Conditions: Ovarian Cancer
Keywords: platinum resistant platinum refractory
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 566
Healthy volunteers: no

Brief summary:
A Phase 3 global study comparing avelumab alone to avelumab plus PLD and to PLD alone to demonstrate that avelumab given alone or in combination with PLD is superior to PLD alone in prolonging Overall Survival in patients with platinum resistant/platinum refractory ovarian cancer.

Detailed description:

Arms:
arm 1: Arm A: avelumab alone arm 2: Arm B: avelumab plus PLD arm 3: Arm C: PLD alone

Interventions: intervention 1: avelumab intervention 2: PLD
Intervention descriptions: intervention 1: 10 mg/kg will be given as a 1 hour intravenous infusion (IV) every 2 weeks (Q2W) in 4 week cycles intervention 2: PLD (Arm B, Arm C) 40 mg/m2 will be given as a 1 hour IV infusion every 4 weeks (Q4W) in 4 week cycles

Protocol document:
Prot_002.pdf: 
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CLINICAL PROTOCOL
A PHASE 3, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY OF 
AVELUMAB* (MSB0010718C) ALONE OR IN COMBINATION WITH 
PEGYLATED LIPOSOMAL DOXORUBICIN VERSUS PEGYLATED LIPOSOMAL 
DOXORUBICIN ALONE IN PATIENTS WITH
PLATINUM-RESISTANT/REFRACTORY OVARIAN CANCER
JAVELIN OVARIAN 200
Compound:
MSB0010718C
Compound Name:
avelumab
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2015-003091-77
Protocol Number:
B9991009
Phase:
Phase 3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
                                                
* Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody 
(MSB0010718C).
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Document History
Document
Version Date
Summary of Changes and Rationale
Protocol
Amendment 2
04 March 2019

Adding the following wording to the Protocol Summary 
and to Section 1.2.3 describing reason for the amendment: 
“The final analysis of this study has been completed; 
however, this study will remain open to allow the remaining 
patients currently enrolled in Arm A or Arm B to continue 
receiving avelumab as a single agent or in combination 
with PLD.  These patients will be allowed to continue 
receiving avelumab based on the investigator’s assessment 
that the anticipated benefit outweighs the risks.
The schedule of activities (SOA) found in Appendix 7 is 
replacing the previous SOA and has been revised to 
decrease the frequency of study procedures while 
maintaining appropriate assessment of patient safety. “

Added the following to Section 9: “The final analysis for 
this study has been completed. The study did not meet its 
primary objectives of demonstrating that avelumab given 
alone or in combination with PLD is superior to PLD alone 
in prolonging OS or PFS in patients with platinum 
resistant/platinum refractory ovarian cancer. In addition, 
avelumab single agent as well as avelumab in combination 
with PLD demonstrated a generally manageable safety 
profile in this study.”

The original SOA has been replaced by a new SOA found 
in Appendix 7.

Updated premedication guidelines for avelumab/PLD to 
state: “In order to mitigate infusion-related reactions, 
patients must be premedicated with an antihistamine and 
with paracetamol (acetaminophen) prior to the first 
4 infusions of avelumab. Premedication will be 
administered for subsequent avelumab doses based upon 
clinical judgment and presence/severity of prior infusion 
reactions.

Patients on Arm B who are discontinued from avelumab 
treatment for any reason, must also be discontinued from 
PLD, within the scope of this study and enter the Safety 
Follow-up Period.

Repeat imaging ≥4 weeks after initial documentation of a 
complete response, a partial response or progressive disease 
is no longer required.

Patients will no longer be permitted to continue study 
treatment post initial site documentation of disease 
progression.

Table 6 Avelumab Management of Immune-Related 
Adverse Events is no longer applicable and has been 
replaced with Appendix 9.


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•
Removed BICR assessment of scans.
•
Added France Contrat Unique as Appendix #8.
•
Stopped Survival Follow-Up portion of the trial.
•
Reduced the number of mandatory laboratory tests listed in 
Table 12.
•
Minor administrator changes for sp elling and grammar
throughout.
Protocol 
Amendment 1
15 December
2016
1.
Include Progression-Free Survival (PFS) as assessed by blinded 
independent central review (BICR) as an additional primary 
objective/endpoint. 
•
PFS is an established efficacy and clinically meaningful
endpoint in this disease setting.
2.
To mitigate the potential for bias in determining disease 
progression, an expedited blinded independent central review
(BICR) for investigator-assessed disease progression was added 
(Section 7.7 and throughout text as appropriate).  
3.
 
 
 
 
 
4.
Add mandatory requirement of chest, abdomen, and pelvic 
imaging. 
•
Reduce bias in PFS assessment due to variability of 
imaging. 
5.
Modify Inclusion/Exclusion Criteria: 
a.
Clarify that malignant mixed Müllerian tumors with 
high-grade serous component is a permitted tumor type.
b.
Clarify that prior lines of therapy include all anti-cancer 
therapies.
•
Since prior lines of therapy include any systemic anti-
cancer therapy, not only chemotherapy.
c.
Add the requirement in inclusion criterion 8 of a de novo
tumor biopsy unless clinically contra-indicated, and that for 
the archived FFPE tumor tissue block, a minimum of 
10 slides is acceptable; clarification that the de novo tumor 
biopsy is not required if a biopsy was performed within 
3 months prior to enrollment.
•
To improve the rate of tumor biopsy collection.
d.
Clarify language in exclusion criteria 12, 14,18, 19, 21, 22, 
and 26.  
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6.
Clarify rules for patients receiving PLD after radiological signs 
of disease progression.
7.
Clarified use of local radiotherapy (limited field) to establish the 
purpose and ensure appropriate identification of disease 
progression. Clarified when the medical monitor should be 
consulted.    
8.
Update dose modification section.
a.
Update platelet count threshold for resuming treatment after 
hematological toxicity, to correct current inconsistency, and 
to align with pegylated liposomal doxorubicin (PLD) label 
and requirements for avelumab.  
b.
Permit delay of avelumab by 1 week in case of PLD delays. 

To keep combination dosing aligned.
c.
Avelumab: Table 8 updated to include myocarditis.
9.
Concomitant Medication section: 
a.
Steroid use clarified to address therapeutic use.

To allow short-term steroid use for therapeutic 
purposes whenever it is medically indicated.
b.
Permit prophylactic use of steroids in the PLD monotherapy 
arm. 

To allow steroids premedication for nausea or infusion-
related reactions for patients who receive PLD alone. 
10. Extend PRO collection throughout safety follow-up period. 

To enable inclusion of PRO data beyond tumor progression 
in analysis of PRO endpoints. 
11. Add a responder analysis based on the abdominal/GI subscale of 
the EORTC QLQ-OV28.

To further understand the positive treatment impact on the 
abdominal/GI symptoms, which are important and 
predominant for this patient population.
12. Allow PLD to be resumed in Arm B if no confirmation of PD 
(Section 5.2.4).

An initial disease progression in patients receiving 
avelumab-PLD combination may be due to lymphocyte 
infiltration (pseudo progression) as reported for other
immunotherapy agents.  If the disease progression is not 
confirmed by repeat imaging after 4 weeks, PLD may now 
be resumed in addition to avelumab.
13. Permit use of strong CYP3A4 and CYP2D6, and P-glycoprotein 
(P-gp) inhibitors and inducers in patients enrolled into the 
avelumab monotherapy arm. 

Since strong CYP3A4, CYP2D6, and P-gp inhibitors and 
inducers can interfere with PLD but not avelumab.


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14. Updated Surgery section: to clarify resumption of avelumab 
after minor and major surgery.

Since no surgical risk has been identified with immune 
checkpoint inhibitors, recommendations for avelumab and 
PLD were aligned, additional guidance was provided, and 
discussion with the Sponsor regarding timing for resuming 
avelumab post-surgery is no longer required.
15. Updated End of Study definition: was updated to the time of at 
least 196 OS events and 325 PFS events by BICR assessments
within each comparison.

Due to addition of PFS as a primary endpoint and the 
revised sample size calculations.
16. Revise Schedule of Activities table:
a.
Remove ANA, ANCA, RF. 

Any findings are non-specific and of unknown clinical 
significance.
b.
Extend PK for avelumab to end of treatment and 30 day 
safety follow-up visit.

To align with ADA sampling in order to assess impact, 
if any, of ADA on PK.
c.
PK for avelumab is no longer required at Day 15 beyond 
Cycle 4. 
d.
Change timing of immunogenicity sampling after Cycle 4.

To align with PK samples after Cycle 4.
e.
Update Banked Blood Biospecimen.

To make clear that all Banked Biospecimens are for 
potential use in analyzing DNA, RNA, proteins, and 
metabolites regardless of the collection tube type, and 
for simplification and alignment of the Schedule of 
Activities table with Sections 7.5.1 and 7.5.2. 
f.
Incorporate administrative and clarifications of collection 
times. 
17. Revise safety reporting period: Period for safety reporting for all 
AEs (serious and non-serious) regardless of investigator’s 
causality is revised as up to 90 days after the last dose of study 
treatment based on request from FDA.  Prior version of the 
protocol indicated safety reporting for all AEs to be performed 
up to 30 days after last dose of study treatment and for AEs 
assessed as treatment related based on investigator’s assessment 
up to 90 days after last dose of study treatment.
18. Corrected the definition of the secondary endpoint Disease 
Control

A preferred approach to estimate DC rate at 24 weeks is to 
calculate a PFS Kaplan-Meier rate at 24 weeks which is
included in the protocol.


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19. Add minor administrative changes, typographical corrections 
and modifications for clarity and consistency.
20. Updated PLD preparation to address weight changes and clarify 
that dose capping is not allowed.
21. In Avelumab; Special Precautions have modified the 
requirement for the 2 hour observation period after the first 
4 infusions. 
Final Protocol
16 September 
2015
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).  


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PROTOCOL SUMMARY
Background and Rationale:
Ovarian cancer is the leading cause of death from gynecologic cancer and the fifth most 
common cause of cancer mortality in women.  The incidence of ovarian cancer increases 
with age and is most prevalent in the eighth decade of life.  The median age at the time of 
diagnosis is 63 years, and 70% of patients present with advanced disease.3  Although 
expectations for long-term survival can be very high if the cancer is identified and treated 
early, the women diagnosed with advanced ovarian cancer continue to have less than 
30% 5-year survival.
Patients are considered to have platinum-sensitive disease if they respond to first-line 
platinum therapy and experience a relapse-free period of greater than 6 months following the 
last dose of platinum therapy.  Platinum-resistant disease is defined by relapse between 0 to 
6 months after the last platinum dose. Platinum-refractory disease is defined by lack of 
response to platinum-based chemotherapy or recurrence prior to completion of 
platinum-based therapy.46
There are no highly effective therapies in the platinum-resistant/refractory population, 
although non-platinum-related agents have demonstrated modest antitumor efficacy in a 
subset of these patients.  
Programmed death ligand 1 (PD-L1, also called B7-H1 or CD274) and its receptor, PD-1, 
have 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 function.7,8,9
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, combination of avelumab with chemotherapies showed improved anti-tumor 
activity.1  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 Objective Response Rate (ORR) of 10.7% (8/75) and stable 
disease in an additional 44% (33/75) of patients with advanced ovarian cancer.  
Certain chemotherapy agents, including doxorubicin, have been shown to have 
immunostimulatory properties.52 Preclinical evaluation of breast tumor and sarcoma 
responses to anthracyclines suggested that immune mechanisms contribute to tumor growth 
inhibition.50  
                                                
* Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody 
(MSB0010718C)


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In addition, expression of genes such as CD8, CD8, and IFN-correlated with response to 
anthracycline chemotherapy in breast cancer patients.50  Enhanced exposure of tumor 
antigens as a result of tumor cell kill may enhance the activity of immune checkpoint 
blockade.47 In preclinical studies, combination of avelumab with chemotherapies showed 
improved anti-tumor activity of chemotherapy (gemcitabine, oxaliplatin, 5FU).1
Taken together, these observations suggest that combination of anthracyclines with avelumab 
may provide added clinical benefit relative to either agent alone.51
Study Objectives 
Primary Objectives

To demonstrate that avelumab given alone or in combination with Pegylated 
liposomal doxorubicin (PLD) is superior to (PLD) alone in prolonging Overall 
Survival (OS) in patients with platinum -resistant/platinum-refractory ovarian cancer.

To demonstrate that avelumab given alone or in combination with PLD is superior to 
PLD alone in prolonging PFS in patients with platinum-resistant/platinum-refractory 
ovarian cancer.
Secondary Objectives

To evaluate anti-tumor activity of avelumab given alone or in combination with PLD 
versus PLD alone in ovarian cancer patients.

To evaluate the overall safety profile of avelumab alone or in combination with PLD 
versus PLD alone in ovarian cancer patients.

To characterize the Pharmacokinetics (PK) of doxorubicin (PLD samples) and 
avelumab when administered in combination, and to assess the effect of avelumab on 
the PK of doxorubicin (PLD samples) and the effect of PLD on PK of avelumab. 

To assess the immunogenicity of avelumab.

To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab 
alone or PLD in combination with avelumab in pre-treatment tumor tissue, that may 
aid in the identification of patient subpopulations most likely to benefit from 
treatment.

To compare the effect of avelumab alone or in combination with PLD versus PLD 
alone on patient-reported outcomes (PRO) in patients with ovarian cancer.


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Exploratory Objectives
 
 
 
Study Endpoints
Primary Endpoints
•
Overall Survival (OS).
•
PFS as determined by blinded independent central review (BICR) according to
RECIST version 1.1.
Secondary Endpoints
•
Efficacy: Objective response, Duration of Response (DR), and Disease Control (DC)
as determined by Blinded Independent Central Review (BICR) and Investigator [as 
assessed by RECIST version 1.1]. (Appendix 3).
•
PFS as determined by Investigator according to RECIST version 1.1.
•
Safety: Adverse Events (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), Echocardiogram (ECHO) or multiple gated 
acquisition (MUGA) scans.
•
Pharmacokinetics: PK parameters, including Ctrough and Cmax for avelumab: Cmax, 
volume of distribution (Vd), clearance (CL), area under the concentration-time curve 
(AUC) for doxorubicin (PLD samples).
•
Immunogenicity: Incidence of 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)).
•
Patient-Reported Outcomes: EORTC QLQ-C30, EORTC QLQ-OV28, and 
EQ-5D-5L.
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Exploratory Endpoints
•
 
 
 
 
 
•
CA-125 levels
 
 
Study Design 
This is a Phase 3, multicenter, randomized, open-label, parallel 3-arm study in which 
approximately 550 patients will be randomized in a 1:1:1 ratio to receive avelumab alone, 
avelumab in combination with PLD, or PLD alone, as follows:  
•
Arm A: avelumab alone.
•
Arm B: avelumab plus PLD.
•
Arm C: PLD alone.
•
Patients will be stratified according to platinum-refractory or platinum-resistant 
status, number of prior regimens (1 vs 2 or 3), and bulky disease (defined as presence 
of a tumor ≥5 cm) vs not. 
•
The final analysis of this study has been completed; however, this study will remain 
open to allow the remaining patients currently enrolled in Arm A or Arm B to 
continue receiving avelumab as a single agent or in combination with PLD.  These 
patients will be allowed to continue receiving avelumab based on the investigator’s 
assessment that the anticipated benefit outweighs the risks.
•
The schedule of activities (SOA) found in Appendix 7 is replacing the previous SOA 
and has been revised to decrease the frequency of study procedures while maintaining
appropriate assessment of patient safety. 
Study Treatments 
Avelumab (Arm A, Arm B) 10 mg/kg will be given as a 1-hour intravenous infusion (IV) 
every 2 weeks (Q2W) in 4-week cycles. 
PLD (Arm B, Arm C) 40 mg/m2 will be given as a 1-hour IV infusion every 4 weeks (Q4W) 
in 4-week cycles. 
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In all patients, study treatment may continue until PD as assessed by the investigator, 
unacceptable toxicity, patient refusal, patient loss to follow up, or termination of the study by 
the Sponsor, whichever comes first (see Section 6.5 Withdrawal). Avelumab and PLD will 
not be continued beyond disease progression.  Patients who are on single-agent avelumab 
post-progression at the time of amendment approval will be discontinued from avelumab 
after documentation of a subsequent disease progression. Cross-over will not be permitted.
Patients on Arm B who are discontinued from avelumab treatment for any reason, must also 
be discontinued from PLD (within the scope of this study, if applicable) and entered into the 
90 Day Safety Follow-up Period. 
Statistical Methods
Sample Size Determination
The primary objectives of this study are to demonstrate that avelumab given alone or in 
combination with PLD is superior to PLD alone in prolonging OS or PFS in patients with 
platinum-resistant/refractory ovarian cancer.  The study is designed to test in parallel four 
hypotheses. 

The first null hypothesis is that the true OS hazard rates for PLD alone and avelumab 
alone arms are the same (([HR]=1) versus the alternative hypothesis that the true 
hazard rate is smaller in the avelumab alone arm than in the PLD alone arm (HR<1).

The second null hypothesis is that the true OS hazard rates for PLD alone and 
avelumab in combination with PLD arms are the same (HR=1) versus the alternative 
hypothesis that the true hazard rate is smaller in the avelumab in combination with 
PLD arm than in the PLD-alone arm (HR<1). 

The third null hypothesis is that the true PFS hazard rate for PLD alone and avelumab 
alone arms are the same (HR=1) versus the alternative hypothesis that the true hazard 
rate is smaller in the avelumab alone arm than in the PLD alone arm (HR<1).

The fourth null hypothesis is that the true PFS hazard rate for PLD alone and 
avelumab in combination with PLD arms are the same (HR=1) versus the alternative 
hypothesis that the true hazard rate is smaller in the avelumab in combination with 
PLD arm than in the PLD alone arm (HR<1).
Approximately 550 patients will be randomized using a 1:1:1 randomization, stratified by 
platinum-refractory or platinum-resistant status, number of prior regimens (1 vs 2 or 3), and 
bulky disease (defined as presence of a tumor 5 cm) vs not.
The sample size is determined based on the following assumptions for OS and PFS.

OS


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It is assumed that the median OS for patients receiving PLD is 12 months24 and that 
treatment with avelumab alone or avelumab in combination with PLD is expected to increase
the median to 20 months, corresponding to a hazard ratio (HR) of 0.6 under the exponential 
model. The sample size further assumes a 5% drop-out rate within each arm, a non-uniform 
patient accrual over a 19-month period and a minimum follow-up of 12 months after the last 
patient is randomized.
If the true HR is 0.6 under the alternative hypothesis, 196 OS events within each comparison 
will be required to have 90% power to detect a HR of 0.6 using a one-sided log rank test at a 
significance level of 0.0115 (overall significance level in the study 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 (-10) -spending function to 
determine the non-binding futility boundary.

PFS
It is assumed that the median PFS for patients receiving PLD is 3.5 months24 and that 
treatment with avelumab alone or avelumab in combination with PLD is expected to increase 
the median PFS to 5.8 months, corresponding to a HR of 0.6 under the exponential model 
assumption.  The sample size further assumes a 15% drop-out rate within each arm, a 
non-uniform patient accrual over a 19-month period and minimum follow-up of 12 months 
after the last patient is randomized.
If the true HR is 0.6 under the alternative hypothesis, 325 PFS events by BICR assessment 
within each comparison will provide 93% power to detect a HR of 0.6 using a one-sided 
logrank test at a significance level of 0.001 (overall significance level in the study 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 
(-10) -spending function to determine the non-binding futility boundary. 
OS time will be summarized using the Kaplan-Meier method and displayed graphically by 
treatment arm.  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 for OS and the corresponding 95% CI. 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 0.0115 (one-sided). 
PFS time by BICR assessment will be summarized using the Kaplan-Meier method and 
displayed graphically by treatment arm.  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 for PFS and the corresponding 95% CI. 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 0.001 (one-sided).


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TABLE OF CONTENTS
PROTOCOL SUMMARY.........................................................................................................7
LIST OF TABLES...................................................................................................................18
LIST OF FIGURES .................................................................................................................19
APPENDICES .........................................................................................................................19
SCHEDULE OF ACTIVITIES................................................................................................20
1. INTRODUCTION ...............................................................................................................26
1.1. Indication.................................................................................................................26
1.2. Background and Rationale ......................................................................................26
1.2.1. Ovarian Cancer ...........................................................................................26
1.2.2. Pharmaceutical and Therapeutic Background ............................................27
1.2.2.1. Avelumab (MSB0010718C) .....................................................27
1.2.2.2. Safety.........................................................................................28
1.2.2.3. Pharmacokinetics ......................................................................31
1.2.2.4. Efficacy and Safety in Patients with Ovarian Cancer ...............31
1.2.2.5. Peglyated Liposomal Doxorubicin............................................32
1.2.3. Study Rationale...........................................................................................33
1.2.4. Rationale for Starting Doses of Avelumab and PLD..................................34
1.2.4.1. Avelumab Starting Dose and Regimen .....................................34
1.2.4.2. PLD Starting Dosing Regimen..................................................34
1.3. Summary of Benefit/Risk Assessment....................................................................35
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................35
2.1. Objectives................................................................................................................35
2.2. Endpoints.................................................................................................................36
3. STUDY DESIGN.................................................................................................................37
3.1. Study Overview.......................................................................................................37
3.1.1. Safety Monitoring.......................................................................................38
3.1.2. Study Treatment..........................................................................................38
3.1.3. Tumor Assessments....................................................................................39
3.1.4. Safety Assessments.....................................................................................39
3.1.5. Biomarker Assessments..............................................................................39
3.1.6. Pharmacokinetics........................................................................................40


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4. PATIENT SELECTION......................................................................................................40
4.1. Inclusion Criteria.....................................................................................................40
4.2. Exclusion Criteria....................................................................................................41
4.3. Lifestyle Guidelines ................................................................................................44
4.3.1. Contraception..............................................................................................44
4.4. Sponsor’s Qualified Medical Personnel..................................................................45
5. STUDY TREATMENTS.....................................................................................................46
5.1. Allocation to Treatment ..........................................................................................46
5.2. Investigational Product Supplies.............................................................................47
5.2.1. Dosage Form(s) and Packaging PLD .........................................................47
5.2.1.1. PLD ...........................................................................................47
5.2.1.2. Avelumab ..................................................................................47
5.2.2. Preparation and Dispensing........................................................................48
5.2.2.1. PLD Preparation........................................................................48
5.2.2.2. Avelumab Preparation...............................................................49
5.2.3. Administration............................................................................................49
5.2.3.1. PLD Administration ..................................................................49
5.2.3.2. Management of PLD Extravasation ..........................................50
5.2.3.3. Avelumab Administration.........................................................50
5.2.4. Treatment after Initial Evidence of Radiologic Disease Progression.........51
5.2.5. Food Requirements.....................................................................................51
5.2.6. Recommended Dose Modifications............................................................51
5.2.7. Guidelines for Avelumab Toxicity Management .......................................53
5.2.7.1. Avelumab: Adverse Drug Reactions Requiring 
Discontinuation or Delays .................................................................53
5.2.7.2. Avelumab: Infusion-related Reactions and 
Hypersensitivity Reactions................................................................54
5.2.8. Guidelines for PLD Single Agent and Avelumab-PLD Combination 
Toxicity Management ......................................................................................60
5.2.8.1. PLD Single Agent and Avelumab-PLD Combination: 
Neutropenia and Thrombocytopenia .................................................60
5.2.8.2. PLD: Infusion-Related Reactions (Hypersensitivity 
Reactions)..........................................................................................61


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5.2.8.3. PLD: Palmar-Plantar Erythrodysesthesia (Hand Foot 
Syndrome) .........................................................................................63
5.2.8.4. PLD: Stomatitis.........................................................................64
5.2.8.5. PLD: Other Non-Hematologic Toxicities and Laboratory 
Abnormalities ....................................................................................65
5.2.9. Left Ventricular Ejection Fraction Decreased............................................65
5.2.10. Tumor Lysis Syndrome ............................................................................65
5.3. Drug Storage and Drug Accountability...................................................................67
5.3.1. Investigational Product Storage..................................................................67
5.3.2. Investigational Product Accountability ......................................................68
5.4. Concomitant Treatments .........................................................................................68
5.4.1. Concomitant Radiotherapy.........................................................................69
5.4.2. Supportive Care ..........................................................................................69
5.4.3. Hematopoietic Growth Factors...................................................................69
5.4.4. Therapy for Nausea, Vomiting, and Diarrhea ............................................69
5.4.5. Surgery........................................................................................................70
5.4.6. Other Prohibited Concomitant Medications...............................................70
5.5. Rescue/Escape/Salvage Medication........................................................................71
5.5.1. Supportive Care Guidelines........................................................................71
6. STUDY PROCEDURES .....................................................................................................71
6.1. Screening.................................................................................................................71
6.1.1. Tumor Biospecimens..................................................................................71
6.2. Study Period ............................................................................................................72
6.3. End of Treatment and Follow-up Visits..................................................................72
6.3.1. Safety..........................................................................................................72
6.3.2. Follow-up Visits .........................................................................................72
6.4. End of Study............................................................................................................72
6.5. Patient Withdrawal..................................................................................................73
7. ASSESSMENTS..................................................................................................................74
7.1. Safety Assessment...................................................................................................74
7.1.1. Pregnancy Testing ......................................................................................74
7.1.2. Adverse Events...........................................................................................75
7.1.2.1. Adverse Events of Special Interest for Avelumab ....................75


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7.1.3. Laboratory Safety Assessments..................................................................75
7.1.4. Vital Signs and Physical Examinations......................................................76
7.1.5. Electrocardiogram Measurements ..............................................................76
7.2. Patient-Reported Outcome Assessments.................................................................77
7.2.1. EORTC QLQ-C30......................................................................................77
7.2.2. EORTC QLQ-OV28...................................................................................77
7.2.3. EQ-5D-5L...................................................................................................77
7.3. Pharmacokinetic Assessments.................................................................................78
7.3.1. Blood Sample Collection for Pharmacokinetic Analysis ...........................78
7.3.2. Immunogenicity Assessment......................................................................78
7.4. Translational and Pharmacodynamic Assessments.................................................78
7.4.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies.................78
7.4.2. BRCA 1/2 Mutation Status.........................................................................78
7.5. Banked Biospecimens .............................................................................................79
7.5.1. Markers of Drug Response.........................................................................79
7.5.2. Additional Research....................................................................................80
7.6. Tumor Response Assessments ................................................................................80
7.7. Expedited Blinded Independent Central Review for Disease Progression .............80
8. ADVERSE EVENT REPORTING......................................................................................81
8.1. Adverse Events........................................................................................................81
8.2. Reporting Period .....................................................................................................81
8.3. Definition of an Adverse Event...............................................................................81
8.4. Medication Errors....................................................................................................82
8.5. Abnormal Test Findings..........................................................................................83
8.6. Serious Adverse Events...........................................................................................84
8.6.1. Protocol-Specified Serious Adverse Events...............................................84
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................84
8.7. Hospitalization ........................................................................................................86
8.8. Severity Assessment................................................................................................87
8.9. Causality Assessment..............................................................................................87
8.10. Exposure During Pregnancy..................................................................................88
8.11. Occupational Exposure .........................................................................................89


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8.12. Withdrawal Due to Adverse Events (Also see Section 6.5 on Patient 
Withdrawal)...............................................................................................................89
8.13. Eliciting Adverse Event Information ....................................................................89
8.14. Reporting Requirements........................................................................................89
8.14.1. Serious Adverse Event Reporting Requirements .....................................89
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................90
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................90
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................90
9.1. Sample Size Determination.....................................................................................91
9.2. Analysis Population.................................................................................................92
9.2.1. Full Analysis Set.........................................................................................92
9.2.2. Safety Analysis Set.....................................................................................92
9.2.3. PK Analysis Set ..........................................................................................92
9.2.4. Immunogenicity Analysis Set.....................................................................92
9.2.5. Biomarker Analysis Set..............................................................................93
9.3. Efficacy Analysis ....................................................................................................93
9.3.1. Analysis of Primary Endpoints...................................................................93
9.3.1.1. Overall Survival ........................................................................93
9.3.1.2. Progression Free Survival by BICR Assessment ......................93
9.3.2. Analysis of Secondary Endpoints...............................................................94
9.4. Analysis of Other Endpoints ...................................................................................98
9.5. Safety Analysis........................................................................................................98
9.6. Interim Analysis ......................................................................................................99
9.6.1. Overall Survival..........................................................................................99
9.6.2. Progression-Free Survival ........................................................................100
9.6.3. Non-Comparative Objective Response Rate Assessment ........................100
9.6.4. Stopping Rules..........................................................................................100
9.7. Data Monitoring Committee .................................................................................101
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................101
11. DATA HANDLING AND RECORD KEEPING ...........................................................101
11.1. Case Report Forms/Electronic Data Record .......................................................101
11.2. Record Retention.................................................................................................102


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12. ETHICS............................................................................................................................102
12.1. Institutional Review Board/Ethics Committee....................................................102
12.2. Ethical Conduct of the Study ..............................................................................103
12.3. Patient Information and Consent.........................................................................103
12.4. Patient Recruitment.............................................................................................104
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................104
13. DEFINITION OF END OF TRIAL.................................................................................104
13.1. End of Trial in a Member State...........................................................................104
13.2. End of Trial in All Participating Countries .........................................................104
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................104
15. PUBLICATION OF STUDY RESULTS........................................................................105
15.1. Communication of Results by Pfizer ..................................................................105
15.2. Publications by Investigators ..............................................................................105
16. REFERENCES ................................................................................................................107
LIST OF TABLES
Table 1.
Most Frequently Reported (Incidence 5% in the Pooled Expansion 
Cohort) Treatment-Related Treatment-Emergent Adverse Events 
(TEAEs) in the Pooled Expansion Cohort (Any Grade) ..........................28
Table 2.
Most Frequently Reported (in 2 Patients in the Pooled Expansion 
Cohort) Grade 3 Treatment-Related TEAEs in the Pooled 
Expansion Cohort .....................................................................................29
Table 3.
Avelumab Treatment Related Adverse Events (Incidence 5%) in 
the Ovarian Cancer Cohort .......................................................................32
Table 4.
Dose Modifications for PLD ....................................................................51
Table 5.
Avelumab: Treatment Modifications for Symptoms of 
Infusion-related Reactions........................................................................55
Table 6.
No Longer Applicable: Avelumab: Management of Immune-related 
Adverse Events .........................................................................................57
Table 7.
PLD Single Agent and Avelumab-PLD Combination: Treatment 
Modification for Neutropenia and Thrombocytopenia.............................61
Table 8.
PLD Single Agent and PLD-avelumab Combination: Treatment 
Modification for PLD Infusion-Related Reactions...................................62


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Table 9.
PLD Single Agent and Avelumab-PLD Combination: Treatment 
modification for Palmar-Plantar Erythrodysesthesia (Hand-Foot 
Syndrome) (HFS)......................................................................................63
Table 10.
PLD Single and Avelumab-PLD Combination: Treatment 
Modification for Stomatitis.......................................................................64
Table 11.
PLD: Treatment Modification for Other Non-Hematologic 
Toxicities and Laboratory Abnormalities.................................................65
Table 12.
Required Laboratory Tests .......................................................................76
Table 13.
Objective Response Status at each Evaluation .......................................120
Table 14.
Objective Response Status at each Evaluation for Patients with Non 
Target Disease Only ...............................................................................120
Table 15.
Overall Response Derived from Changes in Index, Non-index and 
New Lesions ...........................................................................................122
LIST OF FIGURES
Figure 1.
Study Randomization Design ...................................................................38
Figure 2.
Assessment and Initial Management of Tumor Lysis Syndrome.............66
APPENDICES
Appendix 1. Abbreviations....................................................................................................112
Appendix 2. ECOG Performance Status................................................................................115
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 
Guidelines...............................................................................................116
Appendix 5. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ......................................................................123
Appendix 6. Quality of Life...................................................................................................124
Appendix 7. Revised Schedule of Activities Post Final Analysis .........................................133
Appendix 8. France Appendix...............................................................................................136
Appendix 9. Management of Immune-related Adverse Events.............................................137
CCI


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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 for detailed information on each procedure and assessment required for compliance 
with the protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities table, in order to conduct evaluations or assessments required to 
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Effective with Amendment 2 the SOA below is no longer applicable.  Please refer to Appendix 7 for the revised SOA.
Protocol Activities1
Screening2
(28 Days Prior 
to 
Randomization)
Cycle 1
Cycle 2
Cycle 3
Cycles 4
End of 
Treatment/
Withdrawal
Visit4
Safety 
Follow-up
(Day 30, 
Day 60, 
Day 905
Follow-up6
1 cycle = 4 weeks3
Day1
Day 15 Day1
Day15
Day1
Day15
Day1
Day15
Visit Time Window
-2
2
2
2
2
2
2
2
3
±3
7
Informed Consent7
X
Tumor History8
X
Medical History
X
Physical Examination9
X
X
X
X
X
X
X
X
Baseline Signs and Symptoms10
X
Height
X
Vital Signs11
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status12
X
X
X
X
X
X
Contraception Check13
X
X
X
X
X
Hematology14
X
X
X
X
X
X
X
X
X
X
Blood Chemistry15
X
X
X
X
X
X
X
X
X
X
Coagulation16
X
X
X
X
X
X
X
X
X
X
ACTH, Free T4, TSH17
X
X
X
X
X
HBV, HCV18
X
CA-12519
X
X
X
X
X
X
BRCA 1/2 Mutation Status20
X
Urinalysis21
X
X
Pregnancy Test22
X
X
X
X
X
X
Triplicate (12-lead) ECG23
X
X
X
X
X
Single 12-lead ECG23
X
X
LVEF (by MUGA or ECHO) (time 
window 5 days)24
X
X (every 
2 cycles)
X
PK Sampling for avelumab (Arms A 
and B only)25
X
X
X
X
X
X
X
X
Cycle 4 
only25
X
X
Day 30 visit 
only
PK Sampling for doxorubicin (PLD 
samples)
Arm B and C only (18 patients in each 
arm)26
X
X


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Protocol Activities1
Screening2
(28 Days Prior 
to 
Randomization)
Cycle 1
Cycle 2
Cycle 3
Cycles 4
End of 
Treatment/
Withdrawal
Visit4
Safety 
Follow-up
(Day 30, 
Day 60, 
Day 905
Follow-up6
1 cycle = 4 weeks3
Day1
Day 15 Day1
Day15
Day1
Day15
Day1
Day15
Visit Time Window
-2
2
2
2
2
2
2
2
3
±3
7
Anti-Drug Antibody (ADA)27
(Arms A and B only)
X
X
X
X27
X
X
Registration and Treatment
Randomization28
X
Study treatment29
Avelumab (Arms A and B)
X
X
X
X
X
X
X
X
PLD (Arm B and Arm C)
X
X
X
X
Premedications30
X
X
X
X
X
X
X
X
Tumor Assessments
CT or MRI Scan31
X
X every 8 weeks
X
X
Other Clinical Assessments
Patient Reported Outcomes 
Questionnaire32
X
X
X
X
X
X (required 
at all 3 
visits)32
Adverse Events33








X
X
Concomitant Treatments34








X
X
Patient Status Follow-up4,6
X
X
Other Patient Samples
Mandatory Archival FFPE
Tumor Tissue Block35
X
De Novo Tumor Biopsy36
X
X
Banked Biospecimens37
X
X
X
X
X
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Footnotes: Effective with Amendment 2 the footnotes below are no longer applicable. 
Please refer to Appendix 7 for the revised footnotes.
1.
Protocol Activities: All assessments should be performed prior to dosing with study medication unless otherwise 
specified.  There is no need to repeat activity at Day 1 if it was done during the screening timeframe of 28 days unless 
otherwise specified.
2.
Screening: To be performed within 28 days prior to randomization. 
3.
Study Cycle: Cycle length is 4 weeks for each treatment arm. 
4.
End of Treatment/Withdrawal: Obtain these assessments if not completed within the prior week, except for tumor 
assessments, which need not be repeated if performed within the prior 4 weeks. 
5.
Safety Follow-up: All patient safety follow-up visits are scheduled monthly for 90 days after the last dose of study 
treatment (Day 30 3, Day 60 3, Day 90 3).  Final visit is scheduled to occur at least 90 days, and no more than 
93 days, after the last dose of study treatment.  PK sample collection is only required at the first follow-up visit 
(Day 30). 
6.
Follow-up for PFS and OS: Patients without evidence of disease progression at the time of treatment discontinuation 
should remain on the study and continue to have tumor assessment radiological scans every 8 weeks until documented 
progressive disease.  Patients who have discontinued study treatment due to progressive disease should be followed for 
survival every 12 weeks via telephone call until study end.  Additionally, subsequent anti-cancer therapies, surgery, and 
date of initiation and discontinuation of each anti-cancer drug will be recorded in the CRF. 
7.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
8.
Tumor History: Includes collection of tumor history, prior antitumor regimen(s), including treatment duration and best 
response observed.
9.
Physical Examination: Includes an examination of major body systems, and weight (height included at screening 
only). Abnormal findings identified prior to first dose of study treatment should be documented in medical history. 
10. Baseline Signs & Symptoms: Patients will be asked about any signs and symptoms experienced within the 14 days 
prior to study enrollment.  Baseline signs and symptoms will be recorded on the Medical History case report form 
(CRF) page.
11. Vital Signs: Blood pressure (BP) and pulse rate should be taken before any other assessments (eg, PK, laboratory 
blood draws) with the patient in the seated position after the patient has been sitting quietly for at least 5 minutes.  
12. ECOG Performance status: Use Eastern Cooperative Oncology Group (ECOG) – see Appendix 2.
13. 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 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.
14. Hematology: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date. Required 
tests are listed in Table 12 and will be performed every 2 weeks and the results should be available for review prior to 
infusion of treatment. 
15. Blood Chemistry: No need to repeat on C1D1 if screening assessment performed within 7 days prior to that date. Full 
chemistry panel (required tests are listed in Table 12) is required at screening and Day 1 of each cycle and at End of 
Treatment/Withdrawal. Core chemistry panel (required tests are listed in Table 12) is required on Days 1 and 15 of 
each cycle. If full and core chemistry panels are scheduled at the same visit, only the full chemistry will be performed.  
The results should be available for review prior to infusion of study treatment. 
16. Coagulation: No need to repeat on C1D1 if baseline assessment performed within 7 days prior to that date.  Required 
tests are listed in Table 12. 
17. ACTH and Thyroid Function Tests: ACTH, Free T4 and TSH will be measured prior to trial treatment, every 
8 weeks for 2 additional measurements, then every 12 weeks thereafter while on treatment, End of Treatment, at the 
30-, 60-, 90-day post-treatment visits, and as clinically indicated. 
18. HBV serology, and HCV serology: measured prior to study enrollment and then as clinically indicated.


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19. CA-125: Will be assessed locally according to the schedule in the table. 
20. 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.
21. Urinalysis: Dipstick is acceptable.  Microscopic analyses must be performed if dipstick is abnormal. 
22. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a urine or serum 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 and once at the baseline visit, immediately before study treatment administration.  Urine pregnancy tests 
will also be routinely repeated at every treatment cycle during the active treatment period, at the end of study therapy 
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 institutional review board/ethics committee 
(IRB/ECs) or if required by local regulations.  See Section 4.3.1 for contraception guidelines.
23. 12-Lead ECGs: All patients require a triplicate ECG measurement at screening.  On-treatment ECGs will be 
performed on Day 1 of Cycles 1, 2, and 3 pre-infusion and Day 15 of Cycle 1.  At each time point, three (3) 
consecutive 12-lead ECGs (triplicates) will be performed approximately 2 minutes apart (within 10 minutes) to 
determine mean QTc (average of triplicates).  In Cycle 4 and subsequent cycles, a single ECG should be taken pre-dose 
on Day 1.  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be 
performed prior to blood sample collection, such that the blood sample is collected at the nominal time. It is 
recommended that ECGs are performed prior to any blood collection or other invasive procedures. If patient 
experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should be 
obtained at time of the event.  If the mean QTcF is prolonged (>500 msec), the ECGs should be re-evaluated by a 
qualified person at the institution for confirmation and repeated as clinically indicated.  Additional triplicate ECGs may 
be performed as clinically indicated.
24. ECHO/MUGA for LVEF (multiple gated acquisition (MUGA) or echocardiogram (ECHO): An ECHO/MUGA must 
be performed for all patients during screening.  The same assessment technique should be performed throughout the 
study.
25. PK Sampling for avelumab (all patients in Arm A and Arm B): Blood samples (3.5 mL) for avelumab PK will be 
collected in all patients: pre-dose and at the end of infusion (immediately before the end of avelumab infusion) on 
Days 1 and 15 of Cycles 1 to 4.  Pre-dose samples should be collected on Days 1 of Cycles 5, 6, 9, 12, 15, 18, 21 24; at 
the End of Treatment and at Day 30 Safety Follow-up visit. Do not collect blood from the same arm being infused.  
See Section 7.3. 
26. PK Sampling for doxorubicin (PLD samples) (18 patients each, Arm B and Arm C only): Serial blood samples 
(3 mL) for PLD PK will be collected in 18 patients in each arm, pre-dose, immediately prior to end of infusion, and at 
2, 6, 24, and 336 hours (Day 15) post start-infusion of PLD on Day 1 of Cycle 2.  Do not collect blood from the same 
arm being infused.  See Section 7.3.
27. Blood for Avelumab Immunogenicity Testing (anti-avelumab antibodies (ADA); neutralizing antibodies (NaB) (Arm A
and Arm B only): All ADA samples (3.5 mL) should be drawn within 2 hours before the start of the avelumab infusion 
on Day 1 of Cycles 1-4.  Thereafter, a sample will be collected on Day 1 prior to avelumab infusion in Cycles 5, 6, 9, 
12, 15, 18, 21 24 and at the End of Treatment. An additional sample for ADA must be collected at 30 days after the 
last dose of avelumab.  Samples positive for ADA may be analyzed for neutralizing antibody (Nab).  Do not collect 
blood from the same arm being infused.
28. Randomization: Patient number allocation via interactive response technology (IRT) operated by Pfizer Inc. 
Following informed consent, patients who complete baseline studies and are eligible for randomization should start 
study treatment within 3 days of randomization.
29. Study Treatment: Described in the Study Treatments section.  Arm A: Avelumab will be given as a 1-hour 
intravenous infusion every 2 weeks.  In the PLD + avelumab arm (Arm B), PLD will be administered on Day 1 of each 
cycle and on that day it will be administered first before the avelumab infusion. Also in Arm B avelumab will be given 
on Day 15 of each cycle. Arm C: PLD will be given on Day 1 of each cycle. Weight should be collected prior to each 
infusion, assessed and documented in the CRF. There is a plus or minus 3 day window for PLD and avelumab
administration but for avelumab there should not be less than 10 days between doses. See Section 5.2.3.
30. Premedications: For additional information about premedications for PLD and avelumab, see Section 5.2.3.1 and 
Section 5.2.3.3. 


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31. Tumor Assessments: Tumor assessments will include all known or suspected disease sites. Tumor assessments must 
include chest, abdomen and pelvis CT or MRI scans and will be conducted every 8 weeks until documented disease 
progression as assessed by BICR regardless of subsequent anti-cancer therapy.  Brain scans will be performed at 
baseline only 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.  A bone scan 
(bone scintigraphy) or 18FDG-PET/CT is required at baseline only if disease is suspected and then every 16 weeks only 
if bone metastases are present at baseline.  Otherwise, bone imaging is required only if new bone metastases are 
suspected.  Bone imaging is also required at the time of CR confirmation for patients who have bone metastases. MRI 
is acceptable for bone imaging if consistent with local practice. CT or MRI scans to be done every 2 cycles (every 
8 weeks) (window of 5 days prior to dosing is allowed) throughout the study.  In case partial response (PR), complete 
response (CR) or Progressive Disease (PD) is observed according to RECIST v.1.1 (Appendix 3) and 
(Appendix 4) (Nishino 2014),49 confirmation CT or MRI should be performed no sooner than 
4 weeks after the first documentation of response.  Tumor assessment should be repeated at the End of Study visit if 
more than 4 weeks have passed since the last evaluation. All radiographic images will be collected and will be
objectively verified by a BICR independent third-party core imaging laboratory as described in Study Manual.  See 
Section 7.6 for additional information.
32. Patient-Reported Outcome Questionnaire: EORTC QLQ-C30, EORTC QLQ-OV28, and EQ-5D-5L are to be 
administered on Day 1 of Cycle 1, Day 1 of each subsequent cycle, End of Treatment/Withdrawal Visit and the 30, 60 
and 90 day Safety Follow-up visits prior to any study or medical procedure. See Appendix 6.
33. Adverse Event (AE) Assessments: Adverse events should be documented and recorded in the CRF. The National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.03 will be used.  
(Appendix 5).  See Section 8.2 for Reporting Period details.
34. Concomitant Treatments: All concomitant medications and Non-Drug Supportive Interventions should be recorded in 
the CRF.  See Section 5.4 for additional information.
35. Mandatory FFPE Tumor Tissue: A mandatory archived formalin-fixed, paraffin-embedded (FFPE) tumor tissue 
block must be provided that is of sufficient size to allow for sectioning of ten (10) 5-micron tissue sections.  If an FFPE 
tumor tissue block cannot be provided, sites should provide, preferably, fifteen (15), but a minimum of ten (10), 
unstained slides each containing a 5-micron tissue section cut serially from the same FFPE block.  If tissue from 
multiple surgeries is available, the most recent specimen should be submitted.  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.  See Sections 6.1.1 and Section 7.4. 
36. De Novo Tumor Tissue: In addition to the archival specimen a de novo (ie, fresh biopsy) tumor sample must be 
collected prior to enrollment unless clinically contraindicated. An optional de novo tumor sample is encouraged to be 
collected at End of Treatment if a patient discontinues due to disease progression.  Tumor tissue from cytologic 
sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted.  
See Section 6.1.1 and Section 7.4.1.
37. Banked Blood Biospecimens: Blood biospecimens will be collected from patients at Screening (4 mL) and 20.5 mL 
will be collected before the start of the first infusion on Cycle 1, Day 1 and Day 15; Cycle 2, Day 1; Cycle 3, Day 1; 
and at End of Treatment.  The biospecimens will be retained for potential pharmacogenomic/biomarker analyses related 
to drug response, unless prohibited by local regulations or ethics committee decision.  Patients also have the choice to 
allow these specimens to be used in research on additional topics.  See Sections 7.5.1 and 7.5.2.
CCI


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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 Platinum-resistant/refractory epithelial 
ovarian, fallopian tube, or primary peritoneal cancer.
1.2. Background and Rationale
1.2.1. Ovarian Cancer
Ovarian cancer is the leading cause of death from gynecologic cancer and the fifth most 
common cause of cancer mortality in women.  The incidence of ovarian cancer increases 
with age and is most prevalent in the eighth decade of life.  The median age at the time of 
diagnosis is 63 years, and 70% of patients present with advanced disease.3  Although 
expectations for long-term survival can be very high if the cancer is identified and treated 
early, the women diagnosed with advanced ovarian cancer continue to have less than 
30% 5-year survival.54
Ovarian neoplasms consist of several histopathological entities.  Epithelial ovarian cancer 
(EOC) comprises the majority of malignant ovarian neoplasms (about 80%);4 however, other 
less common pathologic subtypes must be considered in treatment recommendations.  
Fallopian tube cancer and primary peritoneal cancer are managed in a similar manner to 
epithelial ovarian cancer.
Patients are considered to have platinum-sensitive disease if they respond to first-line 
platinum therapy and experience a relapse-free period of greater than 6 months following the 
last dose of platinum therapy.  Platinum-resistant disease is defined by relapse between 0 to 
6 months after the last platinum dose. Platinum-refractory disease is defined by lack of 
response to platinum-based chemotherapy or recurrence prior to completion of 
platinum-based therapy.46
There are no highly effective therapies in the platinum-resistant/refractory population,
although non-platinum-related agents have demonstrated modest antitumor efficacy in a 
subset of these patients.  Frequently, these patients have declining performance status and 
bowel dysfunction.  Drugs that have demonstrated activity in ovarian cancer include taxanes 
(paclitaxel, docetaxel, nab-paclitaxel), topoisomerase 1 and 2 inhibitors (topotecan, 
liposomal doxorubicin, and etoposide), epothilones (ixabepilone and ZK-EPO), alkylators 
(hexamethymelamine and ifosfamide), and antimetabolites (pemetrexed and gemcitabine).  
For management of resistant disease, these drugs are used as single agents in sequence and 
have demonstrated response rates in the range of 10% to 20% with median times to 
progression of 3 to 4 months.46  In 2014, bevacizumab plus chemotherapy was approved in 
                                                
* Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody 
(MSB0010718C)


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European Union (EU) and US in combination with paclitaxel, pegylated liposomal 
doxorubicin (PLD), or topotecan, for the treatment of patients with platinum-resistant 
recurrent ovarian cancer.  This approval was based on results of the AURELIA study, which 
randomized patients to physician’s choice of chemotherapy (PLD, paclitaxel, or topotecan) 
with or without bevacizumab, and included patients with more than one prior line of 
platinum based chemotherapy.  This study demonstrated improvement in median 
progression-free survival (PFS) from 3.4 months to 6.7 months (HR=0.48, 95 % CI: 0.38 to 
0.60, p<0.001).  No statistically significant improvement in OS was seen.5  In 2014, olaparib, 
a (Poly ADP ribose polymerase) PARP inhibitor, was approved for the treatment of patients 
with advanced Breast Cancer Angtigen (BRCA)-mutated ovarian cancer by European)
Medicines Agency (EMA and Federal Drug Administration (FDA).6
Single-agent PLD has been extensively studied in platinum-resistant ovarian cancer, with 
response rates of 10-20%, median PFS times of 2.1-3.7 months, and median OS ranging from 
8.4 to 16.8 months.20,21,22,23,24,25 The approved dose of PLD in the US and EU is 50 mg/m2 
intravenously every 4 weeks; however, 40 mg/m2 every 4 weeks is commonly used in 
clinical practice and in clinical trials including the AURELIA study.25
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.  
Compared with anti-PD-1 antibodies, that target T cells, avelumab targets tumor cells and 
therefore, is expected to have fewer side effects, including a lower risk of 
autoimmune-related safety issues, as blockade of PD-L1 leaves the PD-L2/PD-1 pathway 
intact to promote peripheral self-tolerance.2  For complete details of the in vitro and 
nonclinical studies, refer to avelumab Investigator’s Brochure (IB).1
Avelumab is currently in clinical development with 2 ongoing Phase 1 studies in patients 
with solid tumors and a Phase 2 study in patients with Merkel cell carcinoma.
Trial EMR100070-001(conducted by Merck KGaA/EMD Serono (EudraCT number 
2013-002834-19, NCT01772004)) is a Phase 1, open-label, multiple-ascending-dose trial to 
investigate the safety, tolerability, pharmacokinetics, biological, and clinical activity of 
avelumab in patients with locally advanced or metastatic solid tumors.  This trial consisted 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 were 
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As of 05 November 2014, a total of 50 patients were treated in the dose-escalation phase of 
the trial, with 4 patients being treated with 1 mg/kg avelumab, 13 patients being treated with 
3 mg/kg avelumab, 13 patients being treated with 10 mg/kg avelumab, and 20 patients being 
treated with 20 mg/kg avelumab. None of the patients treated with doses up to 10 mg/kg 
experienced a dose-limiting toxicity (DLT), and the 10 mg/kg dose of avelumab was thus 
considered a safe and well-tolerated dose for further investigation in the dose-expansion 
cohorts.  One DLT (Grade 3 AE) was observed in 1 patient at a dose of 20 mg/kg.  This was 
an immune-related AE with creatine kinase increased, myositis, and myocarditis. 
Eleven (11) expansion cohorts are ongoing, including an expansion cohort in EOC (see 
below).  Four hundred and eighty (480) patients have been enrolled and treated as of the data
cutoff date, 05 November 2014, with the recommended dose of 10 mg/kg avelumab once 
every 2 weeks. 
1.2.2.2. Safety
Of the 480 patients treated in the pooled expansion cohort, 218 (45.4%) experienced at least 
1 Grade 3 Treatment Emergent Adverse Event (TEAE), and 330 (68.8%) had
treatment-related TEAEs, of whom 59 (12.3%) had Grade 3 treatment-related TEAEs.
The most frequently reported (incidence 5% in the pooled expansion cohort) 
treatment-related TEAEs (any grade) in the pooled expansion cohort are summarized in 
Table 1.  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 are 
presented in Table 2.
Table 1.
Most Frequently Reported (Incidence 5% in the Pooled Expansion 
Cohort) Treatment-Related Treatment-Emergent Adverse Events (TEAEs)
in the Pooled Expansion Cohort (Any Grade)
MedDRA PT
Pooled Expansion Cohort Patients (n=480)
n (%)
Number of patients with at least 1 TEAE
330 (68.8%)
Fatigue
97 (20.2%)
Nausea
62 (12.9%)
Infusion related reaction
47 (9.8%)
Chills
33 (6.9%)
Diarrhea
33 (6.9%)
Decreased appetite
30 (6.3%)
Pyrexia
27 (5.6%)
Influenza like illness
25 (5.2%)
Arthralgia
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Table 2.
Most Frequently Reported (in 2 Patients in the Pooled Expansion Cohort) 
Grade 3 Treatment-Related TEAEs in the Pooled Expansion Cohort
MedDRA PT
Pooled Expansion Cohort Patients (n=480)
n (%)
Number of patients with at least 1 TEAE
59 (12.3%)
Anemia
5 (1.0%)
Fatigue
5 (1.0%)
Gamma-glutamyltransferase increased
4 (0.8%)
Infusion related reaction
4 (0.8%)
Lipase increased
4 (0.8%)
Lymphocyte count decreased
3 (0.6%)
Autoimmune hepatitis
2 (0.4%)
Constipation
2 (0.4%)
Dyspnea
2 (0.4%)
Hypertension
2 (0.4%)
Hypokalemia
2 (0.4%)
Hypoxia
2 (0.4%)
Pneumonitis
2 (0.4%)
Vomiting
2 (0.4%)
Overall, 176 of the 480 patients (36.7%) treated in the dose expansion cohorts had serious 
TEAEs.  Of these, 22 (4.6%) patients experienced dyspnea, 19 patients (4.0%) disease 
progression, 12 patients (2.5%) pleural effusion, 11 patients (2.3%) pneumonia, 8 patients 
respiratory failure (1.7%) and 7 patients (1.5%) anemia.  All other serious TEAEs were each 
reported in less than 1.5% of patients.  Of the serious TEAEs considered treatment-related by 
the Investigator (31 patients; 6.5%), the following were reported for 2 or more patients: 
infusion-related reaction (4 patients, 0.8%), pneumonitis (3 patients, 0.6%), and disease 
progression, dyspnea, and hypercalcemia (2 patients each, 0.4%).
As of 05 November 2014, 134 patients (27.9%) treated in the dose expansion cohorts died, 
mostly due to disease progression (101 deaths; 21.0%). In 4 patients (0.8%), the primary 
cause of death was attributed to an AE related to study treatment and in 8 patients (1.7%) to 
an AE unrelated to study treatment.  The reason for 13 (2.7%) deaths was “unknown” and for 
8 (1.7%) was “other.”  Of the 134 patients who died, 53 patients (11.0%) died within 30 days 
following the last administration of trial treatment.  Overall there were (14%) patients who 
experienced treatment related AEs with fatal outcome; in 4 patients the treatment-related AE 
was reported as the primary cause of death as noted above. These 7 cases with AEs related 
to study treatment included: pneumonitis radiation induced and dyspnea; acute liver failure 
associated with autoimmune hepatitis (no biopsy/autopsy performed); disease progression; 
fatal anoxic brain injury after cardiac arrest; autoimmune hepatitis with hepatic failure and 
fatigue (no biopsy/autopsy performed); respiratory distress and sepsis; and acute respiratory 
failure, acute exacerbation chronic obstructive pulmonary disease (COPD), and leukocytosis 
(occurred after the end of the on-treatment period).
Eighty (80) patients (16.7%) treated in the dose expansion cohorts withdrew permanently 
from trial treatment due to one or more TEAE.  In 34 (7.1%) of these patients, the TEAEs 
leading to treatment discontinuation were considered related to trial treatment by the 
Investigator.  These TEAEs were infusion-related reaction (8 withdrawals; 1.7%), Gamma 


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glutamyl transferase (GGT) increased and rash (3 withdrawals each, 0.6%), and aspartate
aminotransferase increased, blood creatine phosphokinase increased, and disease progression 
(2 patients each, 0.4%); or other events led a single patient to discontinue trial treatment.
Immune-related Adverse Events: As of 05 November 2014, a cumulative review revealed 
56 patients of potential immune-related AEs in the 480 patients (11.7%) treated in the dose 
expansion part of trial EMR 100070-001, and 4 of 50 patients (8.0%) treated in the dose 
escalation part of trial EMR 100070-001, for a total of 69 events.  Of these 69 events, 
46 events (67%) were assessed as treatment-related by the Investigator and 23 events 
(33.3%) were assessed as not treatment-related by the Investigator.  Twenty-six (26) events 
were assessed as Grade 1, 29 events as Grade 2, 11 events as Grade 3, 2 events as Grade 4, 
and 1 event had fatal outcome (radiation pneumonitis) (note: 2 events of suspicion of 
autoimmune hepatitis, not confirmed by biopsy, assessed as Grade 3 had a fatal outcome).
Infusion-Related Reactions: Two unexpected serious adverse reactions (SUSARs; 
anaphylactic reaction and infusion-related reaction) involving 2 patients were reported in 
December 2013 and triggered a cumulative review of serious and non-serious cases of 
infusion-related reactions/hypersensitivity across the avelumab program.  Following 
evaluation of safety signals, infusion-related reactions/hypersensitivity have been classified 
as a newly identified risk (previously classified as a potential risk) and a mandatory 
premedication regimen of a histamine H1 receptor (H1) blocker plus acetaminophen was 
implemented for all trial patients starting 29 January 2014.
As of 05 November 2014, 49 (10.2%) of the 480 patients in the expansion cohort 
experienced at least 1 episode of an infusion-related reaction when receiving avelumab 
monotherapy.  Most of the events were Grade 1 (8 patients, 1.7%) or Grade 2 (36 patients, 
7.5%) in intensity, and Grade 3 (3 patients, 0.6%) or Grade 4 events (2 patients, 0.4%) were 
less frequent.  No Grade 5 events were reported from the infusion-related reactions.  Most of 
the infusion-related reaction events had an onset after the first (30 patients, 6.3%) or second 
(16 patients, 3.3%) avelumab infusion.  In 8 patients (1.7%), avelumab treatment was 
discontinued because of infusion-related reaction events.  In addition, 1 patient (2.0%) in the 
dose escalation cohort reported an infusion-related reaction event (Grade 2). 
Starting from 29 January 2014, a mandatory premedication with H1 blockers plus 
acetaminophen was implemented for all patients who are to receive avelumab.  This 
premedication procedure was applied to 28/50 patients in the dose escalation phase and to 
440/480 patients in the pooled treatment expansion cohort.  Under this premedication 
procedure, 33 of 440 patients (7.5%) in the expansion cohort experienced infusion-related 
reaction events, with 6 patients (1.4%) having Grade 1, 26 patients (5.9%) having Grade 2, 
and 1 patient (0.2%) having Grade 3 events.  No infusion-related reaction events were 
reported in the 28 patients in the dose escalation cohort.
In addition to the aforementioned patients, one case of Grade 4 cardiac arrest occurred 
1.5 hours after the third infusion of avelumab (10 mg/kg).  The patient died due to an anoxic 
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Guidelines for the management of infusion-related reactions and severe hypersensitivity 
reaction are found in Section 5.2.7.2.  A complete guideline for the emergency treatment of 
anaphylactic reactions according to the Working Group of the Resuscitation Council (United 
Kingdom) and can be found at 
https://www.resus.org.uk/pages/reaction.pdfhttps://www.resus.org.uk/pages/reaction.pdfhttps
://www.resus.org.uk/pages/reaction.pdf.
1.2.2.3. Pharmacokinetics
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab 
have been characterized in 57 Caucasian patients treated in the dose escalation and expansion 
cohort of Study EMR 100070-001 by standard non-compartmental analysis.  This analysis 
revealed that the exposure parameters of Cmax and AUCτ 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 target mediated disposition at lower doses, but terminal half-life of 10 and 
20 mg/kg doses were similar (106-134 hours).  This likely indicates that target mediated 
elimination does not increase at these two doses and target occupancy is very high. 
Target occupancy 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 ug/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 ug/mL).
1.2.2.4. Efficacy and Safety in Patients with Ovarian Cancer
Single-agent avelumab activity at 10 mg/kg Q2W was evaluated in heavily pretreated 
epithelial ovarian cancer (EOC) patients in an ovarian-specific expansion cohort in Study 
EMR100070-001.  Patients with ovarian cancer whose disease progressed on standard 
therapy were eligible.  75 patients were enrolled from Nov 2013 to Nov 2014.  Median age 
was 62 years (range 38-84 years); ECOG performance status was 0 (41%) or 1 (59%); 
median number of prior therapies for locally advanced or metastatic disease (excluding 
adjuvant treatment) was 4 (range, 0-10).  At the data cutoff of February 13, 2015, median 
duration of treatment with avelumab was 12 weeks (range 2-54 weeks), and 8 patients 
remained on treatment.  Eight patients (10.7%, 95% CI, 4.7%, 19.9%) achieved an 
unconfirmed best objective response (BOR) of partial response (PR).  Five out of 8 responses 
were ongoing at the time of data cutoff.  Thirty-three (44%) patients had stable disease.  Two 
additional patients had partial response by immune-related response criteria.  Median 
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Avelumab was well-tolerated in the ovarian cancer expansion cohort (n=75).  Table 3
demonstrates treatment-related adverse events observed in 5% of patients.  The following 
Grade 3 avelumab-related adverse events were observed in a total of 6 patients (8.0%): one 
event each of peripheral edema, localized edema, increased lipase, increased blood creatine 
phosphokinase, arthritis, myositis, hyperglycemia, anemia, tumor pain.  There were no 
Grade 4 or 5 AEs related to avelumab reported in this cohort.  Related serious TEAEs were 
observed in 3 patients (4.0%): Dyspnea (1), pyrexia (1), non-cardiac chest pain (1), flushing 
(1), localized edema (1), and peripheral edema (1).  Immune-related TEAEs were seen in 
8 patients (10.7%) and included hypothyroidism (5; 6.7%), arthritis (2; 2.7%), and myositis 
(1; 1.3%).  No drug-related intestinal obstruction or perforations occurred.  Discontinuation 
related to treatment with avelumab was reported in 9 patients (12.0%) [Pfizer/Merck KGaA 
data on file, cutoff 13 February 2015].45
Table 3.
Avelumab Treatment Related Adverse Events (Incidence 5%) in the 
Ovarian Cancer Cohort
Events (n=75)
Treatment-Related AEs, all grades*, n (%)
Any event
52 (69.3)
Fatigue
12 (16.0)
Chills
9 (12.0)
Nausea
8 (10.7)
Diarrhea
8 (10.7)
Infusion-related reaction
6 (8.0)
Rash
6 (8.0)
Vomiting
4 (5.3)
Constipation
4 (5.3)
Hypothyroidism
4 (5.3)
Source: Table 15.3.1.5C.
Complete information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab Investigator’s Brochure.1
1.2.2.5. Peglyated Liposomal Doxorubicin
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var.
caesius which has been available since the 1960s.  Its main mode of action is to bind with 
topoisomerase II and DNA, forming a complex which results in lethal double-stranded DNA 
breaks.25 Pegylated liposomal doxorubicin (PLD) (trade names Doxil, Caelyx) is a 
formulation of liposomal doxorubicin coated in polyethylene glycol (PEG).  This hydrophilic 
coating protects the liposomes from detection by the body’s reticular endothelial system, 
reducing the rate at which the active substance is broken down, and increasing its circulating 
half-life compared with conventional doxorubicin.25
PLD displayed linear pharmacokinetics over the range of 10 to 20 mg/m2.  Relative to PLD
doses at or below 20 mg/m2, the pharmacokinetics of total PLD following a 50 mg/m2 PLD
dose are nonlinear.  At this dose, the elimination half-life of PLD is longer and the clearance 
lower compared to a 20 mg/m2 dose.  Converse to the pharmacokinetics of doxorubicin, 
which displays a large volume of distribution (700-1100 L/m2), the steady-state volume of 
distribution of PLD is restricted to the vascular fluid volume.  The major metabolite of 


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doxorubicin, doxorubicinol, was detected at negligible levels in patients who received 10 or 
20 mg/m2 PLD.16
The most common toxicities of PLD (>20%) are asthenia, fatigue, fever, anorexia, nausea, 
vomiting, stomatitis, diarrhea, constipation, hand-foot syndrome, rash, neutropenia, and 
anemia.16 Acute Infusion-Related Reactions occur occurred in 11% of patients with solid 
tumors.  Serious, life-threatening, and fatal infusion reactions have been reported.  PLD can 
cause myocardial damage, including congestive heart failure.  The risk of cardiotoxicity is 
11% when the lifetime cumulative anthracycline dose (not limited to PLD) approaches 
450-550 mg/m2.
Single-agent PLD has been extensively studied in platinum-resistant ovarian cancer, 
demonstrating an objective response rate (ORR) of 10-20%, median PFS of 2.1-3.7 months, 
and OS ranging from 8.4 to16.8 months.20,21,22,23,24,25
Complete information for PLD may be found in the single reference safety document 
(SRSD), which for this study is the Caelyx SmPC.
1.2.3. Study Rationale
Programmed death ligand 1 (PD-L1 also called B7-H1 or CD274) and its receptor, PD-1, 
have 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 function.7,8,9
Tumors including ovarian cancer present with various rates of somatic (or genetic) 
mutations.11,12  These genetic alterations result in expression of proteins that are “different 
from self” on cancer cells which may act as antigens enhancing the ability of the host 
immune system to recognize tumor cells as foreign and stimulate T cell response.13  
However, tumors elude immune surveillance through the expression of PD-L1 in the tumor 
microenvironment.17  Several antibodies blocking PD-1 and PD-L1 demonstrated significant 
and durable response in patients with cancer.51
Clinical activity of nivolumab, a PD-1 antibody, was observed in a Phase 2 study in patients 
with advanced or relapsed, platinum–resistant ovarian cancer.  In heavily pretreated patients 
(median number of prior therapies was >4), an ORR of 17% (3 of 18 patients) was 
observed.15
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, combination of avelumab with chemotherapies showed improved anti-tumor 
activity.1  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.  


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Certain chemotherapy agents, including doxorubicin, have been shown to have 
immunostimulatory properties.52  Preclinical evaluation of breast tumor and sarcoma 
responses to anthrcyclines suggested that immune mechanisms contribute to tumor growth
inhibition.50  In addition, expression of genes such as CD8, CD8, and IFN-correlated 
with response to anthracycline chemotherapy in breast cancer patients.50  Enhanced exposure 
of tumor antigens as a result of tumor cell kill may enhance the activity of immune 
checkpoint blockade.47  In preclinical studies, combination of avelumab with chemotherapies 
showed improved anti-tumor activity of chemotherapy (gemcitabine, oxaliplatin, 5FU).1
Taken together, these observations suggest that combination of anthracyclines with avelumab 
may provide added clinical benefit relative to either agent alone.51  PLD has proven activity 
in platinum resistant/refractory ovarian cancer,20,25 and is therefore appropriate to combine 
with avelumab in ovarian cancer patients.
The final analysis of this study has been completed; however, this study will remain open to 
allow the remaining patients currently enrolled in Arm A or Arm B to continue receiving 
avelumab as a single agent or in combination with PLD.  These patients will be allowed to 
continue receiving avelumab based on the investigator’s assessment that the anticipated 
benefit outweighs the risks.
The schedule of activities (SOA) found in Appendix 7 is replacing the previous SOA and has 
been revised to decrease the frequency of study procedures while maintaining appropriate 
assessment of patient safety.
1.2.4. Rationale for Starting Doses of Avelumab and PLD
1.2.4.1. Avelumab Starting Dose and Regimen
In this clinical trial, the avelumab dose will be 10 mg/kg administered as 1-hour intravenous 
infusions every 2 weeks (Q2W).  This dose is the recommended Phase 2 dose based on
experience from 480 patients in the ongoing dose-expansion phase of 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 5.2.3.3 for premedication details.
1.2.4.2. PLD Starting Dosing Regimen
The approved dose of PLD in the US and EU is 50 mg/m2 intravenously 4 weeks; however,
40 mg/m2 every 4 weeks is commonly used in clinical practice and in clinical trials.25  This 
latter dose is associated with significantly reduced frequencies of adverse events, particularly 
hand-foot syndrome, and a lower frequency of dose reductions with a similar objective 
response rate.46,53  The dose of 40 mg/m2 was used in the AURELIA study which formed the 
basis of approval of bevacizumab in platinum-resistant ovarian cancer.
In this clinical trial, the PLD dose will be 40 mg/m2 every 4 weeks.  The first infusion will be 
administered at 1 mg/min to minimize the risk of infusion reactions.  If no infusion-related 
reaction is observed, subsequent PLD infusions may be administered over a 60-minute 
period.  See Section 5.2.3.1 for premedication details.


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1.3. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
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 
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.
Chemotherapy including doxorubicin has recently been shown to have immunostimulatory 
properties.52  In preclinical studies, combination of avelumab with chemotherapies showed 
improved anti-tumor activity of chemotherapy (gemcitabine, oxaliplatin, 5FU).1
PLD is approved multinationally for the treatment of patients with ovarian cancer whose 
disease has progressed or recurred after platinum-based chemotherapy.  PLD is generally 
well-tolerated with a well-characterized toxicity profile.  Currently there are no published 
reports of doxorubicin combined with immune checkpoint inhibitors.  The literature suggests 
a low possibility of overlapping toxicities for avelumab and PLD.  Close safety monitoring 
will be performed throughout the study as outlined in Section 3.1. 
Thus, the projected benefit/risk of avelumab given in combination with PLD is anticipated to 
be favorable for investigation in this advanced cancer patient population.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objectives

To demonstrate that avelumab given alone or in combination with PLD is superior to 
PLD alone in prolonging OS in patients with platinum -resistant/platinum-refractory 
ovarian cancer.

To demonstrate that avelumab given alone or in combination with PLD is superior to 
PLD alone in prolonging Progression Free Survival (PFS) in patients with 
platinum-resistant/platinum-refractory ovarian cancer. 


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Secondary Objectives
•
To evaluate anti-tumor activity of avelumab given alone or in combination with PLD 
versus PLD alone in ovarian cancer patients.
•
To evaluate the overall safety profile of avelumab alone or in combination with PLD 
versus PLD alone in ovarian cancer patients.
•
To characterize the PK of doxorubicin (PLD samples) and avelumab when 
administered in combination, and to assess the effect of avelumab on the PK of 
doxorubicin (PLD sample) and the effect of PLD on PK of avelumab. 
•
To assess the immunogenicity of avelumab.
•
To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab 
or PLD in combination with avelumab in pre-treatment tumor tissue, that may aid in 
the identification of patient subpopulations most likely to benefit from treatment.
•
To compare the effect of avelumab alone or in combination with PLD versus PLD 
alone on patient-reported outcomes (PRO) in patients with ovarian cancer.
Exploratory Objectives
 
 
 
 
2.2. Endpoints
Primary Endpoints
•
Overall survival (OS).
•
Progression Free Survival as determined by Blinded Independent Central Review 
according to RECIST version 1.1.
Secondary Endpoints
•
Efficacy: Objective response (OR), Duration of Response (DR), and Disease Control 
(DC) as determined by Blinded Independent Central Review (BICR) and Investigator
[As assessed by RECIST version 1.1]. (Appendix 3).
CCI


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•
PFS as determined by Investigator according to RECIST version 1.1.
•
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), ECHO or MUGA scans.
•
Pharmacokinetics: PK parameters, including Ctrough and Cmax for avelumab, Cmax, 
volume of distribution (Vd), clearance (CL), area under the concentration-time curve 
(AUC) for doxorubicin (PLD samples).
•
Immunogenicity: Incidence of 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).
•
Patient-Reported Outcomes: EORTC QLQ-C30, EORTC QLQ-OV28, and 
EQ-5D-5L. (Appendix 6).
Exploratory Endpoints
•
 
 
 
•
CA-125 levels.
•
 
 
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 3, multicenter, randomized, open-label, parallel 3-arm study in which 
approximately 550 patients will be randomized in a 1:1:1 ratio to receive avelumab alone, 
avelumab in combination with PLD, or PLD alone, as follows: 
•
Arm A: avelumab alone;
•
Arm B: avelumab plus PLD;
•
Arm C: PLD alone.
CCI
CCI


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Figure 1.
Study Randomization Design
Patients will be stratified by platinum-refractory or platinum-resistant status, number of prior 
regimens (1 vs 2 or 3), and bulky disease (defined as presence of a tumor 5 cm) vs not.  
Cross-over will not be permitted. 
3.1.1. Safety Monitoring
An evaluation of the safety of the avelumab plus PLD arm will be performed during the 
study as follows:
Randomization to all three arms will begin at the start of the study.  When six patients are 
randomized to the combination arm, enrollment in all arms will be held.  After each patient in 
the combination arm has completed a minimum observation period of 4 weeks, the external
data monitoring committee (DMC) will evaluate all available safety data.  If there are no 
safety concerns precluding continuation of the study, enrollment will proceed.  Other options 
may include termination of the combination arm, or enrollment of 6 more patients with an 
enrollment hold. These decisions will be at discretion of the DMC.
A second safety evaluation will be performed by the external DMC after a total of 20 patients 
are enrolled on the combination arm and followed for at least 4 weeks, without an enrollment 
hold.  The frequency of subsequent DMC meetings will be determined by the external DMC 
at the time of the second safety evaluation.
3.1.2. Study Treatment 
Avelumab (Arm A, Arm B) 10 mg/kg will be given as a 1-hour intravenous infusion (IV) 
every 2 weeks (Q2W) in 4-week cycles. 
PLD (Arm B, Arm C) 40 mg/m2 will be given as a 1-hour IV infusion every 4 weeks (Q4W)
in 4-week cycles.
In Arm B, on the days that the patient receives both infusions, PLD should be administered 
prior to avelumab. See Section 5.2.3.3.


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In all patients, study treatment may continue until PD as assessed by the investigator, 
unacceptable toxicity, patient refusal, patient loss to follow up, or termination of the study by 
the Sponsor, whichever comes first (see Section 6.5 Patient Withdrawal).  Avelumab and 
PLD will not be continued beyond initial disease progression.  For those patients who are on 
single-agent avelumab post-progression at the time of amendment approval, if they present 
with a subsequent scan showing disease progression, they must discontinue avelumab.  See 
Section 5.2.4.
For administration information, see Section 5.2.3.  Patients should be monitored closely for 
toxicity and infusion related reactions.  For the management of infusion-related reactions and 
other toxicities, see Section 5.2.6. 
Patients on Arm B who are discontinued from avelumab treatment for any reason, must also 
be discontinued from PLD (within the scope of this study, if applicable) and entered into the 
90 Day Safety Follow-up Period. 
Patients on Arm B who discontinue PLD for reasons other than disease progression may 
continue taking avelumab until withdrawal criteria are met.
3.1.3. Tumor Assessments
Tumor Assessment: Anti-tumor activity will be assessed by radiological tumor assessments 
per local clinical practice using RECIST version 1.1.
In addition, radiological tumor assessments will also be conducted whenever disease 
progression is suspected (eg, symptomatic deterioration).
CA-125 is no longer required per protocol but may be performed as clinically necessary.  
There is no need to record tumor assessments or CA-125 test results in OC-RCD.
All patients’ files and radiologic images will be collected by Parexel.
Please refer to the new SOA in Appendix 7.
3.1.4. Safety Assessments 
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the new SOA, (Appendix 7).
3.1.5. Biomarker Assessments 
Effective with Amendment 2, biomarker assessments will no longer be performed/collected.
A key objective of the biomarker analyses that will be performed in this study is to 
investigate biomarkers that are potentially predictive of treatment benefit with avelumab or
the combination of avelumab and PLD.  In addition, biomarker studies of tumor and blood 
biospecimens will be carried out to help further understand the mechanism of action of the 
PLD plus avelumab combination, as well as potential mechanisms of resistance. 


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Please refer to the new SOA in Appendix 7.
3.1.6. Pharmacokinetics 
Effective with Amendment 2, pharmacokinetic assessments will no longer be 
performed/collected.
Please refer to the new SOA in Appendix 7.
4. PATIENT SELECTION
Patient Selection Criteria are no longer applicable as enrollment in this study is complete. 
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 
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, 
including malignant mixed Müllerian tumors with high-grade serous component.
2. Platinum-resistant/refractory disease, defined as disease progression within 180 days 
following the last administered dose of platinum therapy (resistant), or lack of 
response or disease progression while receiving the most recent platinum-based 
therapy (refractory), respectively.
3. Received up to 3 lines of systemic anticancer therapy for platinum-sensitive disease, 
most recently platinum-containing, and no prior systemic therapy for 
platinum-resistant disease.
4. Measurable disease by investigator assessment with at least 1 unidimensional 
measurable lesion by RECIST v.1.1 that has not previously been irradiated.
5. At least 18 years of age (20 years of age in Japan).
6. ECOG performance status (PS) 0 to 1.
7. Estimated life expectancy of at least 3 months.
8. Mandatory tumor biopsy must be performed prior to enrollment for all patients 
(unless there is a documented clinical contraindication). In addition, availability of 
archived FFPE tumor tissue should be confirmed. If a patient underwent tumor tissue 
collection within 3 months prior to enrollment with no intervening treatment, and the 
sample is provided, then a new de novo tumor biopsy is not required. 


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9. Adequate bone marrow function, including:
a.
Absolute neutrophil count (ANC) 1.5 x 109/L;
b. Platelet count 100 x 109/L;
c.
Hemoglobin 9 g/dL (may have been blood transfused). 
10. Adequate liver function, including:
a.
Total bilirubin level 1.5 × the upper limit of normal (ULN).
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
2.5 x ULN.
11. Adequate renal function as evidenced by:
a.
Creatinine clearance 50 mL/min as calculated using the Cockcroft-Gault 
equation.
12. Serum/urine pregnancy test (for females of childbearing potential) negative at 
screening.
13. Female patients, of childbearing potential and at risk for pregnancy must agree to use 
two highly effective methods of contraception throughout the study and after the last 
dose of assigned treatment for the following lengths of time. 
a.
Patients who receive avelumab only: for at least 60 days after the last avelumab 
dose.
b. Patients who receive PLD (alone or in combination with avelumab): for at least 
6 months after the last PLD dose.
14. Patients who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
15. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Non-epithelial tumor, or ovarian tumors with low malignant potential (ie, borderline 
tumors).


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2. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA 4) antibody (including 
ipilimumab, tremelimumab or any other antibody or drug specifically targeting T-cell 
co-stimulation or immune checkpoint pathways).
3. Patients with PLD-resistant EOC, as evidenced by lack of response or progression 
within 6 months of the last dose of PLD. 
4. Known symptomatic brain metastases requiring steroids.  Patients with previously 
diagnosed brain metastases are eligible if they have completed their treatment and 
have recovered from the acute effects of radiation therapy or surgery prior to study 
entry, have discontinued corticosteroid treatment for these metastases for at least 
4 weeks prior to study entry and are neurologically stable. 
5. Concurrent anticancer treatment within 28 days prior to study entry, eg, cytoreductive 
therapy, radiotherapy [with the exception of palliative radiotherapy], immunotherapy, 
or cytokine therapy (except for erythropoietin); major surgery within 28 days prior to 
study entry (excluding diagnostic biopsy); use of hormonal agents within 7 days prior 
to study entry; or use of any investigational drug within 28 days prior to study entry.  
Note: patients receiving bisphosphonate or denosumab are eligible provided treatment
was initiated at least 14 days prior to study entry.
6. Diagnosis of any other malignancy within 5 years prior to registration, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix.
7. Any one of the following currently or in the previous 6 months: myocardial 
infarction, congenital long QT syndrome, Torsades de Pointes, arrhythmias (including 
sustained ventricular tachyarrhythmia and ventricular fibrillation, bradycardia defined 
as <50 bpm), right bundle branch block and left anterior hemiblock (bifascicular 
block), unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure (CHF New York Heart Association Class III or IV), 
cerebrovascular accident, transient ischemic attack or symptomatic pulmonary 
embolism. 
8. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 3, atrial fibrillation of any 
grade, or QTcF interval >470 msec at screening (average of triplicate ECG). 
9. Left ventricular ejection fraction (LVEF) <50% by MUGA or echocardiography.
10. Prior anthracycline-related cardiotoxicity or prior anthracycline exposure approaching 
the lifetime limit.
11. Prior organ transplantation including allogeneic stem-cell transplantation.
12. Known history of a positive test for human immunodeficiency virus (HIV) or 
acquired immunodeficiency syndrome (AIDS) related illness. 


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13. Active infection requiring systemic therapy.
14. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
15. Administration of a live vaccine within 30 days prior to study entry.
16. Current or prior use of immunosuppressive medication within 7 days prior to 
randomization.  The following are exceptions to this exclusion criterion:
a.
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of 
prednisone or equivalent;
c.
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication). 
17. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agents.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible.
18. Known severe hypersensitivity reactions to monoclonal antibodies or liposomal 
preparations.  Known hypersensitivity to any component of the Investigational 
Products.
19. Persisting Grade 2 toxicity related to prior therapy; however, Grade 2 sensory 
neuropathy or alopecia is acceptable.
20. Severe gastrointestinal conditions such as clinical or radiological evidence of bowel 
obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 
4 weeks prior to enrollment, or history of inflammatory bowel disease.
21. Other severe acute or chronic medical condition including pneumonitis, or psychiatric 
conditions 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 study treatment administration or may interfere with the interpretation 
of study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study. 
22. Known current alcohol or drug abuse at the time of screening.
23. Pregnant or breastfeeding patients.


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24. 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.
25. Current use or anticipated need for treatment with drugs or foods that are known 
strong CYP3A4 inhibitors, (eg, grapefruit juice or grapefruit/grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, 
voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, 
ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, 
troleandomycin, mibefradil, and conivaptan) or inducers (eg, rifampin, St. John’s 
Wort, phenobarbital, and phenytoin) including their administration within 10 days 
prior to patient registration. The topical use of these medications (if applicable), such 
as 2% ketoconazole cream, is allowed.
26. Current use or anticipated need for drugs that are known strong CYP2D6 inducers 
(eg, rifampin) or inhibitors (eg, bupropion, cinacalcet, fluoxetine, paroxetine and 
quinidine and PgP inducers and inhibitors, including their administration with 10 days 
prior to patient registration. 
4.3. Lifestyle Guidelines 
4.3.1. Contraception
The effect of avelumab on reproduction is unknown.  PLD can cause fetal harm when 
administered to pregnant women. 
Patients of childbearing potential must agree to use two (2) methods of highly effective 
contraception throughout the study and continue for 60 days after the last dose of single 
agent avelumab (Arm A) and for 6 months after the last dose of PLD as single agent or in 
combination with avelumab (Arms C and B, respectively). 
The investigator or his or her designee, in consultation with the patient, will select 
2 appropriate methods of contraception for the individual patient and his/her partner from the 
list of permitted contraception methods (see below) and instruct the patients in their 
consistent and correct use.  Patients need to affirm that they meet the criteria for correct use 
of at least 2 of the selected methods of contraception.  The investigator or his or her designee 
will discuss with the patient the need to use highly effective contraception consistently and 
correctly according to Appendix 7 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 
a selected contraception method is discontinued or if pregnancy is known or suspected in the 
patient.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:


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1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is 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).
6. Female 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 female patients (including females with tubal ligations) will be considered 
to be of childbearing potential.
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 Study Manual. 
To facilitate access to appropriately qualified medical personnel regarding 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 


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the study team for advice on medical questions or problems that may arise during the study.  
The contact number is not intended for use by the patient directly, and if a patient calls that 
number, he or she will be directed back to the investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council for Harmonization (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 study treatments are PLD and avelumab (MSB0010718C).
5.1. Allocation to Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular patient or affect the order in which patients are enrolled.
Once the patient has provided a signed Informed Consent Form (ICF) and has met inclusion 
and exclusion criteria, the Investigator or delegate will request the study treatment 
assignment using the Interactive Response Technology (IRT) system.  Qualified patients will 
be randomized in a 1:1:1 ratio to receive avelumab, alone (Arm A) or avelumab plus PLD,
(Arm B) or PLD alone (Arm C). 
Allocation of patients will be stratified by platinum-refractory or platinum-resistant status, 
number of prior regimens (1 vs 2 or 3), and bulky disease (defined as presence of a tumor 
5 cm) vs not.  
Allocation of patients to treatment arms will proceed through the use of an 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 patient’s date of birth. 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. 
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. 


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5.2. Investigational Product Supplies
Clinical Trial supplies will be shipped to the study sites by Pfizer Global Clinical Supply 
(GCS), Worldwide Research and Development (WRD), and will include a Drug Shipment 
and Proof of Receipt form.  This form will be completed, filed, and the shipment confirmed 
as directed on the bottom of the Drug Shipment and Proof of Receipt form.  The Investigator 
shall take responsibility for and take all steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations.
5.2.1. Dosage Form(s) and Packaging PLD
5.2.1.1. PLD 
PLD is a sterile, translucent, red liposomal dispersion in single intravenous (IV) use vials.  
Each vial contains doxorubicin HCl liposome at a concentration of 2 mg/mL.  Packaging and 
labeling will be in accordance with applicable local regulatory requirements and applicable 
Good Manufacturing Practice (GMP) guidelines.
Pfizer GCS, WRD will provide either branded PLD or generic product available in local 
region. PLD may be sourced by study sites and reimbursed by the Sponsor through the 
contractual agreement with the study institution unless local regulations or other limitation 
require direct provision of PLD by the Sponsor.
PLD will be shipped in transport cool containers (2C to 8C) that are monitored with 
temperature monitoring devices.
5.2.1.2. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20 mg/mL solution and is supplied by the Sponsor in single-use glass vials, 
stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off seal.
Avelumab (MSB0010718C) will be supplied for the study by Pfizer GCS, WRD.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable 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 monitoring devices.


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5.2.2. Preparation and Dispensing
See the Investigational Product Manual (IP Manual) for instructions on 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 and investigational agents.  Both PLD and avelumab will be administered 
at the investigational site.  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.
5.2.2.1. PLD Preparation
The appropriate dose of PLD must be diluted in 5% dextrose solution for infusion prior to 
administration. For doses up to 90 mg, dilute PLD in 250 mL, and for doses greater than or 
equal to 90 mg, dilute PLD in 500 mL.
Refer to the IP Manual for instructions on how to prepare the investigational product for 
administration.  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 IP Manual.  
Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permits.  Do not use if a precipitate 
or foreign matter is present.  Do not use with in-line filters. 
The dose amount required to prepare the PLD infusion solution will be based on the patient’s 
body surface area (m2).  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 >10% from the 
weight used for the last dose calculation.  For weight change less than 10% the decision to 
recalculate the PLD 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.
Dose capping should not be performed.60
The use of gloves is required.  If PLD comes into contact with skin or mucosa, wash 
immediately and thoroughly with soap and water.  Aseptic technique must be strictly 
observed since no preservative or bacteriostatic agent is present in PLD.
Vials are single-use.  Any unused portion of the solution should be discarded in biohazard 
waste disposal with final disposal by accepted local and national standards of incineration.
Handle and dispose of PLD in accordance with recommendations for the handling and 
disposal of hazardous drugs as stated in the locally approved package insert. 


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5.2.2.2. Avelumab Preparation
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives. Any spills that occur should be cleaned up using the facility’s 
standard cleanup 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 
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 every cycle to ensure they did not experience either a weight loss or gain 
>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.
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 prohibited.  Vials are single-use.  
Any unused portion of the solution should be discarded in biohazard waste disposal with 
final disposal by accepted local and national standards of incineration.
5.2.3. Administration
All study treatments will be administered at the investigational site on an outpatient basis as 
detailed in the IP Manual. 
5.2.3.1. PLD Administration
At the visits when both PLD and avelumab are infused (every 4 weeks), PLD will be infused 
prior to the administration of avelumab. There is no need for a window between the 
infusions. Adequate visit time should be scheduled for the patients on the combination arm.
PLD may be administered up to 3 days before or after the scheduled day of administration of 
each cycle due to administrative reasons.
PLD will be administered at the starting dose of 40 mg/m2 every 4 weeks, on Day 1 of each 
cycle. The first dose of PLD should be administered at an initial infusion rate of 1 mg/min.  
If no infusion-related adverse reactions are observed, subsequent PLD infusions may be 
administered over a 60-minute period. Do not rapidly flush the infusion line.  Do not mix 
PLD with other drugs.  Do not use with in-line filters. 


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In order to mitigate infusion-related reactions, patients must be premedicated with an 
antihistamine and paracetamol (acetaminophen) prior to the first 4 infusions of avelumab. 
Premedication will be administered for subsequent avelumab doses based upon clinical 
judgement and presence/severity of prior infusion reactions. The locally approved package 
insert should be used for prescribing details, including the special precautions for patients
who reach lifetime maximums of 450 mg/m2.
5.2.3.2. Management of PLD Extravasation
Discontinue PLD for burning or stinging sensation or other evidence indicating perivenous 
infiltration or extravasation.  Manage confirmed or suspected extravasation as follows:

Do not remove the needle until attempts are made to aspirate extravasated fluid;

Do not flush the line;

Avoid applying pressure to the site;

Apply ice to the site intermittently for 15 min 4 times a day for 3 days;

If the extravasation is in an extremity, elevate the extremity. 
5.2.3.3. Avelumab Administration
Avelumab will be administered at 10 mg/kg on Day 1 and Day 15 of each 4-week cycle after 
all procedures/assessments have been completed as described in Appendix 7.  Avelumab may 
be administered up to 3 days before or after the scheduled day of administration of each cycle 
due to administrative reasons but there should not be less than 10 days between doses.
Avelumab will be administered as a 1-hour IV infusion once every 14 days.  
In order to mitigate infusion-related reactions, patients must be premedicated with an 
antihistamine and paracetamol (acetaminophen) prior to the first 4 infusions of avelumab. 
Premedication will be administered for subsequent avelumab doses based upon clinical 
judgment and presence/severity of prior infusion reactions.
When avelumab is administered alone, premedications should be administered 30-60 minutes 
before the infusion. For Arm B patients, on visits when both PLD and avelumab are infused 
(every 4 weeks) avelumab will be infused after PLD.  If premedication was administered 
prior to PLD, 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. 


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Sites should make every effort to target avelumab infusion timing 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 5.2.6.
5.2.4. Treatment after Initial Evidence of Radiologic Disease Progression 
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 PLD and may
manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiologic imaging shows progression, as assessed by the investigator, avelumab and PLD
must be discontinued. For those patients who are on single-agent avelumab post-progression 
at the time of amendment approval, if they present with a subsequent scan showing disease 
progression, they must discontinue avelumab.
5.2.5. Food Requirements
Both study drugs may be administered without regard to food.
5.2.6. 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.
If a PLD dose reduction is necessary, the PLD dose should be reduced initially to 30 mg/m2, 
and then down to 20 mg/m2 if a second dose reduction is required.  Management of patients 
requiring more than 2 PLD dose reductions should be discussed with the Sponsor.  Do not 
increase PLD dose after a prior dose reduction due to toxicity.
Table 4.
Dose Modifications for PLD
Dose Level
PLD
Starting dose
40 mg/m2 
First dose reduction
30 mg/m2
Second dose reduction
20 mg/m2
For avelumab, no dose modifications are permitted in this study, but doses may be omitted 
based on persisting toxicity. 


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For patients on avelumab plus PLD combination treatment, PLD dose modifications as well 
as infusion omissions/ delays for PLD and/or avelumab may occur independently for the two 
drugs according to the guidance provided below for each individual drug and investigator’s 
medical judgment and will be reported in the CRF. If PLD is delayed by 1 week, avelumab 
should also be delayed by 1 week so that PLD and avelumab are administered together.  
Some potential immune-related adverse events described with anti-PD-L1 drugs such as 
avelumab may overlap with PLD toxicities such as rash or diarrhea.  For patients on 
avelumab or combination treatment with avelumab and PLD, any adverse event suspected to 
be immune-related should be managed according to the guidance for management of 
immune-related adverse events Appendix 9: Management of Immune-related Adverse 
Events).  In case of a potential irAE, besides the management related to avelumab therapy, 
PLD doses may also be modified or interrupted based on the guidance provided for PLD 
toxicity management (Section 5.2.8.2 PLD Infusion-related Reaction), product labeling, and 
institutional guidelines according to investigator’s medical judgment.
Additional guidance for the management of avelumab-PLD combination is provided for 
Neutropenia and Thrombocytopenia (Table 7), Palmar-Plantar Erythrodysesthesia 
(Hand-Foot Syndrome) (Table 9), and Stomatitis (Table 10).
For toxicity management, the following tables/appendix should be referenced as appropriate.
Section 5.2.7.1
Avelumab: Adverse Drug Reactions Requiring Avelumab 
Discontinuation or Delays
Section 5.2.7.2.1
Avelumab: Special Precautions for Administration
Section 5.2.7.2
Table 5
Avelumab: Infusion Related Reactions
Section 5.2.7.2.2
Avelumab Severe Hypersensitivity Reactions and Flu like 
Symptoms
Appendix 9
Avelumab: Immune related Adverse Events
Table 7
PLD and avelumab PLD combination: Treatment Modification 
for Neutropenia and Thrombocytopenia
Section 5.2.8.2
Table 8
PLD: Infusion-Related Reactions (Hypersensitivity Reactions)
Table 9
PLD and avelumab PLD combination: Treatment modification 
for Palmar Plantar Erythrodysesthesia Hand Foot Syndrome,
HFS)
Table 10
PLD and avelumab PLD combination: Treatment modification 
for Stomatitis


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Table 11
PLD: Treatment Modification for other Non-Hematologic 
Toxicities and Laboratory Abnormalities
Section 5.2.9
All patients: Treatment modification for Left Ventricular 
Ejection Fraction Decreased
Figure 2
Tumor Lysis Syndrome
5.2.7. Guidelines for Avelumab Toxicity Management 
5.2.7.1. Avelumab: Adverse Drug Reactions Requiring Discontinuation or Delays
The following adverse drug reactions (ADRs) require permanent treatment discontinuation of 
avelumab:
Any Grade 4 ADRs require permanent treatment discontinuation with avelumab 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 permanent treatment discontinuation of avelumab except 
for any of the following:

Transient (6 hours) Grade 3 flu-like symptoms or fever, which are controlled with 
medical management.

Transient (24 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis 
that resolve to Grade 1.

Transient Grade 3 diarrhea (24 hours) that resolves to Grade 1 or less without 
administration of steroids.

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 phenomena defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor.

Change in 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).


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For any Grade 2 ADR, avelumab dosing should be managed as follows:

If a Grade 2 ADR resolves to Grade 1 prior to the next scheduled dose, treatment 
may continue.

If a Grade 2 ADR does not resolve to Grade 1 prior to the next scheduled dose,
infusions should be withheld.  If by the following scheduled infusion the event has 
not resolved to Grade 1, the patient should permanently discontinue treatment (except 
for hematological toxicities and 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 or hematologic toxicities) 
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 5.2.7.2.1, 
5.2.7.2.2, 5.2.10, respectively.
5.2.7.2. Avelumab: Infusion-related Reactions and Hypersensitivity Reactions
5.2.7.2.1. Avelumab: Special Precautions for Administration
In order to mitigate infusion-related reactions, patients must be premedicated with an 
antihistamine and paracetamol (acetaminophen) prior to the first 4 infusions of avelumab. 
Premedication will be administered for subsequent avelumab doses based upon clinical 
judgment and presence/severity of prior infusion reactions. See Section 5.2.3.3 for 
instructions for patients on combination treatment. 
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.
Infusion of avelumab will be stopped in case of Grade 2 infusion-related, allergic, or 
anaphylactic reactions.  Following the first 4 avelumab infusions, patients must be observed 
for 2 hours post-infusion for potential infusion-related reactions.  If no infusion reaction 
occurs in relation to the first 4 infusions, the post-infusion observation period may be 
discontinued.  During this 2-hour observation period the patient should remain in a location
where they can be observed by site staff. Vital sign measurements or other procedures are 
not required unless clinically indicated. 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 


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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. 
Table 5.
Avelumab: Treatment Modifications for Symptoms of Infusion-related 
Reactions
NCI-CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not indicated; 
intervention not indicated.
Decrease Avelumab infusion rate by 50% and monitor 
closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, i.v. fluids); prophylactic medications 
indicated for 24 hours.
Stop Avelumab infusion.
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased to at 
least Grade 1 in severity, and monitor closely for any 
worsening.
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 
infusion tubing from the patient.
Patients have to be withdrawn immediately from 
Avelumab treatment and must not receive any further 
Avelumab treatment.
i.v.=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the Avelumab infusion rate has been decreased by 50% due to an infusion-related 
reaction, it must remain decreased for all subsequent infusions.
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 5 (including reducing the infusion 
rate by 50%), the investigator may consider treatment with corticosteroids and the infusion 
should be stopped for that day.  At the next cycle, the investigator may consider the addition 
of H2-blocker antihistamines (eg, famotidine or ranitidine), in addition to the mandatory 
premedication.  However, prophylactic steroids are NOT permitted.  If the patient has a 
second infusion-related reaction Grade 2 on the slower infusion rate, with or without the 
addition of further medication to the mandatory premedication, the infusion should be 
stopped and the patient removed from avelumab treatment.


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5.2.7.2.2. Avelumab: Severe Hypersensitivity Reactions and Flu-like Symptoms
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 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.
5.2.7.2.3. Avelumab: Immune-related Adverse Events
Because inhibition of PD-L1 stimulates the immune system, irAEs may occur.  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 or avelumab-PLD combination, any event suspected to be 
immune-related should be managed according to the guidance for management of 
immune-related adverse events in this Section 5.2.7.2.3 and Appendix 9.  In case of a 
potential irAE, besides the management related to avelumab therapy, PLD doses may also be 
modified or interrupted based on the guidance provided for PLD toxicity management in 
Section 5.2.8.2, product labeling, and institutional guidelines according to investigator’s best 
medical judgement.
Effective with Amendment 2, Table 6 below is no longer applicable and has been 
replaced with Appendix 9. Please follow Appendix 9 for all management of 
immune-related adverse events. 


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Table 6.
No Longer Applicable: 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 
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 
If improves to Grade 1: 
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic 
infections 


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1.0 to 2.0 mg/kg/day 
methylprednisolone IV or IV 
equivalent 
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 
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 


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opportunistic infections, and resume avelumab 
therapy
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. 
Cardiac irAEs
Myocarditis
Management
Follow-up
New onset of cardiac signs or
symptoms and / or new laboratory
cardiac biomarker elevations 
(eg, troponin, CK-MB, BNP) or 
cardiac imaging abnormalities 
suggestive of myocarditis.
Withhold avelumab therapy
Hospitalize in the presence of
life threatening cardiac
decompensation, consider
transfer to a facility
experienced in advanced
heart failure and arrhythmia
management
Cardiology consult to
establish etiology and rule out
immune-mediated
myocarditis.
Guideline based supportive
treatment as per cardiology
consult.*
Consider myocardial biopsy if
recommended per cardiology
consult.
If symptoms improve and immune-mediated
etiology is ruled out, re-start avelumab therapy.
If symptoms do not improve/worsen, viral
myocarditis is excluded, and immune mediated
etiology is suspected or confirmed following 
cardiology consult, manage as
immune-mediated myocarditis.
Immune-mediated myocarditis
Permanently discontinue
avelumab.
Guideline based supportive
treatment as appropriate as per 
cardiology consult.*
Methylprednisolone 1 to 
2 mg/kg/day
Once improving, taper steroids over at least 
1 month and add prophylactic antibiotics for
opportunistic infections.
If no improvement or worsening, consider
additional immunosuppressants 
(eg, azathioprine, cyclosporine A)
*Local guidelines, or eg. ESC or AHA guidelines
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
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 


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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 
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 Event, anti-inflammatory drugs, T4=free thyroxine, TSH=thyroid-stimulating hormone, 
ULN=upper limit of normal.
5.2.8. Guidelines for PLD Single Agent and Avelumab-PLD Combination Toxicity 
Management 
Dose modification (dose delays and dose change) for PLD due to ADRs should be made in 
accordance with the guidance provided below, product labeling and institutional guidelines.  
Starting dose for PLD and dose reduction levels are described in Table 4 Dose Modification
for PLD. 
5.2.8.1. PLD Single Agent and Avelumab-PLD Combination: Neutropenia and 
Thrombocytopenia
ANC must be 1.5 x 109/L and the platelet count 75 x 109/L prior to the beginning of the 
following course of treatment. For patients who do not achieve haematological recovery on 
scheduled day of PLD treatment, complete blood counts should be performed twice weekly 
until the above defined limits are achieved. If haematological recovery is achieved within 
14 days after the scheduled day of PLD treatment, resume PLD at the previous dose. If 
haematological recovery is not achieved 14 days or more after the scheduled day of the 
course, the patient will discontinue treatment. Administration of G-CSF or EPO is permitted 
according to approved indications and scientific recommendations.


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Table 7.
PLD Single Agent and Avelumab-PLD Combination: Treatment 
Modification for Neutropenia and Thrombocytopenia
Neutropenia and 
Thrombocytopenia
PLD single agent
Avelumab-PLD combination*
Grade 1
No PLD dose 
reduction/delay
No PLD dose reduction/delay
Continue avelumab as per schedule
Grade 2
Delay PLD until 
toxicity resolves to 
ANC 1.5 x 109/L, 
platelets 75 x 
109/L; then resume 
PLD at previous 
dose.**
Delay PLD until toxicity resolves to ANC 1.5 x 109/L, platelets 
75 x 109/L; then resume PLD at previous dose.**  Continue avelumab 
as per schedule.
Grade 3  
Delay PLD until 
toxicity resolves to 
ANC 1.5 x 109/L, 
platelets 75 x 
109/L; then resume 
PLD at previous 
dose.**
If Grade 3 toxicity 
recurs, follow 
institutional 
guidelines. 
Delay PLD until toxicity resolves to ANC 1.5 x 109/L, platelets 
75 x 109/L; resume PLD at previous dose.**  Continue avelumab as per 
schedule.
If Grade 3 toxicity recurs, delay PLD and avelumab until toxicity 
resolves to ANC 1.5 x 109/L, platelets 75 x 109/L; then resume PLD 
at reduced dose** and avelumab at standard dose.
If Grade 3 toxicity recurs with PLD at reduced dose, delay PLD until 
toxicity resolves to ANC 1.5 x 109/L, platelets 75 x 109/L: then
resume PLD at the next reduced dose. **
For avelumab, 

If toxicity resolves to ANC 1.5 x 109/L, platelets 
75 x 109/L within 14 days, resume avelumab at the standard 
dose. 

If toxicity resolves to ANC 1.5 x 109/L, platelets 
75 x 109/L in >14 days, permanently discontinue avelumab. 
Grade 4
Delay PLD until 
toxicity resolves to 
ANC 1.5 x 109/L, 
platelets 75 x 
109/L; then resume
PLD at reduced dose 
level or continue at 
previous dose with 
prophylactic 
granulocyte growth 
factor support.**
Delay PLD and avelumab until toxicity resolves to Grade 1; then
resume PLD at reduced dose level** and avelumab at standard dose.
If Grade 4 toxicity recurs with PLD at reduced dose, delay PLD until 
toxicity resolves to ANC 1.5 x 109/L, platelets 75 x 109/L: then
resume PLD at the next reduced dose.** For avelumab, 

If toxicity resolves to ANC 1.5 x 109/L, platelets 
75 x 109/L within 14 days, resume avelumab at the standard 
dose. 

If toxicity resolves to ANC 1.5 x 109/L, platelets 
75 x 109/L in >14 days, permanently discontinue avelumab.
* For patients on avelumab alone, refer to Section 5.2.7.1.
**If haematological recovery is achieved within 14 days after the scheduled day of PLD treatment, resume PLD 
at the previous dose. If PLD is delayed by 1 week, avelumab should be delayed by 1 week so that PLD and 
avelumab are administered together.  If haematological recovery is not achieved 14 days or more after the 
scheduled day of the course, the patient will permanently discontinue treatment.
5.2.8.2. PLD: Infusion-Related Reactions (Hypersensitivity Reactions)
Serious and sometimes life-threatening infusion-related reactions characterized by one of 
more of the following symptoms can occur with PLD: flushing, shortness of breath, facial 
swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, 
tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and 
hypotension.  The majority of the infusion-related events occur during the first infusion. 


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Ensure that medications to treat infusion-related reactions and cardiopulmonary resuscitative
equipment are available for immediate use prior to initiation of PLD.  Initiate PLD infusion 
at a rate of 1 mg/min and increase rate as tolerated.  In the event of an infusion-related 
reaction, temporarily stop the drug until resolution, then resume at a reduced infusion rate.  
Discontinue PLD infusion for serious or life-threatening infusion-related reactions. 
In order to mitigate PLD infusion-related reactions, a premedication regimen as described in 
Section 5.2.3.1 may be administered.
PLD treatment modifications for infusion-related reactions are presented in Table 8.
Table 8.
PLD Single Agent and PLD-avelumab Combination: Treatment 
Modification for PLD Infusion-Related Reactions
NCI-CTCAE Grade 
Treatment Modification for PLD (both PLD 
single agent and PLD-avelumab 
combination*)
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Temporarily stop PLD until resolution then 
resume at a reduced infusion rate per local 
practice.**
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, i.v. fluids); prophylactic medications 
indicated for 24 hours.
Temporarily stop PLD until resolution then 
resume at a reduced infusion rate per local 
practice.**
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.
Permanently discontinue PLD infusion.**
* If PLD is delayed by 1 week, avelumab should be delayed by 1 week so that PLD and avelumab are 
administered together.  
** Following Grade 1 or Grade 2 infusion reaction to PLD, PLD should be administered as follows: 5% of 
the total dose should be infused slowly over the first 15 minutes. If tolerated without reaction, the infusion 
rate may then be doubled for the next 15 minutes. If tolerated, the infusion rate may then be completed over 
the next hour for a total infusion time of 90 minutes.


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5.2.8.3. PLD: Palmar-Plantar Erythrodysesthesia (Hand Foot Syndrome)
Table 9.
PLD Single Agent and Avelumab-PLD Combination: Treatment 
modification for Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome) 
(HFS)
NCI CTCAE Grade 
PLD single agent
PLD-avelumab combination*
Grade 1: Mild 
erythema, swelling, or 
desquamation not interfering 
with daily activities.
If no previous Grade 3 or 4 HFS: 
Continue PLD as planned.
If previous Grade 3 or 4 HFS: delay 
PLD dose up to 2 weeks, then resume 
PLD at decrease dose level.
If no previous Grade 3 or 4 HFS: Continue 
PLD as planned.
If previous Grade 3 or 4 HFS: delay PLD dose 
up to 2 weeks, then resume PLD at decrease 
dose level.
Continue avelumab as per schedule.**
Grade 2: Erythema,
desquamation, or swelling 
interfering with, but not 
precluding normal physical 
activities; small blisters or 
ulcerations less than 2 cm in 
diameter.
Delay PLD dosing up to 2 weeks or 
until resolved to Grade 1.

If no resolution to Grade 1 within 
2 weeks, discontinue PLD. 

If resolved to Grade 1 within 
2 weeks, and no previous Grade 3 
or 4 HFS: continue PLD treatment 
at previous dose.

If resolved to Grade 1 within 
2 weeks but previous Grade 3 or 4 
HFS: resume PLD treatment at 
decreased dose level.
Delay PLD dosing up to 2 weeks or until 
resolved to Grade 1.

If no resolution to Grade 1 within 2 
weeks, discontinue PLD. 

If resolved to Grade 1 within 2 weeks, 
and no previous Grade 3 or 4 HFS: 
continue PLD treatment at previous dose.

If resolved to Grade 1 within 2 weeks 
but previous Grade 3 or 4 HFS: resume 
PLD treatment at decreased dose level.
Delay avelumab until resolved to Grade 1
then resume avelumab. 
If Grade 2 event HFS recurs, delay avelumab 
until resolved to Grade 1; then and resume 
avelumab.
Grade 3: Blistering, 
ulceration, or swelling 
interfering with walking or 
normal daily activities; 
cannot wear regular 
clothing.
Delay PLD dosing up to 2 weeks or 
until resolved to Grade 1, then resume 
PLD treatment at decreased dose level.
Discontinue PLD if there is no 
resolution after 2 weeks.
Delay PLD dosing up to 2 weeks or until 
resolved to Grade 1, then resume PLD 
treatment at decreased dose level.
Discontinue PLD if there is no resolution after 
2 weeks.
Delay avelumab until resolved to Grade 1; 
then resume avelumab.
If PLD treatment was permanently 
discontinued and Grade 3 HFS subsequently 
recurs, avelumab should also be permanently 
discontinued.
Grade 4: Diffuse or local 
process causing infectious 
complications, or a bed 
ridden state or 
hospitalization.
Delay PLD dosing up to 2 weeks or 
until resolved to Grade 1, then resume 
PLD treatment at decreased dose level.
Discontinue PLD if there is no 
resolution after 2 weeks.
Delay avelumab until resolved to Grade 1;
then resume avelumab.
If PLD treatment was permanently 
discontinued and Grade 4 HFS recur, 
avelumab should also be permanently 
discontinued.
* For PLD-avelumab combination, PLD dosing should be managed as per PLD guidance. 
**If PLD is delayed by 1 week, avelumab should be delayed by 1 week so that PLD and avelumab are 
administered together.  


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5.2.8.4. PLD: Stomatitis
Table 10.
PLD Single and Avelumab-PLD Combination: Treatment Modification for 
Stomatitis
NCI CTCAE Grade
PLD single agent
Avelumab-PLD combination*
Grade 1: Painless ulcers, erythema, or 
mild soreness.
If no previous Grade 3 or 4 stomatitis: 
continue PLD as planned.
If previous Grade 3 or 4 stomatitis: 
delay PLD up to 2 weeks then resume 
PLD at decreased dose level.
Continue avelumab as per 
schedule.**
Grade 2: Painful erythema, edema, or 
ulcers, but can eat.
Delay PLD dosing up to 2 weeks or 
until resolved to Grade 1. 

If no resolution within 2 weeks 
discontinue PLD.

If resolved to Grade 1 within 
2 weeks, and no previous Grade 3 
or 4 stomatitis: resume PLD 
treatment at previous dose level.

If resolved to Grade 1 within 
2 weeks, but previous Grade 3 or 
4 stomatitis, resume PLD 
treatment at decreased dose level.
Delay avelumab until resolved to 
Grade 1, then resume avelumab.
If Grade 2 stomatitis recurs delay 
avelumab until resolved to Grade 1; 
then resume avelumab.
Grade 3: Painful erythema, edema, or 
ulcers, and cannot eat
Delay PLD dosing up to 2 weeks or 
until resolved to Grade 1; then
resume PLD at decreased dose level.
If after 2 weeks there is no resolution, 
discontinue PLD.
Delay avelumab until resolved to 
Grade 1 then resume avelumab.
If PLD treatment was permanently 
discontinued and Grade 3 stomatitis 
recurs, avelumab should also be 
permanently discontinued.
Grade 4: Requires parenteral or 
enteral support
Delay PLD dosing up to 2 weeks or 
until resolved to Grade 1 then resume 
treatment at decreased dose level.
If after 2 weeks there is no resolution, 
discontinue PLD.
Delay avelumab until resolved to 
Grade 1; then resume avelumab.
If PLD treatment was permanently 
discontinued and Grade 4 stomatitis 
recurs, avelumab should also be 
permanently discontinued.
* For PLD-avelumab combination, PLD dosing should be managed as per PLD guidance. 
**If in the combination arm, PLD is delayed by 1 week, avelumab should be delayed by 1 week so that PLD 
and avelumab are administered together.  


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5.2.8.5. PLD: Other Non-Hematologic Toxicities and Laboratory Abnormalities
Table 11.
PLD: Treatment Modification for Other Non-Hematologic Toxicities and 
Laboratory Abnormalities
Other non-hematologic toxicities and laboratory 
abnormalities
PLD
Grade 1
No PLD dose reduction
Grade 2
No PLD dose reduction
Grade 3  
Delay PLD until toxicity resolves to Grade 1; then 
resume PLD at decreased dose level
Grade 4
Delay PLD until toxicity resolves to Grade 1; then 
resume PLD at decreased dose level
5.2.9. Left Ventricular Ejection Fraction Decreased
If a patient’s LVEF drops below institutional limit of normal or by at least 15% (absolute 
percentage points) from baseline value, study treatment (avelumab, PLD or combination) 
should be discontinued.  LVEF should be re-assessed within 45 days and every three months 
until full recovery.  Upon full recovery, defined as LVEF increase to within 5% (absolute 
percentage points) of baseline within 45 days from LVEF nadir, study treatment (avelumab, 
PLD or combination) can be resumed at investigator’s discretion. Continuation of treatment 
should be followed by additional LVEF evaluation within 2 weeks.
5.2.10. Tumor Lysis Syndrome
Tumor lysis syndrome should be treated per the local guidelines and the management 
algorithm published by Howard et al.19


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


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5.3. Drug Storage and Drug Accountability 
5.3.1. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure avelumab and 
PLD are stored in a secured area with controlled access under required storage conditions and 
in accordance with applicable regulatory requirements.
The Investigational Product should be stored in its original container and in accordance with 
the locally approved label.

Refrigerate unopened vials of PLD at 2- 8C (36– 46F).  Do not freeze.  Handle 
and dispose of PLD consistent with recommendations for the handling and disposal of 
hazardous drugs. 

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 stated in the single reference safety document (SRSD) (Investigator 
Brochure) will be superseded by storage conditions stated in the labeling.  Reference the 
locally approved label for PLD storage recommendations. 
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, must be regularly inspected to ensure it 
is maintained in working order. 
Any excursions from the product label storage conditions must be reported upon discovery.  
The site must 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.


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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. 
5.3.2. Investigational Product Accountability
The Investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product.  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.
5.4. 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 
vaccine(s).
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/treatment will not be captured in OC-RDC unless they contribute 
or are associated with the treatment for an AE. 


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Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
The restrictions described within this paragraph apply to patients receiving PLD (Arm B and 
C) and should not be applied to patients receiving avelumab only (Arm A). Doxorubicin is a 
major substrate of cytochrome P450 CYP3A4 and CYP2D6, and P-glycoprotein (P-gp).  
Clinically significant interactions have been reported with inhibitors of CYP3A4 (eg,
ketoconazole, erythromycin, ciprofloxin), CYP2D6 (eg, paroxetine, fluoxetine, and/or P-gp 
(eg, verapamil), resulting in increased concentration and clinical effect of doxorubicin.  
Inducers of CYP3A4 (eg, phenobarbital, phenytoin, St. John’s Wort) and P-gp inducers may 
decrease the concentration of doxorubicin.  Avoid concurrent use of doxorubicin with strong 
inhibitors and strong inducers of CYP3A4, CYP2D6, or P-gp.
5.4.1. Concomitant Radiotherapy
Local radiotherapy (limited field) of isolated lesions with palliative intent is acceptable and 
allowed throughout the study (ie, 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 increased localized pain. If palliative 
radiotherapy is needed to control pain, the site(s) of disease causing pain should be present at 
baseline; otherwise, painful lesion(s) requiring radiotherapy will be considered as a sign of 
disease progression. The sponsor’s Medical Monitor should be consulted prior to starting 
radiotherapy and prior to restarting study treatment after the end of radiotherapy.
5.4.2. Supportive Care 
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines. 
5.4.3. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the first 4 weeks (1 cycle) of treatment but they may be used at any time to treat 
treatment-emergent neutropenia as indicated by the current American Society of Clinical 
Oncology (ASCO) guidelines.42
In subsequent cycles, the use of hematopoietic growth factors is at the discretion of the 
treating physician in line with local guidelines.  Patients who enter the study on stable doses 
of erythropoietin or darbepoietin may continue this treatment, and patients may start either 
drug during the study at the discretion of the treating physician.
5.4.4. Therapy for Nausea, Vomiting, and Diarrhea 
Primary prophylaxis of nausea and vomiting is permitted for PLD according to institutional 
guidelines.  The choice of the prophylactic drug is up to the investigator assuming the drug is 
not included in the Concomitant Treatment(s) section, as well as the duration of treatment 
assuming there is no known or expected drug-drug interaction.  If so it must be approved by 
the sponsor.  


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Primary prophylaxis of diarrhea is not permitted.
5.4.5. Surgery 
No formal studies of the effect of PLD or avelumab on wound healing have been conducted; 
however, caution is advised based on the mechanism of action. Of note, no surgical risk has 
been identified with immune checkpoint inhibitors. No surgical precautions are mentioned in 
pembrolizumab, nivolumab or atezolizumab product labels.  If a major surgery or an 
interventional procedure (eg, endoscopy) is required, treatment with PLD or avelumab must 
be interrupted.  Patients may resume PLD or 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).
Avelumab treatment does not need to be delayed for minor surgical procedures that do not 
involve general anesthesia.
5.4.6. Other Prohibited Concomitant Medications
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 PLD and avelumab. 

Radiation therapy (with the exception noted above in the Concomitant Radiotherapy 
Section 5.4.1). 

Any vaccine therapy for the prevention of infectious disease except for inactivated 
vaccines.

Herbal remedies or vitamins used as anticancer treatments. Herbal remedies with 
immunostimulating properties (eg, mistle toe extract) or known to potentially 
interfere with major organ function (eg, hypericin).
Clarifications About Steroid Use: Data indicate that corticosteroids have an adverse effect 
on T cell function and that they inhibit and damage lymphocytes.26,27 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-CTLA-4 compounds indicate that 
short-term use of steroids may be employed without compromising clinical outcomes.28
Therapeutic and/or prophylactic corticosteroids may be used as needed per standard of care 
at your site.
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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5.5. Rescue/Escape/Salvage Medication
5.5.1. Supportive Care Guidelines 
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.

Nausea/Vomiting: Nausea and vomiting should be treated aggressively in accordance 
with clarifications about steroid use in Section 5.4.6, 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 Appendix 9.

Anti-inflammatory or narcotic analgesics may be offered as needed.  
Acetaminophen/paracetamol to a maximum total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited.

Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anticoagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed. 
6. STUDY PROCEDURES 
6.1. Screening
Screening procedures are no longer applicable at this time. Please refer to the new SOA in 
Appendix 7.
6.1.1. Tumor Biospecimens
Effective with Amendment 2, tumor samples will no longer be performed/collected.
A mandatory archived FFPE tumor tissue block must be provided that is of sufficient size to 
allow, if possible, for sectioning of ten (10) 5-micron tissue sections.  If an FFPE tumor 
tissue block cannot be provided, sites should provide preferably, fifteen (15), but a minimum 
of ten (10) unstained slides each containing a 5-micron tissue section cut serially (and 
numbered accordingly) from the same FFPE block.  If tissue from multiple surgeries is 


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available, the most recent specimen should be submitted.  If archived FFPE tissue is not 
available, a de novo (ie, fresh) tumor sample must be obtained in accordance with the details 
specified in the Study Manual.  These biospecimens should be provided at the time of 
screening.  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.
In this study, archival tissue is expected to come from primary diagnosis, and may be months 
or years old. Therefore, in addition to archival FFPE tumor tissue block, a de novo (ie, fresh 
biopsy) tumor sample must be collected prior to enrollment unless clinically contraindicated. 
If a patient underwent tumor tissue collection within 3 months prior to enrollment with no 
intervening treatment, and the sample is provided, then a new de novo tumor biopsy is not 
required.  Assessments on the de novo biospecimens will mirror the assessments on the 
archival biospecimens to provide more data on tumoral and immunological changes which 
may occur over the course of therapy.  Tumor tissue from cytologic sampling (eg, fine needle 
aspiration, including FFPE cell pellet material), is not adequate and should not be submitted. 
The biopsy sample(s) should be formalin-fixed and paraffin-embedded as specified in the 
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.
Following informed consent, patients who complete baseline studies and are eligible for 
randomization should start study treatment within 3 days of randomization.
Please refer to the new SOA in Appendix 7.
6.2. Study Period 
For On-Treatment procedures, please refer to the new SOA in Appendix 7.
6.3. End of Treatment and Follow-up Visits
6.3.1. Safety
Safety follow-up visits will be scheduled up to 90 days after the last dose of study treatment.
6.3.2. Follow-up Visits
Patients who discontinue study treatment for any reason will be followed for 90 days after 
the last dose of study treatment.   
For End of Treatment and Follow-Up visit procedures, see the new SOA in Appendix 7.
6.4. End of Study
The study will end when all patients have been discontinued from study therapy (avelumab 
and PLD) and have completed the 90 Day Safety Follow-Up period.


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6.5. Patient Withdrawal
Patients may withdraw from treatment 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 discontinuation of study treatment may include:

Objective disease progression, as assessed by the investigator;

Global deterioration of health status;

Unacceptable toxicity.  For patients receiving the avelumab-PLD combination, if the 
unacceptable toxicity is attributed to PLD, the Investigator (in discussion with the 
Sponsor) may continue treatment with avelumab;

Pregnancy;

Significant protocol deviation;

Loss to follow-up;

Refusal of further treatment (follow-up permitted by patient);

Study termination by Sponsor;

Death.
Patients must be withdrawn from the study in case of:

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 the patient to 


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return for a final visit, if applicable, and follow up with the patient regarding any 
unresolved AEs;

If the patient withdraws from the study, and also withdraws consent for disclosure of 
future information, no further evaluations should be performed, and no additional 
data should be collected.  The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
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 
which he/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.
7.1. Safety Assessment
Safety assessments included collection of AEs, Serious Adverse Events (SAEs), vital signs, 
and physical examination, ECG (12-lead), ECHO or MUGA, laboratory assessments, 
including pregnancy tests and verification of concurrent medications. Abnormal findings 
identified prior to first dose of study treatment should be documented in medical history.  
Please see Appendix 7 for current safety assessment requirements. 
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting study 
therapy - once at the start of screening and once at baseline visit immediately before the
investigational product administration.  Following a negative pregnancy test result at 
screening, appropriate contraception must be commenced and another negative pregnancy 
test result will then be required at the baseline visit before the patient may receive the study 
treatment.  Urine pregnancy tests will also be routinely repeated at every treatment cycle 
during the active treatment period, at the end of study treatment, 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 treatment but may remain in the 
study. 
Additional pregnancy tests may also be undertaken if requested by Institutional Review 
Board/IRB/IECs or if required by local regulations.


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7.1.2. Adverse Events
7.1.2.1. Adverse Events of Special Interest for Avelumab

Any AE that is suspected to be a potential irAE is considered an AE of special 
interest (AESI).  Specific guidance for the management of immune-related AEs is 
provided in Section 5.2.7.2.3, Appendix 9 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 the new SOA in Appendix 7 and analyzed at local laboratories.  They may also be 
performed when clinically indicated and need not be recorded in OC-RDC, unless the 
findings support an AE.
The required laboratory tests are listed in Table 12. Chemistry and hematology results 
should be available for review prior to infusion of treatment.


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Table 12.
Required Laboratory Tests
Hematology
Hemoglobin
Platelets
WBC
Absolute Neutrophils
Percentages allowed only if Absolute not available
Chemistry 
(*denotes core chemistry panel)
ALT
AST
Alkaline Phosphatase
Total Bilirubin
Creatinine
Glucose (non-fasted) 
Amylase
Gamma glutamyl transferase (GGT)
Creatine kinase
Lipase 
Pregnancy Tests
For female patients of childbearing potential, serum or urine
Thyroid Function Tests:
TSH, free T4
Other Tests: 
ACTH
°
For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, 
prothrombin time (PT)/INR, alkaline phosphatase.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
GGT=gamma-glutamyltransferase, LDH=lactate dehydrogenase, TSH=thyroid-stimulating hormone, 
WBC=white blood cell.
7.1.4. Vital Signs and Physical Examinations
Effective with Amendment 2, vital signs including weight, blood pressure, and pulse rate 
(height measured at screening only) are to be performed per the new SOA in Appendix 7. 
These need not be recorded in OC-RDC, unless the findings support an AE.
Effective with Amendment 2, PEs and ECOG performance status are not required per 
protocol, but may be performed as clinically necessary. These need not be recorded in 
OC-RDC, unless the findings support an AE.  
Clinically significant findings must be reported as AEs. 
7.1.5. Electrocardiogram Measurements
Effective with Amendment 2, ECG assessments are not required per protocol but may be 
performed as clinically necessary and need not be recorded in OC-RDC, unless the findings 
support an AE.
Clinically significant findings seen on ECGs must be recorded as adverse events. Please 
refer to the new SOA in Appendix 7.


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7.2. Patient-Reported Outcome Assessments 
Effective with Amendment 2, patient reported outcome assessments will no longer be 
performed/collected.
In the treatment of ovarian cancer it is important to increase survival and palliate symptoms 
as disease symptoms have a negative impact on health related quality of life.29,30,31  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 patient 
well-being.  It is critical to assess the PROs using validated instruments.32 In this trial, PROs 
will be assessed using published and validated instruments: EORTC QLQ-C30, EORTC 
QLQ-OV28, and EQ-5D-5L (Appendix 6).
Please refer to the new SOA in Appendix 7.
7.2.1. EORTC QLQ-C30
Effective with Amendment 2, EORTC QLQ-C30 will no longer be performed/collected.
The EORTC QLQ-C30 is a published, validated and self-administered patient reported 
outcome questionnaire.33,34 The EORTC QLQ-C30 is a 30-question survey and includes 
5 functional domain subscales, including a physical functioning sub-scale, a role functioning 
subscale, an emotional functioning sub-scale, a cognitive functioning sub-scale and a social 
functioning subscale.  Higher scores on the functioning domains are indicative of higher 
levels of functioning.  Oncology-related symptoms of the EORTC QLQ-C30 include fatigue 
(3 items), pain (2 items), nausea and vomiting (2 items), and dyspnea, insomnia, appetite 
loss, constipation, diarrhea, and financial impact (1 item each).  Higher scores are reflective 
of a greater presence of symptoms.
7.2.2. EORTC QLQ-OV28
Effective with Amendment 2, EORTC QLQ-OV28 will no longer be performed/collected.
The EORTC QLQ-OV-28 is the ovarian cancer-specific module of the EORTC quality of life 
questionnaire.35,36  The EORTC QLQ-OV-28 is a 28 item instrument with seven (7) 
functional domain subscales.  The 7 subscales include:  (i) an abdominal/gastrointestinal 
symptom subscale (7 items); (ii) a peripheral neuropathy subscale (3 items); (iii) an other 
chemotherapy side effects subscale (7 items); (iv) a hormonal/menopausal symptoms 
subscale (2 items); (v) a body image subscale (2 items); (vi) an attitude to disease and 
treatment subscale (3 items) and (vii) a sexual function subscale (4 items).  Similar to the 
EORTC QLQ-C30 higher scores are reflective of a greater presence of symptoms.
7.2.3. EQ-5D-5L
Effective with Amendment 2, EQ-5D-5L will no longer be performed/collected.
The EQ-5D-5L is a patient-completed questionnaire designed to assess health status in terms 
of a single index value or utility score.37,38,39  There are 2 components to the EQ-5D-5L: a 
Health State Profile which has individuals rate their level of problems (none, slight, 


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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.39
7.3. Pharmacokinetic Assessments 
Effective with Amendment 2, pharmacokinetic assessments will no longer be 
performed/collected.
7.3.1. Blood Sample Collection for Pharmacokinetic Analysis
Effective with Amendment 2, blood sample collection for pharmacokinetic analysis will no 
longer be performed/collected.
7.3.2. Immunogenicity Assessment
Effective with Amendment 2, immunogenicity assessments will no longer be 
performed/collected.
7.4. Translational and Pharmacodynamic Assessments
Effective with Amendment 2, translational and pharmacodynamic assessments will no longer 
be performed/collected.
7.4.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies
Effective with Amendment 2, tumor samples will no longer be collected.
Archived tumor tissue samples and de novo biopsies of primary and/or metastatic 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, the 
presence/absence of tumor-infiltrating CD8+ T lymphocytes and/or expression of PD-L1, 
FoxP3, PD-1, PD-L2 within the tumor microenvironment by immunohistochemistry.
Optional tumor biopsies obtained upon disease progression may be assessed relative to the 
mandatory pre-treatment biospecimens to examine tumoral and immunological changes 
which may occur over the course of therapy, including acquired mechanisms of resistance.  
7.4.2. BRCA 1/2 Mutation Status
Effective with Amendment 2, BRCA 1/2 mutation status assessment is no longer required per 
protocol but may be performed as clinically necessary and need not be recorded in OC-RDC.
Please refer to the new SOA in Appendix 7.


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7.5. Banked Biospecimens
7.5.1. Markers of Drug Response
Effective with Amendment 2, additional collection of banked biospecimens are no longer 
necessary. Please refer to the new SOA in Appendix 7.
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 DNA, 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 badge-swipe.  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 only 
be used 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 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 trial.
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.


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7.5.2. 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 trial, 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 amongst 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 
biospecimens specified in Section 7.5.1 will be used.  Patients may still participate in the 
clinical trial if they elect not to allow their banked biospecimens to be used for the additional 
purposes described in this section.
7.6. Tumor Response Assessments
Please refer to the new SOA in Appendix 7.
Tumor assessments will include all known or suspected disease sites. Imaging will be 
conducted per the local site’s standard of care and need not be recorded in OC-RDC, unless 
the findings support an AE.
Brain CT or MRI scan at baseline is only required when there are suspected brain metastases
or new lesion during the study.  
Bone scan (bone scintigraphy) or 18F-FDG-PET/CT are only required at baseline if bone 
metastases are suspected.  Otherwise, bone imaging is required only if new bone metastases 
are suspected.
The same imaging technique used to characterize each identified and reported lesion at 
baseline should be employed in the following tumor assessments.
In addition, radiological tumor assessments will also be conducted whenever disease 
progression is suspected (eg, symptomatic deterioration). Assessment of response will be 
made using RECIST version 1.1 (Appendix 3). All patients’ files and radiologic images will 
be collected by Parexel.
7.7. Expedited Blinded Independent Central Review for Disease Progression 
Effective with Amendment 2, BICR will no longer be utilized, however all scans will 
continue to be sent to Parexel for storage.


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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of study treatment or suspected causal 
relationship to the study treatment(s) 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 an 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 non-serious adverse event 
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 
trial. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’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 study treatment.  
SAEs occurring to a subject 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 study treatment
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 subject has taken at least 1 dose of study treatment through 90 calendar days after 
the last administration of the study treatment.  
If a patient begins a new anticancer therapy, the AE reporting period for nonserious 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 study treatment, 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, at the wrong dosage strength, or 
inadvertent exposure. 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 immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:


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
Medication errors involving patient exposure to the study treatment;

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 trial, overdose of avelumab or PLD is defined as any dose 5% over the 
calculated dose for that particular administration as described in this clinical trial protocol.  
Acute over dosage with PLD causes increased risk of severe mucositis, leukopenia and 
thrombocytopenia.  
No specific information is available on the treatment of overdose of avelumab.  In the event 
of overdose, the patient should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.  The Study Manual contains 
specific instructions for PLD dose calculation, reconstitution, preparation of the infusion 
fluid, and administration.
If a dose of avelumab meeting the protocol definition of overdose is administered without 
inducing any associated clinical symptoms or abnormal laboratory results, then the overdose 
is reported in CRF as a non-serious adverse event, using the terminology “accidental or 
intentional overdose without adverse effect”.  If the overdose is accompanied by an AE, as 
determined by the Investigator, the associated adverse event(s) has to be captured on an 
adverse event (AE) CRF page.
The IP Manual contains specific instructions for avelumab dose calculation, reconstitution, 
preparation of the infusion fluid, and administration.
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 outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.


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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

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 CTCAE (version 4.03) Grade 5 (see 
Section 8.8 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 the section on SAE 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 


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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:

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 (X ULN) concurrent with a total bilirubin values 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available.

For patients with preexisting ALT OR AST OR total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:

For patients with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 X ULN, or 
8 X ULN (whichever is smaller).

Concurrent with

For patients with pre-existing 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)/ 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 patient, 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 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.


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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.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Routine emergency room admissions;

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 
work-up of persistent pre-treatment lab abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical exam);

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;

Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;


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
Admission exclusively for the administration of blood products.
Diagnostic and therapeutic non-invasive 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.
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 serious adverse 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 study treatment caused the 
event, then the event will be handled as “related to study treatment” for reporting purposes, 
as defined by the Sponsor (see Section 8.14 Reporting Requirements). If the Investigator's 
causality assessment is “unknown but not related to study treatment”, this should be clearly 
documented on study records. 
In addition, if the Investigator determines 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.


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For combination treatment, causality assessment will be performed for each of the individual 
drugs included in the combination.  
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the study treatment; 
or the female becomes or is found to be pregnant after discontinuing and/or being 
exposed to the study treatment.

An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, due to environmental exposure) to the study treatment
prior to or around the time of conception and/or is exposed during his partner’s 
pregnancy. 
If a study patient becomes or is found to be pregnant during the study patient’s treatment 
with the study treatment, the Investigator must submit this information to the Pfizer Drug 
Safety Unit on a Serious Adverse Event report form and an Exposure During Pregnancy 
(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 pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 


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
Spontaneous abortion includes miscarriage and missed abortion.

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
serious adverse events when the Investigator assesses the infant death as related or 
possibly related to exposure to the study treatment. 
Additional information regarding the exposure during pregnancy 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).
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 on 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/legal guardian/legally acceptable representative.  In addition, each study 
patient/legal guardian/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.  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 timeframe 
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as well as to the initial and follow-up reporting of exposure during pregnancy, exposure via 
breastfeeding cases and occupational exposure. 
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/her first awareness of the AE.
For all SAEs, the Investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes 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
Adverse event 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 trial 
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 and/or its analysis will also be reflected in a protocol 
amendment.
The final analysis for this study has been completed. The study did not meet its primary 
objectives of demonstrating that avelumab given alone or in combination with PLD is 
superior to PLD alone in prolonging OS or PFS in patients with platinum resistant/platinum 
refractory ovarian cancer. In addition, avelumab single agent as well as avelumab in 
combination with PLD demonstrated a generally manageable safety profile in this study.


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9.1. Sample Size Determination
The primary objective of this study is to demonstrate that avelumab given alone or in 
combination with PLD is superior to PLD alone in prolonging OS or PFS in patients with 
platinum-resistant/refractory ovarian cancer.
The study is designed to test in parallel 4 hypotheses. 

The first null hypothesis is that the true OS hazard rate for PLD and avelumab alone 
arms are the same (HR=1) versus the alternative hypothesis that the true hazard rate is 
smaller in the avelumab alone arm than in the PLD alone arm (HR<1).

The second null hypothesis is that the true OS hazard rate for PLD and avelumab in 
combination with PLD arms are the same (HR=1) versus the alternative hypothesis 
that the true hazard rate is smaller, in the avelumab in combination with PLD arm 
than in the PLD-alone arm (HR<1). 

The third null hypothesis is that the true PFS hazard rate for PLD and avelumab alone 
arms are the same (HR=1) versus the alternative hypothesis that the true hazard rate is 
smaller in the avelumab alone arm than in the PLD-alone arm (HR<1).

The fourth null hypothesis is that the true PFS hazard rate for PLD and avelumab in 
combination with PLD arms are the same (HR=1) versus the alternative hypothesis 
that the true hazard rate is smaller in the avelumab in combination with PLD arm than 
in the PLD-alone arm (HR<1). 
Approximately 550 patients will be randomized using a 1:1:1 randomization, stratified by 
platinum-refractory or platinum-resistant status, number of prior regimens (1 vs 2 or 3), and 
bulky disease (defined as presence of a tumor 5 cm) vs not.  
The study or an experimental arm is planned to stop early for futility or efficacy only if the 
associated criteria are met for both PFS and OS. The sample size is hence determined based 
on the following assumptions.

OS
It is assumed that the median OS for patients receiving PLD is 12 months,24 and that 
treatment with avelumab alone or  avelumab in combination with PLD is expected to 
increase the median OS to 20 months, corresponding to a hazard ratio (HR) of 0.6 under the 
exponential model assumption.  The sample size further assumes a 5% drop-out rate within 
each arm, a non-uniform patient accrual over a 19-month period and minimum follow-up of 
12 months after the last patient is randomized.
If the true HR is 0.6 under the alternative hypothesis, 196 OS events within each comparison 
will be required to have 90% power to detect a HR of 0.6 using a one-sided log rank test at a 
significance level of 0.0115 (overall significance level in the study one-sided 0.025), and a 
2-look group sequential design with Lan-DeMets (O’Brien-Fleming) -spending function to 


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determine the efficacy boundary and a Gamma Family (-10) -spending function to 
determine the non-binding futility boundary

PFS
It is assumed that the median PFS for patients receiving PLD is 3.5 months,24 and that 
treatment with avelumab alone or avelumab in combination with PLD is expected to increase 
the median PFS to 5.8 months, corresponding to a hazard ratio (HR) of 0.6 under the 
exponential model assumption.  The sample size further assumes a 15% drop-out rate within 
each arm, and non-uniform patient accrual over a 19-month period and minimum follow-up 
of 12 months after the last patient is randomized.
If the true HR is 0.6 under the alternative hypothesis, 325 PFS events by BICR assessment 
within each comparison will provide 93% power to detect a HR of 0.6 using a one-sided log
rank test at a significance level of 0.001 (overall significance level in the study 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 
(-10) -spending function to determine the non-binding futility boundary.
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. Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of study treatment 
(ie, avelumab or PLD).  Patients will be classified according to the treatment assigned at 
randomization unless the incorrect treatment(s) are received throughout the dosing period in 
which case patients will be classified according to the first treatment received. The safety 
analysis set will be the primary population for evaluating treatment 
administration/compliance and safety.
9.2.3. PK Analysis Set
The PK concentration analysis set is a subset of the safety analysis set including patients who 
have at least 1 concentration above the below limit of quantitation (BLQ) of either of the 
study drugs. 
The PK parameter analysis set is a subset of the safety analysis set including patients who 
have at least 1 of the PK parameters of interest of either of the study drugs.
9.2.4. Immunogenicity Analysis Set
The immunogenicity analysis is a subset of the safety analysis set including patients who 
have at least 1 ADA sample collected.


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9.2.5. Biomarker Analysis Set
The biomarker analysis set is a subset of the safety analysis set including patients who have 
at least one screening biomarker assessment.  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. 
Some efficacy analyses will also be performed on the Safety Analysis Set. 
All analyses will be performed by using SASVersion 9.1.3 or higher.  
All secondary endpoints based on radiological assessments of tumor burden (ie, PFS, OR, 
DR, DC) 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.  This information will be used for 
supportive analyses, except for PFS whose assessment by BICR is a primary endpoint.
Sensitivity analyses will be described in the SAP.
9.3.1. Analysis of Primary Endpoints
9.3.1.1. 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.  
The primary analyses of OS will be performed based on the Full Analysis Set.  A stratified 
log-rank test (one-sided) stratified by stratification factors described in Section 3 will be used 
within each comparison at the interim and/or final analyses with the overall significance level 
preserved at 0.0115 (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% CI.  
OS will also be evaluated based on the safety analysis set as a supportive analysis, using a 
stratified log-rank test (one-sided, =0.0115). 
9.3.1.2. Progression Free Survival by BICR Assessment
PFS is defined as the time from randomization to the date of the first documentation of 
objective progression of disease (PD) or death due to any cause, whichever occurs first.  
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start new anti-cancer treatment prior to 
an event, or for patients with an event after two or more missing tumor assessments.  Patients 
who do not have a baseline tumor assessment or who do not have any post-baseline tumor 


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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 based on BICR assessment using the Full 
Analysis Set (FAS).  A stratified log-rank test (one-sided) stratified by stratification factors 
described in Section 3 will be used within each comparison at the interim and/or final 
analyses with the overall significance level preserved at 0.001 (one-sided). PFS time will be 
summarized by treatment arm using the Kaplan-Meier method and displayed graphically 
where appropriate. CIs for the 25th, 50th, and 75th percentiles of the event-free time will be 
reported.  The Cox proportional hazards model will be fitted to compute the treatment hazard 
ratios and the corresponding 95% CI. 
PFS will also be evaluated based on a per-protocol analysis set (a subset of the safety 
analysis set including patients who have measurable disease at baseline per BICR assessment 
and have no key deviations from the protocol expected to impact PFS) as supportive analysis, 
using a stratified log-rank test (one-sided, =0.001).  The full criteria for the per-protocol 
analysis set will be pre-specified in the Statistical Analysis Plan.
9.3.2. Analysis of Secondary Endpoints
The secondary efficacy endpoints and associated analyses described below will be analyzed 
in the FAS.  All analyses except PFS analysis will be performed using investigator’s 
assessment, as well as the review of the BICR. PFS will only be analyzed according to the 
investigator’s assessment as secondary endpoint.
Progression-Free Survival by Investigator Assessment
PFS time will be summarized by treatment arm using the Kaplan-Meier method and 
displayed graphically where appropriate.  CIs for the 25th, 50th, and 75th percentiles of the 
event-free time will be reported.  The Cox proportional hazards model will be fitted to 
compute the treatment hazard ratios and the corresponding 95% CI.
Objective Response (OR)
Objective response is defined as a complete response (CR) or partial response (PR) according 
to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1; Appendix 3) 
recorded from randomization until disease progression or death due to any cause.  Only 
tumor assessments performed prior to start of new anti-cancer therapy will be included. 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 analysis.  Additionally, patients with inadequate data for tumor assessment 
(eg, no baseline assessment or no follow-up assessments) will be considered as 
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The OR rate (ORR) on each randomized treatment arm will be estimated by dividing the 
number of patients with objective response (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.
In addition, the best overall response for each patient will be summarized by treatment arm.
Duration of Response (DR)
Duration of response (DR) is defined, for patients with an objective response per 
RECIST v1.1, 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.
Disease Control (DC)
Disease control (DC) is defined as complete response (CR), partial response (PR), or stable 
disease (SD) according to the RECIST version 1.1 (Appendix 3) recorded from 
randomization until disease progression or death due to any cause.  The DC rate (DCR) on 
each randomized treatment arm will be estimated by dividing the number of patients with 
CR, PR, or SD by the number of patients randomized to the treatment arm.  The 
corresponding exact 2-sided 95% CI for the DC rates will be provided by treatment arm.
Patient-Reported Outcomes
The EORTC QLQ-C30, EORTC QLQ-OV28, and EQ-5D-5L, will be scored according to 
their respective validation papers and user’s guides.33,34,35,36, 37,38,39 All PRO analyses will 
include data from baseline up to EOT assessment (not including EOT).  A sensitivity analysis 
will be conducted including all assessments from baseline to end of treatment and also any 
assessments captured on Days 30, 60, and 90 during the safety follow-up period.
Abdominal/gastrointestinal symptoms (GI) have been regarded as the most frequent and 
clinically relevant disease-related symptoms experienced by patients with ovarian cancer.  As 
such, our primary analysis will focus on measuring Time to Deterioration (TTD) of 
abdominal/GI-related symptoms as measured by items 31 to 37 of the EORTC QLQ-OV28.  
TTD is defined as the time from randomization (baseline) to the first time the patient’s score 
shows a 15 point or higher increase in patient abdominal/GI-related symptoms.  Patients will 
be censored at the last time when they completed a sub-scale assessment if they have not 
deteriorated. 
Osoba et al, established that a 10-point or a greater minimally important difference (MID) 
from baseline on the scales of the EORTC QLQ-C30 would correlate with significant 
(moderate) change in disease symptoms and functioning.40  However, Stockler et al


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established a primary PRO hypothesis threshold of at least a 15% (15-point) 
absolute difference on the QLQ-OV28 abdominal/GI symptom subscale.41 Hence, in 
the analysis of time to deterioration, a minimally important difference (MID) of 15 points or 
greater is proposed for the abdominal/GI symptom subscale of the OV-28.  Sensitivity TTD 
analyses of 20 point, 2-grade increase in the raw score, and 10 point increases will also be 
conducted to assess the robustness of the endpoints. To explore the effect of the open-label 
nature of the study design on the PRO endpoints, additional analyses of the relationship 
between OS (and/or PFS) and the OV-28 GI subscale will be performed TTD of primary 
abdominal/GI symptom sub-scales 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 among the three (3) 
treatment arms.  The median TTD and 2-sided 95% CI for the median will also be provided 
based on the Brookmeyer Crowley method.42
The proportion of patients who improved from baseline, defined as a 10 point decrease on 
the abdominal/GI subscale (items 31-37) of the EORTC QLQ-OV28, will be summarized 
and compared between each of the treatment arms at Cycle 3 (beginning of Week 9).  
Patients with missing questionnaires at Cycle 3 will be counted as not having improved.
Patient reported HRQOL, disease/treatment-related symptoms of ovarian cancer and general 
health status will also be assessed.  Summary statistics (mean (and SE), median, range and 
95% CI) of absolute scores will be reported for the items and subscales of the EORTC 
QLQ-C30 questionnaire, the items and remaining subscales of the EORTC QLQ-OV28, and 
the EQ-VAS 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. 
The number and proportion of patients who improved, worsened, or remained stable for all of 
the symptom and functional domains, global QOL and single items of the EORTC 
QLQ-C30, and the QLQ-OV28 will be summarized over time.  For the EQ-5D-5L health 
state profiles, the proportions of patients reported having none, slight, moderate, severe, 
extreme/unable problems at each time point will be reported.
Additional exploratory analyses may be performed such as repeated measures mixed-effects 
modeling.
Pharmacokinetic Analysis of Avelumab and doxorubicin (PLD samples) 
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.
Standard plasma PK parameters for doxorubicin (PLD samples) will be estimated using 
non-compartmental.  Analysis and will include Cmax, Tmax, AUC336, AUCinf t1/2, plasma 


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clearance (CL), and volume of distribution (Vd).  Dose normalized parameters 
(eg, CDN-Cmax, DN-AUC) will be reported as appropriate.  Descriptive statistics for the PK 
parameters for doxorubicin will be provided by dose in tabular form.
Doxorubicin plasma concentrations will be summarized descriptively (n, mean, SD, CV, 
median, minimum, maximum, geometric mean, its associated CV, and 95% confidence 
interval) by nominal time.  Individual patient and median profiles of the PLD profiles will be 
presented on both linear-linear and log-linear scales.
Ctrough and Cmax for avelumab will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean, its associated CV, and 95% confidence interval) by 
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.
Effect of Avelumab on Doxorubicin (PLD Samples) Pharmacokinetics
The effect of avelumab dosing on doxorubicin PK will be evaluated based on overall 
assessment of the geometric mean ratios and associated 90% CI for Cmax, AUCinf, and 
AUC336 of PLD on Day 1 of Cycle 2 in Arm B (PLD + avelumab) compared to those on 
Day 1 of Cycle 2 of Arm C. 
Effect of PLD on Avelumab Pharmacokinetics
The effect of PLD dosing on avelumab PK will be evaluated based on the overall assessment 
of the geometric mean ratios of Cmax and Ctrough of Arm B on Day 1 of Cycle 2 compared to 
those on Day 1 of Cycle 2 of Arm A.
Immunogenicity Assessment
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized by Arm (A or B).  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.
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.


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Biomarker Analysis for Secondary and Exploratory Endpoints
For baseline continuous endpoint data, such as PD-L1 and CD8, descriptive statistics, 
including the mean, standard deviation, median, minimum, and maximum values, will be 
provided by treatment arm.  For baseline categorical data, the number and percentage of 
patients in each category will be provided by treatment arm.  Appropriate statistical methods 
may be used to investigate any possible relationship of biomarker levels with avelumab 
anti-tumor efficacy relative to appropriate control arms.
9.4. Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed 
graphically, where appropriate.
9.5. 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. 
Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html).
The frequency of patients experiencing treatment emergent adverse events corresponding to 
body systems and MedDRA preferred term will be reported. Adverse events will be graded 
by worst NCI CTCAE v4.03 Grade.  Adverse events will be summarized by cycle and by 
relatedness to trial treatment.  
Emphasis in the analysis will be placed on AEs classified as treatment emergent.  Adverse 
events leading to death or discontinuation of trial treatment, events classified as 
NCI CTCAE v4.03 Grade 3 or higher, trial drug-related events, and serious adverse events 
will be considered with special attention.  As appropriate, the difference in risk between 
treatment arms for AEs of clinical interest may be further assessed as described in the SAP.
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study treatment, action taken, and 
clinical outcome.
Laboratory Abnormalities
The laboratory results will be graded according to the NCI CTCAE v4.03 severity grade.  
The frequency of patients with laboratory test abnormalities will be summarized according to 
the worst grade for each laboratory test. 


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For laboratory tests without an NCI CTCAE grade definition results will be categorized as 
normal (within normal ranges), abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory abnormalities. 
Electrocardiograms
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations. Single ECGs and data obtained from ECGs 
repeated for safety reasons after the nominal time-points will not be averaged along with the 
preceding triplicates. Interval measurements from repeated ECGs will be included in the 
outlier analysis (categorical analysis) as individual values obtained at unscheduled time 
points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate]. Data will be summarized and listed for QT, HR, RR, PR, QRS, and QTc.
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 will be performed based on the Full Analysis Set.  Any safety evaluation 
performed at the time of the IA will be based on the safety analysis set.
The study is designed to have, within each of the 4 hypotheses tested, one formal interim 
analysis and the final analysis based on the primary OS and PFS endpoints.
The goals of the interim analyses are to allow early stopping of one or both experimental 
treatment arms for efficacy or futility (if efficacy or futility boundaries are crossed for both 
OS and PFS) and to assess the safety of avelumab alone or in combination with PLD.
If the results of the interim analyses indicate serious safety concerns, the company will 
communicate with the Health Authorities regarding stopping one of the experimental arms or 
the clinical trial.
9.6.1. Overall Survival
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 


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integrity of the study and to preserve the type-1 error rate, a fraction of alpha (0.002) for 
efficacy will be spent at the interim analysis and accounted for in the overall type I error rate 
if the interim analysis is performed exactly at the planned number of events. The nominal 
significance levels for the interim and final efficacy analyses of OS will be determined by 
using the Lan-DeMets procedure with an O’Brien-Fleming stopping efficacy boundary43 and 
a Gamma Family (-10) -spending function to determine the non-binding futility boundary.  
The overall significance level for the efficacy analysis of OS, within each comparison, will 
be preserved at 0.0115 (1-sided test).
Within each comparison, the interim analysis will be performed after 550 patients have been 
randomized in the study and approximately 131 OS events have occurred (67% of the 
196 events expected for each comparison at the end of the study). 
9.6.2. Progression-Free Survival 
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 (0.0003) for 
efficacy will be spent at the interim analysis and accounted for in the overall type I error rate 
if the interim analysis is performed exactly at the planned number of 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 efficacy boundary43 and 
a Gamma Family (-10) -spending function to determine the non-binding futility boundary.  
The overall significance level for the efficacy analysis of PFS, within each comparison, will 
be preserved at 0.001 (1-sided test).
Within each comparison, the interim analysis will be performed after 550 patients have been 
randomized in the study and approximately 267 PFS events have occurred (82% of the 
325 events expected for each comparison at the end of the study). 
The interim analyses for PFS and OS will occur at the same time.
9.6.3. Non-Comparative Objective Response Rate Assessment
Summary of ORR by treatment arm (based on confirmed partial or complete responses per 
BICR assessment) will be performed on all patients randomized 6 months or more prior to 
the time of the interim analysis for OS and PFS. It is estimated that approximately 
450 patients (150 patients within each treatment arm) will be included in this analysis.
9.6.4. Stopping Rules
At the interim analysis, the experimental treatment (or the study) may be stopped for 
1. Futility, if the value of the test statistics for both OS and PFS exceed the futility 
boundaries. OS futility boundary is (z > -0.2339, p >0.4075) and PFS futility 
boundary is (z > -1.8938, p >0.0291). 


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2. Efficacy, if the value of the test statistics for both OS and PFS exceed the efficacy
boundaries. OS efficacy boundary is (z < -2.8791, p <0.002) and PFS efficacy
boundary is (z < -3.4474, p <0.0003).  
3. Crossing of only one boundary (for either OS or PFS) will not trigger an evaluation of 
early termination for futility or efficacy.
9.7. Data Monitoring Committee
This study will use an external data monitoring committee (E-DMC). 
The E-DMC will be responsible for ongoing monitoring of the safety of patients in the study 
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
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.
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 is true.  Any corrections to entries made in the CRFs, source 


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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 Investigator’s 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, telephone calls reports).  The records should be 
retained by the Investigator according to International Conference on Harmonisation (ICH)
guidelines, according to local regulations, or as specified in the Clinical Study Agreement 
(CSA), whichever is longer.
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
Investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The Investigator must obtain Pfizer’s written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.


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12.2. Ethical Conduct of the Study
The study will be conducted in accordance with 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 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
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 his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patient’s personal data consistent 
with applicable privacy laws.
The informed consent document must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent document(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC 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.


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The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each patient or the patient’s legal 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 which might influence the evaluation of the benefits and risks of the study 
treatment, Pfizer should be informed immediately. 
In addition, the Investigator will inform Pfizer immediately of any urgent safety measures 
taken by the Investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the Investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in 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 Participating Countries
End of Trial in all participating countries is defined as Last Patient Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, study treatment safety problems, or at the discretion of 
Pfizer.  In addition, Pfizer retains the right to discontinue development of PLD or 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.


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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
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 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 


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publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before 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 
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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Disis M., et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with 
previously treated, recurrent or refractory ovarian cancer: a phase Ib, open-label 
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Markman M and Bookman MA. Second-Line Treatment of Ovarian Cancer. The 
Oncologist 2000;5 (1): 26-35.
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62(9):1533-45.
48.
Nishino M, Jagannathan JP, Krajewski KM, O’Regan K, Hatabu H,Shapiro G, et al. 
Personalized tumor response assessment in the era of molecular medicine: 
cancer-specific and therapy-specific response criteria to complement pitfalls of 
RECIST. AJR Am J Roentgenol 2012;198:737–45.
49.
Nishino M, Gargano M, Suda M, Ramaiya NH, Hodi FS. Optimizing immune-related 
tumor response assessment: does reducing the number of lesions impact response 
assessment in melanoma patients treated with ipilimumab?  J Immunother Cancer 
2014;2:17.
50.
Mattarollo SR, Loi S, Duret H, et al. Pivotal Role of Innate and Adaptive Immunity in 
Anthracycline Chemotherapy of Established Tumors. Cancer Res 2011;71(14); 
4809-20.
51.
Zamarin D and Postow M. Immune checkpoint modulation: Rational design of 
combination strategies. Pharmacology & Therapeutics 2015; 
http//dx.doi.org/10.1016/j.pharmthera.2015.01.003.


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52.
Zitvogel L, Galluzzi L, Smyth MJ, et al. Mechanism of Action of Conventional and 
Targeted Anticancer Therapies: Reinstating Immunosurveillance. Immuni 2013; 39; 
74-88.
53.
Rose PG, Maxson JH, Fusco NL, et al. Liposomal Doxorubicin in Ovarian, Peritoneal, 
and Tubal Carcinoma: A Retrospective Comparative Study of Single-Agent Dosages. 
Gynecologic Oncology 2001; 82(2): 323–28.
54.
American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer 
Society; 2015. Online. Cancer statistics.
55.
Hoos A, Egermont AM, Janetzki S, et al. Improved endpoints for cancer 
immunotherapy trials. J Natl Cancer Inst 2010; 102(18):1388-97.
56.
Wolchok JD, et al.: Guidelines for the Evaluation of Immune Therapy Activity in Solid 
Tumors: Immune-Related Response Criteria, Clin Cancer Res 2009; 15(23):7412-7420.
57.
Hodi FS, Bulter M, Oble DA, Seiden MV, haluska FG, Kruse A, et al. Immnologic and 
clinical effects of antibody blockade of cytotoic T lymphocyte-associated antigen 4 in 
previously vaccinated cancer patients. Proc Natl Acad Sci U S A 2008; 105:3005-10.
58.
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. 
59.
Gyorki et al. Surgery for patients receiving ipilimumab: Safety profile and 
immunological insights. J Clin Oncol 30, 2012 (suppl; abstr 8583).
60.
J.J. Griggs, et al. Appropriate Chemotherapy Dosing for Obese Adult Patients with 
cancer:American Society of Clinical Oncology Clinical Practice Guideline. J Clin 
Onocol 30:1 1553-1561, 2012. 


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Appendix 1. Abbreviations
This is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ADA
Anti-Drug Antibody
AE
Adverse event
AESI
Adverse Event of Special Interest
AIDS
Acquired Immune Deficiency Syndrome
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ANC
Absolute Neutrophil Count
AUC 
Area Under the Curve
CRF
Case report form
CSA
Clinical study agreement
BICR
Blinded Independent Central Review
BOR
Best Overall Response
BP
Blood Pressure
BRCA
Breast Cancer Antigen
BUN
Blood Urea Nitrogen 
CRF
Case Report Form
Cmax
Maximum Plasma Concentration
CTA
Clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CR
Complete Response
CT
Computerized Tomography
CI
Confidence Interval
DU
Dispensable Unit
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DLT
Dose-Limiting Toxicity
DR
Duration of Response
EC
Ethics committee
ECG
Electrocardiogram
ECHO
Echocardiogram 
E-DMC
External data monitoring committee 
EDP
Exposure during pregnancy
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
EMA
European Medicines Agency
EOC
Epithelial Ovarian Cancer
EudraCT
European Clinical Trials Database
EU 
European Union
FAS
Full Analyses Set
FDA
Food and Drug Administration (United States)


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Abbreviation
Term
FDAAA
Food and Drug Administration Amendments Act (United States)
FFPE
Formalin Fixed, Paraffin Embedded
GCP
Good Clinical Practice
GGT
Gamma glutamyl transferase
GMP
Good Manufacturing Practice
HCV
Hepatitis C Virus
HBV
Hepatitis B Virus
IB
Investigator’s brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
INR
International normalized ratio
IP
Investigational Product 
irAE
Immune-related Adverse Event
IRB
Institutional review board
IRT
Interactive response technology
IV
Intravenous
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
MUGA
multiple gated acquisition
NSAID
Non-steroidal anti-inflamatory drug
OR(R)
Objective Response (Rate)
OS
Overall Survival
PARP
Poly ADP ribose polymerase
PR
Partial Response
PK
Pharmacokinetics
PCD
primary completion date
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PFS
Progression-Free Survival
PLD
Pegylated Liposomal doxorubicin  
PT
prothrombin time
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
SAE
Serious adverse event
SAP
Statistical analysis plan
SCL
Supply Chain Lead
SIB
Suicidal ideation and behavior
SD
Stable Disease
SD
Standard Deviation
SOA
Schedule of Activities
SOP
Standard operating procedure
CCI


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Abbreviation
Term
SRSD
Single reference safety document
TEAE
Treatment Emergent Adverse Event
ULN
Upper limit of normal
US
United States
USPI
United States package insert
WBC
White Blood Cell


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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. Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Guidelines
Adapted from E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
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.


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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.

Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large target 
lesion splits, the sum of the parts is used.
Measurements for target lesions that become small should continue to be recorded.  If 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’).


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OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 
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. 


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Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

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. 


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Table 13.
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
If the protocol allows enrollment of patients with only non-target disease, the following table 
will be used:
Table 14.
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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CCI


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CCI


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Appendix 5. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study Manual
for this protocol.  Alternatively, the NCI CTCAE may be reviewed online at the following 
NCI website:
http://ctep.cancer.gov/reporting/ctc.html.


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Appendix 6. Quality of Life
EORTC QLQ-C30 (version 3) 
We are interested in some things about you and your health.  Please answer all of the 
questions yourself by circling the number that best applies to you.  There are no "right" or 
"wrong" answers. The information that you provide will remain strictly confidential.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year): 
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
1.
Do you have any trouble doing strenuous activities, 
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a short walk outside of the 
house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4
5.
Do you need help with eating, dressing, washing 
yourself or using the toilet?
1
2
3
4
During the past week:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
6.
Were you limited in doing either your work or other daily 
activities?
1
2
3
4
7.
Were you limited in pursuing your hobbies or 
other leisure time activities?
1
2
3
4
8.
Were you short of breath?
1
2
3
4
9.
Have you had pain?
1
2
3
4


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During the past week:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
10.
Did you need to rest?
1
2
3
4
11.
Have you had trouble sleeping?
1
2
3
4
12.
Have you felt weak?
1
2
3
4
13.
Have you lacked appetite?
1
2
3
4
14.
Have you felt nauseated?
1
2
3
4
15.
Have you vomited?
1
2
3
4
16.
Have you been constipated?
1
2
3
4
17.
Have you had diarrhea?
1
2
3
4
18.
Were you tired?
1
2
3
4
19.
Did pain interfere with your daily activities?
1
2
3
4
20.
Have you had difficulty in concentrating on things, 
like reading a newspaper or watching television?
1
2
3
4
21.
Did you feel tense?
1
2
3
4
22.
Did you worry?
1
2
3
4
23.
Did you feel irritable?
1
2
3
4
24.
Did you feel depressed?
1
2
3
4
25.
Have you had difficulty remembering things?
1
2
3
4
26.
Has your physical condition or medical treatment 
interfered with your family life?
1
2
3
4
27.
Has your physical condition or medical treatment 
interfered with your social activities?
1
2
3
4
28.
Has your physical condition or medical treatment 
caused you financial difficulties?
1
2
3
4


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For the following questions please circle the number between 1 and 7 that best applies 
to you
29.
How would you rate your overall health during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
30.
How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
Very poor
Excellent
©
Copyright 1995 EORTC Quality of Life Group. All rights reserved. Version 3.0


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EORTC QLQ - OV28
Patients sometimes report that they have the following symptoms or problems.  Please 
indicate the extent to which you have experienced these symptoms or problems during the 
past week.
During the past week:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
31.
Did you have abdominal pain?
1
2
3
4
32.
Did you have a bloated feeling in your 
abdomen/stomach?
1
2
3
4
33.
Did you have problems with your clothes feeling 
too tight?
1
2
3
4
34.
Did you experience change in bowel habit as 
a result of your disease or treatment?
1
2
3
4
35.
Were you troubled by passing wind/gas/flatulence?
1
2
3
4
36.
Have you felt full up too quickly after beginning to eat?
1
2
3
4
37.
Have you had indigestion or heartburn?
1
2
3
4
38.
Have you lost any hair?
1
2
3
4
39.
Answer this question only if you had any hair loss: 
Were you upset by the loss of your hair?
1
2
3
4
40.
Did food and drink taste different from usual?
1
2
3
4
41.
Have you had tingling hands or feet?
1
2
3
4
42.
Have you had numbness in your fingers or toes?
1
2
3
4
43.
Have you felt weak in your arms or legs?
1
2
3
4
44.
Did you have aches or pains in your muscles or joints?
1
2
3
4
45.
Did you have problems with hearing?
1
2
3
4


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During the past week:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
46.
Did you urinate frequently?
1
2
3
4
47.
Have you had skin problems (eg, itchy, dry)?
1
2
3
4
48.
Did you have hot flushes?
1
2
3
4
49.
Did you have night sweats?
1
2
3
4
50.
Have you felt physically less attractive as a result 
of your disease or treatment?
1
2
3
4
51.
Have you been dissatisfied with your body?
1
2
3
4
52.
How much has your disease been a burden to you?
1
2
3
4
53.
How much has your treatment been a burden to you?
1
2
3
4
54.
Were you worried about your future health?
1
2
3
4
During the past 4 weeks:
Not at 
All
A 
Little
Quite 
a Bit
Very 
Much
55.
To what extent were you interested in sex?
1
2
3
4
56.
To what extent were you sexually active?
1
2
3
4
Answer the following two questions only if you were sexually active: 
57.
To what extent was sex enjoyable for you?
1
2
3
4
58.
Did you have a dry vagina during sexual activity?
1
2
3
4
Copyright 1997 EORTC Quality of Life Group.  All rights reserved (Phase III module).


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Health Questionnaire
English version for the USA


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Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (eg, work, study, housework, family or leisure 
activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN/DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort



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ANXIETY/DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed



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The worst 
health you can 
imagine

We would like to know how good or bad your health is 
TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is 
TODAY.

Now, please write the number you marked on the scale 
in the box below.
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
YOUR HEALTH TODAY =
The best health 
you can imagine


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Appendix 7. Revised Schedule of Activities Post Final Analysis
The final analysis for this study has been completed. The study did not meet its primary 
objectives of demonstrating that avelumab given alone or in combination with PLD is 
superior to PLD alone in prolonging OS or PFS in patients with platinum resistant/platinum 
refractory ovarian cancer. In addition, avelumab single agent as well as avelumab in 
combination with PLD demonstrated a generally manageable safety profile in this study.
The revised SOA below will be followed in place of the SOA in the Protocol Summary
Section of this protocol.
Protocol Activities1
All Cycles
End of 
Treatment/
Withdrawal 
Visit2
Safety Follow-up 
(Day 30, Day 60, 
Day 903
1 cycle = 4 weeks
Day1
Day 15
Visit Time Window  
-2
±2
±3
±3
Informed Consent4
X
Tumor History
Not applicable at this time
Medical History
Not applicable at this time
Physical Examination11
Assessment not required per protocol but may be performed as clinically 
necessary
Baseline Signs and Symptoms
Not applicable at this time
Height
Not applicable at this time
ECOG Performance Status11
Assessment not required per protocol but may be performed as clinically 
necessary
Vital Signs11
X
X
X
Contraception Check5,11
X
X
X
Hematology10,11
X
X
X
Blood Chemistry10,11
X
X
X
Free T4, TSH, ACTH11
X
X
X
HBV, HCV11
Assessment not required per protocol but may be performed as clinically 
necessary
CA-12511
Assessment not required per protocol but may be performed as clinically 
necessary
BRCA 1/2 Mutation Status11
Assessment not required per protocol but may be performed as clinically 
necessary
Urinalysis11
Assessment not required per protocol but may be performed as clinically 
necessary
Pregnancy Test11
X
X
Triplicate (12-lead) ECG11,12
Assessment not required per protocol but may be performed as clinically 
necessary
Single 12-lead ECG11,12
Assessment not required per protocol but may be performed as clinically 
necessary
LVEF (by MUGA or ECHO)11,13
Assessment not required per protocol but may be performed as clinically 
necessary
PK Sampling for avelumab14
Do Not Perform
PK Sampling for doxorubicin14
Do Not Perform
Anti-Drug Antibody (ADA)14
Do Not Perform
Registration and Treatment
Randomization
Not applicable at this time


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Protocol Activities1
All Cycles
End of 
Treatment/
Withdrawal 
Visit2
Safety Follow-up 
(Day 30, Day 60, 
Day 903
1 cycle = 4 weeks
Day1
Day 15
Visit Time Window  
-2
±2
±3
±3
Study treatment
Avelumab (Arms A and B)6
X
X
PLD (Arm B)6
X
Premedications7
X
X
Tumor Assessments
CT or MRI Scan8,11
Assessment not required per protocol but may be performed as clinically 
necessary
Other Clinical Assessments
Patient Reported Outcomes Questionnaire14
Do Not Complete
Adverse Events9
X
Concomitant Treatments11
Assessment not required per protocol but may be performed as clinically 
necessary
Patient Status Follow-up 
X
X
Other Patient Samples
Mandatory Archival FFPE Tumor Tissue 
Block
Not applicable at this time
De Novo Tumor Biopsy14
Do Not Perform
Banked Biospecimens14
Do Not Perform
Footnotes 
1.
Protocol Activities: All assessments should be performed prior to dosing with study medication unless otherwise 
specified.  
2.
End of Treatment/Withdrawal: Obtain these assessments if not completed within the prior week.
3.
Safety Follow-up: All patient safety follow-up visits are scheduled monthly for 90 days after the last dose of study 
treatment (Day 30 ±3, Day 60 ±3, Day 90 ±3).  Final visit is scheduled to occur at least 90 days, and no more than 
93 days, after the last dose of study treatment. 
4.
Informed Consent: Must be obtained prior to undergoing any study-specific procedures.
5.
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 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. Please see 7.1.1 Pregnancy Testing for further information. 
6.
Study Treatment: See 5.2.3 Administration for further information.  Arm A: Avelumab will be given as a 1-hour 
intravenous infusion every 2 weeks.  In the PLD + avelumab arm (Arm B), PLD will be administered on Day 1 of each 
cycle and on that day it will be administered first before the avelumab infusion.  Also in Arm B avelumab will be given 
on Day 15 of each cycle. Weight should be collected prior to each infusion, assessed and documented in the CRF.  
There is a plus or minus 3 day window for PLD and avelumab administration but for avelumab there should not be less 
than 10 days between doses.  
7.
Premedications: For additional information about premedications for PLD and avelumab, see Section 5.2.3.1 and 
5.2.3.3. These data will not be captured in OC-RDC unless they meet the criteria for an adverse event and or dosing 
toxicity, in which case, the data will be captured as an adverse event in OC-RDC. 
8.
Tumor Assessments: Tumor assessments will be performed according to the local standard of care and when 
progression is suspected, however the tumor assessment data will no longer be entered into OC-RDC. The tumor 
assessment scans should continue to be submitted to Parexel for storage purposes only there will be no additional BICR 
review.
9.
Adverse Event (AE) Assessments: Adverse events should be documented and recorded in the CRF.  The National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version (v) 4.03 will be used.  
(Appendix 5)  See Section 8.2 Reporting Period for Reporting Period details.


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10. Blood Chemistry/Hematology: Required tests are listed in Table 12. The results should be available for review prior 
to infusion of study treatment. These data will not be captured in OC-RDC unless they meet the criteria for an adverse 
event.
 
12. ECG: Refer to Section 7.1.5 Electrocardiogram Measurements for additional information.
13. LVEF: MUGA/ECHO: Refer to Section 5.2.9 for additional information.
14. PRO questionnaires/PK/PD/ADA/Banked Biospecimen Sampling/De Novo Tumor Sample: These assessments 
will no longer be performed/collected.
CCI


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Appendix 8. France Appendix
This appendix applies to study sites located in France.
1. GCP Training
Prior to enrollment of any subjects, the investigator and any sub-investigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the study will 
complete the Pfizer GCP Training or equivalent before performing study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials.
2. Investigational Product
No subjects or third-party payers will be charged for investigational product.
3. Inspections
The investigator(s) will notify Pfizer or its service provider immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with Pfizer or its service provider to prepare the study site for the inspection and will allow 
Pfizer or its service provider (if not prohibited by law) to be present during the inspection. 
The study site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the subject's medical records.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its service provider.  Before response 
submission to the regulatory authorities, the investigator will provide Pfizer or its service 
provider with an opportunity to review and comment on responses to any such findings.
4. SUSARs  
Pursuant to a sponsor’s safety reporting obligations under 21 CFR 312.32(c)(1), Pfizer will 
report to the Investigator all Serious Unexpected Suspected Adverse Reactions (“SUSARs”).  
Investigator will receive and review SUSAR reports and report SUSARs to the responsible 
IRB/IEC according to institution’s guidelines.  Institution will retain SUSAR reports 
consistent with Section 11.2 of the Protocol. 


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Appendix 9. Management of Immune-related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Diarrhea: <4 stools/day over 
Baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment 
(eg, loperamide)
Close monitoring for worsening 
symptoms
Educate subject to report worsening 
immediately
If worsens:
Treat as Grade 2, 3 or 4 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated 
<24 hours; not interfering with 
ADL)
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤1: 
Resume avelumab therapy
If persists >5-7 days or recurs:
Treat as Grade 3 or 4
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over Baseline; incontinence; IV 
fluids ≥24 h; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention 
indicated, peritoneal signs
Grade 4: life-threatening, 
perforation
Withhold avelumab for 
Grade 3
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade ≤1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids 
taper (for initial Grade 3) 
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication). Note: infliximab 
should not be used in cases of 
perforation or sepsis 


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Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤30% body surface area 
Continue avelumab therapy 
Symptomatic therapy (for 
example, antihistamines, 
topical steroids) 
If Grade 2 persists >1 to 2 weeks or 
recurs: 
Withhold avelumab therapy 
Consider skin biopsy 
Consider 0.5-1.0 mg/kg/day prednisone 
or equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy 
following steroids taper.
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4
Grade 3: Covering >30% body 
surface area 
Grade 4: Life threatening 
consequences 
Withhold avelumab for 
Grade 3
Permanently discontinue for 
Grade 4 or recurrent 
Grade 3 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent
Add prophylactic antibiotics 
for opportunistic infections 
If improves to Grade ≤1: 
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3)
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding 
avelumab therapy 
Monitor for symptoms 
every 2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2
Mild to moderate new symptoms 
Withhold avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily; 
consider hospitalization 
1.0 to 2.0 mg/kg/day 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade ≤1, 
taper steroids over at least 1 month, and 
then resume avelumab therapy following 
steroids taper 
If not improving after 2 weeks or 


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


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Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 x 
ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4
Grade 2 to 3
Creatinine increased >1.5 and 
≤6 x ULN
Withhold avelumab therapy
Increase frequency of monitoring to 
every 3 days
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 
1 month, and resume avelumab 
therapy following steroids taper
If worsens: 
Treat as Grade 4
Grade 4
Creatinine increased >6 x ULN
Permanently discontinue avelumab 
therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade ≤1:
Taper steroids over at least 
1 month
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and/or new laboratory 
cardiac biomarker elevations 
(eg, troponin, CK-MB, BNP) or 
cardiac imaging abnormalities 
suggestive of myocarditis 
Withhold avelumab therapy
Hospitalize
In the presence of life threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and arrhythmia 
management
Cardiology consult to establish 
etiology and rule-out immune-
mediated myocarditis 
Guideline based supportive treatment 
as per cardiology consult*
Consider myocardial biopsy if 
If symptoms improve and 
immune-mediated etiology is 
ruled out, re-start avelumab 
therapy
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed 
following cardiology consult, 
manage as immune-mediated 
myocarditis


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recommended per cardiology consult.
Immune-mediated myocarditis
Permanently discontinue avelumab
Guideline based supportive treatment 
as appropriate as per cardiology 
consult*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Once improving, taper steroids 
over at least 1 month
If no improvement or 
worsening, consider additional 
immunosuppressants 
(eg, azathioprine, 
cyclosporine A)
*Local guidelines, or eg, ESC or AHA guidelines 
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue avelumab therapy
Endocrinology consult if needed
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or insulin 
(for Type I diabetes mellitus) as 
appropriate 
Rule-out secondary 
endocrinopathies 
(ie, hypopituitarism/hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids 
(for adrenal insufficiency) or insulin 
(for type I diabetes mellitus) as 
appropriate  
Rule-out secondary 
endocrinopathies 
(ie, hypopituitarism/hypophysitis)
Resume avelumab once 
symptoms and/or laboratory 
tests improve to Grade ≤1 (with 
or without hormone 
replacement/suppression)
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed 
Resume avelumab once 
symptoms and hormone tests 


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(ie, subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH):

Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, testosterone in 
men, estrogens in women) 

Hormone 
replacement/suppressive 
therapy as appropriate 

Perform pituitary MRI and 
visual field examination as 
indicated
If hypophysitis confirmed:

Continue avelumab if mild 
symptoms with normal MRI
Repeat the MRI in 1 month

Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis 
and/or abnormal MRI. 
Consider hospitalization. 
Initiate corticosteroids (1 to 
2 mg/kg/day prednisone or
equivalent) followed by 
corticosteroids taper during at 
least 1 month

Add prophylactic antibiotics for 
opportunistic infections
improve to Grade ≤1 (with or 
without hormone replacement)
In addition, for hypophysitis 
with abnormal MRI, resume 
avelumab only once shrinkage 
of the pituitary gland on 
MRI/CT scan is documented 
Continue hormone 
replacement/suppression 
therapy as appropriate
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical 
signs or symptoms suggestive of 
a potential irAE
Withhold avelumab therapy pending 
clinical investigation
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider 
re-starting avelumab therapy
If irAE is confirmed, treat as 
Grade 2 or 3 irAE
Grade 2 irAE or first 
occurrence of Grade 3 irAE
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent  
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤1: 
Taper steroids over at least 
1 month and resume avelumab 
therapy following steroids taper


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Recurrence of same Grade 3 
irAEs
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 
month.
Grade 4 
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent and/or 
other immunosuppressant as needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult
If improves to Grade ≤1: 
Taper steroids over at least 
1 month
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 
12 weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer
Permanently discontinue avelumab
therapy
Specialty consult
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase 
MB; CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like 
growth factor 1; irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; 
MRI=magnetic resonance imaging; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for 
Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of 
normal.

SAP_000.pdf: 
Avelumab
B9991009 (MSB0010718C) Statistical Analysis Plan    
Page 1
A PHASE 3, MULTICENTER, RANDOMIZED, OPEN-LABEL STUDY OF 
AVELUMAB (MSB0010718C) ALONE OR IN COMBINATION WITH PEGYLATED 
LIPOSOMAL DOXORUBICIN VERSUS PEGYLATED LIPOSOMAL 
DOXORUBICIN ALONE IN PATIENTS WITH PLATINUM-
RESISTANT/REFRACTORY OVARIAN CANCER
JAVELIN OVARIAN 200
STATISTICAL ANALYSIS PLAN
Compounds:
MSB0010718C
Compound Name:
Avelumab
Version:
3.0
Date:
13-Dec-2017
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Avelumab
B9991009 (MSB0010718C) Statistical Analysis Plan    
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
1. VERSION HISTORY............................................................................................................8
2. INTRODUCTION ...............................................................................................................13
2.1. Study Objectives .....................................................................................................13
2.2. Study Design ...........................................................................................................14
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................15
3.1. Primary Endpoints...................................................................................................15
3.2. Secondary Endpoints...............................................................................................15
3.2.1. Safety endpoints..........................................................................................15
3.2.2. Efficacy endpoints ......................................................................................15
3.2.3. Patient reported outcomes...........................................................................16
3.2.4. Pharmacokinetic endpoints.........................................................................16
3.2.5. Immunogenicity endpoints .........................................................................17
3.2.6. Biomarker endpoints...................................................................................17
3.3. Exploratory Endpoints.............................................................................................18
3.4. Baseline Variables...................................................................................................19
3.4.1. Study drug, study treatment and baseline definitions.................................19
3.4.2. Baseline characteristics...............................................................................20
3.5. Safety Endpoints .....................................................................................................21
3.5.1. Adverse events............................................................................................21
4. ANALYSIS SETS ...............................................................................................................22
4.1. Full Analysis Set .....................................................................................................22
4.2. Safety Analysis Set..................................................................................................22
4.3. Other Analysis Sets .................................................................................................23
4.3.1. Per-protocol analysis sets ...........................................................................23
4.3.2. PK analysis sets ..........................................................................................24
4.3.3. Biomarker analysis sets ..............................................................................24
4.3.4. Immunogenicity analysis set.......................................................................24
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Avelumab
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5. GENERAL METHODOLOGY AND CONVENTIONS....................................................24
5.1. Hypotheses and Decision Rules ..............................................................................24
5.1.1. Hypotheses and sample size determination................................................24
5.1.2. Decision rules .............................................................................................26
5.2. General Methods .....................................................................................................29
5.2.1. Data handling after the cut-off date............................................................29
5.2.2. Pooling of centers .......................................................................................29
5.2.3. Presentation of continuous and qualitative variables..................................29
5.2.4. Definition of study day...............................................................................29
5.2.5. Definition of start of new anti-cancer drug therapy....................................30
5.2.6. Definition of start of new anti-cancer therapy............................................30
5.2.7. Definition of on-treatment period...............................................................30
5.2.8. Standard derivations and reporting conventions.........................................31
5.2.9. Unscheduled visits......................................................................................31
5.2.10. Adequate baseline tumor assessment........................................................32
5.2.11. Adequate post-baseline tumor assessment................................................32
5.3. Methods to Manage Missing Data ..........................................................................32
5.3.1. Missing data................................................................................................32
5.3.1.1. Pharmacokinetic concentrations................................................32
5.3.1.2. Pharmacokinetic parameters .....................................................33
5.3.1.3. Biomarker Parameters: Unintentional Duplicate Data..............33
5.3.2. Handling of incomplete dates .....................................................................33
5.3.2.1. Disease history ..........................................................................33
5.3.2.2. Adverse events ..........................................................................34
5.3.2.3. Prior and concomitant medications...........................................34
5.3.2.4. Exposure....................................................................................35
5.3.3. Imputation rules for date of last contact and efficacy assessments ............35
5.3.3.1. Date of last contact....................................................................35
5.3.3.2. Death date..................................................................................36
5.3.3.3. Tumor assessments....................................................................36
5.3.3.4. Date of start of new anti-cancer therapy ...................................36
5.3.3.5. PRO data ...................................................................................38
6. ANALYSES AND SUMMARIES ......................................................................................39
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6.1. Primary Endpoints...................................................................................................39
6.1.1. Overall survival ..........................................................................................39
6.1.1.1. Primary analysis ........................................................................39
6.1.2. Progression-free survival as assessed by BICR per RECIST v1.1.............40
6.1.2.1. Primary analysis ........................................................................40
6.2. Secondary Endpoints...............................................................................................43
6.2.1. Safety endpoints..........................................................................................43
6.2.2. Efficacy endpoints ......................................................................................43
6.2.2.1. Sensitivity analyses for overall survival....................................43
6.2.2.2. Sensitivity analyses for progression-free survival.....................46
6.2.2.3. Objective response and tumor shrinkage...................................48
6.2.2.4. Disease control ..........................................................................51
6.2.2.5. Duration of response .................................................................51
6.2.2.6. Time to response .......................................................................52
6.2.3. Pharmacokinetic endpoints.........................................................................52
6.2.4. Population pharmacokinetic endpoints.......................................................53
6.2.5. Biomarker endpoints...................................................................................53
6.2.6. Endpoints for immunogenicity data of avelumab.......................................54
6.2.6.1. Time to and Duration of ADA and nAb response.....................56
6.2.6.2. ADA titer...................................................................................57
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity 
status..................................................................................................57
6.2.7. PRO endpoints............................................................................................59
6.2.7.1. PRO Scoring Procedure ............................................................60
6.2.7.2. Instrument Completing Rate .....................................................60
6.2.7.3. Descriptive summaries over time..............................................60
6.2.7.4. Time-to-event endpoints ...........................................................61
6.2.7.5. Binary and categorical endpoints ..............................................61
6.2.7.6. Continuous endpoints................................................................62
6.2.7.7. Sensitivity Analysis...................................................................62
6.3. Other Endpoints.......................................................................................................62
6.3.2. CA-125 .......................................................................................................65
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6.4. Subset Analyses.......................................................................................................65
6.5. Baseline and Other Summaries and Analyses.........................................................67
6.5.1. Baseline summaries ....................................................................................67
6.5.1.1. Demographic characteristics .....................................................67
6.5.1.2. Medical history..........................................................................68
6.5.1.3. Disease characteristics...............................................................69
6.5.1.4. Prior anti-cancer therapies.........................................................70
6.5.2. Study conduct and patient disposition........................................................71
6.5.2.1. Patient disposition .....................................................................71
6.5.2.2. Protocol deviations....................................................................72
6.5.3. Study treatment compliance and exposure .................................................72
6.5.3.1. Exposure to avelumab ...............................................................73
6.5.3.2. Exposure to PLD .......................................................................74
6.5.3.3. Dose reductions.........................................................................75
6.5.3.4. Dose delays ...............................................................................76
6.5.3.5. Infusion rate reductions.............................................................76
6.5.3.6. Infusion interruptions ................................................................76
6.5.4. Concomitant medications and non-drug treatments ...................................77
6.5.5. Subsequent anti-cancer therapies................................................................77
6.6. Safety Summaries and Analyses .............................................................................78
6.6.1. Adverse events............................................................................................78
6.6.1.1. All adverse events .....................................................................79
6.6.1.2. Adverse events leading to dose reduction.................................80
6.6.1.3. Adverse events leading to interruption of study treatment .......80
6.6.1.4. Adverse events leading to discontinuation of study 
treatment............................................................................................81
6.6.2. Deaths .........................................................................................................82
6.6.3. Serious adverse events................................................................................82
6.6.4. Other significant adverse events.................................................................82
6.6.5. Laboratory data...........................................................................................84
6.6.5.1. Hematology and chemistry parameters.....................................84
6.6.5.2. Other laboratory parameters......................................................87
6.6.6. Vital signs...................................................................................................88
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6.6.7. Electrocardiogram.......................................................................................88
6.6.8. MUGA/ECHO............................................................................................90
6.6.9. Physical examination..................................................................................90
6.6.10. ECOG performance status........................................................................90
7. INTERIM ANALYSES.......................................................................................................91
7.1. Introduction .............................................................................................................91
7.2. Interim Analyses and Summaries............................................................................91
7.2.1. Interim analysis for OS and PFS ................................................................91
8. REFERENCES ....................................................................................................................93
9. APPENDICES .....................................................................................................................95
LIST OF TABLES
Table 2.
PK Parameters to be Determined for Avelumab and Doxorubicin ......................17
Table 3.
Biomarker Definition and Determination.............................................................18
Table 4.
Statistical Analyses by Analysis Set.....................................................................22
Table 5.      Interim Analysis - Efficacy and Futility Boundaries............................................27
Table 6.
Simulated cumulative probabilities to cross the futility or efficacy 
boundaries at the interim or final OS analysis......................................................28
Table 7.
Simulated cumulative probabilities to cross the futility or efficacy 
boundaries at the interim or final PFS analysis ....................................................28
Table 8.
OS Censoring Reasons and Hierarchy..................................................................40
Table 9.
Outcome and event dates for PFS and DR analyses.............................................41
Table 10.
PFS Censoring Reasons and Hierarchy................................................................42
Table 11.
Possible Outcomes for Investigator vs BICR .......................................................47
Table 12.
Possible BOR Outcomes for Investigator vs BICR..............................................50
Table 13 
Patients Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ...................................................................................................................55
Table 14 
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) ...................................................................................................................56
Table 16.
Case Definition for irAEs.....................................................................................95
Table 17.
Case Definition for IRRs – IV study drugs Administered Alone.........................97
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Table 18.
Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets)......................................................................................98
LIST OF FIGURES
Figure 1 Testing Strategy.........................................................................................................25
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................95
Appendix 2. Infusion Related Reactions .................................................................................97
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991009 is based on the protocol amendment 
01 dated 15-Dec-2016.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991009.  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, ADA, nAb,
, and tumor assessment results 
by the Blinded Independent Central Review (BICR)). 
The primary analysis will include all data up to a cut-off date which is determined by the 
number of events for Progression-Free Survival (PFS) by Blinded Independent Central
Review (BICR) and for Overall Survival (OS) 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 for OS and minimum follow-up of 12 months have occurred. 
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
Primary Objectives

To demonstrate that avelumab given alone or in combination with Pegylated liposomal 
doxorubicin (PLD) is superior to PLD alone in prolonging OS in patients with platinum -
resistant/platinum-refractory ovarian cancer.

To demonstrate that avelumab given alone or in combination with PLD is superior to 
PLD alone in prolonging PFS in patients with platinum-resistant/platinum-refractory
ovarian cancer.
Secondary Objectives

To evaluate anti-tumor activity of avelumab given alone or in combination with PLD 
versus PLD alone in ovarian cancer patients.
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
To evaluate the overall safety profile of avelumab alone or in combination with PLD 
versus PLD alone in ovarian cancer patients.

To characterize the Pharmacokinetics (PK) of doxorubicin (PLD samples) and avelumab 
when administered in combination, and to assess the effect of avelumab on the PK of 
doxorubicin (PLD samples) and the effect of PLD on PK of avelumab.

To assess the immunogenicity of avelumab.

To evaluate candidate predictive biomarkers of sensitivity or resistance to avelumab 
alone or PLD in combination with avelumab in pre-treatment tumor tissue, that may aid 
in the identification of patient subpopulations most likely to benefit from treatment.

To compare the effect of avelumab alone or in combination with PLD versus PLD alone 
on patient-reported outcomes (PRO) in patients with ovarian cancer.
Exploratory Objectives

 
 
2.2. Study Design
This is a Phase 3, multicenter, randomized, open-label, parallel 3-arm study in which 
approximately 550 patients will be randomized in a 1:1:1 ratio to receive avelumab alone, 
avelumab in combination with PLD, or PLD alone, as follows:  

Arm A: avelumab alone;

Arm B: avelumab plus PLD;

Arm C: PLD alone.
Patients will be stratified by platinum-refractory or platinum-resistant status, number of prior 
regimens (1 vs 2 or 3), and bulky disease (defined as presence of a tumor 5 cm) vs not.  
Cross-over will not be permitted.
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints

Overall Survival (OS).
OS is defined as the time from the date of randomization to the date of death due to any 
cause.

Progression Free Survival as determined by BICR according to RECIST version 1.1.
PFS is defined as the time from the date of randomization to the date of the first 
documentation of progressive disease (PD) or death due to any cause, whichever occurs 
first.
3.2. Secondary Endpoints
3.2.1. Safety endpoints

Adverse Events (as graded by NCI CTCAE v.4.03); 
AEs will be graded by the investigator according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for
Regulatory Activities (MedDRA)

Laboratory abnormalities (as graded by NCI CTCAE v.4.03); 

Vital signs (blood pressure, pulse rate); 

Electrocardiograms (ECGs), ECHO or MUGA scans.
3.2.2. Efficacy endpoints

PFS as determined by Investigator according to RECIST version 1.1.

Objective Response (OR), Duration of Response (DR), and Disease Control (DC) as 
determined by Blinded Independent Central Review (BICR) and Investigator [as assessed 
by RECIST version 1.1].
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 the 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 an objective response, as the time from first 
documentation of objective response (CR or PR) to the date of first documentation of PD 
or death due to any cause.  
DC is defined as CR, PR, non-CR/non-PD, or SD.  Both CR and PR must be confirmed 
by repeat assessments performed no less than 4 weeks after the criteria for response are 
first met. Criteria for SD and non-CR/non-PD must have been met at least 6 weeks after 
the date of randomization.
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3.2.3. Patient reported outcomes

EORTC QLQ-C30, EORTC QLQ-OV28, and EQ-5D-5L.
Patient-reported outcomes of HRQoL and ovarian cancer specific disease/treatment-
related symptoms will be evaluated using the European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) and its 
corresponding module for ovarian cancer, the Quality of Life Questionnaire – Ovarian 
Cancer 28 (QLQ-OV28). The EuroQoL 5 Dimensions 5 Levels (EQ-5D-5L) 
questionnaire will also be collected to assess general health status. 
The EORTC QLQ-C30 consists of 30 questions which assess five functional domains 
(physical, role, cognitive, emotional, and social), global health status/quality of life, 
disease/treatment related symptoms (fatigue, pain, nausea/vomiting dyspnea, appetite 
loss, sleep disturbance, constipation, and diarrhoea), and the perceived financial impact 
of disease (Aaronson et al. 1993, Aaronson et al. 1996, Osoba et al. 1997).
The EORTC QLQ-OV28 is the ovarian cancer specific module of the EORTC quality of 
life questionnaire.  The EORTC QLQ-OV28 is a 28 item instrument with seven (7) 
functional domain subscales.  The 7 subscales include:  
(i)
an abdominal/GI symptom subscale (7 items); 
(ii)
a peripheral neuropathy subscale (3 items); 
(iii)
a chemotherapy side effects subscale (7 items); 
(iv)
a hormonal/menopausal symptoms subscale (2 items); 
(v)
a body image subscale (2 items); 
(vi)
an attitude to disease and treatment subscale (3 items); and 
(vii)
a sexual function subscale (4 items).  
Higher scores are reflective of a greater presence of symptoms (Cull et al. 2001, Greimal 
et al. 2003).
The EQ-5D-5L questionnaire consists of the EQ-5D-5L descriptive system and a visual 
analogue scale (the EQ VAS). The EQ-5D-5L descriptive system measures a patient’s 
health state on 5 dimensions which include: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  The respondent’s self-rated health is assessed 
on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by 
the EQ-VAS (The EuroQol Group, 2015).
3.2.4. Pharmacokinetic endpoints

Pharmacokinetic parameters Ctrough for avelumab: Cmax, volume of distribution (Vd), 
clearance (CL), area under the concentration-time curve (AUC) for doxorubicin (PLD 
samples).
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Cmax and Ctrough are calculated after single dose and at steady state. Other parameters will 
be calculated including, but not limited to Tmax, AUC24, AUClast, Tlast, AUCsd,, AUCss,, 
t1/2, CL, and Vdz, Css,av as data permit).  Dose normalized parameters (eg, CDN-Cmax, 
DN-AUC) will be reported as appropriate.  
Table 2.
PK Parameters to be Determined for Avelumab and Doxorubicin
Parameter
Definition
Method of Determination
AUC24
Area under the plasma concentration-time 
profile from time zero to 24 hours
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
AUCsd,
AUCss,
Area under the plasma concentration-time 
profile after single dose from time zero to 
the next dose (after single dose and at 
steady state)
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 / AUCτ for steady state
Vd
Volume of distribution
Dose / (AUCτ ·kel) for steady state
AUC24 (dn)
Dose normalized AUC24
AUC24 / Dose
AUClast(dn)
Dose normalized AUClast
AUClast / Dose
AUCinf(dn)a
Dose normalized AUCinf
AUCinf / Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
a If data permit
3.2.5. Immunogenicity endpoints

Anti-Drug antibodies and neutralizing antibodies against avelumab.
Anti-Drug Antibody (ADA) / Neutralizing antibodies (nAb) titers for 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).
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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 
CD8+ 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
3.3. Exploratory Endpoints

CA-125 levels.
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3.4. Baseline Variables
3.4.1. Study drug, study treatment and baseline definitions
In this study, ‘study drug’ refers to avelumab or PLD and ‘study treatment’ (or ‘treatment 
arm’) refers to one of the following:

Arm A = avelumab alone;

Arm B = avelumab plus PLD;

Arm C = PLD alone.
Start and end dates of study treatment:
For Arm A and Arm C:
The date/time of first dose of study treatment is the earliest date/time of non-zero dosing of 
the study drug.
The date/time of last dose of study treatment is the latest date/time of non-zero dosing of the 
study drug.
For Arm B:
The date/time of first dose of study treatment in the combination arm is the earliest date/time 
of the first non-zero dose date/time for each of the study drugs.
The date/time of last dose of study treatment in the combination arm is the latest date/time of 
the last non-zero dose date/time for each of the study drugs.
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. 
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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. Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
Definition of baseline for biomarker analyses
The last measurement prior to the start of study treatment will serve as the baseline 
measurement for biomarker analyses. For biomarkers that are planned to be measured on 
Cycle 1 Day 1 (eg, soluble proteins), it will be assumed that the measurement was performed 
prior to study treatment administration, if the assessment time point is not collected or is 
missing.
3.4.2. Baseline characteristics
Randomization is stratified by the following, as recorded in the Interactive Response 
Technology (IRT): 
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
Platinum-refractory or platinum-resistant status 

Number of prior regimens (1 vs 2 or 3)

Bulky disease (defined as presence of a tumor 5 cm) vs not
The primary analyses of OS and PFS 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 the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs)
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in 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.  
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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. 
Table 4.
Statistical Analyses by Analysis Set
Endpoints
Full Analysis Set
Per Protocol
Analysis Set
Safety Analysis Set
Baseline Characteristics


Prior and Concomitant Therapies


Exposure

Efficacy: Primary 


Efficacy: Secondary 

Safety

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. 
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4.3. Other Analysis Sets
4.3.1. Per-protocol analysis sets
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 primary 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

Patient without a tumor assessment >7 weeks after randomization (unless PD by BICR or 
death is observed before that time in which case the patient will not be excluded from the 
PP analysis set)

Patient without measurable disease at baseline by BICR

ECOG status > 1

Patient does not meet Inclusion Criteria 1, 2 or 3
1. Histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, 
including malignant mixed Müllerian tumors with high grade serous component.
2. Platinum-resistant/refractory disease, defined as disease progression within 180 days 
following the last administered dose of platinum therapy (resistant), or lack of 
response or disease progression while receiving the most recent platinum-based 
therapy (refractory), respectively.
3. Received up to 3 lines of systemic anticancer therapy for platinum-sensitive disease, 
most recently platinum-containing, and no prior systemic therapy for platinum-
resistant disease.
Note that the protocol only requires that patients have measurable disease at baseline as per 
investigator assessment. However, since PFS by BICR is the primary endpoint, “patient 
without measurable disease at baseline by BICR” will be used as a criterion to exclude 
patients from the PP analysis set for this sensitivity analysis of the PFS by BICR primary 
endpoint. 
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

ECOG status > 1

Patient does not meet Inclusion Criteria 1, 2 or 3
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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 or doxorubicin.
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 or doxorubicin.
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
5.1.1. Hypotheses and sample size determination
The study is designed to test, in parallel, the following hypotheses:
H01: HROS(avelumab/PLD) ≥1, versus Ha1: HROS(avelumab/PLD) <1
H02: HROS(avelumab+PLD/PLD) ≥1, versus Ha2: HROS(avelumab+PLD/PLD) <1
H03: HRPFS(avelumab/PLD) ≥1, versus Ha3: HRPFS(avelumab/PLD) <1
H04: HRPFS(avelumab+PLD/PLD) ≥1, versus Ha4: HRPFS(avelumab+PLD/PLD) <1
where HROS represents the hazard ratio for OS in each of the experimental arms vs the 
control arm, and HRPFS represents the hazard ratio for PFS by BICR assessment in each of 
the experimental arms vs the control arm.
The treatment effects on the primary PRO endpoint, time to deterioration (TTD), will also be 
tested.
H05: HRTTD(avelumab/PLD) ≥1, versus Ha5: HRTTD(avelumab/PLD) <1
H06: HRTTD(avelumab+PLD/PLD) ≥1, versus Ha6: HRTTD(avelumab+PLD/PLD) <1
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where HRTTD represents the hazard ratio for TTD in each of the experimental arms vs the 
control arm.
Approximately 550 patients will be randomized to the treatment arms using a 1:1:1 
randomization, stratified by platinum-refractory or platinum-resistant status, number of prior 
regimens (1 vs 2 or 3), and bulky disease (defined as presence of a tumor 5 cm) vs not. 
Overall type I-error will be maintained at or below 1-sided 0.025 by allocating 0.0115 alpha 
to each of the two OS comparisons and 0.001 to each of the two PFS comparisons. A 
gatekeeping procedure will be used to allow further testing of TTD for patients as described 
in Figure 1. The significance levels for each test will also take into account the group 
sequential nature of the design.
Figure 1 Testing Strategy
For each of the two OS comparisons, 196 OS events will be required to have at least 90% 
power to detect a hazard ratio of 0.6 using a 1-sided log-rank test at a significance level of 
0.0115, and a 2-look group-sequential design with Lan-DeMets (O’Brien-Fleming) -
spending function to determine the efficacy boundary and a Gamma Family (-10) -spending 
function to determine the non-binding futility boundary. 
For each of the two PFS comparisons, 325 PFS events by BICR assessment will provide 93% 
power to detect a HR of 0.6 using a 1-sided log rank test at a significance level of 0.001, and 
a 2-look group sequential design with Lan-DeMets (O’Brien-Fleming) -spending function 
to determine the efficacy boundary and a Gamma Family (-10) -spending function to 
determine the non-binding futility boundary.
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The analysis cut-off date for the test of the 4 primary hypotheses for OS and PFS will be the 
same for the IA and, if applicable, for the final analysis. The hypotheses of TTD will be 
tested at the time of the primary OS and PFS analyses.
The sample size for this study is determined based on the assumptions that the median OS 
and PFS in control arm is 12 months and 3.5 months, respectively (Gordon et al, 2001; 
Colombo et al, 2012), and that treatment with avelumab alone or avelumab in combination 
with PLD is expected to increase the median OS and median PFS to 20 months and 5.8
months, respectively, corresponding to a hazard ratio (HR) of ≤ 0.6 under the exponential 
model assumption. The sample size further assumes a 5% drop-out rate for OS and 15% 
drop-out rate for PFS within each treatment arm and a non-uniform patient accrual over a 19-
month period.  The data cut-off for the primary OS and PFS analyses will occur after the 
target number of events for both endpoints has been reached within each comparison and the 
last patient randomized in the study has been followed for at least 12 months after 
randomization.
5.1.2. Decision rules
OS
To protect the integrity of the study and to preserve the type I error rate, a fraction of alpha 
(0.002) for OS 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 OS events. The 
nominal significance levels for the interim and final efficacy analyses of OS 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 OS, within each 
comparison, will be preserved at 0.0115 (1-sided).
Two analyses will be performed for OS:
1. an interim analysis will  be conducted after all patients have been randomized in the 
study and at least 131 (67%) of the 196 OS events for each of the OS comparisons 
have been documented and
2. the final analysis for OS will be conducted after all patients randomized in the study 
have been followed for 12 months and at least 196 OS events for each of the OS
comparisons have been documented.
PFS based on BICR assessment
All references to PFS in this section pertain to PFS based on BICR assessment even when not 
specifically stated.  
A fraction of alpha (0.0003) 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 0.001 (1-sided).
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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 267 (82%) of the 325 PFS events for each of the PFS comparisons 
have been documented based on BICR assessment, and
2. the final analysis for PFS after all patients randomized in the study have been 
followed for 12 months and at least 325 PFS events for each of the PFS comparisons 
have been documented based on BICR assessment.
The interim analyses for OS and PFS will occur at the same time for both treatment 
comparisons, ie the analysis cut-off date for the test of the 4 hypotheses, H01, H02, H03 and 
H04, will be the same and will be set after all patients have been randomized in the study and 
the target number of events across all endpoints and treatment comparisons have been 
reached. If the value of the test statistic for either of the primary endpoints (either OS or PFS)
exceeds the associated efficacy boundary 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 that endpoint. If the 
value of the test statistics for both OS and PFS exceed 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 5.      Interim Analysis - Efficacy and Futility Boundaries
Efficacy boundary
Futility boundary
z value
p -value
z value
p -value
OS 
Assuming 131 OS events for each 
comparison at the time of the IA
-2.8791
0.002
-0.2339
0.4075
PFS 
Assuming 267 PFS events for each 
comparison at the time of the IA
-3.4474
0.0003
-1.8938
0.0291
Since the observed number of events at the interim analysis for each comparison may not be 
exactly equal to the planned 131 OS events and 267 PFS events, the efficacy and futility 
boundaries will be updated based on the actual number of observed events using the pre-
specified α-and β-spending functions. Therefore, the observed Z-test statistic at the interim 
analysis will be compared with the updated efficacy and futility boundaries. 
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 OS and 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 exactly 131 OS events for each 
comparison, and the study continues until the final analysis, the observed p-value for the 
comparison will have to be < 0.011 to declare statistical significance; if the interim analysis 
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occurs after exactly 267 PFS events for each comparison, and the study continues until the 
final analysis, the observed p-value for the comparison will have to be < 0.001 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 for OS and 82% information fraction for PFS the design has the 
following operating characteristics.
Table 6 presents the simulated cumulative probabilities to cross the futility or efficacy 
boundaries within each comparison for OS at the time of the interim and final analyses and 
Table 7 presents the simulated cumulative probabilities to cross the futility or efficacy 
thresholds within each comparison for PFS at the time of the interim and final analyses. 
Within each comparison, crossing of only one boundary (for either OS or PFS) at interim will 
not trigger early termination for futility but may trigger early declaration of efficacy.
Table 6.
Simulated cumulative probabilities to cross the futility or efficacy 
boundaries at the interim or final OS analysis
Scenario
Look
Number of OS
events a
Calendar 
Time 
(months)
P(Reject H0i)
for OS 
P(Reject Hai)
for OS 
H0i is true (HR=1)
Interim
131
21.5
0.0025
0.5959
Final
196
27
0.0113
0.9887
Hai is true (HR=0.6)
Interim
131
23.5
0.5040
0.0040
Final
196
31
0.9008
0.0992
Simulations performed in EAST with number of simulations = 10,000 and seed = 1234.
a For each comparison; i=1, 2.
Table 7.
Simulated cumulative probabilities to cross the futility or efficacy 
boundaries at the interim or final PFS analysis
Scenario
Look
Number of 
PFS events a
Calendar 
Time 
(months)
P(Reject H0i)
for PFS
P(Reject Hai)
for PFS
H0i is true (HR=1)
Interim
267 (PFS)
21.5
0.0001
0.9693
Final
325 (PFS)
27
0.0011
0.9989
Hai is true (HR=0.6)
Interim
267 (PFS)
23.5
0.7609
0.0117
Final
325 (PFS)
31
0.9302
0.0698
Simulations performed in EAST with number of simulations = 10,000 and seed = 1234.
a For each comparison; i=3, 4.
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5.2. General Methods
As described in Section 3.4, in this study ‘treatment arm’ refers to one of the following:

Arm A = avelumab alone;

Arm B = avelumab plus PLD;

Arm C = PLD alone.
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:
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Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. Definition of start of new anti-cancer drug therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When the start date of anti-cancer drug therapy is missing or partially
missing, the imputation rules described in Section 5.3.3.4 should be applied using only data 
from the ‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of start of new anti-cancer therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.2 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after 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’ 

Surgery date recorded in ‘Follow-up Surgery’ eCRF pages when ‘Surgery Outcome’ 
= ‘Resected’ or ‘Partially Resected’.  
When the 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’, and ‘Follow-up Surgery’ 
eCRF pages.
5.2.7. Definition of on-treatment period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but will not be summarized.  
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5.2.8. Standard derivations and reporting conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

Age [years]: 
-
(date of given informed consent - date of birth + 1) / 365.25
-
In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth)
-
In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth)
The integer part of the calculated age will be used for reporting purposes. 

BMI (kg/m2) = weight (kg)/[height (m)]2

BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits.
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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.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions).
5.2.11. Adequate post-baseline tumor assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.2.2.3).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’. 
5.3.1.1. Pharmacokinetic concentrations
Concentrations Below the Limit of Quantification
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures.
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);
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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.
5.3.1.3. Biomarker Parameters: Unintentional Duplicate Data
If an individual patient has unintentionally duplicated observations for a specific biomarker 
analyte(s) the following procedure will occur:

For continuous data, the duplicate data points will be averaged, and the average added to 
the database;

For non-continuous data (eg, listing of genes identified), the study team will discuss 
which, if any record, to select for analysis.  A flag will be added to the database 
indicating which record is selected (including no record selected.)  
For biomarker analytes for which it is intentional to have 2 samples (eg, denovo and archival 
tumor sample), these two samples will not be considered to be duplicate of each other, 
however, a variable in the database will identify the records. 
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.
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
If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st. 

If the date is completely missing, no imputation will be performed.
5.3.2.2. Adverse events
Incomplete AE-related dates will be imputed as follows:

If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment.

If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015.

If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014.

In all other cases the missing onset day or missing onset month will be replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off, outcome of AE is ongoing at cut-off. 
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 administered after study treatment 
discontinuation

AE start and end dates

Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’)

Study drug start and end dates

Randomization date

Withdrawal of consent date

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up).
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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
For the EORTC QLQ-C30 and QLQ-OV28, in cases where 2 answers are given to 1 item, the 
more severe answer (higher score for symptom domains, and lower score for the 
functioning/QoL domains of QLQ-C30; higher score for the QLQ- OV28) will be counted. If 
less than half of the constituent items on the QLQ-C30 and QLQ-OV28 have been answered 
for a multi-item subscale, that subscale will be considered missing. Single-item subscales 
will be considered missing if the constituent item is incomplete. Item 39 of the EORTC 
QLQ-Ov28 is a conditional question based on response to item 38.  Item 39 should not be 
scored if the patient responded no hair loss (option 1) to item 38.  For the EQ-5D-5L, in cases 
where 2 answers are given to 1 item, the item will be considered missing. For the EQ-5D-
5L, questions not answered will be considered missing items and will not be utilized.
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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. Overall survival
6.1.1.1. Primary analysis
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, 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(x), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 
(0=control arm, 1= experimental arm) and is the unknown regression parameter.
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG).
In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 2000), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of OS.
In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the interim 
and the final analyses for OS.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median OS time with 2-sided 95% CIs.  
In particular, the OS rate at 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 (1982) and the CIs for the survival function estimates at the time points defined 
above will be derived using the log-log transformation according to Kalbfleisch and Prentice
(2011) (conftype=loglog default option in SAS Proc LIFETEST) with back transformation to
a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.  
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Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment arm. Reasons for censoring will be summarized according to 
the categories in Table 8 following the hierarchy shown.
Table 8.
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 > 13
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 6, 12, 18, 24 and 30 months will be estimated with 
corresponding 2-sided 95% CIs.  
6.1.2. Progression-free survival as assessed by BICR per RECIST v1.1
6.1.2.1. Primary analysis
The following analyses will be based on the FAS using the strata assigned at randomization.  
Progression of disease (PD) below refers to PD by BICR assessment.
Progression-Free Survival (PFS) is defined as the time from 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, ≤ 16 weeks after the date of randomization) in which case the death will be 
considered an event. 
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In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every 8 weeks until disease progression regardless of initiation of 
subsequent anti-cancer therapy.  The allowable time window for disease assessments is 5 
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
Table 9.
Outcome and event dates for PFS and DR analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of randomization a
Censored a
PD or death 
-
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR
-
≤ 16 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 ≤16 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 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 
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baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie for the i-
th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(x), where h(i,0;t) defines 
the baseline hazard function for the i-th stratum and x defines the treatment arm (0=control 
arm, 1= experimental arm) and is the unknown regression parameter.
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG).
In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 2000), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of PFS.
In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the interim 
and the final analyses for PFS.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS time with 2-sided 95% CIs.  
In particular, the PFS rate at 3, 6, 9, 12 and 15 months will be estimated with corresponding 
2-sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley (1982) and the CIs for the survival function estimates at the time points defined 
above will be derived using the log-log transformation according to Kalbfleisch and Prentice
(2011) (conftype=loglog default option in SAS Proc LIFETEST) with back transformation to
a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to the categories in Table 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.   
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The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment arm. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment arms reversing the PFS censoring and event 
indicators. Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
arm together with a summary of associated statistics including the median time of follow-up 
for PFS with 2-sided 95% CIs.  In particular, the rate at 3, 6, 9, 12 and 15 months will be 
estimated with corresponding 2-sided 95% CIs.  
6.2. Secondary Endpoints
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.   
Analyses for tumor-related endpoints will be performed based on BICR assessment 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 6.1.2.1 now 
referring to PD by investigator assessment instead of PD by BICR assessment. RCIs will not 
be constructed for the hazard ratio of PFS by investigator assessment.
6.2.2.1. 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 
6.1.1.1 with the modifications below:

PP analysis set for OS;

unstratified;

using strata derived according to eCRF data instead of those entered in IRT. For the 
stratification factor of bulky disease (presence of a tumor ≥5 cm vs not), if the 
investigator identifies in the eCRF a target lesion with diameter ≥5 cm, then this is 
considered bulky disease per eCRF data; since the diameter for non-target lesions is not 
collected in the eCRF, if there are no target lesions with diameter ≥5 cm and there is no 
protocol deviation for bulky disease status then the IRT stratification value for the bulky 
disease strata will be used for this assessment; if there are no target lesions with diameter 
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≥5 cm and there is a protocol deviation for bulky disease status then the opposite of the 
IRT stratification value for the bulky disease strata will be used for this assessment.
Methods for evaluating the validity of model assumptions
The proportional hazards assumption will be checked visually by plotting log(-log(OS)) 
versus log(time) within each randomization stratum.
Schoenfeld residuals for the stratified Cox proportional regression model will be plotted to 
investigate graphically violations from the proportional hazards (PH) assumption; a non-zero 
slope is evidence of departure from PH. The PH assumption will be formally tested using
Schoenfeld’s residual test (Schoenfeld, 1980; Therneau & Grambsch, 2000).  Large 
departures from PH will be evidenced by a p-value <0.05.
If these show large departures from proportional hazards, then OS 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 
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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).

τ3 = midpoint between τ1 and τ2.
The treatment effect between each of the avelumab containing arms and PLD 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.  RMST as a function of τ and the associated 
treatment effect between each of the avelumab containing arms and PLD arm will be plotted 
against time τ .
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 OS 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.
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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 6.1.2.1 with 
the modifications below:

PFS based on BICR assessment and counting all PD and deaths as events regardless of  
missing assessments or timing of the event 

PFS based on BICR assessment on the PP analysis set for PFS

PFS based on BICR assessment using an unstratified analysis

PFS based on BICR assessment using strata derived according to eCRF data instead of 
those entered in IRT. See Section 6.2.2.1 for the derivation associated with the 
stratification factor of bulky disease.

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
Methods for evaluating the validity of model assumptions
The same methodology described in Section 6.2.2.1 for OS will be used for PFS based on 
BICR assessment.
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 11 outlines the possible outcomes by investigator and BICR (Amit et al. 2011). 
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Table 11.
Possible Outcomes for Investigator vs BICR
BICR
Investigator
Event
No Event
Event
a = a1 + a2 + a3
b
No Event
c
d
a1: number of agreements on timing and occurrence of event; 
a2: number of times agreement on event but INV declares event later than BICR; 
a3: number of times agreement on event but INV declares event earlier than BICR; 
N=a+b+c+d.
The timing agreement of event is defined as a window of ± 7 days.
The following measure of discordance will be calculated for each treatment arm:

Total Event Discrepancy Rate: (b+c) / N

Early Discrepancy Rate (EDR): (a3+b) / (a+b)

Late Discrepancy Rate (LDR): (a2+c) / (a2+a3+b+c)

Overall Discrepancy Rate: (a2+a3+b+c) / N
The EDR represents the positive predictive value of investigator assessment and quantifies 
the frequency with which the investigator declares PFS event earlier than BICR within each 
treatment arm as a proportion of the total number of investigator assessed events.
The LDR quantifies the frequency with which the investigator declares PFS event later than 
BICR as a proportion of the total number of discrepancies within the treatment arm. 
Discordance metrics are calculated for each treatment arm and, for each metric, the 
difference in discordance between the experimental and control arms is used to evaluate 
potential bias.  If the discordance is similar across the treatment arms then this suggests the 
absence of evaluation bias favoring a particular treatment arm. A negative differential 
discordance for EDR and/or a positive differential discordance for LDR may be indicative of 
investigator evaluation bias in favor of the experimental arm (Amit et al, 2011).
Exploratory analyses to investigate the impact of potential prognostic or effect 
modifying (predictive) factors
The same methodology described in Section 6.2.2.1 for OS will be used for PFS based on 
BICR assessment.
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6.2.2.3. 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.
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.
Only tumor assessments performed on or before the start of any further anti-cancer therapies
will be considered in the assessment of BOR.  Clinical deterioration will not be considered as 
documented disease progression.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met. 
Objective Response (OR) is defined as a confirmed BOR of CR or PR according to 
RECIST v1.1. Both CR and PR must be confirmed by repeat assessments performed no less 
than 4 weeks after the criteria for response are first met.
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.
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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 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 without further 
evaluable tumor assessments)

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 of insufficient duration’.
The association of study treatment and OR will be tested by the General Association Statistic 
of the Cochran-Mantel-Haenszel test (CMH) with the randomization strata taken into 
account. The null hypothesis of no association in any of the randomization strata is tested 
against the alternative, which specifies that there is an association between study treatment 
and tumor response at least in one randomization stratum. The CMH test will be performed at 
1-sided alpha level of 0.025. 
The stratified odds ratio in terms of OR will also be estimated along with its 95% CI to 
compare study treatments. The odds ratio is defined as the odds of OR with experimental 
treatment divided by the odds of OR with control treatment. The Breslow-Day test will be 
used to check the homogeneity of the odds ratio across the randomization strata. It tests the 
null hypothesis that odds ratios in all strata are equal against the alternative hypothesis that at 
least in one stratum the odds ratio is different.
In case the null hypothesis of homogeneity of odds ratios across strata is not rejected at the 2-
sided alpha level of 0.05, the common odds ratio will be determined using the Mantel-
Haenszel estimate (by the FREQ procedure using CMH option in SAS); if the null hypothesis 
of homogeneity of odds ratio across all strata is rejected, the odds ratio per stratum will be 
calculated with the corresponding exact CI.
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BICR vs Investigator Assessment:
Table 12 outlines the possible BOR outcomes by investigator and BICR. 
Table 12.
Possible BOR Outcomes for Investigator vs BICR
BOR
BICR Assessment
CR
PR
SD
Non-CR/ non-PD
PD
NE
Investigator 
Assessment
CR
n11
n12
n13
n14
n15
n16
PR
n21
n22
n23
n24
n25
n26
SD
n31
n32
n33
n34
n35
n36
Non-CR/ non-PD
n41
n42
n43
n44
n45
n46
PD
n51
n52
n53
n54
n55
n56
NE
n61
n62
n63
n64
n65
n66
∑
(݊௜௜)
଺
௜ୀଵ
is the number of agreements on BOR between BICR and Investigator 
∑
൫݊௜௝൯
଺
௜,௝ୀଵ
for i ≠ j is the number of disagreements on BOR between BICR and Investigator 
N= ∑
൫݊௜௝൯
଺
௜,௝ୀଵ
The following measures of concordance will be calculated for each treatment arm:

Concordance rate for BOR = ∑
(݊௜௜)
଺
௜ୀଵ
/ܰ

Concordance rate for response =  [∑
൫݊௜௝൯+ ∑
൫݊௜௝൯]/ܰ
଺
௜,௝ୀଷ
ଶ
௜,௝ୀଵ
Concordance rates are calculated for each treatment arm and, for each metric, the difference 
in concordance between the experimental and control arms are used to evaluate potential 
bias.  If the concordance is similar across the treatment arms then this suggests the absence of 
evaluation bias favoring a particular treatment arm.
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
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The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment 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.
6.2.2.4. Disease control
Disease Control (DC) is defined as BOR of CR, PR, non-CR/non-PD or SD.   Both CR and 
PR must be confirmed by repeat assessments performed no less than 4 weeks after the 
criteria for response are first met. DC rate (DCR) is the proportion of patients with DC.
DCR will be summarized by frequency counts and percentages.
6.2.2.5. 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 3, 6, 9, 12 and 15 months will be estimated with corresponding 
2-sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley (1982) and the CIs for the survival function estimates at the time points defined 
above will be derived using the log-log transformation according to Kalbfleisch and Prentice
(2011) (conftype=loglog default option in SAS Proc LIFETEST) with back transformation to 
a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.
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.
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6.2.2.6. Time to response
Time to response (TTR) is defined, for patients with OR, as the time from the date of 
randomization to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
TTR (in months) = [first date of OR – date of randomization +1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.3. Pharmacokinetic endpoints
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
arm.  
Ctrough and Cmax for avelumab and doxorubicin will be summarized descriptively (n, mean, 
SD, CV, median, minimum, maximum, geometric mean, its associated CV, and 95% 
confidence interval) by treatment arm, cycle, and day. Other standard parameters will be 
calculated including, but not limited to AUC24, Tmax, AUClast, Tlast, AUCsd,, AUCss,, t1/2, CL,
Vdz, Css,av as data permit.
Dose normalized parameters (eg, CDN- Cmax, DN-AUC) will be reported as appropriate. The 
trough concentrations for avelumab and doxorubicin (for each dose as needed) will be plotted 
using a box whisker plot by cycle and day in order to assess the attainment of steady state.
Pharmacokinetic parameters for avelumab and doxorubicin will be taken from observed 
values or derived from plasma concentration-time data as described in Section 3.2.4.
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 
doxorubicin as needed), cycle, day and nominal time. Additionally similar descriptive 
statistics will also be generated for dose-normalized avelumab and doxorubicin
pharmacokinetic parameters.

Linear-linear and log-linear plots of mean and median plasma concentrations by nominal 
time for avelumab and doxorubicin will be presented for PK sampling days by treatment 
arm, cycle, and study 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 and doxorubicin will be listed and summarized 
by treatment arm/dose level (for doxorubicin as needed), cycle and study day using 
descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean 
and its associated %CV, and 95% confidence interval). 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 their associated %CV. If an intrapatient dose 
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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 and 
doxorubicin doses were administered.

Box plots for AUC and Cmax for avelumab and doxorubicin 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.

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 Doxorubicin (PLD Samples) Pharmacokinetics
The effect of avelumab dosing on doxorubicin PK will be evaluated based on overall 
assessment of the geometric mean ratios and associated 90% CI for Cmax, AUCinf, and AUCτ
of PLD on Day 1 of Cycle 2 in Arm B (avelumab plus PLD) compared to those on Day 1 of 
Cycle 2 of Arm C. 
Effect of PLD on Avelumab Pharmacokinetics
The effect of PLD dosing on avelumab PK will be evaluated based on the overall assessment 
of the geometric mean ratios of Cmax and Ctrough of Arm B on Day 1 of Cycle 2 compared to 
those on Day 1 of Cycle 2 of Arm A.
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.
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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.   
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 (BOR and PFS by BICR assessment, OS) using the methodology outlined 
in Section 6.4.  In addition, for PFS by BICR assessment and OS, 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. Endpoints for immunogenicity data of avelumab 
All analyses described below are performed by treatment arm containing avelumab (Arm A 
and Arm B), and for the avelumab-containing treatment arms combined unless otherwise 
specified. 
Blood samples for avelumab immunogenicity testing will be collected within 2 hours before 
the start of the avelumab infusion on Day 1 of Cycles 1 through 4. Thereafter, a sample will 
be collected on Day 1 prior to avelumab infusion in Cycles 5, 6, 9, 12, 15, 18, 21 24 and at 
the End of Treatment.  An additional sample must be collected at 30 days after the last dose 
of avelumab.
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 13.  
CCI
CCI
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Table 13
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 14. 
For nAb, treatment-boosted is not applicable since no titer result is available.
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Table 14
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 (30 days after the last dose of avelumab) 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 AEA 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 pre-dose and at the end of infusion 
(immediately before the end of avelumab infusion) on Days 1 and 15 of Cycles 1 to 4.  Pre-
dose samples should be collected on Days 1 of Cycles 5, 6, 9, 12, 15, 18, 21 24;, at the End 
of Treatment and at Day 30 Safety Follow-up visit.
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 and the first positive ADA result is observed on Day 1 of 
Cycle 3, then the relative PK day for this Ctrough is -28. 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.
The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status.

TEAEs, by SOC and PT 
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
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.
Patient-reported outcomes of HRQoL and ovarian cancer specific disease/treatment-related 
symptoms will be evaluated using the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) and its corresponding 
module for ovarian cancer, the Quality of Life Questionnaire – Ovarian Cancer 28 (QLQ-
OV28). The EuroQoL (EQ-5D-5L) questionnaire will also be collected to assess general 
health status. 
The primary PRO endpoint will be the time to deterioration analysis of the abdominal/GI 
domain of the EORTC QLQ-OV28 based on the ≥15 points threshold, since abdominal/GI 
symptoms are predominant and burdensome in this patient population (Cella, 2003).  
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6.2.7.1. PRO Scoring Procedure
The subscales of the EORTC QLQ-C30 and the QLQ-OV28 will be scored based on the 
EORTC scoring manual (Fayer et al. 2001). In summary, each scale of the EORTC QLQ-
C30 and the QLQ-OV28 will be transformed so that scale scores will range from 0 to 100. 
The transformation will proceed in two steps. First, the average of the items contributing to a 
subscale will be calculated to compute the raw score of the scale. Next, a linear 
transformation will be applied to ‘standardize’ the raw score. After scores are transformed, 
higher scores on the EORTC QLQ-C30 or the QLQ-OV28 will represent higher (“better”) 
levels of functioning and/or a higher (“worse”) level of symptoms.
The EQ-5D-5L will be scored according to its scoring manual and UK weights will be 
applied. (EuroQol Group, 2015).
6.2.7.2. Instrument Completing Rate
For each treatment arm and at each time point, the number and percentage of patients who 
complete the QLQ-C30, QLQ-OV28, 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. 
For each treatment arm and at each time point, the number and percentage of patients who 
complete a specific subscale of the QLQ-C30 and QLQ-OV28 will also be summarized.  
The summary will include a tabulation of the number and percentage of patients in each 
treatment arm who completed the summary scales at each time point.
For QLQ-OV28, item 39 is a conditional question based on response to item 38 regarding 
hair loss.  Item 39 is only to be completed if patients had indicated hair loss for item 38.  
Therefore, the proportions of those who missed item 39 at each time point will also be 
reported by their response to item 38 (hair loss if response is 2-4, no hair loss if response is 1, 
or missing if no response provided).  The proportion of those who completed item 39, but 
responded no hair loss (option 1) to item 38 will also be reported even though their response 
to item 39 will not be scored.  Items 57 and 58 are also conditional questions based on 
response to item 56 regarding being sexually active.  Items 57 and 58 are only to be 
completed if patients had indicated being sexually active for item 56.   Therefore, the 
proportions of those who missed items 57 and 58 at each time point will also be reported by 
their response to item 56 (sexually active if response is 2-4, not sexually active if response is 
1, or missing if no response provided).  The proportion of those who completed items 57 
and/or 58, but responded not sexually active (option 1) to item 56 will also be reported even 
though their response to items 57 and 58 will not be scored.
6.2.7.3. Descriptive summaries over time
The mean (and SD), and median (and range) of absolute scores and change from baseline of 
the QLQ-C30 and QLQ-OV28 multiple-item and single-item scale scores, and the EQ-VAS
will be summarized for each treatment arm at each time point.  A line chart depicting the 
means along with standard error (SE) error bars over time will be provided for each scale in 
each treatment arm.  For the EQ-5D-5L health state profiles, the proportions of patients 
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having none, slight, some or moderate, severe, extreme/unable problems at each time point 
will be reported for each of the 5 dimensions. 
6.2.7.4. Time-to-event endpoints
Time to deterioration (TTD) is defined as the time from randomization to the first time the 
patient’s score shows a 15 point or higher increase in patient’s EORTC QLQ-OV28 
abdominal/GI symptom subscale.  
TTD data will be censored at the last time when a patient completed a sub-scale assessment 
for patients who have not deteriorated. 
Osoba et al, established that a 10-point or a greater clinical minimally important difference 
(MID) from baseline on the scales of the EORTC QLQ-C30 would correlate with significant 
(moderate) change in disease symptoms and functioning (Osoba, 1998)).  However, Stockler 
et al, in an Ovarian-specific clinical trial, established a more conservative primary PRO 
hypothesis threshold of at least a 15% (15-point) absolute difference on the QLQ-OV28 
abdominal/GI symptom subscale (Stockler et al, 2014). Hence, in the analysis of time to 
deterioration, a minimally important difference (MID) of 15 points or greater is proposed for 
the abdominal/ GI symptom subscale of the OV-28.  Sensitivity TTD analysis of a 10 point 
increase will also be conducted to assess the robustness of the endpoints on the QLQ-OV28 
subscale.
TTD of the abdominal/GI symptom sub-scales will be summarized as follows.
The treatment effect on TTD will be estimated using a Cox’s Proportional Hazard model 
stratified by the randomization strata to calculate the hazard ratio and p-value for each of the 
experimental arms vs control arm. To explore the effect of the open-label nature of the study 
design on the PRO endpoints, an additional analysis will estimate the hazard ratio between 
the two experimental arms.
Each stratum will define a separate baseline hazard function (using the 'STRATA' statement 
in SAS PROC PHREG), ie for the i-th stratum the hazard function is expressed as: h(i;t) = 
h(i,0;t) exp(x), where h(i,0;t) defines the baseline hazard function for the i-th stratum and x 
defines the treatment arm (0=control arm, 1= experimental arm) and is the unknown 
regression parameter.
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG).
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.  The CIs for the median TTD will be calculated according to Brookmeyer and Crowley
(1982).  
6.2.7.5. Binary and categorical endpoints
The proportion of patients who improved from baseline, defined as a ≥10 point decrease on 
the abdominal/GI subscale (items 31-37) of the EORTC QLQ-OV28, will be summarized 
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and compared between each of the treatment arms at Cycle 3 (beginning of Week 9). Patients 
with missing questionnaires at Cycle 3 will be counted as not having improved.
The number and proportion of patients who improved, worsened, or remained stable for all of 
the symptom and functional domains, global QOL and single items of the EORTC QLQ C30, 
the QLQ OV28 and will be summarized and compared between each of the experimental 
arms and the control arm. The definition of improved, worsened, stable will use the 10-point 
MID for all domains and items and considered as an average per patient (as opposed to the 
15-point used in the TTD analyses above).
6.2.7.6. Continuous endpoints
Longitudinal random intercept random slope mixed-effect model will be carried out for the 
total and subscales of the EORTC QLQ-C30, QLQ-OV28, EQ-5D-5L and EQ VAS and will 
compare each of the experimental arms with the control arm. Outcomes are PRO post-
baseline scores and the predictors are the corresponding baseline PRO score, treatment, 
randomization stratification factor, time (treated as a continuous variable in days), and 
treatment-by-time interaction. Intercept and time are considered as random effects particular 
to each subject. All parameter estimates will be obtained using restricted maximum 
likelihood. The unstructured covariance structure will 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 will be 
used (using option “ddfm = kr” as a part of the MODEL statement in PROC MIXED).
6.2.7.7. Sensitivity Analysis
For the TTD and continuous endpoints, the main analysis will include data from baseline up 
to EOT assessment (not including EOT). A sensitivity analysis for these endpoints will be 
conducted including all assessments from baseline to end of the safety follow-up period.
6.3. Other Endpoints
 
 
  
 
 
 
 
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s
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6.3.2. CA-125
CA-125 values and changes from baseline will be summarized using descriptive statistics 
(mean, SD, median, Q1, Q3, minimum, and maximum).
6.4. Subset Analyses
Subset analyses will be performed for OS and for PFS, OR and DR per BICR assessment 
based on the FAS for the subgroups defined below. 
The following subgroups will be defined and used for analyses:

Randomization stratification factors 
-
Platinum-refractory or platinum-resistant status, 
-
Number of prior regimens (1 vs 2 or 3)
-
Bulky disease (defined as presence of a tumor 5 cm) vs not  

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 
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-
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
-
Positive (either BRCA1 or BRCA2 positive, ie, positive for known deleterious 
mutation(s) or genetic variant suspected to be deleterious)
-
Negative (Reference)

Prior Bevacizumab
-
Yes
-
No (Reference)

Bevacizumab-eligible as collected in the eCRF
-
Yes (Reference)
-
No

CA-125 at baseline
-
≤2xULN (Reference)
-
>2xULN

PD-L1 status at baseline
-
Positive (Reference)
-
Negative
      Different cutoffs may be considered for defining PD-L1 status at baseline, including:
o
1%, 5%, 50% and 75% on tumor cells; 
o
5%, 25%, 50% and 75% on immune cells; 
o
5%, 25%, 50% on tumor or immune cells 
Here, for each x=5, 25, 50, or 75, PD-L1 positive status is defined as tumor cell or 
immune cells, as appropriate,  ≥x% and PD-L1 negative status is defined as tumor 
cell or immune cells, as appropriate,  <x%.
Subset analyses for OS, PFS and DR will use the primary censoring rules described in 
Sections 6.1.1 and 6.1.2. All the subgroup analyses are exploratory. Treatment arms will be 
compared for OS and PFS 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. 
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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 of the interaction model parameter. 
The HR for OS and PFS and corresponding 95% CIs for all subgroups will also be presented 
in a forest plot.
The ORR odds ratio for each subgroup and corresponding 95% CIs will also be presented in 
a forest plot for each treatment arm.
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.
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 
-
Gender: Male, Female 
-
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 
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
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)
-
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.
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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

Platinum-free interval (defined as the interval from the date of the last platinum dose to 
the date of documented disease progression): 0-3 months, >3-6 months, > 6 months.
From the RECIST eCRF page (summary will be presented separately based on investigator 
assessment and BICR assessment):

Measurable disease (lesions) at baseline (Yes, No)

Involved tumor sites at baseline
From the ‘Substance Use’ eCRF page:

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
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
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 therapies
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages.
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:

Patients with at least one type of prior anti-cancer therapy

Patients with at least one prior anti-cancer drug therapy

Patients with at least one prior anti-cancer radiotherapy

Patients with at least one prior anti-cancer surgery
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:

At least one prior anti-cancer drug therapy

Number of prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4

Prior bevacizumab (Yes/No)

Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced – Metastatic, Local regional 
Disease-Recurrence

Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived from 
the last treatment regimen.
The prior anti-cancer drug therapies will also be summarized based on the number and 
percentage of patients by the drug class and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. The summary will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used.
Prior anti-cancer therapies will be included in the listings that follow with a flag to identify 
prior therapies. These will include the patient identification number, and all the relevant 
collected data-fields on the corresponding eCRF pages.
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
Listing of anti-cancer drug therapies 

Listing of anti-cancer radiotherapy 

Listing of anti-cancer surgeries
6.5.2. Study conduct and patient disposition
The following analyses will be performed based on the FAS overall and separately by
treatment arm.
6.5.2.1. Patient disposition
The percentages below will be calculated based on the number of patients in the FAS.

Total number of patients screened overall

Number of patients who discontinued from the study prior to randomization overall and 
by the main reason for discontinuation

Number and percentage of randomized patients in each of the analysis sets defined in 
Section 4

Number and percentage of randomized patients with study drug ongoing (separately for 
each study drug in Arm B) 

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 in 
Arm B)

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
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)
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
Cross tabulation: stratum by IRT vs. stratum by eCRF

Cross tabulation: patients randomized (avelumab/avelumab+PLD/PLD/none) vs. patients 
treated (avelumab/avelumab+PLD/PLD/none)
In addition, a cross tabulation of patients who have discontinued/are ongoing treatment with 
avelumab vs patients who have discontinued/are ongoing treatment with PLD in Arm B will 
also be provided. 
6.5.2.2. Protocol deviations
All protocol violations that impact the safety of the patients and/or the conduct of the study 
and/or its evaluation will be reported. These include:

Patients who are dosed on the study despite not satisfying the inclusion criteria;

Patients who develop withdrawal criteria whilst on the study but are not withdrawn;

Patients who receive the wrong treatment or an incorrect dose;

Patients who receive an excluded concomitant medication;

Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study treatment compliance and exposure
The following analyses will be based on the safety analysis set by treatment arm.
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;
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
for the last cycle, actual cycle end date = actual cycle start date +  28 days – 1 day
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of study drug (Arm A and C) or at least one 
of the study drugs (Arm B) should be included.
Exposure may be summarized (per cycle and/or overall) as dose received (cumulative dose, 
actual dose intensity) and as dose received relative to intended dose (relative dose intensity 
[RDI]). 
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical, oral daily, oral cyclical).  
The formulae below should be applied to each study drug separately even when study drugs 
are administered in combination.
The derivations below are provided for the following:

Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg once every 2 
weeks in 4-week cycles. 

PLD administered as 1-hour IV infusion at a dose of 40 mg/m2 once every 4 weeks in 
4-week cycles. 
Analysis of exposure will be based on the calculated actual dose levels

Avelumab - total dose / weight 

PLD - total dose / m2
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.
Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle with non-zero dose of study drug + 28 – 1
Duration of exposure to avelumab (weeks) =  
(last dose date of avelumab – first dose date of avelumab + 14)/7
The cumulative dose (mg/kg) of avelumab per patient in a cycle or overall is the sum of the 
actual doses of avelumab received in a cycle or overall, respectively 
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Each cycle for avelumab is defined by a 4-week period. The dose intensity (DI) and the 
relative dose intensity (RDI) will be calculated for each patient across all cycles. The actual
dose intensity per cycle (mg/kg/4-week cycle) is defined as

By cycle actual DI (mg/kg/4-week cycle) = Cumulative dose in the cycle (mg/kg)/[ cycle 
duration (weeks)/4]

Overall actual DI (mg/kg/4-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/4].  
The relative dose intensity (RDI) is defined as the actual dose intensity divided by the 
intended dose intensity and expressed in %.

Intended DI (mg/kg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [20 (mg/kg)] / [1 (4-week cycle)]  = 20 (mg/kg/4-week 
cycle)

By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [20 (mg/kg/4-week cycle)]  

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [20 (mg/kg/4-week cycle)]
The summary of treatment exposure and compliance for avelumab will include the following 
information:

Treatment duration (weeks)

Total number of infusions received

Cumulative dose (mg/kg)

Dose intensity (mg/kg/cycle)

Relative dose intensity (%).
6.5.3.2. Exposure to PLD
The dose level for PLD is calculated as actual dose administered/m2 (mg/m2).  The last 
available weight and height of the patient on or prior to the day of dosing will be used to 
calculate the BSA. The duration of PLD treatment (in weeks) during the study for a patient is 
defined as:
Intended duration of treatment with PLD (weeks) =
(end date–date of first dose of PLD +1)/7, 
where end date = start date of last cycle with non-zero dose of PLD + 28 – 1.
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Duration of exposure to PLD (weeks) = 
(last dose date of PLD – first dose date of PLD + 28)/7
The cumulative dose (mg/m2) of PLD per patient in a cycle or overall is the sum of the actual 
doses of PLD received in a cycle or overall, respectively.  Each cycle for PLD is defined by a 
4-week period. The dose intensity (DI) and the relative dose intensity (RDI) of PLD will be 
calculated for each patient across all cycles. The actual dose intensity per cycle (mg/m2/4-
week cycle) is defined as

By cycle actual DI (mg/m2/4-week cycle) = Cumulative dose in the cycle (mg/m2)/[cycle 
duration  (weeks)/4]

Overall actual DI (mg/m2/4-week cycle) = overall cumulative dose (mg/m2) / [intended 
duration of treatment with PLD (weeks)/4].  
The relative dose intensity (RDI) is defined as the actual dose intensity divided by the 
intended dose intensity and expressed in %.

Intended DI (mg/ m2/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [40 (mg/m2)] / [1 (4-week cycle)]  = 40 (mg/m2/4-week 
cycle)

By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [40 (mg/m2/4-week cycle)]

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [40 (mg/m2/4-week cycle)]  
The summary of treatment exposure and compliance for PLD will include the following 
information:

Treatment duration (weeks)

Total number of infusions received

Cumulative dose (mg/m2)

Dose intensity (mg/m2/cycle)

Relative dose intensity (%). 
6.5.3.3. Dose reductions 
Applicable to avelumab and PLD. 
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. 
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6.5.3.4. Dose delays 
Applicable to avelumab and PLD.
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) – 14, for avelumab.
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – 28, for PLD.
Delays will be grouped into the following categories based on the deviation of the actual to 
the planned treatment administration day (relative to the previous treatment administration 
date): 

No delay

1-2 days delay

3-6 days delay

7 or more days delay
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab  administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16 or 17, this is considered as 1-2 days delay.  
No delay and 1-2 days delay will also be summarized together. 
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. 
6.5.3.5. Infusion rate reductions
Applicable to avelumab and PLD.
The number and percentage of patients with at least one infusion rate reduction of 50% or 
more compared to the first infusion rate reported in the eCRF as well as the frequency of 
patients with 1, 2, 3, or ≥4 infusion rate reductions of 50% or more will be summarized by 
treatment arm.
6.5.3.6. Infusion interruptions
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of 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.
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6.5.4. Concomitant medications and non-drug treatments
The following analyses will be based on the safety analysis set by treatment arm.
Concomitant medications are medications, other than study medications, which started 
prior to first dose date of study treatment and continued on on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study medications and pre-medications for study drug, which are started before the first dose 
of study treatment. 
Prior and concomitant medications will be summarized from the ‘General Concomitant 
Medications’ eCRF page. Pre-medications for study drug will also be summarized separately
from the ‘Pre-Medication Treatment’ eCRF page. 
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’, 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. 
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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.
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 
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Safety Review Plan and finalized for analysis of the current studies data prior to DB 
lock).
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment arm, primary SOC 
and PT in decreasing frequency based on the frequencies observed for the avelumab 
treatment arm (Arm A). 
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity.
6.6.1.1. All adverse events
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the  latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category. 
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
The following tables will be created: 

The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment arm:
-
TEAEs
-
TEAEs, Grade ≥ 3
-
Related TEAEs
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to dose reduction of avelumab 
-
TEAEs leading to dose reduction of PLD
-
TEAEs leading to interruption of avelumab
-
TEAS leading to interruption of PLD
-
TEAEs leading to discontinuation of avelumab
-
TEAEs leading to discontinuation of PLD
-
TEAEs leading to discontinuation of any study drug
-
TEAEs leading to discontinuation of all study drugs
-
Related TEAEs leading to discontinuation of avelumab
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-
Related TEAEs leading to discontinuation of PLD
-
Related TEAEs leading to discontinuation of any study drug
-
Related TEAEs leading to discontinuation of all study drugs
-
Serious TEAEs
-
Related Serious TEAEs 
-
TEAEs leading to death
-
Related TEAEs leading to death
-
irAEs
-
IRRs  

TEAEs by SOC and PT and worst grade

Related TEAEs by SOC and PT and worst grade 

TEAEs leading to death by SOC and PT

Related TEAEs leading to death by SOC and PT

TEAEs Excluding SAEs, with frequency ≥ 5% in any treatment arm by SOC and PT
6.6.1.2. Adverse events leading to dose reduction
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment arm:

TEAEs leading to dose reduction of avelumab by SOC and PT

TEAEs leading to dose reduction of PLD 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 
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delay (as defined in Section 6.5.3.4). These IRRs will be considered as IRRs leading to 
interruption of infusion.

IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.4).
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 PLD 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 PLD by SOC and PT
This summary will take into account PTs with both actions as defined in Section 6.6.1, 
eventhough 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 PLD by SOC and PT

Related TEAEs leading to discontinuation of PLD by SOC and PT

TEAEs leading to discontinuation of any study drug by SOC and PT

Related TEAEs leading to discontinuation of any study drug by SOC and PT

TEAEs leading to discontinuation of all study drugs by SOC and PT

Related TEAEs leading to discontinuation of all study drugs by SOC and PT
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
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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:

irAEs leading to death, by Cluster and PT  

irAEs, by Cluster and PT
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
irAEs, Grade ≥ 3, by Cluster and PT

irAEs leading to discontinuation of avelumab, by Cluster and PT

irAEs leading to discontinuation of PLD, 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 PLD, 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.
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
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
Point estimate for risk difference and 95% CI for risk difference (experimental arm vs 
comparator arm) for each of the following by PT or Clustered Term:
-
irAEs
-
irAEs Grade ≥ 3
-
IRRs
-
IRRs Grade ≥ 3
-
Tier-2 AEs
-
Tier-2 AEs Grade ≥ 3

2-sided p-value associated with risk difference (experimental arm vs comparator arm) for 
each of the following by PT or Clustered Term:
-
irAEs
-
irAEs Grade ≥ 3
-
IRRs
-
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 
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such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 0 
when the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), 
and vice versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased:  
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 800/mm3

Neutrophil count decreased 
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L])
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
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
(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST)  ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN

TBILI ≥ 2×ULN

Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN 

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤2×ULN or 
missing)
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment arms, by graphically displaying

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. 
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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:
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with: 

shifts from baseline normal to at least one result above normal during on-treatment period 

shifts from baseline normal to at least one result below normal during on-treatment 
period
In this study, these apply to the following parameters: 

Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils

Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH)
6.6.5.2. Other laboratory parameters
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF. 
Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time (INR).
Urinalysis: all urinalysis parameters
Other parameters: hormone, and immunology parameters
Pregnancy test
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The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests. 
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing. 
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided.
6.6.6. Vital signs
Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
pre-dose Day 1 of each cycle. Weight will not be collected at End of Treatment. Height will 
be measured at screening only.
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing. 
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline. 
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). The 
average of the replicate measurements should be determined after the derivation of the 
individual parameter at each time point.
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB 
,
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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

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
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-
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. MUGA/ECHO
LVEF% 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.  In addition, LVEF% will be summarized as frequency (number and percentage) 
of patients with: 

a shift from baseline normal to at least one result below the institutional lower limit of 
normal (LLN) during the on-treatment period

≥10-point decrease from baseline in LVEF% during the on-treatment period

≥10-point decrease from baseline in LVEF% to a post-baseline value < LLN during the 
on-treatment period

≥15-point decrease from baseline in LVEF%

≥15-point decrease from baseline in LVEF% to a post-baseline value < LLN during the 
on-treatment period.
Clinically significant findings will be listed.
6.6.9. Physical examination
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system.
6.6.10. 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.
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7. INTERIM ANALYSES
7.1. Introduction
The goals of the interim analyses are to allow early stopping of treatment arm(s) for futility 
or declare an experimental treatment (or treatments) to be statistically significantly superior 
to the control treatment arm.  The interim analysis of OS and PFS will be performed as 
described in Sections 5.1.1 and 5.1.2 using the methodology described in Section 6.1.1 for 
OS and Section 6.1.2 for PFS.  
The interim analyses for PFS and OS will occur at the same time and will be performed by an 
independent statistician. 
Unblinded results from the interim analysis for OS and PFS 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) OS or 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 the final PFS and OS analyses, both PFS and OS analysis will be performed by 
the Sponsor’s clinical team. 
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 OS and PFS
Let uOS(t1) and uOS(tF) denote the upper critical boundaries based on the test statistics Z1_OS
and ZF_OS for efficacy at the interim and the final analysis of OS, respectively, and let lOS(t1) 
and lOS(tF) denote the lower critical boundary for futility at the interim and final analysis of 
OS, respectively.  For the final analysis of OS, lOS(tF)=uOS(tF). 
Let uPFS(t1) and uPFS(tF) denote the upper critical boundaries based on the test statistics Z1_PFS
and ZF_PFS for efficacy at the interim and the final analysis of PFS, respectively, and let 
lPFS(t1) and lPFS(tF) denote the lower critical boundary for futility at the interim and final
analysis of PFS, respectively.  For the final analysis of PFS, lPFS(tF)=uPFS(tF). 
The critical values uOS(t1) and lOS(t1) for the interim analysis of OS are determined such as
)
(
))
(
(
1
1
_
1
0
OS
OS
OS
t
t
u
Z
P



   and   
)
(
))
(
(
1
1
_
1
OS
OS
OS
a
t
t
l
Z
P



,
and critical values uPFS(t1) and lPFS(t1) for the interim analysis of PFS are determined such as
)
(
))
(
(
1
1
_
1
0
PFS
PFS
PFS
t
t
u
Z
P



   and   
)
(
))
(
(
1
1
_
1
PFS
PFS
PFS
a
t
t
l
Z
P



,
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where P0 and Pa denote the probabilities under the null hypothesis and the alternative 
hypothesis, respectively, and
)
( 1
OS
t

, 
)
( 1
OS
t

and 
)
( 1
PFS
t

, 
)
( 1
PFS
t

denote the α and β spent
for interim analysis of OS and PFS, respectively, based on the predefined spending functions 
at information fraction
OS
t1
and 
PFS
t1
, respectively. (
OS
t1
is calculated as the ratio of the 
number of OS events observed at the time of the cut-off for the interim analysis and the total 
number of OS events targeted for the final analysis; 
PFS
t1
is calculated as the ratio of the 
number of PFS events observed at the time of the cut-off for the interim analysis and the total 
number of PFS events targeted for the final analysis). 
The boundary for the final efficacy analysis of OS will be calculated such that
0115
.0
))
(
),
(
(
)
(
_
1
_
1
0
1




F
OS
OS
F
OS
OS
OS
t
u
Z
t
u
Z
P
t

The boundary for the final efficacy analysis of PFS will be calculated such that 
001
.0
))
(
),
(
(
)
(
_
1
_
1
0
1




F
PFS
PFS
F
PFS
PFS
PFS
t
u
Z
t
u
Z
P
t

As described in Section 5.1.2, if the number of OS or PFS events in the final analysis 
deviates from the target number of OS or PFS events, the final analysis criteria will be 
determined as above taking into account the actual alpha spent at the interim analysis, the 
actual correlation between the two test statistics for OS, Z1_OS and ZF_OS and the actual 
correlation between the two test statistics for PFS, Z1_PFS and ZF_PFS, 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.
Aaronson NK et al. The European Organization for Research and Treatment of Cancer 
QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology.  J Natl Cancer Inst  85:365-76, 1993.
2.
Aaronson NK et al. The European Organization for Research and Treatment of Cancer 
(EORTC) modular approach to quality of life assessment in oncology: an update., in 
Quality of Life and Parmacoeconomics in Clinical Trials. 2nd Ed.  S. B, Editor.  Raven 
Press: New York.  179-89, 1996.
3.
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.
4.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
5.
Cella D, Paul D, Yount S, et al. What are the most important symptom targets when 
treating advanced cancer? A survey of providers in the National Comprehensive Cancer 
Network (NCCN).  Cancer Invest 21:526-535, 2003.
6.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413, 1934.
7.
Colombo N, Kutarska E, Dimopoulos M, et al. Randomized, open-label, phase III study 
comparing patupilone (EPO906) with pegylated liposomal doxorubicin in platinum-
refractory or -resistant patients with recurrent epithelial ovarian, primary fallopian tube, 
or primary peritoneal cancer. J Clin Oncol.Nov 1;30(31):3841-7, 2012.
8.
Cull A, Howat S, Greimel E, Waldenstrom AC, Arraras J, Kudelka A, Chauvenet L, 
Gould A; EORTC Quality of Life Group [European Organization for Research and 
Treatment of Cancer]; Scottish Gynaecological Cancer Trials Group. Development of a 
European Organization for Research and Treatment of Cancer questionnaire module to 
assess the quality of life of ovarian cancer patients in clinical trials: a progress report. 
Eur J Cancer. 37(1):47-53, 2001.
9.
The EuroQol Group. EQ-5D-5L User Guide: Basic Information on how to use the EQ-
5D-5L: User Guide. V 2.1. The EuroQol Group, Rotterdam. 2015.
10.
Fayers P et al. EORTC QLQ-C30 Scoring Manual. EORTC, Brussels. 2001.
11.
Gordon A, Fleagle JT, Guthrie D, et al. Recurrent Epithelia Ovarian Carcinoma: A 
Randomized Phase III Study of Pegylated Liposomal Doxorubicin Versus Topotecan. J 
Clin Oncol,19: 3312-22, 2001.
12.
Greimel E, Bottomley A, Cull A, Waldenstrom AC, Arraras J, Chauvenet L, Holzner B, 
Kuljanic K, Lebrec J, D'haese S; EORTC Quality of Life Group and the Quality of Life 
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Unit. An international field study of the reliability and validity of a disease-specific
questionnaire module (the QLQ-OV28) in assessing the quality of life of patients with 
ovarian cancer. Eur J Cancer. 2003 Jul; 39(10):1402-8. Erratum in: Eur J Cancer. 
39(17):2570, 2003.
13.
Jennison C, Turnbull BW. In: Group Sequential Methods with Applications to Clinical 
Trials. Chapman & Hall/CRC, Boca Raton, 2000.
14.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience, 2011.  
15.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
16.
Osoba D, Aaronson N, Zee B, Sprangers M, te Velde A. Modification of the EORTC 
QLQ-C30 (version 2.0) based on content validity and reliability testing in large samples 
of patients with cancer. The Study Group on Quality of Life of the EORTC and the 
Symptom Control and Quality of Life Committees of the NCI of Canada Clinical Trials 
Group. Qual Life Res. 6(2):103-8, 1997.  
17.
Osoba D et al. Interpreting the significance of changes in health related quality of life 
scores. J. Cin Oncology. 16:139-144, 1998.
18.
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. Stat Med 30:2409-2421, 2011.
19.
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.
20.
Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression 
model. Biometrika 67:145-53, 1980.
21.
Stockler MR et al.  Patient-Reported Outcome Results From the Open-Label Phase III 
AURELIA Trial Evaluating Bevacizumab-Containing Therapy for Platinum-Resistant 
Ovarian Cancer.  J Clin Oncol 32:1309-1316, 2014.
22.
Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. 
Statistics for Biology and Health, 2000.
23.
Uno H, Wei LJ, et al. Moving Beyond the Hazard Ratio in Quantifying the Between-
Group Difference in Survival Analysis. J Clin Oncol 32, 2014.
24.
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 16.   
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step.  
Table 16.
Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment.
This is regardless of start of new anti-cancer drug
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
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, H02C, 
D07, A01AC, S01BA, S01BB, L04AA,  L04AB,  
L04AC,   L04AD,  L04AX) 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”
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5
A) No clear etiology (other than immune 
mediated etiology)
B)
Histopathology / biopsy consistent with 
immune-mediated event
Event is in if 
[Answer to 5B1 and 5B2 is YES  (regardless 
of answer to 5A)]
OR
[Answer to 5B1 is YES AND answer to 5B2 
is NO AND answer to 5A is NO] 
OR
[Answer to 5B1 is NO AND answer to 5A is 
NO]
A) From the AE eCRF page
Is the AE clearly related to an etiology other than 
immune-mediated etiology?    Yes / No
If answer is Yes, check all that apply:
Underlying malignancy / progressive disease.
Other medical conditions. 
Prior or concomitant medications / procedures.  
Other.  Specify.
B) From the AE eCRF page
B1) Was there a pathology /histology evaluation 
performed to investigate the AE?  Y/N
B2) If answer to the above is Yes, does the 
pathology/histology evaluation confirms an 
immune mediated mechanism for the AE?  Y/N
B3) If pathology / histology evaluation 
performed to investigate the AE, provide 
summary of relevant findings of the pathology 
/histology report.  (Free Text)
The data set associated with irAEs may be refined based on medical review.  The final data 
set including any changes based on medical review (eg, addition of cases that are not selected 
by the programmatic algorithm) will be the basis of the irAE analyses.
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Appendix 2. Infusion Related Reactions
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered. 

All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or 
after infusion) and the event resolved with end date within 2 days after onset. 

All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, 
will be considered potential IRRs when onset is on the day of study drug infusion 
(during or after the infusion) or the day after the study drug infusion (irrespective of  
resolution date).
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab. 
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 17
or Table 18 (identified for IV drugs only).     
Table 17.
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 18.
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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