Clinical trial NCT02718417
Conditions: Ovarian Cancer
Keywords: untreated epithelial ovarian fallopian tube primary peritoneal cancer
Sponsor: Pfizer
Start date: 2016-05-19; Completion date: 2019-05-16
Enrollment: 998 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3, open-label, international, multi-center, efficacy, and safety study of avelumab in combination with and/or following platinum-based chemotherapy. Eligible patients must have previously untreated, histologically confirmed Stage III-IV epithelial ovarian (EOC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) and be candidates for platinum-based chemotherapy.

The primary purpose of the study is to demonstrate if avelumab given as single agent in the maintenance setting following frontline chemotherapy or in combination with carboplatin/paclitaxel is superior to platinum-based chemotherapy alone followed by observation in this population of newly diagnosed ovarian cancer patients.

Detailed description:

Arms: arm 1: Chemotherapy followed by observation arm 2: Chemotherapy followed by avelumab in maintenance arm 3: Chemotherapy in combination with avelumab followed by avelumab in maintenance
Interventions: intervention 1: carboplatin intervention 2: paclitaxel intervention 3: Avelumab intervention 4: Avelumab
Intervention descriptions: intervention 1: Given Q3W during chemotherapy phase intervention 2: Investigator choice of weekly or Q3W during chemotherapy phase intervention 3: Given Q3W in combination with carboplatin/paclitaxel during chemotherapy portion intervention 4: Given as single agent in maintenance portion Q2W

Protocol documents:
Prot_000.pdf: 
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A RANDOMIZED, OPEN-LABEL, MULTICENTER, PHASE 3 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB (MSB0010718C) IN 
COMBINATION WITH AND/OR FOLLOWING CHEMOTHERAPY IN PATIENTS 
WITH PREVIOUSLY UNTREATED EPITHELIAL OVARIAN CANCER
JAVELIN OVARIAN 100
Compound:
MSB0010718C 
Compound Name:
Avelumab*
United States (US) Investigational New Drug
(IND) Number:
European Clinical Trials Database 
(EudraCT) Number (if applicable):
EudraCT 2015-003239-36
Protocol Number:
B9991010
Phase:
Phase 3
* Avelumab is the proposed International Nonproprietary Name (INN) for the 
anti-PD-L1 monoclonal antibody (MSB0010718C)
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Document History
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................11
LIST OF FIGURES .................................................................................................................12
APPENDICES .........................................................................................................................12
PROTOCOL SUMMARY.......................................................................................................13
Background and Rationale .............................................................................................13
Study Objectives ............................................................................................................14
Co-Primary Objectives: ........................................................................................14
Secondary Objectives ...........................................................................................14
.........................................................................................15
Study Endpoints .............................................................................................................15
Primary Endpoint..................................................................................................15
Secondary Endpoints ............................................................................................15
Exploratory Endpoints..........................................................................................16
Study Design ..................................................................................................................16
Study Treatments............................................................................................................17
Statistical Methods .........................................................................................................18
Sample Size Determination ..................................................................................18
SCHEDULE OF ACTIVITIES................................................................................................20
1. INTRODUCTION ...............................................................................................................28
1.1. Indication.................................................................................................................28
1.2. Background and Rationale ......................................................................................28
1.2.1. Ovarian Cancer ...........................................................................................28
1.2.2. Pharmaceutical and Therapeutic Background ............................................30
1.2.2.1. Avelumab (MSB0010718C) .....................................................30
1.2.2.2. Safety.........................................................................................31
1.2.2.3. Pharmacokinetics of Avelumab ................................................37
1.2.2.4. Efficacy of Avelumab in Patients with Ovarian Cancer ...........37
1.2.2.5. Carboplatin and Paclitaxel for Ovarian Cancer.........................38
1.2.3. Rationale for Studying Avelumab in Patients with Previously 
Untreated Epithelial Ovarian Cancer...............................................................40
1.2.4. Study Design Rationale ..............................................................................41
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1.2.4.1. Study Population .......................................................................41
1.2.4.2. 3-Arm Design............................................................................42
1.2.4.3. Study Endpoints ........................................................................42
1.2.4.4. Chemotherapy Backbone ..........................................................43
1.2.4.5. Stratification Factors .................................................................43
1.2.4.6. Safety Monitoring .....................................................................44
1.2.5. Rationale for Starting Doses of Avelumab and Chemotherapy 
(Carboplatin and Paclitaxel) ............................................................................44
1.2.5.1. Single Agent Avelumab ............................................................44
1.2.5.2. Avelumab in Combination with Chemotherapy........................44
1.2.5.3. Chemotherapy ...........................................................................44
1.3. Summary of Benefit/Risk Assessment....................................................................44
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................45
2.1. Objectives................................................................................................................45
Co-Primary Objectives .........................................................................................45
Secondary Objectives ...........................................................................................46
Exploratory Objectives .........................................................................................46
2.2. Endpoints.................................................................................................................46
2.2.1. Primary Endpoint........................................................................................46
2.2.2. Secondary Endpoints ..................................................................................47
2.2.3. Exploratory Endpoints................................................................................47
3. STUDY DESIGN.................................................................................................................47
3.1. Study Overview.......................................................................................................47
3.1.1. Safety Monitoring.......................................................................................49
3.1.2. Study Treatment..........................................................................................49
3.1.2.1. Interval Debulking Surgery After Neoadjuvant Treatment.......50
3.1.3. Tumor Assessments....................................................................................50
3.1.4. Safety..........................................................................................................51
4. PATIENT SELECTION......................................................................................................51
4.1. Inclusion Criteria.....................................................................................................51
4.2. Exclusion Criteria....................................................................................................53
4.3. Lifestyle Guidelines ................................................................................................55


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4.4. Sponsor’s Qualified Medical Personnel..................................................................56
5. STUDY TREATMENTS.....................................................................................................56
5.1. Allocation to Treatment ..........................................................................................57
5.2. Patient Compliance .................................................................................................58
5.3. Investigational Product Supplies.............................................................................58
5.3.1. Avelumab....................................................................................................58
5.3.1.1. Avelumab Dosage Form and Packaging ...................................59
5.3.1.2. Avelumab Preparation...............................................................59
5.3.1.3. Avelumab Administration.........................................................60
5.3.2. Paclitaxel and Carboplatin..........................................................................62
5.3.2.1. Premedication for Chemotherapy Administration ....................62
5.3.2.2. Chemotherapy Regimen and Starting Doses.............................62
5.3.3. Recommended Dose Modifications............................................................64
5.3.3.1. Dose Modifications for Avelumab as Single Agent..................65
5.3.4. Guidelines for Avelumab Toxicity Management .......................................65
5.3.4.1. Adverse Drug Reaction Requiring Avelumab 
Discontinuation or Delays .................................................................65
5.3.5. Special Precautions for Avelumab Administration ....................................66
5.3.5.1. Management of Avelumab Infusion-Related Reaction.............67
5.3.5.2. Avelumab: Severe Hypersensitivity Reactions.........................68
5.3.5.3. Avelumab: Tumor Lysis Syndrome ..........................................68
5.3.5.4. Avelumab: Immune-Related Adverse Events...........................70
5.3.6. Guidelines for Chemotherapy Toxicity Management ................................75
5.3.6.1. General Guidelines for Hematologic Toxicity..........................75
5.3.6.2. Use of Hematopoietic Growth Factors......................................75
5.3.6.3. Modifications for Hematologic Toxicities ................................75
5.3.6.4. Dose Modifications and Delays of Chemotherapy: Other 
Non-Hematologic Toxicities and Laboratory Abnormalities............77
5.3.6.5. Dose Modifications for Avelumab in Combination With 
Chemotherapy (Chemotherapy Phase – Arm C)...............................79
5.4. Investigational Product Storage ..............................................................................80
5.5. Investigational Product Accountability...................................................................81


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5.5.1. Destruction of Investigational Product Supplies ........................................82
5.6. Concomitant Treatments .........................................................................................82
5.6.1. Concomitant Radiotherapy.........................................................................83
5.6.2. Supportive Care Guidelines........................................................................83
5.6.3. Concomitant Surgery..................................................................................84
5.6.3.1. Interval Debulking.....................................................................84
5.6.3.2. Other Surgery ............................................................................84
5.6.4. Other Prohibited Concomitant Medications and Treatments .....................84
5.6.4.1. Potential Drug-Drug Interactions..............................................85
6. STUDY PROCEDURES .....................................................................................................86
6.1. Screening.................................................................................................................86
6.1.1. Tumor Biopsies...........................................................................................86
6.2. Treatment Period.....................................................................................................87
6.3. End of Treatment/Withdrawal and Follow-Up Visits.............................................87
6.4. End of Study............................................................................................................88
6.5. Patient Withdrawal..................................................................................................88
7. ASSESSMENTS..................................................................................................................89
7.1. Safety Assessments .................................................................................................90
7.1.1. Pregnancy Testing ......................................................................................90
7.1.2. Adverse Events of Special Interest for Avelumab......................................90
7.1.3. Laboratory Safety Assessments..................................................................90
7.1.4. Vital Signs and Physical Examinations......................................................91
7.1.5. Electrocardigram Assessments...................................................................92
7.2. Tumor Assessments.................................................................................................92
7.3. Pathological Complete Response Assessment ........................................................93
7.4. Pharmacokinetic Assessments.................................................................................93
7.4.1. Blood Sample Collection for Pharmacokinetic Analysis ...........................93
7.4.2. Collection of Avelumab Pharmacokinetic Samples ...................................94
7.4.3. Collection of Carboplatin Pharmacokinetic Samples.................................94
7.4.4. Collection of Paclitaxel Pharmacokinetic Samples....................................94
7.5. Immunogenicity Assessments.................................................................................94


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7.6. Translational and Pharmacodynamic Assessments.................................................94
7.6.1. Tumor Biospecimens..................................................................................94
7.6.2. BRCA 1/2 Mutation Status.........................................................................95
7.7. Banked Biospecimens .............................................................................................95
7.7.1. Markers of Drug Response.........................................................................95
7.7.2. Banked Biospecimens for Soluble Biomarker Assessments ......................96
7.7.3. Additional Research....................................................................................97
7.8. Patient-Reported Outcomes Assessments ...............................................................97
7.8.1. FOSI-18 ......................................................................................................98
7.8.2. EuroQoL EQ-5D-5L...................................................................................98
8. ADVERSE EVENT REPORTING......................................................................................99
8.1. Adverse Events........................................................................................................99
8.2. Reporting Period .....................................................................................................99
8.3. Definition of an Adverse Event...............................................................................99
8.4. Medication Errors..................................................................................................100
8.5. Abnormal Test Findings........................................................................................101
8.6. Serious Adverse Events.........................................................................................101
8.6.1. Protocol-Specified Serious Adverse Events.............................................102
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................102
8.7. Hospitalization ......................................................................................................103
8.8. Severity Assessment..............................................................................................105
8.9. Causality Assessment............................................................................................105
8.10. Exposure During Pregnancy................................................................................106
8.11. Occupational Exposure .......................................................................................107
8.12. Withdrawal Due to Adverse Events (Also See Section 6.5 Patient 
Withdrawal).............................................................................................................107
8.13. Eliciting Adverse Event Information ..................................................................107
8.14. Reporting Requirements......................................................................................107
8.14.1. Serious Adverse Event Reporting Requirements ...................................107
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................108
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............108
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................108


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9.1. Sample Size Determination...................................................................................108
9.2. Analysis Population...............................................................................................110
9.2.1. Full Analysis Set.......................................................................................110
9.2.2. Per-Protocol Analysis Set.........................................................................110
9.2.3. Safety Analysis Set...................................................................................110
9.2.4. Pharmacokinetics Analysis Set.................................................................110
9.2.5. Immunogenicity Analysis Set...................................................................110
9.2.6. Biomarker Analysis Set............................................................................111
9.3. Efficacy Analysis ..................................................................................................111
9.3.1. Analysis of the Primary Endpoint.............................................................111
9.3.2. Analysis of Secondary Endpoints.............................................................112
9.3.2.1. Overall Survival ......................................................................112
9.3.2.2. Objective Response.................................................................112
9.3.2.3. Duration of Response..............................................................113
9.3.2.4. Maintenance Progression-Free Survival .................................113
9.3.2.5. PFS2 ........................................................................................113
9.3.2.6. pCR..........................................................................................113
9.3.2.7. PFS by GCIG Criteria based on Investigator Assessment ......114
9.3.2.8. Patient-Reported Outcomes.....................................................114
9.3.2.9. Pharmacokinetic Analysis.......................................................115
9.3.2.10. Immunogenicity Analysis .....................................................116
9.3.2.11. Exposure/Response Analysis ................................................116
9.3.3. Biomarker Analysis for Secondary and Exploratory Endpoints...............116
9.4. Analysis of Exploratory Endpoints .......................................................................117
9.5. Safety Analysis......................................................................................................117
9.5.1. Adverse Events.........................................................................................117
9.5.2. Laboratory Abnormalities.........................................................................117
9.5.3. Electrocardiograms...................................................................................118
9.6. Interim Analysis ....................................................................................................118
9.7. Data Monitoring Committee .................................................................................119
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................119


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11. DATA HANDLING AND RECORD KEEPING ...........................................................120
11.1. Case Report Forms/Electronic Data Record .......................................................120
11.2. Record Retention.................................................................................................120
12. ETHICS............................................................................................................................121
12.1. Institutional Review Board/Ethics Committee....................................................121
12.2. Ethical Conduct of the Study ..............................................................................121
12.3. Patient Information and Consent.........................................................................121
12.4. Patient Recruitment.............................................................................................122
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................122
13. DEFINITION OF END OF TRIAL.................................................................................123
13.1. End of Trial in a Member State...........................................................................123
13.2. End of Trial in All Other Participating Countries...............................................123
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................123
15. PUBLICATION OF STUDY RESULTS........................................................................123
15.1. Communication of Results by Pfizer ..................................................................123
15.2. Publications by Investigators ..............................................................................124
16. REFERENCES ................................................................................................................126
LIST OF TABLES
Table 1.
Summary of Studies Demonstrating Benefit of Dose-Dense Frontline 
Chemotherapy and Related Studies......................................................................29
Table 2.
Most Frequently Reported (Incidence ≥ 2%) Treatment-Related TEAEs in 
the Pooled Expansion Cohorts and in the Ovarian Cancer Expansion 
Cohort (Any Grade)..............................................................................................33
Table 3.
Most Frequently Reported (in ≥ 2 Patients) Grade ≥ 3 Treatment-Related 
TEAEs in the Pooled Expansion Cohorts and in the Ovarian Cancer 
Expansion Cohort .................................................................................................34
Table 4.
Unconfirmed Tumor Response Observed in Ovarian Cancer Expansion 
Cohort ...................................................................................................................38
Table 5.
Dose Modification Levels for Paclitaxel and Carboplatin ...................................65
Table 6. Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions...............................................................................................................67
Table 7.
Avelumab: Management of Immune-Related Adverse Events ............................71


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Table 8.
Modification Instructions for Hematologic Toxicity: Q3W Chemotherapy 
Regimen................................................................................................................76
Table 9.
Modification Instructions for Hematologic Toxicity: Weekly 
Chemotherapy Regimen .......................................................................................76
Table 10.
Avelumab in Combination with Chemotherapy (Arm C) Toxicity 
Management .........................................................................................................79
Table 11.
Required Laboratory Tests ...................................................................................90
Table 12.
Objective Response Status at each Evaluation...................................................140
Table 13.
Objective Response Status at each Evaluation for Patients with Non Target 
Disease Only.......................................................................................................141
Table 14.
Overall Response Derived from Changes in Index, Non-index and New 
Lesions................................................................................................................143
Table 15.
Criteria for Chemotherapy Response Score .......................................................145
LIST OF FIGURES
Figure 1.
Study Design Schema...........................................................................................48
Figure 2.
Assessment and Initial Management of Tumor Lysis Syndrome.........................69
APPENDICES
Appendix 1. Abbreviations....................................................................................................132
Appendix 2. ECOG Performance Status................................................................................136
Appendix 3. RECIST Version 1.1 .........................................................................................137
 
Appendix 5. Guidelines for Interval Debulking Surgery and Assessment of 
Pathological Complete Response .......................................................................144
Appendix 6. PFS by GCIG Criteria.......................................................................................147
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PROTOCOL SUMMARY
Background and Rationale
Ovarian cancer (OC) is the leading cause of death from gynecologic cancer and the fifth most 
common cause of cancer mortality in women.  Fewer than 40% of women diagnosed with 
ovarian cancer are cured.1 The incidence of ovarian cancer increases with age and is most 
prevalent in the eighth decade of life.  The median age at the time of diagnosis is 63 years, 
and 70% of patients present with advanced disease.2 Although expectations for long-term 
survival can be very high if the cancer is identified and treated early, women who are 
diagnosed with advanced ovarian cancer continue to have poor long-term survival due to 
refractory, resistant, or recurrent disease and most will die within 5 years.
Carboplatin in combination with paclitaxel is the current standard of care in the first-line 
epithelial ovarian cancer (EOC) treatment setting following debulking surgery for patients 
with stage IC or higher, as well as selected stage IA-B patients (those with high grade or 
clear cell histology).  Chemotherapy is administered for a total of 6-8 cycles.3 Complete 
response is achieved in approximately 75% of patients, but most patients ultimately succumb 
to the disease with median progression-free survival (PFS) of approximately 18 months.4
Therefore, there remains a high unmet need for newer agents with novel mechanisms of 
action and combination regimens able to modify the natural history of the disease.
Recently, the dose-dense frontline chemotherapy regimen of weekly paclitaxel combined 
with Q3W carboplatin has been increasing in usage.5,6
The current standard of care in the frontline maintenance treatment setting is 
region-dependent.  Some patients receive bevacizumab in combination with chemotherapy, 
followed by one year of bevacizumab maintenance in regions where bevacizumab is 
approved in this setting. For a significant number of newly diagnosed patients, the standard 
of care remains a platinum doublet chemotherapy followed by observation.
Programmed death ligand 1 (PD-L1, also called B7-H1 or CD274) has a known role in the 
suppression of T-cell responses.  The PD-1 receptor is expressed on activated CD4+ and 
CD8+ T cells.  By interaction with its ligands, PD-L1 and PD-L2, PD-1 delivers a series of 
strong inhibitory signals to inhibit T-cell functions.7,9,10
Avelumab* (MSB0010718C), a fully human antibody of the immunoglobulin G1 (IgG1) 
isotype, specifically targets and blocks PD-L1, the ligand for PD-1 receptor.  In preclinical 
studies, the combination of avelumab with chemotherapy (gemcitabine, oxaliplatin, 5FU) 
showed improved anti-tumor activity over single-agent chemotherapy.11 Preliminary data 
from the ongoing ovarian cancer Study EMR 100070-001, which is being conducted by 
Merck KGaA/EMD Serono (EudraCT number 2013-002834-19, NCT01772004), showed an 
overall response rate (ORR) of 10.7% (8/75) and stable disease in an additional 44% (33/75) 
of patients with advanced ovarian cancer.12
*Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-
L1 monoclonal antibody (MSB0010718C)   


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Preliminary subgroup analysis demonstrated increased activity in patients with lower tumor 
burden, lower number of prior therapies, and platinum sensitivity.12 Therefore, avelumab has 
the potential to change the natural history of disease in the maintenance setting following 
frontline chemotherapy, when tumor burden is small.  Patients with minimal residual disease 
are thought of as the ideal candidates for immunotherapy approaches in ovarian cancer.13
In addition, there are emerging data supporting the rationale for combinations of immune 
checkpoint inhibitors with chemotherapy.14,15 Chemotherapy has been shown to have 
immunostimulatory properties by stimulating the release of neoantigens and adjuvants by 
dying cells, increasing susceptibility to immune attack, and preferentially reducing 
immunosuppressive cells such as T regulatory cells.16,17,18 In summary, avelumab 
demonstrated promising antitumor activity in heavily pretreated patients with ovarian cancer 
and has the potential to improve the durability of response to platinum-based therapy in the 
frontline setting when combined with chemotherapy and in the maintenance setting.
Study Objectives
Co-Primary Objectives:
1. To demonstrate that avelumab in combination with platinum-based chemotherapy 
followed by avelumab maintenance (Arm C) is superior to platinum-based 
chemotherapy alone followed by observation (Arm A) in prolonging progression free 
survival (PFS) in patients with previously untreated epithelial ovarian cancer (EOC).
2. To demonstrate that platinum-based chemotherapy alone followed by avelumab 
maintenance (Arm B) is superior to platinum-based chemotherapy alone followed by 
observation (Arm A) in prolonging PFS in patients with previously untreated EOC.
Secondary Objectives

To compare Arm C and Arm B to Arm A in patients with previously untreated EOC, with 
respect to overall survival (OS).

To evaluate the anti-tumor activity in each treatment arm.

To evaluate the overall safety profile in each treatment arm.

To evaluate the pharmacokinetics (PK) of paclitaxel and carboplatin alone and in 
combination with avelumab. 

To evaluate the PK of avelumab alone and in combination with carboplatin-paclitaxel 
(Arms B and C).

To evaluate the immunogenicity of avelumab alone and in combination with 
carboplatin-paclitaxel (Arms B and C).


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•
To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab in 
combination with and/or following carboplatin-paclitaxel in pre-treatment tumor tissue, 
that may aid in the identification of patient subpopulations most likely to benefit from 
treatment.
•
To evaluate patient reported outcome (PRO) in each treatment arm in patients with 
previously untreated EOC including the assessment of treatment side effects and 
disease-related symptoms.
•
 
 
 
•
 
Study Endpoints
Primary Endpoint
•
Progression-free survival (PFS) as determined by blinded independent central review 
(BICR) by RECIST version 1.1
Secondary Endpoints
•
Efficacy:  Overall survival (OS), PFS by Investigator assessment as well as Objective 
response (OR), Duration of response (DR), Maintenance PFS by BICR assessments 
and Investigator assessment, pathological Complete Response (pCR), PFS2, and PFS 
by Gynecological Cancer Intergroup (GCIG) criteria
•
Safety: AEs (as graded by NCI CTCAE v.4.03); laboratory abnormalities (as graded 
by NCI CTCAE v.4.03); vital signs (blood pressure, pulse rate); electrocardiograms 
(ECGs) 
•
Patient-Reported Outcomes: FOSI-18 and EuroQoL5 Dimension (EQ-5D-5L)
•
Pharmacokinetics: PK parameters, including Ctrough, Cmax, volume of distribution 
(Vd), clearance (CL), area under the concentration time curve (AUC) for avelumab, 
paclitaxel, and carboplatin, as data permit
•
Immunogenicity: anti-drug antibodies (ADA) and neutralizing antibodies (Nab) 
against avelumab
•
Candidate predictive biomarkers in tumor tissue including, but not limited to, 
PD-L1 expression and tumor infiltrating CD8+ T lymphocytes as assessed by 
immunohistochemistry (IHC)
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Exploratory Endpoints
•
CA-125 levels
Study Design
This is a Phase 3, open-label, international, multi-center, efficacy, and safety study of 
avelumab in combination with and/or following platinum-based chemotherapy.  Eligible 
patients must have previously untreated, histologically confirmed Stage III-IV epithelial 
ovarian (EOC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) and be 
candidates for platinum-based chemotherapy.  Patients must meet full eligibility criteria as 
specified in Section 4.
Chemotherapy
Maintenance
In this Phase 3 trial, approximately 951 patients who are candidates for frontline 
platinum-based chemotherapy will be randomized in a 1:1:1 ratio to the above treatment
arms.
Arm A 
Chemotherapy 
Alone
Arm B 
Chemotherapy 
Alone
Arm C
Chemotherapy + 
Avelumab
Arm C
Avelumab 
Arm B
Avelumab 
Arm A
Observation
Treatment 
Until: 
Progressive 
Disease per 
RECIST v1.1
OR
Unacceptable 
Toxicity
OR
Patient 
Withdrawal
If SD, PR, 
or CR after
the 
completion 
of
chemother
apy (+/-
avelumab)
1:1:1
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The assignment to Arm A vs Arm B will be blinded at the time of randomization to patients, 
investigators, and the Sponsor until completion of chemotherapy as described in Section 5.1.  
Crossover between treatment arms will not be permitted.
Intravenous carboplatin-paclitaxel will be used as the chemotherapy backbone, consisting of 
Q3-week (Q3W) carboplatin and the investigator choice of either Q3W or weekly paclitaxel
(see below). Once a paclitaxel regimen is selected for a given patient, it should not be 
changed for the duration of the study.
Patients may be enrolled either following primary debulking surgery, or prior to initiation of 
neoadjuvant chemotherapy.  The latter group will undergo interval debulking surgery after 
3 cycles of chemotherapy (plus or minus avelumab, depending on randomization) to be 
followed by the remainder of chemotherapy (plus or minus avelumab, depending on 
randomization).
Study Treatments
The study period includes two treatment phases, the chemotherapy phase and the 
maintenance phase.  For purposes of consistent on-study assessments, 1 study cycle is 
defined as 3 weeks (21 days) during the chemotherapy phase, and 6 weeks (42 days) during 
the maintenance phase. 
In the chemotherapy phase of the study, study drugs are given as follows:
Arms A and B:  The investigator will have the choice between weekly or Q3W paclitaxel:  

Paclitaxel 175 mg/m2 intravenously (IV) over 3 hours, followed by carboplatin dose 
AUC 5 or AUC 6 as described in Section 5.3.2.2.2 IV over 1 hour on Day 1 of each 
3-week cycle for 6 cycles
OR

Paclitaxel 80 mg/m2 IV over 1 hour on Days 1, 8, 15 plus carboplatin AUC 5 or AUC
6 as described in Section 5.3.2.2.2 IV over 1 hour on Day 1 of each 3-week cycle for 
6 cycles
Arm C: 

Chemotherapy (investigator’s choice as referenced above) + avelumab 10 mg/kg 
administered as a 1-hour IV infusion once every 3 weeks for 6 cycles.
For patients who are enrolled prior to neoadjuvant therapy, the first 3 cycles will be 
administered prior to interval debulking surgery, and the remainder of chemotherapy will be 
administered after surgery.  Upon completion of chemotherapy, patients without evidence of 
disease progression [stable disease (SD), partial response (PR), or complete response (CR)]
will proceed to the maintenance phase of the study.  Disease progression must be confirmed 
by BICR prior to withdrawal.  At this point the assignment to Arms A or B will be unblinded. 
In the maintenance phase of the study, patients randomized to Arms B or C will receive 
avelumab 10 mg/kg administered as a 1-hour IV infusion once every 2 weeks. 


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Patients will receive study treatment until confirmed progressive disease (PD), unacceptable 
toxicity, or withdrawal of consent, or a maximum duration of 24 months (not including 
chemotherapy phase), whichever is earliest (see Section 6.5).
Patients who discontinue study treatment (or, if on Arm A maintenance, reach End of 
Treatment/Withdrawal) will be followed every 12 weeks for survival status until death or 
until study completion, whichever is earlier. 
Statistical Methods
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer. 
Sample Size Determination
The study is designed to test, in parallel, two hypotheses:

The first null hypothesis is that the true PFS hazard rate for both platinum-based 
chemotherapy alone followed by observation (Arm A), and avelumab in combination 
with platinum-based chemotherapy followed by avelumab maintenance (Arm C), are the 
same (HR=1); versus the alternative hypothesis that the true hazard rate is smaller for 
Arm C than for Arm A (HR<1). 

The second null hypothesis is that the true PFS hazard rate for both, platinum-based 
chemotherapy alone followed by observation (Arm A), and platinum-based 
chemotherapy followed by avelumab maintenance (Arm B), are the same (HR =1); 
versus the alternative hypothesis that the true hazard rate is smaller for Arm B than for 
Arm A (HR<1). 
Approximately 951 patients will be enrolled using a 1:1:1 randomization, stratified by 
paclitaxel regimen (Q3W vs QW); and by adjuvant (complete resection/microscopic disease) 
vs adjuvant (incomplete resection 1 cm) vs adjuvant (incomplete resection > 1 cm) vs 
neoadjuvant.  Two hundred and seventy-two (272) PFS events within each comparison will 
be required to have 90% power to detect a hazard ratio of 0.65 using a one-sided log-rank test 
at a significance level of 0.0125. 
The median PFS for patients treated with platinum based chemotherapy alone followed by 
observation was estimated to be 23 months, based on the assumption that 50% of patients 
will receive dose-dense chemotherapy which was demonstrated in JGOG3016 to improve 
median PFS from 18 to 28 months.6 The sample size for this study is determined based on 
the assumptions that treatment with avelumab in combination with platinum-based 
chemotherapy followed by avelumab maintenance, or treatment with platinum-based 
chemotherapy followed by avelumab maintenance is expected to increase the median PFS to 
35.4 months, corresponding to a hazard ratio (HR) of 0.65 under the exponential model 
assumption.  The sample size further assumes a 15% drop-out rate within each treatment arm, 
a non-uniform patient accrual over a 27-month period, and follow-up of approximately 


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13 months after the last patient is randomized.  The data cutoff for the primary PFS analyses 
will occur after the target number of events has been reached in both comparisons and the 
last patient randomized in the study has been followed for at least 12 months after 
randomization.
If the true HR is 0.65 under the alternative hypothesis, 272 PFS events within each 
comparison will be required to have 90% power to detect a HR of 0.65 using a one-sided 
log-rank test at a significance level of 0.0125 (total significance level one sided 0.025), and a 
2-look group-sequential design with Lan-DeMets (O’Brien-Fleming) -spending function to 
determine the efficacy boundary and a Gamma Family (-5) -spending function to determine 
the non-binding futility boundary.
The study will be considered positive if at least one of the primary objectives is met for the 
primary PFS endpoint.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities (SOA) table provides an overview of the protocol visits and procedures.  Refer to the Study Procedures and 
Assessments sections of the protocol (Section 6 and Section 7) for detailed information on each procedure and assessment required for 
compliance with the protocol. Patients who are enrolled prior to neoadjuvant therapy will undergo interval debulking surgery during 
the chemotherapy phase as described in Section 5.6.3.1 and will resume on the schedule of assessments upon recovery.
The investigator may schedule visits (unplanned visits) in addition to those listed in the Schedule of Activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the patient.
Protocol Activities 1
Screening
Study Treatment
Post-Treatment
Chemotherapy Phase 
(1 cycle = 3 weeks = 21 days)
Maintenance Phase 2
(1 cycle = 6 weeks = 42 
days)
Odd cycles
Even cycles
28 Days 
Prior to  
Randomizati
on
Day 1
(3 
days)
Day 8 
(3 
days)
Day 15 
(3 
days)
Day 1
(3 
days)
Day 8
(3 
days)
Day 15
(3 
days)
Day 1
(3 
days)
Day 15 
(3 days)
Day 29 
(3 days)
End of 
Treatment
/Withdraw
al 3
Safety 
Follow-
up (Days 
30, 60, 
and 90 ± 
3 days)4
Survival 
Follow-
Up 5
Clinical Assessments
Informed Consent 6
X
Medical/Oncological History 7  
X
Physical Examination 8
X
X
X
X
X 2
X 2
X
Contraception Check 9
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Blood Pressure, Pulse Rate 10
X
X
X
X
X 2
X 2
X
Laboratory Studies
Hematology 11
X
X
X (for
patients 
on QW 
paclitax
el) 
X (for 
patients 
on QW 
paclitax
el)
X
X (for 
patients 
on QW 
paclitax
el)
X (for 
patients 
on QW 
paclitaxe
l)
X
X 2
X 2
X


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Protocol Activities 1
Screening
Study Treatment
Post-Treatment
Chemotherapy Phase 
(1 cycle = 3 weeks = 21 days)
Maintenance Phase 2
(1 cycle = 6 weeks = 42 
days)
Odd cycles
Even cycles
28 Days 
Prior to  
Randomizati
on
Day 1
(3 
days)
Day 8 
(3 
days)
Day 15 
(3 
days)
Day 1
(3 
days)
Day 8
(3 
days)
Day 15
(3 
days)
Day 1
(3 
days)
Day 15 
(3 days)
Day 29 
(3 days)
End of 
Treatment
/Withdraw
al 3
Safety 
Follow-
up (Days 
30, 60, 
and 90 ± 
3 days)4
Survival 
Follow-
Up 5
Blood Chemistry 11,14
X
X
X
X
X 2
X 2
X
Coagulation 11
X
X
X
X
X
CA-12512
X
X
X
X
X
BRCA 1/2 Mutation Status13
X
Thyroid Function Tests + 
ACTH 15
X
X
X (3rd
cycle,
then 
Q12 
weeks 
thereaft
er)
X
HBV and HCV 
X
X (first 
cycle 
only)
Serum/Urine Pregnancy Test 16
X
X
X
X
X
X
Urinalysis 17
X
X
12-Lead ECG 18
X
X 
X (first 
cycle 
only)
Randomization and Study 
Treatment
Randomization 19
X


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Protocol Activities 1
Screening
Study Treatment
Post-Treatment
Chemotherapy Phase 
(1 cycle = 3 weeks = 21 days)
Maintenance Phase 2
(1 cycle = 6 weeks = 42 
days)
Odd cycles
Even cycles
28 Days 
Prior to  
Randomizati
on
Day 1
(3 
days)
Day 8 
(3 
days)
Day 15 
(3 
days)
Day 1
(3 
days)
Day 8
(3 
days)
Day 15
(3 
days)
Day 1
(3 
days)
Day 15 
(3 days)
Day 29 
(3 days)
End of 
Treatment
/Withdraw
al 3
Safety 
Follow-
up (Days 
30, 60, 
and 90 ± 
3 days)4
Survival 
Follow-
Up 5
Paclitaxel weekly 
Administration 20
X
X
X
X
X
X
Paclitaxel Q3 week
Administration 21
X
X
Carboplatin chemotherapy 
Administration 20, 21
X
X
Administration of Avelumab
(Arms B and C) 22 23
X
X
X
X
X
Disease Assessments
Tumor Assessments (including 
scans) 24
X
Once after 3 cycles of chemotherapy
X
(every 
other 
cycle)
X
Other Clinical Assessments
Adverse Events 25
→ X →
X
X
Concomitant 
Medications/Treatments 26
X
→
→
→
→
→
→
→
→
→
X
X
Other Samplings
PK Blood Sampling  for 
Paclitaxel Pharmacokinetics 27
X
(C2 
only)
PK Blood sampling for 
Carboplatin Pharmacokinetics 
28
X
(C2 
only)


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Protocol Activities 1
Screening
Study Treatment
Post-Treatment
Chemotherapy Phase 
(1 cycle = 3 weeks = 21 days)
Maintenance Phase 2
(1 cycle = 6 weeks = 42 
days)
Odd cycles
Even cycles
28 Days 
Prior to  
Randomizati
on
Day 1
(3 
days)
Day 8 
(3 
days)
Day 15 
(3 
days)
Day 1
(3 
days)
Day 8
(3 
days)
Day 15
(3 
days)
Day 1
(3 
days)
Day 15 
(3 days)
Day 29 
(3 days)
End of 
Treatment
/Withdraw
al 3
Safety 
Follow-
up (Days 
30, 60, 
and 90 ± 
3 days)4
Survival 
Follow-
Up 5
PK Blood Sampling for 
Avelumab Pharmacokinetics 29
X (Arm 
C only)
X (Arm 
C only; 
weekly 
paclitax
el only)
X (Arm 
C only; 
weekly 
paclitax
el only)
X (Arm 
C only)
X (Arm 
C only; 
weekly 
paclitax
el only)
X (Arm 
C only; 
weekly 
paclitaxe
l only)
X
(Arms B 
and C 
only)
X (Arms 
B and C
only; C1
only)
X (Arms 
B and C 
only;C1 
only)
X
Mandatory Archival FFPE 
Tumor Tissue Block 30
X
De Novo Tumor Biopsy 31
X
Banked Blood Biospecimen 
for Genotyping 32
X
Banked Blood Biospecimen 
for Exploratory Biomarker 
Assessments 33
X
X (2nd 
and 4th
cycles 
only)
X (1st
and 2nd
cycles
only)
X (Arms
B and C; 
1st and 
2nd
cycles 
only)
X (Arms
B and C; 
1st and 2nd
cycles
only)
X
Blood for Avelumab ADA 
(Immunogenicity) Testing 34
X
X (Arm 
C only)
X
(Arms B 
and C 
only)
X
X
X
Patient-Reported Outcomes 
(FOSI-18 and EQ-5D-5L) 35
X
X
X
X
X


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Footnotes for Schedule of Activities 
1.
Protocol Activities: All assessments should be performed prior to dosing with study medications unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headers.  Day 1 windows do not apply to Cycle 1 of chemotherapy or maintenance phases.
2.
Maintenance Phase:  Maintenance phase should begin within 4 weeks after the last dose of chemotherapy.  The first visit of maintenance therapy will be 
numbered maintenance Cycle 1 Day 1 even if the last chemotherapy cycle was not completed.  All maintenance Day 15 and Day 29 assessments for patients 
randomized to Arm A are optional.
3.
End of Treatment/Withdrawal:  Performed when criteria for treatment/observation or treatment discontinuation are met (Including Arm A). Obtain these 
assessments if not completed within the prior week, except for tumor assessments which need not be repeated if performed within the prior 6 weeks.
4.
Post-Treatment Safety Follow-up: For patients receiving study treatment within 90 days prior to the End of Treatment (EOT)/Withdrawal visit, post-
treatment safety follow-up must occur monthly for 90 days after the last dose of study treatment (Day 30 3, Day 60   3, Day 90   3).  The safety follow-
up does not need to be performed for a patient who remains in maintainence and is undergoing safety assessments every 6 weeks.
5.
Survival Follow-up: Post-study survival status will be collected every 12 weeks after EOT/Withdrawal visit until death or study closure, whichever occurs 
first.  Includes collection of information on subsequent anticancer therapies.  Telephone contact is acceptable.  
6.
Informed Consent: Must be obtained prior to undergoing any trial-specific procedure.
7.
Medical/Oncological History: To include information on prior systemic chemotherapy regimens, surgery, and radiation therapy.
8.
Physical Examination: Includes an examination of major body systems, assessment of ECOG performance status, and weight (height included at screening 
only).  
9.
Contraception Check:  Patients who are of childbearing potential will need to affirm that they meet the criteria for correct use of 2 of the selected methods 
of contraception.  The investigator or his or her designee will discuss with the patient the need to use 2 highly effective contraception methods consistently 
and correctly during the entire study treatment period including up to at least 60 days after the last avelumab infusion, and document such conversation in 
the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient.
10. Blood Pressure, Pulse Rate: Blood pressure and pulse rate should be taken with the patient in the seated position after the patient has been sitting quietly 
for at least 5 minutes.      
11. Hematology, Blood Chemistry, and Coagulation: No need to repeat on Day 1 of Cycle 1 if screening assessment performed within 7 days prior to that 
date.  Required tests are listed in Table 11.  May also be performed when clinically indicated.  
12. CA-125:  To be assessed locally.  No need to repeat on Day 1 of Cycle 1 if screening assessment performed within 7 days prior to that date.
13. BRCA status. If BRCA1/2 mutation status is known or becomes known for a patient during the study, this information will be recorded in the CRF either 
at screening or at later visits. No BRCA1/2 testing is required for this study.
14. Blood Chemistry: Full chemistry panel (required tests are listed in Table 11) is required at screening, on Day 1 of each chemotherapy study cycle, and at 
End of Treatment/Withdrawal. Core chemistry panel (required tests are listed in Table 11) is required on Days 1, 15, and 29 of each maintenance cycle.  If 
full and core chemistry panels are scheduled at the same visit, only the full chemistry will be performed.  For patients with liver metastases at study entry, 
ALT, AST, total bilirubin, and alkaline phosphatase tests will be performed weekly in the first 6 weeks of treatment.  
15. Thyroid Function Tests and ACTH: Baseline free T4, TSH, and ACTH will be performed at screening or at chemotherapy Cycle 1 Day 1 pre-dose.  
Subsequently, TSH and ACTH should be assessed during the chemotherapy phase on Day 1 of every other chemotherapy cycle.  During the maintenance 
phase, TSH and ACTH should be assessed during 3rd Maintenance cycle, then every 12 weeks thereafter while on treatment; and at end of treatment visit.    
Free T4 should additionally be performed when clinically indicated.  See Table 11. 


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16. Serum/Urine Pregnancy Test: For patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed on two occasions prior to starting study therapy: once at the start of screening (all patients), and once before the administration of study 
treatment.  Urine pregnancy tests will also be routinely repeated at every treatment cycle during the active treatment period, at the End of 
Treatment/Withdrawal visit, during the post-treatment safety follow-up visits up to at least 60 days after the last avelumab infusion for patients receiving 
avelumab at EOT/withdrawal visit, and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
Additional pregnancy tests may also be undertaken if requested by IRB/IECs or if required by local regulations (see Section 7.1.1).
17. Urinalysis (Table 11): Dipstick is acceptable.  If urine dipstick is positive for urine blood, microscopic urinalysis will have to be done (Reflex Testing) and 
the patient will be treated as per local standard of care based on Investigator medical judgment.  May also be performed when clinically indicated.  
18. 12-lead ECG: See Section 7.1.5 for details. All patients require a single ECG measurement at screening (clinically significant abnormal findings in baseline 
ECGs will be recorded as medical history and on Day 1 of every other cycle during chemotherapy after carbo/taxol infusion on Arms A and B and after 
Avelumab infusion on Arm C.  Additional ECGs will be performed on Day 1 of first maintenance cycle and may be performed as clinically indicated.  
Clinically significant findings seen on follow-up ECGs should be recorded as adverse events.
19. Randomization: Randomization operated by the Sponsor via an interactive response technology (IRT) system.  Required information: site and patient 
identifiers, demographic, and stratification information.  Study treatment must begin within 7 days after randomization.  For patients randomized to a 
chemotherapy regimen that does not include avelumab, assignment to Arms A or B will remain blinded during the chemotherapy phase (see Section 5.1)
20. Study Treatment:  Weekly Paclitaxel Administration:  For additional information about pre-medications for paclitaxel, see Section 5.3.2.1. Paclitaxel 80 
mg/m2 IV over 1 hour on Days 1, 8 and 15 of each cycle, with carboplatin dose AUC 5 or AUC 6 as described in Section 5.3.2.2.2, IV on Day 1 of every 
cycle.
21. Study Treatment: Q3W Paclitaxel Administration:  For additional information about pre-medications for paclitaxel, see Section 5.3.2.1.  Paclitaxel 175 
mg/m2 IV over 3 hours, followed by carboplatin dose AUC 5 or AUC 6 as described in Section 5.3.2.2.2, IV on Day 1 of every cycle.  
22. Premedication for Avelumab:  Premedication with an antihistamine and with paracetamol/acetaminophen approximately 30 to 60 minutes prior to each 
dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol/acetaminophen i.v. or oral equivalent).  This may be 
modified based on local treatment standards and guidelines, as appropriate.
23. Study Treatment: Avelumab (for patients randomized to Arms B and C): Patients will receive avelumab 10 mg/kg administered as a 1-hour IV infusion 
(see Section 5).  Avelumab will be administered Q3W on Day 1 of every 3-week cycle during chemotherapy (if on Arm C) and Q2W during maintenance
on Days 1, 15, and 29 of every 6-week maintenance cycle (if on Arm B or Arm C).  


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24. Tumor Assessments: Tumor assessment should be performed at screening, after 3 cycles of chemotherapy, and at the completion of chemotherapy to 
determine eligibility for maintenance (prior to Cycle 1 Day 1 of maintenance).  For patients who undergo IDS, an additional tumor assessment should be 
performed after surgery.   In the maintenance phase, tumor assessments are performed every 12-weeks. Tumor assessments will include all known or 
suspected disease sites.  Imaging may include chest, abdomen, and pelvis CT or MRI scans.  Brain scans and bone scans will be performed at baseline if 
disease is suspected and on study as appropriate to follow disease.  Baseline central nervous system (CNS) imaging is not required with the exception of 
symptomatic patients to rule out CNS metastases.  CT or MRI scans to be done every 12 weeks (window of 7 days prior to dosing is allowed) until 
confirmed disease progression regardless of initiation of subsequent anti-cancer therapy. In addition, radiological tumor assessments will also be conducted 
whenever disease progression is suspected (eg, symptomatic deterioration or rising CA-125 levels), and at the EOT/Withdrawal visit (if not done in the 
previous 6 weeks).  CR and PR must be confirmed with repeated imaging performed at least 4 weeks after initial documentation of response. If radiologic 
imaging shows progressive disease (PD), then tumor assessment should be repeated after at least 4 weeks to confirm PD in the absence of rapid clinical 
deterioration. Assessment of response will be made using RECIST v.1.1 (Appendix 3) 
  All 
radiographic images will be collected and may be objectively verified by an independent third party core imaging laboratory as described in Study Manual.  
See Section 7.2 for additional information.  
25. Adverse Events: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  See Section 8.2).  
26. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and up 
to the end of treatment/withdrawal visit or the end of the safety follow-up period, whichever is later.  For patients on Arm A maintenance, concomitant 
medications will be collected up to the point when treatment discontinuation criteria are met.  All concomitant medications should be recorded in the CRF
including supportive care drugs (eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug 
supportive interventions (eg, transfusions).   See Section 5.6 for further details.
27. Blood Sampling for Paclitaxel Pharmacokinetics: At selected sites, a 3.5 mL of whole blood will be collected in at least 10 patients in each of the 3 
treatment arms, regardless of regimen, at pre-dose, and at 1, 3 4, 5, 6, 10, and 24 hours post-paclitaxel on Day 1 of Cycle 2.  Note: the 1- and the 3-hour 
post-infusion samples represent the end of infusion samples for weekly and 3-weekly paclitaxel administration respectively and should be taken 
immediately before the end of infusion.  Details are outlined in Section 7.4.  
28. Blood Sampling for Carboplatin (Total and Free Platinum) Pharmacokinetics:  At selected sites, a 5 mL whole blood will be collected in at least 10
patients in each of the 3 treatment arms at pre-dose and at, 0.5, and 1 (immediately before the end of infusion), 5, 6, 10, and 24 hours post-carboplatin 
infusion on Day1 of Cycle 2. Details are provided in Section 7.4.
29. Blood Sampling for Avelumab Pharmacokinetics for all patients receiving avelumab:
Chemotherapy Phase (Arm C only):  PK samples (3.5 mL) for avelumab will be collected within 2 hours prior to and immediately before the end of 
avelumab infusion (1 hour post-start of infusion) on Day 1of cycles 1-4. For patient’s reciveing weekly paclitaxel only, an additional avelumab sample will 
be taken on Day 8 and Day 15 of Cycles 1-4 prior to the paclitaxel infusion. 
Maintenance Phase (Arms B and C):   PK samples (3.5 mL) for avelumab will be collected within 2 hours prior to and immediately before the end of 
avelumab infusion (1 hour post-start of infusion) on Days 1, 15, and 29 of the first maintenance cycle. Thereafter, PK samples will be collected pre-dose 
and 1 hour post-start of infusion on Day 1 of every maintenance cycle until Cycle 18, at the end of treatment, and post-treatment safety follow up (30 Days)   
Details are provided in Section 7.4.  
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30. Mandatory Archival FFPE Tumor Tissue Block:  A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from initial 
diagnosis must be provided that is of sufficient size to allow, if possible, for sectioning of fifteen (15) 5-micron tissue sections. If an FFPE tumor tissue 
block cannot be provided, sites should provide fifteen (15) unstained slides each containing a 5-micron tissue section cut serially from the same FFPE block. 
If archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample must be obtained in accord with local institutional practice for tumor biopsies.  
Archived or de novo tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not 
be submitted. For neoadjuvant patients, additional tumor collection for surgical specimen is described in Section 6.1.1.
31. De Novo Tumor Biopsy:  A de novo (ie, fresh biopsy) tumor sample should be collected at End of Treatment if a patient signs a separate informed consent 
document and discontinues due to disease progression unless clinically contraindicated. Tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material), is not adequate and should not be submitted.
32. Banked Blood Biospecimen for Genotyping: A single 4-mL blood sample will be collected at Screening and retained in a biobank for possible 
pharmacogenetic assessments (ie, genotyping), unless prohibited by local regulations or by decision of the Institutional Review Board or Ethics Committee.  
Samples may be used for analyses of DNA sequence variation in genes potentially related to drug response, safety, PK, or mechanism of action (also see 
Section 7.6).  This sample may also be collected on Day 1 prior to dosing if necessary.  
33.
 
 
 
34. Blood for Avelumab Immunogenicity Testing (anti-avelumab antibodies; anti-drug antibodies [ADAs], neutralizing anti-avelumab antibodies 
[NABs]):  All immunogenicity samples (3.5 mL) should be collected pre-dose and within 2 hours before the start of the avelumab infusion.         
Chemotherapy Phase (Arm C only):  Immunogenicity sample (3.5 mL) will be collected predose on Day 1 of chemotherapy cycles 1-4.                      
Maintenance Phase (Arms B and C): Immunogenicity samples (3.5 mL) will be collected predose on Days 1 and 15 of maintenance cycles 1 and 2. 
Thereafter, immunogenicity samples will be collected predose on Day 1 of every maintenance Cycle until cycle 18, at the end of treatment, and post-
treatment safety follow up (30 Days).   All samples that are positive for ADA may also undergo characterization for Nab.  See Section 7.5.
35. FOSI-18 and EQ-5D-5L: All patients will complete these self-administered questionnaires pre-dose on Days 1 of every chemotherapy cycle, and on Day 1 
of every maintenance cycle, at the EOT/Withdrawal visit, and every 6 weeks during the post-treatment safety and survival follow-up period for a total of 3 
years from the date of patient enrollment.  Patients must complete these questionnaires at the clinic prior to any study or medical procedure during the 
chemotherapy and maintenances phases, and at home every 6 weeks thereafter using an ePRO device, during the safety and survival follow-up period.
Abbreviations: →= ongoing/continuous event; ACTH = ;ADAs = anti-drug antibodies; AEs = adverse events; C = cycle; CT = computed tomography; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Group; EOT = end of treatment; FFPE = formalin-fixed, paraffin-embedded; HBV = hepatitis B virus; HCV = 
hepatitis C virus; MRI =  magnetic resonance imaging; Nab = neutralizing antibody; PK = pharmacokinetics
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1. INTRODUCTION
1.1. Indication
Avelumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 isotype that 
is currently being investigated in patients with epithelial ovarian, fallopian tube, or primary 
peritoneal cancer.
1.2. Background and Rationale
1.2.1. Ovarian Cancer
Ovarian cancer (OC) is the leading cause of death from gynecologic cancer and the fifth most 
common cause of cancer mortality in women. Fewer than 40% of women diagnosed with 
ovarian cancer are cured.1 The incidence of ovarian cancer increases with age and is most 
prevalent in the eighth decade of life.  The median age at the time of diagnosis is 63 years, 
and 70% of patients present with advanced disease.2 Although expectations for long-term 
survival can be very high if the cancer is identified and treated early, women who are 
diagnosed with advanced ovarian cancer continue to have poor long-term survival due to 
refractory, resistant, or recurrent disease and most will die within 5 years.
Ovarian neoplasms consist of several histopathological entities.  Epithelial ovarian cancer 
(EOC) comprises the majority of malignant ovarian neoplasms (about 80%);19 however, 
other less common pathologic subtypes must be considered in treatment recommendations.  
Fallopian tube cancer (FTC) and primary peritoneal cancer (PPC), which are less common 
neoplasms, are managed in a similar manner to epithelial ovarian cancer.
Carboplatin in combination with paclitaxel is the current standard of care in the first-line 
EOC treatment setting following debulking surgery for patients with stage IC or higher, as 
well as selected stage IA-B patients (those with high grade or clear cell histology).  
Chemotherapy is administered for a total of 6-8 cycles.3 Complete response is achieved in 
approximately 75% of patients, but most patients ultimately succumb to the disease with 
median progression-free survival (PFS) of approximately 18 months.4 Therefore, there 
remains a high unmet need for newer agents with novel mechanisms of action and 
combination regimens able to modify the natural history of the disease.
Recently, the dose-dense frontline chemotherapy regimen of weekly paclitaxel combined 
with Q3W carboplatin has been increasing in usage.5,6 The Japanese Gynecologic Oncology 
Group (JGOG) 3016 study, conducted in previously untreated Stage II-IV patients with 
ovarian cancer, demonstrated improvement in PFS and OS compared to the traditional Q3W
regimen.  The toxicity profile was similar, with only anemia seen at a higher frequency with 
the weekly regimen.  The GOG2627 study was conducted to confirm these findings in the 
high-risk patient subgroup (Stage IV or suboptimal Stage III) and to examine the role of 
bevacizumab in this treatment setting. Patients were randomized to the dose-dense regimen 
vs traditional Q3W regimen.  Within each treatment arm, patients were allowed to receive 
bevacizumab per physician’s choice made prior to randomization.  Approximately 80% of 
patients received bevacizumab.  In the overall population, no benefit of weekly paclitaxel 
over Q3W regimen was demonstrated. However, pre-specified analysis in patients who did 


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not receive bevacizumab demonstrated statistically significant improvement in PFS in the 
dose-dense arm compared to Q3W regimen (Table 1). Therefore, GOG262 appears to 
confirm the benefit of weekly paclitaxel which was not realized in the presence of 
bevacizumab.  Additional confirmatory studies, ICON8 and ICON8B, are ongoing.
At the present time, the dose-dense regimen is a category 1 National Cancer Comprehensive 
Network (NCCN) recommendation3 and is the standard of care in Japan. 
Several studies have been conducted in the frontline treatment setting (see Table 1).  Due to 
long post-progression survival, PFS is an accepted endpoint in this setting.7 Bevacizumab 
(Avastin) demonstrated improvement in PFS in combination with chemotherapy followed 
by one year of maintenance therapy both in the first-line treatment setting20,21 and in 
platinum-sensitive disease recurrence22 but without an impact on overall survival (OS) in the 
overall patient population. Bevacizumab is currently approved in both the frontline and the 
platinum-resistant treatment settings in Europe, while in the US, it is approved only in the 
platinum-resistant treatment setting. 
Table 1.
Summary of Studies Demonstrating Benefit of Dose-Dense Frontline 
Chemotherapy and Related Studies
Study
Eligibility
Design
Initial Treatment Maintenance 
(1 year)
mPFS
(months)
mOS
(months)
ICON 7
N=1528
Stage III/IV or 
High-Grade stage 
I/II
Carbo-Q3W Paclitaxel-Bevacizumab 
Bevacizumab
vs.
Carbo-Q3W Paclitaxel
20 (16 in 
HR**)
vs.
17.5 (10.5 in 
HR**)
58
vs.
58
JGOG 
3016
N=631
Stage II – IV
Carbo – Q3W Paclitaxel
vs.
Carbo - weekly Paclitaxel
17.5
vs.
28.2
62
vs.
100
GOG 218
N=1873
Suboptimal 
Debulking Stage 
III or Stage IV
Carbo-Q3W Paclitaxel - Bevacizumab
Bevacizumab
vs.
Carbo-Q3W Paclitaxel - Bevacizumab
vs.
Carbo-Q3W Paclitaxel
14*
vs.
10
vs.
11
40
vs.
39
vs.
39
GOG 262
N=692
Suboptimal 
Debulking Stage 
III or Stage IV
Carbo – Q3W Paclitaxel
vs.
Carbo – weekly Paclitaxel
vs.
Carbo – Q3W Paclitaxel + Bevacizumab
vs.
Carbo - weekly Paclitaxel + 
Bevacizumab
10.3
vs.
14.2
vs.
15
vs.
15
** High risk = FIGO Stage IV disease or FIGO Stage III disease and >1.0 cm of residual disease after 
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Neoadjuvant chemotherapy is also increasing in usage and is currently selected for 25% of 
patients with Stage II disease, 40% of patients with Stage III disease, and 50% of patients 
with Stage IV disease.23 A randomized study demonstrated non-inferiority of this approach
with respect to overall survival compared to adjuvant therapy in high-risk patients.24
Typically, 3 cycles of chemotherapy are administered before surgery and 3 cycles after 
surgery.  The same chemotherapy regimens are used in the neoadjuvant treatment setting as 
for the traditional post-surgical approach.3 Other frontline studies have successfully enrolled 
patients undergoing either adjuvant or neoadjuvant therapies (GOG262 and ICON8). 
The current standard of care in the frontline maintenance treatment setting is 
region-dependent.  Some patients receive bevacizumab in combination with chemotherapy, 
followed by one year of bevacizumab maintenance therapy in regions where bevacizumab is 
approved in this setting. For a significant number of newly diagnosed patients, the standard 
of care remains a platinum doublet chemotherapy followed by observation.
1.2.2. Pharmaceutical and Therapeutic Background
1.2.2.1. Avelumab (MSB0010718C)
The investigational product in the present clinical trial is avelumab (MSB0010718C), a fully 
human monoclonal antibody of the immunoglobulin (Ig) G1 isotype. 
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with PD 1.  
Unlike anti-PD-1 antibodies that target T cells, avelumab targets tumor cells, and therefore is 
expected to have fewer side effects, including a lower risk of autoimmune-related safety 
issues, as blockade of PD-L1 leaves the PD L2/PD 1 pathway intact to promote peripheral 
self-tolerance.25 For complete details of the in vitro and nonclinical studies, refer to the 
Investigator’s Brochure for avelumab.11
Avelumab is being developed jointly by Pfizer and Merck KGaA.  The clinical development 
program for avelumab currently includes 5 ongoing studies in patients with various solid 
tumors conducted by Merck KGaA 
 
(2 ongoing Phase 1 studies in 
patients with solid tumors EMR 100070-001 and EMR 100070-002, a Phase 2 study in 
patients with Merkel cell carcinoma EMR 100070-003, and 2 Phase 3 studies in patients with 
non-small cell lung cancer (NSCLC) EMR 100070-004 and EMR100070-005).  In addition 
to these trials, Pfizer is planning to conduct studies of avelumab in patients with ovarian 
cancer (B9991009 and B9991010
), urothelial cancer (B9991001
), renal cell cancer (B9991002 and B9991003
), NSCLC 
(B9991005
), classical Hodgkin lymphoma (B9991007
), and a 
variety of solid tumors (B9991004
).
Trial EMR100070 001 is a global Phase 1, open label, multiple ascending dose clinical study 
aimed to investigate the safety, tolerability, pharmacokinetics, biological, and clinical activity 
of avelumab in patients with metastatic or locally advanced solid tumors.  This trial consists 
of 2 parts, a dose escalation phase and a dose expansion phase, which is performed in 
selected tumor indications.  Avelumab was administered intravenously at the assigned dose 
level as a 1 hour intravenous (IV) infusion once every 2 weeks.  The following dose levels 
(DLs) were investigated: 1.0 mg/kg, 3.0 mg/kg, 10.0 mg/kg, and 20.0 mg/kg.
CCI
CCI
CCI
C
CCI
CCI
CCI
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As of June 2015, treatment emergent adverse events occurred in all 53 patients (100.0%) 
participating in the dose escalation cohort, of which 42 patients (79.2%) reported 
treatment-related treatment-emergent adverse events (TEAEs).  The most frequently 
observed treatment related TEAE was fatigue reported in 20 patients (37.7%), followed by 
influenza-like illness in 10 patients (18.9%), and pyrexia in 7 patients (13.2%).
Nine of the 53 patients (17.0%) in the dose escalation cohort experienced at least one Grade 
≥ 3 treatment-related TEAE.  These included event terms of autoimmune disorder (3 patients; 
5.7%), aspartate aminotransferase (AST) increased and blood creatine phosphokinase (CPK) 
increased (each in 2 patients; 3.8%), and fatigue, abdominal pain lower, lipase increased, 
amylase increased, alanine aminotransferase (ALT) increased, blood alkaline phosphatase 
increased, and lymphocyte count decreased (each in 1 patient; 1.9%).
Of the 9 patients (17.0%) who had Grade ≥ 3 treatment-related TEAEs, 7 (13.2%) had 
Grade 3 events, 2 (3.8%) had Grade 4 events (blood creatine phosphokinase increased and 
autoimmune disorder), and no Grade 5 treatment-related TEAEs were observed.
Overall, the TEAE profile was similar across different dose escalation cohorts and the 
incidences of TEAEs by TEAE category did not increase with increasing dose. 
1.2.2.2. Safety
As of 01 June 2015, safety data of 717 patients who were treated with 10 mg/kg of avelumab 
every 2 weeks and followed up for at least 4 weeks in the pooled tumor expansion cohort of 
Trial EMR 100070-001 were evaluated.  In addition, safety data from the patients enrolled in 
the pooled expansion cohort were also evaluated by tumor type: cohorts for non-small cell 
lung cancer [NSCLC] (n=184), gastric cancer (n=120), ovarian cancer (n=75, see below) and 
urothelial carcinoma (n=44).
Of the 717 patients treated in the pooled expansion cohorts, 218 (45.4%) experienced at least 
1 Grade ≥ 3 treatment emergent adverse event TEAE, and 330 (68.8%) reported 
treatment-related TEAEs, of which 59 (12.3%) reported Grade ≥ 3 treatment-related TEAEs.
The frequently reported (incidence ≥ 2% in the pooled expansion cohort) treatment-related 
TEAEs (any grade) in the pooled expansion cohort and the ovarian tumor expansion cohort
are summarized in Table 2.  The most frequently reported (occurring in at least 2 patients in 
the pooled extension cohort) Grade ≥ 3 treatment-related TEAEs in the pooled expansion 
cohort and the ovarian cancer expansion cohort are presented in Table 3.
Treatment-related TEAEs were observed in 498 (69.5%) patients in the pooled expansion 
cohort.  The most frequently observed treatment-related TEAEs (with an incidence of ≥ 2%) 
of any grade in the pooled expansion cohort were infusion-related reaction (18.7%), fatigue 
(18.1%), nausea (10.3%), diarrhea (6.8%), chills (6.7%), and decreased appetite (5.2%).  
Other frequently seen treatment-related TEAEs with an incidence < 5% but ≥ 2% included 
arthralgia, pyrexia, hypothyroidism, pruritus, vomiting, influenza-like illness, rash, anemia, 
AST increased, myalgia, asthenia, headache, ALT increased, dyspnea, and constipation 
(Table 2).


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Grade ≥ 3 treatment-related TEAEs were observed in 77 patients (10.7%) in the pooled 
expansion cohort (6.7% in the ovarian cancer expansion cohort).  As shown in Table 3, the 
most frequently observed Grade ≥ 3 treatment-related TEAEs in the pooled expansion cohort 
were gamma-glutamyltransferase increased, infusion-related reaction, and lipase increased 
(each occurred in 7 patients; 1.0%), followed by anemia (6 patients; 0.8%), fatigue 
(5 patients; 0.7%), and AST increased and autoimmune hepatitis (each occurred in 4 patients; 
0.6%). Other Grade ≥ 3 treatment-related TEAEs that were observed in ≥ 2 patients included 
ALT increased, lymphocyte count decreased, and pneumonitis (each in 3 patients; 0.4%), and 
asthenia, blood alkaline phosphatase increased, blood creatine phosphokinase increased, 
colitis, constipation, dyspnea, hyperglycemia, hypokalemia, hypoxia, myositis,  and platelet 
count decreased (each in 2 patients; 0.3%).
Of the 77 patients (10.7%) who experienced Grade ≥ 3 treatment-related TEAEs, 60 (8.4%) 
had Grade 3 events, and 14 (2.0%) and 4 (0.6%) reported Grade 4 and Grade 
5 treatment-related TEAEs, respectively.
No Grade 4 or 5 treatment-related TEAEs were reported for any patient in the ovarian cancer 
expansion cohort. 
The 14 patients reporting Grade 4 treatment-related TEAEs included 7 patients (3.8%) in the 
NSCLC expansion cohort with the preferred terms (PTs) of infusion-related reaction 
(2 patients), amylase increased, embolic stroke, frontal lobe epilepsy, monoplegia, syncope, 
dyspnea, pneumonitis, and autoimmune neutropenia (each in 1 patient).  Further Grade 
4 treatment-related TEAEs were seen in 5 patients of the metastatic breast cancer (MBC) 
expansion cohort (3.0%) with the PTs of gamma-glutamyltransferase increased, 
hypokalemia, respiratory failure, anemia, neutropenia, thrombocytopenia, and cardiac arrest 
(each in 1 patient).  The other 2 patients who reported Grade 4 treatment-related TEAEs were 
1 patient in the mesothelioma expansion cohort (blood creatine phosphokinase increased) and 
1 patient in the urothelial carcinoma expansion cohort (myositis).
The 4 patients who experienced Grade 5 treatment-related TEAEs were 2 patients in the 
NSCLC expansion cohort (radiation pneumonitis 
 and acute 
respiratory failure
) and 2 patients in the MBC expansion cohort 
(respiratory distress
 and acute hepatic failure
).
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Table 2.
Most Frequently Reported (Incidence ≥ 2%) Treatment-Related TEAEs in 
the Pooled Expansion Cohorts and in the Ovarian Cancer Expansion Cohort 
(Any Grade)
MedDRA PT
Pooled Expansion Cohort 
Patients 
(n=717), n (%)
Ovarian Cancer
Expansion Cohort
(n=75), n (%)
Number of patients with at least 1 TEAE
498 (69.5)
55 (73.3)
Infusion related reaction
134 (18.7)
8 (10.7)
Fatigue
130 (18.1)
11 (14.7)
Nausea
74 (10.3)
10 (13.3)
Diarrhea
49 (6.8)
10 (13.3)
Chills
48 (6.7)
7 (9.3)
Decreased appetite
37 (5.2)
3 (4.0)
Arthralgia
35 (4.9)
2 (2.7)
Pyrexia
34 (4.7)
3 (4.0)
Hypothyroidism
32 (4.5)
5 (6.7)
Pruritis
28 (3.9)
2 (2.7)
Vomiting
28 (3.9)
5 (6.7)
Influenza-like illness
26 (3.6)
3 (4.0)
Rash
24 (3.3)
6 (8.0)
Anemia
21 (2.9)
1 (1.3)
Aspartate aminotransferase increased
20 (2.8)
1 (1.3)
Myalgia
20 (2.8)
3 (4.0)
Asthenia
18 (2.5)
0
Headache
18 (2.5)
2 (2.7)
Alanine aminotransferase increased
17 (2.4)
1 (1.3)
Dyspnea
17 (2.4)
2 (2.7)
Constipation
15 (2.1)
4 (5.3)
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; TEAE: treatment emergent 
adverse event.
Safety Population.  Only TEAEs started during the on-treatment period are summarized


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Table 3.
Most Frequently Reported (in ≥ 2 Patients) Grade ≥ 3 Treatment-Related 
TEAEs in the Pooled Expansion Cohorts and in the Ovarian Cancer 
Expansion Cohort
MedDRA PT
Pooled Expansion Cohort 
Patients 
(n=480), n (%)
Ovarian Cancer
Expansion Cohort
(n=75), n (%)
Number of patients with at least 1 TEAE
77 (10.7)
5 (6.7)
Gamma-glutamyltransferase increased
7 (1.0)
0
Infusion related reaction
7 (1.0)
0
Lipase increased
7 (1.0)
1 (1.3)
Anemia
6 (0.8)
0
Fatigue
5 (0.7)
0
Aspartate aminotransferase increased
4 (0.6)
0
Autoimmune hepatitis
4 (0.6)
0
Alanine aminotransferase increased 
3 (0.4)
0
Lymphocyte count decreased 
3 (0.4)
0
Pneumonitis
3 (0.4)
0
Asthenia
2 (0.3)
0
Blood alkaline phosphatase increased
2 (0.3)
0
Blood creatinine phosphokinase increased
2 (0.3)
1 (1.3)
Colitis
2 (0.3)
0
Constipation
2 (0.3)
0
Dyspnea
2 (0.3)
0
Hyperglycemia
2 (0.3)
1 (1.3)
Hypokalemia
2 (0.3)
0
Hypoxia
2 (0.3)
0
Myositis
2 (0.3)
1 (1.3)
Platelet count decreased
2 (0.3)
0
MedDRA: Medical Dictionary for Regulatory Activities; PT: preferred term; TEAE: treatment emergent 
adverse event.
Safety Population. Only TEAEs started during the on-treatment period are summarized.
As of 01 June 2015, 289 of 717 patients (40.3%) in the pooled expansion cohorts had at least
1 serious TEAE.  Treatment-related serious TEAEs were reported in 47 of 717 patients 
(6.6%) in the pooled expansion cohort. These included infusion-related reaction and 
pneumonitis (each in 6 patients; 0.8%), pyrexia (4 patients; 0.6%), autoimmune hepatitis and 
dyspnea (each in 3 patients; 0.4%), and colitis and non-cardiac chest pain (each in 2 patients; 
0.3%). All other treatment-related serious TEAEs were reported in a single patient (0.1%) 
only.  The incidence of treatment-related serious TEAEs was 4.0%, in the ovarian cancer 
expansion cohort.
As of 01 June 2015, 290 deaths (40.4%) occurred in the pooled expansion cohorts regardless 
of the cancer type.  Twenty-seven (27) patients died in the ovarian cancer expansion cohort 
(36.0%). 
The majority of deaths in the pooled expansion cohort were due to progressive disease 
(216 patients; 30.1%). In the pooled expansion cohort, overall, a total of 4 deaths (0.6%) for 
TEAEs related to trial treatment were considered as primary reason of the death by the 


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investigator. Two additional cases of death were reported and assessed as treatment-related, 
but the treatment related TEAEs were not considered as the primary reason of the death.  
Overall, of these 6 treatment-related deaths, 2 occurred in the NSCLC cohort, 3 occurred in 
the MBC cohort, and 1 occurred in the gastric cancer expansion cohort.  A total of 81 deaths 
(11.3%) occurred within 30 days of last treatment in the pooled expansion cohort.
As of 01 June 2015, 139 patients (19.4%) in the pooled expansion cohort discontinued 
avelumab treatment for TEAEs.  Of these patients with treatment discontinuations, 
60 patients (8.4%) in the pooled expansion cohorts had treatment discontinuations that were 
due to treatment related TEAEs.
In the pooled expansion cohort, treatment-related events leading to treatment discontinuation 
were infusion-related reaction (19 patients; 2.6%), followed by gamma-glutamyltransferase 
increased (5 patients; 0.7%), autoimmune hepatitis, blood creatine phosphokinase increased, 
and lipase increased (3 patients; 0.4%), and dyspnea (2 patients; 0.3%).  All other 
treatment-related TEAEs leading to treatment discontinuation were observed in a single 
patient (0.1%) only.
Treatment-related TEAEs leading to treatment discontinuation were reported in 13.3% 
patients in the ovarian cancer expansion cohort.
Immune-related Adverse Events: As of 01 June 2015, a cumulative review revealed 
106 patients with potential irAEs out of717 patients (14.8%) treated in the pooled expansion 
cohort of Trial EMR 100070-001 and 8 patients out of 53 patients (15.1%) treated in the dose 
escalation cohort of Trial EMR 100070-001.
Treatment-related potential irAEs were observed in 71 of 717 patients (9.9%) in the pooled 
expansion cohort, and the incidence was 10.7% in the ovarian cancer expansion cohorts.
Hypothyroidism was the most frequent treatment-related irAE, which occurred in 32 patients
(4.5%) in the pooled expansion cohort. The other frequent irAEs, which were considered as 
treatment-related, were pneumonitis (8 patients; 1.1%), autoimmune hepatitis and 
hyperthyroidism (4 patients; 0.6%), and colitis and dry eye (3 patients each; 0.4%).  
Additional treatment-related irAEs were seen in 2 or 1 patients in the pooled expansion 
cohort.
The majority of irAEs were Grade 1 or Grade 2 events.  In the pooled expansion cohort, the 
Grade 3 and Grade 4 events occurred in 1.7% and 1.1% of patients, respectively, for all 
potential irAEs and in 1.4% and 0.6% of patients, respectively, for treatment-related irAEs.  
One patient
 in the NSCLC expansion cohort had a Grade 5 irAE 
radiation pneumonitis, which was considered treatment-related by the investigator.  In 
addition, 2 events of suspicion of autoimmune hepatitis (not confirmed by biopsy/autopsy) 
assessed as Grade 3 had a fatal outcome.
The potential irAE cases with a fatal are described in the avelumab IB.11
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Infusion-related Reactions: Two Grade 4 unexpected serious adverse reactions (anaphylactic 
reaction and infusion-related reaction) involving 2 patients enrolled in Trial EMR 
100070-001 reported in December 2013 triggered a cumulative review of serious and 
non-serious cases of infusion-related reactions/hypersensitivity reactions across the program.  
Following evaluation of the safety signal of infusion-related reactions/hypersensitivity 
reactions, the Sponsor decided to classify infusion-related reactions/hypersensitivity 
reactions as a newly identified risk (previously classified as a potential risk) and to 
implement a mandatory premedication with an antihistamine plus paracetamol 
(acetaminophen) for all patients beginning on 29 January 2014. 
An event was considered an infusion-related reaction if (1) the event had the preferred term 
of “infusion-related reaction, drug hypersensitivity, or anaphylactic reaction” and (2) the 
onset of the event was on the same day or the next day following avelumab administration.
As of 01 June 2015, 138 of 717 patients (19.2%) in the pooled expansion cohort experienced 
at least 1 episode of infusion-related reaction.  Most of the events were Grade 1 (30 patients, 
4.2%) or Grade 2 (101 patients, 14.1%) in intensity, and Grade 3 (5 patients, 0.7%) or Grade 
4 events (2 patients, 0.3%) were less frequent.  No Grade 5 events were reported.  Most of 
the infusion-related reactions had an onset after the first (91 patients, 12.7%) or second 
(35 patients, 4.9%) avelumab infusion, and those with an onset after the third (9 patients, 
1.3%) or fourth avelumab infusion (3 patients, 0.4%) were less frequent.  In 17 patients 
(2.4%), avelumab treatment was discontinued because of infusion-related reaction.
In addition, 4 patients (7.5%) in the dose escalation cohort reported an infusion-related 
reaction (all Grade 2).
After introduction of the mandatory premedication on 29 January 2014, 35 and 677 patients 
in the dose escalation and the pooled expansion cohorts of Trial EMR 100070-001 received
trial treatment, respectively.  Under this premedication procedure, 117 of 677 patients 
(17.3%) in the pooled expansion cohort experienced infusion-related reaction, with 
28 patients (4.1%) having Grade 1, 86 patients (12.7%) having Grade 2, and 3 patients 
(0.4%) having Grade 3 event.  No Grade 4 infusion-related reaction was observed after 
introduction of the mandatory premedication.  Three patients (8.6%) in the dose escalation 
cohort reported infusion-related reactions (all Grade 2) starting from 29 January 2014.
In addition to the aforementioned cases of infusion-related reaction, 1 patient in the MBC 
expansion cohort 
 experienced Grade 4 cardiac arrest 1.5 hours after 
the third infusion of avelumab (10 mg/kg).  This patient died from anoxic brain injury (not 
treatment related) after the cardiac arrest. 
The management of infusion-related reactions and severe hypersensitivity reactions can be 
found in Section 5.3.5, respectively.  A complete guideline for the emergency treatment of 
anaphylactic reactions according to the Working Group of the Resuscitation Council (United 
Kingdom) can be found at https://www.resus.org.uk/pages/reaction.pdf.
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1.2.2.3. Pharmacokinetics of Avelumab
Avelumab pharmacokinetics and dose proportionality following the first 1-hour infusion 
have been characterized in 77 Caucasian patients treated in the dose escalation and expansion 
cohorts of Study EMR 100070-001 by standard non-compartmental analysis.  This analysis 
revealed that the exposure parameters of Cmax and AUCτ generally increased in a dose 
proportionate fashion across the 1, 3, 10, and 20 mg/kg doses.  Apparent half-life tended to 
increase with dose, likely due to the partial contribution of target mediated disposition at 
lower doses.  Terminal half-life of 10 and 20 mg/kg doses were similar (102-120 hours, 
which likely indicates high target occupancy and low target mediated elimination.  In a Phase 
1 study in 17 Japanese patients (EMR 100070-002), exposures at 3, 10, and 20 mg/kg were 
similar to those observed in study EMR 100070-001.
Target occupancy (TO) on peripheral blood CD3+ T cells was investigated in human blood 
in vitro by flow cytometry after spiking of whole blood samples from eight healthy 
volunteers with avelumab over a concentration of 0.003-10 g/mL.  Fifty percent (50%) 
receptor occupancy was observed at a drug concentration of 0.122 g/mL 0.042 g/mL 
with a plateau indicating at least a (95% receptor occupancy reached in all blood samples at 
1 g/mL.  PK profiles obtained from the dose escalation phase of Trial EMR 
100070 001 found all patients at 10 mg/kg dose reached or exceeded the serum level (median 
Ctrough 20-37 g/mL) of avelumab required for >95% TO.  For patients treated with 3 mg/kg 
of avelumab, 10 of 13 patients reached the required serum level (3.7-8.3 g/mL).
1.2.2.4. Efficacy of Avelumab in Patients with Ovarian Cancer
The efficacy analysis of the ovarian cancer expansion cohort had a data cutoff of 13 February 
2015, approximately 13 weeks after the start of avelumab treatment on the last patient who 
was included in this pre-planned interim analysis on this expansion cohort.  The ovarian 
cancer expansion cohort enrolled and treated a total of 75 patients.  This cohort consisted of 
patients with recurrent or refractory ovarian cancer who had progression within 6 months of 
platinum-based therapy or progression after subsequent therapy in previously relapsed 
patients.
Table 4 presents the best overall response (BOR) results of 75 patients in the ovarian cancer 
expansion cohort, together with the ORR according to RECIST 1.1, defined as the proportion 
of patients with a BOR (confirmed or unconfirmed) of PR or CR.  Of note, results of 
8 patients (10.7%) were non-evaluable.  The reasons for non-evaluable tumor response 
results included data missing or not assessable.
The ORR based on confirmed and unconfirmed responses for patients treated in the ovarian 
cancer expansion cohort was 10.7% (8 of 75 patiens).  In 5 of the 8 responders (62.5%), the
responses were ongoing at the time of the data cutoff.  The onset of the response was at 
around 6 weeks in 4 patients.  The onset of the other 4 responders occurred at Weeks 10, 11, 
14, and 18, respectively.
The median PFS for the ovarian cancer expansion cohort was 11.4 weeks (95% CI: 
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Table 4.
Unconfirmed Tumor Response Observed in Ovarian Cancer Expansion
Cohort
BOR by RECIST 1.1 (Unconfirmed)
Ovarian Cancer Expansion
Cohort
(n=75)
n (%)
Complete Response
0
Partial Response
8 (10.7)
Stable Disease
33 (44)
Progressive Disease
26 (34.7)
Non-Evaluable a
8 (10.7)
ORR (%, [95% CI])
8 (10.7)
BOR: best overall response; CI: confidence interval; ORR: objective response rate; RECIST:
Response Evaluation Criteria in Solid Tumors.
a Non-evaluable includes ‘missing’ and ‘not assessable’
Objective response rate was defined as proportion of patients with best overall response of CR or PR
Complete information for avelumab may be found in the single reference safety document
(SRSD), which for this study is the Investigator’s Brochure for avelumab.11
1.2.2.5. Carboplatin and Paclitaxel for Ovarian Cancer
The combination of carboplatin and paclitaxel is one of the most widely used chemotherapy 
regimens and remains a global standard of care for frontline treatment of EOC.  The 
traditional regimen consists of paclitaxel 175 mg/m2 over 3-hour IV infusion, followed by 
carboplatin, administered at an area under the curve (AUC) of 5-7.5 intravenously over 
1 hour on Day 1, given every 3 weeks for 6 cycles.3 In the overall patient population, 
including Stage II-IV patients, this regimen is associated with response rates over 75%, PFS
approximately 18 months and OS approximately 55 months.6,26 The dose-dense regimen (as 
per JGOG 3016) consists of paclitaxel 80 mg/m2 IV over 1 hour on Days 1, 8, and 15, and 
carboplatin administered at an area under the curve (AUC) of 6 intravenously over 1 hour on 
Day 1, given every 3 weeks for 6 cycles.  Compared to traditional Q3W
paclitaxel-carboplatin, the dose-dense regimen was associated with significant improvement 
of PFS (28.2 months vs 17.5 months; hazard ratio [HR] 0.76, 95% CI 0.62–0.91; p=0.0037) 
and OS (100.5 months vs 62.2 months, HR = 0.79, 95% CI 0.63-0.99, p=0.039).6 The 
adverse event profile was similar for these two regimens.  Most common Grade 3/4 toxicities 
included neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, fatigue, 
arthralgia, myalgia, and neuropathy.  With the exception of Grade 3/4 anemia which was 
higher in the dose-dense group (69% vs 44%), no significant differences in the adverse event 
profiles were seen.5
Complete information for carboplatin and paclitaxel may be found in the single reference 
safety documents, (which for this study are the Paraplatinand TaxolUnited States 
Prescribing Information (USPI), respectively).


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1.2.2.5.1. Paclitaxel Pharmacokinetics
Pharmacokinetic parameters of paclitaxel following 3- and 24-hour infusions of paclitaxel at 
dose levels of 135 and 175 mg/m2 were determined in a randomized Phase 3 study in ovarian 
cancer patients.  It appeared that with the 24-hour infusion of paclitaxel, a 30% increase in 
dose (135 mg/m2 versus 175 mg/m2) increased the Cmax by 87%, whereas the AUC (0-∞) 
remained proportional.  However, with a 3-hour infusion, for a 30% increase in dose, the 
Cmax and AUC (0-∞) were increased by 68% and 89%, respectively.  In a study of weekly 
administration of paclitaxel following a 1-hour infusion of 60, 70, 80, and 90 mg/2, paclitaxel 
exposures increased in a dose proportional manner.27
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging 
from 0.1 to 50 μg/mL, indicated that between 89%-98% of drug is bound.
After intravenous administration of 15-275 mg/m2 doses of paclitaxel injection, as 1-, 6-, or 
24-hour infusions, mean values for cumulative urinary recovery of unchanged drug ranged 
from 1.3% to 12.6% of the dose, indicating extensive non-renal clearance.  In 5 patients 
administered a 225 or 250 mg/m2 dose of radiolabeled paclitaxel as a 3-hour infusion, a mean 
of 71% of the radioactivity was excreted in the feces in 120 hours, and 14% was recovered in 
the urine.  Total recovery of radioactivity ranged from 56% to 101% of the dose.  Paclitaxel 
represented a mean of 5% of the administered radioactivity recovered in the feces, while 
metabolites, primarily 6α-hydroxypaclitaxel, accounted for the balance.  In vitro studies with 
human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily 
to 6α-hydroxypaclitaxel by the cytochrome P450 isozyme CYP2C8; and to two minor 
metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxy-paclitaxel, by CYP3A4.  In 
vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of 
agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, 
teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in 
vivo following normal therapeutic doses.  Testosterone, 17α-ethinyl estradiol, retinoic acid, 
and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 
6α-hydroxypaclitaxel in vitro.  The pharmacokinetics of paclitaxel may also be altered in 
vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of 
CYP2C8 and/or CYP3A4. 
The disposition and toxicity of paclitaxel 3-hour infusion were evaluated in 35 patients with 
varying degrees of hepatic function.  Relative to patients with normal bilirubin, plasma 
paclitaxel exposure in patients with abnormal serum bilirubin ≤2 times upper limit of normal 
(ULN) administered 175 mg/m2 was increased, but with no apparent increase in the 
frequency or severity of toxicity.  In 5 patients with serum total bilirubin >2 times ULN, 
there was a statistically nonsignificant higher incidence of severe myelosuppression, even at 
a reduced dose (110 mg/m2), but no observed increase in plasma exposure.  The effect of 
renal or hepatic dysfunction on the disposition of paclitaxel has not been investigated.
1.2.2.5.2. Carboplatin (Total and Free) Pharmacokinetics
In patients with creatinine clearances of about 60 mL/min or greater, plasma levels of intact 
carboplatin decay in a biphasic manner after a 30-minute intravenous infusion of 
300 mg/m2 to 500 mg/m2 of carboplatin.  The initial plasma half-life (alpha) was found to be 


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1.1 to 2 hours, and the post-distribution plasma half-life (beta) was found to be 2.6 to 
5.9 hours.  The total body clearance, apparent volume of distribution and mean residence 
time for carboplatin are 4.4 L/hour, 16 L and 3.5 hours, respectively.  The Cmax values and 
areas under the plasma concentration versus time curves from 0 to infinity (AUC inf) 
increased linearly with dose, although the increase was slightly more than dose proportional.  
Carboplatin, therefore, exhibits linear pharmacokinetics over the dosing range studied 
(300 mg/m2 to 500 mg/m2).
Carboplatin is not bound to plasma proteins.  No significant quantities of protein-free, 
ultrafilterable platinum-containing species other than carboplatin are present in plasma.  
However, platinum from carboplatin becomes irreversibly bound to plasma proteins and is 
slowly eliminated with a minimum half-life of 5 days.
The major route of elimination of carboplatin is renal excretion.  Patients with creatinine 
clearances of approximately 60 mL/min or greater excrete 65% of the dose in the urine 
within 12 hours and 71% of the dose within 24 hours.  All of the platinum in the 24-hour 
urine is present as carboplatin.  Only 3% to 5% of the administered platinum is excreted in 
the urine between 24 and 96 hours.  There are insufficient data to determine whether biliary 
excretion occurs.
In patients with creatinine clearances below 60 mL/min, the total body and renal clearances 
of carboplatin decrease as the creatinine clearance decreases.  Carboplatin dosages should 
therefore be reduced in these patients.
The primary determinant of carboplatin injection clearance is glomerular filtration rate 
(GFR) and this parameter of renal function is often decreased in elderly patients.
1.2.3. Rationale for Studying Avelumab in Patients with Previously Untreated 
Epithelial Ovarian Cancer
Programmed death ligand 1 (PD-L1, also called B7-H1 or CD274) has a known role in the 
suppression of T-cell responses.  The PD-1 receptor is expressed on activated CD4+ and
CD8+ T cells.  By interaction with its ligands, PD-L1 and PD-L2, PD-1 delivers a series of 
strong inhibitory signals to inhibit T-cell functions.7,9,10
Avelumab (MSB0010718C), a fully human antibody of the immunoglobulin G1 (IgG1) 
isotype, specifically targets and blocks PD-L1, the ligand for PD-1 receptor.  Preliminary 
data from the ongoing ovarian cancer Study EMR 100070-001, which is being conducted by
Merck KGaA/EMD Serono (EudraCT number 2013-002834-19, NCT01772004), showed an 
ORR of 10.7% (8/75) and stable disease in an additional 44% (33/75) of patients with 
advanced ovarian cancer.12
Preliminary subgroup analysis demonstrated increased activity in patients with lower tumor 
burden, lower number of prior therapies, and platinum sensitivity.12 Therefore, avelumab has 
the potential to change the natural history of disease in the maintenance setting following 
frontline chemotherapy, when tumor burden is small.  Patients with minimal residual disease 
are thought of as the ideal candidates for immunotherapy approaches in ovarian cancer.13


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In addition, there is emerging data supporting the rationale for combinations of immune 
checkpoint inhibitors with chemotherapy.14,15 Chemotherapy has been shown to have 
immunostimulatory properties by stimulating the release of neoantigens and adjuvants by 
dying cells, increasing susceptibility to immune attack, and preferentially reducing 
immunosuppressive cells such as T regulatory cells.16,17,18 Certain chemotherapy agents 
including platinums are mutagenic.28 Therefore, treatment with chemotherapy may create a 
pro-immunogenic, hypermutated state that may be optimal for activity of checkpoint 
inhibitors. In preclinical studies, the combination of avelumab with chemotherapy
(gemcitabine, oxaliplatin, 5FU) showed improved anti-tumor activity over single-agent
chemotherapy.11
Several checkpoint inhibitors have been combined with chemotherapy agents.  The addition 
of ipilimumab to dacarbazine led to an improvement in overall survival in previously 
untreated melanoma compared to dacarbazine alone.29 Ipilimumab was combined with 
platinum doublet chemotherapy in small cell as well as non-small cell lung cancer with 
encouraging results.30,31 Combinations of PD1 blockers (pembrolizumab, nivolumab) as well 
as PDL1 blocker (atezolizumab) with platinum doublet chemotherapy demonstrated 
acceptable safety profiles with early evidence of clinical activity which appears to be higher 
than expected for platinum doublet therapy alone, particularly for atezolizumab.31-35
In summary, avelumab demonstrated promising antitumor activity in heavily pretreated
patients with ovarian cancer and has the potential to improve the durability of response to 
platinum-based therapy in the frontline setting when combined with chemotherapy and in the 
maintenance setting.
1.2.4. Study Design Rationale
1.2.4.1. Study Population
Frontline chemotherapy in ovarian cancer is associated with high response rates but the 
majority of patients experience disease recurrence.  Therefore, various novel therapeutic 
approaches have been aimed at reducing the risk of recurrence in the maintenance setting and 
therefore modifying the natural history of disease.20,31 To date, for many patients, 
observation remains the standard of care following 6 cycles of frontline chemotherapy, and 
there is a high need for effective maintenance therapies.  For this reason, the study is being 
conducted in the frontline setting.
Two large randomized studies demonstrated non-inferiority in terms of PFS and OS of the 
neoadjuvant approach to the traditional adjuvant approach, EORTC 55971 and 
CHORUS.24, 70 There are no data to suggest whether the adjuvant or neoadjuvant treatment 
is the preferred setting to explore the addition of avelumab to chemotherapy.  Therefore, in 
the current study, both neoadjuvant and adjuvant patients will be eligible.  Patients enrolled 
in the neoadjuvant setting must fulfill eligibility criteria of the EORTC 55971 and CHORUS 
studies as described in the eligibility criteria of this protocol in Section 4.


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1.2.4.2. 3-Arm Design
The current study is designed to evaluate the efficacy of avelumab in the maintenance setting 
following frontline chemotherapy (Arm B), as well as avelumab given concurrently with 
chemotherapy followed by avelumab maintenance (Arm C), compared to chemotherapy 
alone followed by observation (Arm A).  Patients are randomized in a 1:1:1 ratio to one of 
3 arms (A, B, or C).  To prevent biased discontinuation during the chemotherapy portions of 
Arms A and B, assignment to these arms will be blinded until the start of maintenance 
therapy. 
1.2.4.3. Study Endpoints
The primary endpoint of the study is PFS which is an accepted endpoint in the frontline 
setting.32 Primary efficacy analysis will be performed from randomization according to the 
intention-to-treat principle. Secondary analysis will evaluate PFS from the start of 
maintenance therapy. 
Other efficacy endpoints include overall survival (OS), objective reponse (OR), and duration 
of response (DR).  This study will also include additional efficacy endpoints, PFS2, 
pathological complete response (pCR) and PFS by GCIG criteria, as defined below.
PFS2:  PFS2 is defined by the European Medicines Agency (EMA) guidance (EMA, 2012) 
as the time from randomization to second objective disease progression, or death from any 
cause, whichever occurs first.  However, continued collection of scans and RECIST 
assessment after discontinuation from the study is logistically challenging.  In the absence of 
reliable tumor assessments, the end of next-line treatment has been proposed as a surrogate 
(EMA, 2012).  In ovarian cancer patients, however, first subsequent treatment is anticipated 
to mostly consist of a fixed/ planned number of cycles and end of treatment therefore might 
not reflect disease progression.  There is limited experience with PFS2 in ovarian cancer, 
although it has been proposed as an endpoint to explore in future studies.8,71,72   
In this protocol, PFS2 is defined as time from randomization to the start of second 
subsequent treatment after first documentation of objective progression of disease, or death 
from any cause.  In the setting of ovarian cancer, start of second subsequent therapy was 
deemed to be the most reliable and unequivocal evidence of second progression.
pCR: Compared to breast cancer, there is relatively little experience with using the rate of 
pCR as a surrogate endpoint in ovarian cancer.  There are also challenges in standardization 
of pCR assessment, since unlike breast cancer it is difficult to accurately sample the entire 
tumor bed. 
A recent study by Bohm et al, 2015,67 has tested and validated the prognostic significance of 
a 3-tier scoring system for grading pathological response to neoadjuvant therapy in patients 
with high-grade pelvic serous carcinoma.  The study included 60 patients in the test cohort 
and 71 patients in the validation cohort.


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This 3-tier scoring system is reproducible, simple and easy to apply, and shows a significant 
association with clinical outcome when based on pathological assessment of omentum 
samples.
In this protocol, patients are eligible to enroll prior to receiving neoadjuvant chemotherapy.  
Since neoadjuvant chemotherapy is one of the stratification factors, randomized groups of 
patients are expected to receive either chemotherapy alone or chemotherapy + avelumab in a 
2:1 ratio.  These patients will undergo interval debulking surgery after 3 cycles of 
chemotherapy.  pCR will be assessed using the recently developed pathologic response 
score.67,73
PFS by GCIG criteria will also be assessed in this study incorporating both RECIST 1.1 and 
CA-125.68
1.2.4.4. Chemotherapy Backbone
As outlined in Section 1.2.1, the standard of care in the frontline setting is evolving.  Based 
on the results of the JGOG3016 trial, the JGOG regimen (weekly paclitaxel in combination 
with Q3W carboplatin) is becoming more widely adopted in some regions.  In addition, 
neoadjuvant chemotherapy is increasingly used.  There is no data to suggest that avelumab 
activity will be impacted by the chemotherapy backbone or whether avelumab is 
administered before or after debulking surgery.  For this reason, the chemotherapy backbone 
in this study will be selected by the investigator as either the traditional Q3W regimen, or the 
JGOG3016 regimen incorporating weekly paclitaxel. Patients may be enrolled either before 
(neoadjuvant) or after (adjuvant) debulking surgery.  Either the JGOG3016 or the traditional 
Q3W chemotherapy may be selected for the adjuvant or neoadjuvant treatment. Neoadjuvant 
patients will receive 3 cycles of chemotherapy +/- avelumab, followed by interval debulking 
surgery and the remainder of chemotherapy.
The physician’s choice of chemotherapy regimen optimally reflects current clinical practice 
in the frontline setting.  The regimen will be selected prior to randomization, and stratified 
randomization will be performed to minimize potential imbalance between treatment arms.
1.2.4.5. Stratification Factors
Since the JGOG3016 regimen appears to be superior to the traditional Q3W regimen,6 the 
type of chemotherapy backbone will be included as a stratification factor for randomization.  
Presence or absence of residual disease is the most significant prognostic factor in patients 
undergoing adjuvant therapy. Even though the adjuvant vs neoadjuvant approaches appear 
equivalent in terms of OS in high-risk patients,24 it is unclear whether the same is true in 
low-risk patients, and whether other endpoints such as PFS or safety are equivalent.
Therefore, the following stratification factors were selected:
1. Paclitaxel regimen (Q3W vs QW); 
2. Adjuvant (complete resection/microscopic disease) vs adjuvant (incomplete resection 
1 cm) vs adjuvant (incomplete resection > 1 cm) vs neoadjuvant.


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1.2.4.6. Safety Monitoring
Avelumab has not been previously evaluated in combination with platinum doublet 
chemotherapy. Therefore, close safety monitoring with an enrollment hold after 6 patients 
are randomized to arm C will be performed as described in Section 3.1.1.  Overlapping 
toxicity is expected to be minimal (Section 1.3). 
1.2.5. Rationale for Starting Doses of Avelumab and Chemotherapy (Carboplatin and 
Paclitaxel)
1.2.5.1. Single Agent Avelumab 
In this clinical trial, the dose of avelumab will be 10 mg/kg administered as 1-hour 
intravenous infusions every 2 weeks (Q2W) as single-agent in the maintenance phase.  This 
dose is the recommended single-agent Phase 2 dose established in the ongoing study EMR 
100070-001 (see Section 1.2.2.1 for details).  This dose is well tolerated, and signs of 
antitumor activity, including durable responses, have been observed across various solid 
tumors, including ovarian cancer.  See Section 5.3.1.3 for premedication details.
1.2.5.2. Avelumab in Combination with Chemotherapy
In the chemotherapy phase, due to largely non-overlapping toxicity of the chemotherapy 
regimen and avelumab, the recommended dose of 10 mg/kg of avelumab will be used as the 
starting dose in combination with chemotherapy (Arm C).  Full doses of pembrolizumab, 
nivolumab and atezolizumab were successfully combined with platinum doublet 
chemotherapy.34-36
The dose of avelumab in combination with chemotherapy will be 10 mg/kg administered
every 3 weeks (Q3W) to avoid dosing of avelumab during the period of maximum bone 
marrow suppression for patients receiving Q3W chemotherapy.  This schedule of avelumab 
is predicted to achieve therapeutic avelumab levels based upon PK modeling and simulation, 
resulting in exposures of avelumab needed to achieve >95% PD-L1 target occupancy (Pfizer 
data on file).
1.2.5.3. Chemotherapy
Chemotherapy regimen will be chosen by the investigator to be one of the following:
Paclitaxel 175 mg/m2 over 3-hour IV infusion, followed by carboplatin, administered at an 
area under the curve AUC 5 or AUC 6 as described in Section 5.3.2.2.2 intravenously over 
1 hour on Day 1, given every 3 weeks for 6 cycles3 OR 
Paclitaxel 80 mg/m2 IV over 1-hour on days 1, 8, and 15, and carboplatin administered at an 
AUC 5 or AUC 6 as described in Section 5.3.2.2.2 intravenously over 1 hour on Day 1, given 
every 3 weeks for 6 cycles.5
1.3. Summary of Benefit/Risk Assessment
Available adverse event and laboratory abnormality data from patients with advanced solid 
tumors treated with single agent avelumab suggest an acceptable safety profile of the 


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compound.  Most of the observed events were either in line with those expected in patients 
with advanced solid tumors or with similar class effects of monoclonal antibodies blocking 
the PD-1/PD-L1 axis.  Infusion-related reactions including hypersensitivity and immune 
related adverse events (irAEs)/autoimmune disorders have been identified as important risks 
for avelumab.  Respective risk mitigation measures have been implemented in all ongoing 
clinical studies with avelumab, including this clinical trial protocol.  These include a 
treatment algorithm and guidelines for treatment interruption and discontinuation in case of 
irAEs, as well as mandatory pre-treatment with a histamine H1 receptor (H1) blocker and 
acetaminophen.  Avelumab demonstrated clinical activity in heavily pretreated ovarian 
cancer patients in an expansion cohort of an ongoing Phase 1 study.
The combination of carboplatin with either weekly or Q3W paclitaxel is a standard 
chemotherapy regimen for previously untreated epithelial ovarian cancer. This regimen has a 
well characterized toxicity profile.  Adverse events frequently seen with this regimen include 
neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, fatigue, arthralgia, 
myalgia, and neuropathy. Relevant toxicities of avelumab are largely non-overlapping with 
chemotherapy except for diarrhea.
Four other checkpoint inhibitors targeting CTLA4, PD1 and PDL1 (ipilimumab, nivolumab, 
pembrolizumab and atezolizumab) have been combined with platinum doublet chemotherapy 
demonstrating acceptable safety profiles.30,33-36 In particular, no increase in hematologic 
toxicity was observed compared to chemotherapy alone.30,33
Close safety monitoring will be performed throughout the study as outlined in Section 3.1.1,
including a safety analyses by a E-DMC after 6 patients have been enrolled in each arm, with 
a hold in enrollment.
Of note, no surgical risk has been identified with immune checkpoint inhibitors;37 no surgical 
precautions are mentioned in Keytrudaor Opdivoproduct labels. 
Thus, the projected benefit/risk of avelumab given as single agent in the maintenance setting 
following frontline chemotherapy or in combination with carboplatin/paclitaxel is anticipated 
to be favorable for investigation in this population of newly diagnosed ovarian cancer 
patients.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Co-Primary Objectives
1. To demonstrate that avelumab in combination with platinum-based chemotherapy 
followed by avelumab maintenance (Arm C) is superior to platinum-based chemotherapy 
alone followed by observation (Arm A) in prolonging progression free survival (PFS) in 
patients with previously untreated epithelial ovarian cancer (EOC).


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2. To demonstrate that platinum-based chemotherapy alone followed by avelumab
maintenance (Arm B) is superior to platinum-based chemotherapy alone followed by 
observation (Arm A) in prolonging PFS in patients with previously untreated EOC.
Secondary Objectives
•
To compare Arm C and Arm B to Arm A in patients with previously untreated EOC, with 
respect to overall survival (OS).
•
To evaluate the anti-tumor activity in each treatment arm.
•
To evaluate the overall safety profile in each treatment arm.
•
To evaluate the pharmacokinetics (PK) of paclitaxel and carboplatin alone and in 
combination with avelumab. 
•
To evaluate the PK of avelumab alone and in combination with carboplatin-paclitaxel
(Arms B and C).
•
To evaluate the immunogenicity of avelumab alone and in combination with 
carboplatin-paclitaxel (Arms B and C).
•
To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab in 
combination with and/or following carboplatin-paclitaxel in pre-treatment tumor tissue, 
that may aid in the identification of patient subpopulations most likely to benefit from 
treatment.
•
To evaluate PRO in Arm C and Arm B vs Arm A in patients with previously untreated 
EOC including the assessment of treatment side effects and disease-related symptoms.
 
 
 
 
2.2. Endpoints
2.2.1. Primary Endpoint
•
Progression-free survival (PFS) as determined by blinded independent central review 
(BICR) by RECIST version 1.1
C
C
I
CCI


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2.2.2. Secondary Endpoints
•
Efficacy:  Overall survival (OS); PFS by Investigator assessment as well as Objective 
response (OR); Duration of response (DR);Maintenance PFS by BICR assessment 
and Investigator assessment; pCR; PFS2; and PFS by GCIG criteria
•
Safety: AEs (as graded by NCI CTCAE v.4.03); laboratory abnormalities (as graded 
by NCI CTCAE v.4.03); vital signs (blood pressure, pulse rate); electrocardiograms 
(ECGs) 
•
Patient-Reported Outcomes: FOSI-18 and EuroQoL5 Dimension (EQ-5D-5L)
•
Pharmacokinetics: PK parameters, including Ctrough, Cmax, volume of distribution 
(Vd), clearance (CL), area under the concentration time curve (AUC) for avelumab, 
paclitaxel, and carboplatin, as data permit
•
Immunogenicity: anti-drug antibodies (ADA) and neutralizing antibodies (Nab) 
against avelumab
•
Candidate predictive biomarkers in tumor tissue including, but not limited to, 
PD-L1 expression and tumor infiltrating CD8+ T lymphocytes as assessed by 
immunohistochemistry (IHC)
2.2.3. Exploratory Endpoints
•
CA-125 levels
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 3, open-label, international, multi-center, efficacy, and safety study of 
avelumab in combination with and/or following platinum-based chemotherapy in adult 
patients with previously untreated EOC.
In this Phase 3 trial, approximately 951 patients who are candidates for frontline 
platinum-based chemotherapy will be randomized in a 1:1:1 ratio stratified by paclitaxel 
regimen (Q3W vs QW); and by adjuvant (complete resection/microscopic disease) vs 
adjuvant (incomplete resection ≤1 cm) vs adjuvant (incomplete resection > 1 cm) vs 
neoadjuvant to one of the following treatment arms:
CCI
CCI


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
Arm A: platinum-based chemotherapy alone followed by observation

Arm B: platinum-based chemotherapy alone followed by avelumab maintenance 

Arm C: avelumab in combination with platinum-based chemotherapy followed by 
avelumab maintenance. 
The assignment to Arm A vs Arm B will be blinded at the time of randomization to patients, 
investigators, and the Sponsor until completion of chemotherapy as described in Section 5.1.
Crossover between treatment arms will not be permitted.
Intravenous carboplatin-paclitaxel will be used as the chemotherapy backbone, consisting of 
Q3-week (Q3W) carboplatin and the investigator choice of either Q3W or weekly paclitaxel.  
Once a paclitaxel regimen is chosen for a given patient, it should not be changed for the 
duration of the study.
Patients may be enrolled either following primary debulking surgery, or prior to initiation of 
neoadjuvant chemotherapy.  The latter group will undergo interval debulking surgery after
3 study cycles of chemotherapy (plus or minus avelumab, depending on randomization) to be 
followed by the remainder of chemotherapy (plus or minus avelumab, depending on 
randomization).
Figure 1.
Study Design Schema
Chemotherapy
Maintenance
ECOG 
Arm A 
Chemotherapy 
Alone
Arm B 
Chemotherapy 
Alone
Arm C
Chemotherapy + 
Avelumab
Arm C
Avelumab 
Arm B
Avelumab 
Arm A
Observation
Treatment 
Until: 
Progressive 
Disease per 
RECIST v1.1
OR
Unacceptable 
Toxicity
OR
Patient 
Withdrawal
If SD, PR, 
or CR after
the 
completion 
of
chemother
apy (+/-
avelumab)
1:1:1


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3.1.1. Safety Monitoring
The initial evaluation of the safety of the combination of avelumab plus chemotherapy (Arm 
C) will be performed during the study as follows:
Randomization to all 3 treatment arms will begin at the start of the study.  When 6 patients 
are randomized to the chemotherapy plus avelumab combination arm (Arm C) patient 
enrollment in all treatment arms will be temporarily held.  After each of these 6 patients in 
Arm C has completed a minimum observation period of 4 weeks, the external data 
monitoring committee (E-DMC) will evaluate all available safety data.  If there are no safety 
concerns precluding continuation of the study, enrollment for all 3 treatment arms will 
proceed.  Other options may include termination of the combination arm, or enrollment of 
6 more patients into Arm C with another temporary enrollment hold.  These 
recommendations will be made at discretion of the E-DMC.
A second safety evaluation will be performed by the E-DMC after a total of 20 patients are 
enrolled on the chemotherapy plus avelumab combination arm (Arm C) and followed for at 
least 4 weeks without a patient enrollment hold in any arm.  The frequency of subsequent 
E-DMC meetings for the entire study will be determined by the E-DMC at the time of this
second safety evaluation (see Section 9.7).
3.1.2. Study Treatment
The study period includes two treatment phases, the chemotherapy phase and the 
maintenance phase.  For purposes of consistent on-study assessments, 1 study cycle is 
defined as 3 weeks (21 days) for the chemotherapy phase, and 6 weeks (42 days) for the 
maintenance phase. 
In the chemotherapy phase of the study, study drugs will be assigned and given as follows:
Arms A and B: The investigator will have the choice between weekly or Q3W paclitaxel:  
Paclitaxel 175 mg/m2 IV over 3 hours, followed by carboplatin dose AUC 5 or AUC 6 as 
described in Section 5.3.2.2.2 IV over 1 hour on Day 1 of each 3-week cycle for 6 cycles
OR

Paclitaxel 80 mg/m2 IV over 1 hour on Days 1, 8 and 15 plus carboplatin AUC 5 or AUC
6 as described in Section 5.3.2.2.2 IV over 1 hour on Day 1 of each 3-week cycle for 
6 cycles
Arm C: 

Chemotherapy (investigator’s choice as referenced above) + avelumab 10 mg/kg 
administered as a 1-hour IV infusion once every 3 weeks for 6 cycles.


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The assignment to Arms A and B will be blinded at the time of randomization.  In patients 
who are enrolled prior to neoadjuvant therapy, the first 3 cycles will be administered prior to 
interval debulking surgery, and the remainder of chemotherapy will be administered after 
surgery.  Upon completion of chemotherapy, patients without evidence of disease 
progression (SD, PR, or CR) will proceed to the maintenance phase of the study.  Disease 
progression must be confirmed by BICR prior to withdrawal.  At this point the assignment to 
Arms A or B will be unblinded.  Maintenance phase should begin within 4 weeks of the last 
dose of platinum.  The first visit of maintenance therapy will be numbered maintenance 
Cycle 1 Day 1 even if the last chemotherapy cycle was not completed. 
In the maintenance phase of the study, patients randomized to Arms B or C will receive
avelumab 10 mg/kg administered as a 1-hour IV infusion once every 2 weeks.
Patients will receive study treatment until confirmed progressive disease (PD), unacceptable 
toxicity, or withdrawal of consent, or a maximum duration of 24 months (not including 
chemotherapy phase), whichever is earliest (see Section 6.5).  Patients who discontinue 
chemotherapy due to unacceptable toxicity will enter maintenance phase and will be on 
observation (Arm A) or receive avelumab (Arms B and C).  Patients who discontinue 
avelumab due to unacceptable toxicity during the chemotherapy phase may complete 
chemotherapy and may enter the maintenance with observation only.
Patients without evidence of disease progression by BICR assessment at the time of study 
treatment discontinuation should continue to undergo tumor assessment until documented 
radiographic progressive disease by BICR assessment, irrespective of the start of any new 
anticancer treatment.  See Schedule Of Activities (SOA) for details.
Patients who discontinue study treatment (or, if on Arm A maintenance observation, reach 
End of Treatment/Withdrawal) will be followed every 12 weeks for survival status until 
death or until study completion, whichever is earlier.  Additionally the following data will be 
collected:  surgery and/or new anti-cancer therapies including the date of initiation and 
discontinuation of each drug. 
3.1.2.1. Interval Debulking Surgery After Neoadjuvant Treatment 
Patients who are enrolled prior to initiation of neoadjuvant therapy will complete 3 cycles of 
chemotherapy (with avelumab in Arm C), then treatment will be held, and interval debulking 
surgery will be performed.  Minimal requirements for the interval debulking surgical 
procedure and guidelines for pathological assessment are provided in Appendix 5.  
According to institutional practice, upon recovery from surgery, the remainder of 
chemotherapy (with avelumab in Arm C) should be administered for a maximum of 6 cycles
of chemotherapy.
3.1.3. Tumor Assessments
Anti-tumor efficacy will be assessed by radiological tumor assessments conducted at 
screening and according to the SOA table thereafter, using RECIST v1.1, 
 
 
 (see Appendix 3, 
and SOA table). 
CCI
CCI


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CR and PR must be confirmed with repeated imaging performed at least 4 weeks after initial 
documentation of response. If radiologic imaging shows progressive disease (PD), then 
tumor assessment should be repeated after at least 4 weeks to confirm PD in the absence of 
rapid clinical deterioration. In addition, radiological tumor assessments will also be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration or 
rising CA-125 levels), and at the time of End of Treatment/Withdrawal (if not done in the 
previous 12 weeks).  Brain scans and bone scans will be performed at baseline if disease is 
suspected and on study as appropriate to follow disease.  Baseline central nervous system 
(CNS) imaging is not required with the exception of symptomatic patients to rule out CNS 
metastases. 
For patients who undergo interval debulking surgery, an additional tumor assessment should 
be performed after surgery.
CA-125 will be assessed in a local laboratory every 6 weeks.  Rising CA-125 levels alone 
will not be considered evidence of progression.
3.1.4. Safety 
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the SOA table. 
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histologically confirmed Stage III-IV epithelial ovarian, fallopian tube, or primary 
peritoneal cancer (according to AJCC/UICC TNM and International Federation of 
Gynecology and Obstetrics (FIGO) Staging System 2014 edition), including malignant 
mixed Müllerian tumors with high grade serous component.38
2. Patients must be candidates for platinum based chemotherapy and previously untreated. 
3. Patients must have completed a surgical debulking procedure, or be candidates for 
neoadjuvant chemotherapy.
a.
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
The minimum surgery required is an abdominal surgery with an attempt at 
cytoreduction providing tissue for histologic evaluation and establishing and 
documenting the primary site and stage.

Patient must be randomized at a maximum of 8 weeks after surgery.
b. For patients who are candidates for neoadjuvant chemotherapy, the following 
conditions must be met:

A core tissue (not fine needle aspiration) biopsy is required.  The tissue must be 
consistent with a tumor of Müllerian origin. 

Stage IIIC–IV documented via imaging or surgery (without attempt at 
cytoreduction).

Serum CA-125/ CEA ratio > 25.  If the serum CA-125/CEA ratio is < 25, workup 
should be negative for the presence of a primary gastrointestinal or breast 
malignancy (< 6 weeks before randomization).

Plan to receive carboplatin-paclitaxel neoadjuvant chemotherapy.

Randomization must occur within 8 weeks after diagnosis.
4. Availability of an archival formalin-fixed, paraffin-embedded (FFPE) tumor tissue block
or a minimum of 15 slides.  If archived FFPE tissue is not available, a de novo (ie, fresh) 
tumor sample must be obtained in accordance with local institutional practice for tumor 
biopsies.
5. Eastern Cooperative Group (ECOG) performance status 0-1 (see Appendix 2).
6. Age 18 years (or 20 years in Japan).
7. Adequate hematological function (ANC 1.5 x 109/L, Hgb 9.0 g/dL, and platelet count 
100 x 109/L).
8. Adequate liver function tests (ALT/AST 2.5 x ULN, total serum bilirubin level 1.5 x 
ULN).
9. Adequate renal function by estimated creatinine clearance 50 mL/min as calculated 
using the Cockcroft-Gault method.
10. Estimated life expectancy of at least 12 weeks.
11. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects 
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12. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
13. Patients of childbearing potential and at risk for pregnancy must agree to use 2 highly 
effective methods of contraception throughout the study and for at least 60 days after the 
last dose of assigned treatment.
Patients of non-childbearing potential must meet at least one of the following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or physiological 
cause; status may be confirmed by having a serum follicle-stimulating hormone 
(FSH) level confirming the post-menopausal state.
All other patients (including patients with tubal ligations) will be considered to be of 
childbearing potential.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the 
study:
1. Non-epithelial tumors or ovarian tumors with low malignant potential (ie, borderline 
tumors).
2. Mucinous tumors.
3. Patients for whom, in the opinion of the Investigator, there is clinical benefit to 
administer bevacizumab as a first-line treatment and for whom bevacizumab is approved 
and available in this setting.
4. Cancer for which intraperitoneal cytotoxic chemotherapy is planned. 
5. Prior systemic anti-cancer treatment for EOC, FTC, or PPC. 
6. Prior immunotherapy with IL-2, IFN-α, or anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibody 
(including ipilimumab), or any other antibody or drug specifically targeting T cell 
co-stimulation or immune checkpoint pathways. 
7. Major surgery (other than debulking surgery) for any reason within 4 weeks prior to
randomization and/or incomplete recovery from surgery.


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8. Known brain, leptomeningeal, or spinal cord metastases.
9. Current or prior use of immunosuppressive medication within 7 days prior to 
randomization, except the following: intranasal, inhaled, topical steroids, or local steroid 
injections (eg, intra-articular injection); systemic corticosteroids at physiologic doses 
10 mg/day of prednisone or equivalent; steroids as premedication for hypersensitivity 
reactions [eg, computed tomography (CT) scan premedication]. 
10. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agents except patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroidism
not requiring immunosuppressive treatment. 
11. Any of the following in the previous 6 months: myocardial infarction, severe/unstable 
angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, 
cerebrovascular accident, transient ischemic attack, deep vein thrombosis or symptomatic 
pulmonary embolism.
12. Active and clinically significant bacterial, fungal or viral infection, any positive tests for 
hepatitis B (HBV), hepatitis C (HCV) indicating acute or chronic infection (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive), known 
history of a positive test for human immunodeficiency virus (HIV), or acquired 
immunodeficiency syndrome (AIDS) related illness.
13. Administration of a live vaccine within 30 days prior to study entry.
14. Known severe hypersensitivity reactions to monoclonal antibodies, carboplatin, 
paclitaxel, or other platinum-containing compounds (NCI CTCAE v4.03 Grade 3).
15. Persisting NCI CTCAE v4.03 Grade >1 toxicity related to prior therapy.
16. Previous malignant disease other than the target malignancy to be investigated in this trial 
within the last 5 years with the exception of adequately treated basal or squamous cell 
carcinoma of the skin, cervical carcinoma in situ, lobular carcinoma in situ (LCIS), or 
ductal carcinoma in situ (DCIS).
17. Patients who are investigational site staff members directly involved in the conduct of the 
study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of the 
study.
18. Participation in other clinical studies involving investigational drug(s) within 4 weeks
prior to study randomization and/or during study participation.
19. Other severe/severe acute or chronic medical, including colitis, inflammatory bowel 
disease, and pneumonitis, 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 patient inappropriate for entry into this study.


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20. Pregnant patients or breastfeeding patients.
21. Patients with bleeding tumors.
4.3. Lifestyle Guidelines 
In this study, patients who are of childbearing potential will receive avelumab and/or 
carboplatin/paclitaxel.  The effect of avelumab on reproduction is unknown.  Carboplatin and 
paclitaxel are associated with teratogenic risk.
Those, who, in the opionion of the investigator are sexually active and at risk for pregnancy 
must agree to use two (2) methods of highly effective contraception throughout the study and 
continue to do so for 60 days after the last dose of single agent avelumab (Arms B and C).  
The investigator or his or her designee, in consultation with the patient, will confirm the 
patient has selected 2 appropriate methods of contraception for the individual patient and her 
partner from the list of permitted contraception methods (see below) and will confirm the 
patient has been instructed in their consistent and correct use.  Patients need to affirm that 
they meet the criteria for correct use of 2 of the selected methods of contraception.  The 
investigator or his or her designee will discuss with the patient the need to use 2 highly 
effective contraception methods consistently and correctly according to the Schedule Of 
Activities and document such conversation in the patient’s chart.  In addition, the investigator 
or his or her designee will instruct the patient to call immediately if one or both selected 
contraception method are discontinued or if pregnancy is known or suspected in the patient. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception are allowed provided the patient plans to remain on the 
same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).


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4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study portal. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, she 
will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).  For the purpose of this study, the 
investigational product is avelumab (MSC0010718C).
The study period includes two treatment phases, the chemotherapy phase and the 
maintenance phase.  In the chemotherapy phase, a cycle is defined as 3 weeks.  Due to the 
biweekly schedule of avelumab in the maintenance phase, 1 study cycle is defined as 6 weeks
or 42 days.
For the chemotherapy phase of the study, study drugs will be assigned and given as follows:
Arms A and B: The investigator will have the choice between weekly or Q3W paclitaxel:  

Paclitaxel 175 mg/m2 IV over 3 hours followed by carboplatin dose AUC 5 or AUC
6 as described in Section 5.3.2.2.2 IV over 1 hour on Day 1 of each 3-week cycle for 
6 cycles
OR

Paclitaxel 80 mg/m2 IV over 1 hour on Days 1, 8, 15 plus carboplatin AUC 5 or AUC
6 as described in Section 5.3.2.2.2 IV over 1 hour on Day 1 of each 3-week cycle for 
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Arm C: 

Chemotherapy (as referenced above) + avelumab 10 mg/kg administered as a 1-hour 
IV infusion once every 3 weeks for 6 cycles.
Upon completion of chemotherapy, patients without evidence of disease progression (SD, PR 
or CR) will proceed to the maintenance phase of the study Disease progression must be 
confirmed by BICR prior to withdrawal.
For the maintenance phase of the study, patients randomized to Arms B or C will receive
avelumab 10 mg/kg administered as a 1-hour IV infusion once every 2 weeks.  Patients on 
Arm A will be on observation only.
BSC for all patients will be provided as deemed appropriate by the treating physician.  This 
could include treatment with antibiotics, analgesic drugs, transfusions and psychosocial and 
nutritional support, but no active anti-cancer treatment. 
Other treatments for progressive disease including chemotherapy and/or palliative 
radiotherapy will require the patient to be taken off treatment.
All investigational product administration details will be recorded on the case report form 
(CRF).
5.1. Allocation to Treatment
Once the patient has provided a signed informed consent document (ICD) and has met all 
inclusion and none of the exclusion criteria, allocation of patients to treatment arms will 
proceed through the use of an interactive response technology (IRT) system. 
The choice of chemotherapy regimen will be made prior to randomization.  Allocation of 
patients will be stratified according to paclitaxel regimen (Q3W vs QW); and adjuvant 
(complete resection/microscopic disease) vs adjuvant (incomplete resection 1 cm) vs 
adjuvant (incomplete resection > 1 cm) vs neoadjuvant. This stratified randomization will be 
centrally allocated across all centers via the IRT system.
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, the patient number and the date of birth of the patient.  The site personnel 
will then be provided with a treatment assignment and dispensable unit (DU) or container 
number when drug is being supplied via the IRT system.  The IRT system will provide a 
confirmation report containing the patient number and DU or container number assigned.  
The confirmation report must be stored in the site’s files.  IRT will provide a prompt to 
indicate the patient has completed the chemotherapy phase and is proceeding to the 
maintenance phase of the study.  The site personnel (study coordinator or specified designee) 
will then be provided with the Treatment Group assignment. 


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There is a 24-hour-a-day, 365–days-a-year IRT helpdesk available for any questions or 
issues. The study-specific IRT reference manual will provide the contact information and 
further details on the use of the IRT system. 
Note: The IRT is the source of the patient number. The IRT system will provide the patient 
number at the end of the first IRT patient transaction.
Qualified patients will be randomized in a 1:1:1 ratio as follows:
Chemotherapy Phase
Maintenance Phase
Arm A
Chemotherapy Alone
Observation
Arm B
Chemotherapy Alone
Avelumab 
Arm C
Avelumab + Chemotherapy
Avelumab 
The assignment to Arms A vs B will be blinded for the patient, investigator, and Sponsor at 
the time of randomization.  Upon completion of chemotherapy, patients without evidence of 
disease progression by BICR assessment (SD, PR, or CR) will proceed to the maintenance 
phase of the study.  At this point, the assignment to Arms A vs B will be unblinded.
5.2. Patient Compliance
In this trial, patients will receive trial treatment (ie, chemotherapy and avelumab) at the 
investigational site.  Well-trained medical staff will monitor and perform the trial drug 
administration.  The information of each trial drug administration including the date, time, 
and dose of trial drug will be recorded on the eCRF.  The Investigator will make sure that the 
information entered into the eCRF regarding drug administration is accurate for each patient.  
Any reason for noncompliance should be documented.
Noncompliance is defined as a patient missing > 1 infusion of trial treatment for non-medical 
reasons (see Section 6.5).  If 1 infusion is missed and the interval between the subsequent 
infusion and the last administered treatment is longer than 4 weeks for nonmedical reasons, 
the criteria of insufficient compliance are met as well.
5.3. Investigational Product Supplies
5.3.1. Avelumab 
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 take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and usage 
of investigational product in accordance with the protocol and any applicable laws and 
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5.3.1.1. Avelumab Dosage Form and Packaging
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20 mg/mL solution and will be supplied by the Sponsor in single-use glass 
vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines.  Avelumab will be packed in 
boxes each containing one vial.  The information on the study treatment will be in 
accordance with approved submission documents.
Avelumab will be shipped in transport cool containers (2C to 8C) that are monitored with 
temperature control devices.
5.3.1.2. Avelumab Preparation 
See the dosing and administration instruction (DAI) section of the Investigational Product 
Manual (IP Manual) for instructions in how to prepare the investigational product for 
administration.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance.
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 
chemotherapeutic agents.
Avelumab will be administered at the investigational site.
The contents of the avelumab vials are sterile and non-pyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard clean-up procedures for biologic products.
For administration in this trial, avelumab must be diluted with 0.9% sodium chloride (normal 
saline solution).  Detailed information on infusion bags and medical devices to be used for 
the preparation of the dilutions and subsequent administration will be provided in the DAI
section of the IP Manual.  Must use tubing with in line, low protein binding 0.2 micron filter 
made of polyether sulfone (PES) during administration.
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kg).  All patients should be weighed within 3 days prior to 
dosing for each dose to ensure they did not experience either a weight loss or gain of >10% 
from the weight used for the last dose calculation.  For weight change less than 10% the 
decision to recalculate the avelumab dose can be in accordance with institutional practice.  If 
the patient experienced either a weight loss or gain >10% compared to the weight used for 
the last dose calculation, the amount of study drug must be recalculated.


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Avelumab must not be used for any purpose other than the trial.  The administration of trial 
drug to patients who have not been enrolled into the trial is not covered by the trial insurance.
Any unused portion of the solution should be discarded in biohazard waste disposal with 
final disposal by accepted local and national standards of incineration.
5.3.1.3. Avelumab Administration
All study treatments will be administered at the investigational site on an outpatient basis as 
described in the DAI section of the IP Manual.
Avelumab 10 mg/kg will be administered on Day 1 of each 3-week study cycle during the 
chemotherapy phase and on Days 1, 15, and 29 of each 6-week study cycle during the 
maintenance phase and after all procedures/assessments have been completed as described in 
the SOA table.  Avelumab may be administered up to 3 days before or after the scheduled 
day of administration of each cycle due to administrative reasons.
Avelumab will be administered as a 1-hour IV infusion.  In order to mitigate infusion-related 
reactions, a premedication regimen of diphenhydramine 25 to 50 mg IV or oral equivalent 
and acetaminophen/paracetamol 500 to 650 mg IV or oral equivalent (as per local practice) is 
mandatory approximately 30 to 60 minutes prior to each dose of avelumab.  This may be 
modified based on local treatment standards and guidelines, as appropriate.
For patients on Arm C, on visits when both chemotherapy and avelumab are infused (Days
1 and 22) of each 6-week cycle, avelumab will be infused after chemotherapy.  If 
premedication was administered prior to chemotherapy, the decision whether to repeat 
pre-medication prior to avelumab is at the discretion of the investigator depending on the 
elapsed time and the half-life of corresponding premedication agent.  The line should be 
flushed, according to local practice, between infusions, and a new administration set should 
be used for avelumab.
Sites should make every effort to target the timing of avelumab infusion to be as close to 
1 hour as possible.  However, given the variability of infusion pumps from site to site, time 
windows of minus 10 minutes and plus 20 minutes is permitted (ie, infusion time is 
50-80 minutes).  The exact duration of infusion should be recorded in both source documents 
and CRFs.  Possible modifications of the infusion rate for the management of 
infusion-related reactions are described in Section 5.3.5.1.
Patients will receive trial treatment until confirmed progressive disease (PD) per RECIST 
v1.1, unacceptable toxicity, withdrawal of consent, or if any criterion for withdrawal from 
the trial or trial treatment is fulfilled.
Patients who temporarily stop the study treatments due to AE may resume treatments upon 
recovery as described in the relevant protocol section (study drug dose delay or 
discontinuation for drug related toxicities, including irAEs).


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5.3.1.3.1. Treatment After Initial Evidence of Radiologic Disease Progression (Only for 
Patients in the Maintenance Phase)
Immunotherapeutic agents such as avelumab may produce antitumor 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, tumor assessment should be repeated 
≥4 weeks later in order to confirm the observation.  Avelumab may be continued at the 
Investigator’s discretion while awaiting radiologic confirmation of disease progression. 
Before continuation of treatment, the patient must provide new consent and be informed that 
in order to continue receiving the investigational products on study, the patient may be 
foregoing approved therapy with possible clinical benefit(s).
Patients may receive avelumab while waiting for confirmation of PD if they are clinically 
stable as defined by the following criteria:

Absence of clinical signs and symptoms (including worsening of laboratory values) of 
disease progression. 

No decline in ECOG performance status. 

Absence of rapid progression of disease by radiographic imaging. 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.

If repeat imaging no longer shows PD but rather CR, PR, or SD compared to the initial 
scan, treatment may be continued/resumed.  In determining whether or not the tumor 
burden has increased or decreased, Investigators should consider all target as well as 
non-target lesions (refer to the imaging charter). 

If the repeat imaging confirms PD, patients should be discontinued from study treatment.  
However, according to the investigator’s clinical judgment and after discussion between 
the investigator and the sponsor’s medical monitor, if a patient with evidence of PD is 
still experiencing clinical benefit, the patient may be eligible for continued treatment with 
avelumab.  The investigator’s judgment should be based on the overall benefit-risk 
assessment and the patient’s clinical condition, including performance status, clinical 
symptoms, adverse events and laboratory data.

Patients in the maintenance phase who stop avelumab treatment, and then experience 
radiologic disease progression assessed by BICR thereafter, will be eligible for 
re-treatment with avelumab at the discretion of the investigator and after discussion with 


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the sponsor’s medical monitor if 1) no cancer treatment was administered other than BSC 
since the last dose of avelumab, 2) the patient does not meet the safety withdrawal 
criteria, 3) the patient meets all initial eligibility criteria except for exclusion criteria 
#4 and #5, and 4) the trial is still open.
5.3.2. Paclitaxel and Carboplatin
Paclitaxel and carboplatin to be administered during this study will be branded or generic 
product available in the local region.  Note that nanoparticle protein bound paclitaxel 
(nab-paclitaxel, Abraxane) may NOT be substituted for the cremophor formulation of 
paclitaxel.  Paclitaxel and carboplatin are commercially available, and are to be stored, 
prepared, and administered according to locally approved product labeling.
5.3.2.1. Premedication for Chemotherapy Administration
Premedication to ameliorate the toxicities associated with the chemotherapy are to be 
administered according to the local product label or institutional guidelines.
5.3.2.1.1. Paclitaxel
Premedication regimens that are standard for the institution or region will be used.  
Premedication will be supplied by the site.  The effect of steroid premedication in Arm C 
chemotherapy phase on the activity of avelumab is unknown (see Section 5.6.4).
5.3.2.1.2. Carboplatin
Carboplatin can induce emesis, which can be more severe in patients previously receiving 
emetogenic therapy.  The incidence and intensity of emesis have been reduced by using 
premedication with anti-emetics.  Because anti-emetics are given as part of the paclitaxel 
regimen, extra doses as premedication are not necessary, although additional doses may be 
required if the patient develops emesis.  Premedication according to institutional guidelines 
should be used if paclitaxel has been discontinued.  No pre- or post-treatment hydration or 
forced diuresis is required.
5.3.2.2. Chemotherapy Regimen and Starting Doses
In the absence of progressive disease, patients will receive paclitaxel and carboplatin
treatment for 6 cycles during the chemotherapy phase of the study.  Dose reduction for 
toxicity is allowed (see Section 5.3.3).
All patients should be weighed within 3 days prior to dosing for every cycle to ensure they 
did not experience either a weight loss or gain of >10% from the weight used for the last dose 
calculation.  For weight change less than 10% the decision to recalculate the chemotherapy
doses can be in accordance with institutional practice.  If the patient experienced either a 
weight loss or gain >10% compared to the weight used for the last dose calculation, the 
amount of study drug must be recalculated.


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5.3.2.2.1. Paclitaxel
Following pre-medication, paclitaxel is administered as the first drug when chemotherapy is 
administered.  For this study, the investigator has a choice between weekly and Q3W
paclitaxel regimen:

Paclitaxel 175 mg/m2 IV over 3 hours on Day 1 of each 3-week cycle
OR

Paclitaxel 80 mg/m2 IV over 1 hour on Days 1, 8 and 15 of each 3-week cycle 
5.3.2.2.2. Carboplatin
Carboplatin is administered over 1 hour, beginning 60 minutes after completion of the 
paclitaxel infusion on Day 1 of each 3-week study cycle. 
The carboplatin dose should be calculated according to the Calvert39 formula as follows: 
Carboplatin dose = Target AUC x (GFR + 25).
Maximum Carboplatin Dose (mg) = target AUC (mg·min/mL) x (150 mL/min)
The maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients 
with normal renal function.  No higher estimated GFR values should be used.

For a target AUC = 6, the maximum dose is 6 x 150 = 900 mg

For a target AUC = 5, the maximum dose is 5 x 150 = 750 mg

For a target AUC = 4, the maximum dose is 4 x 150 = 600 mg
For the purpose of this protocol the GFR is considered equivalent to the creatinine clearance.  
The exact dose of carboplatin therefore depends on the GFR and the method of calculating 
the GFR will also affect the carboplatin dose.  The GFR can be calculated using a variety of 
different formulae (see below) and should be calculated as per local practice.  Where the 
carboplatin dose is based on a GFR measured by isotopic clearance or calculated using the 
Wright formula, the target AUC is one unit lower than that based on the GFR calculated by 
using the Cockroft-Gault or Jellife formula, or the GFR measured by 24 hour urine 
collection.  This is summarized below.  The reason for this is that the GFR calculated using 
the Cockroft-Gault or Jeliffe formula has been shown to significantly underestimate the GFR 
as measured isotopically, whereas the GFR as calculated by the Wright formula does not 
appear to do so.

If using Cockroft-Gault/Jellife formula, use AUC6

If using the Wright formula, use AUC5


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
If using isotopic method (51Cr EDTA), use AUC5

If using 24hr urine, use AUC6.
GFR Limitations

Isotopic GFR is inaccurate in patients with significant effusions, ascites or edema as 
the isotope distributes into third space fluid collections.

Patients who have had complicated or prolonged post operative recovery and who 
have been maintained on prolonged IV fluids with poor nutrition will have a falsely 
low serum creatinine.

Formulae, such as the Cockroft-Gault formula, are inaccurate at the extremes of age 
and weight.  The calculated GFR may be falsely high in obese young women and 
falsely low in thin elderly women.

It is assumed that clinicians entering patients into this protocol will be aware of these 
issues and the clinical judgement of an experienced clinician should be applied to the 
calculation of the carboplatin dose.
If, therefore, prior to Cycle 1, the serum creatinine is low (≤ 0.6mg/mL or ≤ 53μmol/L) or 
there is evidence of some impairment of renal function (estimated creatinine clearance is 
< 60 mL/minute), then a formal measurement of the GFR is required, using either a 24 hour 
urine collection or an isotopic clearance.  If the isotopic clearance is measured then the value 
uncorrected for body surface area (BSA) should be used in dose calculations.
The dose of carboplatin should be recalculated prior to each infusion unless the isotopic 
method is used, in which case, the dose should be recalculated if the creatinine rises above 
1.5 X ULN.
5.3.3. Recommended Dose Modifications
Every effort should be made to administer study treatment on the planned dose and schedule. 
In the event of significant toxicity, dosing may be delayed and/or dose reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify Investigators at the first occurrence 
of any adverse symptom.  In addition to dose modifications, investigators are encouraged to 
employ best supportive care according to local institutional clinical practices and according 
to the guidance for selected adverse events provided below. 


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Table 5.
Dose Modification Levels for Paclitaxel and Carboplatin
Drug
Starting Dose 
Dose Level -1
Dose Level -2
Paclitaxel Weekly
80 mg/m2
60 mg/m2
45 mg/m2
Paclitaxel Q3W
175 mg/m2
135 mg/m2
110 mg/m2
Carboplatin
AUC 6
AUC 5
AUC 4
Carboplatin
AUC 5
AUC 4
AUC 3
In order to maintain the dose-intensity and cumulative dose-delivery of carboplatin and 
paclitaxel chemotherapy, reasonable efforts should be made to minimize dose reduction and 
treatment delays.  Patients whose treatment is delayed because of adverse events should be 
evaluated at weekly intervals (or less) until adequate recovery has occurred.  Intrapatient 
dose escalations are not permitted (including dose re-escalation after a dose reduction).
Dose levels should be adjusted independently for each drug. Patients who do not tolerate two 
carboplatin and/or paclitaxel dose reductions should discontinue treatment with trial 
chemotherapy.
5.3.3.1. Dose Modifications for Avelumab as Single Agent
For avelumab, no dose reductions are permitted in this study, but doses may be omitted based 
on persisting toxicity.
Any adverse event suspected to be immune related should be managed according to the 
guidance for management of irAEs (see Table 7).
5.3.4. Guidelines for Avelumab Toxicity Management
5.3.4.1. Adverse Drug Reaction Requiring Avelumab Discontinuation or Delays
The following adverse reactions (ADRs) require permanent treatment discontinuation of 
avelumab:
Any Grade 4 ADRs require avelumab treatment discontinuation except for single 
laboratory values out of normal range that are unlikely related to trial treatment as assessed 
by the Investigator, do not have any clinical correlate, and resolve within 7 days with 
adequate medical management.
Any Grade 3 ADRs require avelumab treatment discontinuation except for any of the 
following: 

Transient (6 hours) Grade 3 flu-like symptoms or fever, which is controlled with 
medical management

Transient (24 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that 
resolves to Grade 1


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
Single laboratory values out of normal range (excluding Grade 3 liver function test 
increase) that are unlikely related to trial treatment according to the Investigator, do not 
have any clinical correlate, and resolve to Grade 1 within 7 days with adequate medical 
management

Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor

Change in Eastern Cooperative Oncology Group Performance Status (ECOG PS) to
3 that resolves to 2 within 14 days (infusions should not be given on the following 
cycle, if the ECOG PS is 3 on the day of trial drug administration).
Any Grade 2 ADR should be managed as follows:

If a Grade 2 ADR resolves to Grade 1 within 2 weeks treatment may continue.

If a Grade 2 ADR does not resolve to Grade 1 within 2 weeks, avelumab should be 
held. If after another 2 weeks the event has not resolved to Grade 1, the patient should 
permanently discontinue treatment with an avelumab (except for hormone insufficiencies, 
that can be managed by replacement therapy; for these hormone insufficiencies, up to 
2 subsequent doses may be omitted).

Upon the second occurrence of the same Grade 2 ADR (except for hormone 
insufficiencies that can be managed by replacement therapy) in the same patient, 
treatment with avelumab has to be permanently discontinued.
Avelumab infusion-related reactions, hypersensitivity reactions (Grades 1 to 4), tumor lysis 
syndrome, and irAEs should be handled according to guidelines in Sections 5.3.5.1,
5.3.5.2 and 5.3.5.3.
5.3.5. Special Precautions for Avelumab Administration
In order to mitigate avelumab infusion-related reactions, premedication with an antihistamine 
and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to each dose of 
avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg 
paracetamol [acetaminophen] IV or oral).  This may be modified based on local treatment 
standards and guidelines, as appropriate. 
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications (IV 
antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access. 


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Infusion of avelumab will be stopped in case of Grade 2 infusion-related, allergic, or
anaphylactic reactions.  Following avelumab infusions, patients must be observed for 2 hours 
post-infusion for potential infusion-related reactions.  If an allergic reaction occurs, the 
patient must be treated according to the best available medical practice.  The emergency 
treatment of anaphylactic reactions according to the Working Group of the Resuscitation 
Council (United Kingdom) can be found at https://www.resus.org.uk/pages/reaction.pdf.  
Patients should be instructed to report any delayed reactions to the Investigator immediately.
Treatment recommendations for the management of infusion-related reactions, severe 
hypersensitivity reactions, tumor lysis syndrome, and immune-related AEs are outlined in 
Sections 5.3.5.1, 5.3.5.2, 5.3.5.3 and 5.3.5.4, respectively. 
5.3.5.1. Management of Avelumab Infusion-Related Reaction
Since avelumab is administered IV, infusion-related reactions may occur (with symptoms 
such as fever, chills, rigors, diaphoresis, and headache).  Treatment of the infusion-related 
reaction and modifications of avelumab infusion are mainly dependent upon severity, as 
indicated in Table 6.
Table 6.  Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions 
NCI CTCAE Grade 
Treatment Modification for Avelumab
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.
The total infusion time for avelumab should not 
exceed 120 minutes.
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for 24 hours.
Stop avelumab infusion.
Resume infusion at 50% of previous rate as soon as 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any recurrence or worsening.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (eg, 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 bag infusion tubing from the patient.  
Patients have to be withdrawn immediately form 
avelumab treatment and must not receive any 
further avelumab treatment.
IV=intravenous, NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% due to an infusion related 
reaction, it must remain so for all subsequent infusions. 


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Additional Modifications for Patients with Grade 2 Infusion-Related Reactions: If, in 
the event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 6 (including reducing the infusion 
rate by 50%), the Investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed.  At the next dose, the Investigator may consider the addition of 
H2 blocker antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofen to the 
mandatory premedication.  Prophylactic steroids are NOT permitted.
5.3.5.2. Avelumab: Severe Hypersensitivity Reactions
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice.  A complete guideline for the emergency treatment of anaphylactic 
reactions according to the Working Group of the Resuscitation Council (United Kingdom) 
can be found at https://www.resus.org.uk/pages/reaction.pdf.  Patients should be instructed to 
report any delayed reactions to the Investigator immediately.
Symptoms include impaired airway, decreased oxygen saturation (<92%), confusion, 
lethargy, hypotension, pale or clammy skin, and cyanosis.  These symptoms can be managed 
with epinephrine injection and dexamethasone.  Patients should be placed on monitor 
immediately, and the intensive care unit (ICU) should be alerted for possible transfer if 
required.
For prophylaxis of flu like symptoms, 25 mg of indomethacin or comparable nonsteroidal 
anti-inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, naproxen sodium 
500 mg) may be administered 2 hours before and 8 hours after the start of each dose of 
avelumab IV infusion.  Alternative treatments for fever (for example, paracetamol) may be 
given to patients at the discretion of the investigator.
5.3.5.3. Avelumab: Tumor Lysis Syndrome
Tumor lysis syndrome should be treated per the local guidelines and the management 
algorithm published by Howard et al.40


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Figure 2.
Assessment and Initial Management of Tumor Lysis Syndrome
TLS=tumor lysis syndrome.


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5.3.5.4. Avelumab: Immune-Related Adverse Events
Because inhibition of PD-L1 stimulates the immune system, avelumab may cause toxicity by 
increasing the immune response, leading to inflammatory reactions collectively referred to as 
immune-related adverse events (irAEs).69
Immune-related adverse events described with this class of drugs include drugs include 
pneumonitis, colitis, hepatitis, endocrinopathies including thyroid disorders 
(hyperthyroidism, hypothyroidism, thyroiditis), adrenal insufficiency, hypophysitis, and 
diabetes mellitus or hyperglycemia, rash,  nephritis and renal dysfunction, encephalitis, eye 
disorders (including uveitis, iritis), and other immune-mediated reactions including myositis 
and myocarditis.
Any adverse event which may have an underlying immune-mediated mechanism including 
those described above, and without other confirmed etiologies, should be considered 
immune-related and managed according to guidelines described in this section.
Treatment of irAEs is mainly dependent upon 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 high grade AE (Grades 3 to 4).

Grades 3 to 4: treat with high dose corticosteroids.
For patients receiving avelumab alone or in combination with chemotherapy, any event 
suspected to be immune-related should be managed according to the guidance for 
management of irAEs in this section and Table 7. 
For patients receiving avelumab in combination with chemotherapy (Arm C), in case of a 
potential irAE, besides the management related to avelumab therapy, carboplatin/paclitaxel 
doses may also be modified or interrupted based on the guidance provided for 
carboplatin/paclitaxel toxicity management in Section 5.3.6.5, product labeling, and 
institutional guidelines according to investigator’s best medical judgment.
In cases where use of corticosteroids or other immunosuppressants is required per guidance 
for management of avelumab irAEs, chemotherapy may also be placed on hold until the irAE
resolves to Grade 1 based on investigator’s medical judgment and after discussion with the 
Sponsor.


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Table 7.
Avelumab: Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1
Diarrhea: <4 stools/day over 
Baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment 
(eg, loperamide)
Close monitoring for worsening 
symptoms
Educate patient to report worsening 
immediately
If worsens:
Treat as Grade 2 or 3/4
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 
Delay avelumab therapy
Symptomatic treatment
If improves to Grade 1: 
Resume avelumab therapy
If persists >5 to 7 days or recur:
0.5 to 1.0 mg/kg/day methylprednisolone 
or equivalent 
When symptoms improve to Grade 1, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
avelumab therapy per protocol.
If worsens or persists >3 to 5 days with 
oral steroids:
Treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): 7 stools per 
day over Baseline; incontinence; 
IV fluids 24 hrs; interfering with 
ADL
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs
Grade 4: life-threatening, 
perforation
Discontinue avelumab 
therapy per protocol
1.0 to 2.0 mg/kg/day 
methlyprednisolone 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
If persists >3 to 5 days, or recurs after 
improvement:
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab should 
not be used in cases of perforation or 
sepsis 


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Table 7.
Avelumab: Management of Immune-Related Adverse Events
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4.03)
Management
Follow-up
Grades 1 to 2
Covering 30% body surface area 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
Continue avelumab therapy
If persists >1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay avelumab therapy
Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or oral equivalent.  
Once improving, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for opportunistic infections, 
and resume avelumab therapy
If worsens: 
Treat as Grades 3 to 4
Grades 3 to 4
Covering >30% body surface 
area; life threatening 
consequences
Delay or discontinue 
avelumab therapy
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month and 
add prophylactic antibiotics for 
opportunistic infections 
Resume avelumab therapy
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1
Radiographic changes only 
Consider delay of avelumab 
therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-image at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4
Grade 2
Mild to moderate new symptoms 
Delay avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily, 
consider hospitalization 
1.0 mg/kg/day 
methyl-prednisolone IV or 
oral equivalent 
Consider bronchoscopy, 
lung biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to near Baseline, 
taper steroids over at least 1 month and 
then resume avelumab therapy and 
consider prophylactic antibiotics
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4


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Table 7.
Avelumab: Management of Immune-Related Adverse Events
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Management
Follow-up
Grades 3 to 4
Severe new symptoms; New / 
worsening hypoxia; 
life-threatening 
Discontinue avelumab 
therapy
Hospitalize 
Pulmonary and Infectious 
Disease consults
2 to 4 mg/kg/day 
methylprednisolone IV or 
IV equivalent 
Add prophylactic antibiotics 
for opportunistic infections 
Consider bronchoscopy, 
lung biopsy 
If improves to Baseline: 
Taper steroids over at least 6 weeks 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression (for 
example, infliximab, cyclophosphamide, 
IV immunoglobulin, or mycophenolate 
mofetil). 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4.03)
Management
Follow-up
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 x ULN and / or total bilirubin 
> ULN to 1.5 x ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grades 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 
Delay avelumab therapy
Increase frequency of 
monitoring to every 3 days 
If returns to Baseline: 
Resume routine monitoring, resume 
avelumab therapy
If elevations persist >5 to 7 days or 
worsen: 0.5 to 1 mg/kg/day 
methylprednisolone or oral equivalent and 
when LFT returns to Grade 1 or Baseline, 
taper steroids over at least 1 month, 
consider prophylactic antibiotics for 
opportunistic infections, and resume 
avelumab therapy


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Table 7.
Avelumab: Management of Immune-Related Adverse Events
Grades 3 to 4
AST or ALT >5 x ULN and / or 
total bilirubin >3 x ULN 
Discontinue avelumab 
therapy 
Increase frequency of 
monitoring to every 1 to 
2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone IV or 
IV equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consult gastroenterologist
Consider obtaining MRI/CT 
scan of liver and liver 
biopsy if clinically 
warranted
If returns to Grade 2: 
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily 
If no response within an additional 3 to 
5 days, consider other 
immunosuppressants per local guidelines. 
Endocrine irAEs
Endocrine Disorder
Management
Follow-up
Asymptomatic TSH abnormality 
Continue avelumab therapy 
If TSH <0.5 x LLN, or TSH >2 x ULN, or consistently out of range in 
2 subsequent measurements: include T4 at subsequent cycles as 
clinically indicated; consider endocrinology consult 
Symptomatic endocrinopathy 
Evaluate endocrine function 
Consider pituitary scan 
Symptomatic with 
abnormal lab / pituitary 
scan: 
Delay avelumab therapy
1 to 2 mg/kg/day 
methylprednisolone IV or
by mouth equivalent 
Initiate appropriate 
hormone therapy 
No abnormal lab/pituitary 
MRI scan but symptoms 
persist: 
Repeat labs in 1 to 
3 weeks/MRI in 1 month 
If improves (with or without hormone 
replacement): 
Taper steroids over at least 1 month and 
consider prophylactic antibiotics for 
opportunistic infections 
Resume avelumab therapy 
Patients with adrenal insufficiency may 
need to continue steroids with 
mineralocorticoid component. 
Suspicion of adrenal crisis (for 
example, severe dehydration, 
hypotension, shock out of 
proportion to current illness) 
Delay or discontinue avelumab therapy 
Rule out sepsis 
Stress dose of IV steroids with mineralocorticoid activity 
IV fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic 
endocrinopathy 


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Table 7.
Avelumab: Management of Immune-Related Adverse Events
ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
CT=computed tomography; irAE=immune related adverse event, IV=intravenous, LFT=liver function test, 
LLN=lower limit of normal, MRI=magnetic resonance imaging, NCI CTCAE=National Cancer Institute 
Common Terminology Criteria for Adverse Events, anti-inflammatory drugs, T4=free thyroxine, 
TSH=thyroid-stimulating hormone, ULN=upper limit of normal
5.3.6. Guidelines for Chemotherapy Toxicity Management
Dose modification (dose delays and dose change) for carboplatin/paclitaxel due to ADRs 
should be made in accordance with the guidance provided below, product labeling and 
institutional guidelines.  Starting doses for carboplatin and paclitaxel and dose reduction 
levels are described in Table 5.
5.3.6.1. General Guidelines for Hematologic Toxicity 
Treatment decisions will be based on the absolute neutrophil count (ANC) rather than the
total white blood cell (WBC) count.
Day 1 of each cycle of cytotoxic chemotherapy will not be administered until the ANC is
≥1,000 cells/L and the platelet count is 75,000/L.  All treatment (including avelumab on 
Arm C) will be delayed until these levels are achieved. Chemotherapy can be delayed for a 
maximum of 3 weeks.  Patients who fail to recover adequate ANC despite a 3-week delay
will no longer receive chemotherapy.
Additionally, for patients on dose-dense chemotherapy, the Day 8 and Day 15 paclitaxel 
dose will not be given unless the ANC is at least 500 cells/L and the platelet count is at 
least 50,000/L.  If not given, these doses are to be omitted and not made up.
5.3.6.2. Use of Hematopoietic Growth Factors
It is anticipated that myelosuppression may be a significant side effect of chemotherapy.  
Myeloid growth factors (either filgrastim or pegfilgrastim) can be used (it is recommended 
that that NCCN and/or American Society of Clinical Oncology (ASCO) guidelines41 be 
consulted). Patients may receive erythropoietin (EPO), iron supplements, and/or
transfusions as clinically indicated for management of anemia.
5.3.6.3. Modifications for Hematologic Toxicities
There will be no paclitaxel dose reductions based on hematologic toxicity, however, 
paclitaxel dose omissions may be recommended on the weekly regimen as described in 
Table 9.
Initial occurrence of dose-limiting neutropenia or dose-limiting thrombocytopenia will be 
managed according to Table 8 and Table 9.

Dose-limiting neutropenia (DLT-ANC) is defined by the occurrence of febrile 
neutropenia (as defined within the CTCAE), prolonged Grade 4 neutropenia 
persisting ≥ 7 days, delay of treatment for more than 7 days because of neutropenia, 


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ANC < 1000 cells/l on Day 1, or omission of Day 8 or Day 15 paclitaxel because of 
neutropenia.

Dose-limiting thrombocytopenia (DLT-PLT) is defined by any occurrence of Grade 
4 thrombocytopenia (25,000/l) or bleeding associated with Grade 
3 thrombocytopenia (25,000 to 50,000/l), delay of treatment on Day 1 of a cycle 
by more than 7 days because of thrombocytopenia, platelet count of <75,000/l on 
day 1, or inability to give Day 8 or Day 15 paclitaxel on the dose-dense regimen due 
to thrombocytopenia.  There will be no modifications for uncomplicated Grade 
3 thrombocytopenia.
Table 8.
Modification Instructions for Hematologic Toxicity: Q3W 
Chemotherapy Regimen
DLT
ANC
DLT
PLT
First Occurrence
Second 
Occurrence
Third Occurrence
Yes
No
Reduce carboplatin 
one AUC unit
Add G-CSF and 
maintain all current 
drug doses
Discontinue 
chemotherapy
Yes
Yes
Reduce carboplatin 
one AUC unit
Add G-CSF and 
maintain all current 
drug doses
Discontinue 
chemotherapy
No
Yes
Reduce carboplatin 
one AUC unit
Reduce carboplatin 
one AUC unit
Discontinue 
chemotherapy
Table 9.
Modification Instructions for Hematologic Toxicity: Weekly 
Chemotherapy Regimen
DLT
ANC
DLT
PLT
First Occurrence
Second 
Occurrence
Third Occurrence
Yes
No
Reduce carboplatin 
one AUC unit
Omit day 
15 paclitaxel and 
administer G-CSF 
starting after day 
8 paclitaxel
Reduce caboplatin 
one AUC unit, and 
give G-CSF after 
day 8 paclitaxel. 
Fourth occurrence: 
Discontinue 
chemotherapy.  
Yes
Yes
Reduce carboplatin 
one AUC unit
Omit day 
15 paclitaxel and 
administer G-CSF 
starting after day 
8 paclitaxel, and 
reduce carboplatin 
one AUC unit
Discontinue 
chemotherapy
No
Yes
Reduce carboplatin 
one AUC unit
Reduce carboplatin 
one AUC unit
Discontinue 
chemotherapy


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5.3.6.4. Dose Modifications and Delays of Chemotherapy: Other Non-Hematologic 
Toxicities and Laboratory Abnormalities
5.3.6.4.1. Renal Toxicity
The combination of carboplatin and paclitaxel, with or without avelumab, is not directly 
expected to cause renal toxicity.  There are, therefore, no specific dose modifications for 
renal toxicity. 
The administered dose of carboplatin must however be recalculated each cycle in any patient 
who develops renal insufficiency defined by serum creatinine greater than 1.5 times the 
ULN.
5.3.6.4.2. Hepatic Toxicity
Hepatic toxicity is not expected as a direct complication of chemotherapy; however, in the
event of Grade 3 (or greater) elevation in AST, ALT, alkaline phosphatase, or total bilirubin, 
paclitaxel should be reduced by 1 dose level and chemotherapy should be delayed until 
recovered to Grade 1.  For patients receiving chemotherapy in combination with avelumab, 
any event potentially immune-related should be managed according to the guidance 
described in Section 5.3.5.4 and Table 7 for avelumab irAEs.  In cases where use of 
corticosteroids or other immunosuppressants is required per guidance for management of 
avelumab irAEs, chemotherapy may also be placed on hold until the irAE resolves to Grade 
1 based on investigator’s medical judgment and after discussion with the Sponsor.
5.3.6.4.3. Neuropathy
Grade ≥2 sensory or motor neuropathy requires paclitaxel treatment to be interrupted until
neuropathy has resolved to a maximum of Grade 1. Upon recovery, paclitaxel should be 
reduced by 1 dose level.  If this requires a delay of more than 3 weeks, then paclitaxel
should be omitted from subsequent cycles and treatment continued with single agent
carboplatin at the same AUC used in combination with paclitaxel.
Grade ≥3 sensory or motor neuropathy requires paclitaxel to be omitted from subsequent
cycles, and treatment continued with single-agent carboplatin at the same dose as previously
used.
5.3.6.4.4. Mucositis
For Grade ≥ 3 mucositis, chemotherapy should be delayed until the mucositis has resolved to
Grade ≤ 1.  Paclitaxel may be reduced by one dose level in subsequent cycles based on 
investigator’s medical judgment.
5.3.6.4.5. Hypersensitivity to Paclitaxel
A hypersensitivity reaction to paclitaxel is not a dose-limiting toxicity.  The acute
management should occur as per local practice.


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If a hypersensitivity reaction occurs, then patients may be retreated with paclitaxel at
full dose according to local protocols.  This is likely to include increased prophylactic
medications and/or a slowing of the initial infusion rate with a gradual increase in rate in
the absence of further hypersensitivity reactions.
Emergency resuscitation equipment and personnel should be available during the period of 
re-challenge.
If the re-challenge occurs within 72 hours of the original intended dose and a negligible 
quantity, ie, 50 mL, of the original dose was administered, then re-administer the full
dose.  If a substantial proportion has been given then the balance of the full original dose
should be administered.
If the re-challenge is being considered more than 72 hours after the original intended dose
then a full blood count should be taken to check suitability.
In the case of recurrent hypersensitivity reactions, despite adequate premedication,
paclitaxel may be discontinued at the discretion of the treating physician, and the patient
may continue on treatment with single-agent carboplatin ± avelumab.
5.3.6.4.6. Hypersensitivity to Carboplatin
If there is a hypersensitivity reaction to carboplatin, then this should be managed as per local
institutional protocols.
In the case of recurrent hypersensitivity reactions, despite adequate premedication, 
carboplatin may be discontinued at the discretion of the treating physician, and the patient 
may continue on treatment with single agent paclitaxel ± avelumab.
5.3.6.4.7. Other Toxicities of Chemotherapy
For patients on chemotherapy alone (Arms A and B), there are no dose modifications 
planned for alopecia, nausea, diarrhea, or constipation.  These side effects should be treated 
with supportive medical therapy.  Non-steroidal anti-inflammatory agents may be used 
prophylactically, or symptomatically, as per local practice for the treatment of 
paclitaxel-induced arthromyalgia.
For any other adverse event of NCI CTCAE v4.03 Grade 4 severity considered at least 
possibly related to chemotherapy treatment, the patient should be discontinued from 
chemotherapy treatment.
For any other adverse event of NCI CTCAE v4.03 Grade 3 severity considered at least 
possibly related to chenotherapy treatment, treatment should be withheld until recovery to 
Grade 1 and subsequent treatment should be reduced by one dose level (see Table 5).


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5.3.6.5. Dose Modifications for Avelumab in Combination With Chemotherapy 
(Chemotherapy Phase – Arm C)
For avelumab, no dose reductions are permitted in this study, but doses may be omitted based 
on persisting toxicity.
For patients on Arm C (avelumab in combination with chemotherapy), chemotherapy dose 
modifications as well as infusion omissions/delays for chemotherapy and/or avelumab may 
occur independently according to the guidance provided below and investigator’s medical 
judgment and will be reported in the CRF.
Toxicities of the carboplatin paclitaxel combination and avelumab are generally non-
overlapping.  For patients receiving avelumab either as a single agent or in combination with 
chemotherapy, any adverse event suspected to be immune related should be managed 
according to the guidance for management of irAEs (see Table 7).  For Grade 3 potentially 
immune-related toxicities or where use of corticosteroids or other immunosuppressant is 
required per guidance for management of avelumab irAEs, chemotherapy may also be placed 
on hold until the irAE resolves to Grade 1 based on investigator’s medical judgment and after 
discussion with the Sponsor.
Refer to Table 10 for guidance on management of toxicities in the combination treatment arm 
(Arm C) during the chemotherapy phase.
For any other adverse event not covered in Table 10 below, see Section 5.3.4 for avelumab 
toxicity management and Section 5.3.6.4.7 for chemotherapy toxicity management.
Table 10.
Avelumab in Combination with Chemotherapy (Arm C) Toxicity 
Management
Toxicity
Treatment Modification for 
Chemothrerapy
Treatment Modification for 
Avelumab
Hematologic toxicity
See Section 5.3.6.3.
Delay until ANC is 
1,000 cells/L and the platelet 
count is 75,000/L.  
Adverse events with potential 
immune-related etiology (see 
Section 5.3.5.4) such as 
Colitis/diarrhea, Hepatic/Liver 
test abnormalities, Rash, 
Pneumonitis, Endocrinopathy, 
Nephritis/Renal dysfunction
Continue chemotherapy for 
G1/G2 events.
Chemotherapy may be placed on 
hold for events Grade ≥ 3 or 
events requiring corticosteroids / 
immunosuppressant, until the 
event resolves to Grade ≤ 1 based 
on investigator’s medical 
judgment and after discussion 
with the Sponsor.
See Section 5.3.5.4 and Table 7


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Table 10.
Avelumab in Combination with Chemotherapy (Arm C) Toxicity 
Management
Toxicity
Treatment Modification for 
Chemothrerapy
Treatment Modification for 
Avelumab
Neuropathy (sensory or motor)
Grade 2: Delay paclitaxel until 
event resolves to Grade ≤ 1 and 
then resume paclitaxel at 
1 reduced dose level.  If required 
delay > 3 weeks, paclitaxel should 
be permanently discontinued and 
treatment continued with single 
agent carboplatin. 
Grade ≥ 3: Permanently 
discontinue paclitaxel and 
treatment continued with single 
agent carboplatin (see 
Section 5.3.6.4.3).
Continue avelumab therapy for 
G1/G2 events.
Avelumab may be placed on hold 
for events Grade ≥ 3, until the 
event resolves to Grade ≤ 1 based 
on investigator’s medical 
judgment and after discussion 
with the Sponsor.
Mucositis
Grade ≥ 3: Delay chemotherapy 
until event resolves to Grade ≤ 1. 
Paclitaxel may be reduced by one 
dose level in subsequent cycles 
based on investigator’s medical 
judgment
See Section 5.3.6.4.4.
Continue avelumab therapy for 
G1/G2 events.
Avelumab may be placed on hold 
for events Grade ≥ 3, until the 
event resolves to Grade ≤ 1 based 
on investigator’s medical 
judgment and after discussion 
with the Sponsor.
Hypersensitivity
Managed according to the local 
guidelines.
In case of Grade 
≥3 hypersensitivity reaction to 
paclitaxel or carboplatin, 
avelumab treatment should be 
postponed until symptoms 
resolve. If symptoms do not 
resolve within 72 hours, avelumab 
dose should be skipped
See Section 5.3.6.
See Section 5.3.5.1 and Table 6.
5.4. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products (avelumab) including any comparator and/or marketed products, are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.


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Investigational product should be stored in its original container and in accordance with the 
label.  See the IP Manual for storage conditions of the product.

Avelumab must be stored in the refrigerator at 2- 8C (36- 46F).  Do not freeze.  
Protect from light.  Do not shake vigorously.
Storage conditions for avelumab stated in the single reference safety document (SRSD)
(Investigator’s Brochure [IB]) will be superseded by the storage conditions stated in the 
labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  Once an 
excursion is identified, the investigational product must be quarantined and not used until the 
sponsor provides documentation of permission to use the investigational product.  It will not 
be considered a protocol deviation if the sponsor approves the use of the investigational 
product after the temperature excursion. Use of the investigational product prior to sponsor 
approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions. More specific details will be provided to the sites separately.
All study drug supplies must be kept in a locked, limited access room.  The study drug must 
not be used outside the context of this protocol.  Under no circumstances should the 
Investigator or other site personnel supply study drug to other Investigators, patients, or 
clinics, or allow supplies to be used other than directed by this protocol without prior 
authorization from the Sponsor.  The Investigator and or site staff must report any 
unacceptable condition of the investigational product to the site monitor.
5.5. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.


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Pfizer may supply drug accountability forms that must be used or may approve use of 
standard institution forms.  In either case, the forms must identify the investigational product, 
including batch or code numbers, and account for its disposition on a patient by patient basis, 
including specific dates and quantities. 
The prescribed dose must be recorded in the patient’s medical records.  Drug dispensing 
needs to be verified and documented by a second individual and the forms must be signed by 
both the individual who dispensed the drug and the second individual who verified the 
dispensing.  Copies must be provided to Pfizer. 
At the end of the trial, or at appropriate points during the trial, Pfizer will provide instructions 
as to disposition of any unused investigational product.  If Pfizer authorizes destruction at the 
trial site, the Investigator must ensure that the materials are destroyed in compliance with 
applicable environmental regulations, institutional policy, and any special instructions 
provided by Pfizer.  Destruction must be adequately documented.  If drug destruction is not 
permitted locally, Pfizer should be contacted for further directions.
5.5.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.6. Concomitant Treatments
Medications or vaccinations specifically prohibited in the exclusion criteria are also not 
allowed during the active treatment period, except for administration of inactivated vaccines 
(for example, inactivated influenza vaccine).
If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy may be required.  
The Investigator should consult with the Sponsor about individual cases.  The final decision 
on any supportive therapy or vaccination rests with the Investigator and/or the patient’s 
primary physician.  However, the decision to continue the patient on study therapy or 
medication/vaccination schedule requires the mutual agreement of the Investigator, the 
Sponsor, and the patient. 
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician.
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatment and up to 90 days after the last dose of 
study treatment.  All concomitant medications and non-drug supportive interventions 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, and non-drug 
supportive interventions (eg, transfusions).


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Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
5.6.1. Concomitant Radiotherapy
Local radiotherapy (limited field) of isolated lesions with palliative intent is acceptable (eg, 
bleeding, pain, compression), and allowed throughout the study (starting from the screening 
through end of treatment) if considered medically necessary by the treating physician.  All 
attempts should be made to rule out disease progression in the event of localized pain.  If 
palliative radiotherapy is needed to control pain, the site(s) of disease causing pain should 
also be present at baseline; otherwise, painful lesions requiring radiotherapy will be 
considered as a sign of disease progression.  The Medical Monitor should be consulted prior 
to starting radiotherapy and prior to restarting study treatment after the end of radiotherapy.
5.6.2. Supportive Care Guidelines
Palliative and supportive care for disease-related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines.
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below:

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.

Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice.  Patients should be strongly 
encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Patients with a documented infectious complication should receive oral 
or IV antibiotics or other anti-infective agents as considered appropriate by the treating 
Investigator for a given infectious condition, according to standard institutional practice.  
Prophylactic administration should be considered for the cases outlined in
Table 7 Avelumab Management of Immune related Adverse Events.

Anti-inflammatory or narcotic analgesics may be offered as needed. 
Patients who need to be on anticoagulant therapy during treatment should be treated with low 
molecular weight heparin.  If low molecular weight heparin cannot be administered, 
coumadin or other coumadin derivatives or other anticoagulants (including direct Xa 
inhibitors) may be allowed; however, appropriate monitoring of prothrombin 
time/international normalized ratio (PT/INR) should be performed.


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5.6.3. Concomitant Surgery
5.6.3.1. Interval Debulking 
Patients who are enrolled prior to initiation of neoadjuvant therapy will complete 3 cycles of 
chemotherapy (with avelumab in Arm C), treatment will be held, and patients will proceed to 
have interval debulking surgery.  For those patients who receive the weekly paclitaxel 
regimen, the pre-surgery, D15 paclitaxel dose may be omitted at the investigator’s discretion.  
Upon recovery from surgery, the remaining duration of chemotherapy (with avelumab in 
Arm C) should be administered according to local institutional practice.  A histological 
assessment of response to neoadjuvant chemotherapy must be performed on the surgical 
specimen and will be recorded in the CRF (see Appendix 5).
Patients who cannot undergo planned interval debulking surgery are allowed to continue 
study treatment provided no disease progression is documented.
5.6.3.2. Other Surgery
If a major surgery or an interventional procedure (eg, endoscopy) is required, then treatment 
with avelumab must be interrupted.  Patients may resume avelumab 2-3 weeks after major 
surgery, assuming the wound has completely healed and there are no wound healing 
complications (eg, delayed healing, wound infection or fistula).
In case of a minor surgical procedure, treatment with avelumab does not need to be delayed.
5.6.4. Other Prohibited Concomitant Medications and Treatments
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy. 

Immunotherapy not specified in this protocol. 

Investigational agents other than carboplatin/paclitaxel and avelumab. 

Radiation therapy (with the exception noted above in the Concomitant Radiotherapy 
Section 5.6.1). 

Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs (see
Table 7 and below Clarification about Steroid Use).

Medications or vaccinations specifically prohibited in the exclusion criteria are also 
not allowed during the active treatment period, however, the administration of 
inactivated vaccines (eg, influenza vaccine) is allowed during the study.

Herbal remedies or vitamins used as anticancer treatments.


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
Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin).

For patients on avelumab, acetaminophen/paracetamol to a maximum total daily dose 
of 2 g is permitted.  Daily intake over 2 g is prohibited.
Clarifications About Steroid Use with Avelumab: Data indicate that corticosteroids have 
an adverse effect on T-cell function and that they inhibit and damage lymphocytes.42,43
Furthermore, as with all immunotherapies intended to augment cell mediated immunity, there 
is a risk that concomitant immunosuppressives such as steroids will counteract the intended 
benefit of the proposed study treatment.  However, studies with anti-CTLA4 compounds 
indicate that short term use of steroids may be employed without compromising clinical 
outcomes.44 Therefore, the use of steroids during this trial is restricted as follows:

Premedication: steroid inclusion in the premedication regimen for paclitaxel or 
carboplatin is allowed in all study arms.

Therapeutic use: for the treatment of infusion-related reactions and short term 
treatment of irAEs, steroids are permitted according to the modalities indicated in
Table 7 Avelumab Management of Immune-Related Adverse Events, they are also 
permitted for any other medical condition requiring short-term use of steroids.

Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
10 mg prednisone daily is acceptable.
5.6.4.1. Potential Drug-Drug Interactions 
The pharmacokinetics carboplatin and paclitaxel when co-administered have been evaluated 
in various studies.  No drug-drug interactions were observed between carboplatin and 
paclitaxel.45,46 Addtionally, no drug-drug interactions are expected between chemotherapy 
and a monoclonal antibodies based upon different elimination pathways (ie metabolism vs 
catabolism).  Previous studies where chemotherapy, including paclitaxel/carbotaxol 
combinations, was administered with large molecules (eg, figitimumab, bevacizumab) did 
not show any clinically significant PK drug-drug interactions.47,48,49
5.6.4.1.1. Paclitaxel
The metabolism of paclitaxel is catalyzed by cytochrome P450 isoenzymes CYP2C8 and 
CYP3A4.  In the absence of formal clinical drug interaction studies, caution should be 
exercised when administering paclitaxel concomitantly with known substrates or inhibitors of 
the cytochrome P450 isoenzymes CYP2C8 and CYP3A4. 
Caution should be exercised when paclitaxel is concomitantly administered with known 
substrates (eg, midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, 
simvastatin, and triazolam), inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, 
ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers 
(eg, rifampin and carbamazepine) of CYP3A4.


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Caution should also be exercised when paclitaxel is concomitantly administered with known 
substrates (eg, repaglinide and rosiglitazone), inhibitors (eg, gemfibrozil), and inducers (eg, 
rifampin) of CYP2C8.
Potential interactions between paclitaxel, a substrate of CYP3A4, and protease inhibitors 
(ritonavir, saquinavir, indinavir, and nelfinavir), which are substrates and/or inhibitors of 
CYP3A4, have not been evaluated in clinical trials.
5.6.4.1.2. Carboplatin
There are no anticipated drug-drug interactions or precautions for carboplatin.
5.6.4.1.3. Avelumab
There are no anticipated drug-drug interactions or precautions for avelumab.
6. STUDY PROCEDURES 
All patients must sign an informed consent prior to any study-specific procedures.
6.1. Screening
To allow for additional flexibility in scheduling patient visit and procedures, Screening and 
Cycle 1 Day 1 procedures may be completed on the same day (see SOA table).  However, 
screening assessments for eligibility MUST have already been completed before the patient is 
randomized.
Following informed consent, patients who are screened for treatment and complete screening 
assessments will subsequently be randomized to 1 of the 3 treatment arms for the study.  
Treatment must start within 7 days after randomization.
6.1.1. Tumor Biopsies
Provision of tumor biospecimen will be required as follows:
1. Archival tumor biospecimen:  A mandatory archival FFPE tumor tissue block from the 
initial tumor specimen (debulking surgery or core biopsy for patients planning to undergo 
neoadjuvant therapy) must be provided from all patients prior to randomization.  If an 
FFPE tissue block cannot be provided, 15 unstained slides (10 minimum) will be 
acceptable. If archived FFPE tissue is not available, a de novo (ie, fresh) tumor sample 
must be obtained in accordance with local institutional practice for tumor biopsies.
2. On-study FFPE surgical specimen (for neoadjuvant patients only):
a.
for pCR assesment:  The H&E slides used for the local assessment of pCR performed 
according to the guidelines described in Appendix 5 should be provided (i.e., from 
each of the 4-6 blocks examined for assessment of pCR),  The slides will be digitally 
imaged and returned to the site;


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b. for biomarker assessments:  The FFPE tumor tissue block that was selected for local 
pCR scoring per the guidelines described in Appendix 5 should be provided.  .  If the
block cannot be provided due to local regulations, 15 unstained slides (10 minimum)
will be acceptable.
3.
End of Treatment/Withdrawal Tumor Biospecimen: A de novo tumor sample (ie, fresh 
biopsy) should be collected at End of Treatment/Withdrawal visit unless clinically 
contraindicated.
For all tumor biospecimen, tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material) is not adequate and should not be submitted.  The de 
novo biopsy(ies) should be formalin fixed and paraffin embedded as per routine (see Study 
Manual), and the resulting FFPE tissue block(s) should be submitted to the Central 
Laboratory.  Additional information on tumor biospecimen collection procedures is included 
in the Study Manual.
6.2. Treatment Period
For the purpose of scheduling evaluations, treatment cycles of 3 weeks during chemotherapy 
phase, and 6 weeks during maintenance phase, will be designated.  To allow for patient and 
investigator schedules, holidays, and weather or other emergencies requiring clinical 
facilities to be closed, all patient visits can be performed 3 days of scheduled visits on all 
cycles, as feasible.  For details of on-treatment procedures see SOA table.
Patients will continue with the chemotherapy phase treatment, with or without avelumab, 
until progression of disease, a determination that the patient is no longer receiving clinical 
benefit, unacceptable toxicity, consent withdrawal, or death whichever comes first.  Upon 
completion of chemotherapy, patients without evidence of disease progression (SD, PR or 
CR) will proceed to the maintenance phase of the study.  Disease progression must be 
confirmed by BICR prior to withdrawal.
Patients receiving avelumab (Arms B or C) in the maintenance phase will continue treatment 
until progression of disease and determination that the patient is no longer receiving clinical 
benefit, unacceptable toxicity, consent withdrawal, a maximum duration of 24 months (not 
including chemotherapy phase), or death, whichever comes first.
6.3. End of Treatment/Withdrawal and Follow-Up Visits
In patients receiving avelumab up to the time of End of Treatment/Withdrawal visit, 
additional safety follow up must occur monthly for 90 days after the last dose of avelumab 
(Day 30 3, Day 60 3, Day 90 3).  The safety follow-up does not need to be performed 
for a patient who remains in maintainence and is undergoing safety assessments every 
6 weeks.
Patients continuing to experience treatment related toxicity following discontinuation of 
study treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the investigator, that no further improvement is 
expected.


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Patients who discontinue study treatment for reasons other than disease progression will be 
followed until documented disease progression by BICR assessment regardless of the start of 
a new anti-cancer therapy.  Tumor assessments should continue as specified in the SOA table 
until disease progression is documented by BICR assessment regardless of the start of new 
anti-cancer therapies. 
Patients who discontinue study treatment (or, if on Arm A maintenance, reach End of 
Treatment/Withdrawal) will be followed every 12 weeks for survival status until death or 
until study completion, whichever is earlier will be followed every 12 weeks by telephone 
call for survival and subsequent therapies until death or the end of the study.  The 
information collected for subsequent therapies should include details of the anti-cancer 
therapies, surgery, and date of initiation and discontinuation of each anti-cancer drug, and 
will be recorded in the CRF.
For End of Treatment/Withdrawal and Follow-Up visits procedures, see SOA.
6.4. End of Study
The study may end when at least 376 OS events have occurred within each of the two main 
comparisons (see Section 9.3 for further details). 
For patients who remain on treatment with avelumab at the end of study, another source of 
access to avelumab will be proposed.
6.5. Patient Withdrawal
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the patient to comply with the protocol-required schedule of study 
visits or procedures at a given study site.
Reasons for study treatment/observation discontinuation may include, but are not limited to:

Objective disease progression assessed by BICR.  However, patients in the maintenance 
phase with disease progression who are continuing to derive clinical benefit may be 
eligible to continue with single-agent avelumab, provided that the treating physician has 
determined that the benefit/risk for doing so is favorable (see Section 5.3.1.3.1);

Global deterioration of health status;

Unacceptable toxicity (for patients on chemotherapy and/or avelumab).  Patients who 
discontinue chemotherapy due to unacceptable toxicity in the absence of disease 
progression will enter maintenance phase and will continue to receive BSC (Arm A) or 
avelumab (Arms B and C).  Patients who discontinue avelumab due to unacceptable 
toxicity during the chemotherapy phase may complete chemotherapy and then enter the 
maintenance phase with BSC.

Pregnancy;


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
Significant protocol deviation;

Refusal of further treatment/patient request (patients who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures);

Lost to follow-up (All reasonable efforts must be made to locate patients to determine 
and report their ongoing status.  This includes follow-up with persons authorized by the 
patient as noted above.  Lost to follow-up is defined by the inability to reach the patient 
after a minimum of 2 documented phone calls, faxes, or e-mails as well as lack of 
response by the patient to 1 registered mail letter.);

Study termination by the Sponsor;

Death.
Reasons for withdrawal from study follow-up may include, but not limited to:

Completed study follow-up;

Study terminated by Sponsor;

Lost to follow-up;

Refusal of further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request that the patient return for a final visit, if applicable, 
and follow up with the patient regarding any unresolved adverse events (AEs).
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the patient. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.


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7.1. Safety Assessments
Safety assessments will include collection of AEs, Serious Adverse Events (SAEs), vital 
signs, and physical examination, ECG (12-lead), and laboratory assessments. 
7.1.1. Pregnancy Testing
For patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at 
least 25 mIU/mL and assayed in a certified laboratory, will be performed on 2 occasions 
prior to starting study treatment - once at the start of screening and once at the baseline visit, 
immediately before investigational product administration.  Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and another negative 
pregnancy result will then be required at the baseline visit before the patient may receive the 
investigational product.  Pregnancy tests will also be routinely repeated at every treatment 
cycle during the active treatment period (both chemotherapy and maintenance phases), at the 
end of study treatment, during the post-treatment safety follow-up visits up to at least 60 days 
after the last avelumab infusion for patients receiving avelumab at the EOT/Withdrawal visit,
and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is 
otherwise suspected.  In the case of a positive hCG test, the patient will be withdrawn from 
administration of investigational product but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by institutional review 
boards (IRBs)/ethics committees (EC) or if required by local regulations.
7.1.2. Adverse Events of Special Interest for Avelumab
Patients will be monitored closely for toxicity.  Any AE that is suspected to be a potential 
irAE is considered an AE of special interest (AESI).  Specific guidance for the management 
of irAEs is provided in Section Table 7 Avelumab Management of Immune-Related Adverse 
Events.  AESIs are reported according to the general AE reporting rules specified in 
Section 8.2.
7.1.3. Laboratory Safety Assessments
Hematology, blood chemistry, and urinalysis will be collected at the time points described in 
the SOA and analyzed at local laboratories.  They may also be performed when clinically 
indicated.  The required laboratory tests are listed in Table 11.
Table 11.
Required Laboratory Tests
Hematology
Hemaglobin
Platelets
WBC
Absolute Neutrophils
Absolute Monocytes
Absolute Eosinophils
Absolute Basophils


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Table 11.
Required Laboratory Tests
Chemistry Panel 
(*denotes core chemistry panel)
AST*
ALT*
Alkaline Phosphatase*
Sodium
Potassium*
Magnesium*
Chloride*
Total Calcium*
Total Bilirubin*
BUN or Urea*
Creatinine*
Glucose (non fasted)*
Phosphorus or Phosphate*
Albumin*
Total Protein*
Uric Acid
Amylase
Gamma glutamyl transferase (GGT)
Cholesterol
Creatinine kinase
C reactive protein (CRP)
Lactate dehydrogenase (LDH)
Lipase
Triglycerides
Urinalysis
Protein, glucose, blood
Coagulation Tests
PT or INR
aPTT
Pregnancy Tests
For female patients of childbearing potential, serum 
or urine
Thyroid Function Tests
TSH, free T4
Other Tests
ACTH, HBV, HCV serology, and CA-125
° 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, and alkaline phosphatase.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT=activated partial 
thromboplastin time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, 
GGT=gamma-glutamyltransferase, HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international 
normalized ratio, LDH=lactate dehydrogenase, TSH=thyroid-stimulating hormone, WBC=white blood cell
7.1.4. Vital Signs and Physical Examinations
Patients will have physical examinations to include major body systems (a pelvic exam can 
be performed at the discretion of the Investigator), weight, blood pressure, pulse rate, 
assessment of ECOG performance status, and height (height will be measured at screening 
only) at the time points described in the SOA table.  Blood pressure and pulse rate should be 
taken with the patient in the seated position after the patient has been sitting quietly for at 
least 5 minutes.


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7.1.5. Electrocardigram Assessments
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECG 
assessments.
All patients require a single ECG measurement at screening and on Day 1 of every other
cycle during chemotherapy after carbo/taxol infusion on Arms A and B and after Avelumab 
infusion on Arm C.  Additional ECGs will be performed on Day 1 of first maintenance cycle.  
Thereafter, on-treatment ECGs will be performed as clinically indicated.
Clinically significant findings seen on subsequent ECGs should be recorded as adverse 
events. In case of QTc >500 msec, a subsequent should ECG should be repeated to verify 
the result.  If ECG is confirmed >500 msec, local guidelines (eg, Repeat ECGs, review by 
cardiologist) should be followed. 
7.2. Tumor Assessments
Tumor assessments will include all known or suspected disease sites.  Imaging may include 
chest, abdomen, and pelvis CT or magnetic resonance imaging (MRI) scans.  Brain CT or 
MRI scan at baseline is only required when there is suspected brain metastases or new lesion 
during the study.  The CT scans should be performed with contrast agents unless 
contraindicated for medical reasons. 
The same imaging technique used to characterize each identified and reported lesion at 
baseline will be employed in the following tumor assessments.
Tumor assessment will be performed at screening, after 3 cycles of chemotherapy, and at the 
completion of chemotherapy to determine eligibility for maintenance.  For patients who 
undergo interval debulking surgery, an additional tumor assessment should be performed 
after surgery.  During maintenance, anti-tumor efficacy will be assessed every 12 weeks until 
disease progression by BICR assessment.  In addition, radiological tumor assessments will
also be conducted whenever disease progression is suspected (eg, symptomatic deterioration
or rising CA-125 levels), and at the time of End of Treatment/Withdrawal (if not done in the 
previous 6 weeks).  Complete and partial responses must be confirmed on repeat imaging 
≥4 weeks after initial documentation.  If radiologic imaging shows progressive disease (PD), 
then tumor assessment should be repeated after at least 4 weeks to confirm PD unless there is 
evidence of rapid clinical deterioration.  See Section 5.3.1.3.1 regarding confirmation of 
progressive disease for patients receiving avelumab.  Patients who come off study treatment 
without evidence of disease progression should be followed until progressive disease by 
BICR assessment with continued tumor assessments.
Bone imaging is required only if new bone metastases are suspected.  Bone imaging is also 
required at the time of confirmation of complete response for patients who have bone 
metastases. 
Assessment of response will be made using RECIST version 1.1 (Appendix 3) 
 
 
CCI
CCI


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All patients’ files and radiologic images will be collected for Blinded Independent Central 
review (BICR), whose assessments will be used for the primary endpoint analysis (see 
Section 9.3).
7.3. Pathological Complete Response Assessment
Minimal requirements for interval debulking surgery and guidelines for assessment of 
pathologic complete response are described in Appendix 5.
7.4. Pharmacokinetic Assessments
Plasma/serum samples will be obtained from patients for PK analysis of avelumab, 
carboplatin, and paclitaxel as follows:
Arm A: Serial PK for paclitaxel and carboplatin in the chemotherapy phase in at least 
10 patients at selected sites.
Arm B:  Serial PK for paclitaxel and carboplatin in the chemotherapy phase in at 
least 10 patients at selected sites.  Sparse sampling for avelumab in all patients in the 
maintenance phase.
Arm C: Sparse sampling for avelumab in all patients in both the chemotherapy phase 
and maintenance phase.  Serial PK for paclitaxel and carboplatin in the chemotherapy 
phase in at least 10 patients at selected sites.
Refer to the Schedule Of Activities for timing of the PK collections.  Additional details 
regarding the collection, processing, storage, and shipping of the blood samples will be 
provided in the Study Manual.
7.4.1. Blood Sample Collection for Pharmacokinetic Analysis 
Where noted in the SOA table, blood samples will be collected at approximately the same 
time as other assessments wherever possible.  Blood samples should be drawn from the 
contralateral arm of the IV infusion.
PK samples will be collected from patients in all 3 treatment arms, Arms A, B, and C as 
described in the SOA table. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, samples obtained within 10% of the nominal time (eg, within 6 minutes of 
a 60 minute sample) will be considered protocol compliant, and the exact time of the sample 
collection noted on the CRF.  If a scheduled blood sample collection cannot be completed for 
any reason, the missed sample collection may be rescheduled with agreement of the 
investigator and sponsor.
PK samples will be assayed for avelumab, carboplatin (total and free), and paclitaxel using 
validated analytical methods.  Additional details regarding the collection, processing, storage, 
and shipping of the blood samples will be provided in the study manual.  As part of the 


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understanding of the PK of the study drug, samples may be used for potential qualitative 
and/or quantitative metabolite analyses and/or evaluation of the bioanalytical methods for 
avelumab.  The results of such analyses may be included in the clinical report.
7.4.2. Collection of Avelumab Pharmacokinetic Samples
A total of 3.5 mL of whole blood will be collected into a serum separator tube (SST) at the 
designated times to provide serum for avelumab PK analysis.
7.4.3. Collection of Carboplatin Pharmacokinetic Samples
A total of 5.0 mL whole blood sample will be collected into a plasma separator tube at the 
designated times in the SOA to provide plasma for carboplatin PK analysis.
7.4.4. Collection of Paclitaxel Pharmacokinetic Samples
A total of 3.5 mL whole blood sample will be collected into a plasma separator tube at the 
designated times in the SOA to provide plasma for paclitaxel PK analysis.
7.5. Immunogenicity Assessments
A total of 3.5 mL of whole blood will be collected into an SST at the designated times to 
provide serum for evaluation of avelumab immunogenicity.  Immunogenicity blood samples 
will be assayed for anti-avelumab antibodies using a validated analytical method.  All of the 
samples that are positive for ADA may also undergo characterization for neutralizing 
antibodies.  Additional details regarding the collection, processing, storage, and shipping of 
the blood samples will be provided in the Study Manual.
7.6. Translational and Pharmacodynamic Assessments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers that may identify those patients who benefit from treatment 
with the combination of avelumab and carboplatin/paclitaxel.  In addition, analyses of 
sequentially obtained blood biomarkers will provide an opportunity to investigate 
pharmacodynamic effects.  Samples collected at the End of Treatment/Withdrawal visit will 
also help understand potential acquired mechanisms of resistance to the drug combination.
7.6.1. Tumor Biospecimens 
Tumor biospecimens representing tissue samples from primary or metastatic tumor lesions 
(see Section 6.1.1) will be used to analyze candidate DNA, RNA, or protein markers, or 
relevant signature of markers for their ability to identify those patients who are most likely to 
benefit from treatment with the study drugs. 
Markers that may be analyzed include, but may not necessarily be limited to, 
PD-L1 expression and tumor infiltrating CD8+ T lymphocytes by IHC, and/or tissue 
expression of FoxP3, PD-1, PD-L2, homologous recombination deficiency testing on tumor 
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Samples from interval debulking surgery and optional tumor biopsies obtained upon disease 
progression (End of Treatment/Withdrawal) will be assessed in parallel with the mandatory 
pre-treatment biospecimens to provide data on changes in the tumor that accumulated over 
the course of therapy, including acquired mechanisms of resistance.  For disease progression 
samples, only core needle or excisional biopsies, or resection specimens are suitable.  
Cytologic preparations, such as fine needle aspirate biopsies, are not acceptable.  Additional 
information on tissue collection procedures can be found in the Study Manual.
7.6.2. BRCA 1/2 Mutation Status
BRCA 1/2 test result will be collected if it becomes known during the study.
7.7. Banked Biospecimens
7.7.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of patients who respond 
well and those who respond poorly to treatment may help to better define the most 
appropriate group of patients in which to target a given treatment. Collecting biospecimens 
for exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study. Providing these biospecimens is a required 
study activity for study sites and patients, unless prohibited as such by local regulations or 
ethics committee decision.
To protect patients’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the patient’s study identification (ID) number. Samples will be kept in a 
facility accessible only by swiping a badge. Data will be stored on password-protected 
computer systems. The key between the code and the patient’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information. Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/patient information sheet; any other uses require additional ethical approval. 
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
post-marketing research. Patients can withdraw their consent for the use of their 
biospecimens at any time by making a request to the investigator, in which event any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
continue to be stored to protect the integrity of existing analyses. It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants. Patients are notified in the informed 
consent document/patient information sheet that their results will not be given to them, unless 


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required by local laws or regulations, in which case results will be returned via the 
investigator. Results will not be provided to family members or other physicians, nor will 
they be recorded in the patient’s medical record. There is no intention to contact patients 
after completion of the clinical study.
A 4-mL blood biospecimen Prep D1 (K2 edetic acid [ethylenediaminetetraacetic acid]
[EDTA] whole blood collection optimized for DNA analysis) will be collected at the 
Screening visit to be retained for potential pharmacogenomic/biomarker analyses related to 
drug response, unless prohibited by local regulations or ethics committee decision.  For 
example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
examined.
7.7.2. Banked Biospecimens for Soluble Biomarker Assessments
Additional biospecimens to be retained for exploratory analyses in this study include the 
following:

Prep D1 (K2 edetic acid [ethylenediaminetetraacetic acid][EDTA] whole blood 
collection optimized for DNA analysis): A 4-ml blood biospecimen will be collected 
before start of the first infusion on Day 1 of every odd chemotherapy study cycle (all 
treatment arms).  Additional samples will be collected on Day 1 of the second and 
fourth chemotherapy study cycles (all treatment arms).  During the maintenance
phase, samples will be collected on Day 1 of the first and second maintenance cycles 
only; and on Day 15 and 29 of the first and second maintenance cycles for patients 
randomized to Arms B and C.  Samples to be retained for potential 
pharmacogenomic/biomarker analyses related to drug response, unless prohibited by 
local regulations or ethics committee decision.  For example, putative safety 
biomarkers, drug-metabolizing enzyme genes, drug-transport protein genes, genes 
thought to be related to the mechanism of drug action, gene rearrangements, and 
epigenetic changes may be examined.

Prep B1.5 (EDTA plasma collection optimized for 
biomarker/proteomic/metabonomic analysis):  A 4 mL blood specimen will be 
collected before start of the first infusion on Day 1 of every odd chemotherapy study 
cycle (all treatment arms).  Additional samples will be collected on Day 1 of the 
second and fourth chemotherapy study cycles (all treatment arms).  During the 
maintenance phase, samples will be collected on Day 1 of the first and second 
maintenance cycles only; and on Day 15 and 29 of the first and second maintenance 
cycles for patients randomized to Arms B and C.

Prep B2 (serum collection optimized for biomarker/ proteomics/metabonomic
analysis): A 10-mL blood biospecimen will be collected before the start of the first 
infusion on Day 1 of every odd chemotherapy study cycle (all treatment arms).  
Additional samples will be collected on Day 1 of the second and fourth chemotherapy 
study cycles (all treatment arms).  During the maintenance phase, samples will be 


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collected on Day 1 of the first and second maintenance cycles only; and on Days 
15 and 29 of the first and second maintenance cycles for patients randomized to Arms 
B or C. 

Prep R1 (PAXGene whole blood collection optimized for RNA analysis): A 
2.5-mL blood biospecimen will be collected before start of the first infusion on Day 
1 of every odd chemotherapy study cycle (all arms).  Additional samples will be 
collected on Day 1 of the second and fourth chemotherapy study cycles (all treatment 
arms).  During the maintenance phase, samples will collected on Days 1 of the first 
and second maintenance cycles only; and on Days 15 and 29 of the first and second 
maintenance cycles for patients randomized to Arms B and C.
NOTE: For any of the biospecimens above, if a sample was collected at Screening, then it 
does not have to be collected at Day 1 of the start of chemotherapy prior to the infusion.
The banked biospecimens will be collected from all patients unless prohibited by local 
regulations or ethics committee decision. Detailed collection, processing, storage, and 
shipment instructions are provided in the central laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.7.3. Additional Research
Unless prohibited by local regulations or ethics committee decision, patients will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:

Investigations of the disease under study in the clinical study, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation among people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in the Markers of Drug Response section will be used.  Patients may 
still participate in the clinical study if they elect not to allow their banked biospecimens to be 
used for the additional purposes described in this section.
7.8. Patient-Reported Outcomes Assessments
In the treatment of ovarian cancer it is important to increase survival and palliate symptoms 
while maintaining health related quality of life and minimizing treatment side effects.50,51,52
To assess quality of life in clinical trials, patient reported outcomes (PROs) are frequently 
measured to quantify changes in disease specific symptoms, health related concerns, and 


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patient well- being.  It is critical to assess the PROs using validated instruments.53 In this 
trial, PROs will be assessed using 2 published and validated instruments:  FOSI-18 and 
EUROQol5 dimension (EQ-5D-5L). 
All patients will complete these two self-administered questionnaires pre-dose on Day 1 of 
every cycle during the chemotherapy phase, on Day 1 of every maintenance cycle (every 
6 weeks), the End of Treatment visit, and every 6 weeks during the post treatment safety and 
survival follow-up period up to a total of 3 years from the date of patient enrollment.  
Patients must complete these questionnaires at the clinic prior to any study or medical 
procedure during the chemotherapy and maintenance cycles, and at home during the safety 
and survival follow-up period.
7.8.1. FOSI-18
The FOSI-18 (a revised, more symptom-focused version of the FACT-O) was developed to 
be part of the Functional Assessment of Chronic Illness Therapy (FACIT) system and was 
specifically created with the input from the Food and Drug Administartion (FDA) and 
validated in ovarian cancer patients.  It is specifically designed to be a stand-alone instrument 
to measure disease symptoms, treatment side effects and function/well-being in patients with
ovarian cancer.54 The FOSI-18 Treatment Side Effect (TSE) subscale uses a set of questions 
to assess typical bother or side effects associated with cancer medicines, and the Disease 
Related Symptoms-Physical subscale (FOSI DRS-P), uses a subset of symptoms from the 
FOSI-18, which are considered to be symptoms specific to ovarian cancer.55
The FOSI-18 questionnaire will be administered as noted above and as per the SOA table.  
The amount of time for a patient to complete the questionnaire is estimated to be about 
3 minutes.
7.8.2. EuroQoL EQ-5D-5L
The EuroQol EQ-5D-5Lis a 6-item patient completed questionnaire designed to assess health 
status in terms of a single index value or utility score.56 There are 2 components to the 
EuroQol EQ-5D-5L: a Health State Profile which has individuals rate their level of problems 
(none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self- care, usual 
activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) in 
which patients rate their overall health status from 0 (worst imaginable) to 100 (best 
imaginable).  Published weights are available that allow for the creation of a single summary 
score.57 Overall scores range from 0 to 1, with low scores representing a higher level of 
dysfunction. 
The EuroQol EQ-5D-5Lquestionnaire will be administered as noted on the SOA table.  The 
amount of time for a patient to complete the questionnaire is estimated to be about 2 minutes.


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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 90 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the sponsor 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 are to be reported to the 
sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the patient has taken at least 1 dose of investigational product through 90 calendar days 
after the last administration.
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 


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
Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
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Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
The guidance on reporting of medication errors also applies to the reporting of overdose.
For purposes of this study, an overdose of avelumab is defined as an increase 5% than the 
planned avelumab dose for that particular administration. 
As for paclitaxel and carboplatin, an overdose is defined as a dose greater than the planned 
dose.
There is no specific treatment for avelumab, paclitaxel, or carboplatin overdose.  In the event 
of overdose with any of these study drugs, the patient should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided as clinically indicated.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;


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
Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.

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 
safety reporting 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 safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 5 (see the section on Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section 8.14.1, Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:


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Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with 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).
Concurrent with

For patients with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches ≥3 × ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.


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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.


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8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the study treatment caused or contributed to an AE; 
generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see Section 8.2 and 8.14 on Reporting Requirements).  
If the investigator's causality assessment is "unknown but not related to investigational 
product," this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
For combination treatments, causality assessment will be performed for each of the 
individual drugs included in the combination. 


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8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. 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).
2. 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 study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) 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 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 preprocedure 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 as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;


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
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 investigator.  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 study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. 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 the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (Also See Section 6.5 Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient/legally acceptable representative.  In addition, each study patient/legally 
acceptable representative will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.


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In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
The study is designed to test, in parallel, two hypotheses:


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
The first null hypothesis is that the true PFS hazard rate for both platinum-based 
chemotherapy alone followed by observation (Arm A), and avelumab in combination 
with platinum-based chemotherapy followed by avelumab maintenance (Arm C), are the 
same (HR=1); versus the alternative hypothesis that the true hazard rate is smaller for 
Arm C than for Arm A (HR<1). 

The second null hypothesis is that the true PFS hazard rate for both, platinum-based 
chemotherapy alone followed by observation (Arm A), and platinum-based 
chemotherapy alone followed by avelumab maintenance (Arm B), are the same (HR =1); 
versus the alternative hypothesis that the true hazard rate is smaller for Arm B than for 
Arm A (HR<1). 
Approximately 951 patients will be enrolled using a 1:1:1 randomization, stratified by 
paclitaxel regimen (Q3W vs QW) and by adjuvant (complete resection/microscopic disease) 
vs adjuvant (incomplete resection 1 cm) vs adjuvant (incomplete resection >1 cm) vs 
neoadjuvant. Two hundred and seventy-two (272) PFS events within each comparison will 
be required to have 90% power to detect a hazard ratio of 0.65 using a one-sided log-rank test 
at a significance level of 0.0125. 
The sample size for this study is determined based on the assumptions that the median PFS 
for patients treated with platinum-based chemotherapy alone followed by observation is 
23 months,6 and that treatment with avelumab in combination with platinum-based 
chemotherapy followed by avelumab maintenance, or treatment with platinum-based 
chemotherapy alone followed by avelumab maintenance is expected to increase the median 
PFS to 35.4 months, corresponding to a hazard ratio (HR) of 0.65 under the exponential 
model assumption.  The sample size further assumes a 15% drop-out rate within each 
treatment arm, a non-uniform patient accrual over a 27-month period, and follow-up of 
approximately 13 months after the last patient is randomized.  The data cutoff for the primary 
PFS analyses will occur after the target number of events has been reached in both 
comparisons and the last patient randomized in the study has been followed for at least 
12 months after randomization.
If the true HR is 0.65 under the alternative hypothesis, 272 PFS events within each 
comparison will be required to have 90% power to detect a HR of 0.65 using a one-sided 
log-rank test at a significance level of 0.0125 (total significance level one-sided 0.025), and a 
2-look group-sequential design with Lan-DeMets (O’Brien-Fleming) -spending function to 
determine the efficacy boundary and a Gamma Family (-5) -spending function to determine 
the non-binding futility boundary.
The sample size of 951 patients will also allow the assessment of difference in OS in the 
primary population.  A total of 376 OS events, within each comparison, would be required to 
have 70% power to detect a HR of 0.75 (80% power to detect a HR of 0.725) using a 
one-sided log-rank test at a significance level of 0.0125 and a 5-look group-sequential design 
with Lan-DeMets (O’Brien-Fleming) α-spending function to determine the efficacy 
boundary.  The sample size for OS is justified based on the assumptions that the median OS 
for patients treated with platinum-based chemotherapy alone followed by observation is 
80 months,6 and the median OS for patients treated with avelumab in combination with 


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platinum-based chemotherapy followed by avelumab maintenance, or patients treated with 
platinum-based chemotherapy alone followed by avelumab maintenance, is expected to 
increase the median OS to 106.7 months corresponding to a HR of 0.75 under the 
exponential model assumption. The sample size further assumes a 5% drop-out rate for OS 
in either treatment arm, and a follow-up of approximately 112 months after the last patient is 
randomized.  The data cutoff for the final OS analysis will occur after the target number of 
events has been reached in both comparisons.
The study will be considered positive if at least one of the primary objectives is met.
9.2. Analysis Population
9.2.1. Full Analysis Set
The full analysis set will include all patients who are randomized.  Patients will be classified 
according to the treatment and stratum assigned at randomization.  The full analysis set will 
be the primary population for evaluating all efficacy endpoints and patient characteristics.
9.2.2. Per-Protocol Analysis Set
The per-protocol analysis set is a subset of the full analysis set and includes patients who 
received at least 1 dose of study treatment and do not have major protocol deviations 
expected to impact the primary objective of the study.  Major protocol deviations will be 
pre-specified in the statistical analysis plan.  The per-protocol analysis set will be used for 
sensitivity analyses for the primary efficacy endpoint.
9.2.3. Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of study treatment.  
Patients will be classified according to the treatment assigned at randomization unless the 
incorrect treatment(s) are received throughout the treatment dosing period, in which case 
patients will be classified according to the first treatment received.  The safety analysis set 
will be the primary population for evaluating treatment administration/compliance and 
safety.
9.2.4. Pharmacokinetics Analysis Set
The PK concentration analysis set is defined as all treated patients who have at least 
1 concentration above the below limit of quantitation (BLQ) of avelumab. 
The PK parameter analysis set is defined as all treated patients who have at least 1 of the PK 
parameters of interest of any of the 3 study drugs.
9.2.5. Immunogenicity Analysis Set
The immunogenicity analysis set is defined as all treated patients who have at least 1 ADA 
sample collected.


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9.2.6. Biomarker Analysis Set
The biomarker analysis set is defined as all treated patients who have at least 1 screening 
biomarker assessment, and have received at least 1 dose of any study drug.  Analysis sets will 
be defined separately for blood based and tumor tissue-based biomarkers.
9.3. Efficacy Analysis
All efficacy analyses will be performed on the full analysis set unless otherwise specified. 
All analyses will be performed by using SASVersion 9.1.3 or higher. 
All primary and secondary endpoints based on radiological assessments of tumor burden (ie,
PFS, OR, DR) will be derived using the local radiologist’s/investigator’s assessment.  
Radiographic images and clinical information collected on study will also be reviewed by a 
BICR to verify investigator-reported tumor assessments.  Review by a BICR will be used for 
the primary analyses.
The primary analyses will be repeated on the per-protocol analysis set as a sensitivity 
analyses. All planned sensitivity analyses will be described in the SAP.
9.3.1. Analysis of the Primary Endpoint 
The primary endpoint is PFS which is defined as the time from randomization to the date of 
the first documentation of objective progression of disease or death due to any cause, 
whichever occurs first.
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start new anti-cancer treatment prior to 
an event, or for patients with an event after two or more missing tumor assessments.  Patients 
who do not have a baseline tumor assessment or who do not have any post-baseline tumor 
assessments will be censored on the day of randomization, with a duration of 1 day, unless 
death occurred on or before the time of the second planned tumor assessment in which case 
the death will be considered an event.
The primary analyses of PFS will be performed on the full analysis set, based on BICR 
assessment.  A stratified log rank test (one-sided) stratified by randomization stratification 
factors will be used within each comparison at the interim and/or final analyses with the 
overall significance level preserved at 0.0125 (one-sided).  PFS times associated with each 
treatment arm will be summarized using the Kaplan-Meier method and displayed graphically 
where appropriate.  Confidence intervals (CIs) for the 25th, 50th, and 75th percentiles will be 
reported.  The Cox proportional hazards model will be fitted to compute the treatment hazard 
ratios and the corresponding 95% CIs. 
In addition, the PFS hazard ratio for Arm C vs Arm B will be calculated together with the 
95% confidence interval.
PFS by BICR assessment will also be evaluated based on the per-protocol analysis set as a 
sensitivity analyses, using the stratified log-rank test (one-sided, =0.0125).


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9.3.2. Analysis of Secondary Endpoints
All analyses will be performed using the Full Analysis Set.  The analysis of PFS using the 
Full Analysis Set described in Section 9.3.1 based on BICR assessment will be repeated 
based on the Investigator’s assessment.
The analyses of other tumor-related endpoints will be based on the investigator’s assessment, 
as well as on the review of the BICR.
9.3.2.1. Overall Survival 
Overall Survival (OS) is defined as the time from date of randomization to date of death due 
to any cause.  Patients last known to be alive will be censored at date of last contact.  OS will 
be hierarchically tested for significance at the time of PFS analyses, provided the primary 
endpoint, PFS, is statistically significant at the PFS interim or final analyses.  In addition OS 
will be tested at 50%, 75%, of the OS events and at the OS final analysis.  Within each 
comparison, the analyses of OS will be performed based on the full analysis set.  A stratified 
log-rank test (one-sided) stratified by randomization stratification factors will be used at the 
interim and/or final analyses with the overall significance level preserved at 
0.0125 (one-sided).  OS time associated with each treatment arm will be summarized using 
the Kaplan-Meier method and displayed graphically where appropriate.  Confidence intervals 
(CIs) for the 25th, 50th, and 75th percentiles will be reported.  The Cox proportional hazards 
model will be fitted to compute the treatment hazard ratios and the corresponding 95% CIs.
In addition, the OS hazard ratio for Arm C vs Arm B will be calculated together with the 
95% confidence interval.
9.3.2.2. Objective Response 
Objective response is defined as a complete response (CR) or partial response (PR) per 
RECIST version 1.1 (Appendix 3) recorded from randomization until disease progression or 
death due to any cause. Both CR and PR must be confirmed by repeat assessments 
performed no less than 4 weeks after the criteria for response are first met.  A patient will be 
considered to have achieved an OR if the patient has a sustained complete response (CR) or 
partial response (PR) according to RECIST v.1.1 definitions.  Otherwise, the patient will be 
considered as a non-responder in the OR rate (ORR) analysis.  Additionally, patients with 
inadequate data for tumor assessment (eg, no baseline assessment or no follow up 
assessments) will be considered as non-responders in the ORR analysis. 
The ORR on each treatment arm will be estimated by dividing the number of patients with 
OR (CR or PR) by the number of patients randomized to the respective treatment arm.  The 
corresponding exact 2-sided 95% CIs will be provided by treatment arm. 
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9.3.2.3. Duration of Response 
Duration of response (DR) is defined, for patients with an objective response per RECIST 
v1.1 (Appendix 3), as the time from the first documentation of objective tumor response (CR 
or PR) to the first documentation of objective tumor progression or death due to any cause, 
whichever occurs first.  Censoring rules for DR will follow those described above for PFS. 
DR will be summarized by treatment arm using Kaplan-Meier method and displayed 
graphically, where appropriate. The median DR and 95% CI for the median will be provided 
for each treatment arm.
9.3.2.4. Maintenance Progression-Free Survival
Maintenance PFS is defined, for patients who proceed to maintenance and who do not have 
PD by BICR during the chemotherapy phase, as the time from Cycle 1 Day 1 of the 
maintenance phase to the date of the first documentation of objective progression of disease 
(PD) or death due to any cause, whichever occurs first.
Maintenance PFS data will be censored on the date of the last adequate tumor assessment for 
patients who do not have an event (PD or death), for patients who start new anti-cancer 
treatment prior to an event, or for patients with an event after two or more missing tumor 
assessments.  Patients who do not have a baseline tumor assessment or who do not have any 
on-maintenance tumor assessments will be censored on Cycle 1 Day 1 of the maintenance 
phase, with a duration of 1 day, unless death occurred on or before the time of the second 
planned tumor assessment in which case the death will be considered an event.
Maintenance PFS will be summarized by treatment arm using Kaplan-Meier method and 
displayed graphically, where appropriate.  The median PFS and 95% CI for the median will 
be provided for each treatment arm.
9.3.2.5. PFS2
PFS2 is defined as time from randomization to the start of second subsequent treatment after 
first progression, or death from any cause, whichever occurs first.  If no date of second 
subsequent therapy is available, patients will be censored at date of last contact. 
PFS2 will be summarized by treatment arm using Kaplan-Meier method and displayed 
graphically, where appropriate.  The median PFS and 95% CI for the median will be 
provided for each treatment arm.
9.3.2.6. pCR
pCR is defined for neoadjuvant patients who undergo interval debulking surgery as the 
Chemotherapy Response Score 3 (CSR3) according to Bohm et al, 2015 and will be 
performed locally per guidelines provided in Appendix 5.  An independent review of pCR 
may also be performed as necessary.


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The pCR rate on each treatment arm will be estimated by dividing the number of patients 
who achieved pCR by the number of patients who were stratified as neoadjuvant.  The 
corresponding exact 2 sided 95% CIs will be provided by treatment arm. 
9.3.2.7. PFS by GCIG Criteria based on Investigator Assessment
PFS by GCIG criteria will be assessed in this study incorporating both RECIST 1.1 and 
CA-125 (see Appendix 6).68
PFS by GCIG criteria will be censored if both PFS by RECIST 1.1 and PFS by CA-125 are 
censored, the date of censoring will be the latest of the two censoring dates.
CA-125 data will be censored on the date of the last CA-125 assessment for patients who 
start new anti-cancer treatment prior to an event, or for patients with an event after two or 
more missing CA-125 assessments.  Patients who do not have a baseline CA-125 assessment 
or who do not have any post-baseline CA-125 assessments will be censored on the day of 
randomization, with a duration of 1 day. 
PFS by GCIG criteria will be summarized by treatment arm using Kaplan-Meier method and 
displayed graphically, where appropriate.  The median PFS and 95% CI for the median will 
be provided for each treatment arm.
9.3.2.8. Patient-Reported Outcomes
The FOSI-18 and EuroQol5 dimension (EQ-5D-5L) will be scored according to their 
respective validation papers and user’s guides.54,56,57
As the primary PRO analysis, the FOSI-18 total score will be assessed to determine if overall 
HRQoL has been impacted over the course of the study among the 3 treatment arms for the 
comparisons Arm C vs Arm A and Arm B vs Arm A.  Random coefficient modelling will be 
carried out for the FOSI-18 total score.  Additionally, summary statistics [mean (and standard 
deviation), median, range and 95% CI] of absolute scores will also be reported for this total 
score.  The mean change of absolute scores from baseline (and 95% CI) will also be assessed.  
Line charts depicting the means and mean changes of this score over time will be provided 
for each treatment arm.  The primary analysis will be applied to all cycles, chemotherapy and 
maintenance phases, before progression.  A secondary analysis will include all assessments, 
including post-progression data for those patients who progress during the three year PRO 
follow up period.
Several secondary PRO analyses will be conducted.  A single question within the TSE 
subscale (“I am bothered by side effects of treatment”) will be assessed among the 
3 treatment arms for the comparisons Arm C vs Arm A and Arm B vs Arm A.  The analysis 
will be applied to the post-chemotherapy period until EOT.  Random coefficient modelling 
will be carried out for the single question score.  Additionally, time to development of 
significant side effect bother (TTB) will be analyzed where a TTB event will be defined as 
the first report of a score of ≥ 2 for at least two consecutive assessments on the side effect 
bother item.  Patients will be censored at the last time when they completed a 
FOSI-18 assessment if they have not had a TTB event.  Additionally, summary statistics 
[mean (and standard deviation), median, range and 95% CI] of absolute scores will also be 


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reported for this question.  The mean change of absolute scores from baseline (and 95% CI) 
will also be assessed.  Line charts depicting the means and mean changes of this question 
over time will be provided for each treatment arm.
The FOSI DRS-P subscale will also be used to determine the Time to Deterioration (TTD) of 
disease-related symptoms.  TTD is defined as the time from first dose (baseline) to the first 
time the patient’s score shows a 3-point or higher decrease in the FOSI DRS-P score.  
Patients will be censored at the last time when they completed a sub-scale assessment if they 
have not deteriorated.  Yost & Eton established that a 3-point or a greater group difference on 
a FACT scale of this length (9 items for FOSI DRS-P subscale) constitutes a meaningful 
difference between groups in disease symptoms.58
TTD of the FOSI DRS-P will be summarized using Kaplan-Meier methods.  The estimated 
Kaplan-Meier plots will be provided and the unstratified log rank test will be the primary 
method to compare (pairwise) the time to first deterioration for Arm C vs.  Arm A and Arm 
B vs. Arm A.  The median TTD and 2 sided 95% CI for the median will also be provided 
based on the Brookmeyer Crowley method [Brookmeyer 1982].59
Patient reported disease-related symptoms-emotional (DRS-E), treatment side effects (TSE) 
using all of the questions including the single “treatmentbother’ question, and
function/well-being (FWB) will also be assessed across all three treatment arms.  Summary 
statistics [mean (and standard deviation), median, range and 95% CI] of absolute scores will 
be reported for all of these subscales of the FOSI-18 questionnaire and the EQ-5D-5LVAS 
scale.  The mean change of absolute scores from baseline (and 95% CI) will also be assessed.  
Line charts depicting the means and mean changes of items and subscales over time will be 
provided for each treatment arm.  Additional exploratory analyses may be performed such as 
random coefficient models to assess the pairwise differences among the treatment arms.
For the EQ-5D-5Lhealth state profiles, the proportions of patients reported having “none”, 
“slight”, “moderate”, “severe”, or “extreme/unable” problems at each time point will be 
reported.
9.3.2.9. Pharmacokinetic Analysis 
The central laboratory, analytical laboratories (eg, PK, ADA, NAb), and Pfizer clinical assay 
group (CAG) colleagues will be unblinded.  If the need arises for early analysis of the PK 
data (before database lock and release of the randomization codes for the study), a PK 
unblinding plan will be developed.  A PK analyst, who is not associated with the study team, 
will conduct the analysis to avoid unblinding of the study team.
9.3.2.9.1. Pharmacokinetic Analysis of Avelumab
Cmax and Ctrough for avelumab will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by 
dose, cycle, and day.  The trough concentrations for avelumab will be plotted using a 
box-whisker plot by cycle and day in order to assess the attainment of steady-state.


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9.3.2.9.2. Pharmacokinetic Analysis of Carboplatin and Paclitaxel
Standard plasma PK parameters for carboplatin and paclitaxel will be estimated using 
non-compartmental and/or compartment methods, if needed.  Analysis and will include Cmax, 
Tmax, AUC0-tau, t½, plasma clearance (CL), and volume of distribution (Vd) as data permit. 
Dose-normalized parameters (eg, CDN-Cmax, DN-AUC) will be reported as appropriate). 
Descriptive statistics for the PK parameters for carboplatin (total and free) and paclitaxel will 
be provided by cycle and day of assessment in tabular form.
Carboplatin (total and free) and paclitaxel plasma concentrations will be summarized 
descriptively (n, mean, SD, CV, median, minimum, maximum, geometric mean, its 
associated CV, and 95% confidence interval) by cycle, day, and nominal time. Individual 
patient and median profiles of the profiles will be presented on both linear-linear and 
log-linear scales.
9.3.2.9.3. Effect of Avelumab on Carboplatin/Paclitaxel
The effect of avelumab dosing on carboplatin and paclitaxel PK will be evaluated based on 
overall assessment of the geometric mean ratios for Cmax, AUC24 , AUCi nf of carboplatin and 
paclitaxel on Day 1 of the fourth chemotherapy cycle in Arm C (carboplatin/paclitaxel + 
avelumab) compared to those on Day 1 of the fourth chemotherapy cycle of Arm B.
9.3.2.9.4. Effect of Carboplatin/Paclitaxel on Avelumab Pharmacokinetics
The effect of carboplatin/paclitaxel dosing on avelumab PK will be evaluated based on the 
overall assessment of the geometric mean ratios of Cmax and Ctrough of Arm C on Day 1 of the 
second chemotherapy cycle compared to those on Day 1 of the first maintenance cycle of 
Arms C and B.
9.3.2.10. Immunogenicity Analysis
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized by dose.  For patients with positive ADA, the magnitude 
(titer), time of onset, and duration of ADA response will also be described, if data permit. 
Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection, and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials.
9.3.2.11. Exposure/Response Analysis
In addition, the relationship between exposure and efficacy and safety endpoints may be 
explored, as necessary, based on emerging efficacy and safety data.  Refer to SAP for details 
of the analyses.  The results of these modeling analyses may be reported separately from the 
clinical study report.
9.3.3. Biomarker Analysis for Secondary and Exploratory Endpoints
Biomarker status (ie, positive or negative) may be determined by a predictive biomarker test 
with an established scoring algorithm defining positive and negative that is developed by the 
Sponsor.  Analysis of primary and secondary efficacy endpoints in subgroups defined by 


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biomarker status will be performed and reported as described above.  Comparisons will be 
made between biomarker subgroups (positive and negative) within treatment arms and 
between treatment arms within biomarker subgroups.
9.4. Analysis of Exploratory Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed 
graphically, where appropriate.
9.5. Safety Analysis
The safety analysis set will be the primary population for safety evaluation.  Summaries of 
AEs and other safety parameters will be provided, by treatment arm, as appropriate.
9.5.1. Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html).  The 
frequency of patients experiencing treatment emergent adverse events corresponding to body 
systems and MedDRA preferred term will be reported.  Adverse events will be graded by 
worst NCI CTCAE v4.03 severity grade, and will be summarized by cycle and by relatedness 
to study treatment. 
Emphasis in the analysis will be placed on AEs classified as treatment emergent.  Adverse 
events leading to death or discontinuation of study treatment, events classified as NCI 
CTCAE v4.03 Grade 3, trial drug-related events, and serious adverse events will be 
considered with special attention.  As appropriate, the difference in risk between treatment 
arms for AEs of clinical interest may be further assessed as described in the SAP.
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study treatment, action taken, and 
clinical outcome.
9.5.2. Laboratory Abnormalities
Laboratory test results will be graded according to the NCI CTCAE v4.03 severity grade.  
The frequency of patients with laboratory test abnormalities will be summarized according to 
the worst grade for each laboratory test. 
For laboratory tests without an NCI CTCAE grade definition, results will be categorized as 
normal (within normal ranges), abnormal, or not done.
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9.5.3. Electrocardiograms
ECG measurements will be used for the statistical analysis and all data presentations.  
Interval measurements from repeated ECGs will be included in the outlier analysis 
(categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors [ie, 
Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, QTc. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post baseline corrected QT interval. 
Shift tables will be provided for baseline vs worst on treatment corrected QT.  Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment.  Patients 
experiencing clinically relevant morphological ECG changes will be summarized (including 
frequency and percentage).
9.6. Interim Analysis
The interim analysis (IA) will be performed based on the full analysis set.  Any safety 
evaluation at the time of the IA will be based on the safety analysis set.
The goals of the interim analysis are to allow early stopping of the treatment arm (Arm B or 
Arm C) or the study for futility or efficacy, to assess the safety of avelumab alone or in 
combination with platinum-based chemotherapy. The interim analysis for both comparisons 
will be performed at the same time.
The study is designed to have, within each hypothesis testing, one interim analysis and the 
final analysis based on the primary PFS endpoint.  A formal efficacy boundary 
(O’Brien-Fleming) for rejecting the null hypothesis is constructed by using the spending 
function methodology of Lan-DeMets.  To protect the integrity of the study and to preserve 
the type 1 error rate, a fraction of alpha (0.0022) for efficacy will be spent at the interim 
analysis and accounted for in the overall type 1 error rate if the interim analysis is performed 
exactly at the planned number of PFS events.  The nominal significance levels for the interim 
and final efficacy analyses of PFS will be determined by using the Lan-DeMets procedure 
with an O’Brien-Fleming stopping boundary.60 The overall significance level for the 
efficacy analysis of PFS, within each comparison, will be preserved at 0.0125 (1-sided test).
Within each comparison, the interim analysis will be performed after approximately 181 PFS 
events (2/3 of the 272 events planned for each comparison at the end of the study).  If the 
value of the test statistic exceeds the efficacy boundary (z < -2.848, p < 0.002), then the 
experimental treatment (or the study) may be stopped for efficacy.  If the value of the test 
statistic exceeds the futility boundary (z > -0.804, p > 0.211), then the experimental treatment 
(or the study) may be stopped for futility.61 If the results of the interim analysis indicate 
serious safety concerns, the Sponsor will communicate with the Health Authorities regarding 
stopping the relevant experimental arms or the clinical trial. 


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The secondary OS endpoint will be analyzed within each comparison using a hierarchical 
testing procedure, provided the primary endpoint PFS endpoint is statistically significant 
favoring its respective avelumab-containing arm (ie, Arm B or Arm C).  Within each 
comparison, a maximum of 5 analyses are planned for OS: at the time of the interim PFS 
analysis, at the time of the final PFS analysis, at 50%, 75%, and 100% (final OS analysis) of 
the 376 OS events.  An α-spending function according to Lan-DeMets (O’Brien-Fleming) 
independent of the one used for the primary efficacy analysis will be used to preserve the 
0.0125 overall level of significance across the two hypotheses and the repeated testing of the 
OS hypotheses in the interim and final analyses.  The trial allows for the stopping of the 
study for a superior OS result, provided the primary PFS endpoint has already been shown to 
be statistically significant favouring its respective avelumab-containing arm.
9.7. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC) comprised of 
2 independent clinicians and 1 independent statistician. 
The E-DMC will be responsible for ongoing monitoring of the safety throughout the study,
and the evaluation of efficacy at the IA according to the charter.  The recommendations made 
by the E-DMC to alter the conduct of the study will be forwarded to Pfizer for final decision.  
Pfizer will forward such decisions, which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints, to regulatory authorities, as 
appropriate. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.


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It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.


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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Patients (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, patient
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study patients. The study site 
will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to her actual identity.  In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of patients’ personal data consistent with 
applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.


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The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study patient, or her legally acceptable representative,
is fully informed about the nature and objectives of the study and possible risks associated 
with participation. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide her own consent, the source documents must 
record why the patient did not provide consent (eg, minor, decisionally impaired adult), how 
the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’s assent was obtained, or waived.  If assent is obtained verbally 
it must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient, or the patient's legally acceptable representative, before any 
study-specific activity is performed. The investigator will retain the original of each patient's 
signed consent document.
12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.


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13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of trial in all other participating countries is defined as last patient last visit (LPLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 1 month.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date for 
studies in adult populations or within 6 months of the primary completion date for studies in 
pediatric populations.


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Primary completion date is defined as the date that the final patient was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 


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Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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NCCN ovarian cancer guidelines, 2015.
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Ozol, RJ. Challenges for chemotherapy in ovarian cancer. Annals of Oncology 2006; 
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Katsumata et al, Dose-dense paclitaxel once a week in combination with carboplatin 
every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised 
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Katsumata et al, Long-term results of dose-dense paclitaxel and carboplatin versus 
conventional paclitaxel and carboplatin for treatment of advanced epithelial ovarian, 
fallopian tube, or primary peritoneal cancer (JGOG 3016): a randomised, controlled 
open-label trial. Lancet Oncology 14: 1020 (2013).
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Chan, J., M. Brady, R. Penson, B. Monk, M. Boente, J. Walker, S. Davidson et al. 
Phase III Trial Of Every-3-Weeks Paclitaxel Vs. Dose Dense Weekly Paclitaxel With 
Carboplatin Plus/-Bevacizumab In Epithelial Ovarian, Peritoneal, Fallopian Tube 
Cancer: Gog 262 (Nct01167712). In International Journal of Gynecological Cancer, 
vol. 23, no. 8. 530 Walnut St, Philadelphia, PA 19106-3621 USA: Lippincott Williams 
& Wilkins, 2013.
8.
Herzog et al, Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology 
white paper. Gynecologic Oncology 132: 8-17, 2014.
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Riley JL. PD-1 Signaling in primary T cells. Immunological Reviews 2009; 229: 114-
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Appendix 1. Abbreviations 
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ACTH 
adrenocorticotropic hormone
ADA
anti-drug antibodies
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
target area under the concentration
BICR
Blinded Independent Central Review
BLQ
Below limit of quantitation
BRCA
breast cancer antigen
BSC
best supportive care
BUN
Blood urea nitrogen
CI
confidence interval
CR
complete response
CRF
case report form
CRP
C-reactive protein
CSR3
Chemotherapy Response Score 3
CSA
clinical study agreement
CSF
cerebrospinal fluid
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse 
Events
DAI
Dosing and Administration Instruction
DCIS
ductal carcinoma in situ
DCR
disease control rate
DL
dose level
DLT
dose limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DR
duration of response
DRS-E
disease-related symptoms-emotional 
DRS-P
disease-related symptoms-physical 
DU
dispensable unit


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Abbreviation
Term
EC
ethics committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Group
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EOC
epithelial ovarian cancer
EORTC
European Organisation for Research and 
Treatment of Cancer
EOT
end of treatment
EOS
end of study
EPO
erythropoietin
EU
European Union
EudraCT
European Clinical Trials Database
FACIT
Functional Assessment of Chronic Illness 
Therapy 
FDA
Food and Drug Administration (United 
States)
FDAAA
Food and Drug Administration Amendments 
Act (United States)
FIGO
International Federation of Gynecology and 
Obstetrics
FACIT
Functional Assessment of Chronic Illness 
Therapy
FSH
follicle-stimulating hormone
FTC
fallopian tube cancer
FWB
function/well-being
GCIG
Gynecological Cancer Intergroup
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transferae
GI
gastrointestinal
GMP
Good Manufacaturing Practice
GOG
Gynecologic Oncology Group
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
IB
investigator’s brochure
ICH
International Conference on Harmonisation
ICU
intensive care unit
ID
identification
IFN
interferon


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Abbreviation
Term
IgG1
immunoglobulin G1
IHC
immunohistochemistry
IL-6
interleukin-6
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
irAE
immune-related adverse event
IRB
institutional review board
 
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
JGOG
Japanese Gynecologic Oncology Group 
LCIS
lobular carcinoma in situ
LDH
lactate dehydrogenase
LFT
liver function test
LLN
lower limit of normal
LPLV
last patient last visit 
MID
minimally important difference
MRI
magnetic resonance imaging
N/A
not applicable
Nab
neutralizing antibody
NCCN
National Cancer Comprehensive Network
NCI 
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
OC
ovarian cancer
OR
objective response
ORR
objective response rate
OS
overall survival
PCD
primary completion date
pCR
pathological complete response
PD
progression of disease
PD-L1
programmed death ligand 1
PFS
progression-free survival
PK
pharmacokinetics
CCI


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Abbreviation
Term
PLT
platelet
PPC
primary peritoneal cancer
PR
partial response
PROs
patient-reported outcomes
PT
prothrombin time
PT
preferred term
Q2W
every 2 weeks
Q3W
every 3 weeks
QoL
quality of life
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCL
Supply Chain Lead
SD
stable disease
SOA
Schedule of Activities
SOP
standard operating procedure
SPC
summary of product characteristics
SRSD
single reference safety document
SST
serum separator tube
TEAE
treatment-emergent adverse event
TLS
tumor lysis syndrome
TO
target occupancy
TSE
treatment side effect
TSH
thyroid stimulating hormone
TTB
Time to side effect bother
TTD
time to deterioration
UICC
Union for International Cancer Control
ULN
upper limit of normal
US
United States
USPI
United States Package Insert
VAS
visual analogue scale
WBC
white blood cell count


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Appendix 2. ECOG Performance Status 
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, eg, light house work or office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair
5
Dead


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Appendix 3. RECIST Version 1.1
Adapted from E.A. Eisenhauer, et al.  New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228-247. 
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions 

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5 8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non measurable disease 
Non measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non cystic lesions are also present, these are preferred as target 
lesions.


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


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Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed. 

Stable: 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, but enough that a previously documented 30% decrease no 
longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate.  Progression has not been documented, and 

One or more target measurable lesions have not been assessed; 
or

Assessment methods used were inconsistent with those used at baseline;
or

One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);
or

One or more target lesions were excised or irradiated and have not reappeared 
or increased. 
Non target disease

CR: Disappearance of all non target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non CR/Non PD: Persistence of any non target lesions and/or tumor marker level 
above the normal limits. 


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
PD: Unequivocal progression of pre existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non target 
disease should be rare. 

Indeterminate: Progression has not been determined and one or more non target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR.
If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
Objective/Subjective Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.
Table 12.
Objective Response Status at each Evaluation
Target Lesions
Non-target Disease
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Indeterminate or Missing 
No
PR
PR
Non-CR/Non-PD, 
Indeterminate, or Missing
No
PR
SD
Non-CR/Non-PD, 
Indeterminate, or Missing
No
Stable
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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If the protocol allows enrollment of patients with only non target disease, the following table 
will be used:
Table 13.
Objective Response Status at each Evaluation for Patients with Non 
Target Disease Only
Non-target Disease
New Lesions
Objective status
CR
No
CR
Non-CR/Non-PD
No
Non-CR/Non-PD
Indeterminate
No
Indeterminate
Unequivocal progression
Yes or No
PD
Any
Yes
PD
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest sum 
on study).  For CR and PR, the patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria.  CR and PR must be confirmed 
by 2 measurements at least 4 weeks apart.  In the case of SD, follow up measurements must 
have met the SD criteria at least once after study entry at a minimum interval of 6 weeks.


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Appendix 5. Guidelines for Interval Debulking Surgery and Assessment of Pathological
Complete Response
Pathological complete response has been shown to provide valuable prognostic information 
in patients with various tumor types, such as breast cancer or colorectal cancer, who received 
neoadjuvant therapy.
Compared to breast cancer, there is relatively little experience with using the rate of pCR as a 
surrogate endpoint in ovarian cancer.  There are also challenges in standardization of pCR 
assessment, since unlike breast cancer it is difficult to accurately sample the entire tumor bed.
A recent study by Bohm et al, 2015, has tested and validated the prognostic significance of a 
3-tier scoring system for grading pathological response to neoadjuvant therapy in patients 
with high-grade pelvic serous carcinoma.  The study included 60 patients in the test cohort 
and 71 patients in the validation cohort. 
This 3-tier scoring system is reproducible, simple and easy to apply, and shows a significant 
association with clinical outcome when based on pathological assessment of omentum 
samples. 
This is the grading system currently recommended by the Ovary, Fallopian Tube and Primary 
Peritoneal Carcinoma ICCR (International Collaboration on Cancer Reporting) 
Histopathology Reporting Guide, version 0.5.73,74
In this protocol, the following guidelines for surgery and pathologic assessment, fully aligned 
with the ICCR reporting guide described above, were developed with the aim of 
standardizing the assessment of pCR.
Minimum requirements for interval debulking surgery:

bilateral salpingoophorecotmy

hysterectomy

infracolic omentectomy

palpation and visualization of all entire peritoneal surfaces with resection or biopsy of 
all suspicious areas
The details of the surgery will be collected in the CRF.
Minimum requirements for pathologic assessment of interval debulking surgery 
specimens:
Pathologic assessment should be performed as follows. 


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
Macroscopic description of omentum
Three dimensions of the omentum should be provided in the pathology report to 
document the size of the specimen received for pathological examination.  
Examination of 4-6 blocks of omentum is recommended.  The size of the largest 
tumour deposit should be recorded in the pathology report. 

Response to neoadjuvant therapy
1. Scoring should be carried out on a single H&E-stained section. 
2. A single block of involved omental tissue that shows the least response to 
chemotherapy should be selected (if there is no residual omental tumour a 
Chemotherapy Response Score/CRS score of 3 is given - see table below) 
3. The amount of viable tumour should be assessed; this may or may not show 
degenerative changes in the form of nuclear atypia, smudging of the nuclear 
chromatin and cytoplasmic clearing. 
4. Tumor regression grading should be scored using a 3-tier system as outlined in 
Table 15 below:
Table 15.
Criteria for Chemotherapy Response Score
Score
Definition
CRS1
No or minimal tumor response.  Mainly viable tumor with no or minimal 
regression-associated fibroinflammatory changes, limited to a few foci; cases in which it 
is difficult to decide between regression and tumor-associated desmoplasia or 
inflammatory cell infiltration.
CRS2
Appreciable tumor response amid viable tumor that is readily identifiable.  Tumor is 
regularly distributed, ranging from multifocal or diffuse regression-associated 
fibroinflammatory changes with viable tumor in sheets, streaks, or nodules to extensive 
regression-associated fibroinflammatory changes with multifocal residual tumor, which is 
easily identifiable.
CRS3
Complete or near-complete response with no residual tumor OR minimal irregularly 
scattered tumor foci seen as individual cells, cell groups, or nodules up to 2 mm 
maximum size.  Mainly regression-associated fibroinflammatory changes or, in rare cases 
no or very little residual tumor in the complete absence of any inflammatory response.  It 
is advisable to record whether there is no residual tumor or whether there is microscopic 
residual tumor present.
NOTE: Regression-associated fibroinflammatory changes consist of fibrosis associated with macrophages, 
including foam cells, mixed inflammatory cells, and psammoma bodies, as distinguished from tumor-related 
inflammation or desmoplasia.
5. The presence of fibrosis may be helpful in marking the site of previous tumour 
infiltration. 


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
When found in the absence of tumour, fibrosis is likely to indicate regression. 

If fibrosis occurs in association with tumour, this may simply reflect 
tumour-associated desmoplasia rather than regression. 

However, when fibrosis in association with tumour is accompanied by an 
inflammatory response (so-called 'fibro-inflammatory' response - fibrosis with 
associated macrophages and a mixed population of inflammatory cells), this 
indicates regression. 

Psammoma bodies may mark the site of previous tumour and can sometimes 
appear more numerous because their density increases in areas where tumour 
has disappeared. 
6. As a guide, >95% of tumour should be viable for a score of 1, and <5% for a 
score of 3. 
Assessment of residual viable tumor:
In addition to the Chemotherapy Response Score 3-tier scoring system for grading 
pathological response, all surgical specimens, including the adnexa, will be assessed for the 
presence or absence of residual neoplastic cells (viable tumor present vs. absent). 


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Appendix 6. PFS by GCIG Criteria
As described in published guidelines,68 progression by GCIG criteria will be defined as 
progression by RECIST 1.1 OR progression by CA-125.
Progression or recurrence based on serum CA-125 levels will be defined on the basis of a 
progressive serial elevation of serum CA-125 according to the following criteria:
1. Patients with elevated CA-125 pretreatment and normalization of CA-125 must show 
evidence of CA-125 greater than, or equal to, 2 times the upper limit of the reference 
range on 2 occasions at least 1 week apart, OR
2. Patients with elevated CA-125 before treatment, which never normalizes, must show 
evidence of CA-125 greater than, or equal to, 2 times the nadir value on 2 occasions 
at least 1 week apart, OR
3. Patients with CA-125 in the reference range before treatment must show evidence of 
CA-125 greater than, or equal to, 2 times the upper limit of the reference range on 
2 occasions at least 1 week apart.
CA-125 progression will be assigned the date of the first measurement that meets the criteria 
as noted.  Patients are not evaluable by CA-125 if there has been medical and/or surgical 
interference with their peritoneum or pleura (eg, paracentesis) during the previous 28 days.
A patient may be declared to have PD on the basis of either the objective RECIST 1.1 criteria 
or the CA-125 criteria.  The date of progression will be the date of the earlier of the 2 events 
if both are documented.

SAP_001.pdf: 
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JAVELIN OVARIAN 100
A RANDOMIZED, OPEN LABEL, MULTICENTER, PHASE 3 STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF AVELUMAB (MSB0010718C) IN 
COMBINATION WITH AND/OR FOLLOWING CHEMOTHERAPY IN PATIENTS 
WITH PREVIOUSLY UNTREATED EPITHELIAL OVARIAN CANCER
STATISTICAL ANALYSIS PLAN – B9991010
Compounds:
MSB0010718C
Compound Name:
Avelumab
Version:
V2
Date:
16-Mar-2018
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
1. VERSION HISTORY............................................................................................................8
2. INTRODUCTION ...............................................................................................................11
2.1. Study Objectives .....................................................................................................11
2.2. Study Design ...........................................................................................................12
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................14
3.1. Primary Endpoint ....................................................................................................14
3.2. Secondary Endpoints...............................................................................................14
3.2.1. Safety endpoints..........................................................................................14
3.2.2. Efficacy endpoints ......................................................................................14
3.2.3. Patient Reported Outcomes ........................................................................15
3.2.4. Pharmacokinetic endpoints.........................................................................15
3.2.5. Immunogenicity endpoints .........................................................................16
3.2.6. Biomarker endpoints...................................................................................16
3.3. Exploratory Endpoints.............................................................................................17
3.4. Baseline Variables...................................................................................................17
3.4.1. Study drug, study treatment and baseline definitions.................................17
3.4.2. Baseline characteristics...............................................................................19
3.5. Safety Endpoints .....................................................................................................19
3.5.1. Adverse events............................................................................................19
4. ANALYSIS SETS ...............................................................................................................20
4.1. Full Analysis Set .....................................................................................................21
4.2. Safety Analysis Set..................................................................................................21
4.3. Other Analysis Set...................................................................................................21
4.3.1. Per-protocol analysis set.............................................................................21
4.3.2. PK analysis sets ..........................................................................................22
4.3.3. Biomarker analysis sets ..............................................................................23
4.3.4. Immunogenicity analysis set.......................................................................23
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5. GENERAL METHODOLOGY AND CONVENTIONS....................................................23
5.1. Hypotheses and Decision Rules ..............................................................................23
5.1.1. Hypotheses and sample size determination................................................23
5.1.2. Decision rules .............................................................................................25
5.2. General Methods .....................................................................................................27
5.2.1. Data handling after the cut-off date............................................................28
5.2.2. Pooling of centers .......................................................................................28
5.2.3. Presentation of continuous and qualitative variables..................................28
5.2.4. Definition of study day...............................................................................28
5.2.5. Definition of start of new anti-cancer drug therapy....................................29
5.2.6. Definition of start of new anti-cancer therapy............................................29
5.2.7. Definition of on-treatment period...............................................................29
5.2.8. Standard derivations and reporting conventions.........................................30
5.2.9. Unscheduled visits......................................................................................30
5.2.10. Adequate baseline tumor assessment........................................................31
5.2.11. Adequate post-baseline tumor assessment................................................31
5.3. Methods to Manage Missing Data ..........................................................................31
5.3.1. Missing data................................................................................................31
5.3.1.1. Pharmacokinetic concentrations................................................31
5.3.1.2. Pharmacokinetic parameters .....................................................32
5.3.2. Handling of incomplete dates .....................................................................32
5.3.2.1. Disease history ..........................................................................32
5.3.2.2. Adverse events ..........................................................................33
5.3.2.3. Prior and concomitant medications...........................................33
5.3.2.4. Exposure....................................................................................34
5.3.3. Imputation rules for date of last contact and efficacy assessments ............34
5.3.3.1. Date of last contact....................................................................34
5.3.3.2. Death date..................................................................................35
5.3.3.3. Tumor assessments....................................................................35
5.3.3.4. Date of start of new anti-cancer therapy ...................................35
5.3.3.5. PRO data ...................................................................................37
6. ANALYSES AND SUMMARIES ......................................................................................38
6.1. Primary Endpoints...................................................................................................38
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6.1.1. Progression-free survival as assessed by BICR per RECIST v1.1.............38
6.1.1.1. Primary analysis ........................................................................38
6.2. Secondary Endpoint(s) ............................................................................................41
6.2.1. Safety endpoints..........................................................................................41
6.2.2. Efficacy endpoints ......................................................................................41
6.2.2.1. Overall survival.........................................................................41
6.2.2.2. Sensitivity analyses for progression-free survival.....................42
6.2.2.3. Sensitivity analyses for overall survival....................................46
6.2.2.4. Objective response and tumor shrinkage...................................47
6.2.2.5. Disease control ..........................................................................49
6.2.2.6. Duration of response .................................................................49
6.2.2.7. Maintenance PFS by BICR assessment ....................................49
6.2.2.8. Maintenance PFS by investigator assessment...........................51
6.2.2.9. PFS2 ..........................................................................................52
6.2.2.10. PFS by GCIG criteria based on investigator assessment ........54
6.2.2.11. pCR..........................................................................................55
6.2.3. Pharmacokinetic endpoints.........................................................................55
6.2.4. Population pharmacokinetic endpoints.......................................................57
6.2.5. Biomarker endpoints...................................................................................57
6.2.6. Immunogenicity endpoints .........................................................................58
6.2.6.1. Time to and Duration of ADA and nAb response.....................60
6.2.6.2. ADA titer...................................................................................61
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity 
status..................................................................................................61
6.2.7. PRO endpoints............................................................................................63
6.2.7.1. Scoring procedure .....................................................................64
6.2.7.2. Instrument completing rates......................................................64
6.2.7.3. Descriptive summaries over time..............................................64
6.2.7.4. Time-to-event endpoints ...........................................................64
6.2.7.5. Continuous endpoints................................................................66
6.4. Subset Analyses.......................................................................................................68
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6.5. Baseline and Other Summaries and Analyses.........................................................70
6.5.1. Baseline summaries ....................................................................................70
6.5.1.1. Demographic characteristics .....................................................71
6.5.1.2. Medical history..........................................................................72
6.5.1.3. Disease characteristics...............................................................72
6.5.1.4. Prior anti-cancer surgery ...........................................................73
6.5.2. Study conduct and patient disposition........................................................73
6.5.2.1. Patient disposition .....................................................................74
6.5.2.2. Protocol deviations....................................................................75
6.5.3. Study treatment compliance and exposure .................................................75
6.5.3.1. Exposure to avelumab ...............................................................77
6.5.3.2. Exposure to paclitaxel QW .......................................................78
6.5.3.3. Exposure to paclitaxel Q3W .....................................................79
6.5.3.4. Exposure to carboplatin.............................................................79
6.5.3.5. Dose reductions.........................................................................80
6.5.3.6. Dose delays ...............................................................................80
6.5.3.7. Infusion rate reductions.............................................................81
6.5.3.8. Infusion interruptions ................................................................81
6.5.4. Concomitant medications and non-drug treatments ...................................81
6.5.5. Subsequent anti-cancer therapies................................................................82
6.6. Safety Summaries and Analyses .............................................................................82
6.6.1. Adverse events............................................................................................82
6.6.1.1. All adverse events .....................................................................84
6.6.1.2. Adverse events leading to dose reduction.................................85
6.6.1.3. Adverse events leading to interruption of study treatment .......85
6.6.1.4. Adverse events leading to discontinuation of study 
treatment............................................................................................86
6.6.2. Deaths .........................................................................................................87
6.6.3. Serious adverse events................................................................................87
6.6.4. Other significant adverse events.................................................................87
6.6.5. Laboratory data...........................................................................................90
6.6.5.1. Hematology and chemistry parameters.....................................90
6.6.5.2. Other laboratory parameters......................................................93
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6.6.6. Vital signs...................................................................................................93
6.6.7. Electrocardiogram.......................................................................................94
6.6.8. Physical examination..................................................................................95
6.6.9. ECOG performance status ..........................................................................96
7. INTERIM ANALYSES.......................................................................................................96
7.1. Introduction .............................................................................................................96
7.2. Interim Analyses and Summaries............................................................................96
7.2.1. Interim analysis for PFS .............................................................................96
7.2.2. Interim analysis for OS...............................................................................97
8. REFERENCES ....................................................................................................................98
9. APPENDICES ...................................................................................................................101
LIST OF TABLES
Table 2
PK Parameters to Be Determined for Avelumab.................................................16
Table 3
Biomarker Definition and Determination............................................................16
Table 4
Statistical Analyses by Analysis Set.....................................................................21
Table 5
Power to Detect Specific Hazard Ratios for OS...................................................25
Table 6
Interim Analysis - Efficacy and Futility Boundaries............................................25
Table 7
Simulated Cumulative Probabilities to Stop for Efficacy or Futility at the 
Interim or Final PFS Analysis ..............................................................................26
Table 8
Simulated Cumulative Probabilities to Stop for Efficacy on Overall 
Survival at PFS Interim Analysis, Final PFS Analysis, Third and Fourth 
Interim OS Analyses, or Final OS Analysis .........................................................27
Table 9 
Outcome and Event Dates for PFS and DR Analyses ..........................................39
Table 10
PFS Censoring Reasons and Hierarchy................................................................40
Table 11
OS Censoring Reasons and Hierarchy..................................................................42
Table 12
Possible Outcomes for Investigator vs BICR .......................................................45
Table 13
Outcome and Event Dates for PFS Maintenance Analysis ..................................50
Table 14
Maintenance PFS Censoring Reasons and Hierarchy ..........................................51
Table 15
Outcome, Event Dates, Censoring Reasons and Hierarchy for PFS2 
Analyses................................................................................................................53
Table 16
Censoring Reasons and Hierarchy for PFS by GCIG Criteria Based on 
Investigator Assessment .......................................................................................55
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Table 17 
Patients Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ...................................................................................................................59
Table 18 
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) ...................................................................................................................60
Table 20
Case Definition for irAEs...................................................................................101
Table 21
Case Definition for IRRs – IV study drugs Administered Alone.......................103
Table 22
Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets)....................................................................................104
LIST OF FIGURES
Figure 1
Study Design Schema...........................................................................................13
APPENDICES
Appendix 1. Immune-Related Adverse Events......................................................................101
Appendix 2. Infusion Related Reactions ...............................................................................103
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991010 is based on the protocol amendment 
01 dated 23-Jun-2016.  
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991010.  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,
PK concentration, anti-drug antibodies (ADA; neutralizing antibody [nAb]), 
 
, and tumor assessment results by Blinded Independent Central Review 
(BICR)). 
The primary analysis will include all data up to a cut-off date which is determined by the 
number of events (progression-free survival [PFS] by BICR) and minimum follow-up of 12 
months after the last patient is randomized. The cut-off date is determined once a data extract 
(before database lock) is available which indicates that the required number of events for PFS 
by BICR and minimum follow-up of 12 months is expected to occur by the cut-off date. 
Due to data cleaning activities, the final number of events might deviate from the planned 
number. The data cut-off date will not be adjusted retrospectively in this case.  
2.1. Study Objectives
Co-Primary Objectives:
1. To demonstrate that avelumab in combination with platinum-based chemotherapy 
followed by avelumab maintenance (Arm C) is superior to platinum-based chemotherapy 
alone followed by observation (Arm A) in prolonging PFS in patients with previously 
untreated epithelial ovarian cancer (EOC).
2. To demonstrate that platinum-based chemotherapy alone followed by avelumab 
maintenance (Arm B) is superior to platinum-based chemotherapy alone followed by 
observation (Arm A) in prolonging PFS in patients with previously untreated EOC.
Secondary Objectives
•
To compare Arm C and Arm B to Arm A in patients with previously untreated EOC, with 
respect to overall survival (OS).
•
To evaluate the anti-tumor activity in each treatment arm.
•
To evaluate the overall safety profile in each treatment arm.
•
To evaluate the pharmacokinetics (PK) of paclitaxel and carboplatin alone and in 
combination with avelumab. 
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•
To evaluate the PK of avelumab alone and in combination with carboplatin-paclitaxel 
(Arms B and C). 
•
To evaluate the immunogenicity of avelumab alone and in combination with 
carboplatin-paclitaxel (Arms B and C).
•
To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab in 
combination with and/or following carboplatin-paclitaxel in pre-treatment tumor tissue, 
that may aid in the identification of patient subpopulations most likely to benefit from 
treatment.
•
To evaluate patient reported outcome (PRO) in Arm C and Arm B vs Arm A in patients 
with previously untreated EOC including the assessment of treatment side effects and 
disease-related symptoms.
•
 
 
 
•
 
2.2. Study Design
This is a Phase 3, open-label, international, multi-center, efficacy, and safety study of 
avelumab in combination with and/or following platinum-based chemotherapy in adult 
patients with previously untreated EOC.   
The study design is illustrated in the following figure. 
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Figure 1
Study Design Schema 
Chemotherapy
Maintenance
In this Phase 3 trial, approximately 951 patients who are candidates for frontline 
platinum-based chemotherapy will be randomized in a 1:1:1 ratio stratified by paclitaxel 
regimen (every 3 weeks (Q3W) vs weekly (QW)); and by adjuvant (complete 
resection/microscopic disease) vs adjuvant (incomplete resection ≤1 cm) vs adjuvant 
(incomplete resection > 1 cm) vs neoadjuvant to one of the following treatment arms: 
•
Arm A: platinum-based chemotherapy alone followed by observation 
•
Arm B: platinum-based chemotherapy alone followed by avelumab maintenance 
•
Arm C: avelumab in combination with platinum-based chemotherapy followed by 
avelumab maintenance. 
The assignment to Arm A vs Arm B will be blinded at the time of randomization to patients, 
investigators, and the Sponsor until completion of chemotherapy.  
Crossover between treatment arms will not be permitted.
Intravenous carboplatin-paclitaxel will be used as the chemotherapy backbone, consisting of 
Q3W carboplatin and the investigator choice of either Q3W or weekly paclitaxel.  Once a 
paclitaxel regimen is chosen for a given patient, it should not be changed for the duration of 
the study.
Patients may be enrolled either following primary debulking surgery (PDS), or prior to 
initiation of neoadjuvant chemotherapy.  The latter group will undergo interval debulking 
surgery (IDS) after 3 study cycles of chemotherapy (plus or minus avelumab, depending on 
Arm A 
Chemotherapy 
Alone
Arm B 
Chemotherapy 
Alone
Arm C
Chemotherapy + 
Avelumab
Arm C
Avelumab 
Arm B
Avelumab 
Arm A
Observation
Treatment 
Until: 
Progressive 
Disease per 
RECIST v1.1
OR
Unacceptable 
Toxicity
OR
Patient 
Withdrawal
If SD, PR, 
or CR after
the 
completion 
of
chemother
apy (+/-
avelumab)
1:1:1
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randomization) to be followed by the remainder of chemotherapy (plus or minus avelumab, 
depending on randomization).  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
•
PFS as determined by BICR by RECIST v1.1
PFS is defined as the time from the date of randomization to the date of the first 
documentation of progression of disease (PD) or death due to any cause, whichever 
occurs first.
3.2. Secondary Endpoints
3.2.1. Safety endpoints
•
Adverse events (AEs) (as graded by National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03); laboratory abnormalities (as 
graded by NCI CTCAE v4.03); vital signs (blood pressure, pulse rate); 
electrocardiograms (ECGs)
AEs will be graded by the investigator according to CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).
3.2.2. Efficacy endpoints
•
OS; PFS by Investigator assessment as well as Objective response (OR); Duration of 
response (DR); Maintenance PFS by BICR assessment and Investigator assessment; 
pathological complete response (pCR); PFS2; and PFS by GCIG criteria.
OS is defined as the time from the date of randomization to the date of death due to any 
cause.
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1, from the date of randomization until the date of first documentation of PD. Both CR 
and PR must be confirmed by repeat assessments performed no less than 4 weeks after 
the criteria for response are first met.
DR is defined, for patients with OR, as the time from the first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.
Maintenance PFS is defined, for patients who proceed to the maintenance phase and who 
do not have PD during the chemotherapy phase, as the time from Cycle 1 Day 1 of the 
maintenance phase to the date of the first documentation of PD or death due to any cause, 
whichever occurs first.
pCR is defined for neoadjuvant patients who undergo IDS as the Chemotherapy 
Response Score 3 (CSR3) according to Bohm et al, 2015.
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PFS2 is defined as time from the date of randomization to the start of second subsequent 
treatment after first documentation of PD, or death from any cause, whichever occurs 
first.  
PFS by GCIG criteria will be assessed in this study incorporating both RECIST v1.1 and 
CA-125 (Rustin, G et.al, 2011).
3.2.3. Patient Reported Outcomes 
•
FOSI-18 and EuroQoL5 Dimension (EQ-5D-5L)
Patient reported outcomes of HRQoL, ovarian cancer symptoms, treatment side effects, 
and functioning will be evaluated by FOSI-18 (Jensen 2015) and health status using 
EuroQol 5 Dimension (EQ-5D-5L) (Herdman 2011; Janssen 2013).
The FOSI-18 (a revised, more symptom-focused version of the FACT-O) was developed 
to be part of the Functional Assessment of Chronic Illness Therapy (FACIT) system and 
was specifically created with the input from the Food and Drug Administration (FDA) 
and validated in ovarian cancer patients. It is specifically designed to be a stand-alone 
instrument to measure disease symptoms, treatment side effects and function/well-being 
in patients with ovarian cancer. The FOSI-18 Treatment Side Effect (TSE) subscale uses 
a set of questions to assess typical bother or side effects associated with cancer 
medicines, and the Disease Related Symptoms-Physical subscale (FOSI DRS-P), uses a 
subset of symptoms from the FOSI-18, which are considered to be symptoms specific to 
ovarian cancer.  All FACIT scales are scored so that a high score is good (ie better 
functioning, or lower symptom burden).
The EQ-5D-5L is a patient-completed questionnaire designed to assess health status in 
terms of a single index value or utility score.9  There are 2 components to the EQ-5D-5L, 
a Health State Profile which has individuals rate their level of problems (none, slight, 
moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which 
patients rate their overall health status from 0 (worst imaginable) to 100 (best 
imaginable).  Published weights are available that allow for the creation of a single 
summary score. 
3.2.4. Pharmacokinetic endpoints
•
PK Parameters, including Ctrough, Cmax, volume of distribution, (Vd), clearance (CL), area 
under the concentration time curve (AUC) for avelumab, paclitaxel, and carboplatin, as 
data permit.
Dose-normalized parameters (eg, DN-Cmax, DN-AUC) will be reported as appropriate.
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Table 2
PK Parameters to Be Determined for Avelumab 
Parameter
Definition
Method of Determination
AUCtau
Area under the plasma concentration-time 
profile from time zero to the end of the 
dosing interval (tau)
Linear/Log trapezoidal method
AUClast
Area under the plasma concentration-time 
profile from time zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method
Cmax
Maximum observed plasma concentration 
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of 
first occurrence
t½
a
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.
Ctrough
Predose concentration during multiple 
dosing
Observed directly from data
CL
Clearance
Dose / AUCtau for steady state
Vd
Volume of distribution
Dose / (AUCtau ·kel) for steady state
AUC24 (dn)
Dose normalized AUC24
AUC24 / Dose
AUClast (dn)
Dose normalized AUClast
AUClast / Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
a If data permit
3.2.5. Immunogenicity endpoints
•
Anti-drug antibodies (ADA) and neutralizing antibody (nAb) against avelumab.
3.2.6. Biomarker endpoints
•
Candidate predictive biomarkers in tumor tissue including, but not limited to, PD-L1 
expression and tumor-infiltrating CD8+ T lymphocytes as assessed by 
immunohistochemistry (IHC).
Table 3
Biomarker Definition and Determination 
Parameter
Definition
Method of 
Determination
PD-L1 expression
The number of PD-L1 positive cells and/or 
qualitative assessment of  PD-L1 staining on tumor 
and inflammatory cells in regions of interest that are 
defined by tumor cell morphology and the presence 
or absence of inflammatory cells
Pathologist, assisted 
by image analysis
Tumor infiltrating CD8+ 
lymphocytes
The number of CD8+ cells per unit area and the 
percent of counted cells that are scored as CD8+ 
Pathologist, assisted 
by image analysis
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3.3. Exploratory Endpoints
•
 
 
 
 
•
CA-125 levels
•
 
 
 
 
 
 
 
      
 
 
   
3.4. Baseline Variables
3.4.1. Study drug, study treatment and baseline definitions
In this study, ‘study drug’ refers to avelumab, carboplatin or paclitaxel and ‘study 
treatment’ (or ‘treatment arm’) refers to one of the following:
•
Arm A = platinum-based chemotherapy alone followed by observation 
•
Arm B = platinum-based chemotherapy alone followed by avelumab maintenance 
•
Arm C = avelumab in combination with platinum-based chemotherapy followed by 
avelumab maintenance. 
Start and end dates of study treatment:
The date/time of first dose of study treatment 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 is the latest date/time of the last non-zero dose 
date/time for the study drugs in the combination.
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Definition of baseline: 
Definition of baseline for efficacy and PRO analyses 
The last measurement prior to randomization will serve as the baseline measurement for 
efficacy and PRO analyses. If such a value is missing (since per protocol the first PRO 
assessment is planned to occur prior to dosing on Cycle 1 Day 1), the last measurement prior 
to the first dose of study treatment will be used as the baseline measurement except for 
analyses of tumor assessments data where the baseline assessment would be considered as 
missing. 
Definition of baseline for immunogenicity analyses
The last available assessment prior to the start of treatment with avelumab is defined as 
‘baseline’ result or ‘baseline’ assessment.  If an assessment is planned to be performed prior 
to the first dose of avelumab in the protocol and the assessment is performed on the same day 
as the first dose of avelumab, it will be assumed that it was performed prior to avelumab 
administration, if assessment time point is not collected or is missing.
Definition of baseline for safety analyses
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety analyses.  If an assessment is planned to be 
performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. 
Definition of baseline for biomarker analyses
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for biomarker analyses. For biomarkers that are planned to be 
measured on Cycle 1 Day 1 (eg, soluble proteins), if the assessment time point is not 
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collected or is missing, it will be assumed that the measurement was performed prior to first 
dose of study treatment.
3.4.2. Baseline characteristics
Randomization is stratified by the following, as recorded in the Interactive Response 
Technology (IRT):
•
paclitaxel regimen (Q3W vs QW)
•
adjuvant (complete resection/microscopic disease) vs adjuvant (incomplete resection ≤
1 cm) vs adjuvant (incomplete resection > 1 cm) vs neoadjuvant.  
The primary analyses of PFS and OS will be stratified by these randomization stratification 
factors.
Other 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. 
3.5. Safety Endpoints
3.5.1. Adverse events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period. 
On-treatment period is defined as follows.
•
Arm A: 
o
For patients who entered the observation phase, it is the time from the first dose of 
study treatment through minimum (30 days + the date of end of observation period as 
reported on the observation end of treatment disposition page, start day of new anti-
cancer drug therapy – 1 day). 
o
For patients who did not enter the observation phase, it is the time from the first dose 
of study treatment through minimum (30 days + last dose of study treatment in the 
chemotherapy phase, start day of new anti-cancer drug therapy – 1 day). 
•
Arms B and C: 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.
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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 Appendices 1 and 2, 
respectively.
3-Tier Adverse Events
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analyses are
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates these exploratory analyses.
Adverse events and clusters of adverse events, of any causality and treatment-related, will 
also be summarized following a 3-tier approach.  Under this approach, AEs are classified into 
1 of 3 tiers.  
Tier-1 events: These are pre-specified events or clusters of events of clinical importance and
will be described in the Safety Review Plan.  
Tier-2 events: These are events that are not Tier-1 but are “common”.  A MedDRA PT is 
defined as a Tier-2 event if it is reported by 
a) at least 10% of patients with any grade in any treatment arm, or
b) at least 5% of patients with Grade 3, 4 or 5 in any treatment arm.  
Tier-3 events: All other AEs that are classified neither as Tier-1 nor Tier-2.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
Table 4 summarizes the use of the analysis sets for efficacy, safety, baseline characteristics 
and exposure. 
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Table 4
Statistical Analyses by Analysis Set 
Endpoints
Full Analysis Set
Per Protocol Analysis 
Set
Safety Analysis Set
Baseline Characteristics
9
9
Prior and Concomitant Therapies
9
9
Exposure
9
Efficacy: Primary 
9
9
Efficacy: Secondary 
9
9 (OS only)
Safety
9
4.1. Full Analysis Set
The full analysis set (FAS) will include all randomized patients.  Patients will be classified 
according to the study treatment assigned at randomization.
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug. 
Patients will be classified according to the study treatment assigned at randomization unless 
the incorrect treatment(s) was/were received throughout the dosing period in which case 
patients will be classified according to the first study treatment received.
4.3. Other Analysis Set
4.3.1. Per-protocol analysis set
Per-protocol (PP) analysis set is a subset of the FAS and will include patients who do not 
meet any of the following criteria that could impact the key objectives of the study.  Patients 
who meet any of the following criteria will be excluded from the PP analysis set for PFS by 
BICR. 
•
Patient did not receive at least one dose of the randomized study treatment
•
Patients randomized to Arm A who were treated with avelumab
•
Patients randomized to Arms B or C who did not receive at least one dose of avelumab
•
Patient without a tumor assessment on or after 3 cycles of chemotherapy (unless PD by 
BICR or death is observed before that time in which case the patient will not be excluded 
from the PP analysis set)
•
ECOG status ≥ 2 on or prior to randomization date
•
Patient does not meet Inclusion Criteria 1, 2 or 3:
1. Histologically confirmed Stage III-IV epithelial ovarian, fallopian tube, or primary 
peritoneal cancer (according to AJCC/UICC TNM and International Federation of 
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Gynecology and Obstetrics (FIGO) Staging System 2014 edition), including 
malignant mixed Müllerian tumors with high grade serous component.
2. Patients must be candidates for platinum based chemotherapy and previously 
untreated.
3. Patients must have completed a surgical debulking procedure, or be candidates for 
neoadjuvant chemotherapy.
a.
For patients enrolling after debulking surgery, the following conditions must be 
met
•
The minimum surgery required is an abdominal surgery with an attempt at 
cytoreduction providing tissue for histologic evaluation and establishing and 
documenting the primary site and stage.
•
Patient must be randomized at a maximum of 8 weeks after surgery.
b. For patients who are candidates for neoadjuvant chemotherapy, the following 
conditions must be met:
•
A core tissue (not fine needle aspiration) biopsy is required. The tissue must 
be consistent with a tumor of Müllerian origin.
•
Stage IIIC–IV documented via imaging or surgery (without attempt at 
cytoreduction).
•
Serum CA-125/ CEA ratio > 25. If the serum CA-125/CEA ratio is < 25, 
workup should be negative for the presence of a primary gastrointestinal or 
breast malignancy (< 6 weeks before randomization).
•
Plan to receive carboplatin-paclitaxel neoadjuvant chemotherapy.
•
Randomization must occur within 8 weeks after diagnosis.
Patients who meet any of the following criteria will be excluded from the PP analysis set for 
OS. 
•
Patient did not receive at least one dose of the randomized study treatment
•
Patients randomized to Arm A who were treated with avelumab
•
Patients randomized to Arms B or C who did not receive at least one dose of avelumab
•
ECOG status ≥ 2 on or prior to randomization date
•
Patient does not meet Inclusion Criteria 1, 2 or 3.
4.3.2. PK analysis sets
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for avelumab, carboplatin or paclitaxel.
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The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least one of the PK parameters of interest for avelumab, carboplatin or 
paclitaxel.
4.3.3. Biomarker analysis sets
The biomarker analysis set for biomarkers that are measured only at screening is a subset of
the safety analysis set and will include patients who have at least one screening biomarker 
assessment.
The biomarker analysis set for biomarkers that are measured sequentially is a subset of the 
safety analysis set and will include patients who have at least one baseline and one on-
treatment biomarker assessment for the same marker.
Analysis sets will be defined separately for blood-based and tumor tissue-based biomarkers.
4.3.4. Immunogenicity analysis set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample collected for avelumab in the avelumab 
containing arms.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
All references to PFS in this section pertain to PFS based on BICR assessment even when not 
specifically stated.
5.1.1. Hypotheses and sample size determination
The study is designed to test, in parallel, the following hypotheses:
H01: HRPFS(B/A) ≥1, versus Ha1: HRPFS(B/A) <1
H02: HRPFS(C/A) ≥1, versus Ha2: HRPFS(C/A) <1
where HRPFS (B/A or C/A) represents the hazard ratio (HR) for PFS by BICR assessment in each 
of the experimental arms vs the control arm.
Approximately 951 patients will be randomized to the treatment arms using a 
1:1:1 randomization, stratified by paclitaxel regimen (Q3W vs QW) and by adjuvant 
(complete resection/microscopic disease) vs adjuvant (incomplete resection < 1 cm) versus
adjuvant (incomplete resection ≥1 cm) vs neoadjuvant.  
Overall alpha level for testing hypotheses on the primary endpoint for the 2 treatment 
comparisons was maintained at 1-sided 0.025 by allocating 0.0125 alpha to each of the 
comparisons.
Two hundred and seventy-two (272) PFS events by BICR assessment, within each 
comparison, will be required to have at least 90% power to detect a HR of 0.65 using a 
1-sided log-rank test at a significance level of 0.0125, and a 2-look group-sequential design 
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with Lan-DeMets (O’Brien-Fleming) α-spending function to determine the efficacy 
boundary and a Gamma Family (-5) β-spending function to determine the non-binding 
futility boundary. 
The sample size for this study is determined based on the assumptions that the median PFS in 
control arm (patients treated with platinum-based chemotherapy alone followed by
observation  maintenance) is 23 months, (Katsumata et al, 2013) and that treatment with 
avelumab in combination with platinum-based chemotherapy followed by avelumab
maintenance, or treatment with platinum-based chemotherapy alone followed by avelumab 
maintenance is expected to increase the median PFS to ≥35.4 months, corresponding to a 
HR of 0.65 under the exponential model assumption.  The sample size further assumes a 15% 
drop-out rate within each treatment arm, and a non-uniform patient accrual over a 27-month 
period, and follow-up of approximately 13 months after the last patient is randomized.  
The data cut-off for the primary PFS analysis will occur after the target number of events has 
been reached in both comparisons and the last patient randomized in the study has been 
followed for at least 12 months after randomization.
The study will also include a formal comparison for OS.  The following hypotheses will be 
tested according to a testing strategy that preserves the overall type I error in the study as 
described in Section 5.1.2:
H03: HROS(B/A) ≥1, versus Ha3: HROS(B/A) <1
H04: HROS(C/A) ≥1, versus Ha4: HROS(C/A) <1
where HROS (B/A or C/A) represents the HR for OS in each of the experimental arms vs the 
control arm.
With 376 deaths for each comparison, the study will have 70% cumulative power (unadjusted 
for the pre-testing, in the hierarchical procedure, of PFS) to detect a HR of 0.75 (80% power 
to detect a HR of 0.725) using a 1-sided log-rank test at a significance level of 0.0125 and a 
5-look group-sequential design with Lan-DeMets (O’Brien-Fleming) α-spending function to 
determine the efficacy boundary. The sample size for OS is justified based on the 
assumptions that the median OS in the control arm is 80 months (Katsumata et al, 2013), and 
that treatment with avelumab in combination with platinum-based chemotherapy followed by 
avelumab maintenance, or treatment with platinum-based chemotherapy alone followed by 
avelumab maintenance is expected to increase the median OS to ≥106.7 months, 
corresponding to a HR of 0.75 under the exponential model assumption.  The sample size 
further assumes a 5% drop-out rate for OS in either treatment arm, and a follow-up of 
approximately 112 months after the last patient is randomized.  The data cut-off for the final 
OS analysis will occur after the target number of events has been reached in both 
comparisons.
Table 5 summarizes the power to detect several hazard ratios and the estimated duration of 
the study based on the same number of patients that are planned to be enrolled in the study to 
meet the primary endpoint and assuming a 5% dropout rate for survival follow-up. These 
calculations are conditional on achieving statistical significance for the test of PFS. 
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Table 5
Power to Detect Specific Hazard Ratios for OS
HR under Haj
Power
Calendar time (months) to 376 deaths under Haj
0.75
70%
139
0.73
77 %
140
0. 725
80%
141
Calculations performed using EAST 6.3
j=3, 4
5.1.2. Decision rules
To protect the integrity of the study and to preserve the type I error rate, a fraction of alpha 
(0.002) for PFS efficacy will be spent at the interim analysis and accounted for in the overall 
type I error rate if the interim analysis is performed at the planned number of PFS events. 
The nominal significance levels for the interim and final efficacy analyses of PFS will be 
determined by using the Lan-DeMets procedure with an O’Brien-Fleming stopping 
boundary. The overall significance level for the efficacy analysis of PFS, within each 
comparison, will be preserved at 0.0125 (1-sided test).
Two analyses will be performed for PFS:
1. an interim analysis will be conducted after all patients have been randomized in the study 
and at least 181 (67%) of the 272 PFS events for each of the comparisons have been 
documented based on BICR assessment, and
2. the final analysis for PFS will be conducted after all patients randomized in the study 
have been followed for 12 months and at least 272 PFS events for each of the 
comparisons have been documented based on BICR assessment.
The interim analyses for PFS will occur at the same time for both treatment comparisons, ie
the analysis cut-off date for the test of the 2 hypotheses, H01and H02, will be the same and 
will be set after all patients have been randomized in the study and the target number of 
events across both treatment comparisons have been reached. If the value of the test statistics 
for PFS exceeds the associated efficacy boundaries for a comparison, then the experimental 
treatment associated with that comparison (or treatments if this is met for both comparisons) 
may be declared statistically significantly superior to the control treatment for PFS. If the 
value of the test statistics for PFS exceeds the associated futility boundaries, then the 
experimental treatment associated with that comparison (or the study if this is met for both 
comparisons) may be stopped for futility.
Table 6
Interim Analysis - Efficacy and Futility Boundaries 
Efficacy boundary
Futility boundary
z value
p -value
z value
p -value
PFS 
Assuming 181 PFS events for each comparison at 
the time of the IA
< -2.848
p <0.002
z > -0.804
p > 0.211
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Since the observed number of events at the interim analysis for each comparison may not be 
equal to the planned 181 PFS events, the efficacy and futility boundaries will be updated 
based on the actual number of observed events using the pre-specified α-and β-spending 
functions. 
If the study continues to final analysis, the p-value that will be used to declare statistical 
significance at the final analysis will be based on the actual number of PFS events 
documented at the cut-off date for the final analysis and the α already spent at the interim 
analysis. Therefore, if the interim analysis occurs after 181 events for each comparison, and 
the study continues until the final analysis, the observed p-value for the comparison will have 
to be < 0.012 to declare statistical significance. If the number of events in the final analysis 
deviates from the expected number of events, the final analysis criterion will be determined 
so that the overall significance level across all analyses and comparisons is maintained at 1-
sided 0.025.
Based on the stopping boundaries defined above and the timing of interim analysis at 67% 
information fraction the design has the following operating characteristics.
Table 7
Simulated Cumulative Probabilities to Stop for Efficacy or Futility at the 
Interim or Final PFS Analysis
Scenario
Look
Number 
of PFS 
events a
Calendar Time 
(months)
P(Reject H0i)
P(Reject Hai)
H0i is true (HR=1)
Interim
181
27
0.0018
0.7919
Final
272
35
0.0137
0.9863
Hai is true (HR=0.65)
Interim
181
30
0.5109
0.0176
Final
272
40
0.8961
0.1039
Simulations performed in EAST 6.3 with number of simulations = 10,000 and seed= 93480874, 93660830
a For each comparison; i=1, 2. 
The secondary OS endpoint will be analyzed within each comparison using a hierarchical 
testing procedure, provided the primary endpoint PFS endpoint is statistically significant 
favoring the respective experimental arm. An α-spending function according to Lan-DeMets 
(O’Brien-Fleming) independent of the one used for the primary efficacy analysis will be used
so that the 0.0125 overall 1-sided level of significance across all analyses and comparisons is 
preserved at 0.025. The trial allows for the stopping of the study for a superior OS result, 
provided the primary PFS endpoint has already been shown to be statistically significant 
favoring its respective experimental arm. 
A maximum of five analyses are planned for OS: 
1) an interim analysis at the time of the interim analyses for PFS (provided PFS is 
significant); 
2) an interim analysis at the projected time of the final analysis for PFS (provided PFS is 
significant); 
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3) an interim analysis for OS after 188 deaths (50% of the total 376 OS events) have been
observed for each comparison; 
4) an interim analysis for OS after 282 deaths (75% of the total 376 OS events) have been
observed for each comparison; 
5) a final analysis for OS after 376 deaths have been observed for each comparison.
The exact nominal p-values that will need to be observed to declare statistical significance at 
the time of these analyses for OS will depend on the number of OS events that have been 
observed at the time of these analyses and the α for OS already spent at the time of earlier 
analyses.
If OS is tested alone, independent of the testing strategy for PFS, the design concerning 
overall survival analyses will have the following operating characteristics. These calculations 
are unadjusted for the pre-testing of PFS.  
Table 8
Simulated Cumulative Probabilities to Stop for Efficacy on Overall Survival 
at PFS Interim Analysis, Final PFS Analysis, Third and Fourth Interim OS 
Analyses, or Final OS Analysis
Scenario
Look
Number of 
deaths
Calendar Time 
(months)
P(Reject H0j)
H0j is true (HR=1)
1st Interim PFS
75
30
<0.0001
Final PFS
50% 
75%
124
188
282
40
56
84
<0.0001
0.0002
0.0040
Final OS
376
121
0.0134
Haj is true (HR=0.75)
1st Interim PFS
68
30
<0.0001
Final PFS
50% 
75%
109
188
282
40
62
94
0.0009
0.0804
0.3984
Final OS
376
138
0.6965
Interim and final PFS analyses calendar time expected at 30 and 40 months, respectively, under Hai (HR for 
PFS=0.65)
Simulations performed in EAST 6.3 with number of simulations = 10,000 and randomization seed 
=1131993337, 93862981
i=1, 2; j=3, 4.
5.2. General Methods
As described in Section 3.4, in this study ‘treatment arm’ refers to one of the following:
•
Arm A = platinum-based chemotherapy alone followed by observation 
•
Arm B = platinum-based chemotherapy alone followed by avelumab maintenance 
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•
Arm C = avelumab in combination with platinum-based chemotherapy followed by 
avelumab maintenance. 
Endpoints will be summarized based on the analysis sets described in Table 4 by treatment 
arm, unless otherwise specified.
5.2.1. Data handling after the cut-off date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients randomized at each center.
5.2.3. Presentation of continuous and qualitative variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3). 
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category.
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified.
5.2.4. Definition of study day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment + 1.
The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
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5.2.5. Definition of start of new anti-cancer drug therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of start of new anti-cancer therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.1 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after randomization amongst the 
following:
•
Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ 
eCRF pages
•
Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’
•
For neoadjuvant patients, ie, patients that answer ‘Yes’ to the question ‘Neoadjuvant 
patient’ in the ‘Planned Neoadjuvant Therapy’ eCRF page: Surgery date recorded in 
‘Follow-up Surgery’ eCRF pages when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially 
Resected’. For patients that are NOT neoadjuvant: 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 follows.
•
Arm A: 
o
For patients who entered the observation phase, it is the time from the first dose of 
study treatment through minimum (30 days + the date of end of observation 
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period as reported on the observation end of treatment disposition page, start day 
of new anti-cancer drug therapy – 1 day).
o
For patients who did not enter the observation phase, it is time from first dose of 
study treatment through minimum (30 days + last dose of study treatment in the 
chemotherapy phase, start day of new anti-cancer drug therapy – 1 day). 
•
Arms B and C: the time from the first dose of study treatment through minimum (30 days 
+ last dose of study treatment, start day of new anti-cancer drug therapy – 1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard derivations and reporting conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:
•
Age [years]: 
-
(date of given informed consent - date of birth + 1) / 365.25
-
In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth)
-
In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth)
The integer part of the calculated age will be used for reporting purposes. 
•
BMI (kg/m2) = weight (kg)/[height (m)]2
•
BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits.
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5.2.10. Adequate baseline tumor assessment
Adequate baseline is defined using the following criteria:
•
All baseline assessments must be within 28 days prior to and including the date of 
randomization.
•
For patients with evidence of disease at baseline, all documented lesions must have non-
missing assessments (ie, non-missing measurements for target lesions and non-missing 
lesions assessment status at baseline for non-target lesions).  
5.2.11. Adequate post-baseline tumor assessment
For patients who undergo IDS, the IDS date will be identified as follows:
•
‘Neoadjuvant Patient’ question on ‘Planned Neoadjuvant Therapy’ eCRF page is 
answered ‘Yes’, and
•
IDS date is the first surgery date recorded on the ‘On-Study Cancer Surgery’ eCRF page, 
where treatment intent is ‘Curative Intent’ and surgery outcome is ‘Resected’ or ‘Partially 
Resected’.
For patients who do not undergo IDS, an adequate post-baseline assessment is defined as an 
assessment with no evidence of disease (for patients with no evidence of disease at baseline) 
or where a response of CR, PR, SD, non-CR/non-PD, or PD can be determined (see Section 
6.2.2.4).  Time points where the response is not evaluable (NE) or no assessment was 
performed will not be used for determining the censoring date.
For patients who undergo IDS, since assessments after IDS can only be NE or PD, all post-
IDS tumor assessments will be considered adequate. Time points where no assessment was 
performed will not be used for determining the censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’. 
5.3.1.1. Pharmacokinetic concentrations
Concentrations below the Limit of Quantification
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
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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 patient’s concentration data, the parameter will be coded as NC (ie, 
not calculated).  NC values will not be generated beyond the day that a patient discontinues.
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 patient 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.
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. 
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•
If the date is completely missing, no imputation will be performed.
5.3.2.2. Adverse events
Incomplete AE-related dates will be imputed as follows:
•
If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment.
•
If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015.
•
If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014.
•
In all other cases the missing onset day or missing onset month will be replaced by 1.
•
Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 
•
In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off, outcome of AE is ongoing at cut-off. 
5.3.2.3. Prior and concomitant medications
Incomplete prior/concomitant medication dates will be imputed as follows:
•
If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment.
•
If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015. 
•
If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014.
•
In all other cases the missing medication day or missing medication month will be 
replaced by 1.
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•
Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 
•
In all other cases the incomplete medication stop date will not be imputed. 
5.3.2.4. Exposure
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows:
•
If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date
•
If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date) 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date)
= min (EOT date, death date), for all other cases
5.3.3. Imputation rules for date of last contact and efficacy assessments
5.3.3.1. Date of last contact
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following:
•
All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments)
•
Start and end dates of anti-cancer therapies (drug, surgery, radiation)
•
AE start and end dates
•
Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’)
•
Study drug start and end dates
•
Randomization date
•
Withdrawal of consent date
•
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up).
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Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date.
5.3.3.2. Death date
Missing or partial death dates will be imputed based on the last contact date:
•
If the date is missing it will be imputed as the day after the date of last contact 
•
If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following:
-
Missing day:
1st day of the month and year of death
-
Missing day and month:
January 1st of the year of death
5.3.3.3. Tumor assessments
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates (eg,
X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment. If both a previous and following assessments are not available, this 
assessment will not be used for any calculations.
5.3.3.4. Date of start of new anti-cancer therapy
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery)
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD
date by investigator assessment.
•
The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is
o
completely missing then it will be ignored in the imputations below
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o
partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy
o
partially missing with only month and year  available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy
•
For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below. 
•
If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is derived as follows:
o
Start date of new anti-cancer therapy is completely missing
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy]
o
Only year (YYYY) for start of anti-cancer therapy is available
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY; 
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = 01JANYYYY
o
Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available
IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY ;
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
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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.
5.3.3.5. PRO data
If there are missing items on the FOSI-18, subscale scores can be prorated.  This is done by 
multiplying the sum of the subscale by the number of items in the subscale, then dividing by 
the number of items actually answered, as follows:
Prorated subscale score = [Sum of item scores] × [Number of items in subscale] ÷ [Number
of items answered]
When there are missing data, prorating by subscale in this way is acceptable if > 50% of the 
items were answered.  The total score is then calculated as the sum of the un-weighted 
subscale scores. In addition, a total score should only be calculated if all of the component 
subscales have valid scores.  
For the EQ-5D-5L, questions not answered will be considered missing items and will not be 
utilized.  For EQ-5D-5L, the entire utility score for that cycle is deemed missing if the 
answer to any one of the 5 dimensions is missing.
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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. Progression-free survival as assessed by BICR per RECIST v1.1
6.1.1.1. Primary analysis
The following analyses will be based on the FAS using the strata assigned at randomization.  
PD below refers to PD by BICR assessment.
Progression-Free Survival (PFS) is defined as the time from the date of randomization to the 
date of the first documentation of PD or death due to any cause, whichever occurs first.  
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.  Patients who do not have an adequate baseline tumor assessment or who do not 
have an adequate post-baseline tumor assessment will be censored on the date of 
randomization unless death occurred on or before the time of the second planned tumor 
assessment (ie ≤ 18 weeks after the date of randomization) in which case the death will be 
considered an event. 
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening, after 3 cycles of chemotherapy, and at the completion of 
chemotherapy to determine eligibility for maintenance (prior to cycle 1 day 1 of 
maintenance).  For patients who undergo IDS, an additional tumor assessment should be 
performed after surgery.  In the maintenance phase, tumor assessments are performed every 
12 weeks until PD regardless of initiation of subsequent anti-cancer therapy. The allowable 
time window for disease assessments is 7 days prior to dosing while on treatment and 
whenever disease progression is suspected (eg, symptomatic deterioration).    
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 9.  
PFS (months) = [date of event or censoring– date of randomization +1]/30.4375
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Table 9
Outcome and Event Dates for PFS and DR Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of randomizationa
Censored a
PD or death
-
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR
-
≤ 18 weeks after the date of 
randomization
Date of PD or death
Event
PD or death 
-
after 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
No PD and no death
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression
Not applicable
Information is ignored. 
Outcome is derived based 
on documented 
progression only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a However if the patient dies ≤18 weeks after the date of randomization, the death is an event with date on death 
date
b If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of randomization; if the criteria were met the censoring will be on 
the date of randomization.
The primary efficacy analysis will compare the PFS time based on BICR assessment between 
each of the experimental arms and the control arm, and will be performed using a 1-sided 
stratified log-rank test as described in Section 5.1. 
The treatment effect, as measured by the hazard ratio, will be estimated using a Cox’s 
Proportional Hazard model stratified by the randomization strata. Each stratum will define a 
separate baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie, 
for the i-th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 
(0=control arm, 1= experimental arm) and β is the unknown regression parameter.
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG).
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In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 2000), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of PFS. 
In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the interim 
and the final analyses for PFS.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS time with 2-sided 95% CIs.  
In particular, the PFS rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54 and 60
months will be estimated with corresponding 2-sided 95% CIs.  The CIs for the median will 
be calculated according to Brookmeyer and Crowley and the CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (conftype=loglog default option in SAS Proc 
LIFETEST) with back transformation to a CI on the untransformed scale. The estimate of the 
standard error will be computed using Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to the categories in Table 10 following the hierarchy shown.
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 randomization
Event after 2 or more missing 
assessments a
4
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Subject refused 
further follow-up] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment arm. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment arms reversing the PFS censoring and event 
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indicators.  Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
arm together with a summary of associated statistics including the median time of follow-up 
for PFS with 2-sided 95% CIs.  In particular, the rate at 9 and 18 weeks and at 8, 12, 18, 24, 
30, 36, 42, 48, 54 and 60 months will be estimated with corresponding 2-sided 95% CIs.  
6.2. Secondary Endpoint(s)
6.2.1. Safety endpoints
Refer to Section 6.6.
6.2.2. Efficacy endpoints
The following analyses will be based on the FAS by treatment arm unless otherwise 
specified. Assessment of response will be made using RECIST v1.1.
Response endpoints will be analyzed separately based on BICR assessments and based on 
investigator assessment.  PFS by investigator assessment will be analyzed as a secondary 
endpoint using the same methodology that is described in Section 6.1.1.1 now referring to 
PD by investigator assessment instead of PD by BICR assessment; RCI will not be 
calculated. 
6.2.2.1. Overall survival
The following analyses will be based on the FAS using the strata assigned at randomization.   
Overall survival (OS) is defined as the time from the date of randomization to the date of 
death due to any cause. Patients last known to be alive will be censored at date of last 
contact.
OS (months) = [date of death or censoring– date of randomization +1]/30.4375
The primary analysis of OS will compare the OS time between each of the experimental arms 
and the control arm, and will be performed using a 1-sided stratified log-rank test as 
described in Section 5.1. 
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by 
the randomization strata to calculate the hazard ratio. Each stratum will define a separate 
baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie for the i-
th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) defines 
the baseline hazard function for the i-th stratum and x defines the treatment arm (0=control 
arm, 1= experimental arm) and β is the unknown regression parameter.
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG).
In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 2000), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of OS. 
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In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the interim 
and the final analyses for OS.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median OS time with 2-sided 95% CIs.  
In particular, the OS rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 78, 96, 
120 and 144 months will be estimated with corresponding 2-sided 95% CIs.  The CIs for the 
median will be calculated according to Brookmeyer and Crowley and the CIs for the survival 
function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (conftype=loglog default option in SAS 
Proc LIFETEST) with back transformation to a CI on the untransformed scale. The estimate 
of the standard error will be computed using Greenwood’s formula.  
Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment arm. Reasons for censoring will be summarized according to 
the categories in Table 11 following the hierarchy shown.
Table 11
OS Censoring Reasons and Hierarchy 
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Subject refused 
further follow-up] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 14 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment arms reversing the OS censoring and event indicators.   Kaplan-Meier 
estimates (product-limit estimates) will be presented by treatment arm together with a 
summary of associated statistics including the median time of follow-up for OS with 2-sided 
95% CIs.  In particular, the rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54, 60, 
78, 96, 120 and 144 months will be estimated with corresponding 2-sided 95% CIs.  
6.2.2.2. Sensitivity analyses for progression-free survival
The following sensitivity analyses will be performed to explore the robustness of the primary 
analysis results.  These analyses are regarded as purely exploratory. The sensitivity analyses 
will repeat the primary analysis (p-value, HR and 95% CIs) described in Section 6.1.1.1 with 
the modifications below:
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•
PFS based on BICR assessment and counting all PD and deaths as events regardless of  
missing assessments or timing of the event 
•
PFS based on BICR assessment on the PP analysis set for PFS
•
PFS based on BICR assessment using an unstratified analysis
•
PFS based on BICR assessment using strata derived according to eCRF data instead of 
those entered in IRT
•
PFS based on BICR assessment modifying the censoring rules in Table 9 to consider all 
deaths as events
•
PFS based on BICR assessment modifying the censoring rules in Table 9  with initiation 
of subsequent anti-cancer therapies not used as a censoring reason. 
The two stratification factors will be derived as follows based on eCRF data.
•
Paclitaxel QW vs Q3W 
The intended dose regimen recorded on the paclitaxel dosing eCRF page on Cycle 1 Day 
1 will be used to determine the paclitaxel regimen.
•
Adjuvant (complete resection/microscopic disease) vs adjuvant (incomplete resection ≤1 
cm) vs adjuvant (incomplete resection > 1 cm) vs neoadjuvant 
If the answer to the question ‘Neoadjuvant Patient’ is ‘Yes’ on the ‘Planned Neoadjuvant 
Therapy’ eCRF page, the patient will be classified as neoadjuvant. Otherwise the patient 
will be classified as adjuvant.  Note that some neoadjuvant patients may not undergo the 
planned IDS; this does not impact their classification as neoadjuvant.  
The detailed classification of adjuvant patients by primary debulking surgery result 
cannot be verified by data collected on the eCRF. If the randomization stratification 
information entered by the investigator in the IRT is ‘adjuvant’, then the detailed 
adjuvant classification as recorded in IRT is used; if the randomization stratification 
information entered by the investigator in the IRT is ‘neoadjuvant’, then the protocol 
deviation data will be used to identify the detailed adjuvant classification.
Methods for evaluating the validity of model assumptions
Schoenfeld residuals for the stratified Cox proportional regression model will be plotted to 
investigate graphically violations from the proportional hazards (PH) assumption; a non-zero 
slope is evidence of departure from proportional hazards (PH).  The PH assumption will be 
formally tested using Schoenfeld’s residual test (Schoenfeld, 1980; Therneau & Grambsch, 
2000).  Large departures from PH will be evidenced by a p-value <0.05. 
In addition, the PH assumption will be checked visually by plotting 
-log(log(S(t)) versus log(t) , 
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where S(t) is the estimated survival function (for PFS) at time t.
If these show large departures from proportional hazards, then PFS by BICR assessment will 
also be analyzed based on restricted mean survival time (RMST) differences (Zhang, 2013). 
Restricted Mean Survival Time (RMST)
The hazard ratio estimate from the Cox proportional hazard model is routinely used to 
empirically quantify the between-arm difference under the assumption that the ratio of the 
two hazard functions is constant over time.  When this assumption is plausible, such a ratio 
estimate may capture the relative difference between two survival curves.  However, the 
clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the 
underlying PH assumption is violated (ie, the hazard ratio is not constant over time). 
The RMST is a robust and clinically interpretable summary measure of the survival time 
distribution.  Unlike median survival time, it is estimable even under heavy censoring.  There 
is a considerable body of methodological research (eg, Royston and Parmar, 2011; Uno,Wei, 
et al., 2014; Zhang, 2013) about the use of RMST to estimate treatment effects as an 
alternative to the hazard ratio approach.  
The RMST methodology is applicable independently of the PH assumption and can be used, 
at a minimum, as a sensitivity analysis to explore the robustness of the primary analysis 
results.  However, when large departures from the PH assumption are observed, the log-rank 
test is underpowered to detect differences between the survival distributions for the treatment 
arms, and a test of the difference between the RMST for the experimental arm and the 
control arm may be more appropriate to determine superiority of the experimental arm 
compared to the control arm with respect to the time-to-event endpoint.
In particular, as it pertains to the cut-off point (τ) to evaluate the RMST, it is noted that the 
cut-off point should not exceed the minimum of the largest observed time for both treatment 
arms so that the RMST of all treatment arms being evaluated can be adequately estimated 
and comparison between treatments is feasible; τ should be clinically meaningful and closer 
to the end of the study follow-up so that the majority of survival outcomes will be covered by 
the time interval.  The RMST up to time τ can then be interpreted as the expected survival 
time restricted to the common follow-up time τ among all patients. The selection of τ should 
ensure that the RMST evaluation will not go beyond the maximum time point where the 
evaluation can be performed while also taking into account a large period of time that is 
expected to provide a meaningful assessment of treatment effect.   To avoid arbitrary 
selection of the common cut-off τ for both treatment arms, three sets of analyses will be 
performed:
•
τ1 = minimum of (largest observed survival time for experimental arm, largest observed 
survival time for control arm).    
•
τ2 = minimum of (largest survival event time for experimental arm, largest survival event 
time for control arm).
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•
τ3 = midpoint between τ1 and τ2.
In this section, ‘survival’ is meant to denote PFS.
The treatment effect between each of the experimental arms and the control arm will be 
assessed based on the difference in RMST. The associated 95% CI for the difference in 
means and 1-sided p-value will be generated.  
BICR vs Investigator assessment
A summary of the BICR assessment versus investigator assessment will be provided 
including numbers of concordant and discordant assessments as well as the number of cases 
where PFS event was assessed at different timepoints based on BICR and investigator
assessments.
Table 12 outlines the possible outcomes by investigator and BICR (Amit et al. 2011). 
Table 12
Possible Outcomes for Investigator vs BICR 
BICR
Investigator
Event
No Event
Event
a = a1 + a2 + a3
b
No Event
c
d
a1: number of agreements on timing and occurrence of event; 
a2: number of times agreement on event but INV declares event later than BICR; 
a3: number of times agreement on event but INV declares event earlier than BICR; 
N= a+b+c+d. 
The timing agreement for event is defined as a window of ± 7 days.
The following measure of discordance will be calculated for each treatment arm:
•
Total Event Discrepancy Rate: (b+c) / N
•
Early Discrepancy Rate (EDR): (a3+b) / (a+b)
•
Late Discrepancy Rate (LDR): (a2+c) / (a2+a3+b+c)
•
Overall Discrepancy Rate: (a2+a3+b+c) / N
The EDR represents the positive predictive value of investigator assessment and quantifies 
the frequency with which the investigator declares PFS event earlier than BICR within each 
treatment arm as a proportion of the total number of investigator assessed PFS events.
The LDR quantifies the frequency with which the investigator declares PFS event later than 
BICR as a proportion of the total number of discrepancies within the treatment arm. 
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Discordance metrics are calculated for each treatment arm and, for each metric, the 
difference in discordance between the experimental and control arms is used to evaluate 
potential bias.  If the discordance is similar across the treatment arms then this suggests the 
absence of evaluation bias favoring a particular treatment arm. A negative differential 
discordance for EDR and/or a positive differential discordance for LDR may be indicative of 
investigator evaluation bias in favor of the experimental arm (Amit et al, 2011).
Exploratory analyses to investigate the impact of potential prognostic or effect 
modifying (predictive) factors
See subgroups as defined in Section 6.4.
Multivariable Cox regression analysis will be carried out to assess and adjust the treatment 
effect for relevant baseline factors of potential prognostic impact. A stepwise selection 
procedure will serve to identify explanatory variables of potential prognostic values 
additional to the randomization strata which will be included in all models during the 
selection procedure. The Cox's Proportional Hazard model is defined as: 
h(t) = h(0;t) eXb
where h(0;t) defines the baseline hazard function and X defines the vector of explanatory 
variables and b the unknown vector of regression parameters. 
In the stepwise selection procedure, variables are entered into and removed from the model 
in such a way that each forward selection step can be followed by one or more backward 
elimination steps. The stepwise selection process terminates if no further variable can be 
added to the model or if the variable just entered into the model is the only variable removed 
in the subsequent backward elimination. The level of significance for an explanatory variable 
to enter the model is set to 0.15 (p-value of Score test) and the significance level for 
removing it is set to 0.40 (p-value of Wald test). This analysis will be performed using the 
stepwise selection method in SAS (Proc PHREG). Once this procedure stops, the factor 
'treatment arm' will be added to the last selected model in order to evaluate the effect of 
treatment on PFS time when adjusted for the selected explanatory variables. The hazard 
ratios of all selected explanatory variables and of treatment effects will be reported including 
2-sided 95% CIs. No interactions will be considered. Post-baseline factors will not be 
considered for the model.
6.2.2.3. Sensitivity analyses for overall survival
The following sensitivity analyses will be performed to explore the robustness of the primary 
analysis results for OS.  These analyses are regarded as purely exploratory. The sensitivity 
analyses will repeat the primary analysis (p-value, HR and 95% CIs) described in Section 
6.2.2.1 with the modifications below:
•
PP analysis set;
•
unstratified;
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•
using strata derived according to eCRF data instead of that entered in IRT (as derived in 
Section 6.2.2.2).
Methods for evaluating the validity of model assumptions
The same methodology described in Section 6.2.2.2 for PFS will be used for OS. 
Exploratory analyses to investigate the impact of potential prognostic or effect 
modifying (predictive) factors
The same methodology described in Section 6.2.2.2 for PFS will be used for OS.
6.2.2.4. Objective response and tumor shrinkage
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the date of randomization 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 patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of randomization and before first 
documentation of PD (and not qualifying for CR or PR).  
•
Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the date of 
randomization and before first documentation of PD (and not qualifying for CR or PR).
•
PD = first documentation of PD ≤ 12 weeks after the date of randomization (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.
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Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-tumor therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set.
ORR by treatment arm will be calculated along with the 2-sided 95% CI using the Clopper-
Pearson method (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 patients with a confirmed BOR of CR, 
PR, SD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), PD and NE will be tabulated. Patients with confirmed BOR of NE will be 
summarized by reason for having NE status. The following reasons will be used:
•
No baseline assessment 
•
No evidence of disease at baseline
•
No post-baseline assessments due to death
•
No post-baseline assessments due to other reasons 
•
All post-baseline assessments have overall response NE
•
New anti-cancer therapy started before first post-baseline assessment
•
SD of insufficient duration (<6 weeks after the date of randomization)
•
PD too late (>12 weeks after the date of randomization)
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).
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:
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•
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 arm. These 
plots will display the best percentage change from baseline in the sum of the diameter of all 
target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment.
6.2.2.5. Disease control
Disease Control (DC) is defined as BOR of CR, PR, non-CR/non-PD or SD.   DC rate (DCR) 
is the proportion of patients with DC.   
DCR will be summarized by frequency counts and percentages.
6.2.2.6. Duration of response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are as described for PFS 
in Table 9.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median DR time with 2-sided 95% CIs.  
In particular, the DR rate at 6, 12, 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 and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.
6.2.2.7. Maintenance PFS by BICR assessment
Maintenance PFS by BICR is defined, for patients who proceed to maintenance phase and 
who do not have PD by BICR during the chemotherapy phase, as the time from Cycle 1 Day 
1 of the maintenance phase to the date of the first documentation of PD by BICR or death 
due to any cause, whichever occurs first. Patients who are censored for the PFS analysis by 
BICR during the chemotherapy phase for reasons other than ‘ongoing without an event’, are 
excluded from this analysis.
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Maintenance PFS data will be censored on the date of the last adequate tumor assessment for 
patients who do not have an event (PD or death), for patients who start new anti-cancer 
treatment prior to an event, or for patients with an event after 2 or more missing tumor 
assessments during the maintenance phase. Patients who do not have an adequate tumor 
assessment after the initiation of the maintenance phase will be censored on Cycle 1 Day 1 of 
the maintenance phase, with a duration of 1 day, unless death occurred on or before the time 
of the second planned tumor assessment in the maintenance phase (ie, ≤ 24 weeks after Cycle 
1 Day 1 of the maintenance phase) in which case the death will be considered an event.
The censoring and event date options to be considered for the Maintenance PFS analysis are 
presented in Table 13.
     
Maintenance PFS (months) = [date of event or censoring – Cycle 1 Day 1 of the 
maintenance phase +1]/30.4375
Table 13
Outcome and Event Dates for PFS Maintenance Analysis 
Scenario
Date of event/censoring
Outcome
PD or death a
-
After at most one missing or 
inadequate tumor assessments after 
initiation of the maintenance 
phase, OR 
-
≤ 24 weeks after Cycle 1 Day 1 of 
the maintenance phase
Date of PD or death
Event
PD or death 
-
after 2 or more missing or 
inadequate tumor assessments after 
initiation of the maintenance 
phase 
Date of last adequate tumor
assessmentb 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
assessmentb documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
Treatment discontinuation during the 
maintenance phase 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 
assessmentb documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a If the patient dies ≤24 weeks after Cycle 1 Day 1 of the maintenance phase the death is an event with date on 
death date irrespective of initiation of new anti-cancer therapy.
b If there are no adequate assessments after the initiation of the maintenance phase prior to PD or death, then the 
time without adequate assessment should be measured from the date of Cycle 1 Day 1 of the maintenance 
phase; if the criteria were met the censoring will be on the date of Cycle 1 Day 1 of the maintenance phase.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median Maintenance PFS time with 2-
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sided 95% CIs.  In particular, the Maintenance PFS rate at 3, 6, 9, 12, 24, 36, 48 and 60 
months (from Cycle 1 Day 1 of the maintenance phase) will be estimated with corresponding 
2-sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley and the CIs for the survival function estimates at the time points defined above will 
be derived using the log-log transformation according to Kalbfleisch and Prentice
(conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI 
on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to Table 14 following the hierarchy shown. 
Table 14
Maintenance PFS 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 tumor 
assessments after initiation of  the maintenance phase /date 
of Cycle 1 Day 1 of the maintenance phase
Event after 2 or more missing 
assessments a
3 
No event and [withdrawal of consent date ≥ date of Cycle 1 
Day 1 of the maintenance phase OR End of study (EOS) 
after initiation of  the maintenance phase and reason = 
Subject refused further follow-up] 
Withdrawal of consent
4
No event and lost to follow-up in any disposition page after 
initiation of  the maintenance phase
Lost to follow-up
5
No event and [EOS present after initiation of the 
maintenance phase OR disposition page for any epoch after 
initiation of  the maintenance phase says patient will not 
continue into any subsequent phase of the study] and no 
adequate tumor assessment after initiation of the 
maintenance phase 
No adequate tumor assessment 
after initiation of  the maintenance 
phase
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 tumor assessments after initiation of maintenance phase 
The Maintenance PFS time or censoring time and the reasons for censoring will also be 
presented in a patient listing.
6.2.2.8. Maintenance PFS by investigator assessment
Maintenance PFS by Investigator is defined, for patients who proceed to maintenance phase 
and who do not have PD by Investigator assessment during the chemotherapy phase, as the 
time from Cycle 1 Day 1 of the maintenance phase to the date of the first documentation of 
PD by investigator or death due to any cause, whichever occurs first. Patients who are 
censored for the PFS analysis by Investigator during the chemotherapy phase for reasons 
other than ‘ongoing without an event’, are excluded from this analysis.
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The same analysis described in Section 6.2.2.7 for Maintenance PFS by BICR assessment 
will be used for Maintenance PFS by Investigator assessment.
6.2.2.9. PFS2
PFS2 is defined as time from the date of randomization to the start of second subsequent 
treatment after first PD by Investigator assessment, or death from any cause, whichever 
occurs first.  
PFS2 (months) = [date of event or censoring – date of randomization +1]/30.4375
A patient will be considered to have an event if 
1) the patient had objective PD on or prior to start of next-line anti-cancer treatment, AND 
started a second subsequent anti-cancer treatment
OR
2) the patient died.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS2 time with 2-sided 95% 
CIs.  In particular, the PFS2 rate at 12, 24, 36, 48, 60 and 80 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley and the CIs for the survival function estimates at the time points 
defined above will be derived using the log-log transformation according to Kalbfleisch and 
Prentice (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.
The censoring and event date options to be considered for PFS2, each corresponding 
censoring reason and its hierarchy are presented in Table 15. Frequency (number and 
percentage) of patients with an event (second subsequent anti-cancer treatment or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to Table 15 following the hierarchy shown.
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Table 15
Outcome, Event Dates, Censoring Reasons and Hierarchy for PFS2
Analyses 
Scenario
Date of event/ censoring
Outcome/
Censoring reason/
Censoring hierarchy
(No PDa) and (no death)
Date of last adequate tumor 
assessmentb documenting no 
PD
Censored/
No PD/
1
(No PDa) and death 
Date of death
Event (Death)
(PDa date > NTX1c start date) and (no death)
Start date of NTX1c
Censored/
Start of new anti-cancer 
treatment before PD/
2
(PDa date > NTX1c start date) and death
Date of death
Event (Death)
(PDa date ≤NTX1c start date) and (no death)
•
If NTX2d start date is non-missing
Start date of NTX2d
Event (Start of second 
subsequent anti-cancer 
treatment)
•
Else if [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = 
Subject refused further follow-up]
(Withdrawal of consent
date) or (EOS visit date 
where subject refusal of 
further follow-up is 
recorded)
Censored/
Withdrawal of consent/
3
•
Else if [lost to follow-up in any disposition 
page]
Last contact date
Censored/
Lost to follow-up/
4
•
Else if no prior conditions are met
Last contact date
Censored/
Ongoing without PFS2 
event/
5
(PDa and no NTX1c) and (no death)
Last contact date
Censored/
Ongoing without PFS2 
event/
6
(PDa date ≤NTX1c start date) and death
•
If NTX2d start date is non-missing
Start date of NTX2d
Event (Start of second 
subsequent anti-cancer 
treatment)
•
Else if the prior condition is not met
Date of death
Event (Death)
a PD is the first PD by investigator assessment per RECIST v1.1, without considering any censoring rules.
b If there are no adequate post-baseline assessments, then the censoring date is the date of randomization. If 
patient has initiated next-line anti-cancer treatment, the last adequate post-baseline assessment on or prior to start 
date of next-line anti-cancer treatment will be considered.
c NTX1 is the first new anti-cancer treatment.
d NTX2 is the second new anti-cancer treatment.
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The PFS2 time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
6.2.2.10. PFS by GCIG criteria based on investigator assessment
PFS from the date of randomization by GCIG criteria will be assessed in this study 
incorporating both RECIST v1.1 and CA-125 (Rustin, G et.al.) (see Appendix 6 of the 
protocol) based on Investigator assessment.
PFS by GCIG criteria will be censored if both PFS per RECIST v1.1 and PFS per CA-125 
are censored, the date of censoring will be the latest of the two censoring dates.
CA-125 data will be censored on the date of the last CA-125 assessment for patients who 
start new anti-cancer therapy prior to an event, or for patients with an event after 2 or more 
missing CA-125 assessments. Patients who do not have an adequate baseline CA-125 
assessment or who do not have an adequate post-baseline CA-125 assessment will be 
censored on the day of randomization with a duration of 1 day. 
PFS by GCIG criteria (months) = [date of event or censoring – date of randomization 
+1]/30.4375
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS by GCIG criteria time with 
2-sided 95% CIs.  In particular, the PFS by GCIG criteria rate at 9 and 18 weeks and at 8, 12, 
18, 24, 30, 36, 42, 48, 54 and 60 months will be estimated with corresponding 2-sided 95% 
CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley and 
the CIs for the survival function estimates at the time points defined above will be derived
using the log-log transformation according to Kalbfleisch and Prentice (conftype=loglog 
default option in SAS Proc LIFETEST) with back transformation to a CI on the 
untransformed scale. The estimate of the standard error will be computed using Greenwood’s
formula.
Frequency (number and percentage) of patients with each event type (PD by Investigator 
assessment per RECIST v1.1 or PD by CA-125 or death) and censoring reasons will be 
presented by treatment arm. Reasons for censoring will be summarized according to the 
hierarchy shown in Table 16.
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Table 16
Censoring Reasons and Hierarchy for PFS by GCIG Criteria Based on 
Investigator Assessment
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment per RECIST v1.1 and no 
adequate CA-125 baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy 
Start of new anti-cancer therapy
3 
Event by Investigator assessment per RECIST v1.1 after 2 
or more missing or inadequate post-baseline tumor 
assessments/date of randomization
Event per RECIST v1.1 after 2 or 
more missing assessments a
4
Event per CA-125 after 2 or more (ie, > 12 weeks) missing 
post-baseline assessments 
Event per CA-125 after 2 or more 
missing assessments
5
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Subject refused 
further follow-up] 
Withdrawal of consent
6
No event and lost to follow-up in any disposition page 
Lost to follow-up
7 
No event and [EOS present OR disposition page for any
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment and no post-baseline CA-125 
assessment
No adequate post-baseline tumor 
assessment and no adequate post-
baseline CA-125 assessment
8
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments
The PFS by GCIG criteria time or censoring time and the reasons for censoring will also be 
presented in a patient listing.
6.2.2.11. pCR
pCR is defined for neoadjuvant patients who undergo IDS (see Section 5.2.11) as the 
Chemotherapy Response Score 3 (CSR3) according to (Bohm et. al., 2015) (see Appendix 5 
of the protocol).
pCR by treatment arm will be calculated along with the 2-sided 95% CI using the Clopper-
Pearson method (exact CI for a binomial proportion as computed by default by the FREQ 
procedure using the EXACT option). 
6.2.3. Pharmacokinetic endpoints
The central laboratory, analytical laboratories (eg, PK, ADA, NAb), and Pfizer clinical assay 
group (CAG) colleagues will be unblinded.  If the need arises for early analysis of the PK 
data (before database lock and release of the randomization codes for the study), a PK 
unblinding plan will be developed.  A PK analyst, who is not associated with the study team, 
will conduct the analysis to avoid unblinding of the study team.
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
arm as well as by paclitaxel regimen (weekly vs 3-weekly).  
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Ctrough and Cmax for avelumab will be summarized descriptively. Pharmacokinetic parameters 
for avelumab will be taken from observed plasma concentration-time data as described in 
Section 3.2.4.
Standard plasma PK parameters for carboplatin (total and free) and paclitaxel will be 
estimated using non compartmental and/or compartment methods, if needed. Analysis will 
include Cmax, Tmax, AUCtau, t½, CL, and Vd as data permit. Dose-normalized parameters (eg, 
DN-Cmax, DN-AUC) will be reported as appropriate.
Presentation of pharmacokinetic data will include:
•
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of plasma 
concentrations will be presented in tabular form by treatment arm, dose level (for 
paclitaxel and carboplatin as needed), cycle, day and nominal time. Additionally similar 
descriptive statistics will also be generated for dose-normalized avelumab, paclitaxel and 
carboplatin pharmacokinetic parameters as appropriate.
•
Linear-linear and log-linear plots of mean and median plasma concentrations by nominal 
time for avelumab, paclitaxel and carboplatin (total and free) will be presented for PK 
sampling days by treatment arm, cycle, and day. Similar plots will be presented for each 
individual patient concentrations. Patients who have undergone intrapatient dose 
reduction or escalation will be excluded from the median plasma concentration-time 
plots.
•
Pharmacokinetic parameters for avelumab, paclitaxel and carboplatin (total and free) will 
be listed and summarized by treatment arm/dose level (for paclitaxel and carboplatin as 
needed), cycle and day using descriptive statistics (n, mean, SD, %CV, median, 
minimum, maximum, geometric mean and its associated %CV, and 95% CI). For Tmax, 
the range (min, max) will also be provided. PK parameters with zero values will be 
excluded from the calculation of geometric means and its associated %CV. If an 
intrapatient dose escalation or reduction occurs, dose-dependent PK parameters (AUC 
and Cmax) for that patient may be dose-normalized when it is known that the drug exhibits 
linear PK within the dose range and other PK parameters will be reported as estimated; or 
may only be included in descriptive statistics and summary plots up to the time of the 
dose change. In addition, dose-normalized Cmax and AUC parameters will be summarized 
(as described above) using data pooled across treatment arms in which different 
avelumab, paclitaxel and carboplatin doses were administered.
•
Box plots for AUC and Cmax for paclitaxel and carboplatin (total and free) and Cmax and 
Ctrough for avelumab will be generated. 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 
arm has limited evaluable PK data (n<4), matchstick plots showing changes in AUC and 
Cmax for each drug in individual patients will then be generated. The geometric mean of 
the parameter in each treatment will be overlaid in the plots.
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•
Ctrough and Cmax for avelumab will be plotted for each treatment arm using a box-
whisker plot by cycle and day within cycle in order to assess the attainment of steady-
state.
Assessment of drug-drug interaction
•
Effect of Avelumab on paclitaxel and carboplatin Pharmacokinetics:
The effect of avelumab dosing on paclitaxel and carboplatin PK will be evaluated based on 
overall assessment of the geometric mean ratios and associated 90% CI for Cmax, AUCinf, and 
AUCtau of paclitaxel and carboplatin on Day 1 of Cycle 2 in Arm C compared to those on 
Day 1 of Cycle 2 of Arm A and B. 
•
Effect of paclitaxel and carboplatin on Avelumab Pharmacokinetics:
The effect of paclitaxel and carboplatin dosing on avelumab PK will be evaluated based on 
the overall assessment of the geometric mean ratios and associated 90% CI of Cmax and 
Ctrough of Arm C on Day 1 of Cycle 2 of the chemotherapy phase compared to those on Day
1 of the first maintenance cycle of Arms C
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 exposure and biomarkers or significant safety/efficacy 
endpoints. The results of these analyses, if performed, may be reported separately.
6.2.5. Biomarker endpoints
Secondary endpoints in the study are candidate predictive biomarkers in tumor tissue 
including, but not limited to, PD-L1 expression and tumor infiltrating CD8+ T lymphocytes 
as assessed by immunohistochemistry (IHC).
Biomarker data will be analyzed based on the biomarker analysis sets as defined in Section 
4.3.3, by treatment arm.  
If a patient has more than one result at a visit for a specific biomarker analyte, then:
•
For continuous data, the duplicate results will be averaged, and the average used in the 
analysis;
•
For non-continuous data (eg, identified genes), the study team will select the record 
appropriate for analysis.  A flag will be added to the data sets indicating which record 
was selected for analysis.  
For PD-L1 expression, patients will be classified as positive and negative according to 
scoring algorithms and cut-offs established from internal or external sources. Patients whose 
status cannot be determined are not considered to have screening biomarker assessment per 
the biomarker analysis set definition, and therefore will be excluded.   
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For CD8+, if at the time of reporting an internal or external standard becomes available, the 
above mentioned approach for PD-L1 will be used. Otherwise, data will be categorized using 
quartiles to define CD8+ subgroups. 
The following analyses will be performed for each biomarker secondary endpoint.
Biomarker subgroups as defined above will be used to perform subgroup analyses for 
efficacy endpoints (PFS by BICR assessment, OS) using the methodology outlined in Section 
6.4.  In addition, the hazard ratio for the biomarker subgroup level comparisons and the 
unadjusted 95% CIs for the hazard ratio will be reported for each treatment arm. 
 
 
 
 
CA-125 levels.
6.2.6. Immunogenicity endpoints 
All analyses described below are performed by treatment arm containing avelumab (Arm B
and Arm C), and for the avelumab-containing treatment arms combined unless otherwise 
specified. 
Blood samples for avelumab immunogenicity testing will be collected pre-dose and within 2 
hours before the start of the avelumab infusion. For Arm C during the chemotherapy phase, it 
is collected on Day 1 of Cycles 1 through 4. For Arms B and C during the maintenance 
phase, it is collected on Day 1 and Day 15 of Cycles 1 and 2, and thereafter on Day 1 of each 
subsequent cycle until Cycle 18, at the End of Treatment and at post-treatment safety follow 
up (30 days).  
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.  As of the 
finalization of this SAP, the nAb assay is not yet available, therefore 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.
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 17.  
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Table 17
Patients Characterized Based on Anti-Drug Antibody Results (ADA Status)
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
ADA never-positive 
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint)
Number of patients with at least one 
valid ADA result at any time point
ADA ever-positive 
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint)
Number of patients with at least one 
valid ADA result at any time point
Baseline ADA 
positive
A positive ADA result at baseline
Number of patients with valid baseline 
ADA result
Treatment-boosted 
ADA
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result
Treatment-induced 
ADA
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive past-baseline 
ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Transient ADA 
response
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Persistent ADA 
response
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
ADA: anti-drug antibody, NR = not reportable.
Patients will be characterized into different nAb categories based on the criteria in Table 18. 
For nAb, treatment-boosted is not applicable since no titer result is available.
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Table 18
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
nAb never-positive 
No positive nAb results at any time point
Number of patients with at least one 
valid ADA result at any time point
nAb ever-positive 
At least one positive nAb result at any time 
point
Number of patients with at least one 
valid ADA result at any time point
Baseline nAb 
positive
A positive nAb result at baseline
Number of patients with valid baseline 
ADA result
Treatment-induced 
nAb
Patient is not nAb positive at baseline and  has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive past-
baseline ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
Transient nAb 
response
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive.
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR)
Persistent nAb 
response
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result.
The number and percentage of patients in each ADA and nAb category will be summarized. 
6.2.6.1. Time to and Duration of ADA and nAb response 
The ADA and nAb analyses described below will include patients with treatment-induced 
ADA or nAb, respectively.  
Time (weeks) to ADA response is defined as:
(Date of first positive ADA result – date of first dose of avelumab + 1)/7. 
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).
Duration (weeks) of ADA response is defined as:
(Date of last positive ADA result – date of first positive ADA result + 1)/7. 
Duration of ADA response will be censored if: 
•
the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or
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•
the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (post-treatment 30-day safety follow-up) is after 
the cut-off date.
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result. 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley
(1982) and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2011) (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided
As data permit, the analyses described above will be repeated for patients with treatment-
induced nAb. 
6.2.6.2. ADA titer
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated. The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory. 
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided. The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks. In this categorization, the censoring in duration of ADA response is ignored. 
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity status
The following ADA and nAb status will be used for the analyses described below.
ADA 
•
ADA ever-positive versus ADA never-positive 
•
ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive
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nAb 
•
nAb ever-positive versus nAb never-positive 
•
nAb: treatment-induced nAb versus nAb never-positive or baseline nAb positive
Data listings will include immunogenicity data together with relevant PK, safety and efficacy 
data.
PK parameters and immunogenicity status
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax.  
Blood samples for avelumab PK will be collected within 2 hours prior to and immediately 
before the end of avelumab infusion (1 hour post start of avelumab infusion). For Arm C in 
the chemotherapy phase, it is collected on Day 1 of Cycles 1 to 4.  For patients receiving
weekly paclitaxel only, an additional avelumab sample will be taken on Day 8 and Day 15 of 
Cycles 1 to 4 prior to the paclitaxel infusion. For Arms B and C in the maintenance phase, it 
will be collected on Days 1, 15 and 29 of Cycle 1, and thereafter on Day 1 of every 
subsequent cycle until Cycle 18, at the End of Treatment and at post-treatment safety follow 
up (30 days).
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 patients 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, patients must have the same PK parameter available both before 
and after the first positive ADA assessment.  Relative PK day will be calculated as:
(PK assessment nominal day) – (first positive ADA assessment nominal day).
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is 
collected on Day 1 of Cycle 2 in the chemotherapy phase and the first positive ADA result is 
observed on Day 1 of Cycle 3 in the chemotherapy phase, then the relative PK day for this 
Ctrough is -21. 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 patients in the immunogenicity analysis set.
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The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status.
•
TEAEs, by SOC and PT 
•
TEAEs leading to dose reduction of avelumab, by SOC and PT
•
TEAEs leading to discontinuation of avelumab, by SOC and PT
•
TEAEs leading to discontinuation of study treatment by SOC and PT
•
Grade ≥ 3 TEAEs, by SOC and PT
•
SAEs, by SOC and PT
•
IRRs, by PT
For patients who had at least one IRR and have treatment-induced ADA, time related to first 
onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later) will be summarized 
taking into account whether the  IRR occurred on or after the first ADA positive assessment 
or whether the IRR occurred before the first ADA positive assessment.  
As data permit, the analyses described above will be repeated for nAb.
Efficacy and immunogenicity status
For the ADA ever-positive patients, a listing will be prepared with patient ID, start and stop 
of avelumab treatment, date of first positive ADA result, time to ADA response, duration of 
ADA response, date of last ADA positive result, BOR, DR, PFS time or censoring time and 
reason for censoring, and OS time or censoring time and reason for censoring.   If applicable, 
date of first positive nAb result, time to nAb response, duration of nAb response, date of last 
nAb positive result will also be presented.  Tumor-related endpoints will be presented based 
on BICR assessment and based on Investigator assessment. 
For the ADA ever-positive patients, the percent change from baseline in target lesions as well 
as the first occurrence of a new lesion and patient off avelumab treatment will be displayed 
against time point (weeks) in a line plot. Additional symbols will indicate the first and last 
ADA positive result and, if applicable, the first and last nAb positive result. Plot will be 
presented separately based on BICR assessment and based on Investigator assessment.
6.2.7. PRO endpoints
All PRO analysis will be based on FAS and will include all the assessments per schedule of 
assessment from baseline to the last PRO assessment, unless otherwise specified.  For time-
to-event and continuous endpoints, an analysis including assessments from baseline up to 
EOT (not including EOT) will also be conducted.
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Patient reported outcomes of HRQoL, ovarian cancer symptoms, treatment side effects, 
functioning and time to deterioration will be evaluated by FOSI-18 (Jensen 2015) and health 
status using EuroQol 5 Dimension (EQ-5D-5L) (Herdman 2011; Janssen 2013).
The primary PRO analysis is designed to determine the effect of Arm C or Arm B compared 
to Arm A on overall HRQoL, based on the FOSI-18 total score over the course of the study 
from baseline up to EOT (not including EOT).
6.2.7.1. Scoring procedure
The FOSI-18 and EQ-5D-5L will be scored according to their respective validation papers 
and user’s guides (FACIT 2008; EuroQoL Group 2015). For the EQ-5D-5L, the index scores 
will be calculated using the published weights (tariffs) for the United Kingdom (UK). 
Specific country weights may be applied for country specific analyses as needed.  
6.2.7.2. Instrument completing rates
For each treatment arm and at each time point, the number and percentage of patients who 
complete the FOSI-18 and EQ-5D-5L will be summarized, as will the reasons for non-
completion of these measures.  An instrument is considered complete if at least one item was 
answered by the patient. 
6.2.7.3. Descriptive summaries over time  
Absolute scores and change from baseline for the total, all subscales and the single item “I 
am bothered by side effects of treatment” of the FOSI-18, the EQ-5D-5L, and EQ-VAS will 
be summarized (as described in Section 5.2.3) at each time point by treatment arm.  Line 
charts depicting the means and mean changes from baseline along with SE error bars over 
time will be provided for each scale by treatment arm.  
For the EQ-5D-5L health status, the proportions of patients reported having “none”, “slight”, 
“moderate”, “severe”, or “extreme/unable” problems at each time point will be calculated, by 
treatment arm.
6.2.7.4. Time-to-event endpoints
Time to treatment bother in the maintenance phase
Time to Treatment Bother (TTB) will be evaluated in the maintenance phase. TTB is 
comprised of a single question within the TSE subscale, “I am bothered by side effects of 
treatment”.  TTB in the maintenance phase is defined, for patients who proceed to the 
maintenance phase and who do not have PD by BICR during the chemotherapy phase, as the 
time from Cycle 1 Day 1 of the maintenance phase to the date of first report of a score of ≥ 2 
for at least two consecutive assessments on the side effect bother item. 
Patients will be censored at the time when they last completed the TSE sub-scale assessment 
if they have not reported a TTB score of ≥ 2 for at least two consecutive assessments. 
Additionally patients missing at least 2 consecutive assessments will be censored on the date 
of the last non-missing assessment. 
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TTB (months) = [date of event or censoring – Cycle 1 Day 1 of the maintenance 
phase +1]/30.4375
The analysis will compare the TTB time between each of the experimental arms and the 
control arm, and will be performed using a 1-sided stratified log-rank.  
The treatment effect, as measured by the hazard ratio, will be estimated using a Cox’s 
Proportional Hazard model stratified by the randomization strata. Each stratum will define a 
separate baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie, 
for the i-th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 
(0=control arm, 1= experimental arm) and β is the unknown regression parameter.
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG).
The unadjusted 95% CIs for the hazard ratio will be reported.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median TTB time with 2-sided 95% 
CIs.  In particular, the TTB rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54 and 
60 months will be estimated with corresponding 2-sided 95% CIs.  The CIs for the median 
will be calculated according to Brookmeyer and Crowley and the CIs for the survival 
function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (conftype=loglog default option in 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.
Time to deterioration of physical disease-related symptoms 
The FOSI DRS-P subscale will also be used to determine the Time to Deterioration (TTD) of 
disease-related symptoms. TTD is defined as the time from the randomization date to the first 
time the patient’s score shows a 3-point or higher decrease in the FOSI DRS-P score.
Patients will be censored at the time when they last completed a sub-scale assessment if they 
have not deteriorated. Yost & Eton established that a 3-point or a greater difference on a 
FACT scale of this length (9 items for FOSI DRS-P subscale) constitutes a meaningful 
difference in disease symptoms (Yost, 2005). 
The analysis will compare the TTD time between each of the experimental arms and the 
control arm, and will be performed using a 1-sided stratified log-rank.  
The treatment effect, as measured by the hazard ratio, will be estimated using a Cox’s 
Proportional Hazard model stratified by the randomization strata. Each stratum will define a 
separate baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie, 
for the i-th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 
(0=control arm, 1= experimental arm) and β is the unknown regression parameter.
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Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG).
The unadjusted 95% CIs for the hazard ratio will be reported.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median TTD time with 2-sided 95% 
CIs.  In particular, the TTD rate at 9 and 18 weeks and at 8, 12, 18, 24, 30, 36, 42, 48, 54 and 
60 months will be estimated with corresponding 2-sided 95% CIs.  The CIs for the median 
will be calculated according to Brookmeyer and Crowley and the CIs for the survival 
function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (conftype=loglog default option in 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.
6.2.7.5. Continuous endpoints
Mixed-effects longitudinal modeling will be carried out for the total, subscale (DRS-P, DRS-
E, TSE, FWB) and the single item “treatment bothered” scores of the FOSI-18 and also the 
EQ-5D-5L and EQ-VAS scores, and will compare each of the experimental arms with the 
control arm using PROC MIXED.  Outcomes are PRO post-baseline scores and the 
predictors are the corresponding baseline PRO score, treatment, time (treated as a continuous 
variable), and treatment-by-time interaction. Intercept and time are considered as random 
effects particular to each subject. All parameter estimates should be obtained using restricted 
maximum likelihood. The unstructured covariance structure should be used to define 
covariance between random effects (using option “Type=UN” as a part of the 
RANDOM statement in PROC MIXED). For the degrees-of-freedom calculations the 
Kenward and Roger algorithm should be used (using option “ddfm = kr” as a part of the 
MODEL statement in PROC MIXED). The primary analysis will be applied to all cycles, 
chemotherapy and maintenance phases, prior to EOT to determine if overall HRQoL, 
symptoms, treatment side effect, and functioning,  have been impacted over the course of the 
study for the comparisons Arm C vs Arm A and Arm B vs Arm A.  
 
 
   
 
 
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6.4. Subset Analyses
Subset analyses will be performed for PFS per BICR assessment and OS based on the FAS 
for the subgroups defined below. 
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The following subgroups will be defined and used for analyses:
•
Randomization stratification factors as per IRT
- paclitaxel regimen (Q3W (Reference) vs QW)
- adjuvant (complete resection/microscopic disease (Reference)) vs adjuvant 
(incomplete resection ≤1 cm) vs adjuvant (incomplete resection >1 cm) vs 
neoadjuvant.
•
Age 
-
Age < 65 years (Reference)
-
Age ≥ 65 years 
•
Race
-
Caucasian / White (Reference)
-
Asian
-
Black/African American
-
Other
•
Ethnicity
-
Hispanic/Latino 
-
Non-Hispanic/Latino (Reference)
•
Pooled Geographical Region 
-
North America 
-
Europe (Reference)
-
Asia
-
Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional subgroups if including > 10% of the overall randomized 
population)
•
BRCA 1/2 mutation status
-
Positive (Reference)
-
Negative
-
Unknown
•
Stage
- III (Reference)
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- IV
•
ECOG Performance Status on or prior to randomization date
- 0 (Reference)
- ≥1
•
CA-125 at baseline
-
≤2xULN (Reference)
-
>2xULN
•
PD-L1 status at baseline
-
Positive (Reference)
-
Negative
The cut-off will be pre-specified using external data before the analysis. 
Subset analyses for PFS and OS will use the primary censoring rules described in Sections 
6.1.1.1 and 6.2.2.1. All the subgroup analyses are exploratory. Treatment arms will be 
compared for PFS and OS using a 2-sided unstratified log rank test for each subgroup level 
and the unstratified HR and its corresponding 95% CI will be computed per subgroup level. 
All the subgroup analyses will be exploratory; no adjustment for multiplicity will be 
performed.  In the case of a low number of patients within a category (<5% of the 
randomized population), the categories will be pooled.
To assess the heterogeneity of treatment effects for PFS and OS across the subgroup levels, 
two Cox regression model will be fitted with PFS or OS, respectively, as the dependent 
variable and subgroup, treatment, and with and without the treatment-by-subgroup
interaction as explanatory variables. 
•
Model 1: factors + treatment + subgroup
•
Model 2: factors + treatment + subgroup + treatment × subgroup-variable 
A p-value for the interaction test (Likelihood Ratio test) will be provided together with the 
HR and corresponding 95% CI for the interaction model parameter. 
The HR for PFS and OS and corresponding 95% CIs for all subgroups will also be presented 
in a forest plot.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline summaries
The following analyses will be based on the FAS overall and separately by treatment arm.
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6.5.1.1. Demographic characteristics
Demographic characteristics and physical measurements will be summarized by treatment 
arm using the following information from the ‘Screening/Baseline Visit’ eCRF pages.
•
Demographic characteristics 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Unknown
-
Ethnic origin: Hispanic/Latino (Yes/No)
-
Age (years): summary statistics 
-
Age categories:

< 65 years, ≥ 65 years 

< 65, 65-<75, 75-<85, ≥ 85 years
-
Pooled Geographical Region (as applicable): 

North America 

Europe

Asia

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the 
overall randomized population)
-
Geographic Region (as applicable):

North America

Latin America

Western Europe

Eastern Europe

Middle East

Australasia

Asia

Africa
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4 
•
Physical measurements
-
Height (cm)
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-
Weight (kg)
-
Body Mass Index (BMI) (kg/m2)
-
Body Surface Area (BSA) (m²)
Center codes will be used for the determination of the patient’s geographic region.
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment arm, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), BSA (m²) and ECOG performance status.
6.5.1.2. Medical history
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.
6.5.1.3. Disease characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Abuse’
and RECIST eCRF pages will be summarized overall and by treatment arm. Summary 
statistics will be presented for the following.
From the ‘Primary Diagnosis’ eCRF page:
•
Site of primary tumor
•
Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page)
•
Time since initial diagnosis to date of randomization (months), defined as (date of 
randomization – date of initial diagnosis)/30.4375
•
Time since histopathological diagnosis (months), defined as (date of randomization –date 
of histopathological diagnosis )/30.4375
Separately from the RECIST eCRF page based on Investigator assessment and based on 
BICR assessment:
•
Measurable disease (lesions) at baseline (Yes, No, No disease)
•
Involved tumor sites at baseline
From the ‘Substance Use’ eCRF page:
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•
Smoking history
-
Never smoker vs current vs former smoker 
-
Smoking exposure (pack-years): 0, <20, 20-<40, ≥40 and summary statistics
-
Years since quitting: never smoker, current smoker, <5, 5-<10, ≥10 and summary 
statistics
Specifications for computation:
•
Cigarette equivalents are calculated as follows: one cigar is regarded equivalent to 5 
cigarettes and 1 pipe is regarded equivalent to 3 cigarettes
•
Duration of nicotine consumption [years]:
(end of nicotine consumption – start of nicotine consumption + 1) / 365.25
•
Pack-years:
-
calculate cigarette equivalents per day using the conversion factors given above
-
convert to packs per day where 20 cigarettes are regarded as 1 pack
-
pack-years = packs per day × duration of nicotine consumption [years]
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ and ‘Substance Use’ eCRF pages) and derived variables as above.
6.5.1.4. Prior anti-cancer surgery 
The prior anti-cancer surgeries are collected under the ‘Prior Surgery’ eCRF page.
The number and percentage of patients with at least one prior anti-cancer surgery will be 
tabulated. Treatment intent and surgery outcome will also be summarized.
Prior anti-cancer therapies will be included in the listings that follow with a flag to identify 
prior therapies. 
•
Listing of anti-cancer drug therapies 
•
Listing of anti-cancer radiotherapy 
•
Listing of anti-cancer surgeries
These will include the patient identification number, and all the relevant collected data-fields 
on the corresponding eCRF pages.
6.5.2. Study conduct and patient disposition
The following analyses will be performed based on the FAS overall and separately by
treatment arm.
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6.5.2.1. Patient disposition
The percentages below will be calculated based on the number of patients in the FAS.
•
Total number of patients screened overall
•
Number of patients who discontinued from the study prior to randomization overall and 
by the main reason for discontinuation
•
Number and percentage of randomized patients in each of the analysis sets defined in 
Section 4
•
Number and percentage of randomized patients with study drug ongoing (separately for 
each study drug when administered in combination)
•
Number and percentage of randomized patients who discontinued study drug overall and 
by the main reason for discontinuation of study drug (separately for each study drug 
when administered in combination)
•
Number and percentage of patients who entered follow-up
•
Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation
•
Number and percentage of patients who entered long-term follow-up
•
Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation.
In addition, a summary of patients who have discontinued all study drugs will be provided. 
The results of the randomization algorithm (according to IRT) will be summarized as 
follows:
•
Number and percentage of randomized patients overall, by region (Europe, EEA 
(required by EudraCT), North America, Latin America, Middle East, Asia, Australasia, 
Africa), by country within region 
•
Number and percentage of randomized patients by center
•
Number and percentage of randomized patients by randomization strata (IRT)
•
Number and percentage of randomized patients by randomization strata (eCRF)
•
Cross tabulation: stratum by IRT vs. stratum by eCRF
•
Cross tabulation: patients randomized (Arm A/Arm B/Arm C) vs. patients treated (Arm 
A/Arm B/Arm C/none)
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6.5.2.2. Protocol deviations
All protocol violations that impact the safety of the patients and/or the conduct of a study 
and/or its evaluation will be reported. These include:
•
Patients who are dosed on the study despite not satisfying the inclusion criteria
•
Patients who develop withdrawal criteria whilst on the study but are not withdrawn
•
Patients who receive the wrong treatment or an incorrect dose
•
Patients who receive an excluded concomitant medication
•
Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study treatment compliance and exposure
The following analyses will be based on the safety analysis set by treatment arm.
All dosing calculations and summaries will be based on ‘Parenteral – Drug avelumab’ 
‘Parenteral – Drug paclitaxel’, and ‘Parenteral – Drug carboplatin’ eCRFs pages. A listing of 
study drug administration will be created with the information collected on the ‘Parenteral –
Drug avelumab’, ‘Parenteral – Drug paclitaxel’, or ‘Parenteral – Drug carboplatin’ eCRF 
pages. 
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.
For Cycle X, actual cycle start date for each patient is
•
the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the
patient received study treatment on that visit (ie, any study drug with dose>0 at that visit)
•
the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 
•
for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day;
•
for the last cycle, 
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o
actual cycle end date = actual cycle start date +  21 days – 1 day if the last 
cycle occurred in the chemotherapy phase; 
o
actual cycle end date = actual cycle start date +  42 days – 1 day if the last 
cycle occurred in the chemotherapy phase
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.
Exposure may be summarized (per cycle and overall within a study phase) as dose received 
(cumulative dose, actual dose intensity) and as dose received relative to intended dose 
(relative dose intensity [RDI]). 
The formulae below should be applied to each study drug separately.
The derivations below are provided for the following.
In the chemotherapy phase
•
Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg once every 3
weeks in 3-week cycles for 6 cycles
•
Paclitaxel QW administered as 80 mg/m2 IV over 1 hour on Days 1, 8 and 15 of each 
3-week cycle for 6 cycles
•
Paclitaxel Q3W administered as 175 mg/m2 IV over 3 hours Day 1 of each 3-week cycle 
for 6 cycles
•
Carboplatin dose AUC 5 or AUC 6 IV over 1 hour on Day 1 of each 3-week cycle for 
6 cycles
In the maintenance phase
•
Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg once every 2 
weeks in 6-week cycles. 
Analysis of exposure will be based on the calculated actual dose levels:
•
Avelumab - total dose / weight 
•
Paclitaxel – total dose / m2
•
Carboplatin - AUC.
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6.5.3.1. Exposure to avelumab 
The dose level for avelumab is calculated as actual dose administered/weight (mg/kg). The 
last available weight of the patient on or prior to the day of dosing will be used.
Chemotherapy phase
Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle in chemotherapy phase with non-zero dose of study 
drug + 21 – 1
Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab in chemotherapy phase – first dose date of avelumab + 
21)/7
Cumulative dose in a cycle or overall is the sum of the actual doses of avelumab received in a 
cycle or overall (in the chemotherapy phase), respectively
Actual Dose Intensity (DI) 
•
By cycle actual DI (mg/kg/3-week cycle) = [cumulative dose in the cycle (mg/kg)]/[cycle 
duration (weeks)/3]
•
Overall actual DI (mg/kg/3-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/3].
Relative Dose Intensity (RDI)  
•
Intended DI (mg/kg/3-week cycle) = 10 (mg/kg/3-week cycle)
•
By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [10 (mg/kg/3-week cycle)]  
•
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [10 (mg/kg/3-week cycle)]
Maintenance phase
Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of avelumab in maintenance phase +1)/7, 
where end date = start date of last cycle in maintenance phase with non-zero dose of 
avelumab + 42 – 1
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Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab in maintenance phase – first dose date of avelumab in 
maintenance phase + 14)/7
Cumulative dose in a cycle or overall is the sum of the actual doses of avelumab received in a 
cycle or overall (in the maintenance phase), respectively
Actual Dose Intensity (DI) 
•
By cycle actual DI (mg/kg/6-week cycle) = [cumulative dose in the cycle (mg/kg)]/[cycle 
duration (weeks)/6]
•
Overall actual DI (mg/kg/6-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/6].
Relative Dose Intensity (RDI)  
•
Intended DI (mg/kg/6-week cycle) = 30 (mg/kg/6-week cycle)
•
By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [30 (mg/kg/6-week cycle)]  
•
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [30 (mg/kg/6-week cycle)]
6.5.3.2. Exposure to paclitaxel QW
The dose level for paclitaxel QW is calculated as actual dose administered/m2 (mg/m2). The 
actual paclitaxel regimen (QW vs Q3W) is determined using the Cycle 1 Day 1 paclitaxel 
dose regimen.  
Intended duration of treatment with paclitaxel QW (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle in chemotherapy phase with non-zero dose of study 
drug + 21 – 1
Duration of exposure to paclitaxel (weeks) = 
(last dose date of paclitaxel – first dose date of paclitaxel + 7)/7
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Actual Dose Intensity (DI) 
•
By cycle actual DI (mg/m2/3-week cycle) = [cumulative dose in the cycle 
(mg/m2)]/[cycle duration (weeks)/3]
•
Overall actual DI (mg/m2/3-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with paclitaxel (weeks)/3].
Relative Dose Intensity (RDI)  
•
Intended DI (mg/m2/3-week cycle) = 240 (mg/m2/3-week cycle)
•
By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [240 (mg/m2/3-week cycle)]  
•
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [240 (mg/m2/3-week cycle)]
6.5.3.3. Exposure to paclitaxel Q3W
The dose level for paclitaxel Q3W is calculated as actual dose administered/m2 (mg/m2). The 
actual paclitaxel regimen (QW vs Q3W) is determined using the Cycle 1 Day 1 paclitaxel 
dose regimen. 
Intended duration of treatment with paclitaxel Q3W (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle in chemotherapy phase with non-zero dose of study 
drug + 21 – 1
Duration of exposure to paclitaxel (weeks) = 
(last dose date of paclitaxel – first dose date of paclitaxel + 21)/7
Actual Dose Intensity (DI) 
•
By cycle actual DI (mg/m2/3-week cycle) = [cumulative dose in the cycle 
(mg/m2)]/[cycle duration (weeks)/3]
•
Overall actual DI (mg/m2/3-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with paclitaxel (weeks)/3].
Relative Dose Intensity (RDI)  
•
Intended DI (mg/m2/3-week cycle) = 175 (mg/m2/3-week cycle)
•
By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [175 (mg/m2/3-week cycle)]  
•
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [175 (mg/m2/3-week cycle)]
6.5.3.4. Exposure to carboplatin
The dose level for carboplatin is calculated as actual AUC administered.
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Intended duration of treatment with carboplatin (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle in chemotherapy phase with non-zero dose of study 
drug + 21 – 1
Duration of exposure to carboplatin (weeks) = 
(last dose date of carboplatin – first dose date of carboplatin + 21)/7
Actual Dose Intensity (DI) 
•
By cycle actual DI (AUC/3-week cycle) = [cumulative dose in the cycle (AUC)]/[cycle 
duration (weeks)/3]
•
Overall actual DI (AUC/3-week cycle) = [overall cumulative dose (AUC)] / [intended 
duration of treatment with carboplatin (weeks)/3].
Relative Dose Intensity (RDI)  
•
Intended DI (AUC/3-week cycle) = d (AUC/3-week cycle) 
•
By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [d (AUC/3-week cycle)]  
•
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [d (AUC/3-week cycle)]
where d= 5 or 6  depending on the glomerular filtration rate (GFR) method used for the 
Cycle 1 Day 1 carboplatin dose.
6.5.3.5. Dose reductions 
Applicable to avelumab, paclitaxel, and carboplatin. 
Dose reduction is defined as actual non-zero dose < 90% of the planned dose. The number 
and percentage of patients with at least one dose reduction as well as a breakdown of the 
number of dose reductions (1, 2, 3, ≥4) will be summarized by treatment arm. 
6.5.3.6. Dose delays 
Applicable to avelumab, paclitaxel, and carboplatin. 
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses.
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – Planned days between 
two consecutive doses, where planned days are: 21 for carboplatin, 7 for paclitaxel QW
regimen, 21 for paclitaxel Q3W regimen, 21 for avelumab in the chemotherapy phase, 14 for 
avelumab in the maintenance phase.
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For patients taking IDS, the interval encompassing the IDS date (ie Dose (x-1) Date < 
surgery < Dose x Date) will not be considered for dose delay assessment. 
Delays will be grouped into the following categories: 
•
No delay 
•
1-3 days delays
•
4-6 days delay
•
7 or more days delay
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16, 17 or 18, this is considered as 1-3 days delay. 
No delay and 1-3 days delay will also be summarized together. 
The number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized. 
6.5.3.7. Infusion rate reductions
Applicable to avelumab, paclitaxel, and carboplatin.
The number and percentage of patients with at least one infusion rate reduction of ≥ 50% 
compared to the first infusion rate reported in the CRF as well as the frequency of patients 
with 1, 2, 3, ≥4 infusion rate reductions of ≥50% will be summarized.
6.5.3.8. Infusion interruptions
Applicable to avelumab, paclitaxel, and carboplatin.
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant medications and non-drug treatments
The following analyses will be based on the safety analysis set by treatment arm.
Concomitant medications are medications, other than study medications, which started 
prior to first dose date of study treatment and continued on on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study medications and pre-medications for study drug, which are started before the first dose 
of study treatment. 
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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 patients by Anatomical Therapeutic 
Chemical (ATC) Classification level 2 and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. If any prior or concomitant medication is classified into 
multiple ATC classes, the medication will be summarized separately under each of these 
ATC classes. The summary tables will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. In case any 
specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category. 
A listing of prior medications and a listing of concomitant medications will be created with 
the relevant information collected on the ‘General Concomitant Medications’ eCRF page. A 
listing of pre-medications will be created with the relevant information collected on the ‘Pre-
Medication Treatment’ eCRF page.
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’. 
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page.
6.5.5. Subsequent anti-cancer therapies
The following analyses will be based on the FAS by treatment arm.
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, 
‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages. 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages. 
6.6. Safety Summaries and Analyses
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of 
AEs and other safety parameters will be based on the safety analysis set by treatment arm. 
6.6.1. Adverse events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period as defined in Section 3.5.1.
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All analyses described will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings.
•
Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (ie, no answer to the question 
‘Relationship with study treatment’). Related AEs are those related to any study drug (ie, 
at least one of the study drugs).
•
Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).
•
Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction
of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
= Dose reduced).
•
Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).   IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.
•
Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).
•
Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5).
•
Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan and finalized for analysis of the current studies 
data prior to DB lock)
•
Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs, documented in 
the Safety Review Plan and finalized for analysis of the current studies data prior to DB 
lock).
•
Complications Related to Surgery (CRS): CRS as collected on dedicated AE page.
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment arm, primary SOC 
and PT in decreasing frequency based on the frequencies observed for Arm C. 
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
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strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity.
6.6.1.1. All adverse events
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the  latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category. 
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
The following tables will be created: 
•
The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment arm:
-
TEAEs
-
TEAEs, Grade ≥ 3
-
Related TEAEs
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to dose reduction of avelumab
-
TEAEs leading to dose reduction of paclitaxel
-
TEAEs leading to dose reduction of carboplatin
-
TEAEs leading to interruption of avelumab
-
TEAEs leading to interruption of paclitaxel
-
TEAEs leading to interruption of carboplatin
-
TEAEs leading to discontinuation of avelumab
-
TEAEs leading to discontinuation of paclitaxel
-
TEAEs leading to discontinuation of carboplatin
-
TEAEs leading to discontinuation of any study drug
-
TEAEs leading to discontinuation of all study drugs 
-
Related TEAEs leading to discontinuation of avelumab
-
Related TEAEs leading to discontinuation of paclitaxel
-
Related TEAEs leading to discontinuation of carboplatin
-
Related TEAEs leading to discontinuation of any study drug
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-
Related TEAEs leading to discontinuation of all study drugs 
-
Serious TEAEs
-
Related Serious TEAEs 
-
TEAEs leading to death
-
Related TEAEs leading to death
-
irAEs
-
IRRs 
•
TEAEs by SOC and PT and worst grade
•
Related TEAEs by SOC and PT and worst grade 
•
TEAEs leading to death by SOC and PT
•
Related TEAEs leading to death by SOC and PT
•
TEAEs Excluding SAEs, with frequency ≥ 5% in any treatment arm by SOC and PT
6.6.1.2. Adverse events leading to dose reduction
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug, by treatment arm:
•
TEAEs leading to dose reduction of avelumab by SOC and PT
•
TEAEs leading to dose reduction of paclitaxel by SOC and PT
•
TEAEs leading to dose reduction of carboplatin by SOC and PT
The listing of all AEs leading to dose reduction will also be provided with the relevant 
information. 
6.6.1.3. Adverse events leading to interruption of study treatment
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).   IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay). 
As such, 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 6.5.3.6). These IRRs will be considered as IRRs leading to 
interruption of infusion.
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•
IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.6).
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug, by treatment arm:
•
TEAEs leading to interruption of avelumab by SOC and PT
•
TEAEs leading to interruption of paclitaxel by SOC and PT
•
TEAEs leading to interruption of carboplatin by SOC and PT
The listing of all AEs leading to interruption of study treatment will also be provided with the 
relevant information. 
In addition, the frequency (number and percentage) of patients with each of the following 
will be presented for TEAEs leading to interruption of each study drug by treatment arm:
•
TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT
•
TEAEs leading to both interruption and dose reduction of paclitaxel by SOC and PT
•
TEAEs leading to both interruption and dose reduction of carboplatin by SOC and PT
This summary will take into account PTs with both actions as defined in Section 6.6.1, even
though the actions may be captured for different PT records (ie, different onset for the PT 
with action “drug interrupted” and the PT with action “dose reduced”).
6.6.1.4. Adverse events leading to discontinuation of study treatment
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment, by treatment arm:
•
TEAEs leading to discontinuation of avelumab by SOC and PT
•
Related TEAEs leading to discontinuation of avelumab by SOC and PT
•
TEAEs leading to discontinuation of paclitaxel by SOC and PT
•
Related TEAEs leading to discontinuation of paclitaxel by SOC and PT
•
TEAEs leading to discontinuation of carboplatin by SOC and PT
•
Related TEAEs leading to discontinuation of carboplatin by SOC and PT
•
TEAEs leading to discontinuation of 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
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•
Related TEAEs leading to discontinuation of all study drugs by SOC and PT
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’
eCRFs, by treatment arm.  
•
All deaths 
•
Deaths within 30 days after last dose of study treatment
•
Reason for Death 
-
Disease progression
-
Study treatment toxicity
-
AE not related to study treatment
-
Unknown
-
Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information:
•
AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5), 
•
Flag for death within 30 days of last dose of study treatment.
6.6.3. Serious adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment arm:
•
SAEs by SOC and PT
•
Related SAEs by SOC and PT
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other significant adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment arm:
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•
irAEs leading to death, by Cluster and PT
•
irAEs, by Cluster and PT
•
irAEs, Grade ≥ 3, by Cluster and PT
•
irAEs leading to discontinuation of avelumab, by Cluster and PT
•
irAEs leading to discontinuation of paclitaxel, by Cluster and PT
•
irAEs leading to discontinuation of carboplatin, by Cluster and PT 
•
irAEs leading to discontinuation of any study drug, by Cluster and PT
•
irAEs leading to discontinuation of all study drugs, by Cluster and PT 
•
Serious irAEs, by Cluster and PT
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment arm:
•
IRRs leading to death, by PT
•
IRRs, by PT
•
IRRs, Grade ≥ 3, by PT
•
IRRs leading to discontinuation of avelumab, by PT
•
IRRs leading to discontinuation of paclitaxel, by PT
•
IRRs leading to discontinuation of carboplatin, by PT
•
IRRs leading to discontinuation of any study drug, by PT 
•
IRRs leading to discontinuation of all study drugs, by PT 
•
Serious IRRs, by PT
•
Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later). For IV study drugs administered in combination, the infusion numbers are those 
associated with the regimen, rather than the individual study drugs.
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent CRSs, by treatment arm:
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•
CRSs leading to death, by PT
•
CRSs, by PT
•
CRSs, Grade ≥ 3, by PT
•
CRSs leading to discontinuation of avelumab, by PT
•
CRSs leading to discontinuation of paclitaxel, by PT 
•
CRSs leading to discontinuation of carboplatin, by PT 
•
CRSs leading to discontinuation of any study drug, by PT
•
CRSs leading to discontinuation of all study drugs, by PT
•
Serious CRSs, by PT
The listing of all CRSs will also be provided with the relevant information with a flag for 
CRSs with onset outside of the on-treatment period.
In addition the following analyses will be presented for Tier-1 (irAEs and IRRs as defined in 
Appendices 1 and 2) and Tier-2 events separately. P-values and CIs for risk difference will 
be calculated based on the unconditional exact method by Santner and Snell (1980).  No 
additional analyses will be presented for Tier-3 AEs. 
•
Frequency (number and percentage) of patients with each of the following by treatment 
arm and PT or Clustered Term:
-
Tier-2 AEs
-
Tier-2 AEs Grade ≥ 3
•
Point estimate for risk difference and 95% CI for risk difference (experimental arm vs 
comparator arm) for each of the following by PT or Clustered Term:
-
irAEs
-
irAEs Grade ≥ 3
-
IRRs
-
IRRs Grade ≥ 3
-
Tier-2 AEs
-
Tier-2 AEs Grade ≥ 3
•
2-sided p-value associated with risk difference (experimental arm vs comparator arm) for 
each of the following by PT or Clustered Term:
-
irAEs
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-
irAEs Grade ≥ 3
-
IRRs
-
IRRs Grade ≥ 3
•
The p-values and CIs reported are not adjusted for multiplicity and should be used for 
screening purposes only.  The 95% CIs are provided to help gauge the precision of the 
estimates for the risk difference and should be used for estimation purposes only.
6.6.5. Laboratory data
6.6.5.1. Hematology and chemistry parameters
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9). End of Treatment visit laboratory results will be 
summarized separately. The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories (ie,
Low, Normal, High). 
Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 will be 
described using the worst grade. For those parameters which are graded with two toxicities 
such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 0 
when the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), 
and vice versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows: 
•
Lymphocyte count decreased:  
-
derived absolute count does not meet Grade 2-4 criteria, and
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-
% value < % LLN value, and
-
derived absolute count  ≥ 800/mm3
•
Neutrophil count decreased 
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows
Corrected calcium (mmol/L) = measured total calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L])
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment arm:
•
ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN
•
AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN
•
(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN
•
TBILI ≥ 2×ULN
•
Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN
•
Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN
•
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN 
•
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN
•
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or 
missing)
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
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An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment arms, by graphically displaying
•
peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN. 
•
peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
AST=3×ULN and total bilirubin=2×ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided.
Parameters with NCI-CTC grades available: 
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).
•
The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4), 
laboratory abnormalities during the on-treatment period.
•
The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary. 
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie:
•
Hematology: 
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased).
•
Serum Chemistry:
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase 
(CPK 
increased), 
Potassium 
(hypokalemia/ 
hyperkalemia), 
Sodium 
(hyponatremia/ 
hypernatremia), 
Magnesium 
(hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), 
Gamma Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), 
Phosphates (hypophosphatemia), Triglycerides (hypertriglyceridemia).
Parameters with NCI-CTC grades not available:
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Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with: 
•
shifts from baseline normal to at least one result above normal during on-treatment period 
•
shifts from baseline normal to at least one result below normal during on-treatment 
period
In this study, these apply to the following parameters: 
•
Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils
•
Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH)
6.6.5.2. Other laboratory parameters
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF. 
• Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT) and 
International Normalized Ratio (INR).
• Urinalysis: Protein, glucose, blood and albumin
• Other parameters: ACTH, TSH and free T4
• Pregnancy test
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests. 
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing. 
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided.
6.6.6. Vital signs
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle in the Chemotherapy Phase, and Day 1, Day 15 and Day 29 of 
each cycle in the maintenance phase. Height will be measured at screening only.
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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). 
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB =
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF =
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions. If QTcB and 
QTcF methods do not adequately correct for HR and there are a sufficient number of patients 
(eg >30) with baseline ECGs, an alternate correction to achieve the goal of getting 
uncorrelated QTc and RR is based on a linear regression methods 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
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•
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 arm, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients 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 
•
Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:           
-
QT/QTc increase from baseline >30 ms,  >60 ms
-
QT/QTc > 450 ms, > 480 ms, > 500 ms
-
HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm
-
HR ≥ 120 bpm and increase from baseline ≥ 20 bpm
-
PR ≥ 220 ms and increase from baseline ≥ 20 ms
-
QRS ≥ 120 ms 
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings.
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. Physical examination
Abnormal findings in physical examination are recorded in the Medical history (at screening) 
or Adverse Event eCRF pages. No separate analysis will be performed for physical
examination findings. 
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6.6.9. ECOG performance status
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment arm. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing.
7. INTERIM ANALYSES
7.1. Introduction
The goals of the interim analyses are to allow early stopping of treatment arm(s) for futility 
or efficacy.  The interim analysis of PFS and OS will be performed as described in Sections 
5.1.1 and 5.1.2 using the methodology described in Section 6.1.1 for PFS and 6.2.2.1 for OS.  
At the time of the interim analysis for PFS, the interim analysis for OS will be performed by 
an independent statistician. Unblinded results from the interim analysis for PFS and first 
interim analysis for OS will not be communicated to the Sponsor’s clinical team or to any 
party involved in the study conduct (apart from the independent statistician and E-DMC 
members) until the E-DMC has determined that either (i) PFS analysis has crossed the pre-
specified boundary for efficacy or (ii) the study needs to be terminated due to any cause, 
including futility or safety reasons.  Further details will be described in the E-DMC charter.
At the time of final PFS analyses, both PFS and interim OS analysis will be performed by the 
Sponsor’s clinical team. All patients will continue to be followed for OS until the final OS 
analysis (or earlier if OS reaches statistical significance the 3rd or 4th interim analysis).
7.2. Interim Analyses and Summaries
At each analysis time point, the critical boundaries for the group sequential test will be 
derived from the predefined spending function(s) as described in Section 5.1. The 
calculations of boundaries will be performed using EAST.
7.2.1. Interim analysis for PFS
Let u(t1) and u(tF) denote the upper critical boundaries based on the test statistics Z1 and ZF
for efficacy at the interim and the final analysis, respectively, and let l(t1) and l(tF) denote the 
lower critical boundary for futility at the interim and final analysis, respectively.  For the 
final analysis, l(tF)=u(tF). 
The critical values u(t1) and l(t1) for the interim analysis of PFS are determined such as
)
(
))
(
(
1
1
1
0
t
t
u
Z
P
α
=
≥
   and   
)
(
))
(
(
1
1
1
t
t
l
Z
Pa
β
=
≤
,
where P0 and Pa denote the probabilities under the null hypothesis and the alternative 
hypothesis, respectively, and
)
( 1t
α
and
)
( 1t
β
denote the α and β spent, respectively, based on 
the predefined spending functions at information fraction t1 (t1 is calculated as the ratio of the 
number of PFS events observed at the time of the cut-off for the interim analysis and the total 
number of PFS events targeted for the final analysis). 
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The boundary for the final efficacy analysis will be calculated such that
0125
.0
)
),
(
(
)
(
1
1
0
1
=
≥
<
+
F
F
u
Z
t
u
Z
P
t
α
As described in Section 5.1.2, if the number of PFS events in the final analysis deviates from 
the target number of PFS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analysis and the actual correlation between 
the two test statistics Z1 and ZF, so that the overall 1-sided significance level across all 
analyses and comparisons is preserved at 0.025. 
7.2.2. Interim analysis for OS 
No futility analysis will be performed for OS.   Let u(ti) and u(tF) denote the upper critical 
boundaries based on the test statistics Zi and ZF for efficacy at the ith interim and the final 
analysis, respectively, where i=1, 2, 3, 4.
In what follows P0 denotes the probability under the null hypothesis, and
)
( it
α
denotes the α
spent based on the predefined α-spending function at information fraction ti (ti is calculated 
as the ratio of the number of OS events observed at the time of the cut-off for the ith interim 
analysis and the total number of OS events targeted for the final analysis).
For each comparison, the critical value u(t1) for the 1st interim analysis of OS is determined 
such as
)
(
))
(
(
1
1
1
0
t
t
u
Z
P
α
=
≥
.
Critical boundaries for the additional interim analyses and the final analysis of OS are 
calculated recursively as follows for each comparison 
u(t2) is derived such that 
)
(
))
(
),
(
(
)
(
2
2
2
1
1
0
1
t
t
u
Z
t
u
Z
P
t
α
α
=
≥
<
+
,
u(t3) is derived such that 
)
(
))
(
),
(
),
(
(
)
(
3
3
3
2
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1
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0
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u
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t
u
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t
u
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t
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=
≥
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u(t4) is derived such that 
)
(
))
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4
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u
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,
The boundary for the final efficacy analysis is derived such that
.
0125
.0
))
(
),
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F
t
u
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Z
P
t
α
As described in Section 5.1.2, if the number of OS events in the final analysis deviates from 
the target number of OS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analyses and the actual correlation between 
the five test statistics Zi (i=1, 2, 3, 4) and ZF, so that the overall 1-sided significance level 
across all analyses and comparisons is preserved at 0.025. 
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8. REFERENCES
1.
Amit O, et al.  Blinded independent central review of progression in cancer clinical 
trials: Results from a meta-analysis and recommendation from a PhRMA working 
group. European Journal of Cancer 47:1772-1778, 2011.
2.
Bohm, S., et. al., Chemotherapy Response Score: Development and Validation of a 
System to Quantify Hisptopathologic Response to Neoadjuvant Chemotherapy in Tubo-
Ovarian High-Grade Serous Carcinoma., JCO, 2015 Aug 1;33(22):2457-63.
3.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
4.
Cella DF, Tulsky DS. Quality of life in cancer: definition, purpose, and method of 
measurement. Cancer Investigation 1993;11(3):327-36.
5.
Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy 
scale: development and validation of the general measure. J Clin Oncol 
1993;11(3):570-9.
6.
Cella DF. FACT Symptom Indexes for regulatory and other purposes. FACIT 
Organization Manual 2014.
7.
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika; 26, 404-413.
8.
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall
9.
EuroQol--a new facility for the measurement of health-related quality of life. The 
EuroQol Group. Health Policy. 1990 Dec;16 (3): 199-208.
10.
EuroQoL Group. Prepared by vanReenen M and Janssen B.  EQ-5D-5L User Guide: 
Basic information on how to use the EQ-5D-5L instrument.  Version 2.1. April 2015.
11.
FACIT. NCCN/FACT Ovarian Symptom Index-18 (FOSI-18) Scoring Guidelines 
(Version 2) 2008.
12.
Jennison C, Turnbull BW. In: Group Sequential Methods with Applications to Clinical 
Trials. Chapman & Hall/CRC, Boca Raton, 2000.
13.
Jensen SE, Beaumont JL, Jacobsen PB, et al. Measuring priority symptoms in advanced 
bladder cancer: development and initial validation of a brief symptom index.  The 
Journal of Supportive Oncology 2013; 11(92):86-93.
14.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience.
15.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
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16.
Katsumata et al, Dose-dense paclitaxel once a week in combination with carboplatin 
every 3 weeks for advanced ovarian cancer: a phase 3, open-label, randomised 
controlled trial. Lancet 2009; 374: 1331–38.
17.
Kenward, M. G. and Roger, J. H. (2009), “An Improved Approximation to the Precision 
of Fixed Effects from Restricted Maximum Likelihood,” Computational Statistics and 
Data Analysis, 53, 2583–2595.
18.
Kim K. Study duration for group sequential clinical trials with censored survival data 
adjusting for stratification. Statistics in Medicine 1992: 11, 1477-1488
19.
Lan KKG and DeMets DL (1983). Discrete sequential boundaries for clinical trials. 
Biometrika, 70, 659-663.
20.
 
 
21.
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group.
Ann Med. 2001 Jul;33 (5): 337-43. Review.
22.
Royston P, Parmar MK. The use of restricted mean survival time to estimate the 
treatment effect in randomized clinical trials when the proportional hazards assumption 
is in doubt. Statistics in medicine, 2011 30 (19), pp. 2409-2421 
23.
Rustin, G et.al. Definitions for Repsonse and Progression in Ovrian cancer Clinical 
Trials Incorporating RECIST 1.1 and CA-125 Agreed by the Gynecological Cancer 
Intergroup (GCIG)., Int J Gynecol Cancer. 2011 Feb;21(2):419-23
24.
Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression 
model. Biometrika 1980; 67:145-53.
25.
Santner TJ, Snell MK. Small-sample confidence intervals for p1-p2 and p1/p2 in 2 x 2 
contingency tables. Journal of the American Statistical Association, 75:386–394, 1980.
26.
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. 
Statistics for Biology and Health 2000.
27.
Tsiatis A.A. The asymptotic joint distribution of the efficient scores test for the 
proportional hazards model calculated over time. Biometrika 1981: 68, 1,311-315
28.
Uno H, et al.. Moving Beyond the Hazard Ratio in Quantifying the Between-Group 
Difference in Survival Analysis. J Clin Oncol 2014; 32. 
29.
Yost KJ and Eton DT. Combining Distribution-and Anchor-based approaches to 
determine minimally important differences- The FACIT experience. Evaluation and the 
Health Professions 2005; 28(2):172-189.
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30.
Zhang X. Comparison of restricted mean survival times between treatments based on a 
stratified Cox model. DOI 10.1515/bams-2013-0101 Bio-Algorithms and Med-Systems 
2013; 9(4): 183–9.
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9. APPENDICES
Appendix 1. Immune-Related Adverse Events
The MedDRA PTs and clusters for irAEs are defined in the Safety Review Plan (SRP) for 
avelumab.
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 20.   
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step.  
Table 20
Case Definition for irAEs 
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs if 
A) OR B) below are met then the AE is in for the 
next step
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA,  L04AB,  
L04AC,   L04AD,  L04AX, A07EA) and AE PT 
is in any of the irAE clusters.
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters  associated with 
“Immune-mediated endocrinopathies”
C) conmed ATC code is A10A and AE PT is in the 
irAE cluster associated with “Immune-mediated 
endocrinopathies: Type I Diabetes Mellitus”
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5
A) No clear etiology (other than immune 
mediated etiology)
B)
Histopathology / biopsy consistent with 
immune-mediated event
Event is in if 
[Answer to 5B1 and 5B2 is YES  (regardless 
of answer to 5A)]
OR
[Answer to 5B1 is YES AND answer to 5B2 
is NO AND answer to 5A is NO] 
OR
[Answer to 5B1 is NO AND answer to 5A is 
NO]
A) From the AE eCRF page
Is the AE clearly related to an etiology other than 
immune-mediated etiology?    Yes / No
If answer is Yes, check all that apply:
• Underlying malignancy / progressive disease.
• Other medical conditions. 
• Prior or concomitant medications / procedures.  
• Other.  Specify.
B) From the AE eCRF page
B1) Was there a pathology /histology evaluation 
performed to investigate the AE?  Y/N
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text)
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (eg, addition of cases that are not selected 
by the programmatic algorithm) will be the basis of the irAE analyses.
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Appendix 2. Infusion Related Reactions
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered. 
•
All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or 
after infusion) and the event resolved with end date within 2 days after onset. 
•
All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, 
will be considered potential IRRs when onset is on the day of study drug infusion 
(during or after the infusion) or the day after the study drug infusion (irrespective of  
resolution date).
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab. 
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Tables 21 
and 22 (identified for IV drugs only).     
Table 21
Case Definition for IRRs – IV study drugs Administered Alone 
Condition
Selection criterion
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)]  then AE is classified as an IRR
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list 
2
•
AE onset date = date of infusion of study drug AND
•
AE timing related to study drug (‘DURING’, ‘AFTER’) AND
•
AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND
•
AE  end date – AE onset date <=2 
3
PT is included in the ‘IRRs CORE’ list 
4A
•
AE onset date = date of infusion of study drug AND
•
AE timing related to study drug in (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion
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Table 22
Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets) 
Condition
Selection criterion
IRR can be associated with the first IV drug and/or subsequent IV drugs that are administered in combination.  
Without loss of generality assume triplet IV with D1 administered first then D2 then D3.  The IV study drug or 
drugs associated with the IRR need to be identified in the analysis data set to enable subsequent analysis.
The following are not sequential and an AE can be classified as an IRR associated with multiple DJ  from one 
or more of  I, II, III, IV, V below:
I - If the AE meets [1 AND 2A1] for a DJ then the AE is classified as an IRR associated with the DJ that 
meets the 2A1 criterion 
II - If the AE meets [1 AND 2A2] for a DJ then the AE is classified as an IRR associated with the DJ  and 
associated with DJ+1 that meets the 2A2 criterion 
III - If the AE meets [3 AND 4B] for any DJ then the AE is classified as an IRR associated with all DJ that
meet the 4B criterion.
IV- If the AE meets [3 AND 4A1] for a DJ then the AE is classified as an IRR associated with the DJ that 
meets the 4A1 criterion 
V- If the AE meets [3 AND 4A2] for a DJ then the AE is classified as an IRR associated with the DJ and 
associated with DJ+1 that meets the 4A2 criterion 
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list 
2A1
•
AE onset date = date of infusion of study drug DJ AND
•
AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND
•
[AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion of 
study drug DJ+1]AND
•
AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND
•
AE  end date – AE onset date <=2 
2A2
•
AE onset date = date of infusion of study drug DJ AND
•
AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND
•
AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) AND
•
AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND
•
AE  end date – AE onset date <=2 
3
PT is included in the ‘IRRs CORE’ list 
4A1
•
AE onset date = date of infusion of study drug DJ AND
•
AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND
•
[AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion of 
study drug DJ+1]
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4A2
•
AE onset date = date of infusion of study drug DJ AND
•
AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND
•
AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion of study drug D J
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