; 
ECOG=Eastern Cooperative Oncology Group; ED=early discontinuation; EOI=end of infusion; EOT=end of treatment; 
 
; H&N=head and neck; HBV=hepatitis B virus; HCV=hepatitis C virus; HR=heart rate; IRR=infusion-related reaction; IV=intravenous; NAb=neutralizing 
antibodies; PD=progressive disease; PK=pharmacokinetic;
; RNA=ribonucleic acid; SAE=serious adverse event; RP2D=recommended Phase 2 
dose; SCCHN=squamous cell carcinoma of the head and neck; 
 T4=thyroxine; 
 TSH=thyroid stimulating 
hormone; WOCBP=women of childbearing potential.
1.3.3. Table 6. SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1, and Cycle 2
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Clinical Assessments
CCI
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 45
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Informed consent
X
Refer to Section 10.1.3 in Appendix 1
Medical/Oncological 
History
X
Tumor Assessments 
(including scans)
X
Refer to Section 8.1.1.2, Appendix 9 (RECIST v1.1), and Appendix 10
(PCWG3). Refer to Table 7 regarding continuing assessments for Cycle ≥3 
and post-treatment.
Physical Examination
X
X
Complete physical examination at screening; brief physical exam at C1D1. 
Refer to Section 8.2.1 for details.  Refer to Table 7 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
Contraception Check
X
X
X
Must be performed D1 of each cycle. Refer to Appendix 4 and Section 5.3
for contraceptive guidance.  Refer to Table 7 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
ECOG Performance Status
X
X
X
Refer to Section 8.2.7 and Appendix 8 for ECOG performance status 
criteria.  Refer to Table 7 regarding continuing assessments for Cycle ≥3 and 
post-treatment.
Vital Signs
X
X
X*
X*
X*
X
X
X
Record blood pressure, heart rate, height, and weight at screening; *collect 
BP and HR only on C1 D3, D4 (72-96 hour window from D1 for D4, 
refer to PK assessments) and D8; collect BP and HR pre-dose at all other 
visits, and include weight pre-dose at D1 of each cycle.  Refer to 
Section 8.2.2.  Refer to Table 7 regarding continuing assessments for Cycle 
≥3 and post-treatment.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 46
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
12-Lead ECG
X
X
X
Phase 1b: 12-lead ECGs should be performed at screening (singlet) and on
Day 1 of Cycles 1 and 2 (triplicate), prior to any pre-dose PK collection 
(within 2 hours) and prior to post-dose avelumab PK collection (within 10 
minutes after the end of avelumab infusion); then singlet 12-lead ECGs
should be performed as clinically indicated.
Phase 2: Singlet 12-lead ECGs should be performed if clinically indicated. 
Refer to Section 8.2.5 for details.
ECHO/MUGA (LVEF 
determination)
X*
*Perform prior to six months of screening.  Refer to Section 8.2.6.
 
Laboratory assessments (must be performed pre-dose during the treatment period).
Laboratory tests may be performed up to 3 days prior to the scheduled clinic visit so that results will be available for review before study treatment administration.  Unless 
otherwise noted, refer to Section 8.2.3 and Appendix 2 for additional information on Laboratory Assessments.  Refer to Table 7 regarding continuing assessments for Cycle ≥3 and 
post-treatment.
Hematology/Blood for 
lymphocyte count
X
X
X
X*
X
X
X
X
Collect approximately 8 mL whole blood (*72-96 hour window from D1 
for D4). Refer to Section 8.1.2.1, Section 8.2.3, and Appendix 2 for further 
details.
Prior to study drug administration on Days 1 and 15 of each treatment cycle, 
hematology (ie, hemoglobin, platelets, and white blood cells) tests must be 
performed and results reviewed by the treating physician prior to study drug 
administration.  Refer to Table 7 regarding continuing assessments for Cycle 
≥3 and post-treatment.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 47
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Blood Test for Circulating 
Tumor Cells (CTC)
X
X
Combination C only. Collect approximately 10-mL blood within 2 hours 
pre-dose on D1.  Refer to Section 8.1.2.2. Refer to Table 7 regarding 
continuing assessments for Cycle ≥3.
PSA Antibody Test*
X
X†
X
Collect approximately 5 mL whole blood. Refer to Section 8.1.2.3.  
*Conduct at screening and then every 4 weeks (D1 of each cycle) within 2 
hours pre-dose. †There is a 7-day window allowed for PSA labs from 
C1D1. Refer to Table 7 regarding continuing assessments for Cycle ≥3 and 
post-treatment.  
Testosterone
X
Collect approximately 5 mL whole blood.  Refer to Section 8.1.2.4.
Blood Chemistry
X
X
X
X
X
Collect approximately 4 mL whole blood prior to study drug administration 
on Days 1 and 15 of each treatment cycle.  Chemistry (ie, ALT, AST, 
alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, sodium, 
potassium, lipase, amylase, and glucose) tests must be performed and results 
reviewed by the treating physician prior to study drug administration.  Refer 
to Section 8.2.3 and Appendix 2 for further details.  Refer to Table 7
regarding continuing assessments for Cycle ≥3 and post-treatment.
Coagulation
X
X*
X*
Collect approximately 4 mL whole blood.  Conduct at screening and then
*at D1 for C1 and C2 for Phase 1b only.
Thyroid Function and 
ACTH Tests*
X
Collect approximately 4 mL whole blood.  *Free T4, TSH, and ACTH must 
be performed at screening and at least every 8 weeks during study treatment 
(ie, every two cycles; D1 of C3, C5, C7, etc.).  Refer to Table 7 regarding 
continuing assessments for Cycle ≥ 3 and post-treatment.
Urinalysis
X
Conduct at screening and then additionally if clinically indicated.
Hepatitis B and C Virus 
tests
X
Collect approximately 5 mL whole blood for HBV surface antigen and anti-
HCV antibody tests.  If anti-HCV antibody test is positive, participants must 
be tested for HCV RNA.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 48
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Enrollment, Study Treatment, and Safety
Enrollment/treatment 
assignment
X
Refer to Section 6.3 for details.
Pre-treatment for 
bempegaldesleukin (NKTR-
214)  
X
X
X
X
Participants should receive at least one liter of IV fluids at each dosing of 
bempegaldesleukin (NKTR-214) to prevent hypotension as per 
Section 6.1.2.1.1 (particularly in Cycle 1 and Cycle 2).  Consider if anti-
hypertensive medications should be withheld.  Refer to Table 7 regarding 
continuing treatments for Cycle ≥3.
Study treatment 
(bempegaldesleukin 
[NKTR-214])
X
X
X
X
Refer to Section 6.1.2 for treatment details. Refer to Table 7 regarding 
continuing treatments for Cycle ≥3.
Participants should be carefully monitored for infusion reactions during 
administration. If an acute infusion reaction is noted, participants should be 
managed according to Table 12 in Section 6.6.1
Pre-medication for 
avelumab
X
X
X
X
In order to mitigate IRRs, premedication with an antihistamine and with 
paracetamol (acetaminophen) 30 to 60 minutes prior to the first 4 infusions 
of avelumab is mandatory, as per Section 6.1.1.3.1. Refer to Table 7
regarding continuing treatments for Cycle ≥3.
Study treatment (avelumab)
X
X
X
X
Refer to Section 6.1.1 for treatment details. Refer to Table 7 regarding 
continuing treatments for Cycle ≥3.
Participants should be carefully monitored for infusion reactions during 
administration. If an acute infusion reaction is noted, participants should be 
managed according to Table 11 in Section 6.6.1
Study treatment 
Combination B 
(Talazoparib)








Daily dosing until EOT. Refer to Section 6.1.3.2 for details. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 49
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
Study treatment 
Combination C 
(Enzalutamide)








Daily dosing until EOT. Refer to Section 6.1.4.2 for details.
Concomitant Therapy
X








Refer to Section 6.5 for details.  Refer to Table 7 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
Reporting of AEs and SAEs
X








Refer to Appendix 3 for details. Refer to Table 7 regarding continuing 
assessments for Cycle ≥3 and post-treatment.
Tumor Biopsies
Mandatory Tumor Tissue
X
Refer to Section 8.8.1.2
Mandatory baseline tumor 
tissue for DDR Defect 
Assessment (Combination 
B only)
X
Refer to Section 8.8.1.3
Phase 2 only. 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 sections used should optimally 
measure 5×5 mm and contain minimally 20% and optimally 40% or greater 
tumor nuclei.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 50
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
 
 
 
 
 
 
 
Pharmacodynamic, Biomarker, and Immunogenicity Assessments
Saliva sample for germline 
comparator
X
Collect pre-dose.  Refer to Section 8.8.2.1
Saliva sample for targeted 
germline DDR assessment 
(Combination B only)
X
Collect pre-dose for Phase 2 Combination B only. Refer to
Section 8.8.2.2.
 
 
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 51
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
 
 
 
 
  
 
 
 
 
  
 
 
Immunogenicity for 
avelumab (ADA and NAb)
X
X
Collect approximately 3.5 mL whole blood.  Collections are pre-dose, within 
2 hours prior to infusion.  Refer to Section 8.8.3.1 for details.  Refer to Table 
7 regarding continuing assessments for Cycle ≥3 and post-treatment.
Immunogenicity for 
bempegaldesleukin (NKTR-
214; ADA and NAb)
X
X
Collect approximately 3.5 mL whole blood. Collections are pre-dose, within 
2 hours prior to infusion. Refer to Section 8.8.3.2 for details. Refer to Table 
7 regarding continuing assessments for Cycle ≥3 and post-treatment.
Pharmacokinetic Assessments
PK for avelumab
X
X
X
X
Collect approximately 3.5 mL whole blood. All collections are within 2 
hours prior to IV infusion and within 10 minutes after EOI.  Refer to Section 
8.5.1 for details.  Refer to Table 7 regarding continuing assessments for 
Cycle ≥3 and post-treatment.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 52
Table 6.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Screening, Cycle 1 and Cycle 2
Procedure
Screening
Treatment Period (One Cycle = 28 days)
Notes
Cycle 1
Cycle 2
D1
D3
D4
D8
D15
D1
D8
D15
Visit Window (Days)
-28 to -1
±0
±0
±0
±2
±2
±2
±2
±2
PK for bempegaldesleukin 
(NKTR-214)
X*
X
X†
X
X
X
Phase 1b: all participants.  Phase 2: a subset of approximately 20 
participants from each Combinations B and C receiving RP2D. 
 
 a 
3.5-mL whole blood.  *Collect approximately 3.5 mL whole blood at the 
following timepoints for C1D1: within 2 hours prior to IV infusion, within 
10 minutes after EOI, and 2 hours from start of infusion (approximately 1.5 
hours post-EOI).
For C2D1, collect within 2 hours pre-dose and within 10 minutes after EOI.
†72-96 hour window from C1D1 for C1D4 collection.
Refer to Section 8.5.2 for details.  Refer to Table 7 regarding continuing 
assessments for Cycle ≥3 and post-treatment.  
PK for talazoparib
(Combination B only)
X
X
Collect approximately 3.0-mL whole blood. Collections are within 2 hours 
pre-dose.  Refer to Section 8.5.3 for details.  Refer to Table 7 regarding 
continuing assessments for Cycle ≥3 and post-treatment.
PK for enzalutamide and N-
desmethyl-enzalutamide
(Combination C only)
X
X
Collect approximately 3.0-mL whole blood and isolate plasma for analysis. 
Collections are within 2 hours pre-dose.  Refer to Section 8.5.4 for details.  
Refer to Table 7 regarding continuing assessments for Cycle ≥3 and post-
treatment.
Abbreviations: ACTH=adrenocorticotropic hormone, ADA=anti-drug antibodies; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BP=blood 
pressure; C=Cycle; C1D1=Cycle 1 Day 1; CRF=case report form; CTC=circulating tumor cells; 
 D=Day; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EOI=end of infusion; 
 
HBV=hepatitis B virus; HCV=hepatitis C virus; HR=heart rate; IRR=infused-related reaction; IV=intravenous; LVEF=left ventricular ejection fraction;
mCRPC=metastatic castration-resistant prostate cancer; MUGA=multigated acquisition; NAb=neutralizing antibodies; PK=pharmacokinetic; PCWG3=prostate cancer working 
group 3; PD=progressive disease; PSA=prostate-specific antigen; 
 RNA=ribonucleic acid; RP2D=recommended Phase 2 dose; SAE=serious adverse event;  
 T4=thyroxine; 
 TSH=thyroid stimulating hormone.
CCI
CCI
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 53
1.3.4. Table 7. SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-treatment
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Clinical Assessments
Tumor Assessments 
(including scans)
Every 8 weeks (7 days) after C1D1. 
After 52 weeks from C1D1, then every 12 weeks 
(7 days) until progressive disease, including during 
follow-up and long-term follow-up after end of treatment, 
for participants who discontinue treatment due to reasons 
other than PD.
Refer to Section 8.1.1.2, Appendix 9 (RECIST v1.1) and Appendix 10 (PCWG3) for 
details.
Physical Examination
X
X
X (30 day visit only)
Brief physical exam. Refer to Section 8.2.1 for details.  
Contraception Check
X
X
X (30 day visit only)
Must be performed D1 of each cycle. Refer to Appendix 4 and Section 5.3 for 
contraceptive guidance.
ECOG Performance 
Status
X
X
X (30 day visit only)
Refer to Section 8.2.7 and Appendix 8 for ECOG performance status criteria.
Vital Signs*
X
X
X
X (30 day visit only)
*Collect BP and HR (pre-dose on D1 and D15 of all Cycles) at all visits, and include 
weight pre-dose at D1 of each cycle, EOT, and at the 30-day follow-up visit.  Refer 
to Section 8.2.2.  
12-Lead ECGs
Conduct a 12-lead singlet reading if clinically indicated.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 54
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
 
Laboratory Assessments (must be performed pre-dose during the treatment period).
Laboratory tests may be performed up to 3 days prior to the scheduled clinic visit so that results will be available for review before study treatment administration.  Unless 
otherwise stated, refer to Section 8.2.3 and Appendix 2 for additional information on Laboratory Assessments.
Hematology
X
X
X
X (30 Day Visit only)
Collect approximately 8 mL whole blood.  
Prior to study drug administration on Days 1 and 15 of each treatment cycle, hematology 
(ie, hemoglobin, platelets, and white blood cells) tests must be performed and results 
reviewed by the treating physician prior to study drug administration.  Refer to 
Section 8.1.2.1, Section 8.2.3, and Appendix 2 for details.
Blood Test for 
Circulating Tumor 
Cells (CTC)
X*
Combination C only. Collect approximately 10 mL whole blood within 2 hours pre-
dose *on D1 of C3 and C4 only.  Refer to Section 8.1.2.2.   
PSA Antibody Test*
X
X
Collect approximately 5 mL whole blood.   Refer to Section 8.1.2.3.  *Conduct every 4 
weeks (D1 each cycle) within 2 hours pre-dose, and at EOT.  
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 55
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Blood Chemistry
X
X
X
X (30 Day Visit only)
Collect approximately 4 mL whole blood prior to study drug administration on Days 1 
and 15 of each treatment cycle.  Chemistry (ie, ALT, AST, alkaline phosphatase, total 
bilirubin, blood urea nitrogen, creatinine, sodium, potassium, lipase, amylase, and 
glucose) tests must be performed and results reviewed by the treating physician prior to 
study drug administration.   Refer to Section 8.2.3 and Appendix 2 for details.
Thyroid Function and 
ACTH Tests*
X
X
X (30 Day Visit only)
Collect approximately 4 mL whole blood.  *Free T4, TSH, and ACTH must be 
performed at least every 8 weeks during study treatment (ie, D1 of every two cycles; C3, 
C5, C7, etc.), at EOT, and at the 30-day short-term follow-up visit.
Urinalysis
Conduct if clinically indicated.
Study Treatments and Safety
Pre-treatment for 
bempegaldesleukin 
(NKTR-214)  
X*
X*
Participants may or may not receive at least one liter of IV fluids at each dosing of 
bempegaldesleukin (NKTR-214) to prevent hypotension as per Section 6.1.2.1.1 *as per 
clinical judgement. Consider if anti-hypertensive medications should be withheld.  
Study treatment 
(bempegaldesleukin 
[NKTR-214])
X
X
Refer to Section 6.1.2 for treatment details.  Participants should be carefully monitored 
for infusion reactions during administration. If an acute infusion reaction is noted, 
participants should be managed according to Table 12 in Section 6.6.1


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 56
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Pre-medication for 
avelumab
Not mandatory for Cycles ≥3 (ie, beyond the first four infusions); premedication should 
be administered for subsequent avelumab doses based on clinical judgment and 
presence/severity of prior infusion reactions, as per Section 6.1.1.3.1. 
Study treatment 
(avelumab)
X
X
Refer to Section 6.1.1 for treatment details.  Participants should be carefully monitored 
for infusion reactions during administration. If an acute infusion reaction is noted, 
participants should be managed according to Table 11 in Section 6.6.1
Study treatment 
Combination B 
(Talazoparib)


Daily dosing until EOT. Refer to Section 6.1.3.2 for details.
Study treatment 
Combination C 
(Enzalutamide)


Daily dosing until EOT. Refer to Section 6.1.4.2 for details.
Concomitant Therapy



X
Refer to Section 6.5 for details.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 57
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Reporting of AEs and 
SAEs
→
→
→
X
X
Refer to Appendix 3.
Tumor Biopsies
 
 
 
 
 
 
Pharmacodynamic, Biomarker, and Immunogenicity Assessments
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 58
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
 
 
 
 
 
  
Immunogenicity for 
avelumab (ADA and 
NAb)
X*
X
Collect approximately 3.5 mL whole blood.  *Collections are within 2 hours pre-dose on 
D1 for Cycles 3, 6, 9, and 12, and at EOT.  Refer to Section 8.8.3.1 for details.
Immunogenicity for 
bempegaldesleukin 
(NKTR-214; ADA and 
NAb)
X*
X
Collect approximately 3.5 mL whole blood. *Collections are within 2 hours pre-dose on 
D1 for Cycles 3, 6, 9, and 12, and at EOT.  Refer to Section 8.8.3.2 for details.
Pharmacokinetic Assessments
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 59
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
PK for avelumab
X*
Collect approximately 3.5 mL whole blood. *Collections are within 2 hours pre-dose on 
D1 of Cycles 3, 6, 9, and 12.  Refer to Section 8.5.1 for details.
PK for 
bempegaldesleukin 
(NKTR-214)  
X*
Phase 1b: all participants.  Phase 2: a subset of approximately 20 participants from each 
Combinations B and C receiving RP2D. Collect approximately 3.5 mL whole blood on 
*D1 of Cycles 3, 6, 9, and 12.  Collections are within 2 hours prior to IV infusion and 
within 10 minutes after EOI.  Refer to Section 8.5.2 for details.  
PK for talazoparib 
(Combination B only)
X*
Collect approximately 3.0-mL whole blood *within 2 hours pre-dose on D1 of C3 only.  
Refer to Section 8.5.3 for details.  
PK for enzalutamide 
and N-desmethyl-
enzalutamide 
(Combination C only)
X*
Collect approximately 3.0-mL whole blood and isolate plasma for analysis. *Collections 
are within 2 hours prior to IV infusion on D1 of Cycles 3 and 6 only.  Refer to 
Section 8.5.4 for details. 
Follow-up Assessments


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 60
Table 7.
SoA for mCRPC Phase 1b and Phase 2 (Combinations B and C): Cycle ≥3 and Post-Treatment
Procedure
Treatment 
Period 
(One Cycle 
= 28 Days)
Post-Treatment Period
Notes
Refer to Section 7.1 for additional information regarding ED, EOT, Short-term 
Follow-up, and Long-Term Follow-up.
Cycle ≥ 3
ED 
or 
EOT
Short-Term Follow-
up (30, 60, or 90 days 
post-dose)
Long-
Term 
Follow-
up 
(Every 
12 
Weeks)
D1
D15
Visit Window (Days)
±2
±2
+7
±3
±14
Subsequent Cancer 
Treatment
X
X
Refer to Section 7.1 for details.
Survival Assessment
X
Refer to Section 7.1 for details.
Abbreviations: ACTH=adrenocorticotropic hormone, ADA=anti-drug antibodies; AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BP=blood pressure; C=Cycle; C1D1=Cycle 1 Day 1; CRF=case report form; CTC=circulating tumor cells; 
 D=Day; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; ED=early discontinuation; EOI=end of infusion; EOT=end of treatment; 
 
HBV=hepatitis B virus; HCV=hepatitis C virus; HR=heart rate; IV=intravenous; IRR=infused-related reaction; 
mCRPC=metastatic castration-resistant prostate cancer; NAb=neutralizing antibodies; PCWG3=prostate cancer working group 3; PD=progressive disease; 
PK=pharmacokinetic; 
 PSA=prostate-specific antigen; 
 RNA=ribonucleic acid; RP2D=recommended Phase 2 dose; 
SAE=serious adverse event;  
 T4=thyroxine; 
 TSH=thyroid stimulating hormone.
CCI
CCI
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 61
2. INTRODUCTION
This Phase 1b/2 study will evaluate the combination of avelumab + bempegaldesleukin 
(NKTR-214; Combination A) in locally advanced (not amenable for curative intent) or 
metastatic squamous cell carcinoma of the head and neck (1L SCCHN) in a Phase 1b dose 
finding component followed by Phase 2 and avelumab + bempegaldesleukin (NKTR-214) + 
talazoparib (Combination B) or enzalutamide (Combination C) in metastatic 
castration-resistant prostate cancer (mCRPC) in Phase 1b dose finding components followed 
by Phase 2 in both combinations. 
2.1. Study Rationale
2.1.1. Rationale for Combination A (Avelumab + Bempegaldesleukin [NKTR-214]) for 
SCCHN
 
 
 
 
 
 
 
Currently, there are 2 ongoing Phase 3 studies investigating avelumab and 
chemoradiotherapy in locally advanced (LA) SCCHN, study B9991016 (NCT02952586) and 
the Randomized Trial of Avelumab-cetuximab-radiotherapy versus SOCs in LA SCCHN
(REACH) study (NCT02999087).  
The combination of bempegaldesleukin (NKTR-214) with nivolumab in the PIVOT-02 study 
has shown preliminary evidence of clinical activity when referencing to anti-PD-1/PD-L1 
single agents with significant clinical activity observed also in patients with PD-L1 negative 
disease. Consistent with the mechanisms of actions of both agents, increased T-cell 
infiltration was observed in the tumor micro-environment and conversion of baseline PD-L1 
negative disease to PD-L1 positive disease was reported in serial biopsies from the 
PIVOT-02 study.6  
Similar effect is expected when combining avelumab with bempegaldesleukin, and the 
combination may lead to increased PD-L1 expression and potentially improved anti-tumor 
activity over single-agent checkpoint inhibitors in 1L SCCHN. Indeed, in the 
KEYNOTE-048 Phase 3 study (NCT02358031) of pembrolizumab or pembrolizumab + 
chemotherapy vs. EXTREME (platinum-based chemotherapy + 5-fluorouracil [5-FU]) as 
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 62
first-line systemic therapy for R/M SCCHN the observed clinical benefit was dependent on 
the PD-L1 expression level. The confirmed ORR was (pembrolizumab vs EXTREME) was 
23% vs 36% for PD-L1 combined positive score (CPS) ≥20, 19% vs 35% for CPS ≥1, and 
17% vs 36% for the total population. Also the observed overall survival benefit was 
dependent on the baseline PD-L1 expression level with a reported hazard ratio favoring 
pembrolizumab over EXTREME of 0.61 (95% CI :0.45-0.83) and 0.78 (95% CI: 0.64-0.96) 
for the CPS≥20 and CPS ≥1 populations, respectively.7
Therefore, the avelumab + bempegaldesleukin combination is expected to enhance 
anti-tumor activity over single-agent checkpoint inhibitor and provide a chemotherapy-free 
regimen to study participants with 1L SCCHN whose disease is positive or negative PD-L1 
expression at baseline.
2.1.2. Rationale for Combination B (Avelumab + Bempegaldesleukin [NKTR-214] + 
Talazoparib) for mCRPC
Single agent treatment with immune checkpoint blockers, including avelumab, delivers only 
modest clinical benefit in prostate cancer and correlative studies have demonstrated that the 
prostate tumors are predisposed toward immunosuppression. As discussed above, the 
combination of bempegaldesleukin (NKTR-214) with nivolumab in the PIVOT-02 study 
demonstrated improved clinical activity referencing to anti-PD-1/PD-L1 single agents.  
Combination strategies aimed to enhance the immune recognition of the tumor create the 
potential for a therapeutically relevant treatment in prostate cancer.  One proposed treatment 
combination for evaluation in this study is the triplet of avelumab + bempegaldesleukin  + 
talazoparib (Combination B).  
Proof of concept of PARPi efficacy in mCRPC with DNA Damage Repair (DDR) deficiency 
was established in a Phase 2 study (TOPARP-A) with olaparib, which enrolled men heavily 
pre treated with taxane based chemotherapy and novel hormonal therapy (NHT).11  These 
results were further confirmed with rucaparib in a similar therapeutic setting in the TRITON2 
phase 2 study where the observed confirmed ORR in mCRPC patients with BRCA1/2 defects 
was 45.5.0% (95% CI: 16.7, 76.6).12
A key aim of the Combination B in this study is to extend PARPi activity beyond BRCA 
deficiency to sustain and prolong responses to PARPi in mCRPC participants whose disease 
is positive for DDR defects (DDR+). The proposed triple combination has the potential to 
activate several non-overlapping immune mechanisms to synergize and induce potent 
anti-tumor immune response. Talazoparib would induce the activation of proinflammatory 
dentritic cells (DCs) via stimulation of the interferon genes (STING) pathway to prime and 
differentiate tumor specific CD8 T-cells.15,16 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 NK
cell infiltration and activation in a mouse model of ovarian cancer.17  Bempegaldesleukin 
would allow the expansion of these CD8 T-cells as suggested by pre-clinical evidence that 
demonstrated improved anti-tumor activity for bempegaldesleukin + rucaparib in a BRCA-
deficient and immuno-competent ovarian cancer model.2,3  Additionally, talazoparib 
treatment has been shown to lead to increased expression of PD-L1 by tumor cell18
suggesting that this may represent a mean by which tumors function to inhibit talazoparib-


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 63
mediated anti-tumor immunity. Addition of avelumab would release  the checkpoint break 
with avelumab by overcoming PD-L1-mediated inhibition  resulting in anti-tumor immune 
response.
In summary, the proposed triple combination may produce additive or synergistic anti-tumor 
activity with talazoparib, promoting immune priming and tumor immunogenicity and 
avelumab/bempegaldesleukin enhancing the anti-tumor immune response, so offering a 
therapeutic opportunity to patients with mCRPC after progression to taxane-based 
chemotherapy in the metastatic setting that currently represent an urgent unmet medical need.
2.1.3. Rationale for Combination C (Avelumab + Bempegaldesleukin [NKTR-214] + 
Enzalutamide) for mCRPC
The other proposed treatment combination for mCRPC for this study is the triplet of 
avelumab + bempegaldesleukin + enzalutamide (Combination C).  
Results from the PIVOT-02 study of bempegaldesleukin with nivolumab also support the 
evaluation of avelumab plus bempegaldesleukin as the backbone of this triplet combination.4
Combination of immune checkpoint blockers with androgen receptor blockers and CD8 
T-cell stimulants could improve the therapeutic outcome of mCRPC patients. In a study of 
enzalutamide in biochemically recurrent prostate cancer a preliminary analysis of 12 patients 
treated with a 3-month course of enzalutamide showed increases in NK cells and decreases in 
MDSC.19  In addition, patients who experienced progression during enzalutamide treatment 
showed increased PD-L1 expression on dendritic cells20 and encouraging evidence of clinical 
activity in patients were observed with pembrolizumab plus enzalutamide after progression 
on enzalutamide with prostate specific antigen (PSA) reduction ≥50% reported in 5 out of 28 
(18%) patients and radiographic response observed in 3 out of 12 patients (ORR=25%) with 
measurable disease at baseline.21  Moreover, the combination of pembrolizumab plus 
enzalutamide in mCRPC patients after abiraterone therapy failure induced PSA reduction 
≥50% in 18 out of 54 patients (33%) and radiographic response observed in 5 out of 25 
patients (ORR=20%) with measurable disease at baseline.22
Based on the above data, the proposed triplet combination could represent an effective 
strategy by enzalutamide enhancing NK cells and lowering MDSC, bempegaldesleukin 
generating a robust CD8 and NK cell level in the tumor tissue, and avelumab providing the 
release from the checkpoint blockade resulting from PD-L1-mediated inhibition of 
anti-tumor immune response.  Therefore, Combination C may provide an innovative 
chemo-free treatment option to mCRPC patients after disease progression on abiraterone 
treatment.
2.1.4. Rationale for Phase 1b Study Design: Bayesian Logistic Regression Model 
(BLRM) Design
The relatively distinct safety profiles of avelumab, bempegaldesleukin (NKTR-214), 
talazoparib and enzalutamide support the clinical evaluation of the doublet (Combination A) 
and triplet (Combinations B and C) combinations. Overlapping adverse events observed with 
all 4 study interventions include fatigue and nausea.  Diarrhea is common to avelumab and 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 64
talazoparib.  Additionally, decreased appetite has been observed with avelumab, talazoparib 
and bempegaldesleukin (NKTR-214).  Refer to the Investigator Brochures (IBs) for each 
respective study intervention for further information. In summary, there are a low number of 
overlapping severe adverse events (or immune-related AEs) reported at the dose levels 
proposed for testing in the present study.  
Guidance for dosing (dose level to be evaluated in the next cohort) and enrollment (number
of participants to be enrolled in the next cohort) decisions will be based on a BLRM.  The 
BLRM provides an optimal design for dose finding with combination treatments as it 
incorporates single-agent and available combination DLT data (historical and prospectively 
across dose combinations) to estimate the posterior probability of under-dosing, target-
dosing, and overdosing, thereby reducing patient risk and increasing efficiency and precision 
during dose finding with combination treatments.  
Refer to Appendix 11, Appendix 12, and Appendix 13 for the BLRM designs for 
Combinations A, B, and C, respectively.
2.2. Background
2.2.1. SCCHN
Head and neck cancers, including cancers of the oral cavity, nasopharynx, pharynx, and 
larynx, account for approximately 5% of cancers worldwide (excluding non-melanoma skin 
cancers).23,24  Approximately 680,000 new cases of head and neck cancer were diagnosed in 
2012 with 370,000 deaths attributed to this disease; of these new cases reported, almost 
140,000 were in Europe, and over 90% were squamous cell histology.  In the US, it is 
estimated that over 61,000 people will be diagnosed with head and neck cancer in 2016 and 
over 13,000 will die from this cancer.25  Head and neck cancers are predominately squamous 
carcinomas.  SCCHN involving the oral cavity, larynx, oropharynx, and hypopharynx 
account for 75% SCCHN overall and are closely associated with alcohol and tobacco use.  
Of newly-diagnosed patients with SCCHN, approximately 60% present with locally or 
regionally advanced disease.25,26 Combination modality therapy is generally employed for 
these patients and may include surgery with adjuvant radiotherapy for early stage disease and
which is standard for more advanced disease.25,27 The most widely used standard regimen 
used in this setting consists of 100 mg/m2 cisplatin administered every 3 weeks (Q3W), 
combined with ~70 Gray radiation delivered in 1.8-2.0 Gray daily fractions.  Although 
associated with increased local control rates and overall survival (OS) compared to 
radiotherapy alone, this combination is also associated with increased toxicity.  Additionally, 
depending on the tumor site, stage, and resectability, locoregional failure rates can range 
between 35% and 65%. With a median PFS of 1.9 years and reported 3-year PFS rate of 
61.2%, this disease will ultimately recur locally in a large proportion of treated patients, with 
distant metastases developing in 10% to 30% of these patients.26,28,29
Treatment options for patients with recurrent SCCHN are limited to palliative chemotherapy 
and, in patients suitable for more aggressive treatment, combination systemic chemotherapy
regimens.25  Response rates to single-agent chemotherapy range from 15% to 35%, with a 
median OS of 6 months.  There remains an unmet medical need for improved therapy for 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 65
locally recurrent (not amenable for curative intent) or metastatic SCCHN.  In the 
KEYNOTE-048 study, the activity of pembrolizumab was determined to be dependent on 
PD-L1 expression, as evaluated in participants with squamous cell carcinoma of the head and 
neck (HNSCC).7  The study met a primary endpoint of overall survival (OS) as monotherapy 
in participants whose tumors expressed PD-L1 (combined proportion score [CPS] ≥ 20).
2.2.2. Prostate Cancer
Prostate cancer is the second leading cause of cancer death in men.  The American Cancer 
Society estimates that up to 174,650 men in the United States (US) were diagnosed with 
prostate cancer and approximately 31,620 will die of the disease in 2019.30 In Europe in 2012, 
prostate cancer was the third most common cancer, with an estimated 416,700 new cases and 
92,200 deaths.30,23
The androgen receptor (AR) signaling axis, the principal driver of prostate cancer growth, 
has been targeted by castration and other systemic therapies.  However, a proportion of 
tumors progress despite castrate levels of testosterone, at which point the disease is 
considered castration resistant.  Metastatic castration-resistant prostate cancer (mCRPC) 
represents a lethal transition in the progression of prostate cancer, with most patients 
ultimately succumbing to the disease.31  Molecular profiling studies have revealed that the 
AR remains functional in a majority of progressing tumors.  Rationally designed therapies 
targeting the AR signaling pathway in the castrate setting include enzalutamide, a novel AR 
signaling inhibitor active in the presence of AR overexpression; and abiraterone 
acetate/prednisone, an inhibitor of 17,20 lyase (an androgen biosynthetic enzyme 
overexpressed in castration-resistant prostate cancer (CRPC).32  These therapies have 
conferred improved overall survival and radiographic progression free survival (PFS) benefit 
compared with prednisone or placebo in patients with mCRPC, in both pre- and post-
chemotherapy settings. Enzalutamide plus androgen-derived therapy (ADT) versus ADT 
alone was evaluated also in 1,401 patients with non-metastatic castration-resistant prostate 
cancer (NM CRPC) in the PROSPER study.  This study met its primary endpoint, 
demonstrating that the use of enzalutamide plus ADT significantly reduced the risk of 
developing metastasis or death compared to ADT alone.  The median for the primary 
endpoint, metastasis free survival (MFS), was 36.6 months for men who received 
enzalutamide compared to 14.7 months with ADT alone (n=1401; hazard ratio=0.29 [95% 
CI: 0.24, 0.35]; p<0.0001.33  As such, the Food and Drug Administration (FDA) has
approved enzalutamide also for the treatment of patients with NM CRPC in July 2018 based 
on the results of the study.
In the same setting, in February 2018, the FDA approved apalutamide, next generation 
nonsteroidal antiandrogen, for patients with NM CRPC.  In the SPARTAN study,
apalutamide significantly improved MFS in patients with nonmetastatic castration resistant 
prostate cancer.  The estimated median MFS was 40.5 months for patients receiving 
apalutamide and 16.2 months for those receiving placebo (hazard ratio = 0.28; 95% CI: 0.23, 
0.35; p<0.0001.34
Taxane-based chemotherapy (docetaxel, cabazitaxel) has been shown to improve PFS and 
OS with mCRPC.  At present, patients whose disease progresses on novel hormonal agents 
are recommended treatment with taxane-based chemotherapy, based on retrospective series 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 66
supporting efficacy, although no randomized study data are available.  Additionally, many 
patients with advanced prostate cancer may not be candidates for taxane-based chemotherapy 
due to their comorbidities or performance status or may prefer to delay treatment with such 
chemotherapy as a last resort. Thus, a significant unmet medical need remains for new 
therapeutic options for men with mCRPC whose disease progresses on novel hormonal 
agents or on taxane-based chemotherapy.  In addition to improved characterization of the 
heterogeneity of the disease and advances in predictive biomarkers to better identify specific 
genomic aberrations to inform patient care, innovative combination treatment remains a 
critical need.
2.2.3. Avelumab
Avelumab is a human immunoglobulin (Ig)G1 monoclonal antibody (mAb) directed against 
programmed death ligand 1 (PD-L1).  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.  In March 2017, 
avelumab received accelerated approval by the United States (US) Food and Drug 
Administration (FDA) as the first approved 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 Food and Drug 
Administration (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. In January 2018, avelumab was approved for the same indication in Israel.
2.2.3.1. Avelumab Mechanism of Action
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.  
2.2.3.2. Avelumab Clinical Experience
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.  
 
 
 
 
 
 
 
 
 
 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 67
 
 
2.2.4. Bempegaldesleukin (NKTR-214)
Bempegaldesleukin (NKTR-214) is a CD122-biased cytokine agonist conjugated with 
multiple releasable chains of polyethylene glycol designed to provide sustained signaling 
through the heterodimeric interleukin-2 (IL-2) receptor pathway to preferentially activate and 
expand effector CD8+ T and NK cells over regulatory T-cells in the tumor microenvironment 
developed by Nektar Therapeutics.  
 
 
 
 
 
Bempegaldesleukin (NKTR-214) is currently being evaluated in combination with other anti-
cancer therapies, including anti-PD1 (Nektar study PIVOT-02), in patients with advanced 
locally advanced or metastatic solid tumors. 
2.2.4.1. Bempegaldesleukin (NKTR-214) Mechanism of Action
Bempegaldesleukin (NKTR-214) is a prodrug of a conjugated cancer immunotherapy 
cytokine that exerts its biological activity by binding to the IL-2 receptor and subsequent 
activation of effector T-cells. As a polyethylene glycol (PEG)ylated human recombinant IL-2 
molecule of aldesleukin with six releasable polyethylene glycol chains, bempegaldesleukin 
(NKTR-214) can be administered conveniently in the outpatient setting using an 
antibody-like dosing regimen. The polymer conjugation renders the cytokine initially 
inactive; upon intravenous administration, the PEG chains slowly release via hydrolysis to 
generate the active cytokine species (2-PEG-IL-2 and 1-PEG-IL-2) that have a peak plasma 
concentration 24 to 48 hours after infusion. The slow generation of the 2-PEG-IL-2 and 1 
PEG IL 2 significantly mitigates the rapid-onset, systemic cytokine-related toxicities 
associated with high dose IL-2.
The polymer conjugation of bempegaldesleukin (NKTR-214) promotes biased signaling 
through the IL-2 receptor beta gamma (IL-2Rβγ). This unique feature preferentially increases 
the proliferation, activation, and effector functions of tumor antigen-specific CD8+ T-cells 
and NK cells within the tumor microenvironment without expanding unwanted intra-tumoral 
regulatory T-cells that are activated through IL-2Rαβγ.2,3 Specifically, the location of the 
bempegaldesleukin (NKTR-214) PEG chains interferes with the IL-2 alpha subunit 
responsible for the undesirable effect of activating regulatory T-cells in the tumor while 
continuing to permit binding to the IL-2Rβγ (CD122) receptor. 
Bempegaldesleukin (NKTR-214) also correspondingly promotes expression of PD-1 on the 
surface of CD8+ T cells and induction of a Type II interferon gene signature, driving cell 
surface expression of programmed cell death ligand 1 (PD-L1) on tumor cells.5
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 68
The immunogenic properties of bempegaldesleukin (NKTR-214) with the induction of tumor 
infiltrating lymphocytes and upregulation of the PD-1/PD-L1 axis makes this compound a 
potentially promising combination therapy for use with immune checkpoint inhibitors that 
target and inhibit the PD-1/PD-L1 pathway. Moreover, the side effect profile of 
bempegaldesleukin (NKTR-214) generally does not overlap with that of checkpoint 
inhibitors, further supporting the use of this compound as a potentially complimentary 
combination partner with immune checkpoint inhibitors.
2.2.4.2. Bempegaldesleukin (NKTR-214) Clinical Experience 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2.4.3. Bempegaldesleukin (NKTR-214) plus Nivolumab Clinical Experience
The PIVOT-02 study was a Phase 1/2 open-label, multicenter, dose-escalation and dose 
expansion study of bempegaldesleukin (NKTR-214) in combination with nivolumab in 
patients with local advanced or metastatic solid tumors. 
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 69
 
 
 
 
 
 
 
 
 
 
 
 
The combination of bempegaldesleukin (NKTR-214) with nivolumab in the PIVOT-02 study 
has showed preliminary evidence of improved clinical activity with the observed response 
rates comparing favorably when referencing to anti-PD-1/PD-L1 single agents data sets from 
phase 3 studies; clinical activity was observed also in patients with PD-L1 negative disease.5
Consistent with the mechanisms of actions of both agents, increased T-cell infiltration was 
observed in tumors and conversion of baseline PD-L1 negative disease to PD-L1 positive 
disease at week 3 of treatment was reported in serial biopsies from 7/10 patients in the 
PIVOT-02 study.6
Efficacy data for the dose escalation population alone or for those patients enrolled in the 
dose escalation phase at the RP2D in combination with patients enrolled in dose expansion 
populations are presented below for the efficacy evaluable population (defined as having 
received one dose of study treatment and having undergone at least one scan).
Dose Escalation Phase
 
 
 
 
Dose Expansion Phase
As of the 07 February 2018 cutoff date, ORR and disease control rate (DCR) in 24 RCC (1L) 
patients was 54% and 79%; 20/24 of the RCC patients had known PD-L1 status.  ORR was 
4/7 (57%) for PD-L1(+) patients and 7/13 (54%) for PD-L1(-) pts. ORR and DCR in 6 
NSCLC (1-2L) patients was 50% and 67%; 5/6 patients had known PD-L1 status.  ORR was 
3/5 (60%) in PD-L1(-) patients.5  As of 11 October 2018, in the urothelial cancer (UC) 
expansion cohort, the ORR was 48%, (13 of 27 efficacy-evaluable patients) with 19% (5/27) 
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 70
CR and 30% (8/27) PR. There was no significant difference in the ORR between PD-L1 
negative and PD-L1 positive tumors.6
Refer to the bempegaldesleukin (NKTR-214) IB for additional information on clinical study 
outcomes for efficacy and safety.   
2.2.5. Talazoparib
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.9 Talazoparib was approved by the Food and Drug 
Administration (FDA) on 16 October 2018 for the treatment of adults 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.10
2.2.5.1. Talazoparib Mechanism of Action
Talazoparib is a particularly potent PARP trapper, a property that is associated with 
cytotoxicity in preclinical models.9  Single agent treatment with talazoparib demonstrates 
potent antitumor effects in tissue culture studies, mouse tumor xenograft models, and in 
Phase 1 studies in patients with solid tumors.  Talazoparib has also been shown to enhance 
the cytotoxic effects of DNA damaging chemotherapy. 
PARP1 and PARP2 play important roles in DNA repair.35,36  Following DNA damage, 
PARP1 and PARP2 bind to single stranded DNA breaks, cleave nicotinamide adenine 
dinucleotide, and attach multiple ADP ribose units to the target protein, including 
itself.15,36,37,38  The outcome is a highly negatively charged protein, which leads to the 
unwinding of the DNA strands and recruitment of proteins to repair the damaged DNA 
through the base excision repair process.  When PARP1 and PARP2 are inhibited, single 
strand DNA breaks persist, resulting in stalled replication forks and conversion of single 
strand breaks into double strand breaks.  These breaks must be repaired by homologous 
recombination or nonhomologous end joining or they may become lethal.  Thus, inhibition of 
PARP catalytic activity results in synthetic lethality as defects in homologous recombination 
DNA repair prevent double strand breaks from being repaired, thereby killing the cell, 
including cancer cells. 
In addition, PARP inhibitors bind to PARP DNA complexes (ie, become trapped), thereby 
inhibiting DNA repair, replication, and transcription, which is cytotoxic to cancer cells.  
Although other PARP inhibitors possess both activities (ie, inhibition of PARP catalytic 
activity and PARP trapping), in vitro studies demonstrated that talazoparib is a more potent 
PARP trapper than other PARP inhibitors in clinical development, a property that has been 
associated with significant cytotoxicity in preclinical models.9,39


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 71
2.2.5.2. Talazoparib Clinical Experience
In the Phase 1 Study PRP-001, in patients treated with talazoparib 1.0 mg/day with advanced 
breast cancer, ovarian/peritoneal cancer, and pancreatic cancer, an ORR of 50.0% (7 of 14))
and 20% (2 of 10) was observed, respectively.  
Proof of concept of PARPi efficacy in metastatic castration-resistant prostate cancer 
(mCRPC) with DNA Damage Repair (DDR) deficiency was established in a Phase 2 study 
(TOPARP-A) with olaparib, which enrolled men heavily pre- treated with taxane based 
chemotherapy and novel hormonal therapy (NHT).  Of the 49 patients evaluable for response 
(defined either as an objective response according to Response Evaluation Criteria in Solid 
Tumors [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 [CTC] 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.11  These results were further confirmed with rucaparib in a similar 
therapeutic setting in the TRITON2 Phase 2 study where the observed confirmed objective
response rate (ORR) in mCRPC patients with BRCA1/2 defects was 45.5.0% (95% CI 
16.7-76.6).12  In addition, the combination of durvalumab and olaparib was evaluated in a 
Phase 1/2 study in 17 patients with mCRPC after progression on NHT and chemotherapy.  
Overall, 8 out of 17 patients had a reduction in PSA level ≥50% from baseline.  PSA level 
reductions were observed mainly in patients with mutations in DNA repair pathways, but 
also in some patients without alteration.13  In alignment with these findings, the combination 
of pembrolizumab and olaparib in the KEYNOTE-365 study showed early evidence of 
clinical activity in mCRPC patients whose disease was negative for homologous 
recombination defects (HRD) after treatment with taxane based chemotherapy and NHT with 
a reported ORR of 7% (95% CI 1-23), and disease control rate ≥6 months of 32% (95% CI 
16–52) in patients with measurable disease.14
Study B9991025 is an ongoing 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. During Phase 1b, 12 patients with locally advanced or metastatic 
solid tumors who met eligibility criteria were treated with talazoparib 1.0 mg administered 
orally once daily in combination with a fixed dose of avelumab 800 mg IV Q2W in 28-day 
cycles (dose level D0), and were evaluated for DLTs. The modified toxicity probability 
interval (mTPI) method was used to identify the RP2D for talazoparib in combination with 
avelumab using a DLT rate of <0.33.40  The target patient enrollment for each cohort was 3-6 
patients.  Three DLTs were reported among the 12 DLT-evaluable patients enrolled in phase 
1b (grade 3 neutropenia n=1 and grade 3 thrombocytopenia n=2) so the MTD and RP2D for 
the combination was estimated to be dose level D0.  The most frequently reported 
treatment-emergent adverse events (TEAEs) were cytopenias and chills, which are consistent 
with the risk profiles of talazoparib and avelumab, respectively.  Although Phase 1b was 
comprised of only 12 DLT-evaluable patients, the frequency of the TEAEs following 
administration of avelumab in combination with talazoparib were generally consistent with 
the frequency of TEAEs following administration of the study drugs as single agents.  The 
TEAEs leading most frequently to dose interruptions were thrombocytopenias and 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 72
neutropenias, and were generally consistent with events leading to dose interruptions of 
talazoparib single agent in the talazoparib development program. In summary, the safety 
profile of the combination of avelumab with talazoparib at full dose remains aligned to the 
safety profiles from the individual components and is generally manageable.
In the ongoing Phase 2 study in patients with locally advanced or metastatic breast cancer 
harboring BRCA mutations (Study 673201, ABRAZO), independently assessed objective 
response (OR) has been observed in 21% of 48 participants with disease progression after 
prior response to platinum containing regimens and in 37% of 35 patients with disease 
progression after 3 or more non-platinum cytotoxic regimens.41
In the ongoing Phase 3, open-label, randomized, parallel-group study (protocol no. 673-301 
[EMBRACA]), talazoparib was evaluated in patients with germline BRCA 1/2 mutations 
who received no more than 3 prior chemotherapy regimens for locally advanced or metastatic 
breast cancer.  Median progression-free survival (PFS) was 8.6 months (95% confidence 
interval (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].42
Talazoparib is currently being investigated as a single-agent (including Pfizer Study 
TALAPRO-1 in men with mCRPC positive for DDR defects who have previously received 
taxane-based chemotherapy and progressed on at least 1 novel hormonal agent) and in 
combination with other anti-cancer therapies, including avelumab (Pfizer studies B9991025, 
B9991032, and B9991033) and enzalutamide (Pfizer study TALAPRO-2 in men with 
mCRPC with no prior systemic treatments initiated after documentation of mCRPC) in 
patients with locally advanced or metastatic solid tumors.  Refer to the talazoparib IB for 
additional information on clinical study outcomes for efficacy and safety.43
2.2.6. Enzalutamide
Enzalutamide is an androgen receptor inhibitor currently being evaluated in combination 
with other anti-cancer therapies, including anti-PD1 or anti-PD-L1 and PARPi, in patients 
with mCRPC. Enzalutamide has demonstrated single-agent clinical activity in patients with 
mCRPC.  The benefit of enzalutamide on this population has been consistently observed 
across multiple studies.  The clinical safety profile of enzalutamide supports its use as both a 
single agent and in combination with other cancer therapies. Enzalutamide was approved by 
the FDA in August 2012 for the treatment of patients with late-stage mCRPC, and 
subsequently was approved for the treatment of patients with non-metastatic (NM) CRPC in 
July 2018.       
2.2.6.1. Enzalutamide Mechanism of Action
Enzalutamide acts by inhibiting the binding of androgens to the androgen receptor (AR), 
androgen receptor nuclear translocation, and androgen receptor-mediated DNA binding.  In 
multiple prostate cancer cell lines that specifically model CRPC (LNCaP/AR, VCaP, W741C 
LNCaP), the consequences of enzalutamide treatment include inhibition of AR-induced gene 
transcription, reduced cell proliferation, increased cell death by apoptosis and tumor 
regression.  In a mouse xenograft model of CRPC using prostate cancer cells that 
overexpress the AR (LNCaP/AR), enzalutamide inhibits tumor growth and reduces tumor 
size.44


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 73
2.2.6.2. Enzalutamide Clinical Experience
Enzalutamide prolonged overall survival (OS) versus placebo for chemotherapy-naïve men 
with mCRPC and men who had progressed on docetaxel therapy (PREVAIL and AFFIRM 
studies, respectively). 
The efficacy of enzalutamide in study participants with mCRPC has and continues to be 
assessed in > 10 clinical studies including participants who were chemotherapy-naïve as well 
as those who previously received docetaxel: 3 Phase 4 open-label studies: MDV3100-10, 
9785-CL-0410 and 9785-MA-1008; and 2 additional Phase 3, randomized, 
placebo-controlled studies: 9785-CL-0232 and 9785-MA-1001.
Preliminary results from the ARCHES study (NCT02677896) demonstrated that 
enzalutamide plus androgen deprivation therapy (ADT) also significantly improved 
radiographic progression-free survival (rPFS) compared with ADT alone in patients with 
hormone-sensitive metastatic prostate cancer (mHSPC).  Enzalutamide acts by inhibiting the 
binding of androgens to the androgen receptor, androgen receptor nuclear translocation, and 
androgen receptor-mediated DNA binding and is currently being evaluated in combination 
with other anti-cancer therapies in Phase 3 studies, including atezolizumab (NCT03016312) 
and pembrolizumab (NCT03834493) in patients with mCRPC.  
Efficacy is also being assessed in participants with nonmetastatic prostate cancer in 2 Phase 
3, randomized, placebo-controlled studies (MDV3100-13 and MDV3100-14).  MDV3100-14 
(PROSPER Study) enzalutamide in combination with androgen deprivation therapy (ADT) 
reduced the risk of developing metastases or death by 71% compared to ADT alone in 
participants with non-metastatic (M0) CRPC.  As of the data cutoff date for the IB, data for 
study MDV3100-13 (in participants with high-risk, nonmetastatic hormone sensitive prostate 
cancer progressing after definitive therapy) has not yet been analyzed.  
Enzalutamide has been evaluated in more than 8000 participants enrolled worldwide in 
completed and ongoing clinical trials, including more than 5500 participants with prostate 
cancer who received at least 1 dose of enzalutamide (160 mg daily [QD]).  Refer to the 
enzalutamide IB44 for additional information on clinical study outcomes for efficacy and 
safety.
2.3. Benefit/Risk Assessment
The benefit risk relationship has been carefully considered in the planning of this trial. 
Avelumab was initially dosed per body weight at a dose of 10 mg/kg Q2W in the expansion 
cohorts of the ongoing Phase 1 Study EMR 100070-001, as described in Section 2.2.3.2.  
 
The 10 mg/kg Q2W avelumab dosing regimen was approved by the FDA in 2017 as the first 
treatment for Merkel cell carcinoma.  In this clinical study a flat dose regimen of 800 mg IV 
Q2W, as approved by the FDA in 2018, will be used throughout all combinations.
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 74
 
 
and no differences in the overall safety profile for patients with 
SCCHN and mCRPC relative to all patients.  Most of the observed adverse events in patients
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 (IRRs), 
manifesting most frequently as low grade chills during or shortly after the first infusion and 
managed by infusion interruption and infusion rate reduction, as well as immune-related 
adverse events (irAEs; mostly represented by thyroid 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 study.  These measures include 
guidelines for treatment interruption and discontinuation in case of toxicities, guidelines for 
steroid treatment implementation, and mandatory pre-treatment with an antihistamine and 
acetaminophen prior to the first 4 infusions of avelumab and as clinically indicated thereafter.
The bempegaldesleukin (NKTR-214) clinical development program has included Phase 1/2 
studies in patients with multiple tumor types, including melanoma, renal cell cancer (RCC), 
non-small cell lung cancer (NSCLC), urothelial carcinoma, bladder cancer, triple-negative 
breast cancer (TNBC), colorectal cancer (CRC), and sarcoma.  Bempegaldesleukin (NKTR-
214) has been generally well-tolerated both as single-agent and in combination with 
nivolumab in clinical trials to date at doses up to 0.009 mg/kg Q3W, as described in
Section 2.2.4.2, Section 2.2.4.3, 
 
.  
 
 
 
 
 
 
 
 
 While 
infusion related reactions are reported for both assets, they are expected to be distinguishable 
by the timing of onset of symptoms and risk mitigation measures with mandatory pre-
treatment to prevent events will be implemented. Further close participant monitoring during 
the first 8 days and treatment guidelines in case AEs occur will also be implemented in order 
to safeguard participants.    
Based on the manageable safety profiles of avelumab and bempegaldesleukin (NRTR-214) 
and the anticipated enhanced anti-tumor activity, the benefit-risk relationship of avelumab 
given in combination with bempegaldesleukin (NKTR-214) is expected to be favorable and it 
is considered appropriate to proceed with the proposed clinical investigation in participants
with 1L SCCHN. 
Talazoparib has shown anti-tumor activity in patients with breast, ovarian, peritoneal and 
pancreatic cancers, as described in Section 2.2.5.2
  The anti-tumor 
activity of single agent talazoparib has been demonstrated in the EMBRACA study in 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 75
BRCA1/2 positive patients with locally advanced and/or metastatic breast cancer, in which 
talazoparib provided a significantly superior ORR and PFS benefit as compared to standard 
chemotherapy.42,45  Based on these results, talazoparib was approved by the FDA in 2018 for 
the treatment of adults 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 toxicity profile of talazoparib is not anticipated to overlap with those of avelumab and 
bempegaldesleukin (NKTR-214) and the same mitigation measures and participant
monitoring as described above for the doublet combination will be implemented in order to 
safeguard participants.  
Based on the manageable safety profiles of avelumab, bempegaldesleukin (NRTR-214) and 
talazoparib and the anticipated enhanced anti-tumor activity, the benefit-risk relationship of 
avelumab given in combination with bempegaldesleukin (NKTR-214) and talazoparib is 
expected to be favorable and it is considered appropriate to proceed with the proposed 
clinical investigation in participants with mCRPC. 
Enzalutamide has demonstrated single-agent clinical activity in patients with mCRPC, as 
described in Section 2.2.6.2.  The benefit of enzalutamide on this population has been 
consistently observed across multiple studies and is approved in this indication.  
Enzalutamide was approved in the United States in 2012 for the treatment of patients with 
mCRPC who have previously received docetaxel.  Enzalutamide has subsequently been
approved for the treatment of adult men with mCRPC who are asymptomatic or mildly 
symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is 
not yet clinically indicated.  The clinical safety profile of enzalutamide at a dose of 160 mg 
daily supports its use as both a single agent and in combination with other cancer therapies.
The grade ≥ 3 TEAEs that were identified in ≥ 1% of patients with non-metastatic or 
metastatic CRPC treated with enzalutamide, and with ≥ 0.5% higher incidence over placebo, 
in combined Phase 3 studies (2799 patients total) are as follows: hypertension (4.6% 
enzalutamide vs 1.8% placebo), fatigue (3.5% vs 2.5%), fall (1.0% vs 0.5%), asthenia (1.6% 
vs 1.1%), pneumonia (1.4% vs 0.8%) and spinal cord compression (3.1% vs 2.2%).44  Based 
on the manageable safety profiles of avelumab, bempegaldesleukin (NRTR-214) and 
enzalutamide and the anticipated enhanced anti-tumor activity, the benefit risk relationship of 
avelumab given in combination with bempegaldesleukin (NKTR-214) and enzalutamide is 
expected to be favorable and it is considered appropriate to proceed with the proposed 
clinical investigation in participants with mCRPC.  The toxicity profile of enzalutamide is 
not anticipated to overlap with those of avelumab and bempegaldesleukin (NKTR-214) and 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 76
the same mitigation measures and patient monitoring as described above for the doublet 
combination will be implemented in order to safeguard participants.    
In summary, based on the available clinical safety and efficacy data for each single agent, 
and the strength of the scientific hypotheses under evaluation for the combination of 
avelumab with bempegaldesleukin (NKTR-214) as a doublet in 1L SCCHN participants 
(Combination A) and as triplets adding either talazoparib (Combination B) or enzalutamide
(Combination C), respectively in mCRPC participants, and the anticipated positive 
benefit-risk ratio, this clinical trial is being proposed for evaluation in patient populations 
having currently limited treatment options available.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of avelumab, bempegaldesleukin (NKTR-214), talazoparib, or 
enzalutamide may be found in the Investigator’s Brochures, which are the single reference 
safety documents (SRSDs) for this study.
2.4. Drug-Drug Interactions
 
 
Likewise, the DDI potential among avelumab, bempegaldesleukin (NKTR-214) and 
talazoparib or enzalutamide is minimal because the DDI between small molecule drugs 
(talazoparib & enzalutamide) and biologics (avelumab & bempegaldesleukin (NKTR-214)) 
is uncommon given each class of drug has distinct clearance pathways.
Although no DDI is expected in each combination, PK samples for each drug (avelumab, 
talazoparib and enzalutamide) will be collected from all enrolled participants in Phase 1b and 
Phase 2.  For bempegaldesleukin (NKTR-214), PK samples will be collected from all 
enrolled participants in Phase 1B and a subset of approximately 20 participants receiving 
RP2D in each combination in Phase 2. Concentrations will be measured and compared to 
historical PK data for each drug when administered alone to rule out any potential DDI.
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS
Objectives
Endpoints
Primary
Phase 1b: 
•
To assess the dose-limiting toxicity 
(DLT) rate of avelumab in combination 
with bempegaldesleukin (NKTR-214)
(Combination A) and talazoparib 
Phase 1b: 
•
DLT during the DLT evaluation period 
(Cycle 1)
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 77
(Combination B) or enzalutamide 
(Combination C) in order to determine 
the recommended Phase 2 dose (RP2D) 
for the combinations.
Phase 2:

Combination A: To assess ORR of 
avelumab in combination with 
bempegaldesleukin (NKTR-214) in 
participants with locally recurrent or 
metastatic SCCHN.

Combination B: To assess soft tissue 
ORR of avelumab in combination with 
bempegaldesleukin (NKTR-214) and 
talazoparib in participants with DDR 
defect positive mCRPC.

Combination C: To assess the PSA 
response rate of avelumab in 
combination with bempegaldesleukin 
(NKTR-214) and enzalutamide in 
participants with mCRPC after 
progression on abiraterone.
Phase 2:

Combination A: Confirmed objective 
response (OR) as determined by the 
investigator using RECIST v1.1 
(Appendix 9).

Combination B: Confirmed soft tissue 
OR as determined by the investigator 
using RECIST v 1.1 (Appendix 9) with 
no evidence of confirmed bone disease 
progression on repeat bone scan at least 
6 weeks later per prostate cancer 
working group 3 (PCWG3) criteria
(Appendix 10).

Combination C: Confirmed prostate 
specific antigen (PSA) response 
decrease ≥ 50% from baseline
confirmed by a second consecutive 
assessment at least 3 weeks later.
Secondary

To assess the overall safety and 
tolerability of the combinations (A, B 
and C).

Adverse events (AEs) as characterized 
by type, severity (as graded by National 
Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI 
CTCAE] v4.03), timing, seriousness, 
and relationship to study therapy.

Laboratory abnormalities as 
characterized by type, severity (as 
graded by NCI CTCAE v4.03) and 
timing.

To assess other measures of anti-tumor 

Time-to-event endpoints as determined 
by the investigator, using RECIST v1.1 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 78
activity.
(Combination A) and in participants 
with mCRPC (Combinations B and C), 
RECIST v1.1 (soft tissue disease) and 
PCWG3 (bone disease), including time 
to tumor response (TTR), duration of 
response (DR), progression free survival 
(PFS), and Overall Survival (OS).

Combination B: Confirmed PSA 
response 50% decrease from baseline
confirmed by a second consecutive 
assessment at least 3 weeks later.

Combination C: Confirmed soft tissue 
OR as determined by the investigator 
using RECIST v 1.1 (Appendix 9) with 
no evidence of confirmed bone disease 
progression on repeat bone scan at least 
6 weeks later per PCWG3 criteria
(Appendix 10).

Combination C: Circulating tumor 
cells CTC count conversion (decrease in 
CTC count from ≥ 5 CTC per 7.5 mL of 
blood at baseline to < 5 CTC per 7.5 mL 
of blood at any assessment on 
treatment), and CTC0 (CTC0 is defined 
as a CTC count of ≥1 CTC per 7.5 mL 
of blood at baseline and 0 CTC per 7.5 
mL of blood at any assessment on 
treatment).

Combinations B and C: Time to PSA 
progression (TTPSAP) defined 
according to the consensus guidelines of 
the Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3) criteria.

To characterize the PK of avelumab, 
bempegaldesleukin (NKTR-214), and 
talazoparib or enzalutamide when given 
in combination.

PK parameters including trough 
concentrations (Ctrough) for avelumab, 
bempegaldesleukin (NKTR-214), 
talazoparib, enzalutamide and N-
desmethyl-enzalutamide and maximum 
concentrations (Cmax) for avelumab and 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 79
bempegaldesleukin (NKTR-214).
•
To assess the immunogenicity of 
avelumab and bempegaldesleukin 
(NKTR-214) when combined together 
and with talazoparib or enzalutamide.
•
Anti-drug antibody (ADA) and 
neutralizing antibodies (NAb) against 
avelumab, bempegaldesleukin (NKTR-
214) and IL-2 when combined together 
and with talazoparib or enzalutamide. 
•
To assess the correlation of anti-tumor 
activity with PD-L1 expression level in 
baseline tumor tissue.
•
PD-L1 expression level in baseline
tumor tissue.
•
Combination A: To assess the 
correlation of anti-tumor activity with 
PD-L1 expression level in on-treatment 
tumor tissue.
•
Combination A: PD-L1 expression 
level in on-treatment tumor tissue.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 80
Estimands
This section defines the estimands associated with the primary endpoints of the study.  For all 
estimands, refer to Section 9.1.
The populations associated with estimands for each combination are as follows:
•
Combination A - participants with 1L SCCHN.
•
Combination B Phase 1b - participants with mCRPC after progression on taxane-
based chemotherapy.
•
Combination B Phase 2 - participants with DDR defect positive mCRPC after 
progression on taxane-based chemotherapy.
•
Combination C - participants with mCRPC after progression on abiraterone therapy.
The endpoint definitions, the observations that will be considered in the derivation of the 
endpoint and the associated analyses are described or referenced below.
•
Phase 1b: The primary endpoint (Combinations A, B and C) will be the occurrence of 
DLT during the primary DLT evaluation period (Cycle 1).  DLTs are defined in 
Section 4.1.  DLTs will only be collected during Cycle 1 of Phase 1b and the DLT 
rate will be estimated for participants who are evaluable for DLTs.  DLT-evaluable 
participants are those enrolled in Phase 1b who 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
without DLT.  Participants without DLTs who withdraw from study treatment before 
receiving at least 2 doses of avelumab and bempegaldesleukin (NKTR-214; all 
Combinations) or 75% of the planned dose of talazoparib (Combination B) or 
enzalutamide (Combination C), in Cycle 1 for reasons other than treatment-related 
toxicity are not evaluable for DLT.  All participants deemed non-evaluable for DLT 
may be replaced.
•
Phase 2 Objective Response (Combination A) or soft tissue Objective Response 
(Combination B): The primary estimand is the treatment effect of OR (Combination 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 81
A) or soft tissue OR (Combination B) from the time of first dose until progression is 
met or subsequent anticancer therapy is administered.  Point estimates and confidence 
intervals (following the methodology outlined in Section 9.4.1) will be calculated. 

Phase 2 PSA Response (Combination C): The primary estimand is the treatment 
effect of PSA response from the time of first dose until progression is met or 
subsequent anticancer therapy is administered.  Point estimates and confidence 
intervals (following the methodology outlined in Section 9.4.1) will be calculated. 
4. STUDY DESIGN
     
4.1. Overall Design
This is a Phase 1b/2, open-label, multi-center study of avelumab in combination with 
bempegaldesleukin (NKTR-214) with or without talazoparib or enzalutamide in adult 
participants with 1L SCCHN (Combination A) or with mCRPC (Combinations B and C).  
Refer to the study schema, Section 1.2.
Phase 1b Design
Phase 1b will include 2 sequential dose-finding steps:
Step 1. Combination A will be evaluated in participants with 1L SCCHN to determine the 
recommended Phase 2 dose (RP2D).  Refer to Table 8 for the potential dose levels.  A 
minimum of 9 participants will be enrolled.  
Step 2.  Upon the determination of the RP2D for Combination A, the dose-finding for Phase 
1b for Combinations B and C in participants with mCRPC will commence and will be 
conducted in parallel with the Phase 2 Combination A portion of the study to determine the 
RP2D for Combinations B and C separately.  A minimum of 9 participants will be enrolled in 
each combination.
Guidance for Phase 1b dosing (dose level to be evaluated in the next cohort) and enrollment 
(number of participants to be enrolled in the next cohort) decisions will be based on a 
Bayesian Logistic Regression Model (BLRM).   Refer to Appendix 11, Appendix 12, and 
Appendix 13 for the BLRM designs for Combinations A, B, and C, respectively.  The BLRM 
incorporates single-agent and available combination DLT data (historical and prospectively 
across dose combinations) to estimate the posterior probability of under-dosing, target dosing 
and overdosing, thereby reducing participant risk and increasing efficiency and precision 
during dose finding with combination treatments.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 82
Step 1. Dose-Finding for Combination A
The potential dose levels of avelumab and bempegaldesleukin for dose finding for 
Combination A are shown in Table 8.  The starting dose level is 800 mg avelumab 
intravenous (IV) every 2 weeks (Q2W) plus 0.006 mg/kg bempegaldesleukin IV Q2W, 
which satisfies the Escalation With Overdose Control (EWOC) criterion that the risk for 
excessive toxicity is less than 0.25.  For the starting dose level, the risk of excessive toxicity 
was estimated to be 13.7% based on information from prior single-agent Phase 1 studies and 
a pharmacokinetic (PK) assessment of no potential significant drug-drug interaction.  Dose 
reduction of bempegaldesleukin (NKTR-214) to 0.003 mg/kg Q2W will be triggered if 
higher than expected toxicity is observed at the higher dose (risk of excessive toxicity ≥ 
0.25).
Table 8.
Phase 1b Combination A 1L SCCHN Avelumab + Bempegaldesleukin 
(NKTR-214)  Dose Levels
Dose Level
Avelumab dose IV
(mg Q2W)
Bempegaldesleukin dose IV
(NKTR-214)  
(mg/kg Q2W)
D0
800
0.006
D-1
800
0.003
1L SCCHN= locally recurrent squamous cell carcinoma of the head and neck; D0=starting dose; D-1=reduced 
dose; IV= intravenous; mg= milligram; Q2W= every 2 weeks.
Step 2:  Dose-Finding for Combinations B and C
The potential dose levels of avelumab, bempegaldesleukin (NKTR-214) and talazoparib for 
dose finding for Combination B are listed in Table 9.  The dose level for avelumab is fixed at 
800 mg Q2W. The starting dose level for bempegaldesleukin (NKTR-214) and talazoparib 
will be determined at the completion of the dose finding for Combination A based on 
available clinical data (including but not limited to safety and PK/pharmacodynamic data).  
The lowest allowed dose for bempegaldesleukin (NKTR-214) will be 0.003 mg/kg and the 
lowest allowed dose for talazoparib will be 0.5 mg once daily, in which case participants
with moderate renal impairment cannot be enrolled. The starting dose for talazoparib for 
participants with moderate renal impairment (creatinine clearance [CrCL] 30-59 mL/min) 
will be reduced by 1 dose level unless the determined starting dose for talazoparib for 
participants with no or mild renal impairment is 0.5 mg once daily.   
Table 9.
Phase 1b Combination B mCRPC Avelumab, Bempegaldesleukin (NKTR-
214), and Talazoparib Dose levels
Dose Level
Avelumab Dose IV
(mg Q2W)
Bempegaldesleukin 
(NKTR-214)  IV
(mg/kg Q2W)
Talazoparib Dose PO
(mg once daily)
D0-A*
800
0.006
1.0
D-1A
800
0.006
0.75
D-2A
800
0.006
0.5
D0-B*
800
0.003
1.0
D-1B
800
0.003
0.75
D-2B
800
0.003
0.5


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 83
Table 9.
Phase 1b Combination B mCRPC Avelumab, Bempegaldesleukin (NKTR-
214), and Talazoparib Dose levels
Dose Level
Avelumab Dose IV
(mg Q2W)
Bempegaldesleukin 
(NKTR-214)  IV
(mg/kg Q2W)
Talazoparib Dose PO
(mg once daily)
D0= starting dose; D-1=reduced dose; D-2=second reduced dose; IV= intravenous; mCRPC=metastatic 
castration-resistant prostate cancer; mg= milligram; PO=orally; Q2W= every 2 weeks.
*Dose levels for Combination B designated with ‘A’ are applicable if the bempegaldesleukin (NKTR-214) dose is 0.006 
mg/kg Q2W; dose levels for  Combination B designated with ‘B’ are applicable if the bempegaldesleukin (NKTR-214) dose 
is 0.003 mg/kg Q2W.
The potential dose levels of avelumab, bempegaldesleukin (NKTR-214), and enzalutamide 
for dose finding for Combination C are listed in Table 10.  The starting dose level for 
bempegaldesleukin (NKTR-214) and enzalutamide will be determined at the completion of 
the dose finding for Combination A based on available clinical data (including but not 
limited to safety and PK/pharmacodynamic data).  The approved label dose for enzalutamide 
is 160 mg QD.  The target starting enzalutamide dose to be used in Combination C is 160 mg 
QD unless unexpected safety issues require its lowering according to the BLRM 
recommendation.  In both the KEYNOTE-199 study (pembrolizumab + enzalutamide in 
mCRPC) and the IMbassador250 study (atezolizumab + enzalutamide in mCRPC), the full 
monotherapy dose of enzalutamide was used as the starting dose.  The lowest allowed dose 
for bempegaldesleukin (NKTR-214) will be 0.003 mg/kg and the lowest allowed dose for 
enzalutamide will be 80 mg once daily.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 84
Table 10.
Phase 1b Combination C mCRPC Avelumab, Bempegaldesleukin (NKTR-
214), and Enzalutamide Dose levels
Dose Level
Avelumab Dose IV
(mg Q2W)
Bempegaldesleukin 
(NKTR-214) IV
(mg/kg Q2W)
Enzalutamide Dose PO
(mg once daily)
D0-A*
800
0.006
160
D-1A
800
0.006
120
D-2A
800
0.006
80
D0-B*
800
0.003
160
D-1B
800
0.003
120
D-2B
800
0.003
80
D0= starting dose; D-1=reduced dose; D-2=second reduced dose; IV= intravenous; mCRPC=metastatic 
castration resistant prostate cancer; mg= milligram; PO=orally; Q2W= every 2 weeks.
*Dose levels for this Combination C designated with ‘A’ are applicable if the bempegaldesleukin (NKTR-214) dose is 
0.006 mg/kg Q2W; dose levels for Combination C designated with ‘B’ are applicable if the bempegaldesleukin (NKTR-214) 
dose is 0.003 mg/kg Q2W.
For each combination, beginning with the starting dose level, cohorts of 3-6 participants will 
be enrolled, treated, and monitored during the 28-day DLT evaluation period (Cycle 1) as 
follows:  

Participants who withdraw from study treatment in Cycle 1 before receiving at least 2 
doses of bempegaldesleukin (NKTR-214) and avelumab and at least 75% of the planned 
dose of talazoparib (Combination B) or enzalutamide (Combination C) for reasons other 
than treatment-related toxicity are not evaluable for DLT.    All participants deemed 
non-evaluable for DLT may be replaced.

A minimum of 3 DLT-evaluable participants from each cohort will be required; 
additional participants will be enrolled in the specific enrollment cohort to replace 
participants who are not considered DLT-evaluable, where required. 

When all DLT-evaluable participants treated in a given enrollment cohort have 
completed the DLT observation period or experienced a DLT, whichever occurs first, the 
posterior distribution for the risk of DLT for new participants at different dose levels for 
the combination of interest will be evaluated. 

The posterior distributions will be summarized to provide the posterior probability that 
the risk of DLT lies within the intervals shown below: 

Underdosing: [0, 0.16)

Target toxicity: [0.16, 0.33)

Excessive toxicity or overdosing: [0.33, 1]


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 85
In addition to accumulating safety data and observed DLTs, decisions on further participant 
enrollment and dose level selection will be guided by the EWOC criterion.  A combination 
dose may only be used for newly enrolled participants if the risk of excessive toxicity at that 
combination dose is less than 0.25.
A dose level combination is a potential candidate for being the maximum tolerated dose 
(MTD) level when all the following criteria are met:

≥6 participants have been treated at that dose;

Probability of target dosing >0.50;

Probability of overdosing <0.25.
An RP2D below the MTD may be determined based on other safety, clinical activity, PK, 
and pharmacodynamic (PD) data. Nine DLT-evaluable participants are needed to be treated 
at RP2D if no DLT is observed, and 12 evaluable participants if at least 1 DLT is observed.
Phase 2 Design
Once the Phase 1b component is completed for each combination and the RP2Ds have been 
determined, Phase 2 will be initiated to further evaluate the safety and anti-tumor activity in 
Combinations A, B, and C.  

Combination A will enroll up to approximately 31 participants with 1L SCCHN.

Combination B will enroll up to approximately 20 participants with DDR+ mCRPC 
post taxane-based chemotherapy.

Combination C will enroll up to approximately 40 participants with mCRPC 
post-abiraterone therapy.
Combination A will proceed into Phase 2 once RP2D for Combination A has been 
determined in the Phase 1b dose finding component, in parallel with dose-finding for Phase 
1b for Combinations B and C.  Refer to Table 9 and Table 10 for the potential dose levels for 
Combinations B and C, respectively.
4.1.1. DLT Determination
The Combinations A, B, and C will be administered in 28-day cycles, and the DLT 
evaluation period will be the first treatment cycle. The severity of AEs will be graded 
according to CTCAE v. 4.03.  For the purpose of dose finding, any of the following AEs 
occurring in the first cycle of treatment which are attributable to any or all agents in the 
combination will be classified as DLTs:


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 86
Hematologic:

Grade 4 anemia lasting 5 days (life threatening consequences; urgent intervention 
indicated).

Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 109/L) 
lasting >5 days.

Grade ≥3 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.

Grade ≥3 neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 
infection).

Grade 3 thrombocytopenia (25,000/mm3 or 25.0 x 109/L to <50,000/ mm3 or <50.0 x  
109/L) with bleeding, or grade 4 thrombocytopenia (platelet count <25,000/mm3 or 
<25.0 x 109/L.
Non-Hematologic:

Potential Hy’s Law cases defined as: ALT or AST >3 x upper limit of normal 
(ULN) if normal at baseline OR >3 x ULN and doubling the baseline (if >ULN at 
baseline) associated with total bilirubin >2 x ULN and an alkaline phosphatase 
(AP) <2 x ULN. 

Grade 3 toxicities of any duration except:

Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea that 
resolves in 72 hours;

Grade 3 hypotension that occurs within 5 days post-dosing and resolves with 
adequate medical intervention;

Grade 3 non-hematologic laboratory abnormalities without a clinical correlate.
Non-adherence to Treatment Schedule:

Delay of the subsequent cycle of two weeks or more due to toxicity occurring during 
the DLT observation period.

Failure to deliver at least 75% of the planned doses of all study interventions during 
the first cycle of treatment due to treatment related toxicities.
While the rules for adjudicating DLTs in the context of the Phase 1b 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 based on the emerging safety profile for 
the combination.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 87
4.2. Scientific Rationale for Study Design
Refer to Section 2.1 for the Study Rationale.  
 
 
 
 
 
4.3. Justification for Dose
4.3.1. Avelumab + Bempegaldesleukin (NKTR-214): Combination A
Modeling and simulation was performed to support the use of a flat dose regimen in selected 
clinical studies.  Avelumab was developed using a mg/kg regimen 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,46 pembrolizumab, and 
atezolizumab47 reveal that body weight based dose regimens do not result in less variability 
in measures of exposure compared to fixed (ie, body weight independent) dose regimens.
The same has been confirmed for avelumab using simulations based on population PK 
models.  Simulation showed that exposures to avelumab across the available range of body 
weights are less variable with 800 mg IV Q2W compared with 10 mg/kg IV Q2W; exposures 
were similar near the population median weight.47  Furthermore, the 800 mg IV Q2W dose 
regimen is expected to result in Ctrough > 1 mg/mL required to maintain avelumab serum 
concentrations at > 95% target occupancy (TO) throughout the entire dosing interval in all 
weight categories.  Further, fixed dosing is expected to provide more consistent dosing across 
body weights, minimize drug wastage, facilitate preparation and administration, and reduce 
pharmacy errors.
Furthermore, avelumab has been administered safely as a fixed dose regimen of 800 mg IV 
every 2 weeks in previous Pfizer clinical trials and the fixed dose regimen of 800 mg IV 
every 2 weeks proposed for this study is currently the FDA approved dose for both UC and 
MCC.1  
FDA guidance for co-development of two drugs recommends starting at the maximum dose 
for both agents if a) single agent toxicity profiles are known and b) no overlapping toxicity is 
expected.  Therefore, it is proposed to start at the maximum dose levels of 800 mg IV and 
0.0006 mg/kg IV Q2W for avelumab and bempegaldesleukin (NKTR-214), respectively.
The proposed starting dose level (D0) of 800 mg avelumab intravenous IV Q2W plus 0.006 
mg/kg bempegaldesleukin (NKTR-214) IV Q2W, which satisfies the Escalation With 
Overdose Control (EWOC) criterion.  
 
 
 
 
 
 
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 88
 
 
 
 
  Based 
on these data, the proposed starting dose in Combination A for bempegaldesleukin 
(NKTR-214) is 0.006 mg/kg IV Q2W to match the Q2W dosing schedule of avelumab for 
participant convenience.
 
 
 
 
The observations noted in the studies described in Section 2.2, coupled with the established 
avelumab dosing schedule of Q2W, provide support for exploring the evaluation of 
bempegaldesleukin (NKTR-214) plus avelumab utilizing the Q2W dosing schedule in this 
study.  
4.3.2. Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib (Combination B); 
Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide (Combination C)
The starting dose levels for bempegaldesleukin (NKTR-214), talazoparib and enzalutamide 
will be determined at the completion of the dose finding for the Combination A based on the 
observed clinical data (including but not limited to safety and PK data).  An approved dose 
level for all investigational products as single agents is proposed, provided this is supported 
by both the DLT data and available combination data to support the claim of these dose 
levels.
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure and visit shown in the Schedule of 
Activities, has died, withdrawn consent for any further participation in the study or has been 
lost to follow-up, whichever occurs earlier.
The end of the study is defined as the date of study completion for the last participant in the 
trial globally or at sponsor discretion if the data support ending the study. 
For all combinations, participants clinically benefiting from study treatment without 
unacceptable toxicity, objective disease progression, or withdrawal of consent will be given 
the opportunity to continue treatment after study discontinuation by the sponsor.  Participants 
without other options for treatment may continue on treatment with the combination to which 
they have been assigned upon agreement with the sponsor.
CCI
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 89
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  
The following eligibility criteria are designed to select participants for whom participation in 
the study is considered appropriate.  All relevant medical and nonmedical conditions should 
be taken into consideration when deciding whether a participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Participants must be ≥ 18 years old.
Type of Participant and Disease Characteristics
2. Participants must have histological diagnosis of solid tumors, as follows:
a. Combination A: Locally recurrent (not amenable for curative intent) or 
metastatic squamous cell carcinoma of the oral cavity, oropharynx, 
hypopharynx, or larynx; and both of the following:

No prior systemic treatment for unresectable locally recurrent or metastatic 
disease.  Exception: If prior systemic chemotherapy treatment was given as 
part of chemoradiotherapy treatment, disease-free interval after the last 
administration of systemic chemotherapy treatment must be at least 6 months.

Measurable disease by RECIST v1.1 (Appendix 9) with at least 1 measurable 
lesion.
b. Combination B or C: mCRPC without small cell features meeting all of the 
following criteria:

Castration as defined by both of the following:

Serum testosterone ≤1.73 nmol/L (50 ng/dL) at the time of enrollment 
(prior to treatment with study drug on Cycle 1 Day 1 [C1D1]).

Bilateral orchiectomy or ongoing androgen deprivation therapy with a 
gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or 
medical castration).

Progressive disease at the time of enrollment (prior to treatment with study 
drug on C1D1) defined as 1 or more of the following 3 criteria:


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 90
•
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 
μg/L (2 ng/mL) if qualifying solely by PSA progression;
•
Radiographic soft tissue disease progression as defined by RECIST v1.1 
(Appendix 9) for soft tissue;
•
Radiographic bone disease progression defined by Prostate Cancer 
Working Group 3 (PCWG3; Appendix 10) with 2 or more new metastatic 
lesions on bone scan (confirm ambiguous results by other imaging 
modalities).
•
Combination B participants must meet all of the following:
•
Progressed on at least 1 line of second generation anti-androgen therapy 
(eg, enzalutamide and/or abiraterone acetate/prednisone) for treatment of 
mCRPC.
•
Have received at least 1, but no more than 1, prior taxane-based 
chemotherapy regimen for mCRPC, or were deemed unsuitable, declined, 
or did not have access to these therapies. No other prior chemotherapy 
regimen for mCRPC is allowed. Participants may have received radium-
223 or sipuleucel-T, which does not count for a line of prior chemotherapy 
regimen.
•
Measurable disease by RECIST v1.1 (Appendix 9) with at least 
1 measurable lesion.
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 91
•
Combination C:
•
Participants with non-measurable disease (including disease affecting 
bone only) as determined by RECIST v1.1 (Appendix 9) are allowed.
•
Participants must have progressed on 1 line of abiraterone 
acetate/prednisone anti-androgen therapy for treatment of mCRPC.
•
Participants must have not had any prior chemotherapy for the treatment 
of mCRPC. Prior treatment with radium 223 or sipuleucel-T is allowed 
and it does not count as a prior chemotherapy regimen.
      3. All participants must provide tumor tissue as described in Section 8.1.
      4. Participants must have an Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) 0 or 1 (Appendix 8).
      5. Participants must have adequate bone marrow function without hematopoietic growth 
factor or transfusion support within 14 days prior to and including C1D1:
a. Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L;
b. Platelets ≥100,000/mm3 or ≥100 x 109/L;
c.
Hemoglobin ≥9 g/dL (or ≥5.6 mmol/L).
      6. Participants must have adequate renal function by C1D1, defined by an estimated 
creatinine clearance (CrCl) ≥30 mL/min. CrCl should be estimated according to the 
Cockcroft-Gault formula as:
CrCl={[(140 ̢ age) h weight)]/(72 x SCR[serum creatinine])} h 0.85 (if female), 
where CrCl (creatinine clearance) is measured in mL/min, age is expressed in years, 
weight in kilograms (kg), and SCR in mg/dL.
7.   Participants must have adequate liver function by C1D1, including:
a.
Total serum bilirubin ≤1.5 × the upper limit of normal range 
(ULN); 
b.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 
x ULN (if liver test abnormalities are due to hepatic metastasis, then AST and
ALT ≤5 x ULN)
Sex
  8. Male or Female
Contraceptive use by men with the ability to father a child or women of childbearing 
potential (Combination A only regarding the latter) must meet requirements outlined in 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 92
Appendix 4 and should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies.
     
a.
Male participants:
Male participants are eligible to participate if they agree to the following
requirements during the intervention period and for at least 30 days after the last dose of
avelumab, at least 3 months after the last dose of enzalutamide or bempegaldesleukin
(azospermic males are exempt from contraceptive requirements for bempegaldesleukin 
[NKTR-214]), and at least 4 months after the last dose of talazoparib, which corresponds to 
the time needed to eliminate study interventions.  In addition, male participants MUST:

Refrain from donating sperm

PLUS either:

Be abstinent from intercourse as their preferred and usual lifestyle (abstinent on a 
long term and persistent basis) and agree to remain abstinent
OR

Use an additional highly effective contraceptive method with a failure rate of <1%
per year as described below and in Appendix 4 for a female partner of 
childbearing potential.  The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom when engaging in any activity that allows passage of 
ejaculate to another person.  
b. Female participants (Combination A only):

A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies:

Is not a woman of childbearing potential (WOCBP) 
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), preferably with low user dependency, as 
described in Appendix 4 during the intervention period and for at least 30 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 93
days after the last dose of avelumab and bempegaldesleukin (NKTR-214); and 
agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period. The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention.

A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum]
as required by local regulations) at C1D1.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
Informed Consent
9. Participants must be capable of giving signed informed consent as described in 
Appendix 1 which includes compliance with the requirements and restrictions listed    
in the informed consent document (ICD) and in this protocol.
10. Participants must be willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other procedures.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Known prior sever hypersensitivity to investigational products or any component in 
their formulations, including known severe hypersensitivity reactions to monoclonal 
antibodies (NCT CTCAE v4.03 Grade ≥3).
2. Known history of: immune-mediated colitis, inflammatory bowel disease, 
pneumonitis, or pulmonary fibrosis.
3. Active or prior autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Participants with diabetes type I, vitiligo, psoriasis, or 
hypo or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible.
4. Prior organ transplantation including allogenic stem cell transplantation.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 94
5. Vaccination within 4 weeks prior to C1D1 and while on trial is prohibited except 
for administration of inactivated vaccines.
6. Known symptomatic brain lesions requiring steroids.  Exception: participants with 
previously diagnosed brain lesions are eligible if they meet all of the following 
criteria: have newly diagnosed small brain lesions which do not require treatment;
have completed their treatment and have recovered from the acute effects of 
radiation therapy or surgery prior to C1D1; have discontinued corticosteroid 
treatment for these lesions for at least 4 weeks prior to C1D1; and are 
neurologically stable.
7. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS).
8. Positive hepatitis B virus (HBV) surface antigen, or positive hepatitis C virus 
(HCV) ribonucleic acid (RNA) if anti-HCV antibody screening tests positive.
9. Active infection requiring systemic therapy within 14 days prior to C1D1.
10. 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
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 participant inappropriate for entry 
into this study.
11. Clinically significant (ie, active) cardiovascular disease including the following: 
documented left ventricular ejection fraction (LVEF) 50% by 
echocardiogram/multigated ECHO/MUGA (echocardiogram/multigated 
acquisition; performed within 6 months prior to enrollment); cerebral vascular 
accident/stroke (<6 months prior to C1D1); myocardial infarction (<6 months prior 
to C1D1); unstable angina; congestive heart failure (≥New York Heart Association 
Classification Class II); or serious cardiac arrhythmia (uncontrolled, clinically 
significant) requiring medication.
12. Diagnosis of any other malignancy within 2 years prior to C1D1, except for 
adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the 
breast, bladder or of the cervix and for Combination A only, 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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 95
Prior/Concomitant Therapy
13. Prior immunotherapy with IL-2 agents or anti PD-1, anti PD-L1, anti PD-L2, or 
anti- cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody.  Prior 
treatment with Sipuleucel-T for participants with mCRPC is allowed.
14. Combination B only: Prior treatment with a PARP inhibitor.
15. Combination C only:  Prior treatment with second generation androgen receptor 
antagonist other than abiraterone/prednisone (eg, enzalutamide, apalutamide).
16. Current use of immunosuppressive medication at the time of C1D1, EXCEPT for 
the following permitted steroids:
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).
17. Combination B only: Current (within 7 days prior to C1D1) or anticipated use of 
medications, including strong P-glycoprotein (P-gp) inhibitors (refer to 
Section 6.5.5 for a list of strong P-gp inhibitors), strong P-gp inducers (eg: 
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort), and strong 
inhibitors of breast cancer resistance protein (BCRP; eg: curcumin, cyclosporine, 
elacridar [GF120918], eltrombopag).
18. Combination C only:  Strong (eg: carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifapentine) and moderate (eg: bosentan, efavirenz, etravirine, modafinil,
nafcillin) inducers for CYP3A4; strong CYP2C8 inducers (eg: rifampin); strong 
CYP2C8 inhibitors (eg, clopidogrel, gemfibrozil); substrates of CYP3A4 (eg: 
alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, 
quinidine, sirolimus, tacrolimus); substrates of CYP2C9 (eg, phenytoin; per the 
enzalutamide label, only substrates with narrow therapeutic index [NTI]); and 
substrates of CYP2C19 (eg, S mephenytoin, substrates with a narrow therapeutic 
index).
19. Bisphosphonate or denosumab dosage that was not stable (ie, not the same) for at 
least 2 weeks before C1D1 for participants receiving these therapies.
20. Prior radiation therapy within 14 days prior to C1D1.  Prior palliative radiotherapy 
to metastatic lesion(s) is permitted, provided it has been completed 14 days prior 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 96
to C1D1 and no clinically significant toxicities are expected (eg, mucositis, 
esophagitis).
21. Major surgery within 4 weeks prior to C1D1.
Prior/Concurrent Clinical Study Experience
22. Participation in other studies involving investigational drug(s) within 2 weeks prior 
to C1D1.
23. 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.
Other Exclusions
24. Conditions that may impair intake or absorption of talazoparib (Combination B) or 
enzalutamide (Combination C), as follows: inability to swallow capsules or tablets; 
known malabsorption syndrome; or baseline diarrhea ≤ Grade 1.
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 participants who are Pfizer employees, including their family members, directly 
involved in the conduct of the study.
5.3. Lifestyle Considerations

Contraception: Please refer to Appendix 4 regarding definitions for WOCBP and 
Contraception guidance. The investigator or his or her designee, in consultation with 
the participant, will confirm that the participant has selected an appropriate method of 
contraception for the individual participant and his or her partner(s) from the 
permitted list of contraception methods (refer to Appendix 4 Section 10.4.4) and will 
confirm that the participant has been instructed in its consistent and correct use.  A 
contraception check must be performed on D1 of every cycle during study 
treatment as indicated in the Schedule of Activities (SoA); the investigator or 
designee will inform the participant of the need to use highly effective contraception 
consistently and correctly and document the conversation and the participant’s 
affirmation in the participant’s chart (participants 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 participant to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the 
participant or partner.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 97
Please refer to the Inclusion Criteria (Section 5.1) under “Sex” for details on 
contraception timeframes.

Concomitant Therapy: Refer to Section 6.5.

Special Precautions for Administration: Refer to Section 6.1 and Section 6.6.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened.
6. STUDY INTERVENTION
Study intervention is defined as any investigational product(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
6.1. Study Intervention(s) Administered
6.1.1. Avelumab Administration
Avelumab (MSB0010718C) will be supplied for the study by Pfizer Global Clinical Supply, 
Worldwide Research and Development. Clinical trial 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.
6.1.1.1. Avelumab Dosage and Packaging
Avelumab is a sterile, clear, non-pyrogenic, and colorless solution intended for IV 
administration.  It is presented at a concentration of 20 mg/mL with a nominal volume of 
10 mL in glass vials closed with a rubber stopper and sealed with an aluminum 
polypropylene flip-off seal. Each vial is intended for a single use in a single participant only. 
The contents are free of bacteriostatic preservatives.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Guidelines (GMP) guidelines.  Avelumab will be packed 
in boxes each containing one vial.  The information on the trial drug will be in accordance 
with approved submission documents. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 98
Avelumab will be shipped in transport cool containers (2C to 8C) with temperature 
monitoring devices.
Refer to the dosage and administration instructions in the Investigational Product (IP) 
Manual for instructions on how to prepare the investigational products for administration.  
Investigational products should be prepared and dispensed by an appropriately qualified and 
experienced member of the study staff (eg, physician, nurse, physician’s assistant, nurse 
practitioner, or pharmacist) as allowed by local, state, and institutional guidance, as well as 
trained in the procedures specified in this protocol.
Detailed information on infusion bags to be used for the preparation of the dilutions and 
subsequent administration(s) for avelumab will be provided in the IP Manual. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
study agents.
Any unused portion of the avelumab solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and national standards of incineration.  Any 
spills that occur should be cleaned up using the facility’s standard cleanup procedures for 
biologic products.
6.1.1.2. Administration of Avelumab
Avelumab will be administered at 800 mg as a 1-hour (-10/+20 minutes) IV infusion starting 
after the bempegaldesleukin (NKTR-214) and talazoparib or enzalutamide (where 
applicable) is administered, 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 case report forms (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 Day 1, 
avelumab may be administered up to 2 days before or after the scheduled treatment day of 
each cycle for administrative reasons.  Within the 2-day window, avelumab and 
bempegaldesleukin should be administered on the same day, unless one treatment needs to be 
delayed/withheld due to toxicity reasons.
Participants should be carefully monitored for infusion reactions during administration. If an 
acute infusion reaction is noted, participants should be managed according to Table 11 in
Section 6.6.1.
Participants should be instructed to report any delayed reactions to the Investigator 
immediately.
Please refer to the Pharmacy Manual/current Investigator Brochure for details regarding 
preparation, storage, and administration.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 99
6.1.1.3. Special Precautions for Administration of Avelumab
6.1.1.3.1. Infusion-related reactions
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 (1:1000 dilution), allergy medications (IV antihistamines), 
bronchodilators, or equivalents, and oxygen should be available for immediate access.  If a 
hypersensitivity reaction occurs, the participant must be treated according to the best 
available medical practice.  In order to mitigate avelumab IRRs, participants may need to be 
premedicated.
In order to mitigate IRRs, premedication with an antihistamine and with paracetamol 
(acetaminophen) 30 to 60 minutes prior to the first 4 infusions of avelumab is mandatory.  
Premedication is not mandatory for Cycles ≥3 (ie, beyond the first four infusions), but should 
be administered for subsequent avelumab doses 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, provided it does not 
include systemic corticosteroids.  
Following the infusions of avelumab, participants 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 IRRs is described in Table 11 (Section 6.6.1).  Participants should 
be instructed to immediately report to the Investigator any delayed reactions that may occur 
after they leave the clinic.
6.1.2. Administration of Bempegaldesleukin (NKTR-214)  
Each participant’s bempegaldesleukin (NKTR-214) dose will be determined based on the 
participant’s weight in kilograms on Day 1 of each cycle. If the participant’s weight is within 
10% of the Cycle 1 Day 1 weight, the study drug doses do not need to be recalculated 
depending on institutional guidelines/preference. 
Bempegaldesleukin (NKTR-214) will be administered prior to avelumab. 
Bempegaldesleukin (NKTR-214) will be administered IV over 30 (± 5) minutes every 2 
weeks (+/- 2 days).  Participants should be carefully monitored for infusion reactions during 
bempegaldesleukin (NKTR-214) administration. If an acute infusion reaction is noted, 
participants should be managed according to Section 6.1.2.1.2.  Within the 2-day window, 
avelumab and bempegaldesleukin (NKTR-214) should be administered on the same day, 
unless one treatment needs to be delayed/withheld due to toxicity reasons.
Please refer to the Pharmacy Manual/current Investigator Brochure for details regarding 
preparation, storage, and administration.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 100
6.1.2.1. Special Precautions for Administration of Bempegaldesleukin (NKTR-214)
6.1.2.1.1. Hypotension
Hypotension has been identified as a clinically significant adverse effect of 
bempegaldesleukin (NKTR-214). The majority of hypotension cases occur on Day 2-3 post 
administration of bempegaldesleukin (NKTR-214), are clinically asymptomatic, and are 
rapidly responsive to fluid administration. Cases of syncope in association with post-dose 
blood pressure decline have been reported in patients receiving bempegaldesleukin (NKTR-
214).  Due to the risk of development of hypotension after bempegaldesleukin (NKTR-214) 
administration, the following risk mitigation measures should be taken:

Consideration should be given to withholding antihypertensive medications including 
diuretics, as well as other drugs with hypotensive properties (eg, alpha blockers for 
benign prostatic hyperplasia), particularly when therapy involves multiple 
antihypertensive drugs and classes other than thiazide diuretics. If withholding 
antihypertensive medications, withhold no less than 12 hours and no more than 48 
hours prior to each dose of bempegaldesleukin (NKTR-214). Antihypertensive 
medications may be reinstituted in between doses of bempegaldesleukin (NKTR-214) 
at any time as clinically indicated (eg, based on blood pressure monitoring result).

Adequate hydration mitigates the development of hypotension.  Participants should 
be given at least one liter of IV fluids at each dosing of bempegaldesleukin (NKTR-
214) (Day 1), particularly in Cycles 1 and 2.  During Cycles 3 and beyond, fluids may 
be given to prevent hypotension as per clinical judgement. For the next 3 days (Days 
2-4) after bempegaldesleukin (NKTR-214) administration, instruct participants to 
take at least 2 liters per day of self-administered oral hydration. Advise participants to 
restrain from strenuous activity and avoid long hot showers and saunas for Days 1 to 
4 of every cycle; and advise participants with orthostatic symptoms to call their 
treating oncologist to consider increasing oral hydration.  Per clinical judgment, IV 
fluids may be administered in any cycle.  The Investigator may decide to forego 
administering IV fluids to a participant if this is deemed in the best interest of the
participant (eg, evidence of fluid overload).
6.1.2.1.2. Infusion-related reactions
Symptoms of bempegaldesleukin (NKTR-214) infusion-related reactions include, but are not 
limited to, fever, chills, flushing, hypotension, and pyrexia.  Management of 
bempegaldesleukin (NKTR-214) IRRs is described in Table 12 (Section 6.6). Participants 
should be instructed to immediately report to the Investigator any delayed reactions that may 
occur after they leave the clinic.
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before the infusion. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 101
6.1.3. Talazoparib Administration
6.1.3.1. Talazoparib Pre-medication
No pre-medication is required prior to receiving talazoparib.
6.1.3.2. Administration 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. Participants should be 
advised that oral anticancer agents are toxic substances and that other caregivers (including 
family members) should always use gloves when handling the study treatment.  
Talazoparib will be taken once daily (with a reduced dose for participants with moderate 
renal impairment) starting on Cycle 1 Day 1, and treatment should continue until End of 
Treatment/withdrawal.  On Days 1 and 15 of each maintenance cycle, when the participant
returns to the clinic for bempegaldesleukin (NKTR-214) and 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, before or after the 
bempegaldesleukin (NKTR-214) and avelumab infusions.
Talazoparib can be administered with or without food as 1.0 mg capsules for the 1.0 mg 
dose; 0.25 mg capsules will be used to dispense the 0.25, 0.5, and 0.75 mg doses.  
Talazoparib should be administered at the same time each day. Participants will swallow the 
investigational product whole with a large glass of water (~250 ml), and will not manipulate 
or chew, dissolve, or open the capsules prior to swallowing. 
If a participant forgets his daily dose of talazoparib at the time he typically takes it, 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 the following day. Participants 
should not make up vomited doses; dosing should resume on the next calendar day unless 
otherwise instructed.
Please refer to the Pharmacy Manual/current Investigator Brochure for details regarding 
preparation, storage, and administration.
6.1.4. Enzalutamide Administration
6.1.4.1. Enzalutamide Pre-medication
No pre-medication is required prior to receiving enzalutamide.
6.1.4.2. Administration of Enzalutamide
Enzalutamide will be taken once daily starting on Cycle 1 Day 1 and treatment should 
continue until End of Treatment/withdrawal.  On Days 1 and 15 of each maintenance cycle, 
when the participant returns to the clinic for avelumab and bempegaldesleukin (NKTR-214)
administration, the daily dose of enzalutamide should not be taken prior to the study visit and 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 102
will be taken at the clinic after all procedures/assessments have been completed, and before
or after the avelumab and bempegaldesleukin (NKTR-214) infusions.
Participants should self-administer enzalutamide orally once daily, with or without food.  The 
capsules should be swallowed whole with a glass of water without chewing, dissolving, or 
opening the capsules prior to swallowing.
Participants should be instructed to take enzalutamide at approximately the same time each 
day and to not take more than the prescribed dose at any time.
If a participant misses a day of treatment or vomits any time after taking a dose, he must be 
instructed not to “make it up” but to resume subsequent doses the next day as prescribed.
Please refer to the Pharmacy Manual/current Investigator Brochure for details regarding 
preparation, storage, and administration.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.  Only participants enrolled in 
the study may receive study intervention and only authorized site staff may supply or 
administer study intervention. All study intervention must be stored in a secure, 
environmentally controlled, and monitored (manual or automated recording) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.  At a minimum, daily minimum and maximum temperatures for all 
site storage locations must be documented and available upon request.  Data for 
nonworking days must indicate the minimum and maximum temperature since previously 
documented for all site storage locations upon return to business.
2. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).  All study interventions will be 
accounted for using an investigational product accountability form/record.
3. Further guidance and information for the final disposition of unused study interventions 
are provided in the study reference manual.  The sponsor or designee will also provide 
guidance on the destruction of unused study intervention (eg, at the site).  If destruction is 
authorized to take place at the investigator site, the investigator must ensure that the 
materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Pfizer, and all destruction 
must be adequately documented.
4. Any storage conditions stated in the single reference safety document (SRSD) will be 
superseded by the storage conditions stated on the product label. 
5. Study interventions should be stored in their original containers and in accordance with 
the labels.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 103
6. See the investigational product manual (IP Manual), package insert, or equivalent for 
storage conditions of the study intervention (once reconstituted and/or diluted).
7. Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
8. Deviations from the storage requirements, including any actions taken, must be 
documented and reported to Pfizer upon discovery.  The site should actively pursue 
options for returning the study intervention to the storage conditions described in the 
labeling, as soon as possible.  Once an excursion is identified, the study intervention must 
be quarantined and not used until Pfizer provides permission to use the study 
intervention.  It will not be considered a protocol deviation if Pfizer approves the use of 
the study intervention after the temperature excursion.  Use of the study intervention prior 
to Pfizer approval will be considered a protocol deviation.  Specific details regarding the 
definition of an excursion and information the site should report for each excursion will 
be provided to the site in the IP manual.
6.3. Measures to Minimize Bias: Randomization and Blinding
This is an open-label study that will not be randomized.
Allocation to Treatment
At the time that a participant has signed informed consent and entered screening, the site 
should contact the interactive response technology (IRT) system to obtain the participant
identification number.  Once a participant has met all eligibility criteria, participant 
enrollment and allocation of investigational product will be managed by the IRT system.   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, and the participant number.  
The IRT system will then provide a treatment assignment and dispensable unit (DU) or vial 
or bottle number for each investigational product to be dispensed.  The IRT system will also 
provide a confirmation report containing the participant number and DU or vial or bottle 
numbers assigned.  The confirmation report must be stored in the site’s files. 
There is a 24 hour a day, 365 days a year IRT helpdesk available for any questions or issues.  
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 
6.4. Study Intervention Compliance
Participant compliance with study intervention will be assessed at each visit. Compliance 
will be assessed by using drug accountability form/record. Deviation(s) from the prescribed 
dosage regimen should be recorded in the eCRF.
For Investigational Product Administered by IV:
For avelumab and bempegaldesleukin (NKTR-214), the site will complete the required 
dosage Preparation Record located in the Investigational Product Manual.  The use of the 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 104
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 dose.  
This may be used in place of the Preparation Record after approval from the Pfizer monitor. 
The information related to each trial drug administration, including the date, time, and dose 
of study drug, will be recorded on the electronic case report form (eCRF).  The Investigator 
will ensure that the information entered into the eCRF regarding drug administration is 
accurate for each participant.  Any reason for noncompliance should be documented.
For Investigational Product Administered Orally:
Participants will be required to return all unused talazoparib and enzalutamide capsules (if 
applicable) every cycle.  The number of capsules returned by each participant will be 
counted, documented, and recorded by site personnel in the participant’s medical record and 
reconciled with the participant’s dosing diary to support the talazoparib/enzalutamide 
accountability process.  Study site personnel must make reasonable efforts to obtain study 
drug packaging and any unused tablets or capsules from participants who do not routinely 
return them at study site visits. 
Additionally, a participant dosing diary will be provided to the participants to aid in 
compliance with the dosing instructions.  The diary will be maintained by the participant to 
include missed or changed talazoparib/enzalutamide doses.  The time of each 
talazoparib/enzalutamide dose administration and the total dose of talazoparib/enzalutamide 
taken each day will be recorded in the dosing diary.  Participants will be required to return 
the completed dosing diary on Day 1 and 15 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 participant’s talazoparib/enzalutamide dose is 
given at the clinic due to scheduled PK sample collection, the time of 
talazoparib/enzalutamide dose administration and the total dose of talazoparib/enzalutamide 
taken will be recorded in the participant’s dosing records that are included in the medical 
chart.
Treatment compliance (reported as a percent) will be defined as the number of capsules taken 
during the study divided by the expected number of capsules of talazoparib/enzalutamide 
multiplied by 100%. Tablets that are not returned will be considered to have been taken 
unless reported otherwise by the participant.
6.5. Concomitant Therapy

Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

Dates of administration including start and end dates

Dosage information including dose and frequency


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 105

Concomitant medications and treatments, including herbal supplements, will be 
recorded from 28 days prior to the start of study intervention(s) and up to 90 days 
after the last dose of study intervention(s). All concomitant medications should be 
recorded in the CRF including supportive care drugs (eg, antiemetic treatment and 
prophylaxis), and the drugs used to treat adverse events or chronic diseases, as well as 
non-drug supportive interventions (eg, transfusions).  

Given that recording of non-serious AEs ends when a participant begins a new anti-
cancer therapy (Appendix 3, Section 10.3.3), recording of concomitant medications 
associated with these non-serious AEs should also end.  However, given that SAEs 
must continue to be recorded up to 90 days after the last dose of study treatment(s) 
even if the participant begins a new anti-cancer therapy (Appendix 3, Section 10.3.4), 
concomitant medications associated with these SAEs must also be recorded.  

The sponsor should be contacted if there are any questions regarding concomitant or 
prior therapy.

Medications or vaccinations specifically prohibited in the exclusion criteria are also 
not allowed during the active treatment period, except for administration of 
inactivated vaccines.  

Concomitant treatment considered necessary for the participant’s well-being may be 
given at the discretion of the treating physician.

Concurrent anti-cancer therapy with agents other than study treatments is not allowed.  
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.

Recommended pre-medication for avelumab is reported in Section 6.1.1.3.  
Recommended pre-medication for bempegaldesleukin (NKTR-214) is reported in 
Section 6.1.2.1.

Recommended medications to treat infusion related reactions for avelumab and 
bempegaldesleukin (NKTR-214) are reported in Section 6.1.1.3.1 and 
Section 6.1.2.1.2, respectively.  Recommended medications to treat immune-related 
events are reported in Section 6.6.3.  
6.5.1. Permitted Concomitant Medications 

Prophylaxis for flu-like symptoms with either acetaminophen or ibuprofen is 
permitted on study per the Investigator’s discretion.  Prophylaxis for flu-like 
symptoms can be initiated on either Day 1 or Day 2 of the dosing cycle and may 
continue through Day 5 or longer as needed.

Prophylaxis for rash and/or pruritus with anti-histamines is permitted on study per the 
Investigator’s discretion.  Prophylaxis for rash and/or pruritus can be initiated on 
either Day 1 or Day 2 of the dosing cycle and may continue through Day 5 or longer 
as needed.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 106

Concomitant palliative and supportive care for disease related symptoms (including 
bisphosphonates and nuclear factor kappa-B ligand [RANKL] inhibitors) is allowed.

Participants who need to be on anticoagulant therapy during treatment should be 
treated with low molecular weight heparin.  If low molecular weight heparin cannot 
be administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Factor 10a inhibitors) may be allowed; however, appropriate 
monitoring of prothrombin time/international normalized ratio (PT/INR) should be 
performed as needed.
6.5.2. Concomitant Radiotherapy

Prior palliative radiotherapy must have been completed > 14 days before 
administration of first dose of study drug.  On-study radiotherapy to target lesions is 
not permitted.  Palliative radiotherapy to specific non-target sites of disease is 
permitted if considered medically necessary by the treating physician.  All attempts 
should be made to rule out disease progression in the event of increased localized 
pain.  If palliative radiotherapy is needed to control bone pain, the sites of bone 
disease should be present at screening; otherwise, bone pain requiring radiotherapy 
will be considered as a sign of disease progression.  

Study intervention 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. 
6.5.3. Concomitant Surgery

Caution is advised on theoretical grounds for any surgical procedures during the 
study.  Although involving a limited number of participants, studies have not 
identified an increased surgical risk in participants treated with immune checkpoint 
inhibitors.48,49

The appropriate interval of time between surgery and administration of 
investigational products required to minimize the risk of impaired wound healing and 
bleeding has not been determined.  In case of a surgical procedure, investigational 
products should be delayed.  Postoperatively, the decision to reinitiate investigational 
products should be discussed with the sponsor.

In the case that a surgical procedure is required for palliative care, all attempts should 
be made to rule out disease progression beforehand.
6.5.4. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors (G-CSF) or 
erythropoietin (or darbepoetin) is not permitted during the first cycle of treatment. These 
factors may be used at any time to treat emergent neutropenia or anemia as indicated by the 
current American Society of Clinical Oncology (ASCO) guidelines or as allowed per local 
guidance.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 107
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  
6.5.5. Other Prohibited Concomitant Medicines and Therapies
Participants are prohibited from receiving the following therapies (unless otherwise indicated 
below) during the treatment phase of this trial: 

Anti-cancer chemotherapy or biological therapy.

Immunotherapy not specified in this protocol. 

Investigational agents other than investigational products.

Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs 
(refer to Table 16, Management of Immune-Related Adverse Events for Avelumab 
and Bempegaldesleukin [NKTR-214]).  See below Clarification Regarding Steroid 
Use.

Any vaccine therapies for the prevention of infectious disease (eg, human papilloma 
virus vaccine) except for inactivated vaccines (eg, influenza vaccine).

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or those 
known to potentially interfere with major organ function (eg, hypericin).

Bisphosphonate or denosumab treatment.

Radiation therapy (with the exception noted above in the Concomitant Radiotherapy 
Section).

Combination B only: 

Potent P-gp inhibitors that result in ≥ 2-fold increase in the exposure of an in 
vivo probe P-gp substrate, according to the FDA website 
(https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResourc
es/DrugInteractionsLabeling/ucm093664.htm#table5-2) and University of 
Washington Drug-Drug Interaction database 
(https://www.druginteractioninfo.org/).  Other validated sources can also be 
referenced per local requirements:  amiodarone, carvedilol, clarithromycin, 
cobicistat, dronedarone, erythromycin, glecaprevir/pibrentasvir, indinavir, 
itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, 
ranolazine, ritonavir, saquinavir, sofosbuvir/velpatasvir/voxilaprevir, telaprevir, 
tipranavir, valspodar, and verapamil.

Strong P-gp inducers (eg: avasimibe, carbamazepine, phenytoin, rifampin, St. 
John’s wort)


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 108

Strong inhibitors of breast cancer resistance protein (BCRP; eg: curcumin, 
cyclosporine, elacridar [GF120918], eltrombopag)

Combination C only: 

Strong CYP3A4 inducers (eg: carbamazepine, phenobarbital, phenytoin, 
rifabutin, rifapentine) and moderate (eg: bosentan, efavirenz, etravirine, 
modafinil, nafcillin).

Strong CYP2C8 inducers (eg: rifampin)

Strong CYP2C8 inhibitors (eg: clopidogrel, gemfibrozil)

Substrates of CYP3A4 (eg: alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus)

Substrates of CYP2C9 (eg, phenytoin; per the enzalutamide label, only 
substrates with NTI)

Substrates of CYP2C19 (eg, S mephenytoin, substrates with a narrow 
therapeutic index).
There are no prohibited therapies during the Safety Follow-up or Survival Follow-up Phases.  
6.5.6. Corticosteroids
Data indicate that corticosteroids have an adverse effect on T-cell function and that they 
inhibit and damage lymphocytes.50,51  Furthermore, as for all immunotherapies intended to 
augment T-cell-mediated immunity, there is a risk that concomitant immunosuppressives 
such as steroids will counteract the intended benefit.  However, studies with 
anti-CTLA-4 compounds indicate that short-term use of steroids can be employed without 
compromising clinical outcomes.52  Therefore, the use of steroids during this trial is restricted 
as follows:

Therapeutic use: for the treatment of infusion-related reactions and for the 
treatment of irAEs, steroids are permitted according to the modalities indicated in
Table 16, Management of Immune-Related Adverse Events for Avelumab and 
Bempegaldesleukin (NKTR-214).

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) are permitted.  

Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication) are acceptable.

Physiologic use: replacement for adrenal insufficiency at doses to ≤10 mg 
prednisone or equivalent daily are acceptable.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 109

Participants with pre-existing adrenal impairment requiring corticosteroid 
supplementation may be at increased risk for hypotensive episodes during 
treatment with bempegaldesleukin (NKTR-214).  For these participants, their 
existing corticosteroid dose may be increased by an additional supplementation up 
to a maximum of 10 mg/day of prednisone or equivalent, for the first 4 days after 
administration of bempegaldesleukin (NKTR-214) based on an assessment of the 
degree of adrenal impairment and the extent of existing corticosteroid 
supplementation.  
6.5.7. Rescue Medication and Supportive Care
6.5.7.1. Supportive Care Guidelines

Participants should receive appropriate supportive care measures as deemed 
necessary by the treating Investigator including but not limited to the items outlined 
below: 
o
Diarrhea: All participants 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.
o
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.  
Participants should be strongly encouraged to maintain liberal oral fluid intake. 
o
Anti-infectives: Participants with a documented infectious complication should 
receive oral or IV antibiotics or other anti-infective agents as considered 
appropriate by the treating Investigator for a given infectious condition, 
according to standard institutional practice, assuming there is no expected 
drug-drug interaction with study.
o
Anti-inflammatory or narcotic analgesics may be offered as needed (ie, 
nonsteroidal anti-inflammatory drugs [NSAIDS] and anti-histamines for flu 
like symptoms). 
For supportive care guidelines regarding growth factors, refer to Section 6.5.4.
6.5.7.2. 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, participants may continue to receive 
investigational products, after discussion between the sponsor and Investigator and at the 
Investigator’s discretion, if the following criteria are met: 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 110

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression;

No decline in ECOG performance status (Appendix 8);

Absence of rapid progression of disease by radiographic imaging;

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.
Before continuation of treatment, the participant must be re-consented via informed consent 
addendum and informed that, by continuing to receive the investigational products, the 
participant may be foregoing approved or investigational therapies with possible clinical 
benefit(s).
If the participant is subsequently found to have further disease progression at a subsequent 
tumor assessment, either radiologically according to RECIST v1.1 (Appendix 9) or clinically, 
then treatment with investigational products should be permanently discontinued.  Refer to 
tumor response assessments in Section 8.1.1.
6.6. Dose Modification
6.6.1. Recommended Dose Modifications
Every effort should be made to administer each investigational product at the planned dose 
and schedule. 
In the event of study treatment 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 (CTCAE v4.03) 
and/or the most conservative recommendation for any given toxicity.  Participants 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/delayed based on persisting toxicity.

Bempegaldesleukin (NKTR-214): Dose may be reduced from the starting dose.   
Dose interruptions are allowed if clinically indicated. 

Talazoparib: Dose modifications (dose interruptions, or dose reductions) may be 
implemented to manage toxicities.

Enzalutamide: Dose modifications (dose interruptions, or dose reductions) may be 
implemented to manage toxicities.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 111
All dose modifications must be clearly documented in the participant's medical chart and in 
the CRF.  Appropriate follow-up assessments should be performed until adequate recovery 
occurs as assessed by the Investigator.  In addition to dose modifications, Investigators are 
encouraged to employ best supportive care according to local institutional clinical practices.
Table 11.
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 participant.
Participants 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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 112
Table 12.
Treatment Modification for Symptoms of Infusion related Reactions 
Associated with Bempegaldesleukin (NKTR-214)
NCI CTCAE Severity Grade
Treatment Modification
Grade 1 – mild
Mild transient reaction; infusion interruption not indicated; 
intervention not indicated.
Remain at the bedside and monitor the participant until 
recovery from symptoms.  
The following prophylactic premedications are 
recommended for future infusions: diphenhydramine 
50 mg (or equivalent) and/or acetaminophen/paracetamol 
325 to 1000 mg at least 30 minutes before subsequent 
infusions.
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.
Stop the infusion, begin an IV infusion of normal saline, 
and treat the participant with diphenhydramine 50 mg IV 
(or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at the bedside and monitor the participant 
until resolution of symptoms.  Corticosteroid and/or 
bronchodilator therapy may also be administered as 
appropriate.
If the infusion is interrupted, then restart the infusion at 
50% of the original infusion rate when symptoms resolve. 
If symptoms recur after restarting the infusion, then no 
further bempegaldesleukin (NKTR-214) will be 
administered at that visit. Administer diphenhydramine 
50 mg IV, remain at the bedside, and monitor the 
participant until resolution of symptoms.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.
Immediately discontinue infusion of 
bempegaldesleukin (NKTR-214). 
Begin an IV infusion of normal saline and treat the 
participant as follows: recommend bronchodilators, 
epinephrine 0.2 to 1 mg of a 1:1000 solution for 
subcutaneous administration or 0.1 to 0.25 mg of a 
1:10,000 solution injected slowly for IV administration, 
and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. 
Bempegaldesleukin (NKTR-214) will be permanently 
discontinued. 
The participant should be monitored until the Investigator 
is comfortable that the symptoms will not recur. 
Investigators should follow their institutional guidelines 
for the treatment of anaphylaxis. Remain at the bedside 
and monitor the participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, 
appearance of a localized or generalized pruritus within 
1 week after treatment), symptomatic treatment may be 
given (eg, oral antihistamine or corticosteroids).
a.
If bempegaldesleukin (NKTR-214) 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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 113
6.6.2. Study Treatment Modifications for Drug Related Toxicity (excluding infusion 
related reactions and immune related adverse events)
Infusion-related reactions are addressed in Table 11 and Table 12 for avelumab and 
bempegaldesleukin (NKTR-214), respectively.  Immune-related AEs are addressed in
Section 6.6.3 and Table 16.
Every effort should be made to administer each investigational product at the planned dose
and schedule. 
In the event of study treatment 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 and/or the most 
conservative recommendation for any given toxicity.  Participants 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 per Table 13, 
Table 14, and Table 15 for Combinations A, B, and C, respectively.
6.6.2.1. Dose Modifications for Avelumab + Bempegaldesleukin (NKTR-214) Doublet
(Combination A)
Refer to Table 13 for dose modifications by severity grade for this combination. Participants 
who require delay of avelumab and/or bempegaldesleukin (NKTR-214) should be 
re-evaluated weekly or more frequently if clinically indicated and resume treatment with the
combination of avelumab and bempegaldesleukin (NKTR-214) when re-treatment criteria are 
met.  Immuno-oncology agents are associated with AEs that can differ in severity and 
duration from AEs caused by other therapeutic classes. Avelumab and bempegaldesleukin 
(NKTR-214) are considered immuno-oncology agents.  Early recognition and management 
of AEs associated with immuno-oncology agents may mitigate severe toxicity.
No dose reductions are permitted for avelumab (dose remains fixed at 800 mg Q2W 
administered by IV); however, the next infusion may be omitted based on persisting toxicity. 
Avelumab may be discontinued as clinically indicated.  
Dose delays and reductions are permitted for bempegaldesleukin (NKTR-214).  
Bempegaldesleukin (NKTR-214) may be delayed or the dose reduced from 0.006 mg/kg to 
0.003 mg/kg based on observed drug-related toxicities.  If the bempegaldesleukin dose is 
reduced to 0.003 mg/kg, the dose level should remain at this level throughout the remainder 
of the study.  Sponsor consultation is required for dose reduction.  Bempegaldesleukin 
(NKTR-214) dosing may resume when toxicity resolves to Grade 1 or returns to baseline.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 114
Table 13.
Avelumab and Bempegaldesleukin (NKTR-214) Treatment Modifications 
for Drug Related Toxicity (Excluding Infusion Related Reactions and 
Immune Related AEs)
Avelumab
Bempegaldesleukin (NKTR-214)
Hematologic
toxicities

Grade 1 and 
Grade 2

Continue as per schedule.

Continue as per schedule.
Anemia Grade 3

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.

Hold bempegaldesleukin (NKTR-214).

Re-initiate bempegaldesleukin (NKTR-214) 
once toxicity Grade 1 or baseline.

Permanently discontinue bempegaldesleukin 
(NKTR-214) if toxicity does not resolve to 
Grade 1 or baseline within 12 weeks or if 
the same Grade 3 toxicity recurs.
Neutropenia 
Grade 3
(ANC <1000/L)

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.

Hold bempegaldesleukin (NKTR-214). 

Re-initiate bempegaldesleukin (NKTR-214)
once toxicity Grade 1 (ANC 1500/L) or 
baseline. 

Permanently discontinue bempegaldesleukin 
(NKTR-214) if toxicity does not resolve to 
Grade 1 or baseline within 12 weeks or if 
the same Grade 3 toxicity recurs.
Thrombocytopenia 
Grade 3 (platelets 
<50,000/L)

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.

Hold bempegaldesleukin (NKTR-214). 

Re-initiate bempegaldesleukin (NKTR-214) 
once toxicity Grade ≤1 or baseline.

Permanently discontinue bempegaldesleukin 
(NKTR-214) if toxicity does not resolve to 
Grade 1 or baseline within 12 weeks or if 
the same Grade 3 toxicity recurs.
Lymphopenia Grade 
≥3( lymphocytes <0.5 
x 10e9 /L)

Continue as planned.

Continue as planned.
Eosinophilia

Continue as planned.

If the study participant is suspected to have 
hypereosinophilic syndrome (symptoms 
may involve skin, lungs, digestive tract, 
heart, blood, and nervous system) with AEC 
at or above 5000/µL (5 × 109/L), 
bempegaldesleukin (NKTR-214) treatment 
may need to be held. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 115
Table 13.
Avelumab and Bempegaldesleukin (NKTR-214) Treatment Modifications 
for Drug Related Toxicity (Excluding Infusion Related Reactions and 
Immune Related AEs)
Avelumab
Bempegaldesleukin (NKTR-214)
Non-hematologic
toxicities
Grade 1 
•
Continue as per schedule.
•
For suspected immune-related toxicity
follow guidance in Section 6.6.3 and
Table 16.
•
Continue as per schedule.
•
For suspected immune related toxicity
follow guidance in Section 6.6.3 and 
Table 16.
Grade 2
•
Continue as per schedule.
•
For suspected immune-related toxicity
follow guidance in Section 6.6.3 and 
Table 16.
•
For persistent Grade 2 related toxicity, delay
administration at the discretion of the 
Investigator. 
•
For suspected immune-related toxicity
follow guidance in Section 6.6.3 and 
Table 16.
•
Bempegaldesleukin (NKTR-214) dosing 
may resume at the same dose or at a lower 
dose level when toxicity resolves to Grade 1 
or returns to baseline, except for instances 
where the potential recurrence of the event 
poses an undue risk for the participant.
Grade 3 
•
Hold avelumab.
•
Resume once toxicity is Grade ≤1 or 
baseline.
•
Permanently discontinue if toxicity
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 toxicity 
follow guidance in Section 6.6.3 and
Table 16.
•
Hold bempegaldesleukin (NKTR-214)
•
Resume once toxicity is Grade İ 1 or 
baseline.
•
Permanently discontinue if toxicity 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 toxicity 
follow guidance in Section 6.6.3 and
Table 16.
Grade 4
•
Permanently discontinue avelumab.
•
Exceptions are:  Laboratory values 
that do not have any clinical correlate. 
•
For suspected immune-related toxicity
follow guidance in Section 6.6.3 and
Table 16.
•
Permanently discontinue bempegaldesleukin 
(NKTR-214).
•
Exceptions are: Laboratory values that do 
not have any clinical correlate.
•
For suspected immune-related toxicity
follow guidance in Section 6.6.3 and 
Table 16.
Abbreviations: AEC=absolute eosinophil count; AE=adverse event; ANC=absolute neutrophil count.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 116
6.6.2.2. Dose Modifications for Avelumab + Bempegaldesleukin (NKTR-214) + 
Talazoparib Triplet (Combination B)
Refer to Section 6.6.2.1 for additional information regarding dose delays and reductions for 
avelumab and bempegaldesleukin (NKTR-214).   Refer to Table 13 for dose modifications 
by severity grade for this doublet combination.
Recommended avelumab, bempegaldesleukin (NKTR-214) and talazoparib treatment 
modifications in case of investigational product related toxicity are shown in Table 14.  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 more than one investigational product, the guidelines in the relevant columns should be 
followed.  Participants who stop avelumab, bempegaldesleukin (NKTR-214) or talazoparib 
for unacceptable toxicity may continue treatment with the investigational product that is not 
considered to be responsible for the toxicity observed.
For hematologic toxicities, it is advisable to hold or reduce talazoparib first, before 
avelumab and bempegaldesleukin (NKTR-214), since hematologic toxicities have been 
reported with talazoparib treatment. 
The dose level for avelumab is fixed at 800 mg Q2W.  No dose reductions are permitted for 
avelumab;  however, the next infusion may be omitted/delayed based on persisting toxicity. 
Avelumab may be discontinued as clinically indicated.  Available dose levels for 
bempegaldesleukin (NKTR-214) dose are 0.006 and 0.003 mg/kg Q2W. Available dose 
levels for talazoparib are 1.0, 0.75, and 0.5 mg once daily.  These available dose levels are 
the same regardless of whether the bempegaldesleukin (NKTR-214) dose is 0.006 or 0.003 
mg/kg Q2W.  
Following dosing interruption due to toxicity, talazoparib may need to be resumed at a 
reduced dose as per the recommendations.
The starting dose of talazoparib for this study will be determined by the BLRM; a reduced 
dose will be given to participants with moderate renal impairment (CrCL 30-59 mL/min).  
CrCL may be repeated prior to talazoparib dose reduction, if low results are suspected to be
due to insufficient hydration status of the participant.   
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.  Participants unable to tolerate 0.5 mg QD, will be permanently discontinued from 
the talazoparib, but may continue on avelumab and bempegaldesleukin (NKTR-214).
Site personnel must ensure the participant is instructed how to take the reduced dose and that 
the participant has the correct dosage strength for the reduced dose.
Avelumab infusion-related reactions should be managed according to guidelines in 
Section 6.1.1.3.1.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 117
For participants receiving avelumab and bempegaldesleukin (NKTR-214), as a doublet 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 6.6.3.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 118
Table 14.
Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin 
(NKTR-214) 
Talazoparib
Hematologic toxicities
Grade 1 and Grade 2
Continue as per schedule.
Continue as per schedule.
Continue as per schedule.
Anemia Grade 3

Hold avelumab if 
toxicity does not 
resolve after 
holding/reducing 
talazoparib.

Re-initiate avelumab 
once toxicity is 
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 in 
combination with 
bempegaldesleukin
[NKTR-214]).

Hold 
bempegaldesleukin 
(NKTR-214) if toxicity 
does not resolve after 
holding/reducing 
talazoparib.

Re-initiate 
bempegaldesleukin
(NKTR-214) once 
toxicity is Grade 1 or 
baseline.

Permanently discontinue 
bempegaldesleukin 
(NKTR-214) 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 in 
combination with 
bempegaldesleukin 
[NKTR-214] only).

Hold talazoparib first
(before holding 
avelumab in 
combination with 
bempegaldesleukin 
[NKTR-214]) and 
monitor weekly until 
resolve to Grade ≤1 or 
baseline. 

Resume talazoparib 
based on the following 
recovery times:  1 
week: No change; >1 
week: Talazoparib may 
be reduced by 1 dose 
level, per 
Section 6.6.2.2.

Permanently 
discontinue talazoparib 
if toxicity persists for 
>4 weeks without 
recovery to baseline.  
Refer to hematologist 
for evaluation 
including assessment 
of possible 
MDS/AML.
Neutropenia Grade 3
(ANC <1000/L)

Hold avelumab if 
toxicity does not 
resolve after 
holding/reducing 
talazoparib.

Re-initiate avelumab 
once toxicity is Grade
≤1 (ANC ≥1500/µL) 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 

Hold 
bempegaldesleukin 
(NKTR-214) if toxicity 
does not resolve after 
holding/reducing 
talazoparib.

Re-initiate 
bempegaldesleukin
(NKTR-214) once 
toxicity Grade ≤1 (ANC 
≥1500/µL) or baseline.

Permanently discontinue 
bempegaldesleukin 
(NKTR-214) if toxicity 
does not resolve to 
Grade 1 or baseline 
within 12 weeks or if 
the same Grade 3 
toxicity recurs (if 

Hold talazoparib first 
(before holding 
avelumab in 
combination with
bempegaldesleukin 
[NKTR-214]) 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 6.6.2.2.

Permanently 
discontinue talazoparib 
if persists for >4 weeks 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 119
Table 14.
Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin 
(NKTR-214) 
Talazoparib
recurrent event occurs 
on avelumab in 
combination with 
bempegaldesleukin 
[NKTR-214] only).
talazoparib had already 
been discontinued and 
recurrent event occurs 
on avelumab in 
combination with 
bempegaldesleukin 
[NKTR-214] only).
without recovery to 
ANC 1500/L.  Refer 
to hematologist for 
evaluation including 
assessment of possible 
MDS/AML.
Thrombocytopenia Grade 
3 (platelets <50,000/L)

Hold avelumab if 
toxicity does not 
resolve after 
holding/reducing 
talazoparib.

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 in 
combination with 
bempegaldesleukin 
[NKTR-214] only).

Hold 
bempegaldesleukin 
(NKTR-214) if toxicity 
does not resolve after 
holding/reducing 
talazoparib.

Re-initiate 
bempegaldesleukin 
(NKTR-214) once 
toxicity Grade 1 or 
baseline.

Permanently discontinue 
bempegaldesleukin 
(NKTR-214) 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 in 
combination with 
bempegaldesleukin 
[NKTR-214] only).

Hold talazoparib first 
(before holding 
avelumab in 
combination with 
bempegaldesleukin
[NKTR-214]) and 
monitor weekly until 
platelets 75,000/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 6.6.2.2.

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.
Lymphopenia Grade ≥3 
(lymphocytes <0.5 x 
10e9/L)

Continue as planned.

Continue as planned.

Continue as planned.
Eosinophilia

Continue as planned.

If the study participant 
is suspected to have 
hypereosinophilic 
syndrome (symptoms 
may involve skin, lungs, 
digestive tract, heart, 
blood, and nervous 
system) with AEC at or 
above 5000/µL 
(5 × 109/L), 
bempegaldesleukin 
(NKTR-214) treatment 

Continue as planned.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 120
Table 14.
Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin 
(NKTR-214) 
Talazoparib
may need to be held. 
Non-hematologic toxicities
Grade 1 

Continue as per 
schedule.

For suspected 
immune-related 
toxicity follow 
guidance in 
Section 6.6.3 and
Table 16.

Continue as per 
schedule.

For suspected immune 
related toxicity follow 
guidance in 
Section 6.6.3 and 
Table 16.

Continue as per 
schedule.

For suspected immune 
related toxicity follow 
guidance in 
Section 6.6.3 and 
Table 16.
Grade 2

Continue as per 
schedule.

For suspected 
immune-related 
toxicity follow 
guidance in 
Section 6.6.3 and
Table 16.

Continue as per 
schedule. For persistent 
Grade 2 related toxicity, 
delay administration at 
the discretion of the 
Investigator.

For suspected immune 
related toxicities follow 
guidance in
Section 6.6.3 and
Table 16.

Continue as per 
schedule.

For suspected 
immune-related 
toxicity that requires 
avelumab and/or 
bempegaldesleukin 
(NKTR-214) delay or 
discontinuation as per 
Section 6.6.3 and
Table 16, talazoparib 
should also be placed 
on hold until toxicity 
is Grade 1 or 
baseline.
Grade 3 

Hold avelumab.

Resume once toxicity 
is Grade 1 or 
baseline.

Permanently 
discontinue if toxicity 
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 
toxicity follow 

Hold 
bempegaldesleukin 
(NKTR-214).

Resume once toxicity is 
Grade 1 or baseline.

Permanently discontinue 
if toxicity 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 toxicity due to 
bempegaldesleukin 

Hold talazoparib.

Resume talazoparib 
reduced by 1 dose 
level, per 
Section 6.6.2.2 if 
toxicity resolves to 
Grade 1 or baseline 
within 4 weeks.

If the same Grade 3 
toxicity recurs, reduce 
by 1 dose level.

Permanently 
discontinue if toxicity 
does not improve to 
Grade 1 or baseline 
within 4 weeks.

Exceptions are:
Laboratory values that 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 121
Table 14.
Avelumab + Bempegaldesleukin (NKTR-214) + Talazoparib Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin 
(NKTR-214) 
Talazoparib
guidance in 
Section 6.6.3 and 
Table 16.
(NKTR-214), follow 
guidance in 
Section 6.6.3 and 
Table 16.
do not have any 
clinical correlate.  

Permanently 
discontinue if Grade 3 
liver test abnormality. 

For suspected 
immune-related 
toxicity that requires 
delay or 
discontinuation of 
avelumab and 
bempegaldesleukin 
(NKTR-214) as per 
Section 6.6.3 and
Table 16, talazoparib 
should also be placed 
on hold until toxicity 
is Grade 1 or 
baseline.
Grade 4

Permanently 
discontinue avelumab.

Exceptions are:
Laboratory values that 
do not have any 
clinical correlate. 

For suspected 
immune-related 
toxicity, follow 
guidance in 
Section 6.6.3 and 
Table 16.

Permanently discontinue 
bempegaldesleukin
(NKTR-214).

Exceptions are: 
Laboratory values that 
do not have any clinical 
correlate.

For suspected immune 
related toxicity, follow 
guidance in 
Section 6.6.3 and
Table 16. 

Permanently 
discontinue 
talazoparib.

Exceptions are: 
Laboratory values that 
do not have any 
clinical correlate.
Abbreviations: AEC=absolute eosinophil count; AE=adverse event; AML=acute myeloid leukemia; ANC=absolute
neutrophil count; MDS=myelodysplastic syndrome.
6.6.2.3. Dose Modifications for Avelumab + Bempegaldesleukin (NKTR-214) + 
Enzalutamide Triplet (Combination C)
Refer to Section 6.6.2.1 for additional information regarding dose delays and reductions for 
avelumab and bempegaldesleukin (NKTR-214).  Refer to Table 13 for dose modifications by 
grade for this combination.  
Following dosing interruption due to toxicity, the enzalutamide dose may need to be resumed 
at a reduced dose.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 122
The dose level for avelumab is fixed at 800 mg Q2W.  No dose reductions are permitted for 
avelumab;  however, the next infusion may be omitted/delayed based on persisting toxicity. 
Avelumab may be discontinued as clinically indicated.  . Available dose levels for 
bempegaldesleukin (NKTR-214) dose are 0.006 and 0.003 mg/kg Q2W. Available dose 
levels for enzalutamide are 80, 120, and 160 mg once daily, with a lowest allowable dose of 
80 mg once daily.  These available dose levels are the same regardless of whether the 
bempegaldesleukin (NKTR-214) dose is 0.006 or 0.003 mg/kg Q2W.  Dose reduction of 
enzalutamide by 1 dose level at a time will be allowed depending on the starting dose.  
Since the risk of hematologic toxicities with enzalutamide has been established as low in past 
clinical studies, if a hematologic toxicity occurs, avelumab/bempegaldesleukin (NKTR-214)  
should be withheld first; enzalutamide can then be subsequently withheld if the toxicity does 
not resolve.  Refer to Table 15.
Participants who experience a grade 3 or higher toxicity that is attributed to enzalutamide and 
cannot be ameliorated by the use of adequate medical intervention may interrupt treatment 
with enzalutamide.  Subsequently, the enzalutamide dosing may be restarted at the original 
dose or a reduced dose.  Treatment interruption and reinitiation should be discussed with the 
sponsor.  
Site personnel must ensure the participant is instructed how to take the reduced dose and that 
the participant has the correct dosage strength for the reduced dose.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 123
Table 15.
Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin
(NKTR-214)
Enzalutamide
Hematologic toxicities
Grade 1 and Grade 2
Continue as per schedule.
Continue as per schedule.
Continue as per schedule.
Anemia Grade 3

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.

For suspected 
immune-related 
toxicity follow 
guidance in 
Section 6.6.3 and
Table 16.

Hold 
bempegaldesleukin 
(NKTR-214).

Re-initiate 
bempegaldesleukin  
(NKTR-214) once 
toxicity Grade 1 or 
baseline.

Permanently 
discontinue 
bempegaldesleukin
(NKTR-214) or reduce 
dose as per 
Section 6.6.2.1 if 
toxicity does not 
resolve to Grade 1 or 
baseline within 
12 weeks or if the same 
Grade 3 toxicity recurs.

For suspected 
immune-related 
toxicity follow 
guidance in 
Section 6.6.3 and
Table 16.

Continue as planned.

If toxicity is attributed to 
enzalutamide and does not 
resolve to Grade ≤1 or 
baseline, delay or reduce 
dose as per guidelines in 
Section 6.6.2.3.

Permanently discontinue 
enzalutamide if toxicity 
does not resolve to Grade 
≤1 or baseline within 12 
weeks or if the same 
Grade 3 toxicity recurs (if 
avelumab in 
combination with 
bempegaldesleukin
[NKTR-214] had 
already been 
discontinued and 
recurrent event occurs 
on enzalutamide only).

For suspected 
immune-related toxicity
follow guidance in 
Section 6.6.3 and 
Table 16.
Neutropenia Grade 3
(ANC <1000/L)

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.

For suspected 
immune-related 
toxicity due to 
avelumab, follow 
guidance in 
Section 6.6.3 and 
Table 16.

Hold 
bempegaldesleukin 
(NKTR-214).  

Re-initiate 
bempegaldesleukin 
(NKTR-214) once 
toxicity Grade ≤1 
(ANC ≥1500 µL) or 
baseline.

Permanently 
discontinue 
bempegaldesleukin 
(NKTR-214) or reduce 
dose as per 
Section 6.6.2.1 if 
toxicity does not 
resolve to Grade ≤1 or 
baseline within 12 
weeks or if the same 

Continue with 
enzalutamide if toxicity is 
not attributed to 
enzalutamide.

If toxicity is attributed to 
enzalutamide and does not 
resolve to Grade ≤1 or 
baseline, delay or reduce 
dose as per guidelines in 
Section 6.6.2.3.

Permanently discontinue 
enzalutamide if toxicity 
does not resolve to Grade 
≤1 or baseline within 12 
weeks or if the same 
Grade 3 toxicity recurs (if 
avelumab in 
combination with 
bempegaldesleukin 
[NKTR-214] had 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 124
Table 15.
Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin
(NKTR-214)
Enzalutamide
Grade 3 toxicity recurs.

For suspected 
immune-related 
toxicity due to 
bempegaldesleukin 
(NKTR-214), follow 
guidance in 
Section 6.6.3 and 
Table 16.
already been 
discontinued and 
recurrent event occurs 
on enzalutamide only).

For suspected 
immune-related toxicity
follow guidance in 
Section 6.6.3 and
Table 16.
Thrombocytopenia
Grade 3 (platelets 
<50,000/L)

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.

For suspected 
immune-related 
toxicity follow 
guidance in 
Section 6.6.3 and
Table 16.

Hold
bempegaldesleukin 
(NKTR-214).  

Re-initiate 
bempegaldesleukin
(NKTR-214) once 
toxicity Grade ≤ 1 or 
baseline.

Permanently 
discontinue 
bempegaldesleukin 
(NKTR-214) or reduce 
dose per 
Section 6.6.2.1 if 
toxicity does not 
resolve to Grade ≤1 or 
baseline within 12 
weeks or if the same 
Grade 3 toxicity recurs.

For suspected 
immune-related 
toxicity follow 
guidance in 
Section 6.6.3 and
Table 16.

Continue with 
enzalutamide if toxicity is 
not attributed to 
enzalutamide.

If toxicity does not 
resolve to Grade ≤1 or 
baseline, delay or reduce 
dose as per guidelines in
Section 6.6.2.3.

Permanently discontinue 
enzalutamide if toxicity 
does not resolve to Grade 
≤1 or baseline within 12 
weeks or if the same 
Grade 3 toxicity recurs (if 
avelumab in 
combination with 
bempegaldesleukin
[NKTR-214] had 
already been 
discontinued and 
recurrent event occurs 
on enzalutamide only).

For suspected 
immune-related toxicity
follow guidance in 
Section 6.6.3 and
Table 16.
Lymphopenia Grade 
≥3(lymphocytes <0.5 x 
10e9 /L)

Continue as planned.

Continue as planned.

Continue as planned.
Eosinophilia

Continue as planned.

If the study participant 
is suspected to have 
hypereosinophilic 
syndrome (symptoms 
may involve skin, 
lungs, digestive tract, 

Continue as planned.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 125
Table 15.
Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin
(NKTR-214)
Enzalutamide
heart, blood, and 
nervous system) with 
AEC at or above 
5000/µL (5 × 109/L), 
bempegaldesleukin 
(NKTR-214) treatment 
may need to be held. 
Non-hematologic 
toxicities
Grade 1 

Continue as per 
schedule.

For suspected 
immune-related 
toxicities follow 
guidance in 
Section 6.6.3 and
Table 16.

Continue as per 
schedule.

For suspected immune 
related toxicities follow 
guidance in Section 
6.6.3 and Table 16.

Continue as per schedule.

For suspected immune 
related toxicities follow 
guidance in Section 6.6.3
and Table 16.
Grade 2

Continue as per 
schedule.

For suspected 
immune-related 
toxicities follow 
guidance in 
Section 6.6.3 and 
Table 16.

For persistent Grade 2 
related toxicity, delay 
NK-214 administration 
at the discretion of the 
Investigator.

Bempegaldesleukin 
(NKTR-214) dosing 
may resume at the 
same dose or at a lower 
dose level when 
toxicity resolves to 
Grade 1 or returns to 
baseline, except for 
instances where the 
potential recurrence of 
the event poses an 
undue risk for the 
participant.

For suspected immune 
related toxicities follow 
guidance in Section 
6.6.3 and Table 16.

Continue as per schedule. 

For suspected 
immune-related toxicities
follow guidance in 
Section 6.6.3 and 
Table 16.
Grade 3 

Hold avelumab.

Resume avelumab once 
toxicity is Grade 1 or 
baseline.

Permanently 
discontinue avelumab
if toxicity does not 
resolve to Grade 1 or 
baseline within 

Hold 
bempegaldesleukin 
(NKTR-214).

Resume 
bempegaldesleukin 
(NKTR-214) once 
toxicity is Grade 1 or 
baseline.

Permanently 
discontinue 

Continue with 
enzalutamide if toxicity is 
not attributable to 
enzalutamide.

Resume enzalutamide 
once toxicity is Grade 1 
or baseline.

If toxicity does not 
resolve to Grade ≤1 or 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 126
Table 15.
Avelumab + Bempegaldesleukin (NKTR-214) + Enzalutamide Triplet 
Treatment Modifications for Drug Related Toxicity (Excluding Infusion 
Related Reactions and Immune Related AEs)
Avelumab
Bempegaldesleukin
(NKTR-214)
Enzalutamide
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 6.6.3 and 
Table 16.
bempegaldesleukin 
(NKTR-214) if toxicity
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 
6.6.3 and Table 16.
baseline, delay or reduce 
dose as per guidelines in 
Section 6.6.2.3.

Permanently discontinue 
enzalutamide if toxicity 
does not resolve to Grade 
≤1 or baseline within 12 
weeks or if the same 
Grade 3 toxicity recurs (if 
avelumab in 
combination with 
bempegaldesleukin
[NKTR-214] had 
already been 
discontinued and 
recurrent event occurs 
on enzalutamide only).

For suspected immune 
related toxicities follow 
guidance in Section 6.6.3
and Table 16.
Grade 4

Permanently 
discontinue avelumab.

Exceptions are:
Laboratory values that 
do not have any clinical 
correlate. 

For suspected 
immune-related 
toxicities follow 
guidance in
Section 6.6.3 and
Table 16.

Permanently 
discontinue 
bempegaldesleukin 
(NKTR-214).

Exceptions are:
Laboratory values that 
do not have any clinical 
correlate.

For suspected 
immune-related 
toxicities follow 
guidance in
Section 6.6.3 and 
Table 16.

Permanently discontinue 
enzalutamide.

Exceptions are:
Laboratory values that do 
not have any clinical 
correlate.
Abbreviations: AEC=absolute eosinophil count; AE=adverse event; AML=acute myeloid leukemia; ANC=absolute
neutrophil count; MDS=myelodysplastic syndrome.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 127
6.6.3. Immune-Related AEs
For participants receiving avelumab in combination with bempegaldesleukin (NKTR-214)
only (Combination A), in combination with both bempegaldesleukin (NKTR-214) + 
talazoparib (Combination B) or in combination with both bempegaldesleukin (NKTR-214)+ 
enzalutamide (Combination C), any AE suspected to be immune-related (ie, an irAE) should 
be managed according to the guidance for management of irAEs (refer to Table 16). 
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. 

Grades 3 to 4: treat with high dose corticosteroids.
Table 16.
Management of Immune Related Adverse Events for Avelumab and 
Bempegaldesleukin (NKTR-214)
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 study treatment.
Symptomatic treatment 
(eg loperamide).
Close monitoring for worsening 
symptoms.
Educate participant 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 study treatment.
Symptomatic treatment.
If improves to Grade 1: 
Resume study treatment
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 study treatment for Grade 3.
Permanently discontinue for Grade 4 
or recurrent Grade 3.
1.0 to 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 study 
treatment following steroids taper (for 
initial Grade 3). 
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5mg/kg (if no 
contraindication).  Note: infliximab 
should not be used in cases of 
perforation or sepsis. 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1 to 2
Covering 30% body surface area
Continue symptomatic therapy (for 
example, antihistamines, topical 
If persists >1 to 2 weeks or recurs:
Withhold study treatment


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 128
Table 16.
Management of Immune Related Adverse Events for Avelumab and 
Bempegaldesleukin (NKTR-214)
steroids).
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 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 study treatment for Grade 3.
Permanently discontinue study 
treatment for Grade 4 or recurrent 
Grade 3. 
Consider skin biopsy. 
Dermatology consult. 
1.0 to 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).
Grade 1 to 2 
Covering 30% body surface area 
Continue study treatment
Symptomatic therapy (for example, 
antihistamines, topical steroids). 
If persists >1 to 2 weeks or recurs: 
Withhold study treatment
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 study treatment
following steroids taper.
If worsens: 
Treat as Grade 3 to 4. 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT >ULN to 3.0 x 
ULN and/or Total bilirubin >ULN to 
1.5 x ULN 
Continue study treatment.
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4. 
Grade 2
AST or ALT >3.0 to ≤5 x ULN and/or 
total bilirubin >1.5 to 3 x ULN 
Withhold study treatment
Increase frequency of monitoring to 
every 3 days.
If returns to Grade 1:
Resume routine monitoring; resume 
study treatment.
If elevation persists >5 to 7 days or 
worsens: 
Treat as Grade 3 to 4.
Grade 3 to 4
AST or ALT >5 x ULN and/or total 
bilirubin >3 x ULN 
Permanently discontinue study 
treatment. 
Increase frequency of monitoring to 
every 1 to 2 days. 
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
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 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 129
Table 16.
Management of Immune Related Adverse Events for Avelumab and 
Bempegaldesleukin (NKTR-214)
opportunistic infections. 
Consult gastroenterologist/ 
hepatologist.
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted. 
5 days, consider other 
immunosuppressants per 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 x 
ULN
Continue therapy.
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased >1.5 and 6 x 
ULN
Withhold therapy.
Increase frequency of monitoring to 
every 3 days
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
If returns to Grade 1:
Taper steroids over at least 1 month, and 
resume avelumab therapy following 
steroids taper.
If worsens:
Treat as Grade 4.
Grade 4
Creatinine increased >6 x ULN
Permanently discontinue therapy.
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
Nephrology consult.
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 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 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 therapy.
Guideline based supportive treatment 
as appropriate as per cardiology 
consult.*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Once improving, taper steroids over at 
least 1 month.
If no improvement or worsening, 
consider additional immunosuppressants 
(eg, azathioprine, cyclosporine A).


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 130
Table 16.
Management of Immune Related Adverse Events for Avelumab and 
Bempegaldesleukin (NKTR-214)
Add prophylactic antibiotics for 
opportunistic infections.
*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 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 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 therapy once symptoms and/or 
laboratory tests improve to Grade 1 
(with or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and monitoring 
of endocrine function as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (ie, 
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH):
Refer to endocrinologist for dynamic 
testing as indicated and measurement 
of other hormones (FSH, LH, 
GH/IGF-1, PRL, testosterone in men, 
estrogens in women).
Hormone replacement/suppressive 
therapy as appropriate.
Perform pituitary MRI and visual field 
examination as indicated.
If hypophysitis confirmed:
Continue avelumab if mild symptoms 
with normal MRI.  Repeat the MRI in 
Resume therapy once symptoms and 
hormone tests improve to Grade 1 
(with or without hormone replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented. 
Continue hormone 
replacement/suppression therapy as 
appropriate.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 131
Table 16.
Management of Immune Related Adverse Events for Avelumab and 
Bempegaldesleukin (NKTR-214)
1 month.
Withhold study treatment if moderate, 
severe or life-threatening symptoms of 
hypophysitis and/or abnormal MRI.  
Consider hospitalization.  Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) followed by 
corticosteroids taper during at least 1 
month.
Add prophylactic antibiotics for 
opportunistic infections.
Other irAEs (not described above)
Grade of other irAEs (NCI-CTCAE 
v4.03)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs or 
symptoms suggestive of a potential 
irAE
Withhold therapy pending clinical 
investigation.
If irAE is ruled out, manage as 
appropriate according to the diagnosis 
and consider re-starting therapy
If irAE is confirmed, treat as Grade 2 or 
3 irAE.
Grade 2 irAE or first occurrence of 
Grade 3 irAE
Withhold therapy.
1.0 to 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 therapy following steroids taper.
Recurrence of same Grade 3 irAEs
Permanently discontinue therapy.
to 2.0 mg/kg/day
prednisone or equivalent.
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate.
If improves to Grade 1: 
Taper steroids over at least 1 month.
Grade 4 
Permanently discontinue therapy.
to 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 study 
treatment.
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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 132
6.7. Intervention after the End of the Study
There are no interventions planned after the end of this study. Refer to Section 7.1 for end of 
treatment, short-term follow-up, and long-term follow-up procedures.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
     
7.1. Discontinuation of Study Intervention
Participants who only discontinue study intervention (ie, study treatment) should continue in 
the study and complete all protocol specified activities even after discontinuing study 
treatment, in order to provide the data required for the study estimands (refer to Section 3).
Reasons for discontinuing study intervention (treatment) may include:

Objective disease progression; however, participants with disease progression 
who are continuing to derive clinical benefit from the study treatment will be 
eligible to continue study treatment as described in Section 6.5.7.2, provided that 
the treating physician has determined that the benefit/risk for doing so is 
favorable:

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to 1 of the 
investigational products, the Investigator may continue treatment with the other 
investigational product(s);

Pregnancy;

Significant protocol violation;

Lost to follow-up;

Participant refused further treatment;

Study terminated by sponsor;

Death.
Note that discontinuation of study treatment does not represent withdrawal from the 
study.     
As data on clinical events beyond study treatment discontinuation is required to support the 
study estimands, data should be planned to be collected through the participant’s last 
scheduled follow-up, even if the participant has discontinued study intervention (ie, study 
treatment). The discontinuation of study treatment is defined as the discontinuation of all 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 133
study drugs; if a participant, for example, discontinues one study drug in Combination A, or 
one or two study drugs in Combinations B or C, this is not a study treatment discontinuation.
All participants who discontinue study treatment should still continue to participate in the 
study and complete activities as specified in Section 1.3 - Schedule of Activities.
It may be necessary for a participant to permanently discontinue study intervention (ie, study 
treatment). Subsequent anti-cancer treatments will be documented and recorded for 
participant who discontinue all study treatments and continue in the Follow-up and Long-
term Follow-up.

End of Treatment (discontinuation of all study treatment for any reason):  Obtain 
these assessments as per the Schedule of Activities if not completed in the prior 
7 days.

Short-term Follow-Up (after Last Dose of Study Treatment): All participants will 
be followed for safety every 30 days (±3 days) through 90 days after the last dose of 
study treatment, unless other anti-cancer treatment is initiated; then only SAE and 
SAE treatments should continue to be collected.  Follow-up beyond 30 days and up to 
and including 90 days after last dose of investigational products may be performed 
either via a clinic visit or by remote contact (eg, telephone).  Refer to Section 8.1.1
for guidance on tumor assessment during the Follow-up periods.

Long-term Follow-up: Following completion of the initial 90-day follow-up period, 
all participants will be followed for survival status (independently of time of disease 
progression) and subsequent anti-cancer treatments every 12 weeks (±14 days) for at 
least 2 years after enrollment of the last participant in the study or until death, lost-to-
follow-up, study discontinued by sponsor, or participant withdrawal of consent, 
whichever comes first.  For those participants 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.     
7.1.1. Abnormal Electrocardiograms (ECGs)
If a clinically significant finding is identified (including, but not limited to changes from 
baseline in QT interval corrected using [Bazett’s formula [QTcB] or Fridericia’s formula 
[QTcF]]) after enrollment, the investigator or qualified designee will determine if the 
participant can continue on the study treatment and if any change in participant management 
is needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.  For criteria for clinically 
significant ECG findings for oncology studies, refer to Appendix 7.
Refer to the SoA for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 134
7.2. Participant Discontinuation/Withdrawal from the Study

Reasons from withdrawal from the study include:

Study terminated by sponsor;

Lost to follow-up;

Withdrawal of consent for further collection of follow-up data;

Death.

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons.  This is expected to be uncommon.

At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the 
time of study discontinuation and follow-up and for any further evaluations that need 
to be completed.  

The early discontinuation visit applies only to participants who are enrolled and then 
are prematurely withdrawn from the study.  Participants should be questioned 
regarding their reason for withdrawal. The participant will be permanently 
discontinued both from the study intervention and from the study at that time.

If the participant refuses further visits, they should continue to be followed for 
survival unless the participant 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.

If a participant withdraws from the study, he/she may request destruction of any 
remaining samples but data already generated from the samples will continue to be 
available, and may be used to protect the integrity of existing analyses. The 
investigator must document any such requests in the site study records.

Lack of completion of all or any of the withdrawal/early termination procedures will 
not be viewed as protocol deviations so long as the participant’s safety was preserved. 

If a participant does not return for a scheduled visit, every effort should be made to 
contact them.  All attempts to contact the participant and information received during 
contact attempts must be documented in the participant’s medical record.  In any 
circumstance, every effort should be made to document participant outcome, if 
possible.  The Investigator should inquire about the reason for withdrawal, request 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 135
that the participant return for a final visit, if applicable, and follow up with the 
participant regarding any unresolved AEs.

When a participant withdraws from the study because of an SAE, the SAE must be 
recorded on the CRF and reported on the CT SAE Report.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to 
withdraw consent from future follow-up, whenever possible. The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or posttreatment study follow-up, and entered on the appropriate CRF 
page. In the event that vital status (whether the participant 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.
7.3. Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 136
8. STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the Schedule of Activities
(SoA). Protocol waivers or exemptions are not allowed.

The investigator (or an appropriate delegate at the investigator site) must obtain a 
signed and dated ICD before performing any study-specific procedures.  

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening and applicable C1D1 evaluations must be completed and reviewed to 
confirm that potential participants meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICD may be utilized for screening 
or baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
8.1. Efficacy Assessments
8.1.1. Tumor Efficacy Imaging Assessments
8.1.1.1. Tumor Related Endpoints and Definitions for 1L SCCHN (Combination A)
Participants with SCCHN will undergo tumor assessments as per the requirements described 
in this section.  Tumor related endpoints for SCCHN participants will be based on RECIST 
v1.1 (refer to Appendix 9).
Tumor assessments will include all known or suspected disease sites.  Imaging is required for
the site of the primary tumor and may include neck, chest, abdomen and pelvis CT or MRI 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 137
scans.  A baseline brain CT or magnetic resonance imaging (MRI) scan is required for all 
participants with stable brain lesions and for those for whom Central Nervous System (CNS) 
involvement is suspected; these participants 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. 
CT or 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 screening will be employed in the following tumor assessments. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
screening, during treatment every 8 weeks for 52 weeks from the start of the study treatment, 
and then every 16 weeks thereafter until disease progression.  Anti-tumor activity will also be 
assessed during follow-up and long-term follow-up after end of treatment, for participants
who discontinue treatment due to reasons other than PD, regardless of initiation of 
subsequent anti-cancer therapy, as specified in the Schedule of Activities (Tables 4 and 5), 
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 PD).  Timing of disease assessment should be fixed according to the calendar, 
starting with C1D1, and should not be adjusted for delays in cycle starts.  In case CR or PR, 
is observed according to RECIST v1.1 (refer to Appendix 9), tumor assessments must be 
confirmed by repeated imaging at least 4 weeks after initial documentation.  
The allowable time window for tumor assessments is ±7 days.
Details of treatment after initial evidence of radiological disease progression are provided in
Section 6.5.7.2.
8.1.1.2. Tumor Related Endpoints and Definitions for mCRPC (Combinations B and C)
Assessment of soft tissue response for participants with mCRPC will be made using RECIST 
v1.1 (refer to Appendix 9).  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 (refer to 
Appendix 10).
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.  Brain CT or MRI scans are required for all participants with stable brain lesions 
and for those for whom Central Nervous System (CNS) involvement is suspected.  
Participants with stable brain lesions present at 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.  Bone scans must be performed at every tumor 
assessment.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 138
CT or 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 screening will be employed in the following tumor assessments. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
screening, during treatment every 8 weeks for 52 weeks from the start of the study treatment, 
and then every 12 weeks thereafter until disease progression.  Anti-tumor activity will also be 
assessed during follow-up and long-term follow-up after end of treatment, for participants
who discontinue treatment due to reasons other than PD, regardless of initiation of 
subsequent anti-cancer therapy, as specified in the Schedule of Activities (Tables 6 and 7), 
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 PD).  Timing of disease assessment should follow calendar days, starting with 
C1D1, and should not be adjusted for delays in cycle starts. 
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.
Details of treatment after initial evidence of radiological disease progression are provided in
Section 6.5.7.2.
8.1.2. Clinical Assessments
8.1.2.1. Blood for Lymphocyte Count
Approximately 8 mL whole blood will be collected in a tripotassium 
ethylenediaminetetraacetic acid (K3EDTA) tube as described in the Schedule of Activities
and Appendix 2 and analyzed by a local laboratory. This sample will be used to assess the 
number of lymphocytes.  This is the same sample that will be used for the hematology 
assessment.
8.1.2.2. Circulating Tumor Cells (CTCs) for Participants with mCRPC (Combination 
C)
For participants in Combination C with mCRPC, approximately 10 mL whole blood  will be 
collected at the time points described in the SoA (Tables 6 and 7) to allow quantitation of 
CTCs.
8.1.2.3. PSA Antibody Testing for Participants with mCRPC (Combinations B and C) 
For participants with mCRPC, approximately 5 mL whole blood  will be collected at the time 
points described in the SoA (Tables 6 and 7) and analyzed at a local laboratory for PSA 
levels.  There is a 7-day window allowed for PSA labs from C1D1.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 139
8.1.2.4. Testosterone for Participants with mCRPC (Combinations B and C)
For participants with mCRPC, approximately 5 mL whole blood will be collected at the time 
points described in the SoA (Table 6) and analyzed at a local laboratory for testosterone 
levels.
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the Schedule of Activities.  
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety concerns.
8.2.1. Physical Examinations
•
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems, skin, and 
vital signs at the time points described in the SoA.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 140

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2. Vital Signs

Weight, height, heart rate, and blood pressure will be assessed as per the SoA.

Blood pressure and pulse measurements will be assessed in a supine position with 
a completely automated device. Manual techniques will be used only if an 
automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions.
8.2.3. Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities for the timing and frequency. Samples for all laboratory assessments 
will be drawn at the time points indicated and when clinically indicated.  

Prior to study drug administration on Days 1 and 15 of each treatment cycle, 
hematology (ie, hemoglobin, platelets, and white blood cells) and chemistry (ie, ALT, 
AST, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, sodium, 
potassium, lipase, amylase, and glucose) tests must be performed and results 
reviewed by the treating physician prior to study drug administration.  When 
applicable, results from pregnancy tests must also be available for review prior to 
dosing.  

Repeat samples do not have to be drawn on Cycle 1 Day 1 if these samples were 
drawn in the prior 3 days.  Laboratory tests may be performed up to 3 days prior to 
the scheduled clinic visit, so that results will be available for review before study 
treatment administration.  

Results from pregnancy tests, if taken, must be available for review prior to dosing.  

Laboratory assessments are conducted only through the Day 30 Safety Follow-up 
visit.  Laboratory assessments are not required at the Day 60 or Day 90 Safety 
Follow-up visit.

Laboratory assessments must be performed and results reviewed by the treating 
physician as soon as they are available.

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 141
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 90 days after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or sponsor.
o
If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the Schedule of 
Activities.
o
If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE 
or AE or dose modification), then the results must be recorded in the CRF.
8.2.4. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 25
mIU/mL as required by local regulatory requirements.  Pregnancy tests will be performed in 
WOCBP(Combination A only) at the times listed in the SoA.
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will then be required at the baseline 
visit on C1D1 before the participant may receive the study treatment.  Pregnancy tests will 
also be done whenever 1 menstrual cycle is missed during the active treatment period (or 
when potential pregnancy is otherwise suspected) and at the end of the study.  Pregnancy 
tests may also be repeated if requested by institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.  Refer to Appendix 2.
8.2.5. Electrocardiograms

For Phase 1b participants, 12-lead ECGs should be performed at screening (singlet),
and on Day 1 of Cycles 1 and 2 (triplicate), prior to any pre-dose PK 
collection(within 2 hours) and prior to any post-dose avelumab PK collection (within 
10 minutes after the end of avelumab infusion).  Singlet 12-lead ECGs may be 
performed as clinically indicated for participants in Phase 1b, and only as clinically 
indicated in Cycles 1 and 2 for participants in Phase 2. 

In Cycle ≥3, singlet 12-lead ECGs will be performed only as clinically indicated for 
participants in both Phase 1b and Phase 2.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 142

Refer to the Schedule of Activities for the ECG collection time points.  The 
parameters to be recorded are RR, QT, QTc, PR, and QRS.  A standard 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.  If, 
during a single measurement, the QTc is prolonged (>500 msec, ie, CTCAE 
Grade 3), then a triplicate ECG will be collected to confirm the original 
measurement and repeated as clinically indicated.

Refer to Appendix 7 for QTc withdrawal criteria and any additional QTc readings 
that may be necessary, as well as ECG values of potential clinical concern.

At each time point at which triplicate ECG are required, 3 individual ECG tracings 
should be obtained as closely as possible in succession, but no more than 2 minutes 
apart. The full set of triplicates should be completed in less than 4 minutes.
8.2.6. Echocardiogram/Multigated Acquisition Scan (ECHO/MUGA)
LVEF should be assessed by transthoracic ECHO or MUGA and performed within 6 months
of screening.
8.2.7. ECOG Performance Status
Refer to Appendix 8 for ECOG Performance Status Criteria.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE, or that caused the participant to discontinue 
the study (refer to Section 7).
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’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, 
up to the start of new anti-cancer therapy.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 143
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.  
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the Medical History/Current Medical Conditions 
section of the case report form (CRF) not the AE section.
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.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3. The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
If a participant begins a new anticancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
SAEs occurring in a participant 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.
8.3.1.2. 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.
If a participant begins a new anticancer therapy, the recording period for non-serious AEs 
ends at the time the new treatment is started; however, SAEs must continue to be recorded on 
the CRF during the above-indicated active collection period.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 144
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information 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 participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.
8.3.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the investigator’s brochure and will notify the 
IRB/EC, if appropriate according to local requirements.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 145
8.3.5. Exposure 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.
8.3.5.1. Exposure During Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study intervention and until 90 days 
after the last dose.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. 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.
8.3.5.3. 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 participant enrolled in the study, the information 
is not recorded on a CRF; however, a copy of the completed CT SAE Report Form is 
maintained in the investigator site file.
8.3.6. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength, or 
from inadvertent exposure.
Exposures to the investigational product under study may occur in clinical study settings, 
such as medication errors.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 146
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 include:

Medication errors involving participant 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 participant;

Lack of dose reduction as specified by the protocol;

Continuation of treatment though participant met discontinuation criteria;

Incorrect study treatment taken by participant;
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, refer to intervention-specific overdose guidelines below.
Overdose of Avelumab
There are limited experiences pertaining to overdose with avelumab in clinical studies.  
Treatment is directed to symptoms.  
Overdose of Bempegaldesleukin (NKTR-214)  
The clinical consequences of bempegaldesleukin (NKTR-214) overdose have not been 
clearly identified.  The highest dose to date of bempegaldesleukin administered in the clinic 
is 0.012 mg/kg, which resulted in cytokine release syndrome and DLTs of hypotension and 
syncope in one participant who received this dose.  There is no specific treatment for 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 147
overdose of bempegaldesleukin (NKTR-214).  If hypotension occurs as a result of overdose, 
it should be managed by general supportive measures.
Overdose of Talazoparib
There is no specific treatment in the event of talazoparib overdose, and symptoms of 
overdose are not established.  In the event of overdose, treatment with talazoparib should be 
stopped, and physicians should consider gastric decontamination, follow supportive 
measures, and treat symptomatically.
Overdose of Enzalutamide
There is no specific treatment for overdose of enzalutamide.  In the event of an overdose, 
treatment should be stopped and general supportive measures initiated, taking into 
consideration the amount of overdose and enzalutamide’s half-life (5.8 days).  Participants 
may be at an increased risk of seizure following an overdose. 
In the event of an overdose for any of the above listed study interventions, the treating 
physician should:
1. Contact the sponsor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities 
for at least 28 days.
3. Obtain a plasma sample for PK analysis with clear documentation of the time 
it is collected relative to the date of the last dose of study intervention, if 
requested by the sponsor (determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the 
overdose in the CRF.
5. Overdose is reportable to Safety only when associated with a SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the sponsor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
All efforts should 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 SoA, blood samples for avelumab, bempegaldesleukin (NKTR-214),
talazoparib, and enzalutamide concentrations should be collected after triplicate 12-lead 
ECGs are performed. If a scheduled blood sample collection cannot be completed for any 
reason, the missed sample may be re-scheduled with agreement of clinical investigators, 
participant 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 (SOPs).
Details regarding the collection, processing, storage and shipping of the PK blood samples 
will be provided to the investigator site prior to initiation of the trial. The samples must be 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 148
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 determine whether sample integrity has been 
compromised.  The details of sample collection, processing and storage are presented in the 
laboratory manual only.  If there is any deviation, it should be considered as manual 
deviation instead of the protocol deviation.
As part of understanding the PK of the investigational products, samples may be used for 
metabolite identification and/or further bioanalytical evaluation, as well as for other internal 
exploratory purposes.  These data will not be included in the Clinical Study Report (CSR).
8.5.1. Blood for PK Analysis of Avelumab
Blood samples (approximately 3.5 mL whole blood at each time point) will be collected into
appropriately labeled serum separator tubes (SST) for PK analysis of avelumab, as outlined 
in the Schedule of Activities (Tables 4-7).  Blood for PK samples will be drawn from the 
contralateral arm of the drug infusion.  
8.5.2. Blood for PK Analysis of Bempegaldesleukin (NKTR-214)
Blood samples (approximately 3.5 mL whole blood at each time point from which plasma 
will be isolated and used for analysis) will be collected into appropriately labeled tubes 
containing sodium heparin for PK analysis of bempegaldesleukin (NKTR-214) as outlined in 
the Schedule of Activities (Tables 4-7).  Blood will be collected in standard tubes and 
shipped to Pfizer’s central lab. 
  This 
assessment will be performed for all Phase 1b participants, as well as for a subset of Phase 2 
participants receiving RP2D (approximately 20 participants from each of the three 
combinations, for approximately 60 participants total).
8.5.3. Blood for PK Analysis of Talazoparib
Blood samples (approximately 3.0 mL whole blood at each time point from which plasma 
will be isolated and used for analysis) will be collected into appropriately labeled tubes 
containing K3EDTA for PK analysis of talazoparib as outlined in the Schedule of Activities
(Tables 6-7).
8.5.4. Blood for PK Analysis of Enzalutamide and N-Desmethyl-Enzalutamide
Blood samples (approximately 3.0 mL whole blood at each time point from which plasma 
will be isolated and used for analysis) will be collected into appropriately labeled tubes 
containing dipotassium ethylenediaminetetraacetic acid K2EDTA for PK analysis of 
enzalutamide and N-desmethyl-enzalutamide as outlined in the Schedule of Activities
(Tables 6-7).
Please refer to the Laboratory Manual for instructions for specific details on collection tubes, 
processing and shipping for all samples collected. 
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 149
8.6. Pharmacodynamics
8.6.1. Tumor and other Biospecimens
Refer to Section 8.7 for biomarker analyses for genetics. Refer to Section 8.8 for all other
biomarker analyses, including pharmacodynamics biomarkers.
8.6.2. Collection of Samples for Pharmacodynamic Analysis
Samples should be obtained within 2 hours prior to infusion.  
As part of understanding the PD of the investigational product, samples may be used for 
evaluation of the bioanalytical method, as well as for other internal exploratory purposes.  
These data will not be included in the CSR.
The pharmacodynamic (PD) samples must be processed and shipped as indicated in the 
instructions provided to the investigator site to maintain sample integrity.  Any deviations 
from the PD sample handling procedure (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.
8.7. Genetics
8.7.1. Specified Genetics 
Genetic assessments will be performed utilizing tumor, saliva, and blood samples as
collected and described in the SoA.  Refer to relevant subsections in Section 8.8. 
 
 
 
 
 
 
 
 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 150
8.8. Biomarkers
8.8.1. Tumor Tissue Assessments
The objectives of biomarker analyses applied to pre-treatment (archival or de-novo), on-
treatment and end-of-treatment tumor biospecimen are to evaluate candidate predictive 
biomarkers that may be proven useful in identifying participants who may preferentially 
benefit from the study treatments and to evaluate mechanisms of action and/or resistance for 
each of the combinations being assessed.
 
 
Tumor biospecimens representing tissue samples from tumor resection or biopsy will be used 
to analyze candidate DNA, RNA, or protein markers, or relevant signature of markers for 
their ability to identify those participants who are most likely to benefit from treatment with 
the study drugs. 
8.8.1.1. Mandatory Tumor Tissue (1L SCCHN, Combination A) 
A formalin-fixed paraffin-embedded (FFPE) tumor tissue block from the most recent tumor 
resection or biopsy must be provided for all participants enrolled in the study and submitted 
to the Central Laboratory.  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 participant 
should have received no more than one line of systemic anti-cancer therapy.  If FFPE tissue 
blocks cannot be provided, the tissue should be submitted in the form of 12 unstained, 
unbaked, positively-charged glass slides each containing an FFPE tissue section that is 4-5 
microns thick.  In instances where no such archival tumor sample is available a de novo 
biopsy from a locally recurrent or metastatic tumor site that is not the only RECIST v1.1 
(Appendix 9) target lesion must be performed during screening.
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.
A core biopsy preferably 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. Additional information on 
tissue collection procedures can be found in the Laboratory Manual.
8.8.1.2. Mandatory Tumor Tissue (mCRPC, Combinations B and C)
All participants must submit an FFPE tumor tissue block from the most recent tumor 
resection or biopsy to the Central Laboratory. 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 participant should have received no more than one line of systemic anti-cancer 
therapy.  For mCRPC participants 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 provided. In instances where no such archival tumor sample is available a
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 151
de novo biopsy from a locally recurrent or metastatic tumor site that is not the only RECIST 
v1.1 (Appendix 9) target lesion must be performed during screening, as described in 
Section 8.8.1.1.
A core biopsy, preferably 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. Additional information on 
tissue collection procedures can be found in the Laboratory Manual.
If FFPE tissue blocks cannot be provided, the tissue should be submitted in the form of 12 
unstained, unbaked, positively-charged glass slides each containing an FFPE tissue section 
that is 4-5 microns thick.  
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.
8.8.1.3. Mandatory Baseline Tumor Tissue for DDR Defect Assessment (Combination B 
– Phase 2 only)
All mCRPC study participants in Phase 2 Combination B must provide a tumor tissue sample
for testing of DDR defects 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 152
 
 
 
 
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.
8.8.1.4. On-Study Tumor Tissue (SCCHN, Combination A)
An on-treatment biopsy is required to be collected on Cycle 1 between Days 9 and 14. When 
this is not feasible a biopsy may be collected on Cycle 1 between Day 15 and 21. These on 
treatment biopsies are required except in instances where the procedure poses unacceptable 
risks per Investigator documentation.  Tumor tissue is also requested for those participants 
who undergo a biopsy or tumor resection as part of routine clinical care at any time during 
the treatment period.  De novo biopsies should be FFPE as per routine (see Laboratory 
Manual), and the resulting FPPE tissue block(s) should be submitted to the Central 
Laboratory.
Mandatory paired baseline and on-treatment tumor tissue is required from SCCHN 
participants to assess the ability of the combination therapy to increase PD-L1 expression
while on treatment, as well as to document changes in the tumor microenvironment. Tumor 
samples will be assessed to provide data on changes in the tumor that develop over the course 
of therapy, including acquired mechanisms of resistance that may be demonstrated on 
analysis of tumor tissue collected at the end of treatment.
 
  The End of Treatment tumor 
biopsy should be performed before initiation of subsequent anti-cancer therapy and 
preferably no later than 7 days after the End of Treatment visit.
A core biopsy preferably 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. Additional information on 
tissue collection procedures can be found in the Laboratory Manual.
 
 
CCI
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 153
 
 
 
 
 
 
 
 
8.8.2. Other Biomarker Assessments
The goal of these analyses is to explore potential correlations between molecular profiling 
and response to study treatment, which will help identify potential biomarkers of response 
and biomarkers/mechanisms of acquired resistance to study treatment.
8.8.2.1. Saliva Sample for Germline Comparator
Unless prohibited by local regulations or ethics committee decision, saliva samples will be 
collected from all participants on Cycle 1 Day 1 before the first dose of study treatment and 
will be used for exploratory targeted and/or whole exome/genome sequencing. These 
samples will be used as a germline comparator to identify somatic tumor DNA mutations and 
will not be used to generate free-standing germline sequencing results. 
8.8.2.2. Saliva sample for Targeted Germline DDR Assessment (Phase 2 Combination B 
only)
In Combination B, an additional saliva sample will be collected and will be used to 
characterize the germline status of the DDR genes used to assess participant eligibility or a 
subset thereof in order to explore the potential contribution of germline DDR status to 
efficacy and safety/tolerability with study treatment.  
 
 
 
 
 
 
 
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 154
 
 
 
 
 
 
 
 
8.8.3. Immunogenicity Assessments
Details regarding the collection, processing, storage and shipping of the Immunogenicity 
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 determine whether sample integrity has 
been compromised. Any deviation from the specified sample handling procedure that 
resulted in compromised sample integrity will be considered a protocol deviation.  
As part of understanding the immunogenicity of the investigational products, samples may be 
used for further bioanalytical evaluation, as well as for other internal exploratory purposes. 
These data will not be included in the Clinical Study Report (CSR).
8.8.3.1. Analysis of ADAs and NAbs for Avelumab
Blood samples (approximately 3.5 mL whole blood) will be collected into appropriately 
labeled SSTs for determination of avelumab anti-drug antibodies (ADAs) and neutralizing 
antibodies (NAbs), as outlined in the Schedule of Activities (Tables 4-7).  Please refer to the 
Laboratory Manual for instructions for specific details on collection tubes, processing and 
shipping. The actual date and time (24-hour clock time) of each sample will be recorded.
For all participants, blood for ADA samples will be drawn from the contralateral arm of the 
avelumab infusion.  
Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs.  The sample analysis will follow a tiered approach of screening, confirmation, and 
titer determination.
8.8.3.2. Analysis of ADAs and NAbs for Bempegaldesleukin (NKTR-214)
Blood samples (approximately 3.5 mL whole blood) will be collected into an appropriately 
labeled tubes for serum determination of bempegaldesleukin (NKTR-214) anti-drug 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 155
antibodies (ADAs) and neutralizing antibodies (NAbs), as outlined in the Schedule of 
Activities (Tables 4-7).  Please refer to the Laboratory Manual for instructions for specific 
details on collection tubes, processing and shipping.
For all participants, blood for ADA samples will be drawn from the contralateral arm of the 
bempegaldesleukin (NKTR-214) infusion.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
This section defines the estimands associated with the primary endpoints and the secondary 
efficacy endpoints of the study.
The populations associated with estimands for each combination are as follows:

Combination A - participants with 1L SCCHN.

Combination B Phase 1b - participants with mCRPC after progression on taxane-
based chemotherapy.

Combination B Phase 2 - participants with DDR defect positive mCRPC after 
progression on taxane-based chemotherapy.

Combination C - participants with mCRPC after progression on abiraterone 
therapy.
The endpoint definitions, the observations that will be considered in the derivation of the 
endpoint and the associated analyses are described or referenced below.

Phase 1b: the primary endpoint (Combinations A, B and C) will be the occurrence 
of DLT during the primary DLT evaluation period (Cycle 1).  DLTs are defined 
in Section 4.1.  DLTs will only be collected during Cycle 1 of Phase 1b and the 
DLT rate will be estimated for participants who are evaluable for DLTs.  DLT-
evaluable participants are those enrolled in Phase 1b who 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 without DLT.  Participants without DLTs who withdraw from study 
treatment before receiving at least 2 doses of avelumab and bempegaldesleukin 
(NKTR-214; all Combinations) or 75% of the planned dose of talazoparib 
(Combination B) or enzalutamide (Combination C), in Cycle 1 for reasons other 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 156
than treatment-related toxicity are not evaluable for DLT.  All participants 
deemed non-evaluable for DLT may be replaced.

Phase 2 Objective Response (Combination A) or soft tissue Objective Response 
(Combination B): The primary estimand is the treatment effect of OR 
(Combination A) or soft tissue OR (Combination B) from the time of first dose
until progression is met or subsequent anticancer therapy is administered.  Point 
estimates and confidence intervals (following the methodology outlined in 
Section 9.4.1) will be calculated. 

Phase 2 PSA Response (Combination C): The primary estimand is the treatment 
effect of PSA response from the time of first dose until progression is met or 
subsequent anticancer therapy is administered.  Point estimates and confidence 
intervals (following the methodology outlined in Section 9.4.1) will be calculated. 

Phase 2 tumor-related endpoints: (TTR [Combinations A, B, and C], DR
[Combinations A, B, and C],  TTPSAP [Combinations B and C only], CTC count 
conversion [Combination C only] and CTC0 [Combination C only]) are defined 
in Section 9.4.1.  This is a non-randomized study and there will be no statistical 
comparisons between treatment groups; to address the objectives associated with 
tumor-related endpoints, point estimates and confidence intervals (following the 
methodology outlined in Section 9.4.1) will be calculated for each tumor-related 
endpoint including only assessments on or before start of new anti-cancer therapy 
and on or before progression.

Phase 2:  OS is defined as the time from the first dose of study treatment to the 
date of death due to any cause. This is a non-randomized study and there will be 
no statistical comparisons between treatment groups; to address the OS objective,  
point estimates and confidence intervals (following the methodology outlined in 
Section 9.4.1) will be calculated for OS including survival status for each 
participant at the time of the analysis; survival status is expected to be collected 
irrespective of study treatment discontinuation or participant’s request to 
discontinue study procedures. All participants who have not withdrawn consent 
for further participation in the study should be followed for survival until at least 
2 years after enrollment of the last participant in the study.
9.1.2. Statistical Methods and Properties
9.1.2.1. Statistical Methods for Dose Finding: BLRM
Identification of a recommended dose
The dosing decision and estimation of the MTDs of the doublet (Combination A) and the 
triplets (Combination B and C) will be guided by the estimation of the probability of DLT in 
Cycle 1.  However, other evidence such as safety data beyond DLT, clinical activity, PK, and 
PD data will play an important role in the final decision.  A RP2D below the MTD may be 
determined based on these considerations.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 157
The doublet of avelumab in combination with bempegaldesleukin will be evaluated first to 
determine the RP2D.  Upon the completion of the dose finding of the doublet, the triplets of 
avelumab in combination with bempegaldesleukin (NKTR-214) and talazoparib or 
enzalutamide will then be evaluated to determine the RP2D for these triplet combinations.  
Refer to Appendix 11, Appendix 12 and Appendix 13 for BLRM designs for Combinations 
A, B, and C, respectively.
Bayesian adaptive approach
The dose finding in the Phase 1b of the study will be guided by a Bayesian analysis of Cycle 
1 DLTs in DLT-evaluable participants. 
a.
Doublet combination model:
For the doublet combination of avelumab and bempegaldesleukin (NKTR-214), the Bayesian 
model consists of three parts, representing:

Single-agent avelumab toxicity;

Single-agent bempegaldesleukin (NKTR-214) toxicity;

Interaction between avelumab and bempegaldesleukin (NKTR-214).
b. Triplet combination model:
For the triplet combination of avelumab, bempegaldesleukin [NKTR-214], and talazoparib, 
the Bayesian model consists of seven parts, representing:

Single-agent avelumab toxicity;

Single-agent bempegaldesleukin (NKTR-214) toxicity;

Single-agent talazoparib toxicity;

Interaction between avelumab and bempegaldesleukin (NKTR-214);

Interaction between and bempegaldesleukin (NKTR-214) and talazoparib;

Interaction between talazoparib and avelumab;

Triple interaction between avelumab, and bempegaldesleukin (NKTR-214) and 
talazoparib.
For the triplet combination of avelumab, bempegaldesleukin (NKTR-214), and enzalutamide, 
the Bayesian model consists of seven parts, representing:

Single-agent avelumab toxicity;


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 158

Single-agent bempegaldesleukin (NKTR-214) toxicity;

Single-agent enzalutamide toxicity;

Interaction between avelumab and bempegaldesleukin (NKTR-214);

Interaction between and bempegaldesleukin (NKTR-214) and enzalutamide;

Interaction between enzalutamide and avelumab;

Triple interaction between avelumab, bempegaldesleukin (NKTR-214) and 
enzalutamide.
Single-agent toxicities are modelled using logistic regression for the probability of a 
participant experiencing a DLT against log-dose.  The odds of a DLT are then calculated 
under no interaction for the two/three single-agent toxicities, and interaction is accounted for 
by adjusting these odds with an additional model parameter (odds multiplier). 
Assessment of participant risk
After each cohort of participants completes the DLT evaluation period, the posterior 
distribution for the risk of DLT for different combination doses of interest will be evaluated.  
The posterior distributions will be summarized to provide the posterior probability that the 
risk of DLT lies within the following intervals: 

Underdosing:
[0, 0.16)

Target toxicity:
[0.16, 0.33)

Excessive toxicity or overdosing:
[0.33, 1]
The EWOC principle
Dosing decisions are guided by the EWOC principle.  A combination dose may only be used 
for the next cohort of participants if the risk of excessive toxicity ([0.33, 1]) at that 
combination dose is less than 0.25.
Prior distributions
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent model parameters.  The MAP prior for the logistic model parameters for this 
study is the conditional distribution of the parameters given the historical data. MAP priors 
are derived using Bayesian hierarchical models, which take into account possible differences 
between the studies.
The prior distribution for the interaction parameters (doublet and triplets) were based on the 
prior understanding of possible drug safety interactions.  This prior allows for the possibility 
of either synergistic or antagonistic interaction.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 159
Starting dose levels
The starting dose for the doublet in Combination A is D0 (800 mg avelumab IV Q2W, and 
0.006 mg/kg bempegaldesleukin [NKTR-214] Q2W IV).  For this dose the prior risk of 
excessive toxicity is 13.7%, which satisfies the EWOC criterion.  
The starting dose for the triplets will be determined based on all available data after 
completion of the dose finding for the doublet. 
9.2. Sample Size Determination
Approximately 160 participants will be screened to achieve approximately 127 participants 
assigned to study intervention, with 27-36 participants in Phase 1b and up to approximately 
91 participants in Phase 2.  A given combination size may be expanded in Phase 2 only by a 
limited number of additional participants (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.  
An RP2D below the MTD may be determined based on other safety, efficacy, PK, and 
pharmacodynamic data. Nine evaluable participants are needed to be treated at RP2D if no 
DLT is observed, and 12 evaluable participants if at least a DLT is observed.
During the Phase 1b dose finding, it is estimated that approximately up to 12 and 
15 participants will be enrolled and assigned to treatment in each of the three combinations 
(one doublet combination, two triplet combinations).  Each combination will include at least 
6 participants treated at the MTD level and at least 9 participants at the RP2D.  The actual 
number of participants for the Phase 1b dose finding will depend on the number of DLT 
events and dose levels/combinations that are tested.  An RP2D below the MTD may be 
determined based on other safety, clinical activity, PK, and pharmacodynamic data. 
Phase 1b participants for SCCHN will also be used for the Phase 2 efficacy assessment at the 
RP2D.
In Phase 2, with 20 (Combination B), 40 including Phase 1b participants (Combination A)
and 40 (Combination C) treated participants in combination B, A and C, respectively, soft 
tissue OR, OR, and PSA response rate can be estimated with a maximum standard error of 
0.112 (Combination B) or 0.079 (Combinations A and C), respectively. Assuming beta-
binomial distributions for ORR and PSA response rate and a non-informative beta (0.5, 0.5) 
prior:
1L SCCHN (Combination A): 

if 20 ORs (out of 40 participants, ORR = 50%) are observed, the probability of a true 
ORR≥ 40 % (considered a clinically relevant effect) will be ≥90% (90.1%).  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 160
Combination B: mCRPC post chemotherapy

if 12 ORs (out of 20 participants, ORR = 60%) are observed, the probability of a true 
ORR≥ 50% (considered a clinically relevant effect) will be ≥80% (81.4%).  
Combination C: mCRPC 

if 20 PSA responses (out 40 participants, PSA response rate = 50%) are observed, the 
probability of a true PSA response rate ≥ 40% (considered a clinically relevant effect) 
will be ≥90% (90.1%).   
The determination of what constitutes a clinically meaningful response rate was based 
upon a review of historical PSA response rate and ORR data for clinical studies in 
SSCHN and mCRPC.
Table 17 provides the exact 95% confidence interval for ORR/ PSA response rate based 
on different observed numbers of responders in a given combination.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 161
Table 17.
B9991040 Sample Size and Exact 95% Confidence Interval for ORR/PSA
Response Rate
N per Combination
Number of Responders
Observed ORR/PSA 
response rate
Exact 95% CI for 
ORR/PSA response 
rate
20
6
30%
11.9% - 54.3%
8
40%
19.1% - 63.9%
10
50%
27.2% - 72.8%
12
60%
36.1% - 80.9%
14
70%
45.7% -88.1%
15
75%
50.9% - 91.3%
40
14
35%
20.6% - 51.7%
16
40%
24.9% - 56.7%
18
45%
29.2% - 61.5%
20
50%
33.8% - 66.2%
22
65%
38.5% - 70.7%
24
60%
48.3% - 79.4%
26
65%
43.3% - 75.1%
28
70%
53.5% - 83.4%
30
75%
58.8% - 87.3%
9.3. Populations for Analyses
For purposes of analysis, the following populations are defined:
Defined populations for 
analysis
Description
Full Analysis Set (FAS)
All enrolled participants who take at least 1 dose of study drug.  
Participants will be classified according to the study treatment 
actually received.  
Safety Analysis Set
In this non-randomized study, the Safety Analysis Set is identical to 
the FAS.
DLT-Evaluable
The DLT-evaluable analysis set is a subset of the safety analysis set 
and includes all enrolled participants in Phase 1b who receive at 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 162
Defined populations for 
analysis
Description
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 without 
DLT. 
Participants who withdraw from study treatment in Cycle 1 before 
receiving at least 2 doses of bempegaldesleukin (NKTR-214) and 
avelumab and at least 75% of the planned dose of talazoparib 
(Combination B) or enzalutamide (Combination C) for reasons 
other than treatment-related toxicity are not evaluable for DLT.  All 
participants deemed non-evaluable for DLT may be replaced.
PK Analysis Sets
The PK concentration analysis set is a subset of the safety analysis 
set and will include participants who have at least one post-dose 
concentration measurement above the lower limit of quantitation 
(LLQ) for avelumab, bempegaldesleukin (NKTR-214), talazoparib, 
enzalutamide, or N-desmethyl-enzalutamide. 
The PK parameter analysis set is a subset of the safety analysis set 
and will include participants who have at least one of the PK 
parameters of interest for avelumab, bempegaldesleukin (NKTR-
214), talazoparib, , enzalutamide, or N-desmethyl-enzalutamide.
Biomarker Analysis Set
The biomarker analysis set is a subset of the safety analysis set and 
will include participants who have at least one baseline biomarker 
assessment. 
Analysis sets will be defined separately for blood-based and tumor 
tissue-based biomarkers.
Immunogenicity Analysis 
Set
The immunogenicity analysis set is a subset of the safety analysis 
set and will include participants who have at least one ADA/NAb 
sample collected for avelumab, bempegaldesleukin (NKTR-214), 
or IL-2.
9.4. Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary endpoints.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 163
9.4.1. Efficacy Analyses
Endpoints
Statistical Analysis Methods

Phase 2 Primary

Combination A: Confirmed 
objective response (OR) as 
determined by the 
investigator using RECIST 
v1.1 (Appendix 9).

Combination B: Confirmed 
soft tissue OR as determined 
by the investigator using 
RECIST v 1.1 (Appendix 9) 
with no evidence of 
confirmed bone disease 
progression on repeat bone 
scan at least 6 weeks later per 
PCWG3 criteria 
(Appendix 10).

Combination C: Confirmed 
prostate specific antigen 
(PSA) response decrease ≥ 
50% from baseline confirmed 
by a second consecutive 
assessment at least 3 weeks 

Combination A:   The confirmed objective response rate 
(ORR) of avelumab in combination with 
bempegaldesleukin (NKTR-214) in participants with IL
SCCHN) will be calculated along with the 2-sided 95% CI 
using the Clopper-Pearson method.  ORR is defined as the 
proportion of participants with a confirmed CR or PR 
based on the Investigator’s assessment according to
RECIST v1.1.  Only tumor assessments performed on or 
before the start date of any further anti-cancer therapies 
will be considered in the assessment of response. 
Confirmed responses are those that persist on repeat tumor 
assessments for at least 4 weeks after initial documentation 
of response.  Otherwise, the participant will be counted as 
a non-responder in the assessment of ORR.  Additionally, 
participants 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.

Combination B:  The confirmed soft tissue objective 
response rate (ORR) of avelumab in combination with 
bempegaldesleukin (NKTR-214) and talazoparib in 
participants with DDR defect positive mCRPC will be 
calculated along with the 2-sided 95% CI using the 
Clopper-Pearson method.  Soft tissue OR is determined by 
the investigator using RECIST v 1.1 (Appendix 9) with no 
evidence of confirmed bone disease progression on repeat 
bone scan at least 6 weeks later per PCWG3 criteria 
(Appendix 10).  Only tumor assessments performed on or 
before the start date of any further anti-cancer therapies 
will be considered in the assessment of response.  
Confirmed responses are those that persist on repeat tumor 
assessments for at least 4 weeks after initial documentation 
of response.  Otherwise, the participant will be counted as 
a non-responder in the assessment of soft tissue objective 
response.  

Combination C:  The rate of PSA response decrease 
≥50% from baseline, confirmed by a second consecutive
evaluation ≥ 3 weeks later, in participants with mCRPC 
after progression will be calculated along with the 2-sided 
95% CI using the Clopper- Pearson method. Only PSA 
assessments performed on or before the start of any further 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 164
Endpoints
Statistical Analysis Methods
later.
anti-cancer therapies will be considered in the assessment 
of PSA response.  
Secondary

Time to event endpoints as 
determined by the 
investigator, using RECIST 
v1.1 in participants with 
SCCHN (Combination A) 
and in participants with 
mCRPC (Combinations B 
and C), RECIST v1.1 (soft 
tissue disease) and PCWG3 
(bone disease), including 
time to tumor response 
(TTR), duration of response 
(DR), progression free 
survival (PFS), and Overall 
Survival (OS).

PFS is defined as the time from the first dose of study 
treatment to the date of PD or death due to any cause, 
whichever occurs first.  PFS data will be censored on the 
date of the last adequate tumor assessment for participants 
who do not have an event (PD or death), for participants 
who start new anti-cancer therapy prior to an event, or for 
participants with an event after two or more missing tumor 
assessments.  Participants who do not have an adequate 
baseline tumor assessment or who do not have any 
adequate post-baseline tumor assessments 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, in which case the death will be 
considered an event.  

TTR is defined, for participants with a confirmed OR, as 
the time from the first dose to the first documentation of 
OR (CR or PR) which is subsequently confirmed 
(SSCHN) without evidence of confirmed bone disease on 
bone scan per PCWG3 (mCRPC). The estimate of the 
standard error will be computed using Greenwood’s 
formula.

DR is defined, for participants with a confirmed OR, as the 
time from the first documentation of OR (CR or PR) to the 
date of first documentation of PD or death due to any 
cause.

OS is defined as the time from time from the first dose of 
study treatment to the date of death due to any cause.  
Participants 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.  Kaplan-Meier 
estimates (product-limit estimates) will be presented 
together with a summary of associated statistics including 
the median DR, PFS, or OS with 2-sided 95% CIs.  In 
addition, DR, PFS, and OS rates at different time points 
will be estimated with corresponding 2-sided 95% CIs. 
The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the 95% CIs for the survival 
function estimates at the time points defined above will be 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 165
Endpoints
Statistical Analysis Methods
derived using the log-log transformation according to 
Kalbfleisch and Prentice

Combination B: Confirmed 
PSA response

Combination B: Confirmed PSA response will be 
analyzed as specified above for Combination C. as

Combination C: Confirmed 
soft tissue OR as determined 
by the investigator using 
RECIST v 1.1 (Appendix 9) 
with no evidence of 
confirmed bone disease 
progression on repeat bone 
scan at least 6 weeks later per 
PCWG3 criteria 
(Appendix 10)

Combination C: Confirmed soft tissue OR will be 
analyzed as specified above for Combination B.

Combination C: Circulating 
tumor cells (CTC) count 
conversion (decrease in CTC 
count from ≥ 5 CTC per 7.5 
mL of blood at baseline to < 
5 CTC per 7.5 mL of blood at 
any assessment on 
treatment), and CTC0 
(defined as a CTC count of 
≥1 CTC per 7.5 mL of blood 
at baseline and 0 CTC per 7.5 
mL of blood at any 
assessment on treatment).

Combination C: CTC count conversion is defined as a 
decrease in CTC count from ≥ 5 CTC per 7.5 mL of blood 
at baseline to < 5 CTC per 7.5 mL of blood at any 
assessment on treatment, and CTC0 is defined as a CTC 
count of ≥1 CTC per 7.5 mL of blood at baseline and 0 
CTC per 7.5 mL of blood at any assessment on treatment.
Only the CTC count assessments performed on or before 
the start of any further anti-cancer therapies will be 
considered in the assessment of CTC count conversion. 
The circulating tumor cells (CTC) count conversion rate 
and CTC0 rate will be calculated along with the 2-sided 
95% CI using the Clopper-Pearson method.

Combinations B and C: 
Time to PSA progression 
(TTPSAP) defined according 
to the consensus guidelines 
of the Prostate Cancer 
Clinical Trials Working 
Group 3 (PCWG3) criteria.

Combinations B and C: Time to PSA progression 
(TTPSAP) 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 µg/L (2 ng/mL) above the 
nadir (or baseline for participants with no PSA decline) is 
documented. PSA progression must be confirmed by a 
second, consecutive PSA assessment ≥3 weeks later.  
Early rises (before week 12) should be ignored in 
determining progression.  As such, for participants with no 
PSA declines after baseline, the PSA progression date is 
defined as the date that a ≥ 25% increase and an absolute 
increase of ≥ 2 µg/L (2 ng/mL) above the baseline is 
documented after 12 weeks of treatment, which is 
confirmed by a second consecutive value at least 3 weeks 
later.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 166
Endpoints
Statistical Analysis Methods
•
Time to PSA progression will be censored on the date of 
the last PSA assessment for participants who do not have 
an event (confirmed PSA progression), for participants 
who start a new anti-cancer therapy prior to an event or for 
participants with an event after 2 or more missing PSA 
assessments.  Participants 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.   TTPSAP will be analyzed using Kaplan-
Meier methods.  Kaplan-Meier estimates (product-limit 
estimates) will be presented together with a summary of 
associated statistics including the median TTPSAP with 2-
sided 95% CIs.  In addition, TTPSAP rates at different 
time points will be estimated with corresponding 2-sided 
95% CIs. The CIs for the median will be calculated 
according to Brookmeyer and Crowley and the 95% 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.
9.4.2. Safety Analyses
All safety analyses will be performed on the Safety Population.
Endpoint
Statistical Analysis Methods
Primary
DLT during the DLT evaluation period (Cycle 1). The dose finding in Phase 1b 
of the study will be guided by a Bayesian Logistic Regression Model (BLRM) of 
Cycle 1 DLTs in DLT-evaluable participants.56  After each cohort of participants 
completes the DLT evaluation period, the posterior distribution for the risk of 
DLT for different dose combination doses of interest will be evaluated.  The 
posterior distribution of DLT rate (posterior probabilities that DLT rate is in the 
intervals of underdosing (<0.16), target toxicity [0.16-0.33) and overdosing 
(≥0.33) at the end of Phase 1b will be provided.
Secondary
Simple summary statistics (descriptive) will be presented for participants with
SAEs, AEs of special interest, lab abnormalities and other secondary safety 
endpoints during the on-treatment period (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) unless otherwise described in the 
SAP.
9.4.3. Analysis of Pharmacokinetics, Pharmacodynamics, and Biomarkers
PK, pharmacodynamic, 
 will be described in the 
statistical analysis plan finalized before database lock. The population PK analysis and 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 167
pharmacodynamic analyses, 
will be presented 
separately from the main clinical study report (CSR).
9.4.3.1. Analysis of Pharmacokinetics of Investigational Products
All analyses of Pharmacokinetic will be performed based on the Pharmacokinetic analysis 
set. Pharmacokinetic data analysis will include all PK samples collected for all 
investigational products (avelumab, bempegaldesleukin [NKTR-214], talazoparib and 
enzalutamide) as outlined in the SOA.  Descriptive summary statistics of predose 
concentrations (Ctrough) for avelumab, talazoparib and enzalutamide and end of infusion 
concentration (CEOI) for avelumab and bempegaldesleukin (NKTR-214) will be calculated.  
Additional summary statistics will be presented for avelumab and bempegaldesleukin
(NKTR-214) across all treatment groups by study phase as well as combined across study 
phases.  Pharmacokinetic data of each investigational product will be compared to the 
historical data when each drug is administered alone to assess the effect of each drug on the 
PK of the other drugs.
9.4.3.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/Pharmacodynamic) Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies investigating 
avelumab, bempegaldesleukin (NKTR-214), talazoparib and/or enzalutamide 1) to assess the 
effect of each drug on the PK of other drugs, and 2) explore any association between study 
drug exposure and biomarkers or significant safety endpoints. If performed, the details of 
these analyses will be outlined in a separate pharmacometric analysis plan (PMAP). The 
results of these analyses, if performed, may be reported separately.
9.4.3.3. Analysis of Biomarker Endpoints
All analyses of biomarkers will be performed based on the biomarker analysis set, separately 
by treatment combinations and pooled across treatment combinations. Biomarker data will 
include baseline and on-treatment/end of treatment levels of and changes in biomarkers.  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 and on-treatment/end of treatment time points, as appropriate. 
Appropriate change from baseline measurements will be provided.  For discrete measurement 
biomarkers (eg, tumor marker status), frequencies and percentages of categorical biomarker 
measures will be determined at baseline and on-treatment/post-treatment time points, as 
appropriate; shift tables may also be provided. Data from biomarker assays may be analyzed 
using graphical methods and statistics such as Fisher’s exact test, Wilcoxon rank-sum test, 
Kaplan-Meier estimates, and linear regression as appropriate. The statistical approaches will 
explore the correlations of biomarker results with pharmacokinetic parameters and measures 
of efficacy, such as tumor response and progression free survival.
The correlation of anti-tumor activity with PD-L1 expression level in baseline tumor tissue 
will be calculated as follows:  For PD-L1 expression, participants will be classified as 
positive or negative according to scoring algorithms and cut-offs established from internal or 
external sources. For continuous measurement biomarker results, summary statistics (eg, the 
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 168
mean, standard deviation, median, percent of coefficient of variation, and 
minimum/maximum levels) will be determined at baseline and on-treatment/end of treatment 
time points, as appropriate.
9.4.3.4. Analysis of Avelumab Immunogenicity Data
ADA/NAb data for avelumab will be listed and summarized.
The percentage of participants with positive ADA and NAbs will be summarized by 
combination and, if deemed appropriate, combined across all combinations.  For participants
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 pharmacokinetics may be 
evaluated, if data permit.
9.4.3.5. Analysis of Bempegaldesleukin Immunogenicity Data
ADA/NAb data for bempegaldesleukin (NKTR-214) will be listed and summarized.
The percentage of participants with positive ADA and NAbs will be summarized by 
treatment combination and, if deemed appropriate, combined across all treatment 
combinations. For participants 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 
bempegaldesleukin (NKTR-214) pharmacokinetics may be evaluated, if data permit.
9.5. Interim Analyses
No formal interim analysis will be conducted in this study.  However, as this is an open-label 
Phase 1b/2 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, 
facilitating PK/Pharmacodynamic modeling, or to support clinical development.
9.5.1. Data Monitoring Committee (DMC)
This study will not use a data monitoring committee (DMC).
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the 
following:
o
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 169
o
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
o
Applicable laws and regulations, including applicable privacy laws.

The protocol, protocol amendments, ICD, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants.

The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.
o
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures.
o
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations.

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 participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of.
10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and after completion of the study.
10.1.3. Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative (applicable for subjects only 
where locally acceptable) and answer all questions regarding the study.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 170

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.

The investigator must ensure that each study participant or his or her legally 
authorized representative is fully informed about the nature and objectives of the 
study, the sharing of data related to the study and possible risks associated with 
participation, including the risks associated with the processing of the participant’s 
personal data. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and 
correct his or her personal data and to withdraw consent for the processing of his or 
her personal data.

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICD.

Participants must be re-consented to the most current version of the ICD(s) during 
their participation in the study.

A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide this 
separate signature.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 171
10.1.4. Data Protection

All parties will comply with all applicable laws, including laws regarding the 
implementation of organizational and technical measures to ensure protection of 
participant data.

Participants’ personal data will be stored at the study site in encrypted electronic 
form and will be password protected to ensure that only authorized study staff have 
access.  The study site will implement appropriate technical and organizational 
measures to ensure that the personal data can be recovered in the event of disaster.  
In the event of a potential personal data breach, the study site shall be responsible 
for determining whether a personal data breach has in fact occurred and, if so, 
providing breach notifications as required by law.

To protect the rights and freedoms of natural persons with regard to the processing 
of personal data, participants will be assigned a single, participant-specific 
numerical code. Any participant records or datasets that are transferred to the 
sponsor will contain the numerical code; participant names will not be transferred. 
All other identifiable data transferred to the sponsor will be identified by this single, 
participant-specific code. The study site will maintain a confidential list of 
participants who participated in the study, linking each participant’s numerical code 
to his or her actual identity. In case of data transfer, the sponsor will protect the 
confidentiality of participants’ personal data consistent with the Clinical Study 
Agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study 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 addition, Pfizer reports study results outside of the 
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
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 participants) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally 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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 172
PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements. EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (Clinical Study Report [CSR] synopses in which any 
data that could be used to identify individual participants have 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.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website. Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods. Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  
Policy 0070 applies to new marketing authorization applications submitted via the 
centralized procedure since 01 January 2015 and applications for line extensions and for new 
indications submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contribute to the scientific understanding of 
the disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations.  CSRs will have personally identifiable 
information redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.6. Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 173
data). The investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.

The investigator must ensure that the CRFs are securely stored at the study site in 
encrypted electronic form and are password protected to prevent access by 
unauthorized third parties.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
This verification may also occur after study completion. 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.

Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-
Based Monitoring), methods, responsibilities and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the study monitoring plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.

Records and documents, including signed ICDs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of 
the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. The investigator must ensure that the records 
continue to be stored securely for so long as they are maintained.

When participant data are to be deleted, the investigator will ensure that all copies 
of such data are promptly and irrevocably deleted from all systems.

The investigator(s) will notify sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will 
cooperate with sponsor or its agents to prepare the investigator site for the 
inspection and will allow sponsor 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 participant's 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 174
medical records.  The investigator will promptly provide copies of the inspection 
findings to sponsor or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide sponsor or its agents with an opportunity to 
review and comment on responses to any such findings.
10.1.7. Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available.

Definition of what constitutes source data can be found in the study monitoring 
plan.
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/IEC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol the contract will control as to termination rights.
10.1.9. Publication Policy

The results of this study may be published or presented at scientific meetings by the 
Investigator after publication of the overall study results or one year after end of the 
study (or study termination), whichever comes first. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 175

The investigator agrees to refer to the primary publication in any subsequent 
publications such as secondary manuscripts, and submit all manuscripts or abstracts 
to the sponsor 30 days before submission. This allows the sponsor to protect 
proprietary information and to provide comments and the Investigator will, on 
request, remove any previously undisclosed confidential information before 
disclosure, except for any study- or Pfizer intervention-related information 
necessary to the appropriate scientific presentation or understanding of the study 
results.

For all publications relating to the study, the Investigator will comply with 
recognized ethical standards concerning publications and authorship, including 
those established by the International Committee of Medical Journal Editors.

The sponsor will comply with the requirements for publication of the overall study 
results covering all Investigator sites. In accordance with standard editorial and 
ethical practice, the sponsor will support publication of multicenter studies only in 
their entirety and not as individual site data. In this case, a coordinating investigator 
will be designated by mutual agreement.

Authorship of publications for the overall study results will be determined by 
mutual agreement and in line with International Committee of Medical Journal 
Editors authorship requirements.

If publication is addressed in the clinical study agreement, the publication policy set 
out in this section will not apply.
10.1.10. 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 study portal. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant study 
numbers, contact information for the investigator site, and contact details for a contact center 
in the event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  For sites other than 
a Pfizer clinical research unit (CRU), the contact number is not intended for use by the 
participant directly, and if a participant calls that number, he or she will be directed back to 
the investigator site.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 176
10.2. Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by the local laboratory.
Samples for all laboratory assessments in Table 1 will be drawn at the time points indicated 
in the Schedule of Activities and when clinically indicated.  Laboratory tests may be 
performed up to 3 days prior to the scheduled clinic visit.  All safety laboratory analyses will 
be performed by the local laboratory(ies) for each study center.  

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.  If labs were 
conducted within 3 days of C1D1, they do not need to be repeated.

Prior to study drug administration on Days 1 and 15 of each treatment cycle, 
hematology (ie, hemoglobin, platelets, and white blood cells) and chemistry (ie, 
ALT, AST, alkaline phosphatase, total bilirubin, blood urea nitrogen, creatinine, 
sodium, potassium, lipase, amylase, and glucose) tests must be performed and 
results reviewed by the treating physician prior to study drug administration.  When 
applicable, results from pregnancy tests must also be available for review prior to 
dosing.  

There is a 7-day window allowed for PSA labs from C1D1.
Pregnancy Testing 
Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
monthly intervals (eg Day 1 of each cycle) during intervention as per SoA. Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and a second negative pregnancy test result will then be required at the baseline visit on 
C1D1 before the participant may receive the study treatment.  Pregnancy tests will also be 
done whenever 1 menstrual cycle is missed during the active treatment period (or when 
potential pregnancy is otherwise suspected) and at the end of the study. If a urine test cannot 
be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In 
such cases, the participant must be excluded from participation if the serum pregnancy result 
is positive.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure plus an additional 30 days.

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the subject's participation in the study.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 177
Table 1.
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Hemoglobin
White blood cell (WBC) count with Differential:
Neutrophils (absolute)
Lymphocytes (absolute)
Monocytes (absolute)
Eosinophils (absolute)
Basophils (absolute)
Coagulation
aPTT (in seconds)
INR and/or PT
Clinical 
Chemistry1
ALP
ALT
AST                  
Albumin  
Amylase           
BUN or Urea
Chloride 
Creatinine
CRP                             
Glucose  (non-fasted)      
GGT
LDH
Lipase
Magnesium
Phosphorus/Phosphate       
Potassium
                             
Sodium
Total Bilirubin
Total Calcium 
Total Protein
Uric Acid           
                          
Routine Urinalysis2

Specific gravity

pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, leukocyte 
esterase) by dipstick

Microscopic examination (Only if urine dipstick is positive for blood, protein, nitrites, 
or leukocyte esterase).  
Pregnancy Test
Serum or urine human chorionic gonadotropin (hCG) pregnancy test with a sensitivity 
of at least 25 IU/mL (as needed for women of childbearing potential)2
Hepatitis B and C
Hepatitis B Surface antigen                           Hepatitis C Virus AB
                                                                       HCV RNA (if Hepatitis C Ag
                                                                       tests positive)
Thyroid function 
and ACTH
TSH, Free T4, ACTH
Abbreviations: ACTH=adrenocorticotropic hormone, ALP=alkaline phosphatase; ALT=alanine 
aminotransferase, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein; 
GGT= gamma-glutamyl transferase;HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international 
normalized ratio, LDH=lactate dehydrogenase, PT=prothrombin time, PTT=partial thromboplastin time, 
RNA=ribonucleic acid, TSH=thyroid-stimulating hormone, WBC=white blood cell.
NOTES:


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 178
Table 1.
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 7.1.1 and Appendix 6. All events of ALT 3 × upper limit 
of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international 
normalized ratio (INR) >1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law), 
must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).  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.  Refer to Appendix 6 for 
further details.
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/IEC.
Investigators must document their review of each laboratory safety report.  The results of 
each test must be entered in the CRF.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 179
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a participant or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or 
SAE.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 180
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

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.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 181
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.

Examples of such events include invasive or malignant cancers, 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 Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 5 (see the Severity Assessment section).
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF and 
for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event (SAE) 
Report Form to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) 
SAEs; (2) non-serious adverse events (AEs); and (3) exposure to the investigational product 
under study during pregnancy or breastfeeding, and occupational exposure.  
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.
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


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 182
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
None
All (And exposure during 
pregnancy [EDP]
supplemental form for 
EDP)  

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the Pfizer Safety /AE/SAE 
CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the exception 
of the participant number, will be redacted on the copies of the medical records 
before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
GRADE
Clinical Description of Severity
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
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 183
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Pfizer Safety. However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to Pfizer Safety.

The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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" and "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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 184
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Pfizer 
Safety to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the Pfizer Safety within 24 
hours of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic 
data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to Pfizer Safety by telephone.

Contacts for SAE reporting can be found in the Investigator Site File.
SAE Reporting to Pfizer Safety via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to Pfizer Safety. 

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Investigator Site File.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 185
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
NOTE: Documentation for any of the above conditions can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. The method of documentation should be recorded in the 
participant’s medical record for the study.
3. Postmenopausal female

A postmenopausal state is defined as age 60 or older or no menses for 12 months 
without an alternative medical cause.

A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 186
Contraception Guidance:
The contraception check is an opportunity to confirm that contraception, if assigned, is 
used consistently and correctly.  Also, for studies enrolling adult participants, it is the 
opportunity to assess changing potential to father/bear children and allows for altering 
contraception if new disease contraindicates a selected method of contraception or if 
nonchildbearing status is achieved.
Male Participants
Male participants with the ability to father a child are eligible to participate if they agree to 
the following during the intervention period and for at least 30 days after the last dose of 
avelumab, at least 3 months after the last dose of enzalutamide or bempegaldesleukin
(NKTR-214); (azospermic males are exempt from contraceptive requirements for 
bempegaldesleukin [NKTR-214]), and at least 4 months after the last dose of talazoparib.  In 
addition, male participants MUST:

Refrain from donating sperm

PLUS either:

Be abstinent from intercourse as their preferred and usual lifestyle (abstinent on a 
long term and persistent basis) and agree to remain abstinent 
OR 

Use an additional highly effective contraceptive method with a failure rate of <1% 
per year as described for a female partner of childbearing potential.  The 
investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 

Must agree to use contraception/barrier as detailed below: 

Agree to use a male condom when engaging in any activity that allows passage of 
ejaculate to another person.  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 187
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner
o
Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.
Highly Effective Methodsb That Are User Dependent 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationc
o
oral
o
intravaginal
o
transdermal
o
injectable

Progestogen-only hormone contraception associated with inhibition of ovulationc
o
oral
o
injectable

Sexual abstinence
o
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.
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies.
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly.
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom should not be used together (due to risk of failure with friction)
Collection of Pregnancy Information:
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.

An example of environmental exposure would be a case involving direct contact with a 
Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has been 
exposed to chemotherapeutic products).


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 188

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 participant or participant’s partner becomes or is found to be pregnant during the 
participant’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 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs.  In addition, infant deaths after 1 month should be reported as SAEs 
when the investigator assesses the infant death as related or possibly related to exposure 
to the investigational product.
Additional information regarding the EDP may be requested by the sponsor.  Further follow-
up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner.  The investigator must document in the source documents that the participant
was given the Pregnant Partner Release of Information Form to provide to his partner.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 189
10.5. Appendix 5: Genetics
Use/Analysis of DNA:
•
Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Therefore, where local 
regulations and IRB/IEC allow, blood samples will be collected for DNA analysis.
•
Genetic research may consist of the analysis of   genetic markers throughout the 
genome or analysis of the entire genome (as appropriate).
•
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study interventions of this class, treatments for the 
disease(s) under study or the disease(s) themselves.
•
The results of genetic analyses may be reported in the clinical study report (CSR) or 
in a separate study summary, or may be used for internal decision-making without 
being included in a study report.
•
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
•
The samples will be retained as indicated:
•
Samples for specified genetic analysis (refer to Section 8.7.1) will be
stored for up to 15 years or other period as per local requirements beyond 
the completion of this study (eg, Clinical Study Report finalization).
•
Samples for banking (refer to Section 8.7.2) will be stored for up to 15 
years or other period as per local requirements beyond the completion of 
this study (eg, Clinical Study Report finalization).  
 
 
   
 
 
  
CCI
CC


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 190
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
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 participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants 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:

Participants 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 participants 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:
o
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).
o
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 participant
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 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 191
tests, detailed history, and physical assessment. The possibility of hepatic neoplasia (primary 
or secondary) should be considered.  
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s Law, additional laboratory tests should include albumin, creatine kinase (CK), direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time 
(PT)/international normalized ratio (INR), total bile acids, and alkaline phosphatase. 
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) and collection of serum sample for acetaminophen drug and/or protein 
adduct levels 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 
abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 192
10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ duration.

Frequent premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia.

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods of 
asystole 3.0 seconds or any escape rate <40 bpm, or with an escape rhythm that 
is below the AV node. 

In awake, symptom-free participants with atrial fibrillation and bradycardia with 1 
or more pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 beats per minute (bpm).

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short duration 
with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 
monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 193
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction.

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or notifications 
from the core ECG laboratory to the investigator and Pfizer study team, and not to be considered as all inclusive 
of what to be reported as AEs/SAEs.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 194
10.8. Appendix 8: ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease 
activities without restriction
1
Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of 
a light or sedentary nature; eg, light house 
work or office work
2
Ambulatory and capable of all self-care but 
unable to carry out any work activities.  Up 
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours
4
Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair
5
Dead
From Oken, NM et al (1982)57


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 195
10.9. Appendix 9: Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines
Adapted from E.A. Eisenhauer, et al (2009).58
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 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 196
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.

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 
inevaluable. 
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, INEVALUABLE, PRESENT 
WITHOUT UNEQUIVOCAL PROGRESSION, UNEQUIVOCAL PROGRESSION.
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’).


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 197
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. 

PD: Unequivocal progression of pre-existing lesions.  Generally, the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 198
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
Participants requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document 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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 199
Objective Response Status at Each Assessment for Participants 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 participant’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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 200
10.10. Appendix 10: Assessment of Radiographic Response and Progression in 
Participants with mCRPC
Radiographic imaging for participants with CRPC 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 
(scintigraphy).
The investigator will assess response of soft tissue disease by RECIST v1.1 (refer to
Appendix 9).  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 PCWG3.59 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 
PCWG3a
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 (after 
week 52 on study 
treatment)
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.  
Refer to the following table for the timing of confirmatory imaging requirements.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 201
Confirmatory Imaging Requirements for Participants 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.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 202
10.11. Appendix 11: BLRM Design for Avelumab and Bempegaldesleukin (NKTR-214)
Doublet - Combination A
This appendix provides the details of the statistical model, the derivation of prior 
distributions from historical data, the results of the Bayesian analyses and respective dosing 
decisions for some hypothetical data scenarios, and a simulation study of the operating 
characteristics of the model for the bempegaldesleukin (NKTR-214) + avelumab treatment 
(Combination A).
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 800 
mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose.
Statistical Model
The statistical model for dose-DLT data for this doublet combination comprises single-agent 
toxicity parts, which allow the incorporation of single-agent toxicity data, and an interaction 
part.
Single Agent Parts 
Let ߨଵሺ݀ଵሻbe the risk of DLT for bempegaldesleukin (NKTR-214) given as a single agent at 
dose ݀ଵ; and  ߨଶሺ݀ଶሻbe the risk of DLT for avelumab given as a single agent at dose ݀ଶ.  
These single agent dose-DLT models are logistic:
bempegaldesleukin (NKTR-214):
logit൫ߨଵሺ݀ଵሻ൯ൌlogሺߙଵሻ൅ߚଵlogሺ݀ଵ݀ଵ
∗
⁄
ሻ
avelumab:
logit൫ߨଶሺ݀ଶሻ൯ൌlogሺߙଶሻ൅ߚଶlogሺ݀ଶ݀ଶ
∗
⁄
ሻ
where ݀ଵ
∗=0.006 mg/kg, and ݀ଶ
∗=10 mg/kg, are used to scale the doses of bempegaldesleukin 
(NKTR-214), and avelumab, respectively.  Hence, ߙଵ, ߙଶ(all >0) are the single-agent odds 
of a DLT at ݀ଵ
∗mg/kg, and ݀ଶ
∗mg/kg, respectively; and  ߚଵ,and ߚଶ, (all>0) are the increase in 
the log-odds of a DLT by a unit increase in log-dose.
Interaction Part
Under an assumption that there is no interaction, the risk of a DLT at dose ݀ଵof 
bempegaldesleukin (NKTR-214), and dose ݀ଶof avelumab is:
ߨଵଶ
଴ሺ݀ଵ, ݀ଶ, ሻൌ1 െ൫1 െߨଵሺ݀ଵሻ൯൫1 െߨଶሺ݀ଶሻ൯
To model the interaction between bempegaldesleukin (NKTR-214) and avelumab, the 
following odds multiplier is introduced.
•
ߟଵଶ: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 203
The risk of DLT for combination dose ሺ݀ଵ, ݀ଶሻis then given by:
odds൫ߨଵଶሺ݀ଵ, ݀ଶሻ൯ൌ݃ሺߟଵଶሻൈodds൫ߨଵଶ
଴ሺ݀ଵ, ݀ଶሻ൯
݃ሺߟଵଶሻൌexpሺߟଵଶൈ݀ଵ݀ଵ
∗
⁄
ൈ݀ଶ݀ଶ
∗
⁄
ሻ
where oddsሺߨሻൌߨሺ1 െߨሻ
⁄
; ߟ௜௝is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j.  For example, ߟଵଶis the log-odds 
ratio between the interaction and no interaction model at avelumab = 10 mg/kg, 
bempegaldesleukin (NKTR-214) = 0.006 mg/kg.  Therefore, ߟଵଶis the log-odds ratio 
between the interaction and no interaction model at the reference doses for two drugs.  Here 
ߟൌ0 corresponds to no interaction, with ߟ൐0 and ߟ൏0 representing synergistic and 
antagonistic toxicity, respectively.
Prior Specifications
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters logሺߙଵሻ, logሺߚଵሻfor 
bempegaldesleukin (NKTR-214), and logሺߙଶሻ, logሺߚଶሻfor avelumab, and the interaction 
parameter ሺߟଵଶሻ.  A meta-analytic-predictive (MAP) approach was used to derive the prior 
distribution for the single-agent model parameters.
Prior Distribution for the Logistic Parameters for Single Agent
This section illustrates the derivation of prior distributions for single agent model parameters 
(logሺߙ௦ሻ, logሺߚ௦ሻ)’s using the available single agent dose-DLT information via a MAP 
approach.
Description of the Meta-Analytic-Predictive Approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
൫logሺߙ∗ሻ, logሺߚ∗ሻ൯of the new trial using DLT data from historical studies.  Let ݎௗ௦and ݊ௗ௦
be the number of participants with a DLT, and the total number of participants at dose ݀in 
historical trial ݏ(ݏൌ1, … , 〈ܵ〉).  The corresponding probability of a DLT is ߨௗ௦.  The model 
specifications are as follows:
ݎௗ௦| ߨௗ௦~ Binomialሺߨௗ௦, ݊ௗ௦ሻ
logitሺߨௗ௦ሻൌlogሺߙ௦ሻ൅ߚ௦logሺ݀/݀∗ሻ
൫݈݋݃ሺߙ௦ሻ, ݈݋݃ሺߚ௦ሻ൯หߤ, ߰௚ሺ௦ሻ~ Bivariate Normal ሺBVNሻ൫ߤ, ߰௚ሺ௦ሻ൯,
s ൌ1, … , 〈ܵ〉
൫݈݋݃ሺߙ∗ሻ, ݈݋݃ሺߚ∗ሻ൯หߤ, ߰௚ሺ∗ሻ~ BVN൫ߤ, ߰௚ሺ∗ሻ൯
The historical trials are partitioned into 〈ܩ〉exchangeability groups, with the exchangeability 
group membership of historical trial ݏbeing represented by ݃ሺݏሻ.  The new trial is assigned 
to exchangeability group ݃ሺ∗ሻ.  The parameter ߤൌሺߤଵ, ߤଶሻ  is the mean for the logistic 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 204
parameters, and ߰௚is the between-trial covariance matrix for exchangeability group ݃ൌ
1, … , 〈ܩ〉.  Covariance matrix ߰௚is defined by the standard deviations ሺτ௚ଵ, τ௚ଶሻ, and 
correlation ρ (a common value for ρ is used across all groups).  The parameters τ௚ଵand τ௚ଶ
quantify the degree of between trial heterogeneity for exchangeability group ݃.  With 
different prior distributions for the parameter sets ൫τ௚ଵ, τ௚ଶ൯it is possible to allow for 
differential discounting for the historical strata.  In this way the quality and relevance of 
historical data can be accounted for in the meta-analysis.  The following priors will be used 
for these parameters:  
•
normal priors for ߤଵand ߤଶ, 
•
log-normal priors for τ௚ଵand τ௚ଶ, and 
•
uniform prior for ρ.
The MAP prior for single-agent model parameters in the new trial, ൫݈݋݃ሺߙ∗ሻ, ݈݋݃ሺߚ∗ሻ൯, is the 
predictive distribution 
൫݈݋݃ሺߙ∗ሻ, ݈݋݃ሺߚ∗ሻ൯หሺݎௗ௦, ݊ௗ௦∶ݏൌ1, … , 〈ܵ〉ሻ
Since the predictive distribution is not available analytically, the Markov chain Monte Carlo 
(MCMC) method is used to simulate values from this distribution.  This is implemented 
using Just Another Gibbs Sampler (JAGS) version 4.8.
Single Agent Bempegaldesleukin (NKTR-214)  
Dose-DLT data for bempegaldesleukin (NKTR-214) from study Excel as presented in Table 
1 are used to derive the priors of the single agent logistic parameters for bempegaldesleukin 
(NKTR-214).4 The Q3W schedule was mapped to the Q2W assuming linear relationship 
between PK with accumulation for bempegaldesleukin (NKTR-214) based on clinical-
pharmacology assessment. 
Table 1.
Historical Dose Limiting Toxicity Data From Study EXCEL
Bempegaldesleukin (NKTR-214) 
dose (mg/kg IV)
Number of patients
Number of patients with DLTs
0.003 Q3W
4
0
0.006 Q3W
11
0
0.006 Q2W
6
0
0.009 Q3W
6
0
0.012 Q3W
1
1
Abbreviations: IV=intravenous; mg/kg=milligrams per kilogram; Q2W= every 2 weeks; Q3W= every 3 weeks; DLT=dose 
limiting toxicity.
Weakly informative normal priors are assumed for ߤଵ௕and ߤଶ௕, with means corresponding to 
a 50% chance of DLT at bempegaldesleukin (NKTR-214) =0.006 mg/kg, and a doubling in 
dose leading to a doubling in the odds of the risk of a DLT, respectively.  Priors for τଵ௕and 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 205
τଶ௕are assigned such that (1) their medians correspond to moderate between trial 
heterogeneity, and (2) their uncertainty (95% prior interval) cover plausible between-trial 
standard deviations.
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 2.  
Table 2.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Bempegaldesleukin (NKTR-214) Model 
Parameters
Parameter
Prior distribution
ߤଵ௕
N(mean = 0, sd =2)
ߤଶ௕
N(mean = 0, sd=1)
τଵ௕
log-normal(mean = log(0.25), sd = log(2)/1.96)
τଶ௕
log-normal(mean = log(0.125), sd = log(2)/1.96)
ρ௕
uniform(-1,1)
Abbreviations: N=normally distributed; sd=standard deviation.
Single Agent Avelumab
Dose-DLT data in the avelumab IB from study EMR100070-001 as presented in Table 3 are
used to derive the prior of the single agent logistic parameters for avelumab.  Based on 
clinical assessment, the population of the current study is moderately similar to study 
EMR100070-001. 1
Table 3.
Historical Dose Limiting Toxicity Data from Study EMR100070-001
Avelumab dose (mg/kg Q2W)
Number of patients
Number of patients with DLTs
1
4
0
3
3
0
10
6
0
20
6
1
Abbreviations: mg/kg=milligrams per kilogram; DLT=dose limiting toxicity; Q2W=every 2 weeks.
Weakly informative normal priors are assumed for ߤଵ௔and ߤଶ௔, with means corresponding to 
a 50% chance of DLT at avelumab=10 mg/kg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for τଵ௔and τଶ௔are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations.
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 4.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 206
Table 4.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters
Parameter
Prior distribution
ߤଵ௔
N(mean = 0, sd = 2)
ߤଶ௔
N(mean = 0, sd=1)
τଵ௔
log-normal(mean = log(0.25), sd = log(2)/1.96)
τଶ௔
log-normal(mean = log(0.125), sd = log(2)/1.96)
ρ௔
uniform(-1,1)
Abbreviations: N=normally distributed; sd=standard deviation.
Prior Distribution for the Interaction Parameter
Based on pharmacometrics assessment, no drug-drug interaction is expected between 
avelumab and bempegaldesleukin (NKTR-214), although uncertainty remains.  Based upon 
this, normal prior for the log-odds multiplier ߟଵଶ  is used.  The prior is centered on an 
assumption of no drug-drug interaction, but with appropriate uncertainty that allows for both 
synergistic and antagonistic toxicity.  The prior for ࣁ૚૛is specified as percentiles of increase 
in the odds of DLT due to possible interaction in combination therapy at reference doses:
ߟଵଶis normally distributed, with mean 0 and standard deviation 0.561 (corresponds to no 
increase in DLT odds at median and 3.0-fold increase in DLTs at 97.5th percentile).
Summary of Prior Distributions 
The prior distributions of the model parameters are provided in Table 5.  Table 6 illustrates
the resulting prior distribution of DLT rate derived from the priors given in Table 5.   Based 
on the available information, the starting dose avelumab= 10 mg/kg and bempegaldesleukin 
(NKTR-214) = 0.006 mg/kg satisfies the EWOC criterion. 
Table 5.
Prior Distribution for the Model Parameters
Parameter
Mean
Standard deviations
Correlation
Bempegaldesleukin (NKTR-214) single agent parameters: BVN MAP  Prior 
൫logሺߙଵሻ, logሺߚଵሻ൯
-2.612, 0.946
0.932, 1.153
0.056
Avelumab single agent parameters: BVN MAP Prior
൫logሺߙଶሻ, logሺߚଶሻ൯
-2.67, -0.047
0.972, 0.822
-0.233
Interaction parameter: Normal prior
ߟଵଶ
0
0.561
η12: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab.
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 207
Table 6.
Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Doublet Combination of Avelumab in Combination with Bempegaldesleukin 
(NKTR-214) 
Bempegaldesleukin 
(NKTR-214) dose 
(mg/kg Q2W IV)
Prior probabilities that DLT rate is 
in the interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
0.003
0.771
0.192
0.037
0.115
0.093
0.015
0.089
0.369
0.006
0.528
0.335
0.137
0.186
0.132
0.029
0.151
0.529
Avelumab dose fixed at 10 mg/kg every 2 weeks. 
Abbreviations: IV=intravenous; mg/kg=milligrams per kilogram; Q2W=every 2 weeks; DLT=dose limiting toxicity; 
SD=Standard Deviation.
Hypothetical on-Study Data Scenarios
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next cohort 
of participants is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future participants, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data.
Table 7 shows some hypothetical dose escalation data scenarios for Combination A and the 
corresponding recommendations for the next dose.  For example, in Scenario 1, if no DLT is 
observed among 3 DLT-evaluable participants at the starting dose, the recommendation is to 
remain at the same dose level with probability of overdosing of 0.044.  Note that the starting 
dose is already the maximum possible dose for Combination A.  In Scenario 3, if 2 
participants experience a DLT out of 3 DLT-evaluable participants at the starting dose, the 
recommendation is to de-escalate the dose of bempegaldesleukin (NKTR-214) to 0.003 
mg/kg with avelumab remaining at 10 mg/kg; this lower dose combination has a probability 
of overdosing of 0.139.  Scenarios 1 through 7 show clinically plausible next dose 
recommendations.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 208
Table 7.
Combination A: Data Scenarios, Next Dose Recommendation, and the 
Interval Probability of Target Toxicity and Overdosing at Next Dose.
Dose Evaluated
D/N*
Next Dose (ND)  
Pr(TT) 
at ND
Pr(OD) 
at ND
Scenarios
Ave 
(mg/kg 
IV 
Q2W)
NKTR
(mg/kg  
IV 
Q2W)
Ave 
(mg/kg 
IV 
Q2W)
NKTR
(mg/kg 
IV 
Q2W)
1
(10)
0.006
0/3
(10)
0.006
0.265
0.044
2
(10)
0.006
1/3
(10)
0.006
0.435
0.179
3
(10)
0.006
2/3
(10)
0.003
0.378
0.139
4
(10)
0.006
2/6
(10)
0.006
0.518
0.210
5
(10)
0.006
3/6
(10)
0.003
0.418
0.121
6
(10)
0.006
0.003
3/6
1/3
(10)
0.003
0.518
0.164
7
(10)
0.006
1/6
0/3
(10)
0.006
0.309
0.027
Abbreviations: Ave=avelumab;  NKTR=bempegaldesleukin (NKTR-214); *D=number of participants with DLT, 
N=number of DLT-evaluable participants; IV=intravenous; mg/kg=milligrams per kilogram; ND=next dose; 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Q2W=every 2 weeks.
Operating Characteristics 
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated and in each scenario 1000 trials were 
simulated.
Simulation Scenarios 
Several scenarios are considered for Combination A (Table 8).  Scenario 1 represents the 
case when the distribution of DLT coincides with prior, ie, the true DLT probability equals to 
mean of prior DLT.  Scenarios 2-3 represent an increase in DLT rate compared to Scenario 1.  
Table 8.
Combination A: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab Dose 
10 mg/kg every 2 Weeks)
Scenarios 
Bempegaldesleukin (NKTR-214)   
mg/kg Q2W IV
0.003
0.006
1.    Prior means
0.115
0.186
2.   25% more toxic
0.144
0.232
3.  Higher dose is overly toxic
0.250
0.500
Abbreviations: IV=intravenous; mg/kg=milligrams per kilogram; Q2W=every 2 weeks


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 209
Simulation Details 
Simulations were performed using R version 3.5.3 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the MCMC analyses. 
For each scenario, data for 1000 trials were generated, with a cohort size of 3-6.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria.
For Combination A, the starting dose was avelumab 10 mg/kg and bempegaldesleukin 
(NKTR-214) 0.006 mg/kg.  The maximum number of participants per trial was set to 30.  
The trial was stopped when the following criteria were met:
•
At least 6 participants have been treated at the recommended MTD ݀ሚ.
•
The dose ݀ሚsatisfies one of the following conditions:
o
The probability of target toxicity at dose ݀ሚexceeds 50%, 
ie, Pr(0.16 ≤ߨௗ෨<0.33)≥50%; 
o
A minimum of 9 participants have been treated in the trial;
The following metrics were assessed in the simulations:
•
Percentage of participants receiving dose combination(s) in the target toxicity 
interval; 
•
Percentage of participants receiving an overdose;
•
Percentage of participants receiving an under dose;
•
Probability that recommended MTD at the end of the trial is in the target toxicity 
interval;
•
Probability that recommended MTD is an overdose;
•
Probability that recommended MTD is an under dose;
•
Percentage of trials stopped without MTD declaration;
•
Average sample size.
Simulation Results 
Operating characteristics for Combination A are presented in Table 9.  The percentage of 
trials with a correctly identified MTD ranges from 67.3% to 84.4%.  The average sample size 
is 10-11 participants.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 210
Table 9.
Combination A: Operating Characteristics
Scenarios 
Participant allocation 
(%)
% declare MTD
% stop 
(no 
MTD)
Average 
sample 
size
TT
OD
UD
TT
OD
UD
1.    Prior means
91.1
0
8.9
84.4
0
15.0
0.6
10
2.   25% more toxic
87.8
0
12.2
78.4
0
20.6
1.0
10
3.   Higher dose is 
overdose
40.7
59.3
0
67.3
9.5
0
23.2
11
Abbreviations: MTD=maximum tolerated dose: OD=overdose; TT=target toxicity; UD=under dose.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 211
10.12. Appendix 12: BLRM Design for Talazoparib Triplet - Combination B
This appendix provides the details of the statistical model, the derivation of prior 
distributions from historical data, the results of the Bayesian analyses and respective dosing 
decisions for some hypothetical data scenarios, and a simulation study of the operating 
characteristics of the model for the talazoparib, bempegaldesleukin (NKTR-214), and 
avelumab triplet combination (Combination B).
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 
800 mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose.
Statistical Model
The statistical model for Combination B dose-DLT data comprises single-agent toxicity 
parts, which allow the incorporation of single-agent toxicity data, and interaction parts.
Single Agent Parts 
Let ߨଵሺ݀ଵሻbe the risk of DLT for talazoparib given as a single agent at dose ݀ଵ; ߨଶሺ݀ଶሻbe 
the risk of DLT for bempegaldesleukin (NKTR-214) given as a single agent at dose ݀ଶ; and 
ߨଷሺ݀ଷሻbe the risk of DLT for avelumab given as a single agent at dose ݀ଷ.  These single 
agent dose-DLT models are logistic:
talazoparib:
logit൫ߨଵሺ݀ଵሻ൯ൌlogሺߙଵሻ൅ߚଵlogሺ݀ଵ݀ଵ
∗
⁄
ሻ
bempegaldesleukin (NKTR-214):
logit൫ߨଶሺ݀ଶሻ൯ൌlogሺߙଶሻ൅ߚଶlogሺ݀ଶ݀ଶ
∗
⁄
ሻ
avelumab:
logit൫ߨଷሺ݀ଷሻ൯ൌlogሺߙଷሻ൅ߚଷlogሺ݀ଷ݀ଷ
∗
⁄
ሻ
where ݀ଵ
∗=1.0 mg, ݀ଶ
∗=0.006 mg/kg, and ݀ଷ
∗ൌ10 mg/kg are used to scale the doses of 
talazoparib, bempegaldesleukin (NKTR-214), and avelumab, respectively.  Hence, ߙଵ, ߙଶ, 
and ߙଷ(all >0) are the single-agent odds of a DLT at ݀ଵ
∗mg, ݀ଶ
∗mg/kg, and ݀ଷ
∗mg/kg, 
respectively; and  ߚଵ, ߚଶ, and ߚଷ(all >0) are the increase in the log-odds of a DLT by a unit 
increase in log-dose.
Interaction Parts
Under an assumption that there is no interaction, the risk of a DLT at dose ݀ଵof talazoparib, 
dose ݀ଶof bempegaldesleukin (NKTR-214), and dose ݀ଷof avelumab is:
ߨଵଶଷ
଴ሺ݀ଵ, ݀ଶ, ݀ଷሻൌ1 െ൫1 െߨଵሺ݀ଵሻ൯൫1 െߨଶሺ݀ଶሻ൯൫1 െߨଷሺ݀ଷሻ൯
To model the interaction between talazoparib, bempegaldesleukin (NKTR-214), and 
avelumab, the following four odds multipliers are introduced.
•
ߟଵଶ: Two-way interaction between talazoparib and bempegaldesleukin (NKTR-214)
•
ߟଵଷ: Two-way interaction between talazoparib and avelumab
•
ߟଶଷ: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 212
•
ߟଵଶଷ: Three-way interaction between talazoparib, bempegaldesleukin (NKTR-214)
and avelumab
The risk of DLT for combination dose ሺ݀ଵ, ݀ଶ, ݀ଷሻis then given by:
odds൫ߨଵଶଷሺ݀ଵ, ݀ଶ, ݀ଷሻ൯ൌ݃ሺߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷሻൈodds൫ߨଵଶଷ
଴ሺ݀ଵ, ݀ଶ, ݀ଷሻ൯
݃ሺߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷሻൌexpሺߟଵଶൈ݀ଵ݀ଵ
∗
⁄
ൈ݀ଶ݀ଶ
∗
⁄
ሻ
                                                                ൈexp ሺߟଵଷൈ݀ଵ݀ଵ
∗
⁄
ൈ݀ଷ݀ଷ
∗ሻ
⁄
                                                                ൈexp ሺߟଶଷൈ݀ଶ݀ଶ
∗
⁄
ൈ݀ଷ݀ଷ
∗ሻ
⁄
                                                              ൈexp ሺߟଵଶଷൈ݀ଵ݀ଵ
∗
⁄
ൈ݀ଶ݀ଶ
∗
⁄
ൈ݀ଷ݀ଷ
∗
⁄
ሻ
where oddsሺߨሻൌߨሺ1 െߨሻ
⁄
; ߟ௜௝is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j and a zero dose of the third drug.  For 
example, ߟଶଷis the log-odds ratio between the interaction and no interaction model at 
avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg, and talazoparib=0 
mg.  Therefore, ߟଵଶ൅ߟଵଷ൅ߟଶଷ൅ߟଵଶଷis the log-odds ratio between the interaction and no 
interaction model at the reference doses for all three drugs.  Here ߟൌ0 corresponds to no 
interaction, with ߟ൐0 and ߟ൏0 representing synergistic and antagonistic toxicity,
respectively.
Inclusion of the Doublet Data
Based on the preliminary data from the Phase 1b portion of study B9991025, a total 12 
participants were enrolled at the starting dose level of 800 mg avelumab Q2W in 
combination with talazoparib at 1.0 mg once daily. All 12 participants were DLT-evaluable 
with a DLT rate of 3/12. This information from study B9991025 was incorporated in the 
assessment of prior distribution of DLT, starting dose, data scenarios, and simulations of 
Combination B via a direct down-weighting approach. The weight was calculated using the 
formula below assuming substantial heterogeneity between the populations included in the 
avelumab + talazoparib doublet and Combination B in terms of DLT; 
ݓൌ
1
1 ൅2߬ଶ
ߪଶܰ
where, N= Total number of participants enrolled in the B9991025 avelumab + talazoparib 
doublet combination (N=12) 
        σ = population standard deviation (σ =2)
        τ = heterogeneity between populations in the B9991025 doublet and triplet (τ =0.5)


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 213
The on-study bempegaldesleukin (NKTR-214) and avelumab doublet DLT data was also 
utilized in the assessment of starting dose and data scenarios of Combination B via a 
direct down-weighting approach, assuming a moderate heterogeneity between the 
populations included in this on-trial doublet and Combination B in terms of DLT.  The 
weight was calculated using the down-weighting formula shown above with (σ =2) and (τ 
= 0.25).
The on-study bempegaldesleukin (NKTR-214) and avelumab doublet DLT data was not 
considered in the simulations.
Prior Specifications
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters logሺߙଵሻ, logሺߚଵሻfor talazoparib, 
logሺߙଶሻ, logሺߚଶሻfor bempegaldesleukin (NKTR-214), logሺߙଷሻ, logሺߚଷሻfor avelumab, and 
the interaction parameters ߟൌሺߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷሻ.  A meta-analytic-predictive (MAP) 
approach was used to derive the prior distribution for the single-agent model 
parameters. 
Prior Distribution for the Logistic Parameters for Single Agent Avelumab and 
Bempegaldesleukin (NKTR-214)  
For derivation of the prior distribution of the logistic parameters for single agent avelumab 
and single agent bempegaldesleukin (NKTR-214), refer to Appendix 11.
Single Agent Talazoparib
Dose-DLT data from study PRP-001 (C3441007)60 presented in Table 1 are used to derive 
the prior of the single agent logistic parameters for talazoparib.
Table 1.
Historical Dose Limiting Toxicity data from study NCT01286987
Talazoparib dose (mg 
QD)
Number of Patients
Number of Patients with DLTs
0.025
3
0
0.05
3
0
0.1
3
0
0.2
3
0
0.4
3
0
0.6
6
0
0.9
6
1
1.0
6
0
1.1
6
2
Abbreviations: DLT=dose limiting toxicity; mg=milligrams; QD=once daily.
    
Weakly informative normal priors are assumed for ߤଵ௧and ߤଶ௧, with means corresponding to 
a 50% chance of DLT at talazoparib=1.0 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  Priors for τଵ௧and τଶ௧are assigned such that (1) 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 214
their medians correspond to moderate between trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.
Table 2.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters
Parameter
Prior distribution
ߤଵ௧
N(mean = 0, sd = 2)
ߤଶ௧
N(mean = 0, sd=1)
τଵ௧
log-normal(mean = log(0.25), sd = log(2)/1.96)
τଶ௧
log-normal(mean = log(0.125), sd = log(2)/1.96)
ρ௧
uniform(-1,1)
Abbreviations: N=normally distributed; sd=standard deviation.
Prior Distribution for the Interaction Parameters
Normal priors for the log-odds multipliers ߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷ  are used.    The prior for 
ߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷare specified as percentiles of increase in the odds of DLT due to possible 
interaction in combination therapy at reference doses;
ߟଵଶis normally distributed, with mean 0.095 and standard deviation 0.305 
(corresponds to 10% increase in DLT odds at median and 2.0 fold increase in DLTs at 
97.5th percentile)
ߟଵଷis normally distributed, with mean 0.095 and standard deviation 0.305 
(corresponds to 10% increase in DLT odds at median and 2.0 fold increase in DLTs at 
97.5th percentile)
ߟଶଷis normally distributed, with mean 0 and standard deviation 0.561 (corresponds to 
no increase in DLT odds at median and 3.0 fold increase in DLTs at 97.5th percentile)
ߟଵଶଷis normally distributed, with mean 0 and standard deviation 0.093 (corresponds 
to no increase in DLT odds at median and 1.20 fold increase in DLTs at 97.5th
percentile).
Summary of Prior Distributions 
The prior distributions of the model parameters are provided in Table 3.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 215
Table 3.
Prior Distribution for the Model Parameters
Parameter
Mean
Standard deviations
Correlation
Talazoparib single agent parameters: BVN MAP  Prior 
൫logሺߙଵሻ, logሺߚଵሻ൯
-1.770, 0.651
0.720, 0.890
0.188
Bempegaldesleukin (NKTR-214) single agent parameters: BVN MAP Prior
൫logሺߙଶሻ, logሺߚଶሻ൯
-2.612, 0.946
0.932, 1.153
0.056
Avelumab single agent parameters: BVN MAP Prior
൫logሺߙଷሻ, logሺߚଷሻ൯
-2.672, -0.047  
0.972, 0.822
-0.233
Interaction parameters: Normal prior
ߟଵଶ
0.095
0.305
ߟଵଷ
0.095
0.305
ߟଶଷ
0
0.561
ߟଵଶଷ
0
0.093
ߟଵଶ: Two-way interaction between talazoparib and bempegaldesleukin (NKTR-214);
ߟଵଷ: Two-way interaction between avelumab and talazoparib;
ߟଶଷ: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab;
ߟଵଶଷ: Three-way interaction between avelumab, bempegaldesleukin (NKTR-214) and talazoparib.
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive.
From Table 4, in absence of the B9991025 avelumab + talazoparib doublet data and the on-
trial avelumab + bempegaldesleukin (NKTR-214) data, avelumab= 10 mg/kg, 
bempegaldesleukin (NKTR-214) = 0.003 mg/kg and talazoparib= 0.75 mg or talazoparib= 
0.50 mg are acceptable starting doses for Combination B.  However, the final starting dose 
for Combination B will be determined after the dose-DLT data for the on-trial doublet is 
available.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 216
Table 4.
Summary of Prior Distribution of DLT Rates for the Triplet Combination of Avelumab 10 
mg/kg) in Combination with Bempegaldesleukin (NKTR-214) and Talazoparib
NKTR 
dose 
(mg/kg 
Q2W)
Tala 
dose 
(mg 
QD)
Prior probabilities that DLT rate is in 
the interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
0.003
0.5
0.547
0.359
0.094
0.173
0.111
0.031
0.148
0.454
0.003
0.75
0.379
0.450
0.171
0.218
0.123
0.049
0.194
0.520
0.003
1.0
0.187
0.457
0.356
0.294
0.145
0.078
0.271
0.627
0.006
0.5
0.344
0.403
0.253
0.246
0.151
0.045
0.214
0.617
0.006
0.75
0.243
0.400
0.357
0.292
0.165
0.058
0.262
0.677
0.006
1.0
0.139
0.341
0.521
0.364
0.185
0.079
0.341
0.761
Avelumab dose fixed at 10 mg/kg every 2 weeks. 
Abbreviations: mg=milligrams; mg/kg=milligrams per kilogram; Q2W= Every 2 weeks; NKTR=
bempegaldesleukin (NKTR-214); QD=once daily; SD=Standard Deviation; Tala=Talazoparib
Hypothetical on-Study Data Scenarios
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next group 
of participants is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future participants, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data.
Table 5 shows the plausible starting dose level(s) for Combination B given hypothetical data 
from the on-study bempegaldesleukin (NKTR-214) and avelumab doublet (Combination A).  
If the dose-DLT profile of Combination A is safe at avelumab= 10 mg/kg, 
bempegaldesleukin (NKTR-214) = 0.006 mg/kg (Scenario 1), triplet dose escalation can 
begin at avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg and talazoparib= 
0.75 mg, or avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.003 mg and 
talazoparib= 1.0 mg.  If 2 participants with DLT observed out of 12 DLT-evaluable 
participants at avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg, the 
starting dose can be avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg 
and talazoparib= 0.5 mg (Scenario 2) or avelumab= 10 mg/kg, bempegaldesleukin (NKTR-
214) = 0.003 mg/kg and talazoparib= 0.75 mg. All other scenarios (3, 4, and 5) are plausible 
starting doses for Combination B.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 217
Table 5.
Combination B: Clinically Meaningful Starting Dose Given Hypothetical 
Data from the Doublet Combination, and the Interval Probability of Target 
Toxicity and Overdosing at Starting Dose.
Doublet Dose 
D/N*
Triplet starting dose (SD) 
Pr(TT) at 
SD
Pr(OD) 
at SD
Scenario
Ave 
(mg/kg 
Q2W)
NKTR
(mg/kg 
Q2W)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
NKTR(
mg/kg 
Q2W)
Tala
(mg 
QD)
1
(10)
0.006
-
0/9
(10)
(10)
0.006
0.003
0.75
1.0
0.443
0.553
0.137
0.196
2
(10)
0.006
-
2/12
(10)
(10)
0.006
0.003
0.50
0.75
0.517
0.534
0.175
0.107
3
(10)
0.006
-
3/12
(10)
0.003
0.75
0.567
0.160
4
(10)
(10)
0.006
0.003
-
2/4
1/12
(10)
0.003
0.75
0.569
0.155
5
(10)
(10)
0.006
0.003
-
2/4
3/12
(10)
0.003
0.50
0.607
0.187
Abbreviations: Ave=avelumab;  NKTR= bempegaldesleukin (NKTR-214); *D=number of participants with 
DLT; N=number of DLT-evaluable participants; mg=milligrams; mg/kg=milligrams per kilogram; ND=next 
dose; Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Tala= Talazoparib; QD=once 
daily; Q2W=every 2 weeks.
Table 6 shows data scenarios for Combination B and the corresponding recommendations for 
the next dose.  The recommended next dose is adequate for all considered scenarios.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 218
Table 6.
Combination B: Data Scenarios (Given Hypothetical Doublet Data), Next 
Dose Recommendation, and the Interval Probability of Target Toxicity and 
Overdosing at Next Dose.
Dose evaluated 
D/N*
Next Dose (ND)
Pr(TT) 
at ND
Pr(OD) at 
ND
Scenarios
Ave 
(mg/kg 
Q2W)
NKTR
(mg/kg 
Q2W)
Tala
(mg 
QD)
Ave 
(mg/kg 
Q2W)
NKTR
(mg/kg 
Q2W)
Tala
(mg 
QD)
1
(10)
0.006
-
0/9
(10)
0.006
1.0
0.477
0.190
(10)
0.006
0.75
0/3
2
(10)
0.006
-
0/9
(10)
0.006
0.75
0.527
0.171
(10)
0.006
0.75
1/3
3
(10)
0.006
-
0/9
(10)
0.006
0.50
0.554
0.189
(10)
0.006
0.75
2/3
(10)
0.003
0.75
0.601
0.150
4
(10)
0.006
-
0/9
(10)
0.003
0.50
0.564
0.111
(10)
0.006
0.75
3/3
5
(10)
0.006
-
3/12
(10)
0.006
0.50
0.553
0.197
(10)
0.003
0.75
0/3
(10)
0.003
0.75
0.530
0.075
6
(10)
0.006
-
3/12
(10)
0.003
0.75
0.617
0.186
(10)
0.003
0.75
1/3
7
(10)
0.006
-
3/12
(10)
0.003
0.50
0.618
0.177
(10)
0.003
0.75
2/3
Abbreviations: Ave=avelumab; NKTR= bempegaldesleukin (NKTR-214); *D=number of participants with 
DLT; N=number of DLT-evaluable participants; mg=milligrams; mg/kg=milligrams per kilogram; ND=next 
dose Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; QD=once daily; Q2W=every 2 
weeks; Tala=Talazoparib.   
Operating Characteristics 
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated and each scenario 1000 trials were 
simulated, with results summarized below.
Simulation Scenarios 
Several scenarios are considered for Combination B (Table 7).  Scenario 1 represents the 
case when the distribution of DLT coincides with prior, ie, the true DLT probability equals to 
mean of prior DLT.  Scenario 2 represents an increased DLT rate compared to Scenario 1.  
Scenario 3 represents a true toxicity profile with dose combinations in both under-dose and 
over-dose regions.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 219
Table 7.
Combination B: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab 
Dose 10 mg/kg Every 2 Weeks)
NKTR-214 
(mg/kg Q2W)
Talazoparib (mg QD)
0.5
0.75
1.0
0.5
0.75
1.0
Scenario 1. prior means
Scenario 2. 50% more toxic
0.003
0.173
0.218
0.294
0.259
0.327
0.441
0.006
0.246
0.292
0.364
0.370
0.438
0.545
Scenario 3. With under dose and 
overdose
0.003
0.10
0.20
0.45
0.006
0.15
0.30
0.55
Abbreviations:  mg/kg=milligrams per kilogram; QD=once daily; 
Q2W=every 2 weeks.
Simulation Details 
Simulations were performed using R version 3.5.3 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the Markov Chain Monte Carlo 
(MCMC) analyses. 
For each scenario, data for 1000 trials were generated, with a cohort size of 3-6.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria.
A simulation of Combination B is performed using the starting dose of avelumab 10 mg/kg, 
bempegaldesleukin (NKTR-214) 0.003 mg/kg, and talazoparib 0.5 mg.  B9991025 doublet 
data is considered in this exercise.  The maximum number of participants per trial was set to 
60.  Each trial was stopped when the following criteria were met:
•
At least 6 participants have been treated at the recommended MTD ݀ሚ. 
•
The dose ݀ሚsatisfies one of the following conditions:
•
The probability of target toxicity at dose ݀ሚexceeds 50%, 
ie, Pr(0.16 ≤ߨௗ෨<0.33)≥50%;
•
A minimum of 15 participants have been treated in the trial.
The following metrics were assessed in the simulations:
•
Percentage of participants receiving dose combination(s) in the target toxicity interval; 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 220

Percentage of participants receiving an overdose;

Percentage of participants receiving an under dose;

Probability that recommended MTD at the end of the trial is in the target toxicity 
interval;

Probability that recommended MTD is an overdose;

Probability that recommended MTD is an under dose;

Percentage of trials stopped without MTD declaration;

Average sample size.
Simulation Results 
Operating characteristics for Combination B are presented in Table 8.  The percentage of 
trials with a correctly identified MTD ranges from 61.2% to 95.1%.  The percentage of 
participants treated at overly toxic doses is well controlled.  The average sample size is 
between 10 to 14 participants.
Table 8.
Combination B: Operating Characteristics
Scenarios 
Participant allocation 
(%)
% declare MTD
% stop (no 
MTD)
Average 
sample size
TT
OD
UD
TT
OD
UD
1.
Prior means
100
0
0
95.1
0
0
4.9
13
2.
50% more toxic
91.6
8.4
0
89.5
0
0
10.5
10
3.
With under dose 
and overdose
46.4
6.0
47.6
61.2
0
37.3
1.5
14
Abbreviations: MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; UD=under dose.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 221
10.13. Appendix 13: BLRM Design for Enzalutamide Triplet – Combination C
This appendix provides the details of the statistical model, the derivation of prior 
distributions from historical data, the results of the Bayesian analyses and respective dosing 
decisions for some hypothetical data scenarios, and a simulation study of the operating 
characteristics of the model for the avelumab +bempegaldesleukin (NKTR-214) + 
enzalutamide treatment combination (Combination C).
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 
800 mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose.
Statistical Model
The statistical model for Combination C dose-DLT data comprises single-agent toxicity 
parts, which allow the incorporation of single-agent toxicity data, and interaction parts.
Single Agent Parts 
Let ߨଵሺ݀ଵሻbe the risk of DLT for enzalutamide given as a single agent at dose ݀ଵ; ߨଶሺ݀ଶሻbe 
the risk of DLT for bempegaldesleukin (NKTR-214) given as a single agent at dose ݀ଶ; and 
ߨଷሺ݀ଷሻbe the risk of DLT for avelumab given as a single agent at dose ݀ଷ.  These single 
agent dose-DLT models are logistic:
Enzalutamide:
  logit൫ߨଵሺ݀ଵሻ൯ൌlogሺߙଵሻ൅ߚଵlogሺ݀ଵ݀ଵ
∗
⁄
ሻ
Bempegaldesleukin (NKTR-214):   
logit൫ߨଶሺ݀ଶሻ൯ൌlogሺߙଶሻ൅ߚଶlogሺ݀ଶ݀ଶ
∗
⁄
ሻ
Avelumab:
logit൫ߨଷሺ݀ଷሻ൯ൌlogሺߙଷሻ൅ߚଷlogሺ݀ଷ݀ଷ
∗
⁄
ሻ
where ݀ଵ
∗=160 mg, ݀ଶ
∗=0.006 mg/kg, and ݀ଷ
∗ൌ10 mg/kg are used to scale the doses of 
enzalutamide, bempegaldesleukin (NKTR-214), and avelumab, respectively.  Hence, ߙଵ, ߙଶ, 
and ߙଷ(all >0) are the single-agent odds of a DLT at ݀ଵ
∗mg, ݀ଶ
∗mg/kg, and ݀ଷ
∗mg/kg, 
respectively; and  ߚଵ, ߚଶ, and ߚଷ( all>0) are the increase in the log-odds of a DLT by a unit 
increase in log-dose.
Interaction Parts
Under an assumption that there is no interaction, the risk of a DLT at dose ݀ଵof avelumab, 
dose ݀ଶof bempegaldesleukin (NKTR-214), and dose ݀ଷof enzalutamide is:
ߨଵଶଷ
଴ሺ݀ଵ, ݀ଶ, ݀ଷሻൌ1 െ൫1 െߨଵሺ݀ଵሻ൯൫1 െߨଶሺ݀ଶሻ൯൫1 െߨଷሺ݀ଷሻ൯
To model the interaction between avelumab, bempegaldesleukin (NKTR-214), and 
enzalutamide, the following four odds multipliers are introduced.
•
ߟଵଶ: Two-way interaction between enzalutamide and bempegaldesleukin (NKTR-
214)  


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 222
•
ߟଵଷ: Two-way interaction between enzalutamide and avelumab
•
ߟଶଷ: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab
•
ߟଵଶଷ: Three-way interaction between avelumab, bempegaldesleukin (NKTR-214) and 
enzalutamide
The risk of DLT for combination dose ሺ݀ଵ, ݀ଶ, ݀ଷሻis then given by:
odds൫ߨଵଶଷሺ݀ଵ, ݀ଶ, ݀ଷሻ൯ൌ݃ሺߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷሻൈodds൫ߨଵଶଷ
଴ሺ݀ଵ, ݀ଶ, ݀ଷሻ൯
݃ሺߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷሻൌexpሺߟଵଶൈ݀ଵ݀ଵ
∗
⁄
ൈ݀ଶ݀ଶ
∗
⁄
ሻ
                                                                ൈexp ሺߟଵଷൈ݀ଵ݀ଵ
∗
⁄
ൈ݀ଷ݀ଷ
∗ሻ
⁄
                                                                ൈexp ሺߟଶଷൈ݀ଶ݀ଶ
∗
⁄
ൈ݀ଷ݀ଷ
∗ሻ
⁄
                                                              ൈexp ሺߟଵଶଷൈ݀ଵ݀ଵ
∗
⁄
ൈ݀ଶ݀ଶ
∗
⁄
ൈ݀ଷ݀ଷ
∗
⁄
ሻ
where oddsሺߨሻൌߨሺ1 െߨሻ
⁄
; ߟ௜௝is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j and a zero dose of the third drug.  For 
example, ߟଶଷis the log-odds ratio between the interaction and no interaction model at 
avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg, and enzalutamide=0 
mg.  Therefore, ߟଵଶ൅ߟଵଷ൅ߟଶଷ൅ߟଵଶଷis the log-odds ratio between the interaction and no 
interaction model at the reference doses for all three drugs.  Here ߟൌ0 corresponds to no 
interaction, with ߟ൐0 and ߟ൏0 representing synergistic and antagonistic toxicity 
respectively.
Inclusion of the Doublet Data
The addition of the DLT information from the doublet dose escalation of avelumab and 
bempegaldesleukin (NKTR-214) was included in the assessment of starting dose and data 
scenario of Combination C using a direct down-weighting approach (for details, please refer 
to Appendix 12).  
Prior Specifications
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters logሺߙଵሻ, logሺߚଵሻfor enzalutamide, 
logሺߙଶሻ, logሺߚଶሻfor bempegaldesleukin (NKTR-214), logሺߙଷሻ, logሺߚଷሻfor avelumab, and 
the interaction parameters ߟൌሺߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷሻ.  A meta-analytic-predictive (MAP) 
approach was used to derive the prior distribution for the single-agent model 
parameters. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 223
Prior Distribution for the Logistic Parameters for Single Agent Avelumab and 
Bempegaldesleukin (NKTR-214)  
For information regarding the prior distribution of the logistic parameters for single agent 
avelumab and single agent bempegaldesleukin (NKTR-214), refer to Appendix 11.
Single Agent Enzalutamide
Dose-DLT data from Study S-3100-1-01 (for ENZA) presented in Table 1 are used to derive 
the prior of the single agent logistic parameters for enzalutamide.61
Table 1.
Historical Dose Limiting Toxicity data from Study S-3100-1-01
Enzalutamide dose (mg)
Number of patients
Number of patients with DLTs
30
3
0
60
27
0
150
28
0
240
29
0
360
28
1
480
22
1
600
3
2
Abbreviations: DLT=dose limiting toxicity; mg=milligram.
Weakly informative normal priors are assumed for ߤଵ௘and ߤଶ௘, with means corresponding to 
a 50% chance of DLT at enzalutamide=160 mg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for τଵ௘and τଶ௘are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations.
Table 2.
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Enzalutamide Model Parameters
Parameter
Prior distribution
ߤଵ௘
N(mean = 0, sd = 2)
ߤଶ௘
N(mean = 0, sd =1 )
τଵ௘
log-normal(mean = log(0.25), sd = log(2)/1.96)
τଶ௘
log-normal(mean = log(0.125), sd = log(2)/1.96)
ρ௘
uniform(-1,1)
Abbreviations: N=normally distributed; sd=standard deviation.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 224
Prior Distribution for the Interaction Parameters
Normal priors for the log-odds multipliers ߟଵଶ, ߟଵଷ, ߟଶଷ, ߟଵଶଷ  are used.    The priors for 
ࣁ૚૛, ࣁ૚૜, ࣁ૛૜, ࣁ૚૛૜are specified as percentiles of increase in the odds of DLT due to possible 
interaction in combination therapy at reference doses;
ߟଵଶis normally distributed, with mean 0.095 and standard deviation 0.519 (corresponds to 
10% increase in DLT odds at median and 3.0-fold increase in DLTs at 97.5th percentile).
ߟଵଷis normally distributed, with mean 0.095 and standard deviation 0.519 (corresponds to 
10% increase in DLT odds at median and 3.0-fold increase in DLTs at 97.5th percentile).
ߟଶଷis normally distributed, with mean 0 and standard deviation 0.561 (corresponds to no 
increase in DLT odds at median and 3.0-fold increase in DLTs at 97.5th percentile).
ߟଵଶଷis normally distributed, with mean 0 and standard deviation 0.354 (corresponds to no 
increase in DLT odds at median and 2.0-fold increase in DLTs at 97.5th percentile).
Summary of Prior Distributions 
The prior distributions of the model parameters provided in Table 3.  
Table 3.
Prior Distribution for the Model Parameters
Parameter
Mean
Standard deviations
Correlation
Enzalutamide single agent parameters: BVN MAP  Prior 
൫logሺߙଵሻ, logሺߚଵሻ൯
-4.299, 0.359
0.917, 0.657
-0.619
Bempegaldesleukin (NKTR-214)  single agent parameters: BVN MAP Prior
൫logሺߙଶሻ, logሺߚଶሻ൯
-2.612, 0.946
0.932, 1.153
0.056
Avelumab single agent parameters: BVN MAP Prior
൫logሺߙଷሻ, logሺߚଷሻ൯
-2.672,-0.047
0.972, 0.822
-0.233
Interaction parameters: Normal prior
ߟଵଶ
0.095
0.519
ߟଵଷ
0.095
0.519
ߟଶଷ
0
0.561
ߟଵଶଷ
0
0.354
ߟଵଶ: Two-way interaction between Enzalutamide and bempegaldesleukin (NKTR-214);
ߟଵଷ: Two-way interaction between avelumab and enzalutamide;
ߟଶଷ: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab;
ߟଵଶଷ: Three-way interaction between avelumab, bempegaldesleukin (NKTR-214) and enzalutamide.
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive.
From Table 4, in absence of avelumab + bempegaldesleukin (NKTR-214) doublet data, all 6 
but the highest potential dose levels of Combination C are acceptable starting doses.  
However, the final starting dose for this triplet will be determined after the dose-DLT data 
for the avelumab + bempegaldesleukin (NKTR-214) doublet is available. 


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 225
Table 4
Summary of Prior Distribution of DLT Rates for the Triplet Combination of
Enzalutamide in Combination with Bempegaldesleukin (NKTR-214) and 
Avelumab (Combination C)
NKTR 
dose 
(mg/kg 
Q2W)
Enza dose 
(mg once 
daily)
Prior probabilities that DLT 
rate is in the interval:
Mean
SD
Quantiles
[0, 
0.16)
[0.16, 
0.33)
[0.33,1]
2.5%
50%
97.5%
0.003
80
0.705
0.237
0.058
0.134
0.105
0.019
0.104
0.417
0.003
120
0.665
0.257
0.078
0.146
0.116
0.020
0.113
0.458
0.003
160
0.620
0.273
0.107
0.161
0.130
0.019
0.123
0.511
0.006
80
0.461
0.345
0.194
0.213
0.152
0.030
0.173
0.602
0.006
120
0.434
0.329
0.237
0.230
0.169
0.028
0.185
0.660
0.006
160
0.412
0.305
0.283
0.250
0.191
0.024
0.199
0.724
Avelumab dose fixed at 10 mg/kg every 2 weeks. 
Abbreviations: DLT=dose-limiting toxicity; mg/kg=milligrams per kilogram; Q2W=twice a week; 
NKTR=Bempegaldesleukin (NKTR-214); SD=Standard Deviation; Enza=Enzalutamide
Hypothetical on-Study Data Scenarios
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose(s) that can be used in the next 
cohort of participants is shown.  These recommended doses are determined using the model-
based assessment of the risk of DLT in future participants, EWOC criteria and maximum 
amount of escalation allows (100% of current dose).  In practice, the dose recommended by 
the adaptive Bayesian logistic model may be regarded as guidance.  The final 
recommendation will be based on overall safety profile, PK data and other relevant evidence.
Table 5 shows the plausible starting dose level(s) for Combination C given hypothetical data 
in the doublet combination.  If the dose-DLT profile of the doublet is safe at avelumab = 10
mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg (Scenario 1 ), triplet dose escalation 
can begin at avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg and 
enzalutamide = 160 mg.  If moderate DLT is observed in the dual combination (3participants 
with DLT out of 12 DLT-evaluable participants at avelumab = 10 mg/kg, bempegaldesleukin 
(NKTR-214) = 0.006 mg/kg, Scenario 3), the starting dose can be avelumab = 10 mg/kg, 
bempegaldesleukin (NKTR-214) = 0.006 mg/kg and enzalutamide = 80 mg, or avelumab = 
10 mg/kg, bempegaldesleukin (NKTR-214) = 0.003 mg/kg and enzalutamide = 160 mg.  
Scenarios 4 and 5 also show plausible starting triplet dose levels.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 226
Table 5.
Combination C: Clinically Meaningful Starting Dose Given 
Hypothetical Data from the Doublet Combination, and the 
Interval Probability of Target Toxicity and Overdosing at 
Starting Dose.
Doublet Dose
D/N*
Triplet Starting Dose 
(SD)
Pr(TT) at 
ND
Pr (OD) at 
ND
Scenarios
Ave 
mg/kg 
(Q2W)
NKTR 
mg/kg 
(Q2W)
Enza 
(mg 
QD)
Ave 
mg/kg 
(Q2W)
NKTR 
mg/kg 
(Q2W)
Enza 
(mg 
QD)
1
(10)
0.006
-
0/9
(10) 
(10)
0.006
0.006
160
120
0.268
0.262
0.118
0.071
2
(10)
0.006
-
2/12
(10)
0.006
120
0.393
0.188
3
(10)
0.006
-
3/12
(10) 
(10)
0.006
0.003 
80
160 
0.479
0.340 
0.222
0.119
4
(10)
(10)
0.006
0.003
-
2/4
1/12
(10) 
0.003
160
0.343
0.105
5
(10)
(10)
0.006
0.003
-
2/4
3/12
(10) 
(10)
0.003
0.003
120
80
0.475
0.507
0.195
0.145
Abbreviations: Ave=avelumab; NKTR=Bempegaldesleukin (NKTR-214); *D=number of participants 
with DLT, N=number of DLT-evaluable participants; mg=milligram; mg/kg=milligram per kilogram; 
ND=next dose; Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Enza= 
Enzalutamide; Q2W=every 2 weeks; QD=once daily.
Table 6 shows data scenarios for Combination C and the corresponding recommendations for 
the next dose.  The recommended next doses are adequate for all considered scenarios 
(Scenarios 1-7).


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 227
Table 6.
Combination C: Data Scenarios (Given Hypothetical Doublet Data), Next 
Dose Recommendation, and the Interval Probability of Target Toxicity and 
Overdosing at Next Dose.
Dose evaluated 
D/N*
Next Dose (ND)
Pr(TT) 
at ND
Pr(OD) 
at ND
Scenarios
Ave
(mg/kg 
Q2W)
NKTR 
(mg/kg 
Q2W)
Enza
(mg 
once 
daily)
Ave
(mg/kg 
Q2W)
NKTR 
(mg/kg 
Q2W)
Enza
(mg 
once 
daily)
1
(10)
(10)
0.006
0.006
-
120
0/9
0/3
(10)
0.006
160
0.213
0.047
2
(10)
(10)
0.006
0.006
-
120
0/9
1/3
(10)
(10)
0.006
0.006
160
120
0.378
0.393
0.186
0.109
3
(10)
(10)
0.006
0.006
-
120
0/9
2/3
(10) 
(10)
0.006
0.003
80
160
0.524
0.414
0.188
0.139
4
(10)
(10)
0.006
0.006
-
120
0/9
3/3
(10)
0.003
120
0.476
0.186
5
(10)
(10)
0.006
0.003
-
120
3/12
0/3
(10)
(10)
0.006
0.006
120
160
0.426
0.374
0.196
0.249
6
(10)
(10)
0.006
0.006
-
120
3/12
1/3
(10)
(10)
0.003
0.003
160
120
0.441
0.453
0.171
0.112
7
(10)
(10)
0.006
0.003
-
120
3/12
2/3
(10)
0.003
80
0.560
0.203
Abbreviations: Ave=avelumab; mg=milligrams; mg/kg=milligrams per kilogram; NKTR=bempegaldesleukin (NKTR-214); 
*D=number of participants with DLT; N=number of DLT-evaluable participants; ND=next dose Pr(TT)=probability of 
target toxicity; Pr(OD)=probability of overdosing; Q2W=every 2 weeks; Enza=enzalutamide.
  
Operating Characteristics 
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated and in each scenario 1000 trials were 
simulated.
Simulation Scenarios 
Several scenarios are considered for Combination C (Table 7).  Scenario 1 represents the 
case when the distribution of DLT coincides with prior, ie, the true DLT probability equals to 
mean of prior DLT.  Scenario 2 represents a 50% increased DLT rate compared to Scenario 
1.  Scenario 3 represents a true toxicity profile with dose combinations in both under-toxicity 
and over-toxicity intervals.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 228
Table 7.
Combination C: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab Dose 
10 mg/kg Every 2 Weeks)
Bempegaldesleukin 
(NKTR-214) (mg/kg 
Q2W)
Enzalutamide (mg once daily)
80
120
160
80
120
160
Scenario 1. prior means
Scenario 2. 50% more toxic
0.003
0.134
0.146
0.161
0.201
0.219
0.241
0.006
0.213
0.230
0.250
0.319
0.345
0.376
Scenario 3. With under  and over  toxicity
0.003
0.10
0.20
0.30
0.006
0.15
0.25
0.40
Abbreviations:  Q2W=every 2 weeks; mg=milligrams; mg/kg=milligrams per 
kilogram.
Simulation Details 
Simulations were performed using R version 3.5.3 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the MCMC analyses. 
For each scenario, data for 1000 trials were generated, with a cohort size of 3-6.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria.
A simulation of the triplet combination is performed using the starting dose of avelumab 
10 mg/kg (fixed), bempegaldesleukin (NKTR-214) 0.003 mg/kg, and enzalutamide 80 mg.  
No doublet combination data is considered in this exercise.  The maximum number of 
participants per trial was set to 60.  Each trial was stopped when the following criteria were 
met:
•
At least 6 participants have been treated at the recommended MTD ݀ሚ.
•
The dose ݀ሚsatisfies one of the following conditions:
•
The probability of target toxicity at dose ݀ሚexceeds 50%, 
ie, Pr(0.16 ≤ߨௗ෨<0.33)≥50%;
•
A minimum of 15 participants have been treated in the trial.
The following metrics were assessed in the simulations:
•
Percentage of participants receiving dose combination(s) in the target toxicity 
interval; 
•
Percentage of participants receiving an overdose;


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 229

Percentage of participants receiving an underdose;

Probability that recommended MTD at the end of the trial is in the target toxicity 
interval;

Probability that recommended MTD is an overdose;

Probability that recommended MTD is an underdose;

Percentage of trials stopped without MTD declaration;

Average sample size.
Simulation Results 
Operating characteristics for Combination C are presented in Table 8.  The percentage of 
trials with a correctly identified MTD ranges from 86.3% to 94.5%.  The percentage of 
participants treated at overly toxic doses is well controlled.  The average sample size for this 
triplet combination is between 11 to 14 participants.
Table 8.
Combination C: Operating Characteristics
Scenarios 
Participant allocation (%)
% declare MTD
% Stop 
(no 
MTD)
Average 
sample 
size
TT
OD
UD
TT
OD
UD
1. Prior means
64.5
0
35.5
89.9
0
3.4
7.0
14
2. 50% more toxic
89.4
10.6
0
86.3
0
0
13.7
11
3.With under dose 
and overdose
46.9
15.4
37.7
94.5
0
1.6
3.9
12
Abbreviations: MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; UD=under dose


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 230
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 231
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 232
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 233
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 234
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 235
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 236
CCI
CCI


PFIZER CONFIDENTIAL
Page 237
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 238
10.17. Appendix 17: Abbreviations
     
ACTH
Adrenocorticotropic Hormone
ADA
Anti-Drug Antibody
ADP
Adenosine Diphosphate
ADT
Androgen-deprived therapy
AE
Adverse Event
AIDS 
Acquired Immune Deficiency Syndrome
ALT 
Alanine Aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
AR
Androgen receptor
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
BCRP
Breast Cancer Resistance Protein
BID
Twice daily
BLRM
Bayesian Logistic Regression Model
BNP
B-type natriuretic peptide
BP
Blood Pressure
BPM
Beats per Minute
BRAF
B-Raf proto-oncogene serine/threonine-protein kinase
BRCA
Breast Cancer Susceptibility Gene
BRCA 1/2
Breast Cancer Susceptibility Gene 1/2
BUN
Blood Urea Nitrogen
BVN
Bivariate Normal 
C1D1
Cycle 1 Day 1


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 239
CAP
College of American Pathologists
CEOI
Concentration at End of Infusion
CFR
Code of Federal Regulations
CI
Confidence Interval
CK
Creatine Kinase
CL
Clearance
CLIA
Clinical Laboratory Improvement Amendments
Cmax
Maximum Plasma Concentration
CPS
Combined Positive Score
CR
Complete Response
CRC
Colorectal Cancer
CRCL
Creatinine Clearance
CRF
Case Report Form
CRO
Contract Research Organization
CRP
C-Reactive Protein
CRPC
Castration Resistant Prostate Cancer
CRU
Clinical Research Unit
CSR
Clinical Study Report
CT
Computed Tomography
CTC
Circulating Tumor Cell
CTCAE 
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte Associated Protein 4
Ctrough
Trough Concentration
CV
Coefficient of Variation
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 240
DCs
Dendritic cells
DCR
Disease Control Rate
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
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDP
Exposure During Pregnancy
 
EOT
End of Treatment
EWOC
Escalation With Overdose Control
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FFPE
Formalin-Fixed Paraffin-Embedded 
FSFV
First Subject First Visit
FSH
Follicle Stimulating Hormone
GCP 
Good Clinical Practice
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 241
GGT
Gamma-Glutamyl Transferase
GnRH
Gonadotropin-Releasing Hormone
GMP
Good Manufacturing Practice
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
H&E
Hematoxylin and Eosin
HER2
Human Epidermal Growth Factor Receptor 2
HIV 
Human Immunodeficiency Virus
HNSCC
Squamous Cell Carcinoma of the Head and Neck
HR 
Heart rate
HRD
Homologous recombination defects
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
ID
Identification
IEC 
Independent Ethics Committee
IERC
Independent Endpoint Review Committee
Ig
Immunoglobulin
IgF
Immunoglobulin F
IgG1
Immunoglobulin G1
IL-2
Interleukin-2
IL-2R
Interleukin-2 receptor beta gamma
IND
Investigational New Drug
INR
International Normalized Ratio
IP
Investigational Product


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 242
irAE
Immune-Related Adverse Event
IRB
Institutional Review Board
IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
IUD
Intra-Uterine Device
IUS
Intra-Uterine System
IV
Intravenous
JAGS
Just Another Gibbs Sampler
K2EDTA
Dipotassium Ethylenediaminetetraacetic Acid
K3EDTA
Tripotassium Ethylenediaminetetraacetic Acid
1L SCCHN
Locally recurrent squamous cell carcinoma of the head and neck
L/A SCCHN
Locally Advanced squamous cell carcinoma of the head and neck
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLQ
Lower Limit of Quantitation
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal Antibody
MAP
Meta-Analytic-Predictive
MCMC
Markov Chain Monte Carlo
mCRPC
Metastatic castration-resistant prostate cancer
MDSC
Myeloid-derived suppressor cells
MedDRA
Medical Dictionary for Regulatory Activities
MFS
Metastatic-free survival
mHSPC
Hormone-sensitive metastatic prostate cancer
MRI 
Magnetic Resonance Imaging


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 243
MSKCC
Memorial Sloan Kettering Cancer Center
MTD
Maximum Tolerated Dose
MUGA
Multigated Acquisition
N/A
Not Applicable
NAb
Neutralizing Antibody
NCI 
National Cancer Institute
NE
Not Evaluable
NHT
Novel hormone therapy
NGS
Next-generation sequencing
NK
Natural Killer
NM CRPC
Non-metastatic castration-resistant prostate cancer
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
NTI
Narrow Therapeutic Index
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PARP
Poly (ADP-Ribose) Polymerase
PARPi
Poly (ADP Ribose) Polymerase inhibitor
PCD
Primary Completion Date
PCWG3
Prostate cancer working group 3
PD
Progressive Disease 
PD-1
Programmed Death Receptor 1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 244
PEG
Polyethylene Glycol
PFS
Progression-Free Survival
P-gp
P-glycoprotein
PK
Pharmacokinetics
PMAP
Pharmacometric analysis plan
PO
Orally
PR
Partial Response
PS
Performance Status
PSA
Prostate-specific antigen
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
QD
Once Daily
RANKL
Nuclear Factor Kappa-B Ligand
RCC
Renal Cell Carcinoma
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
R/M SCCHN
Recurrent/metastatic squamous cell carcinoma of the head and neck
RNA
Ribonucleic Acid
rPFS
Radiographic progression-free survival
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCLC
Small Cell Lung Cancer
SCR
Serum Creatinine


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 245
SD
Stable Disease
SOA
Schedule of Assessments
SOC
Standard of Care
SOPs
Standard Operating Procedures
SRSD
Single Reference Safety Document
STING
Stimulation of Interferon Genes
TBili
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
Tmax
Time to Maximum Plasma Concentration
TNBC
Triple-Negative Breast Cancer
TO
Target Occupancy
TSH
Thyroid Stimulating Hormone
TTPSAP
Time to PSA Progression
TTR
Time-to-Tumor Response
UC
Urothelial Cancer
ULN 
Upper Limit of Normal
US
United States
V/F
Apparent Volume of Distribution
WBC
White Blood Cell
WDC
Withdrawal of Consent
WHO
World Health Organization
     
     
     
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 246
11. REFERENCES   
                                                
1
. 
2
Charych DH, Rubas W, Dixet V et al.  Immune memory in nonclinical models after 
treatment with NKTR-214, an engineered cytokine biased towards expansion of CD8+ 
T-cells in tumors.  J Clin Oncol 2016; 34(15, Suppl):11545.
3
Charych DH, Hoch U, Langowski JL et al. NKTR-214, an Engineered Cytokine with 
Biased IL-2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in 
Mouse Tumor Models. Clin Can Res 2016; 22(3):680-90.
4
 
5
Diab A, Hurwitz M, Cho D, et al. NKTR-214 (CD122-biased agonist) plus nivolumab in 
patients with advanced solid tumors: Preliminary Phase 1/2 results of PIVOT.   In: 
Society for Immunotherapy of Cancer annual meeting; 10-12 Nov 2017; National 
Harbor, MD. 2017.  
6
Siefker-Radtke A.  Clincal data presented from PIVOT-02 study of bempegaldesleukin 
(NKTR-214) with nivolumab in metastatic urothelial carcinoma patients at the 2019 
ASCO genitourinary cancers symposium.  In: ASCO Annual meeting, February 15, 
2019, San Francisco, CA. Available upon request.
7
Burness B, Harrington KJ, Greil R et al. KEYNOTE-048: Phase III study of first-line 
pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma 
(R/M HNSCC). Ann Oncol 2018; 29(8):viii729.
8
Vitkin N, Nersesian S, Siemens DR, et al. The tumor immune contexture of prostate 
cancer. Front Immunol 28 March 2019 doi.org/10.3389/fimmu.2019.00603.  Available 
upon request.
9
Murai J, Huang SY, Renaud A, et al. Stereospecific PARP trapping by BMN 673 and 
comparison with olaparib and rucaparib. Mol Cancer Ther 2014; 13(2):433-43.
10
FDA approves Talazoparib for gBRCAm HER2-negative locally advanced or metastatic 
breast cancer.  Available: 
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm623540.htm 
Access date: April 15, 2019.
11
Mateo J, Carreira S, Sandhu S, et al. DNA repair defects and olaparib in metastatic 
prostate cancer. N Engl J Med. 2015; 373(18):1697-708.
12
Abida W, Bryce AH, Vogelzang NJ. Preliminary Results from TRITON2: A Phase 2 
Study of Rucaparib in Patients with Metastatic Castration-Resistant Prostate Cancer 
CCI
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 247
(mCRPC) Associated with Homologous Recombination Repair (HRR) Gene Alterations.  
Ann Oncol 2018; 29(Suppl 8):viii272.
13
Karzai F, Madan RA, Owens H et al. A Phase 2 study of olaparib and durvalumab in 
metastatic castrate-resistant prostate cancer (mCRPC) in an unselected population.  In: 
ASCO 2018 Genitourinary Cancers Symposium; 8-10 Feb 2018; San Francisco, CA. 
2018: Abstr 163.  Available upon request.
14
Yu EY, Massard C, Retz M et al. KEYNOTE-365 Cohort A: Pembrolizumab (Pembro) 
plus Olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant 
prostate cancer (mCRPC).  In: ASCO GU annual meeting; 14-16 Feb 2019; San 
Francisco, CA. 2019: Abstr 145.  Available upon request.
15
Hartlova A, Erttmann SF, Raffi FA, et al. DNA damage primes the type I interferon 
system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. 
Immunity 2015; 42(2):332-43.
16
Parkes EE, Walker SM, Taggart LE, et al. Activation of STING-dependent innate 
immune signaling by S-phase-specific DNA damage in breast cancer. J Natl Cancer Inst 
2017; 109(1):djw199.
17
Huang J, Wang L, Cong Z, et al. The PARP1 inhibitor BMN 673 exhibits 
immunoregulatory effects in a BRCA1(-/-) murine model of ovarian cancer. Biochem 
Biophys Res Commun 2015; 463(4):551-6.
18
Jiao S, Xia W, Yamaguchi H, et al. PARP Inhibitor Upregulates PD-L1 Expression and 
Enhances Cancer-Associated Immunosuppression. Clin Cancer Res 2017; 23(14):3711-
20.
19
Madan RA, Donahue RN, Singh H et al. Clinical and immunologic impact of short 
course enzalutamide without androgen deprivation therapy for biochemically recurrent 
prostate cancer. J Clin Oncol 2016; 334(Suppl):Abstr 214.  Available upon request.
20
Bishop JL, Sio A Angeles A, et al. PD-L1 is highly expressed in Enzalutamide resistant 
prostate cancer. Oncotarget 2015; 6(1):234-42.
21
Graff JN, Alumkal JJ, Thompson RF et al. Pembrolizumab (Pembro) plus Enzalutamide 
(Enz) in metastatic castration resistant prostate cancer (mCRPC): extended follow-up.  J 
Clin Oncol 2018; 36(15 Suppl):5047.  Available upon request.
22
Fong PCC, Retz M, Drakaki A et al. Keynote-365 cohort C: Pembrolizumab (pembro) 
plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic 
castrate resistant prostate cancer (mCRPC).  In: 2019 ASCO GU Annual Meeting, 
February 14, 2019, San Francisco, CA; abstract 171.
23
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality 
patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013; 49(6):1374-
403.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 248
24
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: 
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 
136(5):E359-86.
25
Gregoire V, Lefebvre J-L, Licitra L, et al. EHNS-ESMO-ESTRO Guidelines Working 
Group.  Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical 
Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol 2010; 21(Suppl 
5):v184-6.
26
NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. Version 
2.2013 ed. National Comprehensive Cancer Network, Inc.; 2019. Available: 
http:///www.nccn.org. Accessed April 16, 2019.
27
Seiwert TY, Salama JK, Vokes EV.  The chemoradiation paradigm in head and neck 
cancer.  Nature Clin Prac Oncol 2007; 4(3):156-71.
28
Espeli V, Zucca E, Ghielmini M, et al.  Weekly and 3-weekly cisplatin concurrent with 
intensity-modulated radiotherapy in locally advanced head and neck squamous cell 
cancer.  Oral Oncol 2012; 48(3):266-71.
29
Ang KK, Zhang Q, Rosenthal, DI, et al. Randomized Phase III trial of concurrent 
accelerated radiation plus cisplatin with or without cetuximab for stage III and IV head 
and neck carcinoma: RTOG 0522. J Clin Oncol 2014; 32(27):2940-50.
30
American Cancer Society. Cancer Facts & Figures 2019. Available at: 
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-
statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf. 
Accessed on June 20, 2019.
31
Scher HI, Solo K, Valant J, et al. Prevalence of prostate cancer clinical states and 
mortality in the United States: estimates using a dynamic progression model. PLoS One 
2015; 10(10):e0139440-e0139440.
32
Dai C, Heemers H, Sharifi N. Androgen signaling in prostate cancer. Cold Spring Harb 
Perspect Med 2017;7(9):a030452.
33
Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-
resistant prostate cancer. N Engl J Med 2018; 378(26):2465-74.
34
Smith MR, Saad F, Chowdhury S et al. Apalutamide Treatment and Metastasis-free 
Survival in Prostate Cancer. N Engl J Med 2018; 378(15):1408-18.
35
Gibson BA, Kraus WL. New insights into the molecular and cellular functions of 
poly(ADP ribose) and PARPs. Nat Rev Mol Cell Biol. 2012; 13(7):411-24.
36
Schreiber V, Amé JC, Dollé P, et al. Poly(ADP ribose) polymerase 2 (PARP-2) is 
required for efficient base excision DNA repair in association with PARP-1 and 
XRCC1. J Biol Chem 2002; 277(25):23028-36.


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 249
37
Amé JC, Rolli V, Schreiber V, et al. PARP 2, A novel mammalian DNA damage 
dependent poly(ADP ribose) polymerase. J Biol Chem 1999; 274(25):17860-8.
38
Hopkins TA, Shi Y, Rodriguez LE, et al. Mechanistic dissection of PARP1 trapping and 
the impact on in vivo tolerability and efficacy of PARP inhibitors. Mol Cancer Res 
2015; 13(11):1465-77.
39
Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high 
grade serous or poorly differentiated ovarian carcinoma or triple negative breast cancer: 
a phase 2, multicentre, open label, non randomised study. Lancet Oncol 2011; 
12(9):852-61.
40
Ji Y, Wang SJ. 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):1785-91.
41
Turner NC, Telli ML, Rugo HS, et al. Final results of a phase 2 study of talazoparib 
(TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer 
patients (pts) with germline BRCA1/2 mutations (ABRAZO). J Clin Oncol 2017; 
15(Suppl):Abstr 1007.
42
Litton JK, Rugo HS, Ettl J, et al.  A Phase 3 trial comparing talazoparib, an oral PARP 
inhibitor, to physician’s choice of therapy in patients with advanced breast cancer and a 
germline BRCA-mutation.  In: 2017 San Antonio Breast Cancer Symposium; 5-9 Dec 
2017; San Antonio, TX. 2017: Abstr GS6-07.  Available upon request.
43
.
44
Investigator’s Brochure, Enzalutamide (MDV3100). Medivation/Pfizer, 18 June 2018.
45
Litton JK, Rugo HS, Ettl J et al.  Talazoparib in patients with advanced breast cancer 
and a germline BRCA mutation. N Engl J Med 2018; 379(8):753-63.
46
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):1098.
47
Sheng J, Srivastava S, Sanghavi K et al. Clinical pharmacy considerations for the 
development of immune checkpoint inhibitors. J Clin Pharm 2017; 57(S10):S26-S42.
48
Elias AW, Kasi PM, Stauffer JA, et al.  The feasibility and safety of surgery in patients 
receiving immune checkpoint inhibitors:  a retrospective study.  Front Oncol 2017; 
7:121.
49
Gyorki DE, Yuan J, Mu Z, et al. Immunological insights from patients undergoing 
surgery on ipilimumab for metastatic melanoma.  Ann Surg Oncol 2013; 20(9):3106-11.
CCI


Avelumab, Bempegaldesleukin (NKTR-214), Talazoparib, and Enzalutamide
B9991040
Final Protocol,  Amendment 1 27-JUN-2019
PFIZER CONFIDENTIAL
Page 250
50
Khan MM. Immunosuppressive Agents.  In: Immunopharmacology. New York: 
Springer; 2008: p. 87-105.
51
Schleimer RP, Jacques A, Shin HS, et al.  Inhibition of T cell-mediated cytotoxicity by 
anti-inflammatory steroids.  J Immunol 1984; 132(1):266-71.  
52
Weber JS, Kahler KC, Hauschild A.  Management of immune-related adverse events 
and kinetics of response with ipilimumab.  J Clin Oncol 2012; 30(21):2691-97.
53
 
 
54
 
 
55
 
 
56
Neuenschwander B, Matano A, Tang Z, et al. A Bayesian Industry Approach to Phase I 
Combination Trials in Oncology.  Statistical Methods in Drug Combination Studies.  
Zhao W and Yang H (eds); Chapman & Hall/CRC; 2014:95-135.
57
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649–55.
58
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228-47.   
59
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; 34(12):1402-18.
60
de Bono J, Ramanathan RK, Mina L. Phase I, Dose-Escalation, Two-Part Trial of the 
PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations 
and Selected Sporadic Cancers. Cancer Discov. 2017;7(6):620-9.
61
Clinical Study Report, S-3100-1-01 (MDV3100/Enzalutamide).  Medivation, Inc. 10-
Feb-2012.
CCI
CCI
CCI

SAP_001.pdf: 
Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 1 
 
 A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of Avelumab in Combination 
with Bempegaldesleukin (NKTR-214) with or without Talazoparib or Enzalutamide in 
Participants with Locally Advanced or Metastatic Solid Tumors  
STATISTICAL ANALYSIS PLAN – B9991040 
 
Compounds:  
MSB0010718C 
NKTR-214 
PF-04998299 
PF-06944076  
 
Compound Name: 
Avelumab  
Bempegaldesleukin (NKTR-214)  
Talazoparib 
Enzalutamide 
 
Version: 
1.0 
Date: 
03-Sep-2019 
 
 
 
 
 
 
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. 
 
 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 2 
TABLE OF CONTENTS 
LIST OF TABLES.............................................................................................................. 6 
LIST OF FIGURES ............................................................................................................ 8 
1. VERSION HISTORY ..................................................................................................... 9 
2. OBJECTIVES, ENDPOINTS AND STUDY DESIGN..................................................... 9 
2.1. Study Objectives, Endpoints, and Estimands ........................................................ 9 
2.2. Study Design .................................................................................................... 13 
3. BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS............................... 14 
3.1. Baseline Variables............................................................................................. 14 
3.1.1. Study drug, study treatment and baseline definitions ............................... 14 
3.1.2. Baseline characteristics.......................................................................... 17 
3.2. Safety Endpoints ............................................................................................... 17 
3.2.1. Adverse events ...................................................................................... 17 
4. ANALYSIS SETS ........................................................................................................ 17 
4.1. Full Analysis Set ............................................................................................... 17 
4.2. Safety Analysis Set ........................................................................................... 17 
4.3. Other Analysis Set ............................................................................................ 18 
4.3.1. DLT-evaluable set ................................................................................. 18 
4.3.2. PK analysis sets..................................................................................... 18 
4.3.3. Biomarker analysis set ........................................................................... 18 
4.3.4. Immunogenicity analysis set .................................................................. 18 
5. GENERAL METHODOLOGY AND CONVENTIONS ................................................ 19 
5.1. Hypotheses and Decision Rules ......................................................................... 19 
5.1.1. Hypotheses and sample size determination ............................................. 19 
5.1.2. Decision rules ....................................................................................... 20 
5.2. General Methods ............................................................................................... 22 
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 ............................... 24 
5.2.4. Definition of study day .......................................................................... 24 
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 ........................................................... 25 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 3 
5.2.8. Standard derivations and reporting conventions ...................................... 25 
5.2.9. Unscheduled visits................................................................................. 26 
5.2.10. Adequate baseline tumor assessment .................................................... 26 
5.2.11. Adequate post-baseline tumor assessment............................................. 26 
5.3. Methods to Manage Missing Data ...................................................................... 26 
5.3.1. Missing data.......................................................................................... 26 
5.3.1.1. Pharmacokinetic concentrations............................................. 27 
5.3.1.2. Pharmacokinetic parameters .................................................. 27 
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 ........................................ 28 
5.3.2.4. Exposure............................................................................... 29 
5.3.3. Imputation rules for date of last contact and efficacy assessments ........... 29 
5.3.3.1. Date of last contact................................................................ 29 
5.3.3.2. Death date............................................................................. 30 
5.3.3.3. Tumor assessments ............................................................... 30 
5.3.3.4. Date of start of new anti-cancer therapy ................................. 30 
6. ANALYSES AND SUMMARIES................................................................................. 32 
6.1. Primary Endpoints............................................................................................. 32 
6.1.1. DLT for Phase 1b .................................................................................. 32 
6.1.1.1. Primary analysis.................................................................... 32 
6.1.2. Objective response as assessed by the Investigator per RECIST v1.1 
in participants with SCCHN ....................................................................... 34 
6.1.2.1. Primary analysis.................................................................... 34 
6.1.3. Soft tissue objective response as assessed by the Investigator per 
RECIST v1.1 and PCWG3 criteria in participants with mCRPC................... 35 
6.1.3.1. Primary analysis.................................................................... 35 
6.1.4. PSA response for participants with mCRPC ........................................... 37 
6.1.4.1. Primary analysis.................................................................... 37 
6.2. Secondary Endpoint(s) ...................................................................................... 38 
6.2.1. Safety endpoints .................................................................................... 38 
6.2.2. Efficacy endpoints ................................................................................. 38 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 4 
6.2.2.1. Tumor shrinkage from baseline.............................................. 38 
6.2.2.2. PSA reduction from baseline ................................................. 38 
6.2.2.3. Disease control ..................................................................... 39 
6.2.2.4. Duration of tumor response ................................................... 39 
6.2.2.5. Duration of PSA response ..................................................... 42 
6.2.2.6. Time to tumor response ......................................................... 44 
6.2.2.7. Time to PSA response ........................................................... 44 
6.2.2.8. Progression-free survival ....................................................... 45 
6.2.2.9. Time to PSA progression for participants with mCRPC .......... 47 
6.2.2.10. Overall Survival .................................................................. 49 
6.2.2.11. CTC count conversion and CTC0 for participants with 
mCRPC ........................................................................................ 50 
6.2.3. Pharmacokinetic endpoints .................................................................... 51 
6.2.4. Population pharmacokinetic endpoints ................................................... 53 
6.2.5. Biomarker endpoints ............................................................................. 53 
6.2.6. Endpoints for immunogenicity data of avelumab, bempegaldesleukin 
(NKTR-214), and IL-2 ............................................................................... 54 
6.2.6.1. Time to and Duration of ADA and nAb response ................... 56 
6.2.6.2. ADA titer.............................................................................. 57 
6.2.6.3. Analysis of PK and safety by immunogenicity status .............. 57 
 
 
 
6.4. Subset Analyses ................................................................................................ 59 
6.5. Baseline and Other Summaries and Analyses ..................................................... 60 
6.5.1. Baseline summaries ............................................................................... 60 
6.5.1.1. Demographic characteristics .................................................. 60 
6.5.1.2. Medical history ..................................................................... 61 
6.5.1.3. Disease characteristics........................................................... 61 
6.5.1.4. Prior anti-cancer therapies ..................................................... 62 
6.5.2. Study conduct and participant disposition............................................... 63 
6.5.2.1. Patient disposition ................................................................. 63 
6.5.2.2. Protocol deviations................................................................ 63 
CCI


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 5 
6.5.3. Study treatment compliance and exposure .............................................. 64 
6.5.3.1. Exposure to avelumab ........................................................... 65 
6.5.3.2. Exposure to NKTR-214......................................................... 65 
6.5.3.3. Exposure to talazoparib ......................................................... 66 
6.5.3.4. Exposure to enzalutamide...................................................... 66 
6.5.3.5. Dose reductions .................................................................... 67 
6.5.3.6. Dose interruptions ................................................................. 67 
6.5.3.7. Dose delays .......................................................................... 68 
6.5.3.8. Infusion rate reductions ......................................................... 68 
6.5.3.9. Infusion interruptions ............................................................ 68 
6.5.4. Concomitant medications and non-drug treatments ................................. 69 
6.5.5. Subsequent anti-cancer therapies............................................................ 69 
6.6. Safety Summaries and Analyses ........................................................................ 70 
6.6.1. Adverse events ...................................................................................... 70 
6.6.1.1. All adverse events ................................................................. 71 
6.6.1.2. Adverse events leading to dose reduction ............................... 72 
6.6.1.3. Adverse events leading to interruption of study treatment ....... 73 
6.6.1.4. Adverse events leading to discontinuation of study 
treatment ...................................................................................... 74 
6.6.2. Deaths................................................................................................... 74 
6.6.3. Serious adverse events ........................................................................... 75 
6.6.4. Other significant adverse events ............................................................. 75 
6.6.5. Laboratory data ..................................................................................... 76 
6.6.5.1. Hematology and chemistry parameters................................... 76 
6.6.5.2. Other laboratory parameters .................................................. 79 
6.6.6. Vital signs ............................................................................................. 79 
6.6.7. Electrocardiogram ................................................................................. 79 
6.6.8. ECOG performance status ..................................................................... 81 
7. INTERIM ANALYSES ................................................................................................ 81 
8. REFERENCES ............................................................................................................. 82 
9. APPENDICES .............................................................................................................. 83 
 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 6 
LIST OF TABLES 
Table 1. 
Summary of Major Changes in SAP Amendments ............................................. 9 
Table 2. 
Treatment Groups ........................................................................................... 15 
Table 3. 
Study Summaries ............................................................................................ 23 
Table 4. 
Outcome and Event Dates for DR Analyses ..................................................... 40 
Table 5. 
Criteria for Evidence of Radiographic Progression for Participants with 
mCRPC .......................................................................................................... 41 
Table 6.  
DR Censoring Reasons and Hierarchy ............................................................. 42 
Table 7. 
Outcome and Event Dates for Duration of PSA Response Analysis .................. 43 
Table 8. 
Duration of PSA Response Censoring Reasons and Hierarchy .......................... 44 
Table 9. 
Outcome and Event Dates for PFS Analyses .................................................... 46 
Table 10. 
PFS Censoring Reasons and Hierarchy ............................................................ 47 
Table 11. 
Outcome and Event Dates for Time to PSA Progression Analysis..................... 48 
Table 12. 
PSA Progression Censoring Reasons and Hierarchy ......................................... 49 
Table 13. 
OS Censoring Reasons and Hierarchy.............................................................. 50 
Table 14. 
PK Parameters to be Determined for Avelumab, Bempegaldesleukin 
(NKTR-214), IL-2, Talazoparib and Enzalutamide........................................... 52 
Table 15. 
Biomarker Definition and Determination ......................................................... 54 
Table 16.  Participants Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ............................................................................................................ 55 
Table 17.  Participants Characterized Based on Neutralizing Antibody Results (nAb 
Status) ............................................................................................................ 56 
Table 18. 
Case Definition for irAEs................................................................................ 83 
Table 19. 
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs .......................................................... 85 
Table 20. 
Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets) ................................................................................ 86 
Table 21.  Historical Dose Limiting Toxicity Data From Study EXCEL ............................. 89 
Table 22.  Prior Distributions for the Parameters of the MAP Model Used to Derive the 
Prior for the Single-Agent Bempegaldesleukin (NKTR-214) Model 
Parameters...................................................................................................... 90 
Table 23.  Historical Dose Limiting Toxicity Data from Study EMR100070-001 ................ 90 
Table 24.   Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters............................. 91 
Table 25.   Prior Distribution for the Model Parameters...................................................... 91 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 7 
Table 26.   Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Doublet Combination of Avelumab in Combination with 
Bempegaldesleukin (NKTR-214) .................................................................... 92 
Table 27.   Combination A: Data Scenarios, Next Dose Recommendation, and the 
Interval Probability of Target Toxicity and Overdosing at Next Dose. .............. 93 
Table 28. 
Combination A: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab 
Dose 10 mg/kg every 2 Weeks) ....................................................................... 93 
Table 29. 
Combination A: Operating Characteristics ....................................................... 95 
Table 30. 
Historical Dose Limiting Toxicity data from Study PRP-001............................ 98 
Table 31. 
Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters .......................... 99 
Table 32. 
Prior Distribution for the Model Parameters................................................... 100 
Table 33. 
Summary of Prior Distribution of DLT Rates for the Triplet Combination 
of Avelumab in Combination with Bempegaldesleukin (NKTR-214) and 
Talazoparib .................................................................................................. 101 
Table 34. 
Combination B: Clinically Meaningful Starting Dose Given Hypothetical 
Data from the Combination A, and the Interval Probability of Target 
Toxicity and Overdosing at Starting Dose. ..................................................... 102 
Table 35. 
Combination B: Data Scenarios (Given Hypothetical Combination A Data), 
Next Dose Recommendation, and the Interval Probability of Target 
Toxicity and Overdosing at Next Dose. ......................................................... 103 
Table 36.   Combination B: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab 
Dose 10 mg/kg Every 2 Weeks) .................................................................... 104 
Table 37.   Combination B: Operating Characteristics ...................................................... 105 
Table 38.   Historical Dose Limiting Toxicity data from Study S-3100-1-01 ..................... 108 
Table 39.  Prior Distributions for the Parameters of the MAP Model Used to Derive the 
Prior for the Single-Agent Enzalutamide Model Parameters ........................... 108 
Table 40.   Prior Distribution for the Model Parameters.................................................... 109 
Table 41.  Summary of Prior Distribution of DLT Rates for the Triplet Combination of 
Enzalutamide in Combination with Bempegaldesleukin (NKTR-214) and 
Avelumab (Combination C) .......................................................................... 110 
Table 42. 
Combination C: Clinically Meaningful Starting Dose Given Hypothetical 
Data from the Doublet Combination, and the Interval Probability of Target 
Toxicity and Overdosing at Starting Dose. ..................................................... 111 
Table 43.  Combination C: Data Scenarios (Given Hypothetical Doublet Data), Next 
Dose Recommendation, and the Interval Probability of Target Toxicity and 
Overdosing at Next Dose. ............................................................................. 111 
Table 44.  Combination C: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab 
Dose 10 mg/kg Every 2 Weeks) .................................................................... 112 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan     
 
PFIZER CONFIDENTIAL 
Page 8 
Table 45.  Combination C: Operating Characteristics ....................................................... 113 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schema ..................................................................................... 13 
 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan   
PFIZER CONFIDENTIAL 
Page 9 
 
1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study B9991040 is based on the protocol amendment 
1 dated 27JUN2019.   
Table 1. 
Summary of Major Changes in SAP Amendments 
Version 
Version Date 
Summary of Changes 
1 
03-Sep-2019 
Not applicable (N/A) 
 
2. OBJECTIVES, ENDPOINTS AND STUDY DESIGN 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991040.  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, immunogenicity, and biomarker data). The primary analysis will include 
all data up to a cut-off date corresponding to 24 months after the last participant receives the 
first dose of study treatment.  The final analysis of the data will be performed after last 
participant last visit (LPLV).  
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes. 
2.1. Study Objectives, Endpoints, and Estimands 
Objectives 
Endpoints 
Primary 
 
Phase 1b:  
• To assess the dose-limiting toxicity (DLT) rate of 
avelumab in combination with 
bempegaldesleukin (NKTR-214) (Combination 
A) and talazoparib (Combination B) or 
enzalutamide (Combination C) in order to 
determine the recommended Phase 2 dose 
(RP2D) for the combinations. 
Phase 1b:  
• DLT during the DLT evaluation period (Cycle 1) 
 
Phase 2: 
• Combination A: To assess objective response 
rate (ORR) of avelumab in combination with 
bempegaldesleukin (NKTR-214) in participants 
with locally recurrent or metastatic squamous 
cell carcinoma of the head and neck (SCCHN). 
• Combination B: To assess soft tissue ORR of 
avelumab in combination with 
bempegaldesleukin (NKTR-214) and talazoparib 
in participants with DDR defect positive 
metastatic castration-resistant prostate cancer 
(mCRPC). 
Phase 2: 
• Combination A: Confirmed objective response 
(OR) as determined by the investigator using 
RECIST v1.1. 
 
• Combination B: Confirmed soft tissue OR as 
determined by the investigator using RECIST v 1.1 
with no evidence of confirmed bone disease 
progression on repeat bone scan at least 6 weeks 
later per prostate cancer working group 3 
(PCWG3) criteria. 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan   
PFIZER CONFIDENTIAL 
Page 10 
 
 
• Combination C: To assess the prostate specific 
antigen (PSA) response rate of avelumab in 
combination with bempegaldesleukin (NKTR-
214) and enzalutamide in participants with 
mCRPC after progression on abiraterone. 
• Combination C: Confirmed PSA response 
decrease ≥ 50% from baseline confirmed by a 
second consecutive assessment at least 3 weeks 
later.  
Secondary 
 
• To assess the overall safety and tolerability of the 
combinations (A, B and C). 
• Adverse events (AEs) as characterized by type, 
severity (as graded by National Cancer Institute 
Common Terminology Criteria for Adverse Events 
[NCI CTCAE] v4.03), timing, seriousness, and 
relationship to study therapy. 
• Laboratory abnormalities as characterized by type, 
severity (as graded by NCI CTCAE v4.03) and 
timing. 
• To assess other measures of anti-tumor activity. 
• 
Time-to-event endpoints as determined by the 
investigator, using RECIST v1.1 (Combination A) 
and in participants with mCRPC (Combinations B 
and C), RECIST v1.1 (soft tissue disease) and 
PCWG3 (bone disease), including time to tumor 
response (TTR), duration of response (DR), 
progression free survival (PFS), and Overall 
Survival (OS). 
• 
Combination B: Confirmed PSA response ≥50% 
decrease from baseline confirmed by a second 
consecutive assessment at least 3 weeks later. 
• Combination C: Confirmed soft tissue OR as 
determined by the investigator using RECIST v 1.1 
with no evidence of confirmed bone disease 
progression on repeat bone scan at least 6 weeks 
later per PCWG3 criteria. 
• Combination C: Circulating tumor cells CTC 
count conversion (decrease in CTC count from ≥ 5 
CTC per 7.5 mL of blood at baseline to < 5 CTC 
per 7.5 mL of blood) at any assessment on 
treatment), and CTC0 (CTC0 is defined as a CTC 
count of ≥1 CTC per 7.5 mL of blood at baseline 
and 0 CTC per 7.5 mL of blood at any assessment 
on treatment). 
• Combinations B and C: Time to PSA progression 
(TTPSAP) defined according to the consensus 
guidelines of the Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3) criteria. 
• To characterize the pharmacokinetic (PK) of 
avelumab, bempegaldesleukin (NKTR-214), and 
talazoparib or enzalutamide when given in 
combination. 
 
• PK parameters including trough concentrations 
(Ctrough) for avelumab, bempegaldesleukin (NKTR-
214),  IL-2 (active form of NKTR-214), 
talazoparib, enzalutamide, and N-desmethyl-
enzalutamide and maximum concentrations (Cmax) 
for avelumab and bempegaldesleukin (NKTR-214) 
and IL-2 (active form of NKTR-214). 
• To assess the immunogenicity of avelumab and 
bempegaldesleukin (NKTR-214) when combined 
together and with talazoparib or enzalutamide. 
• Anti-drug antibody (ADA) and neutralizing 
antibodies (NAb) against avelumab, 
bempegaldesleukin (NKTR-214) and IL-2 (active 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan   
PFIZER CONFIDENTIAL 
Page 11 
 
form of NKTR-214) when combined together and 
with talazoparib or enzalutamide.  
• To assess the correlation of anti-tumor activity 
with PD-L1 expression level in baseline tumor 
tissue. 
• PD-L1 expression level in baseline tumor tissue. 
• Combination A: To assess the correlation of 
anti-tumor activity with PD-L1 expression level 
in on-treatment tumor tissue. 
• Combination A: PD-L1 expression level in on-
treatment tumor tissue. 
Estimands  
The estimands associated with the primary endpoints and the secondary efficacy endpoints of 
the study are described below. 
The populations associated with estimands for each combination are as follows: 
• Combination A - participants with 1L SCCHN. 
• Combination B Phase 1b - participants with mCRPC after progression on taxane-
based chemotherapy. 
CCI


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan   
PFIZER CONFIDENTIAL 
Page 12 
 
• Combination B Phase 2 - participants with DNA Damage Repair (DDR) defect 
positive (DDR+) mCRPC after progression on taxane-based chemotherapy. 
• Combination C - participants with mCRPC after progression on abiraterone therapy. 
The endpoint definitions, the observations that will be considered in the derivation of the 
endpoint and the associated analyses are described or referenced below.   
• Phase 1b: The primary endpoint (Combinations A, B and C) will be the occurrence of 
DLT during the primary DLT evaluation period (Cycle 1).  DLTs are defined in 
Section 6.1.1.  DLTs will only be collected during Cycle 1 of Phase 1b and the DLT 
rate will be estimated for participants who are evaluable for DLTs.  DLT-evaluable 
participants are those enrolled in Phase 1b who 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 
without DLT.  Participants without DLTs who withdraw from study treatment before 
receiving at least 2 doses of avelumab and bempegaldesleukin (NKTR-214; all 
Combinations) or 75% of the planned dose of talazoparib (Combination B) or 
enzalutamide (Combination C), in Cycle 1 for reasons other than treatment-related 
toxicity are not evaluable for DLT.  All participants deemed non-evaluable for DLT 
may be replaced. 
• Phase 2 Objective Response (Combination A) or soft tissue Objective Response 
(Combination B): The primary estimand is the treatment effect of OR (Combination 
A) or soft tissue OR (Combination B) from the time of first dose until progression is 
met or subsequent anticancer therapy is administered.  Point estimates and confidence 
intervals (following the methodology outlined in Sections 6.1.2.1 and 6.1.3.1) will be 
calculated.  
• Phase 2 PSA Response (Combination C): The primary estimand is the treatment 
effect of PSA response from the time of first dose until progression is met or 
subsequent anticancer therapy is administered.  Point estimates and confidence 
intervals (following the methodology outlined in Section 6.1.4.1) will be calculated.  
• Phase 2 Tumor related endpoints: (TTR[Combinations A, B, and C], DR 
[Combinations A, B, and C],  time to PSA progression [TTPSAP, Combinations B 
and C only], CTC count conversion  [Combination C only]) and CTC0  [Combination 
C only]) are defined in Section 6.2.2.  This is a non-randomized study and there will 
be no statistical comparisons between treatment groups; to address the objectives 
associated with tumor-related endpoints, point estimates and confidence intervals 
(following the methodology outlined in Section 6.2.2) will be calculated for each 
tumor-related endpoint including only assessments on or before start of new anti-
cancer therapy and on or before progression. 
• Phase 2:  OS is defined as the time from the first dose of study treatment to the date 
of death due to any cause. This is a non-randomized study and there will be no 
statistical comparisons between treatment groups; to address the OS objective,  point 
estimates and confidence intervals (following the methodology outlined in 


Avelumab 
B9991040 (MSB0010718C,  NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan   
PFIZER CONFIDENTIAL 
Page 13 
 
Section 6.2.2) will be calculated for OS including survival status for each participant 
at the time of the analysis; survival status is expected to be collected irrespective of 
study treatment discontinuation or participant’s request to discontinue study 
procedures. All participants who have not withdrawn consent for further participation 
in the study should be followed for survival until at least 2 years after enrollment of 
the last participant in the study. 
2.2. Study Design 
This is a Phase 1b/2, open-label, multi-center study of avelumab in combination with 
bempegaldesleukin (NKTR-214) with or without talazoparib or enzalutamide in adult 
participants with 1L SCCHN (Combination A) or with mCRPC (Combinations B and C)  
(Figure 1). 
Figure 1. Study Design Schema  
 
 
 
 
 
 
 
 
 
 
 
 
Step 2: Phase 1b 
Combination B 
Phase 2 
Combination B 
Step 2: Phase 1b 
Combination C 
Phase 2 
Combination C 
1L SCCHN  
Combination A 
 
Step 1:  Dose finding 
Phase 1b for avelumab + 
bempegaldesleukin 
(NKTR-214)    
BLRM to guide dose  
de-escalation/escalation 
decisions 
 
Avelumab (800 mg IV, 
Q2W) 
Bempegaldesleukin 
(NKTR-214; TBD, 
Q2W) 
Avelumab (800 mg IV, 
Q2W) 
Bempegaldesleukin 
(NKTR-214; TBD, Q2W) 
 
Note: Combination A Phase 
2 will be conducted in 
parallel with the Phase 1b 
for Combinations B and C 
mCRPC  (Combinations 
B and C) 
 
Step 2:  Parallel dose-
finding Phase 1b for 
avelumab + talazoparib + 
bempegaldesleukin 
(NKTR-214) and 
avelumab + enzalutamide 
+ bempegaldesleukin 
(NKTR-214)  
BLRM to guide dose de-
escalation/escalation 
decisions 
Avelumab (800 mg IV, Q2W) 
Bempegaldesleukin (NKTR-
214); TBD, Q2W) 
Talazoparib (TBD, QD) 
Avelumab (800 mg IV, 
Q2W) 
Bempegaldesleukin 
(NKTR-214; TBD, 
Q2W) 
Talazoparib (TBD, QD) 
Avelumab (800 mg IV, Q2W) 
Bempegaldesleukin (NKTR-
214; TBD, Q2W) 
Enzalutamide (TBD, QD) 
Avelumab (800 mg IV, 
Q2W) 
Bempegaldesleukin 
(NKTR-214; TBD, Q2W) 
Enzalutamide (TBD, QD) 
DDR+ 
Abbreviations: 1L SCCHN== locally recurrent (not amendable for treatment with curative intent) or 
metastatic squamous cell carcinoma of the head and neck; BLRM= Bayesian Logistic Regression Model;  
DDR=DNA damage repair; DDR+=positive for DNA damage repair defects; IV=intravenous; 
mCRPC=metastatic castration-resistant prostate cancer;  Q2W=every two weeks; QD=once daily; 
TBD=to be determined. 
Step 1: Phase 1b 
Combination A 
Phase 2 
Combination A 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 14 
Phase 1b Design 
Phase 1b will include 2 sequential dose-finding steps: 
Step 1. Combination A will be evaluated in participants with 1L SCCHN to determine 
RP2D.  There are two possible levels for this combination (Table 2). 
Step 2.  Upon the determination of the RP2D for Combination A, the Phase 1b dose-finding 
for Combinations B and C in participants with mCRPC will commence to determine the 
RP2D for Combinations B and C separately.  Combinations B and C each have 6 possible 
dose levels (Table 2). 
Phase 2 Design 
Once Phase 1b is completed for each combination and the RP2Ds have been determined, 
Phase 2 will be initiated to further evaluate the safety and anti-tumor activity in 
Combinations A, B, and C.    
• Combination A will enroll up to approximately 31 participants with 1L SCCHN.  
• Combination B will enroll up to approximately 20 participants with DDR+ mCRPC 
post taxane-based chemotherapy. 
• Combination C will enroll up to approximately 40 participants with mCRPC 
post-abiraterone therapy.  
Combination A will proceed into Phase 2 once RP2D for Combination A has been 
determined in the Phase 1b dose finding component, in parallel with dose-finding for Phase 
1b for Combinations B and C.  
3. BASELINE VARIABLES: DEFINITIONS AND CONVENTIONS 
3.1. Baseline Variables 
3.1.1. Study drug, study treatment and baseline definitions 
In this study, ‘study drug’ refers to avelumab, bempegaldesleukin (NKTR-214), talazoparib, 
or enzalutamide and ‘study treatment’ (or ‘treatment group’) refers to one of the treatment 
groups in Table 2. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 15 
Table 2. 
Treatment Groups 
Phase  
Treatment 
groups 
(Dose 
Level) 
Tumor Type 
Avelumab 
(mg IV 
Q2W) 
Bempegaldesleukin 
(NKTR-214) 
(mg/kg IV Q2W) 
Talazoparib 
(mg QD PO) 
Enzalutamide 
 (mg QD PO) 
1b 
A1 (D0) 
SCCHN 
800 
0.006 
- 
- 
1b 
A2 (D-1) 
SCCHN 
800 
0.003 
- 
- 
1b 
B1 (D0-A*) 
mCRPC post PD 
on chemo therapy 
800 
0.006 
1.0 
- 
1b 
B2 (D-1A) 
mCRPC post PD 
on chemo therapy 
800 
0.006 
0.75 
- 
1b 
B3 (D-2A) 
mCRPC post PD 
on chemo therapy 
800 
0.006 
0.5 
- 
1b 
B4 (D0-B*) 
mCRPC post PD 
on chemo therapy 
800 
0.003 
1.0 
- 
1b 
B5 (D-1B) 
mCRPC post PD 
on chemo therapy 
800 
0.003 
0.75 
- 
1b 
B6 (D-2B) 
mCRPC post PD 
on chemo therapy 
800 
0.003 
0.5 
- 
1b 
C1 (D0-A*) 
mCRPC post PD 
on abiraterone 
800 
0.006 
- 
160 
1b 
C2 (D-1A) 
mCRPC post PD 
on abiraterone 
800 
0.006 
- 
120 
1b 
C3 (D-2A) 
mCRPC post PD 
on abiraterone 
800 
0.006 
- 
80 
1b 
C4 (D0-B*) 
mCRPC post PD 
on abiraterone 
800 
0.003 
- 
160 
1b 
C5 (D-1B) 
mCRPC post PD 
on abiraterone 
800 
0.003 
- 
120 
1b 
C6 (D-2B) 
mCRPC post PD 
on abiraterone 
800 
0.003 
- 
80 
2 
Cohort A 
SCCHN 
800 
RP2D for 
Combination A 
- 
- 
2 
Cohort B 
DDR+ mCRPC 
post PD on 
chemotherapy 
800 
RP2D for 
Combination B 
RP2D for 
Combination 
B 
- 
2 
Cohort C 
mCRPC post PD 
on abiraterone 
800 
RP2D for 
Combination C 
- 
RP2D for 
Combination C 
1L SCCHN= locally recurrent squamous cell carcinoma of the head and neck; mCRPC=metastatic castration-resistant 
prostate cancer; mg=milligram; Q2W= every 2 weeks; IV= intravenous;  QD=once daily; PD = progressive disease;  
PO=orally; RP2D=recommended phase 2 dose. 
D0= starting dose; D-1=reduced dose; D-2=second reduced dose. 
*Dose levels for Combinations B and C designated with ‘A’ are applicable if the bempegaldesleukin (NKTR-214) dose is 
0.006 mg/kg Q2W; dose levels for Combinations B and C designated with ‘B’ are applicable if the bempegaldesleukin 
(NKTR-214) dose is 0.003 mg/kg Q2W. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 16 
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 safety and efficacy analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment 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. 
Participants 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 Phase 1b of the study and the 
baseline for each ECG parameter 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.  
Definition of baseline for immunogenicity analyses 
The last available assessment prior to the start of treatment with avelumab and 
bempegaldesleukin (NKTR-214) is defined as ‘baseline’ result or ‘baseline’ assessment.  If 
an assessment is planned to be performed prior to the first dose of avelumab and   
bempegaldesleukin (NKTR-214) in the protocol and the assessment is performed on the same 
day as the first dose of avelumab and bempegaldesleukin (NKTR-214),  it will be assumed 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 17 
that it was performed prior to administration of avelumab and bempegaldesleukin (NKTR-
214), if assessment time point is not collected or is missing.   
3.1.2. Baseline characteristics 
Baseline characteristics (including demographics, physical measurements, 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.   
3.2. Safety Endpoints 
3.2.1. 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 participants will be assessed to determine if participants 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 participants who signed informed consent will be included in the analysis sets below. 
4.1. Full Analysis Set 
The FAS will include all participants who receive at least one dose of study drug.  
Participants will be classified according to the study treatment actually received.  If a 
participant receives more than one treatment the participant will be classified according to 
the first study treatment received.  
4.2. Safety Analysis Set 
The safety analysis set will include all participants who receive at least one dose of study 
drug.  Participants will be classified according to the study treatment actually received.  If a 
participant receives more than one study treatment, the participant will be classified 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 18 
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-evaluable analysis set is a subset of the safety analysis set and includes all enrolled 
participants in Phase 1b who 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 without a DLT.  
Participants without DLTs who withdraw from study treatment before receiving at least 2 
doses of avelumab and bempegaldesleukin (NKTR-214; all Combinations) or 75% of the 
planned dose of talazoparib (Combination B) or enzalutamide (Combination C) in Cycle 1 
for reasons other than treatment-related toxicity are not evaluable for DLT.  All participants 
deemed non-evaluable for DLT may be replaced. 
4.3.2. PK analysis sets 
The PK concentration analysis set is a subset of the safety analysis set and will include 
participants who have at least one post-dose concentration measurement above the lower 
limit of quantitation (LLQ) for avelumab, bempegaldesleukin (NKTR-214), IL-2, 
talazoparib, enzalutamide, or N-desmethyl-enzalutamide.  
The PK parameter analysis set is a subset of the safety analysis set and will include 
participants who have at least one of the PK parameters of interest for avelumab, 
bempegaldesleukin (NKTR-214), IL-2, talazoparib, enzalutamide, or N-desmethyl-
enzalutamide. 
4.3.3. Biomarker analysis set  
The biomarker analysis set for biomarkers that are only measured at screening is a subset of 
the safety analysis set and will include participants who have at least one baseline biomarker 
assessment.  
The biomarker analysis set for biomarkers that are measured sequentially is a subset of the 
safety analysis set and will include participants who have at least one baseline and one on-
treatment biomarker assessment for the same marker.  
The biomarker analysis set is defined separately for each biomarker of interest. 
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 
participants who have at least one ADA/nAb sample collected for avelumab, 
bempegaldesleukin (NKTR-214), or IL-2.   


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 19 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and sample size determination 
There is no formal hypothesis testing in this study. 
Approximately 160 participants will be screened to achieve approximately 127 participants 
assigned to study intervention, with 27-36 participants in Phase 1b and up to approximately 
91 participants in Phase 2.  A given combination size may be expanded in Phase 2 only by a 
limited number of additional participants (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.   
During the Phase 1b dose finding, it is estimated that approximately up to 12 and 
15 participants will be enrolled and assigned to treatment in each of the three combinations 
(one doublet combination, two triplet combinations).  Each combination will include at least 
6 participants treated at the Maximum Tolerated Dose (MTD) level and at least 9 participants 
at the RP2D.  The actual number of participants for the Phase 1b dose finding will depend on 
the number of DLT events and dose levels/combinations that are tested.  For each 
combination, beginning with the starting dose level,  cohorts of 3-6 participants will be 
enrolled, treated, and monitored during the 28-day DLT-evaluation period (Cycle 1).  
Nine evaluable participants are needed to be treated at RP2D if no DLT is observed, and 12 
evaluable participants if at least 1 DLT is observed.  
Data from Phase 1b participants with SCCHN will also be used for the Phase 2 efficacy 
assessment at the RP2D. 
In Phase 2, with 20 (Combination B), 40 including Phase 1b participants (Combination A) 
and 40 (Combination C) treated participants in Combinations B, A and C, respectively, soft 
tissue ORR, ORR, and PSA response rate can be estimated with a maximum standard error 
of 0.112 (Combination B) or 0.079 (Combinations A and C), respectively.   
Assuming beta-binomial distributions for ORR (Combination A), soft tissue ORR 
(Combination B), and PSA response rate (Combination C) and a non-informative beta (0.5, 
0.5) prior: 
• For Combination A (1L SCCHN), if 20 responders (out of 40 participants, ORR = 
50%) are observed, the probability of a true ORR≥ 40 % (considered a clinically 
relevant effect) will be ≥90% (90.1%).   
• For Combination B (DDR defect positive mCRPC post chemotherapy), if 12 
responders (out of 20 participants, soft tissue ORR = 60%) are observed, the 
probability of a true soft tissue ORR≥ 50% (considered a clinically relevant effect) 
will be ≥80% (81.4%).   


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 20 
• For Combination C (mCRPC post abiraterone), if 20 PSA responders (out 40 
participants, PSA response rate = 50%) are observed, the probability of a true PSA 
response rate ≥ 40% (considered a clinically relevant effect) will be ≥90% (90.1%).    
The determination of what constitutes a clinically meaningful response rate was based upon a 
review of historical ORR (for SSCHN), soft tissue ORR (for mCRPC, Combination B), PSA 
response rate (for mCRPC, Combination C) in clinical studies. 
5.1.2. Decision rules 
Identification of a recommended dose 
The dosing decision and estimation of the MTDs of the doublet (Combination A) and the 
triplets (Combination B and C) will be guided by the estimation of the probability of DLT in 
Cycle 1.  However, other evidence such as safety data beyond DLT, clinical activity, PK, and 
PD data will play an important role in the final decision.  A RP2D below the MTD may be 
determined based on these considerations. 
A dose level combination is a potential candidate for being the MTD level when all the 
following criteria are met: 
• ≥6 participants have been treated at that dose; 
• Probability of target dosing >0.50; 
• Probability of overdosing <0.25. 
Combination A will be evaluated first to determine the RP2D.  Upon the completion of the 
dose finding of the doublet, Combinations B and C will then be evaluated to determine the 
RP2D for these triplet combinations.  Guidance for Phase 1b dosing (dose level to be 
evaluated in the next cohort) and enrollment (number of participants to be enrolled in the 
next cohort) decisions will be based on a Bayesian Logistic Regression Model (BLRM).   
The BLRM incorporates single-agent and available combination DLT data (historical and 
prospectively across dose combinations) to estimate the posterior probability of under-
dosing, target dosing and overdosing, thereby reducing participant risk and increasing 
efficiency and precision during dose finding with combination treatments. Refer to 
Appendix 3, Appendix 4, and Appendix 5 for the full details of the BLRM designs for 
Combinations A, B, and C, respectively. 
Bayesian adaptive approach 
Doublet combination model: 
For Combination A, the Bayesian model consists of three parts, representing: 
• Single-agent avelumab toxicity; 
• Single-agent bempegaldesleukin (NKTR-214) toxicity; 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 21 
• Interaction between bempegaldesleukin (NKTR-214) and avelumab. 
Triplet combination model: 
For Combination B, the Bayesian model consists of seven parts, representing: 
• Single-agent talazoparib toxicity; 
• Single-agent bempegaldesleukin (NKTR-214) toxicity; 
• Single-agent avelumab toxicity; 
• Interaction between talazoparib and bempegaldesleukin (NKTR-214); 
• Interaction between talazoparib and avelumab; 
• Interaction between bempegaldesleukin (NKTR-214) and avelumab; 
• Triple interaction among talazoparib, bempegaldesleukin (NKTR-214), and 
avelumab. 
For the Combination C, the Bayesian model consists of seven parts, representing: 
• Single-agent enzalutamide toxicity; 
• Single-agent bempegaldesleukin (NKTR-214) toxicity;  
• Single-agent avelumab toxicity; 
• Interaction between enzalutamide and bempegaldesleukin (NKTR-214); 
• Interaction between enzalutamide and avelumab; 
•  Interaction between bempegaldesleukin (NKTR-214) and avelumab; 
• Triple interaction among enzalutamide, bempegaldesleukin (NKTR-214), and 
avelumab. 
Single-agent toxicities are modelled using logistic regression for the probability of a 
participant experiencing a DLT against log-dose.  The odds of a DLT are then calculated 
under no interaction for the two/three single-agent toxicities, and interaction is accounted for 
by adjusting these odds with an additional model parameter (odds multiplier).   
Assessment of participant risk 
After each cohort of participants completes the DLT-evaluation period, the posterior 
distribution for the risk of DLT for different combination doses of interest will be evaluated.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 22 
The posterior distributions will be summarized to provide the posterior probability that the 
risk of DLT lies within the following intervals:  
• Underdosing:  
 
 
[0, 0.16) 
• Target toxicity: 
 
 
[0.16, 0.33) 
• Excessive toxicity or overdosing: 
[0.33, 1] 
The EWOC principle 
Dosing decisions are guided by the EWOC principle1.  A combination dose may only be used 
for the next cohort of participants if the risk of excessive toxicity ([0.33, 1]) at that 
combination dose is less than 0.25. 
Prior distributions 
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent model parameters.  The MAP prior for the logistic model parameters for this 
study is the conditional distribution of the parameters given the historical data9, 10, 11.  MAP 
priors are derived using Bayesian hierarchical models, which take into account possible 
differences between the studies. 
The prior distribution for the interaction parameters (doublet and triplets) were based on the 
prior understanding of possible drug safety interactions.  This prior allows for the possibility 
of either synergistic or antagonistic interaction. 
Starting dose levels 
The starting dose for the Combination A is 800 mg avelumab IV Q2W, and 0.006 mg/kg 
bempegaldesleukin [NKTR-214] Q2W IV.  For this dose the prior risk of excessive toxicity 
is 0.137, which satisfies the EWOC criterion.   
The starting dose for the triplets (Combinations B and C) will be determined based on all 
available data after completion of the dose finding for Combination A.  
5.2. General Methods 
The definition of ‘treatment group’ in this study is provided in Table 2. 
 
Table 3  provides an overview of the planned summaries for this study for each endpoint, 
treatment group and study phase. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 23 
Table 3. 
Study Summaries  
Summaries  
Analysis Sets 
Phase 1b 
Phase 2 
Phase 1b and 
Phase 2 combined 
Baseline characteristics  
FAS 
- by treatment group  
- pooled: A1+A2 
- pooled: B1 +…+ B6 a  
- pooled: C1 +…+ C6 b 
- pooled: all participants 
- by treatment group  
- pooled: all 
participants 
All participants 
treated at the RP2D 
for each 
combination 
Disposition 
FAS 
- by treatment group  
- pooled: A1+A2 
- pooled: B1 +…+ B6 a  
- pooled: C1 +…+ C6 b 
- by treatment group   All participants 
treated at the RP2D 
for each 
combination 
DLTs 
DLT-evaluable set 
- by treatment group  
- pooled: A1+A2 
- pooled: B1 +…+ B6 a  
- pooled: C1 +…+ C6 b  
Not Done 
Not Done 
Efficacy data 
FAS 
- by treatment group   
 
- by treatment group  
All participants 
treated at the RP2D 
for Combination A 
and for 
Combination C 
Other safety data 
(including AESI), 
exposure data, 
concomitant 
medications, non-drug 
treatments 
Safety analysis set 
- by treatment group  
- pooled: A1+A2 
- pooled: B1 +…+ B6 a  
- pooled: C1 +…+ C6 b  
- by treatment group  
  
All participants 
treated at the RP2D 
for each 
combination  
PK data for avelumab 
PK analysis set 
- by treatment group  
- by treatment group  
 
Not Done  
PK data for 
bempegaldesleukin 
(NKTR-214) and IL-2 
PK analysis set 
- by treatment group  
- by treatment group  
 
Not Done 
PK data for talazoparib 
PK analysis set 
- by treatment group  
- by treatment group  
 
Not Done 
PK data for 
enzalutamide and N-
Desmethyl-
Enzalutamide 
PK analysis set 
- by treatment group  
- by treatment group  
 
Not Done 
Biomarker data 
Biomarker analysis 
set 
- pooled: A1+A2 
- pooled: B1 +…+B6 a  
- pooled: C1 +…+C6 b  
- by treatment group   
 
- by combination c  
 
Immunogenicity for 
avelumab 
Immunogenicity 
analysis set 
 - pooled: A1+A2 
- pooled: B1 +…+B6 a  
- pooled: C1 +…+C6 b 
- pooled: all participants 
- by treatment group  
- pooled: all 
participants 
- by combination c 
- pooled: all 
participants 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 24 
Immunogenicity for 
bempegaldesleukin 
(NKTR-214) and IL-2 
Immunogenicity 
analysis set 
- pooled: A1+A2 
- pooled: B1 +…+B6 a  
- pooled: C1 +…+C6 b  
- pooled: all participants 
- by treatment group  
- pooled: all 
participants  
- by combination c 
- pooled: all 
participants 
 
a B1 +…+B6 = B1+ B2+ B3+ B4+ B5+ B6; 
b C1 +…+C6 = C1+ C2+ C3+ C4+ C5+ C6; 
c Combination A=A1+A2+ cohort A; Combination B= B1+ B2+ B3+ B4+ B5+ B6 + Cohort B; Combination C= C1+ C2+ 
C3+ C4+ C5+ C6 + Cohort C. 
 
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 
participants treated at each center. 
5.2.3. Presentation of continuous and qualitative variables 
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3).  
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore, counts of missing observations will be included in the denominator and presented 
as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of 
participants 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. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 25 
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 Sections 6.1.2, 6.1.3, 6.1.4, 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 
• 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. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 26 
Demographics and physical measurements: 
• Age [years]:  
- (date of given informed consent - date of birth + 1) / 365.25 
- In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth) 
- In case only year of birth is given: Age [years]: (year of given informed consent - 
year of birth) 
The integer part of the calculated age will be used for reporting purposes.  
• BMI (kg/m2) = weight (kg)/[height (m)]2 
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6. 
5.2.9. Unscheduled visits 
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits. 
5.2.10. Adequate baseline tumor assessment 
Adequate baseline is defined using the following criteria: 
• All baseline assessments must be within 28 days prior to and including the date of 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, SD, non-CR/non-PD, or PD can be determined (see Section 6.1.2.1 and Section 6.1.3.1).  
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. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 27 
In all participant data listings imputed values will be presented.  In all listings imputed 
information will be flagged. 
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’.  
5.3.1.1. Pharmacokinetic concentrations 
Concentrations Below the Limit of Quantification 
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures. 
Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true: 
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample); 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist. 
Summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data. 
5.3.1.2. Pharmacokinetic parameters 
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.  If a PK parameter 
cannot be derived from a participant’s concentration data, the parameter will be coded as NC 
(ie, not calculated).  NC values will not be generated beyond the day that a participant 
discontinues. 
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing. 
If an individual participant has a known biased estimate of a PK parameter (due for example 
to a deviation from the assigned dose level), this will be footnoted in summary tables and 
will not be included in the calculation of summary statistics or statistical analyses. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 28 
5.3.2. Handling of incomplete dates 
5.3.2.1. Disease history 
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
• If the day is missing, it will be imputed to the 15th day of the month.  
• If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st. 
• If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st.  
• If the date is completely missing, no imputation will be performed. 
5.3.2.2. Adverse events 
Incomplete AE-related dates will be imputed as follows: 
• If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment. 
• If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015. 
• If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014. 
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of participant'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.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 29 
• 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 participant's death. In the latter case 
the date of death will be used to impute the incomplete stop date.  
• In all other cases the incomplete medication stop date will not be imputed.  
5.3.2.4. Exposure 
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows: 
• If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the participant 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 participants not known to have died at the analysis 
cut-off using the latest complete date among the following: 
• All participant 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 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 30 
• 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 participant will be used in the 
derivation.  Dates associated with a technical operation unrelated to participant status such as 
the date a blood sample was processed will not be used. Assessment dates after the cut-off 
date will not be applied to derive the last contact date. 
5.3.3.2. Death date 
Missing or partial death dates will be imputed based on the last contact date: 
• If the date is missing it will be imputed as the day after the date of last contact  
• If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following: 
- Missing day:  
 
1st day of the month and year of death 
- Missing day and month: 
January 1st of the year of death 
5.3.3.3. Tumor assessments 
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year. 
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
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. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 31 
• 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 participants who have not discontinued study treatment at the analysis cut-off date, 
last dose of study treatment is set to the analysis cut-off date in the imputations below.  
• If the start date of new anti-cancer therapy is completely or partially missing, then the 
imputed start date of new anti-cancer therapy is derived as follows: 
o Start date of new anti-cancer therapy is completely missing 
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy] 
o Only year (YYYY) for start of anti-cancer therapy is available 
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY;  
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
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 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 32 
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]); 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy],  AND 
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = 01 MMM YYYY; 
ELSE IF 
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
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 
In Phase 1b, any of the following AEs occurring in the first cycle of treatment which are 
attributable to any or all study drugs administered in the combination will be classified as 
DLTs. 
Hematologic: 
• Grade 4 anemia lasting >5 days (life threatening consequences; urgent intervention 
indicated). 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 33 
• Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5×109/L) 
lasting >5 days. 
• Grade ≥3 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. 
• Grade ≥3 neutropenic infection (ANC <1,000/mm3 or <1.0×109/L, and Grade >3 
infection). 
• Grade 3 thrombocytopenia (25,000/mm3 or 25.0×109/L to <50,000/ mm3 or 
<50.0×109/L) with bleeding, or grade 4 thrombocytopenia (platelet count 
<25,000/mm3 or <25.0×109/L). 
Non-Hematologic: 
• Potential Hy’s Law cases defined as: ALT or 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.  
• Grade ≥3 toxicities of any duration except: 
o Grade 3 nausea, vomiting, or diarrhea and Grade 4 vomiting or diarrhea that 
resolves in 72 hours; 
o Grade 3 hypotension that occurs within 5 days post-dosing and resolves with 
adequate medical intervention; 
o  Grade 3 non-hematologic laboratory abnormalities without a clinical correlate. 
Non-adherence to Treatment Schedule: 
• Delay of the subsequent cycle of two weeks or more due to toxicity occurring during 
the DLT observation period. 
• Failure to deliver ≥75% of the planned doses of all study interventions during the first 
cycle of treatment due to treatment related toxicities. 
While the rules for adjudicating DLTs in the context of the Phase 1b 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 based on the emerging safety profile for 
the combinations. 
The following analyses will be based on the DLT-evaluable set for participants in the Phase 
1b.  DLTs by SOC and PT will be listed and summarized by number and percentage of 
participants in decreasing frequency as shown in Table 3. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 34 
The posterior distribution of DLT rate [posterior probabilities that DLT rate is in the intervals 
of underdosing (<0.16), target toxicity (≥0.16 and <0.33) and overdosing (≥0.33 and ≤1)] at 
the end of Phase 1b will be provided as shown in Table 3. 
6.1.2. Objective response as assessed by the Investigator per RECIST v1.1 in 
participants with SCCHN  
6.1.2.1. Primary analysis 
The following analyses will be based on the FAS for participants with SCCHN in 
Combination A as shown in Table 3.  Assessment of response will be made based on 
investigator assessment using RECIST v1.1.   
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. 
BOR Based on Confirmed Responses:  
• 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 participants 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 participants 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.   


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 35 
Participants 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 participant will have 
an objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of 
participants with OR in the analysis set. 
ORR by treatment group will also be calculated along with the 2-sided 95% CI using the 
Clopper-Pearson method3 (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option).  
In addition, the frequency (number and percentage) of participants with a confirmed BOR of 
CR, PR, SD, non-CR/non-PD (applicable only to participants with non-measurable disease at 
baseline), PD, and NE will be tabulated. Participants 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  
• 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). 
6.1.3. Soft tissue objective response as assessed by the Investigator per RECIST v1.1 
and PCWG3 criteria in participants with mCRPC 
6.1.3.1. Primary analysis 
The following analyses will be based on the FAS for participants with mCRPC as shown in 
Table 3.  Assessment of response will be made based on investigator assessment. 
Soft tissue best overall response (BOR) (for Combinations B and C) will be assessed based 
on reported overall soft tissue responses and bone scan assessment at different evaluation 
time points from the date of first dose of study treatment until the first documentation of 
radiographic PD, according to the following rules. The documentation required for the 
determination of PD is shown in Table 5.  Only assessments performed on or before the start 
date of any further anti-cancer therapies will be considered in the assessment of soft tissue 
BOR. Clinical deterioration will not be considered as documentation of disease progression. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 36 
• 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 (PD in soft tissue per RECIST v1.1 or in bone 
by PCWG3 criteria). 
• 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 (PD in soft tissue per RECIST v1.1 or in bone by PCWG3 criteria), and not 
qualifying for a CR. 
• SD (applicable only to participants 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 (PD in soft tissue per RECIST v1.1 or in bone by PCWG3 
criteria), and not qualifying for CR or PR. 
• Non-CR/non-PD (applicable only to participants 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 (PD in soft tissue per 
RECIST v1.1 or in bone by PCWG3 criteria), and not qualifying for CR or PR. 
•  PD = progression ≤ 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. 
Soft tissue Objective Response (OR) is defined as confirmed BOR of CR or PR in soft tissue.  
Participants who do not have a post-baseline radiographic assessment of soft tissue or bone 
lesions 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 soft 
tissue OR. Each participant will have an objective response status (0: no OR; 1: OR). Soft 
tissue OR rate (ORR) is the proportion of participants with soft tissue OR in the analysis set. 
Soft tissue ORR by treatment group will also be calculated along with the 2-sided 95% CI 
using the Clopper-Pearson method3 (exact CI for a binomial proportion as computed by 
default by the FREQ procedure using the EXACT option).  
In addition, the frequency (number and percentage) of participants with a confirmed soft 
tissue BOR of CR, PR, SD, non-CR/non-PD (applicable only to participants with non-
measurable disease at baseline), PD, and NE will be tabulated. Participants with confirmed 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 37 
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  
• 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 soft tissue 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). 
6.1.4. PSA response for participants with mCRPC  
6.1.4.1. Primary analysis 
The following analyses will be based on the FAS for participants with mCRPC as shown in 
Table 3.   
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 on or before the start of any further anti-cancer therapies will be considered in the 
assessment of PSA response and PSA progression. 
• 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 participant will have a PSA response status (0: no PSA response; 1: PSA response). 
PSA response rate is the proportion of participants with PSA response in the analysis set.  
PSA response rate by treatment group will be calculated along with the 2-sided 95% CI using 
the Clopper-Pearson method3 (exact CI for a binomial proportion as computed by default by 
the FREQ procedure using the EXACT option). 
For patients with PSA declines after baseline, the PSA progression date is defined as the date 
that a ≥ 25% increase and an absolute increase of ≥ 2 µg/L (2 ng/mL) above the nadir is 
documented, which is confirmed by a second consecutive value obtained at least 3 weeks 
later. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 38 
Early rises (before week 12) should be ignored in determining progression.  As such,  for 
patients with no PSA declines after baseline, the PSA progression date is defined as the date 
that a ≥ 25% increase and an absolute increase of ≥ 2 µg/L (2 ng/mL) above the baseline is 
documented after 12 weeks of treatment, which is confirmed by a second consecutive value 
at least 3 weeks later. 
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 as shown in Table 3.  Assessment of tumor 
response will be made using RECIST v1.1 (for Combination A) and PCWG3 criteria (for 
Combinations B and C).  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 diameter 
of all target lesions for each participant with measurable disease at baseline and at least one 
post-baseline assessment. 
6.2.2.2. PSA reduction from baseline 
For patients with mCRPC, the level of PSA will be summarized as the percent change from 
baseline per time point. It will be derived as: 
• ((PSA at week XX – PSA at baseline)/PSA at baseline) × 100 
The maximum reduction in PSA from baseline will be derived across all the post-baseline 
assessments until PSA progression, excluding assessments after start of subsequent anti-
cancer therapy, as: 
• Minimum of ((PSA at week XX – PSA at baseline)/PSA at baseline) × 100 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 39 
A waterfall plot of maximum percent decrease in PSA value from baseline will be created. 
The plot will display the best percentage change from baseline in PSA value for each 
participant with a baseline assessment and at least one post-baseline assessment. 
6.2.2.3. Disease control 
Disease Control (DC) is defined as BOR (for Combination A) or soft tissue BOR (for 
Combinations B and C) of CR, PR, non-CR/non-PD or SD.  DC rate (DCR) is the proportion 
of participants with DC.     
DCR will be summarized by frequency counts and percentages. 
6.2.2.4. Duration of tumor response 
For participants with SCCHN in Combination A, Duration of Response (DR) is defined, for 
participants 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. The documentation of 
PD is defined using RECIST v1.1. 
If a participant 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 4. 
 
DR (months) = [date of event or censoring– first date of OR +1]/30.4375 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 40 
Table 4. 
Outcome and Event Dates for DR Analyses 
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. 
 
For participants with mCRPC who achieve soft tissue OR in Combinations B and C, DR is 
defined as the time from the first documentation of soft tissue response per RECIST v1.1 and 
no evidence of confirmed bone disease progression by PCWG3 criteria to the first 
subsequent documentation of PD by soft tissue evaluated per RECIST v1.1 or bone disease 
evaluated per PCWG3 criteria, or death due to any cause. The documentation of PD is 
defined by either soft tissue progression using RECIST v1.1 or by bone disease using 
PCWG3 criteria, as described in Table 5. 
If a participant 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 4. 
 
DR (months) = [date of event or censoring– first date of soft tissue OR +1]/30.4375 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 41 
Table 5. 
Criteria for Evidence of Radiographic Progression for Participants with 
mCRPC 
Date Progression 
Detected a 
 
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 a 
Timing: At least 6 weeks 
after progression 
identified or at Week 16 
visit b  
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 point b 
Persistent or increase in 
number of bone lesions 
on bone scan compared 
to prior scan c 
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). 
 
Kaplan-Meier estimates6 (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 event free rates at 2, 4, 6, 8, 10, 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)2 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)5 (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 participants with OR (for participants with SCCHN in Combination A) and soft 
tissue OR (for participants with mCRPC in Combinations B and C) 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 participants 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 6 following the hierarchy shown. 
  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 42 
Table 6.  
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) = Participant 
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 participant 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.     
 
The DR time or censoring time and the reasons for censoring will also be presented in a 
participant listing. 
6.2.2.5. Duration of PSA response 
For participants with mCRPC in Combinations B and C and PSA response, duration of PSA 
response is defined as the time from the first documentation of PSA response to the date of 
the date that a ≥25% increase in PSA with an absolute increase of ≥2 μg/L (2 ng/mL) above 
the nadir (or baseline for participants with no PSA decline) is documented. PSA progression 
must be confirmed by a second, consecutive PSA assessment ≥3 weeks later.  
Duration of PSA response will be censored on the date of the last PSA assessment for 
participants who do not have an event (confirmed PSA progression), for participants who 
start a new anti-cancer therapy prior to an event (see Section 5.2.6) or for participants with an 
event after 2 or more missing PSA assessments.  The censoring rules for duration of PSA 
response are described in Table 7.   
Duration of PSA response (months)= [date of event or censoring– first date of PSA 
response +1]/30.4375 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 43 
Table 7. 
Outcome and Event Dates for Duration of PSA Response Analysis 
Scenario  
Date of event/censoring  
Outcome  
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 estimates6 (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median duration of PSA 
response time with 2-sided 95% CIs.  In particular, the event free rates at 2, 4, 6, 8, 10, 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)2 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)5 (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula. 
Duration of PSA will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of participants with PSA response 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 participants with an event and censoring reasons will 
be presented.  Reasons for censoring will be summarized according to the categories in Table 
8 following the hierarchy shown. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 44 
Table 8. 
Duration of PSA Response 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 post-baseline PSA 
assessments/date of first dose of study treatment 
Event after missing assessments a 
3 
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = 
Participant 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 participant will not continue into 
any subsequent phase of the study] and no post-baseline 
PSA assessment  
No post-baseline PSA assessment 
6 
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
a 2 or more missing post-baseline PSA assessments.     
 
The duration of PSA response time or censoring time and the reasons for censoring will also 
be presented in a participant listing. 
6.2.2.6. Time to tumor response 
For participants with SCCHN in Combination A, time to tumor response (TTR) is defined, 
for participants 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.  
        TTR (in months) = [first date of OR – date of first dose of study treatment +1]/30.4375 
For participants with mCRPC in Combinations B and C who achieve soft tissue OR, TTR is 
defined is defined as the time from the date of first dose of study treatment to the first 
documentation of soft tissue response which is subsequently confirmed with no evidence of 
bone disease progression per PCWG3 criteria. 
TTR (in months) = [first date of soft tissue 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). 
6.2.2.7. Time to PSA response 
For participants with mCRPC in Combinations B and C and PSA response, time to PSA 
response (TTPSAR) is defined as the time from the date of first dose of study treatment to 
the date that PSA decline ≥50% compared to baseline which is subsequently confirmed a 
second, consecutive PSA assessment ≥ 3 weeks later.  
 TTPSAR (in months) = [first date of PSA response – date of first dose of study 
treatment +1]/30.4375 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 45 
TTPSAR will be summarized using simple descriptive statistics (mean, SD, median, min, 
max. Q1, Q3). 
6.2.2.8. Progression-free survival 
For participants with SCCHN in Combination A, 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.    
PFS for participants with mCRPC in Combinations B and C is defined as the time from the 
date of first dose of study treatment to the date of the first documentation of radiographic 
progression in soft tissue per RECIST v1.1, or bone per PCWG3 criteria, or death due to any 
cause, whichever occurs first. 
PFS data will be censored on the date of the last adequate tumor assessment for participants 
who do not have an event (PD or death), for participants who start a new anti-cancer therapy 
prior to an event (see Section 5.2.6) or for participants with an event after 2 or more missing 
tumor assessments.  Participants 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.  
Antitumor activity in participants with SCCHN will be assessed through radiological tumor 
assessments conducted at screening and every 8 weeks (± 7 days) until PD regardless of 
initiation of subsequent anti-cancer therapy.  After 52 weeks from the date of first dose of 
study treatment, tumor assessments will be conducted less frequently, ie, at 16-week (± 7 
days) intervals. 
Antitumor activity in participants with mCRPC will be assessed through radiological tumor 
assessments conducted at screening and every 8 weeks (± 7 days) until PD regardless of 
initiation of subsequent anti-cancer therapy.  After 52 weeks from the date of first dose of 
study treatment, tumor assessments will be conducted less frequently, ie, at 12-week (± 7 
days) intervals. 
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 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 46 
Table 9. 
Outcome and Event Dates for PFS Analyses 
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 participant 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 
 
Kaplan-Meier estimates6 (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 2, 4, 6, 8, 10, 12, 15, 18, and 24 months will be 
estimated with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982)2 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)5 (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 participants 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. 
  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 47 
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) = 
Participant 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 participant 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.     
 
The PFS time or censoring time and the reasons for censoring will also be presented in a 
participant listing. 
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.  Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
group together with a summary of associated statistics including the median time of follow-
up for PFS with 2-sided 95% CIs.  In particular, the rates at 2, 4, 6, 8, 10, 12, 16, 18, and 24 
months will be estimated with corresponding 2-sided 95% CIs. 
6.2.2.9. Time to PSA progression for participants with mCRPC 
Time to PSA progression for participants with mCRPC is defined as the time from the date of 
first dose of study treatment to the date of PSA progression, as defined in Section 6.1.4.1.  
Time to PSA progression will be censored on the date of the last PSA assessment for 
participants who do not have an event (confirmed PSA progression), for participants who 
start a new anti-cancer therapy prior to an event (see Section 5.2.6) or for participants with an 
event after 2 or more missing PSA assessments. Participants 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 ± 7 days and at EOT.  
The censoring and event date options to be considered for the time to PSA progression 
analysis are presented in Table 11.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 48 
 
Time to PSA progression (months) = [date of PSA progression or censoring– date of first 
dose of study treatment +1]/30.4375 
Table 11. 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 estimates66 (product-limit estimates) will be presented together with a 
summary of associated statistics including the median time to PSA progression with 2-sided 
95% CIs. In particular, the PSA progression rates at 2, 4, 6, 8, 10, 12, 15, 16, 18, and 24 
months will be estimated with corresponding 2-sided 95% CIs. The CIs for the median will 
be calculated according to Brookmeyer and Crowley (1982)2 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)5 (conftype=loglog default option 
in SAS Proc LIFETEST). The estimate of the standard error will be computed using 
Greenwood’s formula.  
Frequency (number and percentage) of participants with an event and censoring reasons will 
be presented.  Reasons for censoring will be summarized according to the categories in Table 
12  following the hierarchy shown. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 49 
Table 12. PSA Progression Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No baseline PSA assessment 
No baseline PSA assessment 
2 
Start of new anti-cancer therapy  
Start of new anti-cancer therapy 
3  
Event after 2 or more missing post-baseline PSA 
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) = 
Participant 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 participant will not continue into 
any subsequent phase of the study] and no post-baseline 
PSA assessment  
No post-baseline PSA assessment 
7  
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
a 2 or more missing post-baseline PSA assessments.     
 
The PSA progression-free interval or censoring time and the reasons for censoring will also 
be presented in a participant listing. 
6.2.2.10. 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. Participants 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 estimates6 (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, 18, 24, and 30 months will be 
estimated with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982)2 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)5 (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 participants 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 13 following the hierarchy shown. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 50 
Table 13. 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) = 
Participant 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 
participant 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.  Kaplan-Meier 
estimates6 (product-limit estimates) will be presented by treatment group together with a 
summary of associated statistics including the median time of follow-up for OS with 2-sided 
95% CIs.  In particular, the rates at 3, 6, 9, 12, 15, 18, 24, and 30 months will be estimated 
with corresponding 2-sided 95% CIs. 
6.2.2.11. CTC count conversion and CTC0 for participants with mCRPC 
CTC count conversion is defined as a decrease in CTC count from ≥ 5 CTC per 7.5 mL of 
blood at baseline to < 5 CTC per 7.5 mL of blood on study. Only the CTC count assessments 
performed on or before the start of any further anti-cancer therapies will be considered in the 
assessment of CTC count conversion. The analysis set will include all participants with CTC 
count ≥ 5 CTC per 7.5 mL at baseline. All other participants will be considered as non-
evaluable. The participants in the analysis set will be counted as:  
• CTC count conversion = one or more post-baseline assessment(s) of CTC count < 5 
CTC per 7.5 mL  
• No CTC count conversion = all other cases.  
Participants with CTC count ≥ 5 CTC per 7.5 mL at baseline and who do not have a post-
baseline CTC count assessment will be counted as no CTC count conversion. Each 
participant in the analysis set will have a CTC count conversion status (0: no CTC count 
conversion; 1: CTC count conversion). The CTC count conversion rate is the proportion of 
participants with CTC count conversion rate in the analysis set.  
A waterfall plot of maximum percent decrease in CTC count from baseline will be created 
for all participants with CTC count ≥ 5 CTC per 7.5 mL at baseline. The plot will display the 
best percentage change from baseline in CTC count for each participant with a baseline 
assessment and at least one post-baseline assessment. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 51 
CTC0 is defined as a decrease in CTC count from ≥ 1 CTC per 7.5 mL of blood at baseline 
to an undetectable level on study. Only the CTC count assessments performed on or before 
the start of any further anti-cancer therapies will be considered in the assessment of CTC0. 
The analysis set will include all participants with CTC count ≥ 1 CTC per 7.5 mL at baseline. 
All other participants will be considered as non-evaluable. The participants in the analysis set 
will be counted as:  
• CTC0 = one or more post-baseline CTC count are at undetectable level(s)  
• No CTC0 = all other cases.  
Participants with CTC count ≥ 1 CTC per 7.5 mL at baseline and who do not have a post-
baseline CTC count assessment will be counted as no CTC0. Each participant in the analysis 
set will have a CTC0 status (0: no CTC0; 1: CTC0). The CTC0 rate is the proportion of 
participants with CTC0 in the analysis set. 
The CTC count conversion rate and CTC0 rate will be calculated along with the 2-sided 95% 
CI using the Clopper-Pearson method3 exact CI for a binomial proportion as computed by 
default by the FREQ procedure using the EXACT option). 
6.2.3. Pharmacokinetic endpoints 
The following pharmacokinetic analyses will be based on the PK analysis sets by treatment 
group as shown in Table 3.   
PK parameters to be determined for avelumab, bempegaldesleukin (NKTR-214), IL-2, 
talazoparib, enzalutamide, and N-desmethyl-enzalutamide are defined in Table 14.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 52 
Table 14. PK Parameters to be Determined for Avelumab, Bempegaldesleukin 
(NKTR-214), IL-2, Talazoparib and Enzalutamide 
Parameter 
Definition 
Method of Determination 
Cmax for avelumab, 
bempegaldesleukin 
(NKTR-214) and IL-2 
Maximum observed plasma 
concentration at the end of infusion  
Observed directly from data 
Ctrough for avelumab, 
bempegaldesleukin 
(NKTR-214), IL-2, 
talazoparib, 
enzalutamide, and N-
desmethyl-enzalutamide 
Predose concentration at the end of 
dosing interval 
Observed directly from data 
Ctrough (dn) a for 
talazoparib, 
enzalutamide, and N-
desmethyl-enzalutamide 
Dose-normalized Ctrough 
Ctrough/dose 
Tmax a for 
bempegaldesleukin and 
IL-2 
Time for Cmax 
Observed directly from data as time 
of first occurrence 
AUClast a for 
bempegaldesleukin and 
IL-2 
Area under the plasma 
concentration-time profile from time 
zero to the time of the last quantifiable 
concentration (Clast) 
Linear/Log trapezoidal method 
t½ a for 
bempegaldesleukin and 
IL-2 
Terminal half-life 
Loge(2)/kel, 
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the log-linear 
concentration-time curve.  Only those 
data points judged to describe the 
terminal log-linear decline were used 
in the regression. 
a If data permit. 
IL-2 is the active form of (NKTR-214) 
Ctrough for avelumab, bempegaldesleukin (NKTR-214),  IL-2, talazoparib, enzalutamide and 
N-desmethyl-enzalutamide, and Cmax for avelumab, bempegaldesleukin (NKTR-214) and IL-
2 will be summarized descriptively (n, mean, SD, CV, median, minimum, maximum, 
geometric mean, its associated CV, and 95% CI) by treatment group, dose level, cycle, day 
and nominal time. Other PK parameters including Tmax, AUClast, and t1/2 will be calculated for 
bempegaldesleukin (NKTR-214) and IL-2 after first dose as appropriate, and summarized 
using similar descriptive statistics. 
Concentration dose normalized Ctrough (CDN- Ctrough) will be reported for talazoparib, 
enzalutamide, and N-desmethyl-enzalutamide, as appropriate, using similar descriptive 
statistics described above.  
Pharmacokinetic parameters for avelumab, bempegaldesleukin (NKTR-214), IL-2, 
talazoparib, enzalutamide, and N-desmethyl-enzalutamide will be taken from observed 
values. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 53 
Presentation of pharmacokinetic data will include: 
• Linear-linear plots of mean and median plasma concentrations by nominal time for 
bempegaldesleukin (NKTR-214) and IL-2 after the first dose will be presented for PK 
sampling days by treatment group, cycle, and study day.  Similar plots will be presented 
for each individual participant concentrations. Participants who have undergone 
intraparticipant dose reduction or escalation will be excluded from the median plasma 
concentration-time plots. 
• Pharmacokinetic parameters for avelumab, bempegaldesleukin (NKTR-214), IL-2, 
talazoparib, enzalutamide, and N-desmethyl-enzalutamide will be listed and summarized 
by treatment group/dose level, cycle and study day using descriptive statistics (n, mean, 
SD, %CV, median, minimum, maximum, geometric mean and its associated %CV, and 
95% CI). PK parameters with zero values will be excluded from the calculation of 
geometric means and its associated %CV. For talazoparib, enzalutamide, and N-
desmethyl-enzalutamide, if an intraparticipant dose escalation or reduction occurs, dose-
dependent PK Ctrough for that participant may be dose-normalized or may only be 
included in descriptive statistics and summary plots up to the time of the dose change.  
• Box plots for Ctrough for avelumab, bempegaldesleukin (NKTR-214), IL-2, talazoparib, 
enzalutamide, and N-desmethyl-enzalutamide and Cmax for avelumab, bempegaldesleukin 
(NKTR-214) and IL-2 will be generated by treatment group/dose level, cycle and study 
day to assess the attainment of steady-state. 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 and Cmax for avelumab, bempegaldesleukin (NKTR-214) and IL-2 and Ctrough for each 
drug and its active metoblites in individual participants will then be generated.  
• PK parameters of avelumab, bempegaldesleukin (NKTR-214), IL-2 talazoparib, 
enzalutamide, and N-desmethyl-enzalutamide from this study may be compared with the 
historical PK parameters when avelumab, bempegaldesleukin (NKTR-214), IL-2, 
talazoparib, and enzalutamide were administered as single agents. 
6.2.4. Population pharmacokinetic endpoints 
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab, bempegaldesleukin (NKTR-214), IL-2, talazoparib 
enzalutamide and N-desmethyl-enzalutamide exposure and biomarkers or significant 
safety/efficacy endpoints. The results of these analyses, if performed, may be reported 
separately. 
6.2.5. Biomarker endpoints 
Secondary biomarker endpoints include PD-L1 expression level in baseline tumor tissue for 
combinations A, B, and C, and PD-L1 expression level in on-treatment tumor tissue for 
Combination A as described in Table 15. 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 54 
Table 15. Biomarker Definition and Determination 
Parameter 
Definition 
Method of Determination 
PD-L1 expression level in 
baseline tumor tissue, and in 
on-treatment tumor tissue 
(Combination A only) 
The number of PD-L1 positive cells and/or 
qualitative assessment of PD-L1 staining on 
tumor and/or inflammatory cells in regions 
of interest  
Pathologist, assisted by 
image analysis  
 
Biomarker data will be analyzed based on the biomarker analysis sets as defined in Section 
4.3.3.  Data will be summarized as shown in Table 3. 
Biomarker values at screening will be listed and summarized. 
For PD-L1 expression, participants will be classified as positive or negative according to 
scoring algorithms and cut-offs established from internal or external sources.   
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 and on-treatment/end of treatment time points, as appropriate.  
For discrete measurement biomarker results, frequencies and percentages of categorical 
biomarker measures will be determined at baseline and on-treatment/end of treatment time 
points.  Shift tables may also be provided as appropriate. 
Change from baseline measurements will be provided, as appropriate. 
BOR rate (for participants with SCCHN in Combination A) and soft tissue BOR rate (for 
participants with mCRPC in Combinations B and C) will be summarized and for each 
category following the methodology outlined in Section 6.1.2 and Section 6.1.3.  The number 
of responders (participants with BOR of CR or PR) will be tabulated relative to biomarker 
classifications using a contingency table. 
PSA response rate (for participants with mCRPC in Combinations B and C) will be 
summarized and for each category following the methodology outlined in Section 6.1.4.  The 
number of responders  will be tabulated relative to biomarker classifications using a 
contingency table. 
DR, duration of PSA response (for participants with mCRPC only), PFS, time to PSA 
progression (for participants with mCRPC only), and OS (if meaningful) will be summarized for 
each category of the biomarkers following the methodology outlined in Sections 6.2.2.4, 6.2.2.5, 
6.2.2.8, 6.2.2.9, and 6.2.2.10. 
6.2.6. Endpoints for immunogenicity data of avelumab, bempegaldesleukin (NKTR-
214), and IL-2 
All analyses described below are performed as shown in Table 3. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 55 
Blood samples for avelumab, bempegaldesleukin (NKTR-214), and IL-2 immunogenicity 
testing will be collected pre-dose on day 1 of Cycle 1, 2, 3, 6, 9, 12 and EOT. All samples 
should be drawn within 2 hours before start of infusion for avelumab and bempegaldesleukin 
(NKTR-214).  
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.  The 
analyses of nAb data described in the following sections will only be conducted contingent 
upon assay and data availability at the time of reporting.  
Participants will be characterized into different ADA categories based on the criteria defined 
in Table 16.   
Table 16.  Participants Characterized Based on Anti-Drug Antibody Results (ADA 
Status) 
Category 
Definition 
Participants at Risk (Denominator 
for Incidence) 
ADA never-positive  No positive ADA results at any time point; 
ADA-negative participants (titer < cutpoint) 
Number of participants 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 participants (titer ≥ 
cutpoint) 
Number of participants with at least 
one valid ADA result at any time 
point 
Baseline ADA 
positive 
A positive ADA result at baseline 
Number of participants 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/ bempegaldesleukin (NKTR-
214) 
Number of participants with valid 
baseline ADA results and at least one 
valid post-baseline ADA result 
Treatment-induced 
ADA 
Participant is ADA-negative at baseline and has 
at least one positive post-baseline ADA result; 
or if participant does not have a baseline 
sample, the participant has at least one positive 
post-baseline ADA result 
Number of participants with at least 
one valid post-baseline ADA result 
and without positive baseline ADA 
result (including missing, NR) 
Transient ADA 
response 
If participants 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 participants with at least 
one valid post-baseline ADA result 
and without positive baseline ADA 
result (including missing, NR) 
Persistent ADA 
response 
If participants 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 participants 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. 
 
Participants will be characterized into different nAb categories based on the criteria in Table 
17. For nAb, treatment-boosted is not applicable since no titer result is available. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 56 
Table 17.  Participants Characterized Based on Neutralizing Antibody Results (nAb 
Status) 
Category 
Definition 
Participants at Risk (Denominator 
for Incidence) 
nAb never-positive  
No positive nAb results at any time point 
Number of participants 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 participants with at least 
one valid ADA result at any time point 
Baseline nAb 
positive 
A positive nAb result at baseline 
Number of participants with valid 
baseline ADA result 
Treatment-induced 
nAb 
Participant is not nAb positive at baseline and 
has at least one positive post-baseline nAb 
result; or if participant does not have a 
baseline sample, the participant has at least 
one positive past-baseline ADA result 
Number of participants with at least 
one valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR) 
Transient nAb 
response 
If participants 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 participants with at least 
one ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR) 
Persistent nAb 
response 
If participants 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 participants with at least 
one valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR) 
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result. 
 
The number and percentage of participants in each ADA and nAb category will be 
summarized.  
6.2.6.1. Time to and Duration of ADA and nAb response  
The ADA and nAb analyses described below will include participants with treatment-
induced ADA or nAb, respectively.   
Time (weeks) to ADA response is defined as: 
(Date of first positive ADA result – date of first dose of avelumab + 1)/7.  
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).   
Duration (weeks) of ADA response is defined as: 
(Date of last positive ADA result – date of first positive ADA result + 1)/7.  
Duration of ADA response will be censored if:  
• the last ADA assessment is positive AND participant is ongoing treatment with 
avelumab, or 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 57 
• the last ADA assessment is positive AND participant discontinued treatment with 
avelumab AND the last planned ADA assessment (End of Treatment) is after the cut-off 
date. 
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result.  
Kaplan-Meier estimates6 (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley 
(1982)2 and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)5 (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula. 
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of participants with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided 
As data permit, the analyses described above will be repeated for participants with treatment-
induced nAb.  
6.2.6.2. ADA titer 
For participants who are ADA ever positive, the maximum observed ADA titer for a 
participant will be summarized, overall and by ADA subcategories (baseline ADA positive, 
treatment-boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA 
response) of participants having each discrete maximum titer value will be tabulated. The 
denominator to calculate the percentages will be the total number of participants in the 
associated ADA subcategory.  
For participants with treatment-induced ADA, a cross tabulation of duration of ADA 
response and maximum ADA titer will be provided. The following categories for duration of 
ADA response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to 
≤25, >25 weeks. In this categorization, the censoring in duration of ADA response is ignored.  
6.2.6.3. Analysis of PK and safety by immunogenicity status 
The following ADA and nAb status will be used for the analyses described below. 
ADA  
• ADA ever-positive versus ADA never-positive  
• ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 58 
nAb  
• nAb ever-positive versus nAb never-positive  
• nAb: treatment-induced nAb versus nAb never-positive or baseline nAb positive 
Data listings will include immunogenicity data together with relevant PK, and safety data. 
PK parameters and immunogenicity status 
The following analyses will include participants in both the immunogenicity analysis set and 
in the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity 
analyses are Ctrough and Cmax for avelumab, bempegaldesleukin (NKTR-214) and IL2.  
Blood samples for avelumab PK will be collected as outlined in the “Schedule for 
Pharmacokinetic Sample Collection” table of the Schedule of Assessments section of the 
protocol. 
Ctrough and Cmax will be summarized descriptively (n, mean, SD, CV, median, minimum, 
maximum, geometric mean, its associated CV, and 95% CI) by nominal time and ADA 
status. Linear-linear and log-linear plots of mean and median for Ctrough and Cmax over 
nominal time and by ADA status will be presented.  
Among participants with treatment-induced ADA, analyses will be conducted to assess 
whether Ctrough and Cmax have any changes before and after the first positive ADA assessment. 
To be included in this analysis, participants must have the same PK parameter available both 
before and after the first positive ADA assessment.  Relative PK day will be calculated as: 
(PK assessment nominal day) – (first positive ADA assessment nominal day). 
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is 
collected on Day 1 of Cycle 2 and the first positive ADA result is observed on Day 1 of 
Cycle 3, then the relative PK day for this Ctrough is -14. Linear-linear and log-linear plots of 
mean and median for Ctrough and Cmax over relative PK day will be presented.  
As data permit, the analyses described above will be repeated for nAb. 
Safety and immunogenicity status 
The following analyses will include participants in the immunogenicity analysis set. 
The frequency (number and percentage) of participants with each of the following will be 
presented by ADA status. 
• TEAEs, by SOC and PT  
• TEAEs leading to dose reduction of avelumab, by SOC and PT 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 59 
• TEAEs leading to dose reduction of bempegaldesleukin (NKTR-214), by SOC and PT 
• TEAEs leading to discontinuation of avelumab, by SOC and PT 
• TEAEs leading to discontinuation of bempegaldesleukin (NKTR-214), by SOC and PT 
• TEAEs leading to discontinuation of any study drug, by SOC and PT 
• Grade ≥ 3 TEAEs, by SOC and PT  
• SAEs, by SOC and PT 
• IRRs, by PT 
For participants who had at least one IRR and have treatment-induced ADA, time related to 
first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later) will be 
summarized taking into account whether the IRR occurred on or after the first ADA positive 
assessment or whether the IRR occurred before the first ADA positive assessment.   
As data permit, the analyses described above will be repeated for nAb. 
 
 
 
 
 
 
 
 
 
 
 
6.4. Subset Analyses 
Applicable to efficacy assessments only.  For Combinations A and C, phase 1b participants 
treated at the RP2D will combined with Phase 2 participants. For Combination B, the subset 
analyses will only include Phase 2 participants. 
The following efficacy endpoints (if meaningful) will be summarized by PD-L1 expression at 
baseline (negative vs positive) 
• OR and DR in participants with SCCHN in Combination A 
CCI


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 60 
• Soft tissue OR and DR in participants after progression on taxane-based chemotherapy 
with mCRPC in Combination B 
• Soft tissue OR and DR, PSA response and duration of PSA response in participants with 
mCRPC after progression on abiraterone in Combination C 
In addition, soft tissue OR and DR in participants with mCRPC after progression on 
abiraterone in Combination C will be summarized for participants with measurable disease at 
baseline. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline summaries 
The following analyses will be based on the FAS as shown in Table 3. 
6.5.1.1. Demographic characteristics 
Demographic characteristics and physical measurements will be summarized by treatment 
group using the following information from the ‘Screening/Baseline Visit’ eCRF pages. 
• Demographic characteristics  
- Gender: Male, Female  
- Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiracial, Not Reported 
- Ethnic origin:  
• Hispanic or Latino  
• Not Hispanic or Latino 
• 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 
treated population) 
- Geographic Region (as applicable): 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 61 
 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  
• Physical measurements 
- Height (cm) 
- Weight (kg) 
- Body Mass Index (BMI) (kg/m2) 
Center codes will be used for the determination of the participant’s geographic region. 
The listing of demographics and baseline characteristics will include the following 
information: participant identifier, treatment group, age, sex, race, ethnicity, height (cm), 
weight (kg), BMI (kg/m2), and ECOG performance status. 
6.5.1.2.  Medical history 
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’ 
eCRF page. Medical history will be summarized as the numbers and percentages of 
participants by MedDRA preferred term (PT) as event category and MedDRA primary 
system organ class (SOC) as summary category. Each participant will be counted only once 
within each PT or SOC. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order. 
6.5.1.3.  Disease characteristics 
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Use’ and 
RECIST eCRF pages will be summarized overall and by treatment group. Summary statistics 
will be presented for the following. 
From the ‘Primary Diagnosis’ eCRF page: 
• Site of primary tumor 
• Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page) 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 62 
• Time since initial diagnosis to date of first dose of study treatment (months), defined as 
(date of first dose of study treatment – 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 
From the ‘Substance Use’ eCRF page: 
• Smoking history (never smoker vs current vs former smoker)  
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ and ‘Substance Use’ eCRF pages) and derived variables as above. 
6.5.1.4.  Prior anti-cancer 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 participants in each of the following anti-cancer therapy 
categories will be tabulated: 
• Participants with at least one type of prior anti-cancer therapy 
• Participants with at least one prior anti-cancer drug therapy 
• Participants with at least one prior anti-cancer radiotherapy 
• Participants with at least one prior anti-cancer surgery 
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of participants with the following: 
• At least one prior anti-cancer drug therapy 
• Number of prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4 
• 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 
participants by the drug class and preferred term. A participant 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 therapies will be included in the listings that follow with a flag to identify 
prior therapies. These will include the participant identification number, and all the relevant 
collected data-fields on the corresponding eCRF pages. 
• Listing of anti-cancer drug therapies  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 63 
• Listing of anti-cancer radiotherapy  
• Listing of anti-cancer surgeries 
6.5.2. Study conduct and participant disposition 
The following analyses will be performed based on the FAS as shown in Table 3. 
6.5.2.1. Patient disposition 
The percentages below will be calculated based on the number of participants in the FAS. 
• Total number of participants screened overall 
• Number of participants who discontinued from the study prior to treatment with study drug  
overall and by the main reason for discontinuation 
• Number and percentage of treated participants in each of the analysis sets defined in 
Section 4 
• Number and percentage of participants with study drug ongoing (separately for each study 
drug administered in combination) 
• Number and percentage of participants 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 participants who entered follow-up 
• Number and percentage of participants who discontinued follow-up overall and by the 
main reason for discontinuation 
In addition, the following will be summarized: 
• Number and percentage of treated participants 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 participants by center 
6.5.2.2. Protocol deviations 
All protocol violations that impact the safety of the participants and/or the conduct of the 
study and/or its evaluation will be reported. These include: 
• Participants who are dosed on the study despite not satisfying the inclusion criteria 
• Participants who develop withdrawal criteria whilst on the study but are not withdrawn 
• Participants who receive the wrong treatment or an incorrect dose 
• Participants 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. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 64 
6.5.3. Study treatment compliance and exposure 
The following analyses will be based on the safety analysis set as shown in Table 3. 
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is participant-dependent, rather than study-drug-
dependent when study drugs are administered in combination.   
For Cycle X, actual cycle start date for each participant is 
• the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the 
participant received study treatment on that visit (ie, any study drug with dose>0 at that 
visit) 
• the first day of assessments in the Cycle X day 1 visit, if the participant did not receive 
study treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in 
the exposure page if available; if start date is not available then use date of collection of 
vital signs on Cycle X day 1 visit. 
Actual cycle end date for each participant is,  
• for all cycles X except the last cycle, actual cycle end date =  actual cycle (X+1) start date 
– 1 day; 
• for the last cycle, 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 as dose received (cumulative dose, actual dose intensity) and 
as dose received relative to intended dose (relative dose intensity [RDI]).   
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical, oral daily, oral cyclical).   
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: 
• Avelumab administered as a 1-hour IV infusion at a dose of 800 mg once every 2 weeks in 
4-week cycles.  
• NKTR-214 administered as a 30-minute IV infusion at a dose of 0.006 or 0.003 mg/kg 
once every 2 weeks in 4-week cycles.  
• Talazoparib administered orally QD PO at a dose of 0.5, 0.75, or 1.0 mg.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 65 
• Enzalutamide administered orally QD PO at a dose of 80, 120 or 160 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 study drug +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 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] = [1600 (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 NKTR-214  
The dose level for NKTR-214 is calculated as actual dose administered/weight (mg/kg). The 
last available weight of the participant on or prior to the day of dosing will be used. 
Intended duration of treatment with NKTR-214 (weeks) =  
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of NKTR-214 + 28 – 1 
Duration of exposure to NKTR-214  (weeks) =  
(last dose date of NKTR-214 – first dose date of NKTR-214 + 14)/7   
Cumulative dose is the sum of the actual doses of NKTR-214 received.   


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 66 
Actual Dose Intensity (DI)  
• Overall actual DI (mg/kg/4-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with NKTR-214(weeks)/4].   
Relative Dose Intensity (RDI)   
• Intended DI (mg/kg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [d (mg/kg)] / [1 (4-week cycle)] = d (mg/kg/4-week 
cycle) 
• Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [d (mg/kg/4-week cycle)]  
Where d=0.006 mg/kg or 0.003 mg/kg 
6.5.3.3. 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   
Cumulative dose is the sum of the actual doses of talazoparib received in the study.   
Actual Dose Intensity (DI)  
• Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)]    
Relative Dose Intensity (RDI) 
• RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of talazoparib to last dose of talazoparib]  
 = 100 × [overall cumulative dose] / [7 × d × duration of exposure to talazoparib in 
weeks]  
where d=0.5 mg, 0.75 mg, or 1.0 mg. 
6.5.3.4. Exposure to enzalutamide 
The dose level is calculated as actual dose administered (mg/day). 
Intended duration of treatment with enzalutamide (weeks)= (end date – date of first dose 
of enzalutamide +1)/7,  
where end date = date of last dose of enzalutamide. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 67 
Duration of exposure to enzalutamide (weeks) =  
(last dose date of enzalutamide – first dose date of enzalutamide + 1)/7   
Cumulative dose is the sum of the actual doses of enzalutamide 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 enzalutamide to last dose of enzalutamide]  
 = 100 × [overall cumulative dose] / [7 × d × duration of exposure to enzalutamide in 
weeks]  
where d=160 mg, 120 mg, or 80 mg. 
6.5.3.5. Dose reductions  
Applicable to  avelumab and NKTR-214.  Dose reduction is defined as actual non-zero dose 
< 90% of the planned dose.  
Applicable to talazoparib  and enzalutamide.  Dose reduction is defined as a change to a non-
zero dose level lower than that planned in the protocol. 
The number and percentage of participants with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized.  
6.5.3.6. Dose interruptions 
Applicable to talazoparib and enzalutamide only.   
An interruption is defined a 0 mg dose administered on one or more days for talazoparib or 
enzalutamide. 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 not 0 mg 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, ie there 
is at least one dosing day in between, then each dose interruption will be counted as a 
different occurrence (example: If the actual dose on days 1, 3 and 5, is not 0 mg 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 participants with dose interruptions will be summarized. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 68 
6.5.3.7. Dose delays  
Applicable to avelumab and NKTR-214. 
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 1: 
Dose Delay (days) = day of the first day of study drug -1 
After Cycle 1 Dose 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 – Date of Dose (x-1) – 14.  
 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 participant receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the participant receives avelumab at Day 16 or 17, this is considered as 1-2 days delay.   
No delay and 1-2 days delay will also be summarized together.  
The number and percentage of participants with delayed study drug administration and 
maximum length of delay, ie, the worst case of delay if participants have multiple dose 
delays will be summarized.  
6.5.3.8. Infusion rate reductions 
Applicable to avelumab and NKTR-214. 
The number and percentage of participants 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 
participants with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized. 
6.5.3.9. Infusion interruptions 
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded). 
The number and percentage of participants with at least one infusion interruption as well as 
the frequency of participants with 1, 2, 3, or ≥4 infusion interruptions will be summarized. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 69 
6.5.4. Concomitant medications and non-drug treatments 
The following analyses will be based on the safety analysis set as shown in Table 3. 
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.  
Prior and concomitant medications will be summarized from the ‘General Concomitant 
Medications’ eCRF page. Pre-medications for study drug will also be summarized separately 
from the ‘Pre-Medication Treatment’ eCRF page.  
Summary of prior medications, summary of concomitant medications and summary of pre-
medications will include the number and percentage of participants by Anatomical 
Therapeutic Chemical (ATC) Classification level 2 and preferred term. A participant will be 
counted only once within a given drug class and within a given drug name, even if he/she 
received the same medication at different times. If any prior or concomitant medication is 
classified into multiple ATC classes, the medication will be summarized separately under 
each of these ATC classes. The summary tables will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used. In 
case any specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category.  
A listing of prior medications and a listing of concomitant medications will be created with 
the relevant information collected on the ‘General Concomitant Medications’ eCRF page.  A 
listing of pre-medications will be created with the relevant information collected on the ‘Pre-
Medication Treatment’ eCRF page. 
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’.  
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page. 
6.5.5. Subsequent anti-cancer therapies 
The following analyses will be based on the FAS as shown in Table 3. 
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, 
‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages.  
Number and percentage of participants 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.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 70 
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 as shown in Table 3.   
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 3.2.1. 
All analyses will be based on TEAEs (started during the on-treatment period) if not otherwise 
specified. The AE listings will include all AEs (whether treatment-emergent or not). AEs 
outside the on-treatment period will be flagged in the listings. 
• Related Adverse Events: adverse events with relationship to study treatment (as recorded 
on the AE eCRF page, Relationship with study treatment = Related) reported by the 
investigator and those of unknown relationship (ie, no answer to the question ‘Relationship 
with study treatment’).  Related AEs are those related to any study drug (ie, at least one of 
the study drugs).  
• Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes). 
• Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction of 
study treatment (as recorded on the AE eCRF page, Action taken with study treatment = 
Dose reduced). 
• Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).  IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion. 
• Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).   
• Adverse Events Leading to Death: adverse event leading to death (as recorded on the AE 
eCRF page, Outcome = Fatal, as well as AEs of Grade 5). 
• Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan (SRP) and finalized for analysis of the current 
studies data prior to DB lock) 
• Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
SRP and finalized for analysis of the current study data prior to DB lock. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 71 
Unless otherwise specified, AEs will be summarized by number and percentage of 
participants with the AE in the category of interest as described above, primary SOC and PT 
in decreasing frequency.  
Each participant will be counted only once within each SOC or PT. If a participant 
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 participant, 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 participant 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 
participants with each of the following by treatment group: 
- TEAEs 
- TEAEs, Grade ≥ 3 
- Related TEAEs 
- Related TEAEs, Grade ≥ 3 
- TEAEs leading to dose reduction of avelumab  
- TEAEs leading to dose reduction of NKTR-214  
- TEAEs leading to dose reduction of talazoparib  
- TEAEs leading to dose reduction of enzalutamide  
- TEAEs leading to interruption of avelumab 
- TEAEs leading to interruption of NKTR-214 
- TEAEs leading to interruption of talazoparib 
- TEAEs leading to interruption of enzalutamide 
- TEAEs leading to discontinuation of avelumab 
- TEAEs leading to discontinuation of NKTR-214 
- TEAEs leading to discontinuation of talazoparib 
- TEAEs leading to discontinuation of enzalutamide 
- TEAEs leading to discontinuation of any study drug 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 72 
- TEAEs leading to discontinuation of all study drugs 
- Related TEAEs leading to discontinuation of avelumab 
- Related TEAEs leading to discontinuation of NKTR-214 
- Related TEAEs leading to discontinuation of talazoparib 
- Related TEAEs leading to discontinuation of enzalutamide 
- Related TEAEs leading to discontinuation of any study drug 
- Related TEAEs leading to discontinuation of all study drugs 
- Serious TEAEs 
- Related Serious TEAEs  
- TEAEs leading to death 
- Related TEAEs leading to death 
- irAEs 
- IRRs  
• TEAEs by SOC and PT and worst grade 
• TEAEs related to avelumab by SOC and PT and worst grade 
• TEAEs related to NKTR-214 by SOC and PT and worst grade 
• TEAEs related to talazoparib by SOC and PT and worst grade  
• TEAEs related to enzalutamide 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 participants with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment group: 
• TEAEs leading to dose reduction of avelumab by SOC and PT 
• TEAEs leading to dose reduction of NKTR-214 by SOC and PT 
• TEAEs leading to dose reduction of talazoparib by SOC and PT  
• TEAEs leading to dose reduction of enzalutamide by SOC and PT 
 
The listing of all AEs leading to dose reduction will also be provided with the relevant 
information.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 73 
6.6.1.3. Adverse events leading to interruption of study treatment 
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).  IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay).  
As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding  
• IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.7). These IRRs will be considered as IRRs leading to 
interruption of infusion. 
• IRRs occurring on the day after infusion and subsequent dose administration had no delay 
(as defined in Section 6.5.3.7). 
The frequency (number and percentage) of participants with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment group: 
• TEAEs leading to interruption of avelumab by SOC and PT 
• TEAEs leading to interruption of NKTR-214 by SOC and PT 
• TEAEs leading to interruption of talazoparib by SOC and PT  
• TEAEs leading to interruption of enzalutamide by SOC and PT 
 
The listing of all AEs leading to interruption of study treatment will also be provided with the 
relevant information. 
In addition, the frequency (number and percentage) of participants with each of the following 
will be presented for TEAEs leading to dose interruption and dose reduction of each study 
drug by treatment group: 
• TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT 
• TEAEs leading to both interruption and dose reduction of NKTR-214 by SOC and PT 
• TEAEs leading to both interruption and dose reduction of talazoparib by SOC and PT 
• TEAEs leading to both interruption and dose reduction of enzalutamide by SOC and PT 
 
This summary will take into account PTs with both actions as defined in Section 6.6.1, even 
though the actions may be captured for different PT records (ie, different onset for the PT 
with action “drug interrupted” and the PT with action “dose reduced”.   


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 74 
6.6.1.4. Adverse events leading to discontinuation of study treatment 
The frequency (number and percentage) of participants 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 avelumab by SOC and PT 
• Related TEAEs leading to discontinuation of avelumab by SOC and PT 
• TEAEs leading to discontinuation of NKTR-214 by SOC and PT 
• Related TEAEs leading to discontinuation of NKTR-214 by SOC and PT 
• TEAEs leading to discontinuation of talazoparib by SOC and PT 
• Related TEAEs leading to discontinuation of talazoparib by SOC and PT 
• TEAEs leading to discontinuation of enzalutamide by SOC and PT 
• Related TEAEs leading to discontinuation of enzalutamide by SOC and PT 
• TEAEs leading to discontinuation of any study drug by SOC and PT 
• Related TEAEs leading to discontinuation of any study drug by SOC and PT 
• TEAEs leading to discontinuation of all study drugs by SOC and PT 
• Related TEAEs leading to discontinuation of all study drugs by SOC and PT 
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information.  
6.6.2. Deaths 
The frequency (number and percentage) of participants 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 
- Study treatment toxicity 
- AE not related to study treatment 
- Unknown 
- Other. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 75 
In addition, date and cause of death will be provided in individual participant 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 participants 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 participants 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 
• irAEs leading to discontinuation of avelumab, by Cluster and PT  
• irAEs leading to discontinuation of NKTR-214, by Cluster and PT  
• irAEs leading to discontinuation of talazoparib, by Cluster and PT  
• irAEs leading to discontinuation of enzalutamide, by Cluster and PT  
• irAEs leading to discontinuation of any study drug, by Cluster and PT 
• irAEs leading to discontinuation of all study drugs, by Cluster and PT 
• Serious irAEs, by Cluster and PT  
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period.  
The frequency (number and percentage) of participants with each of the following will be 
presented for IRRs, by treatment group: 
• IRRs leading to death, by PT  
• IRRs, by PT 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 76 
• IRRs, Grade ≥ 3, by PT 
• IRRs leading to discontinuation of avelumab, by PT  
• IRRs leading to discontinuation of NKTR-214, by PT  
• IRRs leading to discontinuation of any study drug, by PT  
• IRRs leading to discontinuation of all study drugs, by PT 
• Serious IRRs, by PT 
• Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later).  
For IV study drugs administered in combination the infusion numbers are those associated 
with the regimen, rather than the individual study drugs. 
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period. 
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 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 77 
- 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]) 
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 participants 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 participant with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages.  
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying 
• peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin =2×ULN.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 78 
• peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
AST=3×ULN and total bilirubin =2×ULN .  
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with concurrent 
(ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (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 participants 
and percentages) during the on-treatment period.  The denominator to calculate percentages 
for each laboratory parameter is the number of participants evaluable for CTCAE grading (ie 
those participants for whom a Grade 0, 1, 2, 3 or 4 can be derived). 
• The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of participants with Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4), 
laboratory abnormalities during the on-treatment period. 
• The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered as 
the worst grade for the summary.  
• The number and percentage of participants 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:  
Hemoglobin (HB), white blood cell count (white blood cell count 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), Potassium (hypokalemia/ hyperkalemia), 
Sodium (hyponatremia/ hypernatremia), Magnesium 
(hypomagnesemia/hypermagnesemia), Calcium (hypocalcemia/ hypercalcemia), Glucose 
(hypoglycemia/hyperglycemia, non-fasted), Gamma Glutamyl Transferase (GGT) (GGT 
increased), Lipase (lipase increased), Phosphates (hypophosphatemia). 
Parameters with NCI-CTC grades not available: 
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of participants with:  
• shifts from baseline normal to at least one result above normal during on-treatment period  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 79 
• 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 
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 participant. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests.  
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing.  
For all tests not mentioned above but present in the clinical data, a listing of participants with 
at least one result for the relevant test will be provided. 
6.6.6. Vital signs 
Weight for the purposes of dose calculation will be recorded pre-dose on Day 1 of each 
cycle.  Weight will also be recorded at screening, End of Treatment, and at the 30-day 
follow-up visit. Height will be measured at screening only. 
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing.  
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline.  
6.6.7. Electrocardiogram 
ECG summaries will include all ECG assessments from the on-treatment period.  All ECG 
assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing.  QTcB and QTcF will be derived based on RR and QT (see below).  When 
triplicate ECG are performed, 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 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 80 
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 
participants (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.   
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 participants evaluable for the category. 
• Pearson correlation between QT and HR, QTc (QTcB, QTcF and, if applicable, QTcP) and 
HR using individual (non-averaged) baseline assessments  
• For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 81 
• Frequency (number and percentage) of participants 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  
Participants with notable ECG interval values and qualitative ECG abnormalities will be 
listed for each participant and time point and the corresponding notable values and 
abnormality findings will be included in the listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters. 
6.6.8. ECOG performance status 
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment group.  
7. INTERIM ANALYSES 
There is no formal interim analysis planned for this study. 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 82 
8. REFERENCES 
1. 
Babb J, Rogatko A, Zacks S. Cancer Phase I clinical trials: efficient dose escalation 
with overdose control. Statistics in Medicine 17(10):1103-20, 1998. 
2. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982. 
3. 
Clopper CJ, Pearson ES . The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413, 1934. 
4. 
de Bono J, Ramanathan RK, Mina L. Phase I, Dose-Escalation, Two-Part Trial of the 
PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations 
and Selected Sporadic Cancers. Cancer Discov;7(6):620-9, 2017. 
5. 
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience. 2002.   
6. 
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958. 
 
 
 
  
9. 
Neuenschwander B, Capkun-Niggli G, Branson M, and Spiegelhalter DJ. Summarizing 
Historical Information on Controls in Clinical Trials. Clinical Trials 7:5-18, 2010. 
10. Neuenschwander B, Matano A, Tang Z, et al. A Bayesian Industry Approach to Phase I 
Combination Trials in Oncology.  In Statistical Methods in Drug Combination Studies.  
Zhao W and Yang H (eds); Chapman & Hall/CRC; 2014. 
11. Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation. John Wiley & Sons; New York; 2004. 
12. S-3100-1-01 clinical study report. Medivation, Inc. 10 Feb 2012. 
 
CCI


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 83 
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 18.  
This case definition is hierarchical, ie, each step is only checked for participants and events 
that have already met the prior step.   
Table 18. Case Definition for irAEs 
Step 
Selection Criteria 
Additional Notes 
1 
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list, then it is in for the next 
step 
 
2 
AE onset during 1st study drug 
administration or anytime thereafter through 
90 days after last dose of study treatment. 
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications 
3 
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’ 
 
4 
AE treated with corticosteroids or other 
immunosuppressant therapy.   
For endocrinopathies only: AE required 
hormone replacement 
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs 
if A) OR B) 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” 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 84 
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. 
 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 85 
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 19 
or Table 20 and will be identified for IV drugs only.      
Table 19. 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 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 86 
Table 20. Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets) 
Condition 
Selection criterion 
IRR can be associated with the first IV drug and/or subsequent IV drugs that are administered in 
combination.  Without loss of generality assume triplet IV with D1 administered first then D2 then D3.  The 
IV study drug or drugs associated with the IRR need to be identified in the analysis data set to enable 
subsequent analysis. 
The following are not sequential and an AE can be classified as an IRR associated with multiple DJ from one 
or more of I, II, III, IV, V below: 
I - If the AE meets [1 AND 2A1] for a DJ then the AE is classified as an IRR associated with the DJ that 
meets the 2A1 criterion  
II - If the AE meets [1 AND 2A2] for a DJ then the AE is classified as an IRR associated with the DJ and 
associated with DJ+1 that meets the 2A2 criterion  
III - If the AE meets [3 AND 4B] for any DJ then the AE is classified as an IRR associated with all DJ 
that meet the 4B criterion. 
IV- If the AE meets [3 AND 4A1] for a DJ then the AE is classified as an IRR associated with the DJ 
that meets the 4A1 criterion  
V- If the AE meets [3 AND 4A2] for a DJ then the AE is classified as an IRR associated with the DJ  and 
associated with DJ+1 that meets the 4A2 criterion  
1 
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list  
2A1 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion 
of study drug DJ+1]AND 
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND  
• AE end date – AE onset date ≤2  
2A2 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) AND 
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND  
• AE end date – AE onset date ≤2  
3 
PT is included in the ‘IRRs CORE’ list  
4A1 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion 
of study drug DJ+1] 
4A2 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion of study drug D J 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 87 
Appendix 3. BLRM Design for Avelumab and Bempegaldesleukin (NKTR-214) Doublet 
- Combination A 
This appendix provides the details of the statistical model, the derivation of prior 
distributions of the single-agent model parameters from historical data, the results of the 
Bayesian analyses and respective dosing decisions for some hypothetical data scenarios, and 
a simulation study of the operating characteristics of the model for the bempegaldesleukin 
(NKTR-214) + avelumab treatment (Combination A). 
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 800 
mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose. 
Statistical Model 
The statistical model for dose-DLT data for this doublet combination comprises single-agent 
toxicity parts, which allow the incorporation of single-agent toxicity data, and an interaction 
part. 
Single Agent Parts  
Let 𝜋𝜋1(𝑑𝑑1) be the risk of DLT for bempegaldesleukin (NKTR-214) given as a single agent at 
dose 𝑑𝑑1; and  𝜋𝜋2(𝑑𝑑2) be the risk of DLT for avelumab given as a single agent at dose 𝑑𝑑2.  
These single agent dose-DLT models are logistic: 
bempegaldesleukin (NKTR-214): 
logit൫𝜋𝜋1(𝑑𝑑1)൯ =  log(𝛼𝛼1) + 𝛽𝛽1 log(𝑑𝑑1 𝑑𝑑1
∗
⁄
) 
avelumab: 
 
 
 
logit൫𝜋𝜋2(𝑑𝑑2)൯ =  log(𝛼𝛼2) + 𝛽𝛽2 log(𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
where 𝑑𝑑1
∗=0.006 mg/kg, and 𝑑𝑑2
∗ =10 mg/kg, are used to scale the doses of bempegaldesleukin 
(NKTR-214), and avelumab, respectively.  Hence, 𝛼𝛼1,  𝛼𝛼2 (all >0) are the single-agent odds 
of a DLT at 𝑑𝑑1
∗ mg/kg, and 𝑑𝑑2
∗ mg/kg, respectively; and  𝛽𝛽1,and 𝛽𝛽2,  (all>0) are the increase in 
the log-odds of a DLT by a unit increase in log-dose. 
Interaction Part 
Under an assumption that there is no interaction, the risk of a DLT at dose 𝑑𝑑1 of 
bempegaldesleukin (NKTR-214), and dose 𝑑𝑑2 of avelumab is: 
𝜋𝜋12
0 (𝑑𝑑1,𝑑𝑑2, ) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯ 
To model the interaction between bempegaldesleukin (NKTR-214) and avelumab, the 
following odds multiplier is introduced. 
• 𝜂𝜂12: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab   
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 88 
The risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2) is then given by: 
odds൫𝜋𝜋12(𝑑𝑑1,𝑑𝑑2)൯= 𝑔𝑔(𝜂𝜂12) × odds൫𝜋𝜋12
0 (𝑑𝑑1,𝑑𝑑2)൯ 
𝑔𝑔(𝜂𝜂12) =   exp(𝜂𝜂12 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
where odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; 𝜂𝜂𝑖𝑖𝑖𝑖 is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j.  For example, 𝜂𝜂12 is the log-odds 
ratio between the interaction and no interaction model at avelumab = 10 mg/kg, 
bempegaldesleukin (NKTR-214) = 0.006 mg/kg.  Therefore, 𝜂𝜂12 is the log-odds ratio 
between the interaction and no interaction model at the reference doses for two drugs.  Here 
𝜂𝜂= 0 corresponds to no interaction, with 𝜂𝜂> 0 and 𝜂𝜂< 0 representing synergistic and 
antagonistic toxicity, respectively. 
Prior Specifications 
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters log(𝛼𝛼1), log(𝛽𝛽1) for 
bempegaldesleukin (NKTR-214), and log(𝛼𝛼2), log(𝛽𝛽2) for avelumab, and the interaction 
parameter (𝜂𝜂12).  A meta-analytic-predictive (MAP) approach was used to derive the prior 
distribution for the single-agent model parameters. 
Prior Distribution for the Logistic Parameters for Single Agent 
This section illustrates the derivation of prior distributions for single agent model parameters 
(log(𝛼𝛼𝑠𝑠), log(𝛽𝛽𝑠𝑠))’s using the available single agent dose-DLT information via a MAP 
approach. 
Description of the Meta-Analytic-Predictive Approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
൫log(𝛼𝛼∗),  log(𝛽𝛽∗)൯ of the new trial using DLT data from historical studies.  Let 𝑟𝑟𝑑𝑑𝑠𝑠 and 𝑛𝑛𝑑𝑑𝑑𝑑 
be the number of participants with a DLT, and the total number of participants at dose 𝑑𝑑 in 
historical trial 𝑠𝑠 (𝑠𝑠= 1,… ,〈𝑆𝑆〉).  The corresponding probability of a DLT is 𝜋𝜋𝑑𝑑𝑑𝑑.  The model 
specifications are as follows: 
𝑟𝑟𝑑𝑑𝑑𝑑 | 𝜋𝜋𝑑𝑑𝑑𝑑 ~ Binomial(𝜋𝜋𝑑𝑑𝑑𝑑,𝑛𝑛𝑑𝑑𝑑𝑑) 
logit(𝜋𝜋𝑑𝑑𝑑𝑑) = log(𝛼𝛼𝑠𝑠) + 𝛽𝛽𝑠𝑠 log(𝑑𝑑/𝑑𝑑∗) 
 ൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼𝑠𝑠),𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽𝑠𝑠)൯ ห 𝜇𝜇,𝜓𝜓𝑔𝑔(𝑠𝑠) ~ Bivariate Normal (BVN)൫𝜇𝜇,𝜓𝜓𝑔𝑔(𝑠𝑠)൯,
s = 1,… ,〈𝑆𝑆〉 
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห 𝜇𝜇, 𝜓𝜓𝑔𝑔 (∗) ~ BVN൫𝜇𝜇, 𝜓𝜓𝑔𝑔 (∗)൯ 
The historical trials are partitioned into 〈𝐺𝐺〉 exchangeability groups, with the exchangeability 
group membership of historical trial 𝑠𝑠 being represented by 𝑔𝑔(𝑠𝑠).  The new trial is assigned 
to exchangeability group 𝑔𝑔(∗).  The parameter 𝜇𝜇 = (𝜇𝜇1,𝜇𝜇2)  is the mean for the logistic 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 89 
parameters, and 𝜓𝜓𝑔𝑔 is the between-trial covariance matrix for exchangeability group 𝑔𝑔=
1, … ,〈𝐺𝐺〉.  Covariance matrix 𝜓𝜓𝑔𝑔 is defined by the standard deviations (τ𝑔𝑔1, τ𝑔𝑔2), and 
correlation ρ (a common value for ρ is used across all groups).  The parameters τ𝑔𝑔1 and τ𝑔𝑔2 
quantify the degree of between trial heterogeneity for exchangeability group 𝑔𝑔.  With 
different prior distributions for the parameter sets ൫τ𝑔𝑔1,τ𝑔𝑔2൯ it is possible to allow for 
differential discounting for the historical strata.  In this way the quality and relevance of 
historical data can be accounted for in the meta-analysis.  The following priors will be used 
for these parameters:   
• normal priors for 𝜇𝜇1 and 𝜇𝜇2,  
• log-normal priors for τ𝑔𝑔1 and τ𝑔𝑔2, and  
• uniform prior for ρ. 
The MAP prior for single-agent model parameters in the new trial, ൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯, is the 
predictive distribution  
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห (𝑟𝑟𝑑𝑑𝑑𝑑, 𝑛𝑛𝑑𝑑𝑑𝑑∶𝑠𝑠= 1, …, 〈𝑆𝑆〉) 
Since the predictive distribution is not available analytically, the Markov chain Monte Carlo 
(MCMC) method is used to simulate values from this distribution.  This is implemented 
using Just Another Gibbs Sampler (JAGS) version 4.8. 
Single Agent Bempegaldesleukin (NKTR-214)   
Dose-DLT data for bempegaldesleukin (NKTR-214) from study EXCEL8 as presented in 
Table 21 are used to derive the priors of the single agent logistic parameters for 
bempegaldesleukin (NKTR-214). In deriving the priors, the Q3W schedule was mapped to 
the Q2W schedule assuming linear relationship between PK with accumulation for 
bempegaldesleukin (NKTR-214) based on clinical-pharmacology assessment.  
Table 21.  Historical Dose Limiting Toxicity Data From Study EXCEL 
Bempegaldesleukin (NKTR-214) 
dose (mg/kg IV) 
Number of patients 
Number of patients with DLTs 
0.003 Q3W 
4 
0 
0.006 Q3W 
11 
0 
0.006 Q2W 
6 
0 
0.009 Q3W 
6 
0 
0.012 Q3W 
1 
1 
Abbreviations: IV=intravenous; mg/kg=milligrams per kilogram; Q2W= every 2 weeks; Q3W= every 3 weeks; 
DLT=dose limiting toxicity. 
 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑏𝑏 and 𝜇𝜇2𝑏𝑏, with means corresponding to 
a 50% chance of DLT at bempegaldesleukin (NKTR-214) =0.006 mg/kg, and a doubling in 
dose leading to a doubling in the odds of the risk of a DLT, respectively.  Priors for τ1𝑏𝑏 and 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 90 
τ2𝑏𝑏 are assigned such that (1) their medians correspond to moderate between trial 
heterogeneity, and (2) their uncertainty (95% prior interval) cover plausible between-trial 
standard deviations10.  
The prior distributions for the model used for deriving the MAP priors are specified in Table 
22.   
Table 22.  Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Bempegaldesleukin (NKTR-214) Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑏𝑏 
N(mean = 0, sd =2) 
𝜇𝜇2𝑏𝑏 
N(mean = 0, sd=1) 
τ1𝑏𝑏 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑏𝑏 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑏𝑏 
uniform(-1,1) 
Abbreviations: N=normally distributed; sd=standard deviation. 
 
Single Agent Avelumab 
Dose-DLT data in the avelumab IB from study EMR100070-0017 as presented in Table 23 
are used to derive the prior of the single agent logistic parameters for avelumab.  Based on 
clinical assessment, the population of the current study is moderately similar to study 
EMR100070-001.  
 Table 23.  Historical Dose Limiting Toxicity Data from Study EMR100070-001 
Avelumab dose (mg/kg Q2W) 
Number of patients 
Number of patients with DLTs 
1 
4 
0 
3 
3 
0 
10 
6 
0 
20 
6 
1 
Abbreviations: mg/kg=milligrams per kilogram; DLT=dose limiting toxicity; Q2W=every 2 weeks. 
 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑎𝑎 and 𝜇𝜇2𝑎𝑎, with means corresponding to 
a 50% chance of DLT at avelumab=10 mg/kg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for τ1𝑎𝑎 and τ2𝑎𝑎 are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations10.  
The prior distributions for the model used for deriving the MAP priors are specified in. 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 91 
 
Table 24.   Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Avelumab Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑎𝑎 
N(mean = 0, sd = 2) 
𝜇𝜇2𝑎𝑎 
N(mean = 0, sd=1) 
τ1𝑎𝑎 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑎𝑎 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑎𝑎 
uniform(-1,1) 
Abbreviations: N=normally distributed; sd=standard deviation. 
 
Prior Distribution for the Interaction Parameter 
Based on pharmacometrics assessment, no drug-drug interaction is expected between 
avelumab and bempegaldesleukin (NKTR-214), although uncertainty remains.  Based upon 
this, normal prior for the log-odds multiplier 𝜂𝜂12 is used.  The prior is centered on an 
assumption of no drug-drug interaction, but with appropriate uncertainty that allows for both 
synergistic and antagonistic toxicity.  The prior for 𝜼𝜼𝟏𝟏𝟏𝟏 is specified as percentiles of increase 
in the odds of DLT due to possible interaction in combination therapy at reference doses: 
𝜂𝜂12 is normally distributed, with mean 0 and standard deviation 0.561 (corresponds to no 
increase in DLT odds at median and 3.0-fold increase in DLTs at 97.5th percentile). 
Summary of Prior Distributions  
The prior distributions of the model parameters are provided in Table 25.  Table 26 illustrates 
the resulting prior distribution of DLT rate derived from the priors given in Table 25.   Based 
on the available information, the starting dose avelumab = 10 mg/kg and bempegaldesleukin 
(NKTR-214) = 0.006 mg/kg satisfies the EWOC criterion.   
Table 25.   Prior Distribution for the Model Parameters 
Parameter 
Mean 
Standard deviations 
Correlation 
Bempegaldesleukin (NKTR-214) single agent parameters: BVN MAP  Prior  
 
൫log(𝛼𝛼1), log(𝛽𝛽1)൯ 
-2.612, 0.946 
0.932, 1.153 
0.056 
Avelumab single agent parameters: BVN MAP Prior 
 
൫log(𝛼𝛼2), log(𝛽𝛽2)൯ 
-2.67, -0.047 
0.972, 0.822 
-0.233 
Interaction parameter: Normal prior 
𝜂𝜂12 
0 
0.561 
 
 
η12: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab. 
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive. 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 92 
Table 26.   Summary of Prior Distribution of Dose Limiting Toxicity Rates for the 
Doublet Combination of Avelumab in Combination with 
Bempegaldesleukin (NKTR-214)  
 
Bempegaldesleukin 
(NKTR-214) dose 
(mg/kg Q2W IV) 
Prior probabilities that DLT rate 
is in the interval: 
Mean 
SD 
Quantiles 
 
[0, 0.16) 
[0.16, 0.33) 
[0.33,1] 
 
 
2.5% 
50% 
97.5% 
0.003 
0.771 
0.192 
0.037 
0.115 
0.093 
0.015 
0.089 
0.369 
0.006 
0.528 
0.335 
0.137 
0.186 
0.132 
0.029 
0.151 
0.529 
Avelumab dose fixed at 10 mg/kg every 2 weeks.  
Abbreviations: IV=intravenous; mg/kg=milligrams per kilogram; Q2W=every 2 weeks; DLT=dose limiting toxicity; 
SD=Standard Deviation. 
 
Hypothetical on-Study Data Scenarios 
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next cohort 
of participants is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future participants, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data. 
Table 27 shows some hypothetical dose escalation data scenarios for Combination A and the 
corresponding recommendations for the next dose.  For example, in Scenario 1, if no DLT is 
observed among 3 DLT-evaluable participants at the starting dose, the recommendation is to 
remain at the same dose level with probability of overdosing of 0.044.  Note that the starting 
dose is already the maximum possible dose for Combination A.  In Scenario 3, if 2 
participants experience a DLT out of 3 DLT-evaluable participants at the starting dose, the 
recommendation is to de-escalate the dose of bempegaldesleukin (NKTR-214) to 0.003 
mg/kg with avelumab remaining at 10 mg/kg; this lower dose combination has a probability 
of overdosing of 0.139.  Scenarios 1 through 7 show clinically plausible next dose 
recommendations. 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 93 
Table 27.   Combination A: Data Scenarios, Next Dose Recommendation, and the 
Interval Probability of Target Toxicity and Overdosing at Next Dose. 
 
 
Dose Evaluated 
 
 
D/N* 
Next Dose (ND)   
Pr(TT) 
at ND 
Pr(OD) 
at ND 
Scenarios 
Ave 
(mg/kg  
IV 
Q2W) 
NKTR 
(mg/kg   
IV 
Q2W) 
 
 
Ave 
(mg/kg 
IV 
Q2W) 
NKTR 
(mg/kg 
IV 
Q2W) 
 
 
 
1 
(10) 
0.006 
 
0/3 
(10) 
0.006 
 
0.265 
0.044 
2 
(10) 
0.006 
 
1/3 
(10) 
0.006 
 
0.435 
0.179 
3 
(10) 
0.006 
 
2/3 
(10) 
0.003 
 
0.378 
0.139 
4 
(10) 
0.006 
 
2/6 
(10) 
0.006 
 
0.518 
0.210 
5 
(10) 
0.006 
 
3/6 
(10) 
0.003 
 
0.418 
0.121 
6 
(10) 
(10) 
0.006 
0.003 
 
3/6 
1/3 
(10) 
0.003 
 
0.518 
0.164 
7 
(10)  
0.006 
 
1/6 
0/3 
(10) 
0.006 
 
0.309 
0.027 
Abbreviations: Ave=avelumab;  NKTR=bempegaldesleukin (NKTR-214); *D=number of participants with DLT, 
N=number of DLT-evaluable participants; IV=intravenous; mg/kg=milligrams per kilogram; ND=next dose; 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Q2W=every 2 weeks. 
 
Operating Characteristics  
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated and in each scenario 1000 trials were 
simulated. 
Simulation Scenarios  
Several scenarios are considered for Combination A (Table 28).  Scenario 1 represents the 
case when the distribution of DLT coincides with prior, ie, the true DLT probability equals to 
mean of prior DLT.  Scenarios 2-3 represent an increase in DLT rate compared to Scenario 1.   
Table 28. Combination A: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab 
Dose 10 mg/kg every 2 Weeks) 
 
Ture DLT rate scenarios  
Bempegaldesleukin (NKTR-214)    
mg/kg Q2W IV 
 
0.003 
0.006 
1.    Prior means 
0.115 
0.186 
2.   25% more toxic than prior means 
0.144 
0.232 
3.  Higher dose is overly toxic 
0.250 
0.500 
Abbreviations: IV=intravenous; mg/kg=milligrams per kilogram; Q2W=every 2 weeks 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 94 
Simulation Details  
Simulations were performed using R version 3.5.3 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the MCMC analyses.  
For each scenario, data for 1000 trials were generated, with a cohort size of 3-6.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria. 
For Combination A, the starting dose was avelumab 10 mg/kg and bempegaldesleukin 
(NKTR-214) 0.006 mg/kg.  The maximum number of participants per trial was set to 30.  
The trial was stopped when the following criteria were met: 
• At least 6 participants have been treated at the recommended MTD 𝑑𝑑̃. 
• The dose 𝑑𝑑̃ satisfies one of the following conditions: 
o The probability of target toxicity at dose 𝑑𝑑̃ exceeds 50%, 
ie, Pr(0.16 ≤ 𝜋𝜋𝑑𝑑෨ <0.33)≥50%;  
o A minimum of 9 participants have been treated in the trial; 
The following metrics were assessed in the simulations: 
• Percentage of participants receiving dose combination(s) in the target toxicity 
interval;  
• Percentage of participants receiving an overdose; 
• Percentage of participants receiving an under dose; 
• Probability that recommended MTD at the end of the trial is in the target toxicity 
interval; 
• Probability that recommended MTD is an overdose; 
• Probability that recommended MTD is an under dose; 
• Percentage of trials stopped without MTD declaration; 
• Average sample size. 
Simulation Results  
Operating characteristics for Combination A are presented in Table 29.   The percentage of 
trials with a correctly identified MTD ranges from 67.3% to 84.4%.  The average sample size 
is 10-11 participants. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 95 
Table 29. Combination A: Operating Characteristics  
 
True DLT rate 
scenarios  
%  Participant allocation   
%  declare MTD 
%  stop 
(no 
MTD) 
Average 
sample 
size 
TT 
OD 
UD 
TT 
OD 
UD 
1.    Prior means 
91.1 
0 
8.9 
84.4 
0 
15.0 
0.6 
10 
2.   25% more toxic 
than prior means 
87.8 
0 
12.2 
78.4 
0 
20.6 
1.0 
10 
3.   Higher dose is 
overdose 
40.7 
59.3 
0 
67.3 
9.5 
0 
23.2 
11 
Abbreviations: MTD=maximum tolerated dose: OD=overdose; TT=target toxicity; UD=under dose. 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 96 
Appendix 4. BLRM Design for Talazoparib Triplet - Combination B 
This appendix provides the details of the statistical model, the derivation of prior 
distributions for the single agent model parameters from historical data, the results of the 
Bayesian analyses and respective dosing decisions for some hypothetical data scenarios, and 
a simulation study of the operating characteristics of the model for the talazoparib, 
bempegaldesleukin (NKTR-214), and avelumab triplet combination (Combination B). 
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 
800 mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose. 
Statistical Model 
The statistical model for Combination B dose-DLT data comprises single-agent toxicity 
parts, which allow the incorporation of single-agent toxicity data, and interaction parts. 
Single Agent Parts  
Let 𝜋𝜋1(𝑑𝑑1) be the risk of DLT for talazoparib given as a single agent at dose 𝑑𝑑1; 𝜋𝜋2(𝑑𝑑2) be 
the risk of DLT for bempegaldesleukin (NKTR-214) given as a single agent at dose 𝑑𝑑2; and 
𝜋𝜋3(𝑑𝑑3) be the risk of DLT for avelumab given as a single agent at dose 𝑑𝑑3.  These single 
agent dose-DLT models are logistic: 
talazoparib: 
 
 
 
logit൫𝜋𝜋1(𝑑𝑑1)൯ =  log(𝛼𝛼1) + 𝛽𝛽1 log(𝑑𝑑1 𝑑𝑑1
∗
⁄
) 
bempegaldesleukin (NKTR-214): 
logit൫𝜋𝜋2(𝑑𝑑2)൯ =  log(𝛼𝛼2) + 𝛽𝛽2 log(𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
avelumab: 
 
 
 
logit൫𝜋𝜋3(𝑑𝑑3)൯ =  log(𝛼𝛼3) + 𝛽𝛽3 log(𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where 𝑑𝑑1
∗=1.0 mg, 𝑑𝑑2
∗ =0.006 mg/kg, and 𝑑𝑑3
∗=10 mg/kg are used to scale the doses of 
talazoparib, bempegaldesleukin (NKTR-214), and avelumab, respectively.  Hence, 𝛼𝛼1,  𝛼𝛼2 , 
and 𝛼𝛼3 (all >0) are the single-agent odds of a DLT at 𝑑𝑑1
∗ mg, 𝑑𝑑2
∗ mg/kg, and 𝑑𝑑3
∗ mg/kg, 
respectively; and  𝛽𝛽1, 𝛽𝛽2, and 𝛽𝛽3(all >0) are the increase in the log-odds of a DLT by a unit 
increase in log-dose. 
Interaction Parts 
Under an assumption that there is no interaction, the risk of a DLT at dose 𝑑𝑑1 of talazoparib, 
dose 𝑑𝑑2 of bempegaldesleukin (NKTR-214), and dose 𝑑𝑑3 of avelumab is: 
𝜋𝜋123
0 (𝑑𝑑1,𝑑𝑑2,𝑑𝑑3) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯൫1 −𝜋𝜋3(𝑑𝑑3)൯ 
To model the interaction between talazoparib, bempegaldesleukin (NKTR-214), and 
avelumab, the following four odds multipliers are introduced. 
• 𝜂𝜂12: Two-way interaction between talazoparib and bempegaldesleukin (NKTR-214) 
• 𝜂𝜂13: Two-way interaction between talazoparib and avelumab 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 97 
• 𝜂𝜂23: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab  
• 𝜂𝜂123: Three-way interaction among talazoparib, bempegaldesleukin (NKTR-214), and 
avelumab 
The risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3) is then given by: 
odds൫𝜋𝜋123(𝑑𝑑1,𝑑𝑑2,𝑑𝑑3)൯= 𝑔𝑔(𝜂𝜂12, 𝜂𝜂13,𝜂𝜂23,𝜂𝜂123) × odds൫𝜋𝜋123
0 (𝑑𝑑1,𝑑𝑑2,𝑑𝑑3)൯ 
𝑔𝑔(𝜂𝜂12,𝜂𝜂13,𝜂𝜂23, 𝜂𝜂123) =   exp(𝜂𝜂12 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
                                                                × exp ( 𝜂𝜂13 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                                × exp (𝜂𝜂23 × 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                              × exp (𝜂𝜂123 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; 𝜂𝜂𝑖𝑖𝑖𝑖 is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j and a zero dose of the third drug.  For 
example, 𝜂𝜂23 is the log-odds ratio between the interaction and no interaction model at 
avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg, and talazoparib=0 
mg.  Therefore, 𝜂𝜂12 + 𝜂𝜂13 + 𝜂𝜂23 + 𝜂𝜂123 is the log-odds ratio between the interaction and no 
interaction model at the reference doses for all three drugs.  Here 𝜂𝜂= 0 corresponds to no 
interaction, with 𝜂𝜂> 0 and 𝜂𝜂< 0 representing synergistic and antagonistic toxicity, 
respectively. 
Inclusion of the Doublet Data 
Based on the preliminary data from the Phase 1b portion of study B9991025, a total 12 
participants were enrolled at the starting dose level of 800 mg avelumab Q2W in 
combination with talazoparib at 1.0 mg once daily. All 12 participants were DLT-evaluable 
with a DLT rate of 3/12. This information from study B9991025 was incorporated in the 
assessment of prior distribution of DLT, starting dose, data scenarios, and simulations of 
Combination B via a direct down-weighting approach. The weight was calculated using the 
formula below assuming substantial heterogeneity between the populations included in the 
avelumab + talazoparib doublet and Combination B in terms of DLT;  
𝑤𝑤= 
1
1 + 2𝜏𝜏2
𝜎𝜎2  𝑁𝑁
 
where, N= Total number of participants enrolled in the B9991025 avelumab + talazoparib 
doublet combination (N=12)  
        σ = population standard deviation (σ =2) 
        τ = heterogeneity between populations in the B9991025 doublet and triplet (τ =0.5) 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 98 
The on-study bempegaldesleukin (NKTR-214) and avelumab doublet DLT data was also 
utilized in the assessment of starting dose and data scenarios of Combination B via a direct 
down-weighting approach, assuming a moderate heterogeneity between the populations 
included in this on-trial doublet and Combination B in terms of DLT.  The weight was 
calculated using the down-weighting formula shown above with (σ =2) and (τ = 0.25). 
The on-study bempegaldesleukin (NKTR-214) and avelumab doublet DLT data was not 
considered in the simulations. 
Prior Specifications 
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters log(𝛼𝛼1), log(𝛽𝛽1) for talazoparib, 
log(𝛼𝛼2), log(𝛽𝛽2) for bempegaldesleukin (NKTR-214), log(𝛼𝛼3), log(𝛽𝛽3) for avelumab, and 
the interaction parameters 𝜂𝜂= (𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123).  A meta-analytic-predictive (MAP) 
approach was used to derive the prior distribution for the single-agent model 
parameters.  
Prior Distribution for the Logistic Parameters for Single Agent Avelumab and 
Bempegaldesleukin (NKTR-214)   
For derivation of the prior distribution of the logistic parameters for single agent avelumab 
and single agent bempegaldesleukin (NKTR-214), refer to Appendix 3. 
Single Agent Talazoparib 
Dose-DLT data from study PRP-001 (C3441007, NCT01286987)4 presented in Table 30 are 
used to derive the prior of the single agent logistic parameters for talazoparib. 
Table 30. Historical Dose Limiting Toxicity data from Study PRP-001 
 
Talazoparib dose (mg 
QD) 
Number of Patients 
Number of Patients with DLTs 
0.025 
3 
0 
0.05 
3 
0 
0.1 
3 
0 
0.2 
3 
0 
0.4 
3 
0 
0.6 
6 
0 
0.9 
6 
1 
1.0 
6 
0 
1.1 
6 
2 
Abbreviations: DLT=dose limiting toxicity; mg=milligrams; QD=once daily. 
     
Weakly informative normal priors are assumed for 𝜇𝜇1𝑡𝑡 and 𝜇𝜇2𝑡𝑡, with means corresponding to 
a 50% chance of DLT at talazoparib=1.0 mg, and a doubling in dose leading to a doubling in 
the odds of the risk of a DLT, respectively.  Priors for τ1𝑡𝑡 and τ2𝑡𝑡 are assigned such that (1) 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 99 
their medians correspond to moderate between trial heterogeneity, and (2) their uncertainty 
(95% prior interval) cover plausible between-trial standard deviations.   
 
Table 31. Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Talazoparib Model Parameters 
Parameter 
Prior distribution 
𝜇𝜇1𝑡𝑡 
N(mean = 0, sd = 2) 
𝜇𝜇2𝑡𝑡 
N(mean = 0, sd=1) 
τ1𝑡𝑡 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑡𝑡 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑡𝑡 
uniform(-1,1) 
Abbreviations: N=normally distributed; sd=standard deviation. 
 
Prior Distribution for the Interaction Parameters 
Normal priors for the log-odds multipliers 𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123  are used. The prior for 
𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123 are specified as percentiles of increase in the odds of DLT due to possible 
interaction in combination therapy at reference doses: 
• 𝜂𝜂12 is normally distributed, with mean 0.095 and standard deviation 0.305 
(corresponds to 10% increase in DLT odds at median and 2.0 fold increase in 
DLTs at 97.5th percentile) 
• 𝜂𝜂13 is normally distributed, with mean 0.095 and standard deviation 0.305 
(corresponds to 10% increase in DLT odds at median and 2.0 fold increase in 
DLTs at 97.5th percentile) 
• 𝜂𝜂23 is normally distributed, with mean 0 and standard deviation 0.561 
(corresponds to no increase in DLT odds at median and 3.0 fold increase in DLTs 
at 97.5th percentile) 
• 𝜂𝜂123 is normally distributed, with mean 0 and standard deviation 0.093 
(corresponds to no increase in DLT odds at median and 1.20 fold increase in 
DLTs at 97.5th percentile). 
𝜂𝜂12: Two-way interaction between talazoparib and bempegaldesleukin (NKTR-214); 
𝜂𝜂13: Two-way interaction between talazoparib and avelumab; 
𝜂𝜂23: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab; 
𝜂𝜂123: Three-way interaction between talazoparib, bempegaldesleukin (NKTR-214) and avelumab. 
 
Summary of Prior Distributions  
The prior distributions of the model parameters are provided in Table 32.   
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 100 
Table 32. Prior Distribution for the Model Parameters 
Parameter 
Mean 
Standard deviations 
Correlation 
Talazoparib single agent parameters: BVN MAP  Prior  
 
 ൫log(𝛼𝛼1), log(𝛽𝛽1)൯ 
-1.770, 0.651  
0.720, 0.890 
0.188 
Bempegaldesleukin (NKTR-214) single agent parameters: BVN MAP Prior 
 
൫log(𝛼𝛼2), log(𝛽𝛽2)൯  
-2.612, 0.946 
0.932, 1.153 
0.056 
Avelumab single agent parameters: BVN MAP Prior 
 
൫log(𝛼𝛼3), log(𝛽𝛽3)൯ 
-2.672, -0.047   
0.972, 0.822 
-0.233 
Interaction parameters: Normal prior 
𝜂𝜂12 
0.095 
0.305 
 
𝜂𝜂13 
0.095 
0.305 
 
𝜂𝜂23 
0 
0.561 
 
𝜂𝜂123 
0 
0.093 
 
𝜂𝜂12: Two-way interaction between talazoparib and bempegaldesleukin (NKTR-214); 
𝜂𝜂13: Two-way interaction between talazoparib and avelumab; 
𝜂𝜂23: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab; 
𝜂𝜂123: Three-way interaction between talazoparib, bempegaldesleukin (NKTR-214) and avelumab. 
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive. 
 
From  Table 33, in absence of the B9991025 avelumab + talazoparib doublet data and the on-
trial avelumab + bempegaldesleukin (NKTR-214) data, the dose levels of avelumab= 10 
mg/kg, bempegaldesleukin (NKTR-214) = 0.003 mg/kg and talazoparib= 0.75 mg or 
talazoparib= 0.50 mg are acceptable starting doses for Combination B.  However, the final 
starting dose for Combination B will be determined after the dose-DLT data for the on-trial 
doublet is available. 
 
 
 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 101 
Table 33. Summary of Prior Distribution of DLT Rates for the Triplet Combination of Avelumab in 
Combination with Bempegaldesleukin (NKTR-214) and Talazoparib 
NKTR 
dose 
(mg/kg 
Q2W) 
Tala 
dose 
(mg 
QD) 
Prior probabilities that DLT rate is in the 
interval: 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
0.003 
0.5 
0.547 
0.359 
0.094 
0.173 
0.111 
0.031 
0.148 
0.454 
0.003 
0.75 
0.379 
0.450 
0.171 
0.218 
0.123 
0.049 
0.194 
0.520 
0.003 
1.0 
0.187 
0.457 
0.356 
0.294 
0.145 
0.078 
0.271 
0.627 
0.006 
0.5 
0.344 
0.403 
0.253 
0.246 
0.151 
0.045 
0.214 
0.617 
0.006 
0.75 
0.243 
0.400 
0.357 
0.292 
0.165 
0.058 
0.262 
0.677 
0.006 
1.0 
0.139 
0.341 
0.521 
0.364 
0.185 
0.079 
0.341 
0.761 
Avelumab dose fixed at 10 mg/kg every 2 weeks.  
Abbreviations: mg=milligrams; mg/kg=milligrams per kilogram; Q2W= Every 2 weeks; NKTR= bempegaldesleukin 
(NKTR-214); QD=once daily; SD=Standard Deviation; Tala=Talazoparib 
 
Hypothetical on-Study Data Scenarios 
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose that can be used in the next group 
of participants is shown.  These recommended doses are determined using the model-based 
assessment of the risk of DLT in future participants, EWOC criteria and maximum amount of 
escalation allows (100% of current dose).  In practice, the dose recommended by the adaptive 
Bayesian logistic model may be regarded as guidance.  The final recommendation will be 
based on overall safety profile and PK data. 
Table 34 shows the plausible starting dose level(s) for Combination B given hypothetical 
data from the on-study bempegaldesleukin (NKTR-214) and avelumab doublet (Combination 
A).  If the dose-DLT profile of Combination A is safe at avelumab= 10 mg/kg, 
bempegaldesleukin (NKTR-214) = 0.006 mg/kg (Scenario 1), triplet dose escalation can 
begin at avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg and talazoparib= 
0.75 mg, or avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.003 mg and 
talazoparib= 1.0 mg.  If 2 participants with DLT observed out of 12 DLT-evaluable 
participants at avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg 
(Scenario 2), the starting dose can be avelumab= 10 mg/kg, bempegaldesleukin (NKTR-214) 
= 0.006 mg/kg and talazoparib= 0.5 mg or avelumab= 10 mg/kg, bempegaldesleukin 
(NKTR-214) = 0.003 mg/kg and talazoparib= 0.75 mg. All other scenarios (3, 4, and 5) are 
plausible starting doses for Combination B. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 102 
Table 34. Combination B: Clinically Meaningful Starting Dose Given Hypothetical 
Data from the Combination A, and the Interval Probability of Target 
Toxicity and Overdosing at Starting Dose. 
Scenarios 
Doublet Dose  
 
 
D/N* 
Triplet starting dose (SD)  
Pr(TT) at 
SD 
Pr(OD)  
at SD 
Ave 
(mg/kg 
Q2W) 
NKTR 
(mg/kg 
Q2W) 
Tala 
(mg 
QD) 
Ave 
(mg/kg 
Q2W) 
NKTR(
mg/kg 
Q2W) 
Tala 
(mg 
QD) 
1 
(10) 
0.006 
- 
0/9 
(10) 
(10) 
0.006 
0.003 
0.75 
1.0 
0.443 
0.553 
0.137 
0.196 
2 
(10) 
0.006 
- 
2/12 
(10) 
(10) 
0.006 
0.003 
0.50 
0.75 
0.517 
0.534 
0.175 
0.107 
3 
(10) 
0.006 
- 
3/12 
(10) 
0.003 
0.75 
0.567 
0.160 
4 
(10) 
(10) 
0.006 
0.003 
- 
2/4 
1/12 
(10) 
 
0.003 
0.75 
0.569 
0.155 
5 
(10) 
(10) 
0.006 
0.003 
- 
2/4 
3/12 
(10) 
 
0.003 
0.50 
0.607 
0.187 
Abbreviations: Ave=avelumab;  NKTR= bempegaldesleukin (NKTR-214); *D=number of participants with DLT; 
N=number of DLT-evaluable participants; mg=milligrams; mg/kg=milligrams per kilogram; ND=next dose; 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Tala= Talazoparib; QD=once daily; 
Q2W=every 2 weeks. 
 
Table 35 shows data scenarios for Combination B and the corresponding recommendations 
for the next dose.  The recommended next dose is adequate for all considered scenarios.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 103 
Table 35. Combination B: Data Scenarios (Given Hypothetical Combination A 
Data), Next Dose Recommendation, and the Interval Probability of Target 
Toxicity and Overdosing at Next Dose. 
Scenarios 
Dose evaluated  
 
 
D/N* 
Next Dose (ND) 
Pr(TT) 
at ND 
Pr(OD) at 
ND 
Ave  
(mg/kg 
Q2W) 
NKTR 
(mg/kg 
Q2W) 
Tala 
(mg 
QD) 
Ave  
(mg/kg 
Q2W) 
NKTR 
(mg/kg 
Q2W) 
Tala 
(mg 
QD) 
1 
(10) 
0.006 
- 
0/9 
(10) 
0.006 
1.0 
0.477 
0.190 
  
(10) 
0.006 
0.75 
0/3 
 
 
 
 
 
2 
(10) 
0.006 
- 
0/9 
(10) 
0.006 
0.75 
0.527 
0.171 
  
(10) 
0.006 
0.75 
1/3 
 
 
 
 
 
3 
(10) 
0.006 
- 
0/9 
(10) 
0.006 
0.50 
0.554 
0.189 
 
(10) 
0.006 
0.75 
2/3 
(10) 
0.003 
0.75 
0.601 
0.150 
4 
(10) 
0.006 
- 
0/9 
(10) 
0.003 
0.50 
0.564 
0.111 
 
(10) 
0.006 
0.75 
3/3 
 
 
 
 
 
5 
(10) 
0.006 
- 
3/12 
(10) 
0.006 
0.50 
0.553 
0.197 
 
(10) 
0.003 
0.75 
0/3 
(10) 
0.003 
0.75 
0.530 
0.075 
6 
(10) 
0.006 
- 
3/12 
(10) 
0.003 
0.75 
0.617 
0.186 
 
(10) 
0.003 
0.75 
1/3 
 
 
 
 
 
7 
(10) 
0.006 
- 
3/12 
(10) 
0.003 
0.50 
0.618 
0.177 
 
(10) 
0.003 
0.75 
2/3 
 
 
 
 
 
Abbreviations: Ave=avelumab; NKTR= bempegaldesleukin (NKTR-214); *D=number of participants with 
DLT; N=number of DLT-evaluable participants; mg=milligrams; mg/kg=milligrams per kilogram; ND=next 
dose Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; QD=once daily; Q2W=every 2 
weeks; Tala=Talazoparib.    
 
Operating Characteristics  
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated and each scenario 1000 trials were 
simulated, with results summarized below. 
Simulation Scenarios  
Several scenarios are considered for Combination B (Table 36).  Scenario 1 represents the 
case when the distribution of DLT coincides with prior, ie, the true DLT probability equals to 
mean of prior DLT.  Scenario 2 represents an increased DLT rate compared to Scenario 1.  
Scenario 3 represents a true toxicity profile with dose combinations in both under-dose and 
over-dose regions. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 104 
Table 36.   Combination B: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab Dose 
10 mg/kg Every 2 Weeks) 
 
 
NKTR-214 
(mg/kg Q2W) 
Talazoparib (mg QD) 
0.5 
0.75 
1.0 
0.5 
0.75 
1.0 
 
Scenario 1. prior means 
Scenario 2. 50% more toxic than prior means 
0.003 
0.173 
0.218 
0.294 
0.259 
0.327 
0.441 
0.006 
0.246 
0.292 
0.364 
0.370 
0.438 
0.545 
 
Scenario 3. With under dose and overdose 
0.003 
0.10 
0.20 
0.45 
0.006 
0.15 
0.30 
0.55 
Abbreviations:  mg/kg=milligrams per kilogram; QD=once daily; 
Q2W=every 2 weeks. 
 
Simulation Details  
Simulations were performed using R version 3.5.3 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the Markov Chain Monte Carlo 
(MCMC) analyses.  
For each scenario, data for 1000 trials were generated, with a cohort size of 3-6.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria. 
A simulation of Combination B is performed using the starting dose of avelumab 10 mg/kg, 
bempegaldesleukin (NKTR-214) 0.003 mg/kg, and talazoparib 0.5 mg.  B9991025 doublet 
data is considered in this exercise.  The maximum number of participants per trial was set to 
60.  Each trial was stopped when the following criteria were met: 
• At least 6 participants have been treated at the recommended MTD 𝑑𝑑̃.  
• The dose 𝑑𝑑̃ satisfies one of the following conditions: 
• The probability of target toxicity at dose 𝑑𝑑̃ exceeds 50%, 
ie, Pr(0.16 ≤ 𝜋𝜋𝑑𝑑෨ <0.33)≥50%; 
• A minimum of 15 participants have been treated in the trial. 
The following metrics were assessed in the simulations: 
• Percentage of participants receiving dose combination(s) in the target toxicity interval;  
• Percentage of participants receiving an overdose; 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 105 
• Percentage of participants receiving an under dose; 
• Probability that recommended MTD at the end of the trial is in the target toxicity 
interval; 
• Probability that recommended MTD is an overdose; 
• Probability that recommended MTD is an under dose; 
• Percentage of trials stopped without MTD declaration; 
• Average sample size. 
 
Simulation Results  
Operating characteristics for Combination B are presented in Table 37.  The percentage of 
trials with a correctly identified MTD ranges from 61.2% to 95.1%.  The percentage of 
participants treated at overly toxic doses is well controlled.  The average sample size is 
between 10 to 14 participants. 
Table 37.   Combination B: Operating Characteristics 
 
True DLT rate scenarios  
% Participant 
allocation   
% declare MTD  
% stop (no 
MTD) 
Average 
sample size 
TT 
OD 
UD 
TT 
OD 
UD 
1.  Prior means 
100 
0 
0 
95.1 
0 
0 
4.9 
13 
2. 50% more toxic than 
prior means 
91.6 
8.4 
0 
89.5 
0 
0 
10.5 
10 
3. With under dose and 
overdose 
46.4 
6.0 
47.6 
61.2 
0 
37.3 
1.5 
14 
Abbreviations: MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; UD=under dose.  
 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 106 
Appendix 5. BLRM Design for Enzalutamide Triplet – Combination C 
This appendix provides the details of the statistical model, the derivation of prior 
distributions for the single agent model parameters from historical data, the results of the 
Bayesian analyses and respective dosing decisions for some hypothetical data scenarios, and 
a simulation study of the operating characteristics of the model for the enzalutamide 
+bempegaldesleukin (NKTR-214) + avelumab treatment combination (Combination C). 
In this appendix, the reported avelumab dose is 10 mg/kg.  Note that the fixed dose of 
800 mg to be investigated in this study is expected to be equivalent to the 10 mg/kg dose. 
Statistical Model 
The statistical model for Combination C dose-DLT data comprises single-agent toxicity 
parts, which allow the incorporation of single-agent toxicity data, and interaction parts. 
Single Agent Parts  
Let 𝜋𝜋1(𝑑𝑑1) be the risk of DLT for enzalutamide given as a single agent at dose 𝑑𝑑1; 𝜋𝜋2(𝑑𝑑2) be 
the risk of DLT for bempegaldesleukin (NKTR-214) given as a single agent at dose 𝑑𝑑2; and 
𝜋𝜋3(𝑑𝑑3) be the risk of DLT for avelumab given as a single agent at dose 𝑑𝑑3.  These single 
agent dose-DLT models are logistic: 
Enzalutamide:  
 
 
  logit൫𝜋𝜋1(𝑑𝑑1)൯ =  log(𝛼𝛼1) + 𝛽𝛽1 log(𝑑𝑑1 𝑑𝑑1
∗
⁄
) 
Bempegaldesleukin (NKTR-214):     logit൫𝜋𝜋2(𝑑𝑑2)൯ =  log(𝛼𝛼2) + 𝛽𝛽2 log(𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
Avelumab: 
 
 
 
logit൫𝜋𝜋3(𝑑𝑑3)൯ =  log(𝛼𝛼3) + 𝛽𝛽3 log(𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where 𝑑𝑑1
∗=160 mg, 𝑑𝑑2
∗ =0.006 mg/kg, and 𝑑𝑑3
∗=10 mg/kg are used to scale the doses of 
enzalutamide, bempegaldesleukin (NKTR-214), and avelumab, respectively.  Hence, 𝛼𝛼1,  𝛼𝛼2, 
and 𝛼𝛼3 (all >0) are the single-agent odds of a DLT at 𝑑𝑑1
∗ mg, 𝑑𝑑2
∗ mg/kg, and 𝑑𝑑3
∗ mg/kg, 
respectively; and  𝛽𝛽1, 𝛽𝛽2, and 𝛽𝛽3( all>0) are the increase in the log-odds of a DLT by a unit 
increase in log-dose. 
Interaction Parts 
Under an assumption that there is no interaction, the risk of a DLT at dose 𝑑𝑑1 of avelumab, 
dose 𝑑𝑑2 of bempegaldesleukin (NKTR-214), and dose 𝑑𝑑3 of enzalutamide is: 
𝜋𝜋123
0 (𝑑𝑑1,𝑑𝑑2,𝑑𝑑3) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯൫1 −𝜋𝜋3(𝑑𝑑3)൯ 
To model the interaction between avelumab, bempegaldesleukin (NKTR-214), and 
enzalutamide, the following four odds multipliers are introduced. 
• 𝜂𝜂12: Two-way interaction between enzalutamide and bempegaldesleukin (NKTR-
214)   


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 107 
• 𝜂𝜂13: Two-way interaction between enzalutamide and avelumab 
• 𝜂𝜂23: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab 
• 𝜂𝜂123: Three-way interaction among enzalutamide, bempegaldesleukin (NKTR-214), 
and avelumab  
The risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3) is then given by: 
odds൫𝜋𝜋123(𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3)൯= 𝑔𝑔(𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123) × odds൫𝜋𝜋123
0 (𝑑𝑑1, 𝑑𝑑2,𝑑𝑑3)൯ 
𝑔𝑔(𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123) =   exp(𝜂𝜂12 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
                                                                × exp ( 𝜂𝜂13 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                                × exp (𝜂𝜂23 × 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗)
⁄
 
                                                              × exp (𝜂𝜂123 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
× 𝑑𝑑3 𝑑𝑑3
∗
⁄
) 
where odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; 𝜂𝜂𝑖𝑖𝑖𝑖 is the log-odds ratio between the interaction and no 
interaction model at the reference doses of drug i and j and a zero dose of the third drug.  For 
example, 𝜂𝜂23 is the log-odds ratio between the interaction and no interaction model at 
avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg, and enzalutamide=0 
mg.  Therefore, 𝜂𝜂12 + 𝜂𝜂13 + 𝜂𝜂23 + 𝜂𝜂123 is the log-odds ratio between the interaction and no 
interaction model at the reference doses for all three drugs.  Here 𝜂𝜂= 0 corresponds to no 
interaction, with 𝜂𝜂> 0 and 𝜂𝜂< 0 representing synergistic and antagonistic toxicity 
respectively. 
Inclusion of the Doublet Data 
The addition of the DLT information from the doublet dose escalation of avelumab and 
bempegaldesleukin (NKTR-214) was included in the assessment of starting dose and data 
scenario of Combination C using a direct down-weighting approach (for details, please refer 
to Appendix 4).   
Prior Specifications 
The Bayesian approach requires the specification of prior distributions for all model 
parameters, which include the single agent parameters log(𝛼𝛼1), log(𝛽𝛽1) for enzalutamide, 
log(𝛼𝛼2), log(𝛽𝛽2) for bempegaldesleukin (NKTR-214), log(𝛼𝛼3), log(𝛽𝛽3) for avelumab, and 
the interaction parameters 𝜂𝜂= (𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123).  A meta-analytic-predictive (MAP) 
approach was used to derive the prior distribution for the single-agent model 
parameters.  


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 108 
Prior Distribution for the Logistic Parameters for Single Agent Avelumab and 
Bempegaldesleukin (NKTR-214)   
For information regarding the prior distribution of the logistic parameters for single agent 
avelumab and single agent bempegaldesleukin (NKTR-214), refer to Appendix 3. 
Single Agent Enzalutamide 
Dose-DLT data from Study S-3100-1-01 (for ENZA)12 presented in Table 38 are used to 
derive the prior of the single agent logistic parameters for enzalutamide.  
Table 38.   Historical Dose Limiting Toxicity data from Study S-3100-1-01 
 
Enzalutamide dose (mg) 
Number of patients 
Number of patients with DLTs 
30 
3 
0 
60 
27 
0 
150 
28 
0 
240 
29 
0 
360 
28 
1 
480 
22 
1 
600 
3 
2 
Abbreviations: DLT=dose limiting toxicity; mg=milligram. 
 
Weakly informative normal priors are assumed for 𝜇𝜇1𝑒𝑒 and 𝜇𝜇2𝑒𝑒, with means corresponding to 
a 50% chance of DLT at enzalutamide=160 mg, and a doubling in dose leading to a doubling 
in the odds of the risk of a DLT, respectively.  Priors for τ1𝑒𝑒 and τ2𝑒𝑒 are assigned such that 
(1) their medians correspond to moderate between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations.  
Table 39.  Prior Distributions for the Parameters of the MAP Model Used to Derive 
the Prior for the Single-Agent Enzalutamide Model Parameters  
Parameter 
Prior distribution 
𝜇𝜇1𝑒𝑒 
N(mean = 0, sd = 2) 
𝜇𝜇2𝑒𝑒 
N(mean = 0, sd =1 ) 
τ1𝑒𝑒 
log-normal(mean = log(0.25), sd = log(2)/1.96) 
τ2𝑒𝑒 
log-normal(mean = log(0.125), sd = log(2)/1.96) 
ρ𝑒𝑒 
uniform(-1,1) 
Abbreviations: N=normally distributed; sd=standard deviation. 
 
 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 109 
Prior Distribution for the Interaction Parameters 
Normal priors for the log-odds multipliers 𝜂𝜂12, 𝜂𝜂13, 𝜂𝜂23,𝜂𝜂123  are used.  The priors for 
𝜼𝜼𝟏𝟏𝟏𝟏,𝜼𝜼𝟏𝟏𝟏𝟏,𝜼𝜼𝟐𝟐𝟐𝟐,𝜼𝜼𝟏𝟏𝟏𝟏𝟏𝟏 are specified as percentiles of increase in the odds of DLT due to possible 
interaction in combination therapy at reference doses; 
• 𝜂𝜂12 is normally distributed, with mean 0.095 and standard deviation 0.519 
(corresponds to 10% increase in DLT odds at median and 3.0-fold increase in DLTs 
at 97.5th percentile). 
• 𝜂𝜂13 is normally distributed, with mean 0.095 and standard deviation 0.519 
(corresponds to 10% increase in DLT odds at median and 3.0-fold increase in DLTs 
at 97.5th percentile). 
• 𝜂𝜂23 is normally distributed, with mean 0 and standard deviation 0.561 (corresponds to 
no increase in DLT odds at median and 3.0-fold increase in DLTs at 97.5th 
percentile). 
• 𝜂𝜂123 is normally distributed, with mean 0 and standard deviation 0.354 (corresponds 
to no increase in DLT odds at median and 2.0-fold increase in DLTs at 97.5th 
percentile). 
• 
𝜂𝜂12: Two-way interaction between enzalutamide and bempegaldesleukin (NKTR-214); 
• 
𝜂𝜂13: Two-way interaction between avelumab and enzalutamide; 
• 
𝜂𝜂23: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab; 
• 
𝜂𝜂123: Three-way interaction between avelumab, bempegaldesleukin (NKTR-214) and enzalutamide 
Summary of Prior Distributions  
The prior distributions of the model parameters are provided in Table 40.   
Table 40.   Prior Distribution for the Model Parameters  
Parameter 
Mean 
Standard deviations 
Correlation 
Enzalutamide single agent parameters: BVN MAP  Prior  
 
൫log(𝛼𝛼1), log(𝛽𝛽1)൯ 
-4.299, 0.359 
0.917, 0.657 
-0.619 
Bempegaldesleukin (NKTR-214)   single agent parameters: BVN MAP Prior 
 
൫log(𝛼𝛼2), log(𝛽𝛽2)൯ 
-2.612, 0.946 
0.932, 1.153 
0.056 
Avelumab single agent parameters: BVN MAP Prior 
 
൫log(𝛼𝛼3), log(𝛽𝛽3)൯ 
-2.672,-0.047 
0.972, 0.822 
-0.233 
Interaction parameters: Normal prior 
𝜂𝜂12 
0.095 
0.519 
 
𝜂𝜂13 
0.095 
0.519 
 
𝜂𝜂23 
0 
0.561 
 
𝜂𝜂123 
0 
0.354 
 
𝜂𝜂12: Two-way interaction between enzalutamide and bempegaldesleukin (NKTR-214); 
𝜂𝜂13: Two-way interaction between avelumab and enzalutamide; 
𝜂𝜂23: Two-way interaction between bempegaldesleukin (NKTR-214) and avelumab; 
𝜂𝜂123: Three-way interaction between avelumab, bempegaldesleukin (NKTR-214) and enzalutamide. 
Abbreviations: BVN=bivariate normal; MAP=meta-analytic-predictive. 
 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 110 
From Table 41, in absence of avelumab + bempegaldesleukin (NKTR-214) doublet data, 
all 6 but the highest potential dose levels of Combination C are acceptable starting doses.  
However, the final starting dose for this triplet will be determined after the dose-DLT data 
for the avelumab + bempegaldesleukin (NKTR-214) doublet is available.    
Table 41.  Summary of Prior Distribution of DLT Rates for the Triplet Combination 
of Enzalutamide in Combination with Bempegaldesleukin (NKTR-214) and 
Avelumab (Combination C) 
 
NKTR 
dose 
(mg/kg 
Q2W) 
Enza 
dose 
(mg 
once 
daily) 
Prior probabilities that 
DLT rate is in the interval: 
Mean 
SD 
Quantiles 
[0, 
0.16) 
[0.16, 
0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
0.003 
80 
0.705 
0.237 
0.058 
0.134 
0.105 
0.019 
0.104 
0.417 
0.003 
120 
0.665 
0.257 
0.078 
0.146 
0.116 
0.020 
0.113 
0.458 
0.003 
160 
0.620 
0.273 
0.107 
0.161 
0.130 
0.019 
0.123 
0.511 
0.006 
80 
0.461 
0.345 
0.194 
0.213 
0.152 
0.030 
0.173 
0.602 
0.006 
120 
0.434 
0.329 
0.237 
0.230 
0.169 
0.028 
0.185 
0.660 
0.006 
160 
0.412 
0.305 
0.283 
0.250 
0.191 
0.024 
0.199 
0.724 
Avelumab dose fixed at 10 mg/kg every 2 weeks.  
Abbreviations: DLT=dose-limiting toxicity; mg/kg=milligrams per kilogram; Q2W=twice a week; 
NKTR=Bempegaldesleukin (NKTR-214); SD=Standard Deviation; Enza=Enzalutamide 
 
Hypothetical on-Study Data Scenarios 
To illustrate the performance of the Bayesian model used to guide dose finding, hypothetical 
dose finding scenarios following the provisional dose levels specified in the protocol are 
displayed.  In each case, the possible recommended dose(s) that can be used in the next 
cohort of participants is shown.  These recommended doses are determined using the model-
based assessment of the risk of DLT in future participants, EWOC criteria and maximum 
amount of escalation allows (100% of current dose).  In practice, the dose recommended by 
the adaptive Bayesian logistic model may be regarded as guidance.  The final 
recommendation will be based on overall safety profile, PK data and other relevant evidence. 
Table 42 shows the plausible starting dose level(s) for Combination C given hypothetical 
data in the doublet combination.  If the dose-DLT profile of the doublet is safe at avelumab = 
10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg (Scenario 1 ), triplet dose 
escalation can begin at avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 
mg/kg and enzalutamide = 160 mg.  If moderate DLT is observed in the dual combination 
(3participants with DLT out of 12 DLT-evaluable participants at avelumab = 10 mg/kg, 
bempegaldesleukin (NKTR-214) = 0.006 mg/kg, Scenario 3), the starting dose can be 
avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.006 mg/kg and enzalutamide = 
80 mg, or avelumab = 10 mg/kg, bempegaldesleukin (NKTR-214) = 0.003 mg/kg and 
enzalutamide = 160 mg.  Scenarios 4 and 5 also show plausible starting triplet dose levels. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 111 
Table 42. Combination C: Clinically Meaningful Starting Dose Given Hypothetical 
Data from the Doublet Combination, and the Interval Probability of 
Target Toxicity and Overdosing at Starting Dose.  
Scenarios 
Doublet Dose 
D/N* 
Triplet Starting Dose (SD) 
Pr(TT) at 
ND 
Pr (OD) 
at ND 
Ave 
mg/kg 
(Q2W) 
NKTR 
mg/kg 
(Q2W) 
Enza 
(mg 
QD) 
Ave 
mg/kg 
(Q2W) 
NKTR 
mg/kg 
(Q2W) 
Enza 
(mg 
QD) 
1 
(10) 
0.006 
- 
0/9 
(10)  
(10) 
0.006 
0.006 
160 
120 
0.268 
0.262 
0.118 
0.071 
2 
(10) 
0.006 
- 
2/12 
(10) 
 0.006 
120 
0.393 
0.188 
3 
(10) 
0.006 
 
- 
3/12 
(10)  
(10) 
0.006 
0.003  
80 
160  
0.479 
0.340  
0.222 
0.119 
4 
(10) 
(10) 
0.006 
0.003 
- 
2/4 
1/12 
(10)  
  
0.003 
160 
0.343 
0.105 
5 
(10) 
(10) 
0.006 
0.003 
- 
2/4 
3/12 
(10)  
(10) 
0.003 
0.003 
120 
80 
0.475 
0.507 
0.195 
0.145 
Abbreviations: Ave=avelumab; NKTR=Bempegaldesleukin (NKTR-214); *D=number of participants with DLT, 
N=number of DLT-evaluable participants; mg=milligram; mg/kg=milligram per kilogram; ND=next dose; 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Enza= Enzalutamide; Q2W=every 2 weeks; 
QD=once daily. 
 
Table 43 shows some data scenarios for Combination C and the corresponding 
recommendations for the next dose.    
Table 43.  Combination C: Data Scenarios (Given Hypothetical Doublet Data), Next 
Dose Recommendation, and the Interval Probability of Target Toxicity and 
Overdosing at Next Dose. 
 
Dose evaluated  
 
 
D/N* 
Next Dose (ND) 
Pr(TT) 
at ND 
Pr(OD) 
at ND 
Scenarios 
Ave 
(mg/kg 
Q2W) 
NKTR 
(mg/kg 
Q2W) 
Enza 
(mg 
once 
daily) 
 
Ave 
(mg/kg 
Q2W) 
NKTR 
(mg/kg 
Q2W) 
Enza 
(mg 
once 
daily) 
 
 
1 
(10) 
(10) 
0.006 
0.006 
- 
120 
0/9 
0/3 
(10) 
 
0.006 
160 
 
0.213 
 
0.047 
 
2 
(10) 
(10) 
0.006 
0.006 
- 
120 
0/9 
1/3 
(10) 
(10) 
0.006 
0.006 
160 
120 
0.378 
0.393 
0.186 
0.109 
3 
(10) 
(10) 
0.006 
0.006 
- 
120 
0/9 
2/3 
(10) 
(10) 
0.006 
0.003 
80 
160 
0.524 
0.414 
0.188 
0.139 
4 
(10) 
(10) 
0.006 
0.006 
- 
120 
0/9 
3/3 
(10) 
 
0.003 
120 
 
0.476 
 
0.186 
 
5 
(10) 
(10) 
0.006 
0.003 
- 
120 
3/12 
0/3 
(10) 
(10) 
0.006 
0.006 
120 
160 
0.426 
0.374 
0.196 
0.249 
6 
(10) 
(10) 
 
0.006 
0.006 
- 
120 
3/12 
1/3 
(10) 
(10) 
 
0.003 
0.003 
 
160 
120 
 
0.441 
0.453 
 
0.171 
0.112 
 
7 
(10) 
(10) 
0.006 
0.003 
- 
120 
3/12 
2/3 
(10) 
 
0.003 
80 
0.560 
0.203 
Abbreviations: Ave=avelumab; mg=milligrams; mg/kg=milligrams per kilogram; NKTR=bempegaldesleukin (NKTR-
214); *D=number of participants with DLT; N=number of DLT-evaluable participants; ND=next dose 
Pr(TT)=probability of target toxicity; Pr(OD)=probability of overdosing; Q2W=every 2 weeks; Enza=enzalutamide. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 112 
   
Operating Characteristics  
A simulation study is used to illustrate the properties of the dose finding model guided by 
BLRM.  Several example scenarios were investigated and in each scenario 1000 trials were 
simulated. 
Simulation Scenarios  
Several scenarios are considered for Combination C (Table 44).  Scenario 1 represents the 
case when the distribution of DLT coincides with prior, ie, the true DLT probability equals 
to mean of prior DLT.  Scenario 2 represents a 50% increased DLT rate compared to 
Scenario 1.  Scenario 3 represents a true toxicity profile with dose combinations in both 
under-toxicity and over-toxicity intervals. 
Table 44.  Combination C: Dose Limiting Toxicity Rate Scenarios (Fixed Avelumab 
Dose 10 mg/kg Every 2 Weeks) 
Bempegaldesleukin 
(NKTR-214) 
(mg/kg Q2W) 
 
Enzalutamide (mg once daily) 
80 
120 
160 
80 
120 
160 
Scenario 1. prior means 
Scenario 2. 50% more toxic than prior 
means 
0.003 
0.134 
0.146 
0.161 
0.201 
0.219 
0.241 
0.006 
0.213 
0.230 
0.250 
0.319 
0.345 
0.376 
 
Scenario 3. With under  and over  toxicity 
0.003 
0.10 
0.20 
0.30 
0.006 
0.15 
0.25 
0.40 
Abbreviations:  Q2W=every 2 weeks; mg=milligrams; 
mg/kg=milligrams per kilogram. 
 
Simulation Details  
Simulations were performed using R version 3.5.3 (The R-project for Statistical Computing.  
https://www.r-project.org/), and JAGS 4.8 to perform the MCMC analyses.  
For each scenario, data for 1000 trials were generated, with a cohort size of 3-6.  At any time 
during the course of dose finding, escalation to doses where the risk of overdose exceeds 
25% is not permitted.  The ‘next dose recommendation’ is the dose with maximum 
probability of overdose among all dose levels that meet the EWOC criteria. 
A simulation of the triplet combination is performed using the starting dose of avelumab 
10 mg/kg (fixed), bempegaldesleukin (NKTR-214) 0.003 mg/kg, and enzalutamide 80 mg.  
No doublet combination data is considered in this exercise.  The maximum number of 
participants per trial was set to 60.  Each trial was stopped when the following criteria were 
met: 
• At least 6 participants have been treated at the recommended MTD 𝑑𝑑̃. 


Avelumab 
B9991040 (MSB0010718C, NKTR-214, PF-04998299, and PF-06944076) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 113 
• The dose 𝑑𝑑̃ satisfies one of the following conditions: 
• The probability of target toxicity at dose 𝑑𝑑̃ exceeds 50%, 
ie, Pr(0.16 ≤ 𝜋𝜋𝑑𝑑෨ <0.33)≥50%; 
• A minimum of 15 participants have been treated in the trial. 
The following metrics were assessed in the simulations: 
• Percentage of participants receiving dose combination(s) in the target toxicity 
interval;  
 
• Percentage of participants receiving an overdose; 
 
• Percentage of participants receiving an underdose; 
 
• Probability that recommended MTD at the end of the trial is in the target toxicity 
interval; 
 
• Probability that recommended MTD is an overdose; 
 
• Probability that recommended MTD is an underdose; 
 
• Percentage of trials stopped without MTD declaration; 
 
• Average sample size. 
 
Simulation Results  
Operating characteristics for Combination C are presented in Table 45.  The percentage of 
trials with a correctly identified MTD ranges from 86.3% to 94.5%.  The percentage of 
participants treated at overly toxic doses is well controlled.  The average sample size for this 
triplet combination is between 11 to 14 participants. 
Table 45.  Combination C: Operating Characteristics 
 
 
True DLT rate 
scenarios  
%  Participant allocation   
%  declare MTD 
%  Stop 
(no MTD) 
Average 
sample 
size 
TT 
OD 
UD 
TT 
OD 
UD 
1. Prior means 
64.5 
0 
35.5 
89.9 
0 
3.4 
7.0 
14 
2. 50% more toxic 
than prior means 
89.4 
10.6 
0 
86.3 
0 
0 
13.7 
11 
3.With under dose 
and overdose 
46.9 
15.4 
37.7 
94.5 
0 
1.6 
3.9 
12 
Abbreviations: MTD=maximum tolerated dose; OD=overdose; TT=target toxicity; UD=under dose