Clinical trial NCT03317496
Conditions: Non-small Cell Lung Cancer Urothelial Cancer
Keywords: Avelumab, immunotherapy, PD-L1 inhibitor, non-small cell lung cancer (NSCLC), urothelial cancer (UC), carboplatin, pemetrexed, gemcitabine, cisplatin
Sponsor: Pfizer
Start date: 2017-12-21; Completion date: 2022-12-20
Enrollment: 67 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1b/2, open label, multicenter, safety and clinical activity study of avelumab in combination with chemotherapy as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and in combination with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial (bladder) cancer (UC) (Cohort A2). As more information is learned about other anti-cancer immunotherapy agents, in future portions of the study, avelumab may be combined with chemotherapy and other anti-cancer immunotherapy agents in patients with these same or different tumor types.

Detailed description:
This is a Phase 1b/2, open label, multicenter, safety, clinical activity, pharmacokinetic (PK), and pharmacodynamics (PD) study of avelumab in combination with chemotherapy with or without other anti-cancer immunotherapies, as first-line treatment of adult patients with locally advanced or metastatic solid tumors. Initially, avelumab will be evaluated in combination with pemetrexed and carboplatin in patients with advanced non-squamous non-small cell lung cancer (NSCLC) (Cohort A1) and with gemcitabine and cisplatin in patients with cisplatin-eligible urothelial cancer (UC) (Cohort A2).

Given the growing preclinical and clinical indications that combinations of anti-cancer immunotherapies potentially improve patient outcomes compared to results seen with single agents, in portions of the study to be added in the future, avelumab will be evaluated in combination with both standard-of-care chemotherapy and other anti-cancer immunotherapies in patients with advanced malignancies. Each cohort in the study will consist of a Phase 1b lead-in portion to evaluate safety and a Phase 2 cohort expansion to evaluate safety and efficacy.

In the Phase 1b safety lead-in portion, up to 12 patients will be enrolled into each cohort and evaluated for dose-limiting toxicities (DLT) during the first 2 cycles of treatment. If investigational products administration in a cohort is deemed safe in the Phase 1b lead-in, enrollment may be expanded into the Phase 2 cohort expansion. Up to approximately 40 patients in each cohort (including those enrolled in the Phase 1b lead-in and those enrolled in the Phase 2 cohort expansion) will be enrolled and treated with avelumab plus chemotherapy in the initial portion of the study and, in future portions of the study, with avelumab plus chemotherapy with or without other anti-cancer immunotherapies.

In the Phase 1b lead-in portions of NSCLC Cohort A1 and UC Cohort A2, avelumab is dosed at 800 mg fixed dose every 3 weeks. Under Protocol Amendment 4, avelumab is dosed at 1200 mg fixed dose every 3 weeks in the Phase 1b lead-in portions of NSCLC Cohort A3 and in UC Cohort A4, in combination with the same standard-of-care chemotherapy doublets used in Cohort A1 and Cohort A2, respectively. For each tumor type, the study treatment combination with the highest avelumab dose determined to be safe may be advanced into Phase 2 cohort expansion.

Arms: arm 1: Non-squamous non-small cell lung cancer (NSCLC) patients treated with 800 mg avelumab plus pemetrexed/carboplatin arm 2: Cisplatin-eligible urothelial cancer (UC)patients treated with 800 mg avelumab plus gemcitabine/cisplatin arm 3: Non-squamous non-small cell lung cancer (NSCLC) patients treated with 1200 mg avelumab plus pemetrexed/carboplatin arm 4: Cisplatin-eligible urothelial cancer (UC) patients treated with 1200 mg avelumab plus gemcitabine/cisplatin
Interventions: intervention 1: Avelumab 800 mg in combination with pemetrexed / carboplatin intervention 2: Avelumab 800 mg in combination with gemcitabine / cisplatin. intervention 3: Avelumab 1200 mg in combination with pemetrexed/carboplatin intervention 4: Avelumab 1200 mg in combination with gemcitabine/cisplatin
Intervention descriptions: intervention 1: Avelumab Pemetrexed Carboplatin intervention 2: Avelumab Gemcitabine Cisplatin intervention 3: Avelumab Pemetrexed Carboplatin intervention 4: Avelumab Gemcitabine Cisplatin

Protocol documents:
Prot_000.pdf: 
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A MULTICENTER, OPEN-LABEL, PHASE 1B/2 STUDY TO EVALUATE SAFETY 
AND EFFICACY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH 
CHEMOTHERAPY WITH OR WITHOUT OTHER ANTI-CANCER 
IMMUNOTHERAPIES AS FIRST-LINE TREATMENT IN PATIENTS WITH 
ADVANCED MALIGNANCIES
JAVELIN CHEMOTHERAPY MEDLEY
Investigational Product Number:
MSB0010718C
Investigational Product Name:
Avelumab (MSB0010718C)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2017-001741-27
Protocol Number:
B9991023
Phase:
1b/2 
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version 
Date
Summary of Changes and Rationale
Original 
Protocol
26 May 2017 
Not applicable (N/A)
Protocol 
Amendment 1
07 August 
2017
The following changes to the original protocol were 
requested by the FDA:

In response to the request that the protocol focus only 
on Group A (avelumab plus chemotherapy), all text 
and all table content, as well as Figure 2, pertaining to 
Group B (avelumab plus chemotherapy plus 
PF-06840003), any study treatment to be used in 
Group B, and any background information pertaining 
to any part of Group B were removed throughout the 
protocol. 

In response to the request that carboplatin/pemetrexed 
dosing in Cohort A1 be limited to 4-6 cycles with the 
option to continue pemetrexed dosing as maintenance 
therapy, text reflecting this request was added to the 
Phase 2 Cohort Expansion section of the Protocol 
Summary, Study Treatment Section of the Protocol 
Summary, Table 1 and Footnote 16 of Table 1, 
Section 3 Study Design, and Section 5.2 Treatment 
Duration.

In response to the request that premedication 
instructions be included in the protocol, instructions 
from the pemetrexed United States Prescribing 
Information were added to Section 5.4.2.1 Dosage 
and Administration for chemotherapy agents.  Text 
was also added indicating that local guidelines are to 
be followed if different if from the USPI. 
In addition, the following changes were implemented:

In Section 1.2.1.3, Clinical Experience in Patients 
with Locally Advanced or Metastatic UC, text was 
revised to include information about recent FDA 
approval.  Efficacy data were updated to reflect that 
presented in avelumab (Bavencio®) prescribing 


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information. 

Section 1.2.1.4, Clinical Experience in Patients with 
Recurrent or Metastatic SCCHN, was removed given 
this tumor type will not be evaluated in the amended 
study. 

Section 4.1 Inclusion Criteria, the words “OR and 
have” were removed from Criterion 10a to clarify that 
postmenopausal status may be confirmed with a 
follicle-stimulating hormone level test. 

Section 4.2 Exclusion Criteria, the words “and/or 
during study participation” were removed from 
Criterion 18 because this text referred to the patient’s 
status after enrollment rather than serving as 
eligibility guidance. 

Section 5.2, Treatment Duration, text concerning 
treatment discontinuation/continuation was updated 
to improve clarity.

In Table 14 in Section 7.1.4, Laboratory Safety 
Assessments, “bile acids” was added to Footer “a” for 
potential Hy’s law evaluation to align table with 
guidance in Section 8.4.2 Potential Cases of 
Drug-Induced Liver Injury.
Protocol 
Amendment 2
19 January 
2018
The following changes to the 07 August 2017 Protocol 
Amendment 1 will be introduced in response to the 
United Kingdom (UK) Medicines and Healthcare 
products Regulatory Agency (MHRA) observations for 
UK sites and will apply only to UK sites:

In response to the request that the protocol is limited 
to the evaluation of the Group A study drug 
combinations or to a limited number of groups and 
number of cohorts within a group, the sentence “For 
the UK: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and 
chemotherapy, in up to 4 tumor-specific cohorts, will 
be included” is added in several Sections.


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Summary of Changes and Rationale

In response to the request that condom plus 
spermicide not be noted as a highly effective method 
of contraception, the sentence “For countries where 
spermicide is not available or condom plus 
spermicide is not accepted as highly effective 
contraception, this option is not appropriate” in 
Section 4.3 has been modified to read “For countries 
where spermicide is not available or condom plus 
spermicide is not accepted as highly effective 
contraception (eg, the UK), this option is not 
appropriate.”
Protocol 
Amendment 3
15 March 
2018
In response to the Czech Republic State Institute for Drug 
Control’s (SUKL) observations, the phrase “and the 
Czech Republic” is added to the same changes included 
in Protocol Amendment 2 for sites in the UK, as 
indicated in the text below:

The sentence “For the UK: Only 1 additional 
anti-cancer immunotherapy, in combination with 
avelumab and chemotherapy, in up to 4 
tumor-specific cohorts, will be included” which was 
added in several Sections in Protocol Amendment 2 is 
modified to read “For the UK and the Czech 
Republic: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and 
chemotherapy, in up to 4 tumor-specific cohorts, will 
be included” to indicate that only a limited number of 
study drug combinations and tumor types will be 
evaluated at sites in the Czech Republic.

In Section 4.3, the sentence “For countries where 
spermicide is not available or condom plus 
spermicide is not accepted as highly effective 
contraception (eg, the UK), this option is not 
appropriate” is modified to read “For countries where 
spermicide is not available or condom plus 
spermicide is not accepted as highly effective 
contraception (eg, the UK and the Czech Republic), 
this option is not appropriate” in response to the 
request that, in the Czech Republic, condom plus 
spermicide not be noted as a highly effective method 


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of contraception.
Protocol 
Amendment 4
02 October
2018
The following changes to the 15 March 2018 Protocol 
Amendment 3 are introduced:

Introduction of a higher fixed dose of avelumab 
(based on US FDA feedback). The Phase 1b portion 
of the study is amended to include the evaluation of 
1200 mg fixed dose avelumab administered Q3W in 
combination with chemotherapy in both the NSCLC 
(Cohort A3) and UC (Cohort A4) cohorts, after the 
initial 800 mg Q3W dose has cleared the 
dose-limiting toxicity (DLT) assessment period and is 
deemed safe, according to the current study design.  
Feedback from the FDA’s review of the original 
protocol included a recommendation to evaluate 
additional avelumab doses, indicating that target 
occupancy alone is insufficient to support dose 
selections.  All text and all tables’ content, as well as 
Figure 1 mentioning Cohorts A1 and A2, are updated 
to introduce Cohorts A3 and A4 and the rules 
allowing enrollment in those cohorts, throughout the 
protocol.

The total number of patients enrolled in the two 
cohorts (NSCLC and UC) in Phase 1b and Phase 2 
remains unchanged at up to approximately 
80 patients. However, a higher number of patients 
will be enrolled in Phase 1b overall to permit 
evaluation of the safety of the combination of the 
fixed dose avelumab administered at 800 mg and at 
1200 mg Q3W with chemotherapy. Therefore, in 
order to keep the total number of enrolled patients at 
80 and to retain the cohort size of 40 patients with UC 
(in Phase 1b and Phase 2), the number of patients in 
the NSCLC cohort (Phase 2) is reduced. All text and 
all tables’ content mentioning sample size are updated 
to reflect this modification.

In order to add flexibility about expansion of the 
cohorts from Phase 1b Lead-in to Phase 2, the 
following sentences “enrollment will be initiated” or 
“expansion will be initiated” have been updated to 


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read “enrollment may be initiated” or “expansion may 
be initiated” respectively, at various points 
throughout the protocol.

Section 1.2.3 Study Rationale as well as the Protocol 
Summary, are updated to present the introduction of 
the 1200 mg fixed dose avelumab administered Q3W 
in combination with chemotherapy.

Section 1.3 Summary of Benefit/Risk Assessment, 
text is revised to include safety information from
clinical trials for the 20 mg/kg every 2 weeks dose of 
avelumab.
In addition, the following changes are implemented:

Section 1.4 Biomarker Rationale, text is revised to 
include information about the use of biopsy data from 
patients receiving the 1200 mg avelumab fixed dose.

Section 4.1 Inclusion Criteria, Criterion 1 is updated 
to accept archived tumor sample of 18 months instead 
of 1 year. A clarification is added about eligibility of 
patients with only one measurable (target) lesion.

Section 4.1 Inclusion Criteria, Criterion 10b is 
updated to include “and/or bilateral salpingectomy” to 
align text with current Pfizer standard protocol 
template for Phase 1-4 studies.

Section 4.1 Exclusion Criteria, Criterion 22 is 
updated to be in line with latest version of the Pfizer 
protocol template language for contraception. 

Section 4.3 Lifestyle Guidelines, text is revised to be 
in line with latest version of the Pfizer protocol 
template language for contraception.

Section 5.4.3 Timing of Investigational Product 
Administrations, text is updated to clarify 
administration interval beween chemotherapy and 
avelumab infusions.


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
Sections 5.4.4.1, 5.4.4.7.1, 5.4.4.7.2, 5.4.4.8.1, and 
5.4.4.8.2, have been updated to specify that dose 
modifications due to adverse drug reactions should be 
made in accordance with the guidance in the protocol, 
product labeling, and institutional guidelines.

Section 5.4.4.2 Dose Delays: All Investigational 
Products text is revised to add clarifications to the 
recommended dose delays guidelines.

Section 5.4.4.7.1 Hematological Toxicities, text is 
revised to add clarifications to the recommended dose 
modifications guidelines.

Sections 5.4.4.8.1 and 5.4.4.8.2, have been updated to 
specify that dose adjustments following dose delays 
due to toxicities, should start at the subsequent dose 
rather than “start of a subsequent cycle”.

Table 11 Pemetrexed, Carboplatin, Avelumab 
(Cohorts A1 and A3) Non- Hematologic Toxicity 
Management, text is revised to add clarifications to 
the recommended dose modifications guidelines.

Section 5.4.4.8.1 Hematological Toxicities, text is 
revised to add clarifications to the recommended dose 
modifications guidelines.

Table 12 Cisplatin, Gemcitabine, Avelumab 
(Cohorts A2 and A4) Hematologic Toxicity 
Management, text is revised to add clarifications to 
the recommended dose modifications guidelines.

Table 13 Cisplatin, Gemcitabine, Avelumab 
(Cohorts A2 and A4) Non-Hematologic Toxicity 
Management, text is revised to add clarifications to 
the recommended dose modifications guidelines.

Section 5.4.5 Treatment after Initial Evidence of 
Radiological Disease Progression, text is updated to 
clarify that avelumab should be permanently 
discontinued in case of further disease progression.  A 
clarification is also added about the timelines of 


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subsequent radiologic imaging.

Section 5.7 Concomitant Medications, text is updated 
to clarify that the collection of concomitant 
medications should end when a patient begins a new 
anti-cancer therapy.

Section 6.1.1 Tumor Biospecimens, text is updated to 
accept archived tumor sample of 18 months instead 
of 1 year. A clarification is added about eligibility of 
patients with only one measurable (target) lesion.

Section 7.1.2 Contraceptive Check, text is updated to 
be in line with latest version of the Pfizer protocol 
template language for contraception.

Section 7.1.6 (12-Lead) Electrocardiogram, text is 
updated for procedure clarification.

Section 7.6 Tumor Response Assessments, text is 
updated to clarify the methods to be used for bone 
imaging and the time schedule for bone imaging 
assessments.

Section 9.5.1 Analysis of Pharmacokinetics of Study 
Drugs, text is updated to remove time to maximum 
plasma concentration (Tmax) estimation for avelumab 
and chemotherapy agents as all drugs are 
administered intravenously.

Appendix 3 Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 Guidelines, update is 
added to clarify that all required scans must be done 
within 28 days prior to first dose of study treatment 
instead of prior to enrollment. 

At various points throughout protocol, all text 
pertaining to immune-related response criteria 
(irRECIST) including objectives, endpoints, tumor 
assessments, and Appendix 4, is removed in an effort 
to reduce burden on sites for determining and 
reporting tumor response per irRECIST criteria. 


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Summary of Changes and Rationale
•
Additional procedural clarifications, not previously
mentioned, are added according to two previously
issued Protocol Administrative Changes Letters as
follow:
•
Section 6.2 Treatment Period, text is updated for
inclusion of a statement about study treatment
continuation at the end of study.
•
Section 7.6 Tumor Response Assessments, text is
updated for clarification of windows around
scheduled tumor assessments.
•
Section 8.1.4 Time Period for Collecting AE/SAE
Information, text is updated for clarification of
wording for guidance for AE/SAE information
collection.
•
Schedule of Activities Table 1 and Table 3
Footnote 9, text is updated for clarification of
laboratory results that must be available and
reviewed prior to study drug administration.
•
Schedule of Activities Table 1 and Table 3
Footnote 39 (deleted), text is updated for removal
of collection of blood sample for analysis of
kynurenine and tryptophan.
•
Schedule of Activities Table 1 and Table 3
Footnote 39, text is updated for clarification of
window for Day 1 visits post Cycle 1.
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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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................15
LIST OF FIGURES .................................................................................................................16
APPENDICES .........................................................................................................................16
PROTOCOL SUMMARY.......................................................................................................17
SCHEDULE OF ACTIVITIES................................................................................................26
1. INTRODUCTION ...............................................................................................................43
1.1. Indication.................................................................................................................43
1.2. Background and Rationale ......................................................................................43
1.2.1. Avelumab....................................................................................................43
1.2.1.1. Avelumab Clinical Experience..................................................43
1.2.1.2. Clinical Experience in Patients with Locally Advanced or 
Metastatic NSCLC.............................................................................46
1.2.1.3. Clinical Experience in Patients with Locally Advanced or 
Metastatic UC....................................................................................47
1.2.1.4. Pharmacokinetics of Avelumab in Humans..............................47
1.2.2. Chemotherapy.............................................................................................48
1.2.3. Study Rationale...........................................................................................48
1.2.3.1. Rationale for Combining Avelumab with Chemotherapy.........48
1.2.3.2. Rationale for the Tumor Types Under Evaluation....................49
1.2.3.3. Rationale for the Chemotherapy Doublets to be Evaluated 
in this Study.......................................................................................49
1.2.3.4. Rationale for Investigational Product Dose...............................51
1.3. Summary of Benefit/Risk Assessment....................................................................52
1.4. Biomarker Rationale ...............................................................................................55
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................57
2.1. Objectives................................................................................................................57
2.2. Endpoints.................................................................................................................58
3. STUDY DESIGN.................................................................................................................59
3.1. Study Overview.......................................................................................................59
3.1.1. Tumor Assessments....................................................................................62
3.1.2. Safety Assessments.....................................................................................62
3.1.3. Pharmacokinetic/Immunogenicity Assessments ........................................62


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3.1.4. Biomarker Assessments..............................................................................63
3.2. Study Designs for Each Group................................................................................63
3.2.1. Group A (Avelumab plus Chemotherapy)..................................................63
3.3. Dose-Limiting Toxicity Definition .........................................................................64
4. PATIENT SELECTION......................................................................................................65
4.1. Inclusion Criteria.....................................................................................................65
4.2. Exclusion Criteria....................................................................................................67
4.3. Lifestyle Guidelines ................................................................................................69
4.4. Sponsor’s Qualified Medical Personnel..................................................................71
5. STUDY TREATMENTS.....................................................................................................71
5.1. Allocation to Treatment ..........................................................................................72
5.2. Treatment Duration .................................................................................................73
5.3. Patient Compliance .................................................................................................73
5.3.1. Avelumab and Chemotherapy ....................................................................73
5.4. Investigational Product Supplies and Administration.............................................74
5.4.1. Avelumab....................................................................................................74
5.4.1.1. Dosage Form and Packaging.....................................................74
5.4.1.2. Preparation ................................................................................75
5.4.1.3. Administration...........................................................................75
5.4.2. Chemotherapies ..........................................................................................76
5.4.2.1. Dosage and Administration.......................................................76
5.4.3. Timing of Investigational Product Administrations ...................................77
5.4.4. Recommended Dose Modifications............................................................77
5.4.4.1. Guidelines for Chemotherapy Toxicity Management...............78
5.4.4.2. Dose Delays: All Investigational Products................................78
5.4.4.3. Dose Reductions: Chemotherapy..............................................79
5.4.4.4. Dose Modifications for Avelumab............................................79
5.4.4.5. Avelumab: Infusion-Related Reactions/Hypersensitivity 
Reactions ...........................................................................................80
5.4.4.6. Avelumab: Immune-Related Adverse Events Toxicity 
Management ......................................................................................82
5.4.4.7. Recommended Treatment Modifications for Pemetrexed, 
Carboplatin, Avelumab (Cohorts A1 and A3)...................................90


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5.4.4.8. Recommended Treatment Modifications for Cisplatin, 
Gemcitabine, Avelumab (Cohorts A2 and A4) .................................92
5.4.5. Treatment after Initial Evidence of Radiological Disease Progression......96
5.4.6. Food Requirements.....................................................................................97
5.5. Investigational Product Storage ..............................................................................98
5.6. Investigational Product Accountability...................................................................98
5.6.1. Destruction of Investigational Product Supplies ........................................99
5.7. Concomitant Medications .......................................................................................99
5.7.1. Hematopoietic Growth Factors.................................................................100
5.7.2. Concomitant Surgery................................................................................100
5.7.3. Concomitant Radiotherapy.......................................................................100
5.7.4. Other Prohibited Concomitant Medicines and Therapies.........................100
5.8. Rescue Medications and Supportive Care.............................................................101
5.8.1. Supportive Care Guidelines......................................................................101
6. STUDY PROCEDURES ...................................................................................................102
6.1. Screening...............................................................................................................102
6.1.1. Tumor Biospecimens................................................................................102
6.2. Treatment Period...................................................................................................103
6.3. Short-Term and Long-Term Follow-up ................................................................103
6.4. Patient Withdrawal................................................................................................104
7. ASSESSMENTS................................................................................................................105
7.1. Safety Assessments ...............................................................................................106
7.1.1. Pregnancy Testing ....................................................................................106
7.1.2. Contraceptive Check.................................................................................106
7.1.3. Adverse Events.........................................................................................106
7.1.4. Laboratory Safety Assessments................................................................107
7.1.5. Vital Signs and Physical Examination......................................................109
7.1.6. (12-Lead) Electrocardiogram....................................................................109
7.2. Pharmacokinetics Assessments.............................................................................110
7.2.1. All Groups: Blood for PK Analysis of Avelumab....................................111
7.2.2. All Groups: Blood for PK Analysis of Chemotherapies ..........................112
7.2.2.1. Cohorts A1 and A3: Blood for PK Analysis of
Carboplatin ......................................................................................112


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7.2.2.2. Cohorts A1 and A3: Blood for PK Analysis of 
Pemetrexed ......................................................................................112
7.2.2.3. Cohorts A2 and A4: Blood for PK Analysis of 
Gemcitabine.....................................................................................112
7.2.2.4. Cohorts A2 and A4: Blood for PK Analysis of Cisplatin .......112
7.3. Immunogenicity Assessments...............................................................................112
7.4. Biomarker and Pharmacodynamic Assessments...................................................113
7.4.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies...............113
7.6. Tumor Response Assessments ..............................................................................116
8. ADVERSE EVENT REPORTING....................................................................................117
8.1. Requirements.........................................................................................................117
8.1.1. Additional Details On Recording Adverse Events on the CRF................118
8.1.2. Eliciting Adverse Event Information........................................................118
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal section)...........................................................................119
8.1.4. Time Period for Collecting AE/SAE Information....................................119
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................119
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF ...............119
8.1.5. Causality Assessment ...............................................................................120
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ................120
8.2. Definitions.............................................................................................................120
8.2.1. Adverse Events.........................................................................................120
8.2.2. Abnormal Test Findings ...........................................................................121
8.2.3. Serious Adverse Events ............................................................................122
8.2.4. Hospitalization..........................................................................................122
8.3. Severity Assessment..............................................................................................124
8.4. Special Situations ..................................................................................................124
8.4.1. Protocol-Specified Serious Adverse Events.............................................124
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8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................124
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................126
8.4.3.1. Exposure During Pregnancy....................................................126
8.4.3.2. Exposure During Breastfeeding ..............................................127
8.4.3.3. Occupational Exposure ...........................................................127
8.4.4. Medication Errors .....................................................................................128
8.4.4.1. Medication Errors....................................................................128
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................129
9.1. Analysis Sets .........................................................................................................129
9.1.1. Full Analysis Set.......................................................................................129
9.1.2. Safety Analysis Set...................................................................................129
9.1.3. Evaluable for DLT Analysis Set...............................................................129
9.1.4. Pharmacokinetics Analysis Sets ...............................................................129
9.1.5. Immunogenicity Analysis Set...................................................................130
9.1.6. Biomarker Analysis Set............................................................................130
9.2. Statistical Methods and Properties ........................................................................130
9.3. Sample Size Determination...................................................................................132
9.4. Efficacy Analysis ..................................................................................................133
9.4.1. Analysis of the Primary Endpoint.............................................................133
9.4.2. Analysis of the Secondary Endpoints.......................................................134
9.5. Analysis of Pharmacokinetics and Pharmacodynamics ........................................134
9.5.1. Analysis of Pharmacokinetics of Study Drugs .........................................134
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling ..............................135
9.5.3. Analysis of Immunogenicity Data of Avelumab and Other Study 
Drugs..............................................................................................................135
9.6. Biomarker Analyses for Secondary 
 Endpoints...........................135
9.7. Safety Analysis......................................................................................................136
9.7.1. Analysis of the Primary Endpoint in the Phase 1b Lead-in......................136
9.7.2. Analysis of Secondary Safety Endpoints..................................................136
9.7.2.1. Adverse Events........................................................................136
9.7.2.2. Laboratory Test Abnormalities ...............................................136
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9.7.2.3. Electrocardiograms..................................................................136
9.8. Analysis of Other Endpoints .................................................................................137
9.9. Data Safety Monitoring Committee ......................................................................137
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................137
11. DATA HANDLING AND RECORD KEEPING ...........................................................138
11.1. Case Report Forms/Electronic Data Record .......................................................138
11.2. Record Retention.................................................................................................139
12. ETHICS............................................................................................................................139
12.1. Institutional Review Board/Ethics Committee....................................................139
12.2. Ethical Conduct of the Study ..............................................................................139
12.3. Patient Information and Consent.........................................................................140
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................140
13. DEFINITION OF END OF TRIAL.................................................................................140
13.1. End of Trial in a Member State...........................................................................140
13.2. End of Trial in All Other Participating Countries...............................................141
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................141
15. PUBLICATION OF STUDY RESULTS........................................................................141
15.1. Communication of Results by Pfizer ..................................................................141
15.2. Publications by Investigators ..............................................................................142
16. REFERENCES ................................................................................................................144
LIST OF TABLES
Table 1.
SCHEDULE OF ACTIVITIES: Non-squamous NSCLC – Avelumab + 
Pemetrexed/Carboplatin, Cohort A1 and A3........................................................27
Table 2.
PK and ECG ASSESSMENTS (Only for Subset of Patients Undergoing 
Serial PK): Non-squamous NSCLC – Avelumab + 
Pemetrexed/Carboplatin, Cohorts A1 and A3 ......................................................33
Table 3.
SCHEDULE OF ACTIVITIES: UC – Avelumab + Gemcitabine/Cisplatin, 
Cohorts A2 and A4...............................................................................................35
Table 4.
PK and ECG ASSESSMENTS (Only for Subset of Patients Undergoing 
Serial PK): UC – Avelumab + Gemcitabine/Cisplatin, Cohorts A2 and A4........41
Table 5.
Investigational Products........................................................................................72


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Table 6.
Dose Modification Levels for Chemotherapy (Cisplatin, Carboplatin, 
Pemetrexed, and Gemcitabine).............................................................................79
Table 7.
Avelumab Treatment Modifications for Drug-Related Toxicity..........................80
Table 8.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions...............................................................................................................82
Table 9.
Management of Immune-Related Adverse Events...............................................83
Table 10.
Pemetrexed, Carboplatin, Avelumab (Cohorts A1 and A3) Hematologic 
Toxicity Management...........................................................................................90
Table 11.
Pemetrexed, Carboplatin, Avelumab (Cohorts A1 and A3) 
Non-Hematologic Toxicity Management.............................................................91
Table 12.
Cisplatin, Gemcitabine, Avelumab (Cohorts A2 and A4) Hematologic 
Toxicity Management...........................................................................................92
Table 13.
Cisplatin, Gemcitabine, Avelumab (Cohorts A2 and A4) Non-Hematologic 
Toxicity Management...........................................................................................94
Table 14.
Laboratory Tests .................................................................................................108
Table 15.
Probability of Escalating Dose Level of Avelumab to 1200 mg Q3W after 
Phase 1b Lead-in of Each Cohort (A1 and A2)..................................................131
Table 16.
Sample Size and Exact 90% CI for ORR in each Cohort...................................133
LIST OF FIGURES
Figure 1.
Group A (Avelumab plus Chemotherapy)............................................................63
APPENDICES
Appendix 1. Abbreviations and Definitions of Terms...........................................................149
Appendix 2. ECOG Performance Status................................................................................153
Appendix 3. Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 Guidelines .......................................................................................154
Appendix 4. Calculation of Carboplatin Dose Based on Calvert Formula............................159


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PROTOCOL SUMMARY
Indication
Avelumab is a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) 
of the immunoglobulin (Ig) G1 isotype that is currently being investigated in combination 
with other anti-cancer immunotherapies to enhance antitumor activity over that expected by 
avelumab alone in patients with locally advanced or metastatic solid tumors.  Avelumab is 
expected to increase the effectiveness of antitumor T cells by preventing inhibition of T cell 
activation.  Combination of avelumab with agents that enhance the immune response by 
different mechanisms would be expected to lead to an increase in antitumor activity over that 
seen with avelumab alone.  This study will initially investigate avelumab in combination with 
standard-of-care chemotherapy and, in portions of the study to be added in the future, with or 
without other anti-cancer immunotherapies as first-line therapy for patients with advanced or 
metastatic solid tumors.  For the United Kingdom (UK) and the Czech Republic: Only 
1 additional anti-cancer immunotherapy, in combination with avelumab and chemotherapy, 
in up to 4 tumor-specific cohorts, will be included. 
Background and Rationale
There are emerging data supporting the rationale for combinations of immune checkpoint 
inhibitors with chemotherapy.4,5  Chemotherapy has been shown to have immunostimulatory 
properties via its ability to promote the release of neoantigens and to enhance antigen uptake 
and presentation via the process of immunogenic cell death, hence leading to an increase in 
immune priming against the tumor.  In addition, a number of chemotherapies have been 
shown to alter the immunogenicity of tumor cells both at the cell intrinsic level, through 
modulation of cell surface proteins like major histocompatibility complex (MHC), and also at 
the cell extrinsic level, through depletion of suppressive elements within the 
microenvironment such as regulatory T cells (Tregs) and myeloid derived suppressor cells 
(MDSCs).6-9  
Several immune checkpoint inhibitors have been combined with chemotherapy agents.  Of 
particular relevance to Study B9991023 are results from studies of programmed 
death-1 (PD-1)/PD-L1 inhibitors plus platinum doublet chemotherapy as first-line therapy in 
patients with advanced or metastatic non-small cell lung cancer (NSCLC).  In a Phase 2 
cohort of the KEYNOTE-021 study,27 the combination of carboplatin and pemetrexed with 
or without pembrolizumab was evaluated in patients with advanced non-squamous NSCLC.  
A significant increase in objective response rate (objective response rate [ORR], 55%; 
95% confidence interval [CI] 42-68%) was noted for the triplet therapy relative to ORR for 
chemotherapy alone (29%; 95% CI 18-41%).  In addition, progression-free survival (PFS) for 
patients treated with the triplet was significantly greater than that for chemotherapy-treated 
patients (hazard ratio [HR] 0.53 [95% CI 0.31-0.91] p=0.010).  Based on data from the 
KEYNOTE-021 study, on 10 May 2017, the Food and Drug Administration (FDA) approved 
pembrolizumab in combination with carboplatin and pemetrexed for the first-line treatment 
of patients with metastatic non-squamous NSCLC, irrespective of PD-L1 expression.52  


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Overall these clinical and preclinical data are supportive of the potential for increased 
antitumor activity through the combination of chemotherapy and avelumab.
This study will investigate avelumab in combination with standard-of-care chemotherapy 
with or without other anti-cancer immunotherapies as first-line therapy for patients with 
advanced malignancies.  Initially, avelumab will be evaluated in combination with 
standard-of-care chemotherapy in patients with advanced non-squamous NSCLC and 
cisplatin-eligible urothelial cancer (UC).  These two tumor types were selected for study 
because they are responsive to chemotherapy, which currently is first-line standard-of-care 
for these indications.  In addition, avelumab has shown preliminary evidence of clinical 
activity in both non-squamous NSCLC and UC.
Given the growing preclinical and clinical findings that combinations of anti-cancer 
immunotherapies potentially improve patient outcomes compared to results seen with single 
agents, in portions of the study to be added in the future, avelumab will be evaluated in 
combination with both standard-of-care chemotherapy and other anti-cancer 
immunotherapies in patients with advanced malignancies.
Initially avelumab will be dosed at 800 mg every 3 weeks (Q3W). Once the safety of this 
dose of avelumab in combination with each of the two chemotherapy regimens has been 
determined, additional cohorts of patients will be enrolled at the higher avelumab dose of 
1200 mg Q3W.  The proposed avelumab fixed dosing regimens of 800 mg Q3W and 
1200 mg Q3W are expected to reach >90% target occupancy (TO) throughout the 21-day 
dosing interval in the majority of patients, including when used in combination with 
chemotherapy or other anti-cancer immunotherapies.  The 1200 mg Q3W dosing regimen is 
being explored additionally in this Phase 1b/2 trial as it is projected to maintain the avelumab 
average exposures close to those observed with the approved dose of 10 mg/kg every 
2 weeks (Q2W) while extending the dosing interval for use in combination with Q3W 
chemotherapy regimens.
Addition of new therapy combinations will be based on emerging preclinical and clinical 
data supportive of the tolerability and potential clinical benefit of each agent to be combined 
(eg, chemotherapy, anti-cancer immunotherapy agents) with avelumab and will be 
accomplished by protocol amendment.  For the UK and the Czech Republic: Only 
1 additional anti-cancer immunotherapy, in combination with avelumab and chemotherapy, 
in up to 4 tumor-specific cohorts, will be included.
Study Objectives and Endpoints
Primary Objectives

Phase 1b lead-in: To assess dose limiting toxicity (DLT) rate of avelumab in 
combination with chemotherapy, as first-line treatment in patients with locally 
advanced or metastatic solid tumors.


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•
To assess, per Response Evaluation Criteria in Solid Tumors (RECIST) version 
(v) 1.1, the ORR of avelumab in combination with chemotherapy, as first-line 
treatment in patients with locally advanced or metastatic solid tumors.
Secondary Objectives
•
To assess the overall safety and tolerability of avelumab in combination with 
chemotherapy; 
•
To characterize the pharmacokinetics (PK) of avelumab and chemotherapy when 
given in combination;
•
To evaluate the immunogenicity of avelumab, when given in combination with 
chemotherapy;
•
To assess the antitumor activity, per RECIST v1.1, of avelumab in combination with 
chemotherapy;
•
To assess the correlation of antitumor activity, per RECIST v1.1, of avelumab in 
combination with chemotherapy, with mutational load in baseline tumor tissue; 
•
To assess the correlation of PD-L1expression in baseline tissue and changes in this 
marker on-treatment, with antitumor activity, per RECIST v1.1, of avelumab in 
combination with chemotherapy.
Endpoints
Primary Endpoints
•
Phase 1b lead-in: First 2 cycles DLT. 
•
Confirmed objective response (OR), as assessed by the Investigator using 
RECIST v1.1.
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Secondary Endpoints
•
Adverse events (AEs) as characterized by type, severity (as graded by National 
Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] 
v.4.03), timing, seriousness, and relationship to study treatments;
•
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v.4.03), and timing;
•
PK parameters of avelumab;  
•
PK parameters of chemotherapies, as data permit;
•
Anti-drug antibody (ADA) levels;
•
Time-to-event endpoints including PFS, duration of response (DR), and time to tumor 
response (TTR), as assessed by the Investigator using RECIST v1.1; and overall 
survival (OS);
•
Mutational load within baseline tumor tissue;
•
PD-L1 expression in baseline and on-treatment tumor tissue.
Study Design
This is a Phase 1b/2, open-label, multi-center, safety, clinical activity, PK, and PD study of 
avelumab in combination with chemotherapy with or without other anti-cancer 
immunotherapies, as first-line treatment of adult patients with locally advanced or metastatic 
solid tumors.  Incorporation of the chemotherapy and other anti-cancer immunotherapies into 
this study is based on preclinical and clinical data supportive of the tolerability and potential 
clinical benefit of each agent to be combined (eg, chemotherapy, anti-cancer immunotherapy 
agents) with avelumab.  Initially, avelumab will be evaluated in Group A in combination 
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with standard-of-care chemotherapy in patients with advanced malignancies as described 
below.  Additional combinations of avelumab plus standard-of-care chemotherapy with or 
without other anti-cancer immunotherapy agent(s), other than other anti-PD-1/PD-L1 mAb, 
may be incorporated via protocol amendment into future portions of the study based on 
emerging preclinical and clinical data.  For the UK and the Czech Republic: Only 
1 additional anti-cancer immunotherapy, in combination with avelumab and chemotherapy, 
in up to 4 tumor-specific cohorts, will be included.

Group A: avelumab plus chemotherapy:

Cohort A1: avelumab 800 mg Q3W plus pemetrexed/carboplatin in patients with 
non-squamous NSCLC;

Cohort A2: avelumab 800 mg Q3W plus gemcitabine/cisplatin in patients with 
cisplatin-eligible UC;

Cohort A3: avelumab 1200 mg Q3W plus pemetrexed/carboplatin in patients with 
non-squamous NSCLC;

Cohort A4: avelumab 1200 mg Q3W plus gemcitabine/cisplatin in patients with 
cisplatin-eligible UC.
Each combination cohort will be studied in 2 phases: 1) a Phase 1b lead-in to evaluate 
preliminary safety of the combination, and 2) a Phase 2 cohort expansion to evaluate 
preliminary efficacy and further evaluate safety. Phase 2 cohort expansion may be initiated 
only for the highest dose level of avelumab deemed safe for the combination.
Phase 1b Lead-in
The safety of avelumab will be assessed independently in combination with each of the two 
different chemotherapy regimens.
The 1200 mg Q3W dosing regimen is being explored additionally in this Phase 1b/2 trial 
since it is projected to maintain the avelumab average exposures close to those observed with 
the approved dose of 10 mg/kg Q2W while extending the dosing interval for use in 
combination with Q3W chemotherapy regimens.
Up to 12 patients will be enrolled into each cohort and evaluated for DLT during the first 
2 cycles of treatment as follows:
Cohorts A1 and A2

Enroll and treat up to 6 DLT-evaluable patients in each cohort:

If 1 of 6 patients experience DLT in Cohort A1 (or A2), enrollment may be initiated 
in Phase 1b Cohort A3 (or A4); 


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
If 3 of up to 6 patients experience DLT in Cohort A1 (or A2), enrollment in 
Cohort A1 (or A2) will be discontinued; there will be no further enrollment of 
patients with the combination;

If 2 of 6 patients experience DLT in Cohort A1 (or A2), the cohort will be expanded 
to enroll up to 6 additional DLT-evaluable patients in the Phase 1b Cohort A1 (or 
A2);

If 3 of 12 patients experience DLT in Cohort A1 (or A2), enrollment may be 
initiated in Phase 1b Cohort A3 (or A4);

If 4 of up to 12 patients experience DLT in Cohort A1 (or A2), enrollment in the 
Cohort A1 (or A2) will be discontinued; there will be no further enrollment of 
patients with the combination. 
Cohorts A3 and A4

Enroll and treat up to 6 DLT-evaluable patients in each cohort:

If 1 of 6 patients experience DLT in Cohort A3 (or A4), enrollment may be initiated 
in Phase 2 Cohort A3 (or A4) expansion with the study treatment of avelumab 
1200 mg Q3W in combination with chemotherapy; there will not be any enrollment 
in Phase 2 Cohort A1 (or A2) expansion with the study treatment of avelumab 
800 mg Q3W in combination with chemotherapy.

If 3 of up to 6 patients experience DLT in Cohort A3 (or A4), enrollment in 
Cohort A3 (or A4) will be discontinued; enrollment may be initiated in Phase 2 
Cohort A1 (or A2) expansion with the study treatment of avelumab 800 mg Q3W in 
combination with chemotherapy.

If 2 of 6 patients experience DLT in Cohort A3 (or A4), the Cohort A3 (or A4) will 
be expanded to enroll up to 6 additional DLT-evaluable patients:

If 3 of 12 patients experience DLT in Cohort A3 (or A4), enrollment may be 
initiated in Phase 2 Cohort A3 (or A4) expansion with the study treatment of 
avelumab 1200 mg Q3W in combination with chemotherapy; there will not be 
any enrollment in Phase 2 Cohort A1 (or A2) expansion with the study treatment 
of avelumab 800 mg Q3W in combination with chemotherapy;

If 4 of up to 12 patients experience DLT in Cohort A3 (or A4), enrollment may
be initiated in Phase 2 Cohort A1 (or A2) expansion with the study treatment of 
avelumab 800 mg Q3W in combination with chemotherapy.


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Phase 2 Cohort Expansion
If investigational products administration in the Phase 1b Lead-in portion of a given cohort is 
deemed safe based on the criteria described in “Phase 1b Lead-in” Section, then enrollment 
into that cohort may continue into the Phase 2 Cohort Expansion.  The dose of avelumab to 
be administered in the Phase 2 Cohort Expansion (800 mg Q3W for Cohorts A1 and A2 or 
1200 mg Q3W for Cohorts A3 and A4) will be determined based on the number of observed 
DLTs as described in “Study Design”. The highest dose level of avelumab deemed safe for 
the combination will be advanced.
For the cohort of patients with cisplatin-eligible UC selected to expand into Phase 2, up to 
approximately 40 patients including those enrolled in the Phase 1b Lead-in and those 
enrolled in the Phase 2 Cohort Expansion, will be treated with avelumab plus chemotherapy 
in the initial portion of the study and, in future portions of the study, with avelumab plus 
chemotherapy with or without other anti-cancer immunotherapies. For the cohort of patients 
with non-squamous NSCLC selected to expand into Phase 2, approximately 20 patients 
including those enrolled in the Phase 1b Lead-in and those enrolled in the Phase 2 Cohort 
Expansion will be treated with avelumab plus chemotherapy in the initial portion of the study 
and, in future portions of the study, with avelumab plus chemotherapy with or without other 
immunotherapies. Up to approximately 80 patients with cisplatin-eligible UC and 
non-squamous NSCLC will be enrolled in Group A (Phase 1b Lead-in and Phase 2 Cohort 
Expansion).
In future portions of the study, up to approximately 40 patients in each cohort (including 
those enrolled in the Phase 1b Lead-in and those enrolled in Phase 2) will be enrolled and 
treated with avelumab plus chemotherapy in the initial portion of the study and, in future 
portions of the study, with avelumab plus chemotherapy with or without other anti-cancer 
immunotherapies.  For the UK and the Czech Republic: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and chemotherapy, in up to 4 tumor-specific 
cohorts, will be included.
For both Phase 1b lead-in and Phase 2 cohort expansion, all patients will initially receive 
either avelumab in combination with chemotherapy (Group A) or avelumab in combination 
with chemotherapy and other anti-cancer immunotherapies in future portions of the study.  
Patients will continue to receive study treatment until disease progression is confirmed by the 
Investigator, patient refusal, unacceptable toxicity, or until the study is terminated by the 
Sponsor, whichever occurs first.  In Cohorts A1 and A3, treatment with carboplatin and 
pemetrexed will continue for a maximum of 4-6 cycles; in addition, maintenance therapy 
with pemetrexed may be administered at the discretion of the Investigator.  In Cohorts A2 
and A4, treatment with chemotherapy will continue until optimal response is achieved.
If discontinuation of chemotherapy is required for any reasons other than progressive disease 
(PD) or protocol-specified limits, treatment with avelumab (Group A) (or avelumab and/or 
the other anti-cancer immunotherapies in future portions of the study) should be continued. 


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Patients who stop avelumab (or the other anti-cancer immunotherapies in future portions of 
the study) for unacceptable toxicity may continue treatment with the investigational 
product(s) (eg, chemotherapy) that is/are not considered to be responsible for the toxicity 
observed. 
Tumor Assessments
Antitumor activity will be assessed by radiological tumor assessments at 6-week intervals, 
using RECIST v1.1.  In case partial response (PR) or complete response (CR) is observed 
according to RECIST v1.1, tumor assessments should be repeated at least 4 weeks after 
initial documentation.  After 1 year from the first dose of study treatment, tumor assessments 
will be conducted at 12-week intervals until PD per RECIST v1.1.  In addition, radiological 
tumor assessments will also be conducted whenever disease progression is suspected 
(eg, symptomatic deterioration). 
Safety Assessments
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as reported in the Schedule of Activities.
Pharmacokinetic/Immunogenicity Assessments
PK and immunogenicity blood sampling will be collected for each combination as described 
in the Schedule of Activities and Section 7.2.
Biomarker Assessments
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 the 
combination of avelumab and chemotherapy with or without other immunotherapies. 
 
 
 
 For the UK and the Czech Republic: 
Only 1 additional anti-cancer immunotherapy, in combination with avelumab and 
chemotherapy, in up to 4 tumor-specific cohorts, will be included.
Study Treatments
Avelumab 800 mg (Cohorts A1 and A2) or 1200 mg (Cohorts A3 and A4) fixed dose will be 
administered as a 1-hour (hr) intravenous (IV) infusion on Day 1 of each 21-day cycle.
Each chemotherapy doublet will be administered IV as shown below per local guidelines.
C
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Investigational Product
Dose(s) and Schedule (21-day 
cycle)a,b
Cohorts
Tumor Type
Avelumabc
800 mg or 1200 mg, Day 1
IV over 60 minutes
All
All
Pemetrexed/Carboplatin
A1, A3
Non-squamous 
NSCLC
Pemetrexed
500 mg/m2, Day 1
IV over 10 minutes
Carboplatin
AUC 5, Day 1
IV over 60 minutes
Gemcitabine/Cisplatin
A2, A4
UC
Gemcitabine
1000 mg/m2, Day 1 and Day 8
IV over 30 minutes
Cisplatin
70 mg/m2, Day 1
IV over 60 minutes
AUC=area under the curve; IV=intravenous; NSCLC=non-small cell lung cancer; UC=urothelial cancer
a
Order of administration is as appears in the table.  For example, for the pemetrexed/carboplatin doublet, 
pemetrexed is administered prior to carboplatin. 
b
Durations of chemotherapy infusions shown are recommended.  Sites are advised to follow their local 
guidelines. 
c
Avelumab dosed at 800 mg Q3W in Cohorts A1 and A2 and at 1200 mg Q3W in Cohorts A3 and A4.
Treatment with chemotherapy in Cohorts A1 and A3 will continue for a maximum of 
4-6 cycles, with pemetrexed continuing as maintenance at the Investigator’s discretion, and 
in Cohorts A2 and A4 until optimal response is achieved.  For all cohorts (A1, A2, A3 and 
A4), chemotherapy and avelumab may be discontinued in the event of disease progression 
confirmed by the Investigator, patient refusal, unacceptable toxicity, patient lost to follow-up, 
or until the study is terminated by the Sponsor, whichever occurs first.
Statistical Methods
Phase 1b Lead-in: DLTs will be assessed in the DLT-evaluable patients in each cohort then 
enrollment into the cohort will be expanded into Phase 2 cohort expansion. 
The table below shows the probability of meeting DLT requirements to escalate to the dose 
level of avelumab 1200 mg Q3W in combination with chemotherapy. For example, for a 
DLT that occurs in 10% of patients, the probability of confirming safety and escalating to 
avelumab 1200 mg Q3W is approximately 0.97.
Probability of Escalating Dose Level of Avelumab to 1200 mg Q3W after Phase 1b 
Lead-in of Each Cohort (A1 and A2)
True underlying DLT ratea
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose level 
of avelumab
0.97
0.82
0.56
0.31
0.14
0.05
0.01
0.002
<0.0001
a True underlying DLT rate for the combination of avelumab 800 mg Q3W with chemotherapy.
Phase 1b Lead-in and Phase 2 Cohort Expansion combined: The primary endpoint for the 
Phase 1b lead-in and the Phase 2 cohort expansion combined is the confirmed OR as 
assessed by the Investigator using RECIST v1.1. 


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OR is defined as a CR or PR per RECIST v1.1, from the first dose of study treatment until 
disease progression or death due to any cause.  Both CR and PR must be confirmed by repeat 
assessments performed no less than 4 weeks after the criteria for response are first met.  ORR 
is defined as the proportion of patients with a confirmed CR or PR per Investigator’s 
assessment according to RECIST v.1.1.
Based on safety data for patients with cisplatin-eligible UC, the Phase 1b lead-in from either 
Cohort A2 (800 mg avelumab plus chemotherapy) or Cohort A4 (1200 mg avelumab plus 
chemotherapy) may be selected to continue enrollment into the Phase 2 cohort expansion. 
Up to approximately 40 patients with cisplatin-eligible UC, including Phase 1b lead-in and 
Phase 2 cohort expansion patients, may receive the selected avelumab dose plus 
chemotherapy.
Based on safety data for patients with non-squamous NSCLC, the Phase 1b lead-in from 
either Cohort A1 (800 mg avelumab plus chemotherapy) or Cohort A3 (1200 mg avelumab 
plus chemotherapy) may be selected to continue enrollment into the Phase 2 cohort 
expansion. Up to approximately 20 patients with non-squamous NSCLC, including Phase 1b 
lead-in and Phase 2 cohort expansion patients, may receive the selected avelumab dose plus 
chemotherapy.
With 40 patients in the UC cohort and 20 patients in the NSCLC cohort, with Phase 1b and 
Phase 2 combined, ORR can be estimated with a maximum standard error of 0.079 and 
0.112, respectively. Within each cohort, ORR will be estimated and the two-sided exact 
90% confidence interval will be calculated.
SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to the Assessments section of the protocol for detailed information on each assessment 
required for compliance with the protocol. 
The Investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities table in order to conduct evaluations or assessments required to 
protect the well-being of the patient.


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Table 1.
SCHEDULE OF ACTIVITIES: Non-squamous NSCLC – Avelumab + Pemetrexed/Carboplatin, Cohort A1 
and A3
On-Treatment: One cycle = 21 days
Post-Treatment
Screening
Immunotherapy + Chemotherapy
Immunotherapy 
Protocol Activities1
Within 28 
Days Prior to 
Enrollment
Pemetrexed/Carboplatin/Avelumab
Avelumab 
End of 
Treatment 
+7 days22
Short-Term 
Follow-up 
(Day After 
Last Dose 
303, 603, 
903)23
Long-Ter
m 
Follow-up 
(Every 
12 weeks 
14 days24
Cycles 1 – 3
Cycles 4
Day 1
2 days39
Day 8
2 days
Day 15
2 days
Day 1 
2 days
Day 1 of each 
cycle
2 days
Clinical Assessments
Informed Consent2
X
Medical/Oncological History3
X
Baseline Signs/Symptoms4
X
Physical Examination5
X
X
X
X
X
X
X
ECOG Performance Status6
X
X
X
X
X
X
X (Day 30 
only)
Vital Signs and Weight7
X
X
X
X
X
X
X
Contraceptive Check8
X
X
X
X
X
X
Laboratory Studies
Hematology9
X
X
X
X
X
X
X
X
Blood Chemistry9
X
X
X
X
X
X
X
X
Coagulation9
X
X
X
X
X
X
Thyroid Function/ACTH10
Day 1 of Cycle 1, Cycle 4 and every 3 cycles thereafter
X
X
Urinalysis11
X
If clinically indicated
X
Pregnancy Test12
X
X
X
X
X
X
HBV and HCV Tests13
X
12-Lead ECG14
X
X
If clinically indicated
Enrollment and Study Treatment
Enrollment15
X
Pemetrexed Administration16
X
X
X16
Carboplatin Administration16
X
X
Avelumab Administration17
X
X
X  
Disease Assessments
Tumor Assessments/Scans18
X
Cycle 3 Day 1 (2 days), then every 6 weeks (2 days).  After 1 year from first dose of study drug, every 12 weeks 
(14 days) until progressive disease regardless of initiation of new anti-cancer treatment


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Table 1
SCHEDULE OF ACTIVITIES: Non-squamous NSCLC - Avelumab + Pemetrexed/Carboplatin, Cohorts A1 and 
A3 (continued)
On-Treatment: One cycle = 21 days
Post-Treatment
Screening
Immunotherapy + Chemotherapy
Immunotherapy 
Protocol Activities1
Within 28 
Days Prior to 
Enrollment
Pemetrexed/Carboplatin/Avelumab
Avelumab 
End of 
Treatment 
+ 7 days22
Short-Term 
Follow-up 
(Day After 
Last Dose 
30±3, 60±3, 
90±3)23
Long-Term 
Follow-up 
(Every 
12 weeks 
±14 days)24
Cycles 1 – 3
Cycles ≥4
Day 1
±2 days39
Day 8
±2 days
Day 15
±2 days
Day 1 
±2 days
Day 1 of each 
cycle
±2 days
Other Clinical Assessments
Serious and Non-serious 
Adverse Event Monitoring19
X
Monitored and recorded throughout treatment
X
X
Concomitant Treatments20
X
Monitored and recorded throughout treatment
X
X
Short- and Long-Term Follow-up After Last Dose of Study Treatment
Subsequent Anti-Cancer 
Treatments21
X
X
Short-term Follow-up 
Assessments23
X
Long-term/Survival 
Assessment24
X
X
Samples for Pharmacodynamic, Pharmacokinetic, 
 Analyses
De Novo Tumor Biopsy or 
Archival FFPE Tumor Tissue 
Block25
X
On-Treatment Tumor Biopsy26
X Cycle 2 
only 
(-7 days to 
+2 days) 
End of Treatment Tumor 
Biopsy27
X
Avelumab PK28
X
X
X
(select 
cycles)
X
(select cycles)
Anti-Avelumab Antibodies 
(ADA)29
X 
X
(select 
cycles)
X
(select cycles)
X
Pemetrexed PK30
X 
(Cycle 2 
subset 
patients)
X 
(Cycle 2 
subset 
patients)
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Table 1
SCHEDULE OF ACTIVITIES: Non-squamous NSCLC – Avelumab + Pemetrexed/Carboplatin, Cohorts A1 and 
A3 (continued)
On-Treatment: One cycle = 21 days
Post-Treatment
Screening
Immunotherapy + Chemotherapy
Immunotherapy
Protocol Activities1
Within 28 
Days Prior to 
Enrollment
Pemetrexed/Carboplatin/Avelumab
Avelumab
End of 
Treatment 
+7 days22
Short-Term 
Follow-up 
(Day After 
Last Dose 
30±3, 60±3, 
90±3)23
Long-Ter
m 
Follow-up 
(Every 
12 weeks 
±14 days24
Cycles 1 – 3
Cycles ≥4
Day 1
±2 days39
Day 8
±2 days
Day 15
±2 days
Day 1 
±2 days
Day 1 of each 
cycle
±2 days
Carboplatin PK31
X 
(Cycle 2 
subset 
patients)
X 
(Cycle 2 
subset 
patients)
ACTH=adrenocorticotropic hormone; BID=twice daily; ECG=electrocardiogram; DNA=deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; 
FFPE=formalin-fixed, paraffin-embedded; HBV=Hepatitis B virus; HCV=Hepatitis C virus; PK=pharmacokinetics; 
 
 
Footnotes for Table 1 SCHEDULE OF ACTIVITIES
1.
Protocol Activities: All assessments should be performed prior to study treatment dosing unless otherwise indicated.  Acceptable time windows for 
performing each assessment are provided in the column headers. 
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2.
Informed Consent: Must be obtained prior to the patient undergoing any study-specific procedure.
3.
Medical/Oncological History: Both medical and oncological histories are to be collected within 28 days prior to first dose of study treatment.  Medical 
history should include history of other disease (active or resolved) as well as concomitant illnesses.  Oncological history should include information on prior 
regimens (including dosing and duration of therapy, best overall response, and disease recurrence/progression date), surgery, and radiation therapy. 
4.
Baseline Signs/Symptoms: To be recorded on the Medical History CRF form.  Patients will be asked about any signs and symptoms experienced within the 
14 days prior to signing the informed consent document.  After signing the informed consent document, any new or worsening conditions since baseline 
should be reported on the AE CRF.
5.
Physical Examination: Includes an examination of major body systems (height included at screening only). 
6.
ECOG Performance Status: ECOG performance scale may be found in Appendix 2.  Determination of ECOG Performance Status will continue through 
the 30-day Follow-Up visit unless the patient has started on a new anti-cancer therapy.
7.
Vital Signs and Weight: See Section 7.1.5.
8.
Contraception Check: See Section 4.3 and Section 7.1.2.
9.
Coagulation, Hematology, and Blood Chemistry (full panel): Cycle 1 Day 1 tests do not need to be repeated if they have been conducted in the prior 
3 days and data are available for review.  Full hematology and full clinical chemistry tests must be performed.  Full hematology panel as well as AST, ALT, 
and creatinine results must be reviewed by medically-qualified study personnel prior to each administration of study drug.  Results from all other laboratory 
assessments are not required to be reviewed prior to study drug dosing, unless there are signs or symptoms to suggest an underlying lab abnormality.  
However, all lab results should be reviewed as soon as they are available.  Laboratory tests may be performed up to 3 days prior to each scheduled visit so 
that results will be available for review.  Required tests are listed in Section 7.1.4.  Full chemistry panel is required at Screening, Day 1, Day 8, and Day 15 
of Cycles 1 through 3; Day 1 of every subsequent cycle; End of Treatment; and at the 30-day follow-up visit. Core chemistry panel (required tests are listed 
in Section 7.1.4) is required at Follow-Up Day 60 and Day 90.  Coagulation and hematology are required as noted in this table.  If the patient permanently 
discontinues chemotherapy before Cycle 4, but continues on avelumab and/or other anti-cancer immunotherapies in future portions of the study, then 
chemistry and hematology samples should be obtained at Day 1 of subsequent cycles. Any test may also be performed when clinically indicated.  For the 
UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in combination with avelumab and chemotherapy, in up to 4 tumor-specific 
cohorts, will be included.
10. Thyroid Function/ACTH Tests.  Additional tests should be performed when clinically indicated.  See Section 7.1.4.
11. Urinalysis: Required only at Screening and End of Treatment.  To be performed if clinically indicated at other time points.  Required tests are listed in
Section 7.1.4.
12. Serum/Urine Pregnancy Test: Results of the pregnancy test must be available prior to each study treatment dosing.  See Section 7.1.1.
13. HBV and HCV Tests: HBV surface antigen and anti-HCV antibody will be performed at Screening.  HCV RNA will be performed if anti-HCV antibody 
test is positive (Section 7.1.4, Table 14). 
14. 12-Lead Electrocardiogram (ECG): All patients require triplicate ECG measurements at screening and on treatment.  On treatment triplicate ECGs will be 
performed on Day 1 of Cycles 1 to 3, before (pre-dose) and at the end of avelumab infusion for all patients.  See Table 2 for ECG monitoring of subset of 
patients undergoing serial PK collection in Cohorts A1 and A3.  See Section 7.1.6.
15. Enrollment: Study treatment must be initiated preferably on the day of enrollment, but no later than 3 days after enrollment.  Patients meeting all entry 
criteria will be registered and enrolled using the Interactive Response Technology system.  See Section 5.1.


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16. Pemetrexed/Carboplatin Administration: Pemetrexed 500 mg/m2 and carboplatin area under curve (AUC) 5 will be administered IV both on Day 1 of 
every 21-day cycle for a maximum of 4-6 cycles.  After this time, pemetrexed therapy may continue as maintenance at the Investigator’s discretion.  
Premedication will be administered as specified in Section 5.4.2.1.  On visits when both chemotherapy and avelumab are infused (Day 1 of each 21-day 
cycle), chemotherapy will be infused before avelumab.  See Section 5.4.3.  See Section 5.2 for guidance on treatment duration. 
17. Avelumab Administration: Avelumab 800 mg will be administered Q3W (Day 1 of each 21-day cycle).  All safety assessments must be performed and 
results reviewed by the treating physician prior to study treatment administration.  Avelumab will be administered as a 1-hour intravenous infusion on 
Day 1 of each 21-day cycle.  On visits when both chemotherapy and avelumab are infused (Day 1 of each 21-day cycle), avelumab will be infused after
chemotherapy but within 30 minutes (+20-minute time window if needed) of the end of the chemotherapy infusion, see Section 5.4.3.  See Section 5.4.1.3
for guidance on required premedication for avelumab infusion.  See Section 5.2 for guidance on treatment duration. 
18. Tumor Assessments: For patients with NSCLC, tumor assessments by CT or MRI scans will include chest and abdomen at all time points.  For patients 
with NSCLC, pelvic assessments will be conducted only if clinically indicated at baseline or at any subsequent point.  Baseline scans must be performed 
within 28 days prior to first dose of study drug.  See Section 7.6 for complete information. 
19. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v 4.03.  See Section 8.1.4 for guidance on the time period for collecting and reporting AE and SAEs.  If a patient 
begins a new anti-cancer therapy, the recording period for non-serious AEs ends at the time the new treatment is started; however, SAEs must continue to be 
recorded on the CRF during the active collection period. 
20. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded for all patients from 28 days prior to the start of study 
treatment and up to 90 days after the last dose of study treatment, see Section 5.7. 
21. Subsequent Anti-Cancer Treatments: These treatments will be documented and recorded for patients who discontinue all study treatments and continue in 
the Short –term and Long-Term Survival periods of the study.
22. End of Treatment (discontinuation of all study drugs for any reason): Obtain these assessments if not completed in the prior 7 days.
23. Short-Term Follow-Up after Last Dose of Study Treatment: All patients will be followed for safety every 30 days (3 days) through 90 days after the 
last dose of study treatment or until the start of new anti-cancer treatment whichever occurs first. See Section 6.3 for guidance on tumor assessment during 
Short-term Follow-up.
24. Long-Term Follow-up (Survival): Following completion of the end of treatment visit, all patients will be followed for survival and subsequent anti-cancer 
treatments every 12 weeks (±14 days) until death, end of the study, or patient withdrawal of consent, whichever comes first.  See Section 6.3 for guidance on 
tumor assessment during Long-term Follow-up.
25. De Novo Tumor Biopsy and Archival FFPE Tumor Tissue Block: See Section 6.1.1.
26. On-Treatment Tumor Biopsy: See Section 6.1.1.
27. At Progression Tumor Biopsy: An optional de novo tumor sample is encouraged to be collected at End of Treatment if a patient discontinues due to disease 
progression.  See Section 6.1.1.
28. Blood for Avelumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each specified time point) will be collected from all patients in the study at 
pre-dose and 1 hour post-start of avelumab infusion (ie, at the end of infusion) on Day 1 of Cycles 1, 2, 3, 6, 10, and 14; an additional sample will be 
collected during the Day 15 visit of Cycle 1, 2, and 3.  See Section 7.2.1.


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29. Blood for Anti-Avelumab Antibodies (Anti-Drug Antibodies: ADA): Blood samples (3.5 mL whole blood at each specified time point) for avelumab 
immunogenicity testing will be collected from all patients pre-dose on Day 1 of Cycles 1, 2, 3,  6, 10, and 14, and at End of Treatment.  See Section 7.3.
30. Blood for Pemetrexed Pharmacokinetics (only in subset of patients undergoing serial PK): See Table 2 and Section 7.2.2.2.
31. Blood for Carboplatin Pharmacokinetics (only in subset of patients undergoing serial PK): See Table 2 and Section 7.2.2.1.
39. The visit window for Day 1 visits post Cycle 1 during study treatment is ±2 days.
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Table 2.
PK and ECG ASSESSMENTS (Only for Subset of Patients Undergoing Serial PK): Non-squamous NSCLC –
Avelumab + Pemetrexed/Carboplatin, Cohorts A1 and A3
Cycle 1
Cycle 2
Day 1
Day 15
Day 1
Day 86
Day 156
Time after start of 
pemetrexed infusion (hr)
Time after start of pemetrexed infusion (hr)
Pre-dose
3.0
Pre-dose
0.17
(10 min)
1.5
3.0
5.5
All Cohorts:
Blood for Pemetrexed PK1
X
X
X
X
X
Blood for Carboplatin PK2
X
X
X
X
X
Blood for Avelumab PK3
X
X
X 
X
X
X
Blood for Avelumab ADA4
X
X
12-Lead ECG collection5
X
X
X
X
ADA=anti-drug antibody; AM=morning; ECG=electrocardiogram; PK=pharmacokinetic
Table 2 provides guidance specifically for subset of patients in Cohorts A1 and A3 who will undergo serial PK collection and matching ECG measurements, and 
includes required assessments for Cycle 1 and Cycle 2 only.  For assessments conducted in the remainder of patients and remaining cycles/visits beyond 
Cycle 2, see Schedule of Activities Table 1. 
The assessment schedule is to be used with the following administration schedule for Cycle 2 Day 1: administration of pemetrexed IV over 10 min, followed by 
carboplatin IV over 1 hr starting 20 min after end of pemetrexed infusion, followed by avelumab IV over 1 hr starting 30 min after end of carboplatin infusion. If 
an infusion time is increased for a given agent, end of infusion and subsequent post-dose PK samples (and time-matched ECGs, if applicable) for that drug only 
should shift accordingly.
1.
Blood for Pemetrexed Pharmacokinetics: Blood samples (2 mL whole blood at each specified time point) will be collected at pre-dose, 10 min post-start of pemetrexed 
infusion (ie, at the end of infusion), and at 1.5 hrs and 5.5 hrs post-start of pemetrexed infusion (corresponding to 1 hr 40 min and 5 hrs 40 min post-end of pemetrexed 
infusion) on Day 1 of Cycle 2; an additional sample will be collected during the Day 8 visit of Cycle 2. End of infusion PK samples for pemetrexed must be collected within 
10 min post end of infusion of pemetrexed. 
2.
Blood for Carboplatin Pharmacokinetics: Blood samples (3 mL whole blood at each specified time point) will be collected at pre-dose, 1 hr post-start of carboplatin 
infusion (ie, at the end of infusion), and at 2.5 hrs and 5 hrs post-start of carboplatin infusion (corresponding to 1.5 hrs and 4 hrs post-end of carboplatin infusion) on Day 1 of 
Cycle 2; an additional sample will be collected during the Day 8 visit of Cycle 2. End of infusion PK samples for carboplatin must be collected within 10 min post end of 
infusion of carboplatin. 
3.
Blood for Avelumab Pharmacokinetics: In all patients, blood samples (3.5 mL whole blood at each specified time point) will be collected at pre-dose and 1 hr post-start of 
avelumab infusion (ie, at the end of avelumab infusion) on Day 1 of Cycle 1 and Cycle 2; an additional sample will be collected during the Day 15 visit of Cycle 1 and 2. End 
of infusion PK samples must be collected within 30 min post end of avelumab infusion (after completion of triplicate ECG). 
4.
Blood for Anti-Avelumab Antibodies (Anti-Drug Antibodies: ADA): In all patients, blood samples (3.5 mL whole blood at each specified time point) for avelumab 
immunogenicity testing will be collected pre-dose on Day 1 of Cycles 1 and 2.


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5.
12-Lead Electrocardiogram (ECG) Time-Matched with PK: On-treatment triplicate ECGs will be performed before (pre-dose) administration of any study drug and 1 hr 
post-start of avelumab infusion (ie, at the end of avelumab infusion) for all patients on Day 1 of Cycles 1 and 2.  All pre-dose ECGs are to be collected prior to administration 
of any study drug (along with any pre-dose PK or ADA samples). At each time point, three (3) consecutive 12-lead ECGs (triplicates) will be performed approximately 
2 minutes apart to determine mean QTc (average of triplicates).  When the ECG measurements coincide with blood sample draws for PK, the PK sample should be taken as 
close as possible to the end of infusion time for the investigational product, with an allowance of 10 minutes.  ECG assessment should be performed prior to blood sample 
collection, such that the blood sample is collected at the nominal time.
6.
PK samples on Day 8 and Day 15 may be collected at any time during the visit.


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Table 3.
SCHEDULE OF ACTIVITIES: UC – Avelumab + Gemcitabine/Cisplatin, Cohorts A2 and A4  
On-Treatment: One cycle = 21 days
Post-Treatment
Screening
Immunotherapy + Chemotherapy
Immunotherapy
Protocol Activities1
Within 28 
Days Prior to 
Enrollment
Gemcitabine/Cisplatin/Avelumab
Avelumab
End of 
Treatment 
+7 days22
Short-Term 
Follow-up 
(Day After 
Last Dose 
303, 603, 
903)23
Long-Term 
Follow-up 
(Every 12 
weeks 
14 days)24
Day 1
2 days39
Day 8 
2 days
Day 15 
2 days 
Cycles 1-3 
only
Day 1 of each 
cycle
2 days
Clinical Assessments
Informed Consent2
X
Medical/Oncological 
History3
X
Baseline Signs/Symptoms4
X
Physical Examination5
X
X
X
X
X
X
ECOG Performance Status6
X
X
X
X
X
X (Day 30 
only)
Vital Signs and Weight7
X
X
X
X
X
X
Contraceptive Check8
X
X
X
X
X
X
Laboratory Studies
Hematology9
X
X
X
X
X
X
X
Blood Chemistry9
X
X
X
X
X
X
X
Coagulation9
X
X
X
X
X
Thyroid function/ACTH10
Day 1 of Cycle 1, Cycle 4, and then every 3 cycles thereafter
X
X
Urinalysis11
X
If clinically indicated
X
Pregnancy Test12
X
X
X
X
X
X
HBV and HCV Tests13
X
12-Lead ECG14
X
X
If clinically indicated
Enrollment and Study Treatment
Enrollment15
X
Gemcitabine 
Administration16
X
X
Cisplatin Administration16
X
Avelumab Administration17
X
X 


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Table 3
SCHEDULE OF ACTIVITIES: UC – Avelumab + Gemcitabine/Cisplatin, Cohorts A2 and A4 (continued)
On-Treatment: One cycle = 21 days
Post-Treatment
Screening
Immunotherapy + Chemotherapy
Immunotherapy
Protocol Activities1
Within 28 
Days Prior to 
Enrollment
Gemcitabine/Cisplatin/Avelumab
Avelumab 
End of 
Treatment 
+7 days22
Short-Term 
Follow-up 
(Day After 
Last Dose 
30±3, 60±3, 
90±3)23
Long-Term 
Follow-up 
(Every 12 
weeks 
±14 days)24
Day 1
±2 days39
Day 8 
±2 days
Day 15 
±2 days 
Cycles 1-3 
only
Day 1 of each 
cycle
±2 days
Disease Assessments
Tumor Assessments/Scans18
X
Cycle 3 Day 1 (±2 days), then every 6 weeks (±2 days).  After 1 year from first dose of study drug, every 12 weeks 
(±14 days) until progressive disease regardless of initiation of new anti-cancer therapy.
Other Clinical Assessments
Serious and Non-serious 
Adverse Event Monitoring19
X
Monitored and recorded throughout treatment
X
X
Concomitant Treatments20
X
Monitored and recorded throughout treatment
X
X
Short- and Long-Term Follow-up After Last Dose of Study Treatment
Subsequent Anti-Cancer 
Treatments21
X
X
Short-term Follow-up 
Assessments23
X
Long-term/Survival
Assessment24
X
X
Samples for Pharmacodynamic, Pharmacokinetic, 
 Analyses
De Novo Tumor Biopsy or 
Archival FFPE Tumor Tissue 
Block25
X
On-Treatment Tumor 
Biopsy26
X Cycle 2 only 
(–7days to 
+2 days)
End of Treatment Tumor 
Biopsy27
X
Avelumab PK28
X 
(select cycles)
X
X
(select cycles)
Anti-Avelumab Antibodies 
(ADA)29
X 
(select cycles)
X
(select cycles)
X
Gemcitabine PK30
X
(Cycle 2 subset 
patients)
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Table 3
SCHEDULE OF ACTIVITIES: UC – Avelumab + Gemcitabine/Cisplatin, Cohorts A2 and A4 (continued)
On-Treatment: One cycle = 21 days
Post-Treatment
Screening
Immunotherapy + Chemotherapy
Immunotherapy
Protocol Activities1
Within 28 
Days Prior to 
Enrollment
Gemcitabine/Cisplatin/Avelumab
Avelumab
End of 
Treatment 
+7 days22
Short-Term 
Follow-up 
(Day After 
Last Dose 
30±3, 60±3, 
90±3)23
Long-Term 
Follow-up 
(Every 
12 weeks 
±14 days)24
Day 1
±2 days39
Day 8 
±2 days
Day 15 
±2 days 
Cycles 1-3 
only
Day 1 of each
cycle
±2 days
Cisplatin PK31
X
(Cycle 2 subset 
patients)
X 
(Cycle 2 subset 
patients)
ACTH=adrenocorticotropic hormone; BID=twice daily; ECG=electrocardiogram; DNA=deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; 
FFPE=formalin-fixed, paraffin-embedded; HBV=Hepatitis B virus; HCV=Hepatitis C virus; PK=pharmacokinetics; 
 
 
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Footnotes for Table 3 SCHEDULE OF ACTIVITIES
1.
Protocol Activities: All assessments should be performed prior to study treatment dosing unless otherwise indicated.  Acceptable time windows for 
performing each assessment are provided in the column headers. 
2.
Informed Consent: Must be obtained prior to the patient undergoing any study-specific procedure.
3.
Medical/Oncological History: Both medical and oncological histories are to be collected within 28 days prior to first dose of study treatment.  Medical 
history should include history of other disease (active or resolved) as well as concomitant illnesses.  Oncological history should include information on prior 
regimens (including dosing and duration of therapy, best overall response, and disease recurrence/progression date), surgery, and radiation therapy. 
4.
Baseline Signs/Symptoms: To be recorded on the Medical History CRF form.  Patients will be asked about any signs and symptoms experienced within the 
14 days prior to signing the informed consent document. After signing the informed consent document, any new or worsening conditions since baseline 
should be reported on the AE CRF.
5.
Physical Examination: Includes an examination of major body systems (height included at screening only). 
6.
ECOG Performance Status: ECOG performance scale may be found in Appendix 2.  Determination of ECOG Performance Status will continue through 
the 30-day Follow-Up visit unless the patient has started on a new anti-cancer therapy.
7.
Vital Signs and Weight: See Section 7.1.
8.
Contraception Check: See Section 4.3 and Section 7.1.2.
9.
Coagulation, Hematology, and Blood Chemistry (full panel): Cycle 1 Day 1 tests do not need to be repeated if they have been conducted in the prior 
3 days and data are available for review. Full hematology and full clinical chemistry tests must be performed. Full hematology panel as well as AST, ALT, 
and creatinine results must be reviewed by medically-qualified study personnel prior to each administration of study drug.  Results from all other laboratory 
assessments are not required to be reviewed prior to study drug dosing, unless there are signs or symptoms to suggest an underlying lab abnormality. 
However, all lab results should be reviewed as soon as they are available. Laboratory tests may be performed up to 3 days prior to each scheduled visit so 
that results will be available for review.  All lab results should be reviewed as soon as they are available.  Required tests are listed in Section 7.1.4.  Full 
chemistry panel is required at Screening, Day 1, Day 8, and Day 15 of Cycles 1 through 3; Day 1 of every subsequent cycle; End of Treatment; and at the 
30-day follow-up visit.  Core chemistry panel (required tests are listed in Section 7.1.4) is required at Follow-Up Day 60 and Day 90.  Coagulation and 
hematology are required as noted in this table.  If the patient permanently discontinues chemotherapy before Cycle 4, but continues on avelumab and/or 
other anti-cancer immunotherapies in future portions of the study, then chemistry and hematology samples should be obtained at Day 1 of subsequent cycles.  
Any test may also be performed when clinically indicated.  For the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be included.
10. Thyroid Function/ACTH Tests.  Additional tests should be performed when clinically indicated.  See Section 7.1.4.
11. Urinalysis: Required only at Screening and End of Treatment.  To be performed if clinically indicated at other time points.  Required tests are listed in 
Section 7.1.4.
12. Serum/Urine Pregnancy Test: Results of the pregnancy test must be available prior to each study treatment dosing.  See Section 7.1.1.
13. HBV and HCV Tests: HBV surface antigen and anti-HCV antibody will be performed at Screening.  HCV RNA will be performed if anti-HCV antibody 
test is positive (Section 7.1.4, Table 14). 


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14. 12-Lead Electrocardiogram (ECG): All patients require triplicate ECG measurements at screening and on treatment.  On treatment triplicate ECGs will be 
performed on Day 1 of Cycles 1 to 3, before (pre-dose) and at the end of avelumab infusion for all patients.  See Table 4 for ECG monitoring of subset of 
patients undergoing serial PK collection in Cohorts A2 and A4.  See Section 7.1.6.
15. Enrollment: Study treatment must be initiated preferably on the day of enrollment, but no later than 3 days after enrollment.  Patients meeting all entry 
criteria will be registered and enrolled using the Interactive Response Technology system.  See Section 5.1.
16. Gemcitabine/cisplatin: Gemcitabine 1000 mg/m2 will be administered IV on Day 1 and Day 8 of each 21-day cycle.  Cisplatin 70 mg/m2 will be 
administered IV on Day 1 of the 21-day cycle.  On visits when both chemotherapy and avelumab are infused (Day 1 of each 21-day cycle), chemotherapy 
will be infused before avelumab.  Patients will receive any premedications as per local guidance.  See Section 5.4.3.  See Section 5.2 for guidance on 
treatment duration. 
17. Avelumab Administration: Avelumab 800 mg will be administered Q3W (Day 1 of each 21-day cycle).  All safety assessments must be performed and 
results reviewed by the treating physician prior to study treatment administration.  Avelumab will be administered as a 1-hour intravenous infusion on 
Day 1 of each 21-day cycle.  On visits when both chemotherapy and avelumab are infused (Day 1 of each 21-day cycle), avelumab will be infused after
chemotherapy but within 30 minutes (+20-minute time window if needed) of the end of the chemotherapy infusion, see Section 5.4.3.  See Section 5.4.1.3
for guidance on required premedication for avelumab infusion.  See Section 5.2 for guidance on treatment duration. 
18. Tumor Assessments: For patients with UC, tumor assessments by CT or MRI scans will include chest, abdomen, and pelvis CT or MRI scans at all time 
points.  Baseline scans must be performed within 28 days prior to first dose of study drug.  See Section 7.6 for complete information.
19. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v 4.03.  See Section 8.1.4 for guidance on the time period for collecting and reporting AE and SAEs.  If a patient 
begins a new anti-cancer therapy, the recording period for non-serious AEs ends at the time the new treatment is started; however, SAEs must continue to be 
recorded on the CRF during the active collection period. 
20. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded for all patients from 28 days prior to the start of study 
treatment and up to 90 days after the last dose of study treatment, see Section 5.7.
21. Subsequent Anti-Cancer Treatments: These treatments will be documented and recorded for patients who discontinue all study treatments and continue in 
the Short –term and Long-Term Survival periods of the study.
22. End of Treatment (discontinuation of all study drugs for any reason): Obtain these assessments if not completed in the prior 7 days.
23. Short-Term Follow-Up after Last Dose of Study Treatment: All patients will be followed for safety every 30 days (±3 days) through 90 days after the 
last dose of study treatment or until the start of new anti-cancer treatment whichever occurs first.  See Section 6.3 for guidance on tumor assessment during 
Short-term Follow-up.
24. Long-Term Follow-up (Survival): Following completion of the end of treatment visit, all patients will be followed for survival and subsequent anti-cancer 
treatments every 12 weeks (±14 days) until death, end of the study, or patient withdrawal of consent, whichever comes first.  See Section 6.3 for guidance on 
tumor assessment during Long-term Follow-up.
25. De Novo Tumor Biopsy and Archival FFPE Tumor Tissue Block: See Section 6.1.1.
26. On-Treatment Tumor Biopsy: See Section 6.1.1.
27. At Progression Tumor Biopsy: An optional de novo tumor sample is encouraged to be collected at End of Treatment if a patient discontinues due to disease 
progression.  See Section 6.1.1.


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28. Blood for Avelumab Pharmacokinetics: Blood samples (3.5 mL whole blood at each specified time point) will be collected from all patients in the study at 
pre-dose and 1 hour post-start of avelumab infusion (ie, at the end of infusion) on Day 1 of Cycles 1, 2, 3, 6, 10, and 14; an additional sample will be 
collected during the Day 15 visit of Cycle 1, 2, and 3.  See Section 7.2.1.
29. Blood for Anti-Avelumab Antibodies (Anti-Drug Antibodies: ADA): Blood samples (3.5 mL whole blood at each specified time point) for avelumab 
immunogenicity testing will be collected from all patients pre-dose on Day 1 of Cycles 1, 2, 3,  6, 10, and 14, and at End of Treatment, see Section 7.3.
30. Blood for Gemcitabine Pharmacokinetics (only in subset of patients undergoing serial PK): See Table 4 and Section 7.2.2.3.
31. Blood for Cisplatin Pharmacokinetics (only in subset of patients undergoing serial PK): See Table 4 and Section 7.2.2.4.
39. The visit window for Day 1 visits post Cycle 1 during study treatment is ±2 days.
CCI


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Table 4.
PK and ECG ASSESSMENTS (Only for Subset of Patients Undergoing Serial PK): UC – Avelumab + 
Gemcitabine/Cisplatin, Cohorts A2 and A4
Cycle 1
Cycle 2
Day 1
Day 15
Day 1
Day 86
Day 156
Time after start of 
gemcitabine infusion (hr)
Time after start of gemcitabine infusion (hr)
Pre-dose
3.5
Pre-dose
0.5
1.0
2.0
3.5
6.0
All Cohorts:
Blood for Gemcitabine PK1
X
X
X
X
Blood for Cisplatin PK2
X
X
X
X
X
Blood for Avelumab PK3
X
X
X
X
X
X
Blood for Avelumab ADA4
X
X
12-Lead ECG collection5
X
X
X
X
ADA=anti-drug antibody; AM=morning; ECG=electrocardiogram; PK=pharmacokinetic
Table 4 provides guidance specifically for subset of patients in Cohorts A2 and A4 who will undergo serial PK collection and matching ECG measurements and 
includes required assessments for Cycle 1 and Cycle 2 only.  For assessments conducted in the remainder of patients and remaining cycles/visits beyond 
Cycle 2, see Schedule of Activities Table 3. 
This assessment schedule is to be used with the following administration schedule for Cycle 2 Day 1: administration of gemcitabine IV over 30 min, followed by 
administration of cisplatin IV over 1 hour starting 30 min after end of gemcitabine infusion, followed by avelumab IV over 1 hour starting 30 min after end of 
cisplatin infusion. If an infusion time is increased for a given agent, end of infusion and subsequent post-dose PK samples (and time-matched ECGs, if 
applicable) for that drug only should shift accordingly.
1.
Blood for Gemcitabine Pharmacokinetics: Blood samples (3 mL whole blood at each specified time point) will be collected at pre-dose, 0.5 hr (30 min) post-start of 
infusion (ie, at the end of infusion), and at 1 hr and 2 hrs post-start of gemcitabine infusion (corresponding to 0.5 hr (30 min) and 1.5 hrs post-end of infusion) on Day 1 of 
Cycle 2. End of infusion PK samples for gemcitabine must be collected within 10 min post end of infusion of gemcitabine.
2.
Blood for Cisplatin Pharmacokinetics: Blood samples (3 mL whole blood at each specified time point) will be collected at pre-dose, 1 hr post-start of infusion (ie, at the end 
of infusion), and at 2.5 hrs and 5 hrs post-start of cisplatin infusion (corresponding to 1.5 hrs and 4 hrs post-end of infusion) on Day 1 of Cycle 2; an additional sample will be 
collected during the Day 8 visit of Cycle 2. End of infusion PK samples for cisplatin must be collected within 10 min post end of infusion of cisplatin.
3.
Blood for Avelumab Pharmacokinetics: In all patients, blood samples (3.5 mL whole blood at each specified time point) will be collected at pre-dose and 1 hr post-start of 
avelumab infusion (ie, at the end of avelumab infusion) on Day 1 of Cycles 1 and 2; an additional sample will be collected during the Day 15 visit of Cycle 1 and Cycle 2. 
End of infusion PK samples must be collected within 30 min post end of infusion of avelumab (after completion of triplicate ECG).
4.
Blood for Anti-Avelumab Antibodies (Anti-Drug Antibodies: ADA): In all patients, blood samples (3.5 mL whole blood at each specified time point) for avelumab 
immunogenicity testing will be collected pre-dose on Day 1 of Cycles 1 and 2.


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5.
12-Lead Electrocardiogram (ECG) Time-Matched with PK: On-treatment triplicate ECGs will be performed before (pre-dose) administration of any study drug and 1 hr 
post-start of avelumab infusion (ie, at the end of avelumab infusion) for all patients on Day 1 of Cycles 1 and 2.  All pre-dose ECGs are to be collected prior to administration 
of any study drug (along with any pre-dose PK or ADA samples).  At each time point, three (3) consecutive 12-lead ECGs (triplicates) will be performed approximately 
2 minutes apart to determine mean QTc (average of triplicates).  When the ECG measurements coincide with blood sample draws for PK, the PK sample should be taken as 
close as possible to the end of infusion time for the investigational product, with an allowance of 10 minutes.  ECG assessment should be performed prior to blood sample 
collection, such that the blood sample is collected at the nominal time.
6.
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1. INTRODUCTION
This is a Phase 1b/2, open-label, multi-center, safety, clinical activity, pharmacokinetic (PK), 
and pharmacodynamic (PD) study of avelumab (MSB0010718C), a programmed 
death-ligand 1 (PD-L1) monoclonal antibody (mAb), in combination with standard-of-care 
chemotherapy with or without other anti-cancer immunotherapies as first-line therapy in 
patients with locally advanced or metastatic solid tumors.  Avelumab is expected to increase 
the effectiveness of antitumor T cells by preventing inhibition of T cell activation.  
Combination of avelumab with agents that enhance the immune response by different 
mechanisms would be expected to lead to an increase in antitumor activity over that seen 
with avelumab alone.  Initially, avelumab will be evaluated in combination with 
standard-of-care chemotherapy in patients with advanced malignancies.  In portions of the 
study to be added in the future, additional combinations of avelumab plus standard-of-care 
chemotherapy with or without other anti-cancer immunotherapy agent(s), other than other 
anti-PD-1/PD-L1 mAb, may be incorporated via protocol amendment based on emerging 
preclinical and clinical data.  See Section 3.1 for additional details.  For the United Kingdom 
(UK) and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in combination 
with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be included.
1.1. Indication
This study will investigate avelumab in combination with standard-of-care chemotherapy 
with or without other anti-cancer immunotherapies as first-line therapy for patients with 
advanced or metastatic solid tumors.  For the UK and the Czech Republic: Only 1 additional 
anti-cancer immunotherapy, in combination with avelumab and chemotherapy, in up to 
4 tumor-specific cohorts, will be included. 
1.2. Background and Rationale
1.2.1. Avelumab 
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with 
programmed death protein-1 (PD-1).  Compared with anti-PD-1 antibodies that target 
T-cells, avelumab targets tumor cells, and, therefore, is expected to have fewer side effects, 
including a lower risk of autoimmune related safety issues, as blockade of PD-L1 leaves the 
programmed death-ligand 2 (PD-L2)/PD-1 pathway intact to promote peripheral 
self-tolerance.1  For complete details of the in vitro and nonclinical studies, refer to the 
avelumab Investigator’s Brochure (IB).2
1.2.1.1. Avelumab Clinical Experience
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in Phase 1, 2, and 3 clinical protocols in a variety of adult cancers, including NSCLC, 
gastric cancer, Merkel cell carcinoma (MCC), renal cell carcinoma (RCC), ovarian cancer, 
UC, head and neck cancer, and non-Hodgkin’s Lymphoma, as single agent or in combination 
with chemotherapy, tyrosine kinase inhibitors (TKIs), or other immune-modulating agents. 


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On 23 March 2017, avelumab received accelerated approval from the FDA for the treatment 
of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma, 
including those who have not received prior chemotherapy.  In addition, on 09 May 2017, 
avelumab was also approved by the FDA for the treatment of patients with locally advanced 
or metastatic urothelial carcinoma who experience disease progression during or after 
platinum-containing chemotherapy, or who experience disease progression within 12 months 
of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
The safety profile of avelumab administered intravenously (IV) as single agent at a dose of 
10 mg/kg every 2 weeks (Q2W) has been characterized primarily in 1738 adult patients from 
studies EMR100070-001 in various solid tumors (N=1650) and EMR100070-003 Part A in 
MCC (N=88).  Study EMR100070-001 consists of 2 parts, a dose escalation phase and a dose 
expansion phase, which is performed in selected tumor types. 
As of 09 June 2016, a total of 53 patients were treated in the dose escalation phase of the 
EMR100070-001 study, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3, 
10, and 20 mg/kg Q2W, respectively.  None of the patients treated with doses up to 
10 mg/kg experienced a dose limiting toxicity (DLT), and the 10 mg/kg dose of avelumab 
was thus considered a safe and well tolerated dose for further investigation in the dose 
expansion cohorts.  One DLT (a Grade 3 immune related adverse event characterized by 
increased creatine kinase, myositis, and myocarditis) was observed in 1 patient at the dose of 
20 mg/kg.
The dose expansion phase of study EMR100070-001 included patients with NSCLC, gastric 
cancer, breast cancer, colorectal cancer, castration resistant prostate cancer, adrenocortical 
carcinoma, melanoma, mesothelioma, UC, ovarian cancer, RCC, and SCCHN.  Study 
EMR100070-003 Part A was conducted in patients with MCC. 
A summary of pooled safety data from patients treated at 10 mg/kg Q2W in studies 
EMR100070- 001 and EMR100070-003 (N=1738) is provided here. 
Treatment-emergent adverse events (TEAEs) were observed in 1697 (97.6%) patients, with 
the most frequent (10%) being fatigue (32.4%), nausea (25.1%), diarrhea (18.9%), 
constipation (18.4%), decreased appetite (18.4%), infusion related reaction (17.1%), weight 
decreased (16.6%), vomiting (16.2%), anemia (14.9%), abdominal pain (14.4%), cough 
(13.8%), pyrexia (13.6%), dyspnea (13.2%), edema peripheral (11.9%), back pain (11.8%), 
and arthralgia (10.4%). 
Treatment-related TEAEs were observed in 1164 (67.0%) patients, and the most frequent 
(5%) were fatigue (17.7%), infusion related reaction (17.0%), nausea (8.6%), diarrhea 
(7.1%), chills (6.7%), pyrexia (6.1%), decreased appetite (5.2%), and hypothyroidism 
(5.0%). 


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A total of 177 patients (10.2%) experienced Grade 3 treatment-related TEAEs, and the most 
frequent (0.5%) were fatigue (1.0%), lipase increased (1.0%), gamma-glutamyl transferase 
(GGT) increased (0.6%), infusion related reaction (IRR, 0.6%), and aspartate transaminase 
(AST) increased (0.5%). 
A total of 777 (44.7%) patients had at least 1 serious TEAE.  Treatment-related serious 
TEAEs were reported in 108 (6.2%) patients, with the most frequent (0.2%) being IRR 
(0.9%), pneumonitis (0.6%), pyrexia (0.3%), adrenal insufficiency (0.3%), and 
hypothyroidism, diarrhea, vomiting, autoimmune disorder, autoimmune hepatitis, 
transaminases increased, dyspnea, and colitis (0.2% each). 
There were 911 deaths (52.4%) in the pooled safety data set.  The majority of deaths were 
due to progressive disease (744, 42.8%).  There were 59 (3.4%) deaths attributed to TEAEs 
not related to trial treatment, and 4 deaths (0.2%) attributed to a treatment-related TEAE by 
the Investigator and which occurred up to 30 days after the last dose of avelumab: 
pneumonitis (1 case), acute liver failure (1 case), respiratory distress (in the context of sepsis) 
(1 case), and autoimmune hepatitis with hepatic failure (1 case).  In addition, 1 patient died 
with acute respiratory failure (in the context of lung cancer progression) considered related to 
avelumab by the Investigator 37 days after the last dose of avelumab.  The cause of death 
was marked as “other” or “unknown” in 17 (1.0%) and 83 (4.8%) of cases, respectively.
A total of 244 patients (14.0%) permanently discontinued avelumab treatment due to TEAEs, 
including 107 patients (6.2%) discontinuing because of treatment-related TEAEs.  The most 
frequent treatment related TEAEs leading to treatment discontinuation were infusion related 
reaction (1.8%), GGT increased (0.4%), and diarrhea, fatigue, autoimmune disorder, alanine 
aminotransferase (ALT) increased, blood creatinine phosphokinase (CPK) increased, lipase 
increased, arthralgia, and pneumonitis (0.2% each).
Immune-related adverse events (irAEs): in the pooled safety data (N=1738), a total of 
247 patients (14.2%) experienced irAEs, defined as adverse events requiring use of 
corticosteroids (and/or hormonal therapy for endocrinopathies), and no clear alternate 
etiology.  The median time to first onset of an irAE was 11.7 weeks.  The most frequent 
irAEs were thyroid disorders including hypothyroidism (5.2%), hyperthyroidism (0.4%) and 
thyroiditis (0.2%), immune-related rash (5.2%), immune-related colitis (1.5%), 
immune-related pneumonitis (1.2%), immune-related hepatitis (0.9%), adrenal insufficiency 
(0.5%) and immune-related myositis (0.5%).  In addition, irAEs reported in 0.1% of patients 
in the pooled safety dataset included: type 1 diabetes mellitus, immune-related nephritis/renal 
dysfunction, hypopituitarism, uveitis and Guillain-Barre Syndrome.  The majority of irAEs 
were Grade 1 or Grade 2 in severity, with 39 (2.2%) being of Grade 3 severity.  Fatal 
outcome was reported in 1 patient (0.1%) with immune-related pneumonitis, and 2 patients 
(0.1%) with immune-related hepatitis.  Other relevant irAEs reported with avelumab outside 
the pooled safety dataset included 1 case of fatal immune-related myocarditis in Study 
B9991002 (avelumab in combination with axitinib for RCC), 1 case of non-fatal 
immune-related myocarditis in the 20 mg/kg cohort of the dose escalation phase of Study 
EMR100070-001, and 2 patients with non-fatal graft versus host disease (GVHD) in Study 
B9991007 (avelumab in patients with classical Hodgkin’s lymphoma).


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Infusion-related reactions (IRRs): a total of 439 patients (25.3%) experienced at least 1 IRR, 
defined as a TEAE coded under the preferred terms (PTs) of IRR, drug hypersensitivity, 
hypersensitivity, anaphylactic reaction, type I hypersensitivity, chills, pyrexia, back pain, 
dyspnea, hypotension, flushing, and abdominal pain according to a predefined case 
definition.  The most common PTs that met the definition for an IRR included: IRR (17.0%), 
chills (5.4%), and pyrexia (3.6%).  Most of the events were of Grade 1 or Grade 2 severity.  
Grade 3 IRRs occurred in 12 patients (0.7%) including 3 patients (0.2%) who experienced 
Grade 4 IRRs.  No Grade 5 IRRs were reported.  In most cases, the first occurrence of an 
IRR was related to the first infusion, with only 6 patients experiencing the first IRR at the 
fifth or later infusion.  All Grade 3 IRRs occurred with the first (7 patients) or second 
(5 patients) infusion.  Overall, 21.6% of patients had 1 IRR, 2.6% of patients had 2 IRRs, 
14 patients (0.8%) had 3 IRRs, and 3 patients had >3 IRRs.  IRR recurrence after the fourth 
infusion was rare (15 patients) and all recurrent IRRs were of Grade 1 or 2 severity.  In 
35 patients (2.0%), treatment was permanently discontinued because of an IRR.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the avelumab IB.2
Immunogenicity of Avelumab in Humans: Immunogenicity assessment included all patients 
from Studies EMR100070-001 and EMR100070-003 treated with 10 mg/kg of avelumab 
Q2W who had at least one valid anti-drug antibody (ADA) result as of the data cut-off date 
of 09 June 2016.  Of the 1738 patients treated with avelumab, 1558 were evaluable for 
treatment-emergent ADAs and 64 (4.1%) tested positive.  Titers were generally low across 
ADA ever-positive patients, with no clear relationship between the duration of 
immunogenicity response and the maximum observed titer.  Current data suggest there is no 
clinically meaningful impact of ADA positivity on PK, efficacy, or safety. 
1.2.1.2. Clinical Experience in Patients with Locally Advanced or Metastatic NSCLC
Avelumab has been evaluated in first-line NSCLC patients in a tumor-specific expansion 
cohort of Study EMR 100070-001.  As of 19 February 2016, 156 patients with advanced 
NSCLC not previously treated systemically for metastatic or recurrent disease, without an 
activating epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase 
(ALK) rearrangement, and not preselected for PD-L1 expression were enrolled in this cohort. 
The objective response rate (ORR) based on confirmed and unconfirmed responses was 
22.4% (35 [2 complete response {CR} and 33 partial response {PR}] of 156 patients 
[95% confidence interval (CI) 16.2-29.8%]).  In 24 of 35 responders (68.6%), the responses 
were ongoing at the time of the data cutoff.  The onset of the response was rapid, with 28 of 
35 responders (80%) having their first documented response by the first or second tumor 
assessments (Weeks 6 and 12, respectively).  An additional 67 patients (42.9%) had a best 
overall response (BOR) of stable disease (SD).  The median progression-free survival (PFS) 
as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 was 
17.6 weeks (95% CI: 11.6, 23.6).  The PFS rate at 24 weeks by Kaplan-Meier estimate was 
37.2% (95% CI 28.6-45.7%).2


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1.2.1.3. Clinical Experience in Patients with Locally Advanced or Metastatic UC
On 09 May 2017, avelumab received FDA approval for the treatment of patients with locally 
advanced or metastatic UC who have disease progression during or following 
platinum-containing chemotherapy or have disease progression within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 
This approval was based on data from 2 cohorts of Study EMR 100070-001 into which 
242 patients were enrolled.  In the pooled group of 226 patients who had at least 13 weeks 
follow-up, the confirmed ORR by Independent Endpoint Review Committee (IERC) was 
13.3% (30 [9 CR and 21 PR] of 226 patients [95% CI 9.1-18.4%]).  The median time to 
response was 2.0 months (range: 1.3 to 11.0).  Among the total 30 responding patients, 
22 patients (73%) had ongoing responses of 6 months or longer and 4 patients (13%) had 
ongoing responses of 12 months or longer. 
In the pooled group of 161 patients who had at least 6 months follow-up, the confirmed ORR 
by IERC was 16.1% (26 [9 CR and 17 PR] of 161 patients [95% CI 10.8-22.8%]).  As for 
those patients who had at least 13 weeks follow-up, the median time to response was 
2.0 months (range: 1.3 to 11.0).  Among the total 26 responding patients, 22 patients (85%) 
had ongoing responses of 6 months or longer and 4 patients (15%) had ongoing responses of 
12 months or longer.3
1.2.1.4. Pharmacokinetics of Avelumab in Humans 
Available PK data from EMR100070-001 show that the concentration at the end of the 
dosing interval (Ctrough) increased more than proportionally to dose between 1 to 
10 mg/kg and proportionally to dose for doses above 10 mg/kg.  The terminal half-life (t1/2) 
also increased with dose; however, the geometric mean values for t1/2 were similar for the 
10 mg/kg and 20 mg/kg dose levels, at 94.6 hours (3.96 days) and 99.1 hours (4.1 days), 
respectively.  This PK characteristic suggests that target mediated drug disposition is 
involved in the clearance of avelumab and that high PD-L1 target receptor occupancy (TO) is 
likely achieved throughout the dosing interval at doses of 10 mg/kg and 20 mg/kg given 
every 2 weeks.
The 10 mg/kg dose Q2W achieved high TO (mean TO >90%) of PD-L1 in peripheral blood 
mononuclear cells (PBMC) during the entire dosing interval, as determined from ex vivo 
studies.  Based on the in vitro TO data and the observed trough serum avelumab levels in the 
dose escalation cohorts of Study EMR100070-001, TO was predicted to reach or exceed 
95% throughout the entire dosing interval in more patients in the 10 mg/kg dose group than 
in the 3 mg/kg dose group.
Avelumab is eliminated by intracellular lysosomal proteolytic degradation throughout the 
entire body and therefore is not expected to be affected by small molecule drugs that are 
cytochrome P450 (CYP) enzyme modulators or by transporter modulators.  Population PK 
analysis did not show any meaningful effects on clearance of avelumab from premedication 
with acetaminophen (paracetamol) or diphenhydramine, nor from concomitant medication 


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with ibuprofen, acetylsalicylic acid, opioids, corticosteroids, or biological therapies evaluated 
to date. 
Complete information for avelumab may be found in the SRSD, which for this study is the 
avelumab IB.2
1.2.2. Chemotherapy
For the specified chemotherapy agents used in this study, please refer to the product local 
label for clinical experience and pharmacokinetics information.  Complete information for 
carboplatin, cisplatin, pemetrexed and gemcitabine may be found in the single reference 
safety documents (which for this study are the Paraplatin, Platinol, Alimta, and Gemzar
United States Prescribing Information [USPI], respectively).38,39,41,42
1.2.3. Study Rationale
1.2.3.1. Rationale for Combining Avelumab with Chemotherapy
There are emerging data supporting the rationale for combinations of immune checkpoint 
inhibitors with chemotherapy.4,5  Chemotherapy has been shown to have immunostimulatory 
properties via its ability to promote the release of neoantigens and to enhance antigen uptake 
and presentation via the process of immunogenic cell death, hence leading to an increase in 
immune priming against the tumor.  In addition, a number of chemotherapies have been 
shown to alter the immunogenicity of tumor cells both at the cell intrinsic level, through 
modulation of cell surface proteins like major histocompatibility complex (MHC), and also at 
the cell extrinsic level, though depletion of suppressive elements within the 
microenvironment such as regulatory T cells (Tregs) and myeloid derived suppressor cells 
(MDSCs).6-9  Cisplatin has been shown in preclinical models to lead to increased 
intratumoral CD8 T cell cytotoxicity and to increased antitumor activity in combination with 
checkpoint blockade.10  Platinum-based chemotherapy regimens in general have been 
suggested to promote immune priming, as evidenced by increased MHC class I and PD-L1 
expression and increased CD8 T-cell infiltration into tumors post-treatment.11  In addition, 
gemcitabine has been shown in preclinical models to reduce the levels of suppressive 
MDSCs within the tumor,12 and has been shown in patients to reduce the circulating levels of 
both MDSCs and tumor growth factor (TGF)-β, which can be a suppressive signal for 
T cells.13  The combination of avelumab with several chemotherapies including gemcitabine, 
oxaliplatin, and 5-fluorouracil, showed improved antitumor activity relative to single-agent 
chemotherapy in preclinical studies.2  
Several immune checkpoint inhibitors have been combined with chemotherapy agents.  
Single-arm studies investigating the combination of PD-1 blockers (pembrolizumab, 
nivolumab) as well as a PD-L1 blocker (atezolizumab) with platinum doublet chemotherapy 
demonstrated acceptable safety profiles with early evidence of clinical activity which appears 
to be higher than expected for platinum doublet therapy alone, especially for 
atezolizumab.14-18  Of particular relevance to Study B9991023 are results from studies of 
PD-1/PD-L1 inhibitors plus platinum doublet chemotherapy as first-line therapy in patients 
with advanced or metastatic NSCLC.  In one randomized, open-label, Phase 2 cohort of the 
KEYNOTE-021 study,27 the combination of carboplatin and pemetrexed with or without 


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pembrolizumab was evaluated in patients with advanced non-squamous NSCLC.  A 
significant increase in ORR (55%; 95% CI 42-68%) was noted for the triplet therapy relative 
to the ORR for chemotherapy alone (29%; 95% CI 18-41%).  In addition, median PFS for 
patients treated with the triplet (13.0 months; (95% CI 8.3-not reached)) was significantly 
longer than that for chemotherapy-treated patients (8.9 months; (95% CI 4.4-10.3)).  The PFS 
hazard ratio (HR) was 0.53 (95% CI 0.31-0.91; p=0.010).  Results from OS data were not yet 
mature at the time of publication.  In this patient population, the observed increase in ORR 
for patients treated with the triplet as compared to chemotherapy-treated patients was 
demonstrated along with PFS prolongation, suggesting that this magnitude of ORR increase 
would translate into a clinically meaningful and statistically significant difference in a 
time-to-event efficacy endpoint.  Based on data from the KEYNOTE-021 study, on 10 May 
2017, the FDA approved pembrolizumab in combination with carboplatin and pemetrexed 
for the first-line treatment of patients with metastatic non-squamous NSCLC, irrespective of 
PD-L1 expression.52  
In independent cohorts of a separate study,19,20 nivolumab alone or in combination with 
3 different platinum doublets was tested as first-line therapy in patients with advanced 
NSCLC.  Improvements in both ORR and median PFS were noted for nivolumab in 
combination with gemcitabine/cisplatin, pemetrexed/cisplatin, or paclitaxel/carboplatin over 
those seen with nivolumab alone.  Notable ORRs were also observed when atezolizumab was 
combined with pemetrexed/carboplatin, carboplatin/paclitaxel, or carboplatin/nab-paclitaxel 
as first-line therapy for patients with advanced NSCLC.21  
Overall these clinical and preclinical data are supportive of the potential for increased 
antitumor activity through the combination of chemotherapy and avelumab.  Avelumab is 
currently under investigation in 2 Phase 3 ovarian cancer trials in combination with 
carboplatin/paclitaxel in one trial and with pegylated liposomal doxorubicin in the second 
trial.  While results from both studies are blinded to the Pfizer teams, early safety data have 
been reviewed by external data monitoring committees and both studies have been approved 
to continue. 
1.2.3.2. Rationale for the Tumor Types Under Evaluation
The specific tumor types to be enrolled in Group A were selected because:

These tumor types are responsive to chemotherapy, which currently is first-line 
standard-of-care for these indications;

Avelumab has shown preliminary evidence of clinical activity as monotherapy in the 
specific tumor types (NSCLC2 and UC;3 see Section 1.2.1.2 and Section 1.2.1.3
respectively).
1.2.3.3. Rationale for the Chemotherapy Doublets to be Evaluated in this Study
Chemotherapy doublets selected for use in Group A represent standard-of-care first-line 
therapies for the 2 tumor types that will initially be evaluated in this study. 


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The doublet carboplatin plus pemetrexed will be used to treat patients with advanced or 
metastatic non-squamous NSCLC.  In 2005, Scagliotti et al24 reported the results of a 
multicenter, randomized, Phase 2 trial of pemetrexed in combination with either oxaliplatin 
or carboplatin as first-line treatment of patients with advanced NSCLC.  The intent of this 
study was to identify new treatment regimens that provided the same level of efficacy as that 
seen with cisplatin chemotherapy doublets, but with an improved toxicity profile.  The ORRs 
were 26.8% (95% CI 14.2-42.9%) for patients treated with pemetrexed/oxaliplatin and 
31.6% (95% CI 17.5-48.7%) for patients treated with pemetrexed/carboplatin.  These rates 
were similar to those seen in 4 randomized Phase 3 trials evaluating the following platinum 
doublets: paclitaxel and cisplatin; gemcitabine and cisplatin; docetaxel and cisplatin; 
paclitaxel and carboplatin; vinorelbine and cisplatin; and docetaxel and carboplatin.  In 
addition, the oxaliplatin/pemetrexed and carboplatin/pemetrexed doublets had improved 
safety profiles relative to those from other platinum-based doublets – for both hematologic 
and non-hematologic toxicities.22-25 These results indicated a favorable risk/benefit profile 
for these 2 doublets.  In 2016, Gadgeel et al26 published results from early cohorts of
KEYNOTE-021 in which the PD-1 inhibitor pembrolizumab was combined with 3 different 
chemotherapy regimens (carboplatin/paclitaxel, carboplatin/paclitaxel/bevacizumab, and 
pemetrexed/carboplatin) as first-line therapy for patients with advanced NSCLC.  The
combination of pemetrexed/carboplatin demonstrated the most promising activity.  Based on 
these results and as part of KEYNOTE-021, Langer et al27 evaluated the combination of 
pemetrexed/carboplatin plus pembrolizumab in a larger randomized cohort of patients with 
advanced non-squamous NSCLC and observed an increase in ORR and longer PFS for the 
triplet therapy compared to chemotherapy alone (See Section 1.2.3.1).  Given these 
cumulative results, carboplatin/pemetrexed was selected for first-line treatment of patients 
with non-squamous NSCLC enrolled in this study. 
Gemcitabine/cisplatin has long been established as the standard first-line chemotherapy 
regimen for those patients with advanced or metastatic UC who are eligible to receive this 
combination.32,33  Comparison of gemcitabine/cisplatin to methotrexate/vinblastine/ 
doxorubicin/cisplatin (MVAC) revealed similar OS, time to PD, time to treatment failure, 
and response rate for the 2 regimens.  The safety profile and tolerability of the 
gemcitabine/cisplatin doublet was better than those for the MVAC regimen resulting in 
adoption of the doublet as standard of care first-line therapy.  In the von der Maase 
studies,32,33 gemcitabine/cisplatin was dosed on a 4-week cycle with gemcitabine 
administered on Day 1, 8, and 15 and cisplatin administered on Day 2.  Gemcitabine dosing, 
however, was associated with a high rate of hematologic toxicity.  In an effort to determine if 
a 3-week cycle of gemcitabine dosed on Day 1 and 8 and cisplatin on Day 2 would be 
feasible, Als et al34 conducted a retrospective analysis of patients with advanced UC who had 
been treated with either the standard 4-week cycle or a modified 3-week cycle.  There was no 
statistical difference in OS between the two dosing schedules (HR=1.15, 95% CI 0.83 to 
1.59, p=0.4).  Response rates also were similar (3-week cycle: 59.7%; 4-week cycle 55.6%, 
p=0.61).  The authors reported “an improved compliance profile, adequate dose intensity, and 
no differences in efficacy parameters for the 3-week schedule compared with the 4-week 
schedule”.  Given these findings, patients with advanced or metastatic UC will receive 
gemcitabine/cisplatin on a 3-week schedule in this study.


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1.2.3.4. Rationale for Investigational Product Dose
1.2.3.4.1. Avelumab
In this study, avelumab will be administered initially as an 800 mg fixed dose via 1-hour 
infusion Q3W in combination with chemotherapy, with or without other anti-cancer 
immunotherapies. After the initial avelumab dose of 800 mg Q3W in combination with 
chemotherapy has been evaluated and deemed safe according to the study design, avelumab 
1200 mg Q3W will be explored as the next dose level.
For the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be 
included. 
To date, avelumab has been administered at the clinically active, safe and tolerable dose of 
10 mg/kg Q2W to more than 1700 patients across multiple indications.  Furthermore, this 
10 mg/kg Q2W avelumab dosing regimen has been approved by the US FDA for treatment 
of patients with MCC and UC. The preliminary data from clinical studies suggest 
>90% target occupancy (TO) is required for clinical benefit.  Based on in vitro evidence, 
90% TO is reached at avelumab blood concentrations >1 g/mL; 10 mg/kg Q2W has been 
shown to achieve avelumab serum trough concentration (Ctrough) >1 g/mL. 
Avelumab was originally dosed on a mg/kg basis in order to reduce inter-subject variability 
in drug exposure.  However, emerging data for mAbs, including marketed PD-1 and 
PD-L1 immune checkpoint inhibitors nivolumab, pembrolizumab and atezolizumab, reveal 
that body weight-based dosing regimens do not result in less variability in measures of 
exposure over fixed (ie, body weight-independent) dosing regimens.35,36,37 Additionally, 
fixed dosing offers the advantages of less potential for dispensing errors, shorter dose 
preparation times in a clinical setting, and greater ease of administration.  Population PK 
analysis was conducted based on the acquired PK data across 3 single-agent avelumab 
studies in patients with 14 different types of cancer.  PK simulations suggest that exposures 
to avelumab across the available range of body weights are similar with 800 mg Q2W (fixed 
dose) compared to 10 mg/kg Q2W (weight-based dose), and 1600 mg Q2W compared to 
20 mg/kg Q2W. Low-weight patients tended to have marginally lower exposures relative to 
the rest of the population when weight-based dosing was used, and marginally higher 
exposures when fixed dosing was applied.  However, the implications of these exposure 
differences are not expected to be clinically meaningful. 
Based on emerging data of avelumab and other PD-1 and PDL-1 inhibitors, other avelumab 
dosing regimens continue to be explored in various clinical studies in efforts to optimize 
clinical benefit in individual indications and treatment regimens, such as when used in 
combination with standard-of-care therapies given in a frequency which differs from Q2W.  
For example the Q3W dosing schedule has been evaluated in several other clinical studies of 
an immune checkpoint inhibitor mAb (eg, ipilimumab, nivolimumab, pembrolizumab) with 
platinum doublet chemotherapy; in each of these studies, the combination therapy was 
associated with acceptable safety.56,57,58 A Q3W dosing schedule for avelumab will likewise 
be used in this study in combination with Q3W standard-of-care doublet chemotherapy 


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regimens as Q2W administration would result in avelumab dosing during the period of 
chemotherapy-induced myelosuppression nadir.  Given that the safety of avelumab in 
patients with myelosuppression is currently unknown, a Q3W administration schedule avoids
dosing of avelumab during the nadir period; the intent to avoid treating myelosuppressed 
patients aligns with the current avelumab dose modification guidelines for management of 
hematologic toxicities. The 800 mg Q3W dosing regimen (initial dose level) is still expected 
to provide median plasma Ctrough >1 g/mL at 21 days, yielding a mean TO >90% over the 
entire Q3W dosing interval for the majority of patients (Pfizer, data on file).
Additionally, other marketed PD-1 and PD-L1 immune checkpoint inhibitors 
(eg, nivolumab,53 pembrolizumab54 and durvalumab55) have demonstrated an ability to 
extend the dosing interval paired with an increase in dose. Such efforts are also being 
explored for avelumab. In two clinical studies, including the dose escalation trial, avelumab 
was administered at 20 mg/kg Q2W (highest tested dose) to a total of 27 patients that had 
shown acceptable safety profiles, and no maximum tolerated dose (MTD) was reached. For 
an extended dosing interval of Q3W, the projected avelumab average plasma concentration 
(Cavg) values from PK simulations following 1200 mg Q3W are similar to those observed 
with the 10 mg/kg Q2W dosing regimen approved in MCC and UC, and exposures following 
1200 mg Q3W are projected to not exceed those observed at the highest tested dose of 
20 mg/kg Q2W. 
The proposed avelumab fixed dosing regimens of 800 mg Q3W and 1200 mg Q3W are 
expected to reach >90% TO throughout the 21-day dosing interval in the majority of patients, 
including when used in combination with chemotherapy or other anti-cancer 
immunotherapies; the 1200 mg Q3W dosing regimen is being explored additionally in this 
Phase 1b/2 trial since it is projected to maintain the avelumab average exposures observed 
with the approved dose of 10 mg/kg Q2W while extending the dosing interval for use in 
combination with Q3W chemotherapy regimens.
1.3. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The benefit-risk relationship has been carefully considered in the planning of the trial.  As 
part of this effort, the clinical efficacy and safety profile of each of the study drugs when 
used individually was reviewed. 
Avelumab has demonstrated clinical activity in patients with advanced solid tumors in an 
expansion cohort of a Phase 1 study.  The available clinical safety data for single-agent 
avelumab dosed at 10 mg/kg Q2W in 1738 patients with advanced solid tumors demonstrate 
an acceptable safety profile of the compound.  Most of the observed events were low grade 
and manageable and were either in line with those expected in patients with advanced solid 
tumors or with similar class effects of mAbs blocking the PD-1/PD-L1 axis.  IRRs including 
hypersensitivity and irAEs/autoimmune disorders have been identified as important risks for 
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Although most clinical safety data are from patients treated with avelumab at 
10 mg/kg Q2W, there are also limited data for patients treated at the higher dose of 
20 mg/kg Q2W.  Data at 20 mg/kg Q2W support a safety profile similar to that seen at 
10 mg/kg Q2W. Twenty-one patients were treated with 20 mg/kg Q2W in the dose 
escalation portion of Study EMR100070-001, and 6 patients were treated at this dose in the 
Japanese Study EMR100070-002.  Based on a data cut-off of 20 November 2015, for the 
pooled data set for EMR100070-001 and EMR100070-002 (3, 10 and 20 mg/kg Q2W), the 
incidence of TEAEs was similar in patients treated at doses of 10 and 20 mg/kg Q2W, with 
the exception of related TEAEs (90.5% at 10 mg/kg vs. 74.1% at 20 mg/kg) and related 
TEAEs Grade 3 (23.8% at 10 mg/kg vs 11.1% at 20 mg/kg) that were reported at a higher 
percentage in the 10 mg/kg Q2W group and related TEAEs leading to permanent 
discontinuation (4.8% at 10 mg/kg vs. 14.8% at 20 mg/kg) that were reported at a higher 
percentage in the 20 mg/kg Q2W group.  Overall, irAEs were reported at similar percentages 
in the 10 mg/kg Q2W and 20 mg/kg Q2W dose groups (14.3% and 14.8%, respectively).
The rate of infusion-related reactions was higher in the 10 mg/kg Q2W group (28.6%) than in 
the 20 mg/kg Q2W group (14.8%).
Respective risk mitigation measures have been implemented in all clinical studies with 
avelumab, including this clinical trial protocol.  These include guidelines for treatment 
interruption and discontinuation in case of irAEs, as well as mandatory pre-treatment with a 
H1 blocker and acetaminophen prior to the first 4 avelumab infusions. All avelumab-specific 
guidelines apply to both the 800 mg Q3W dose and the 1200 mg Q3W dose. 
There is extensive literature on the clinical utility and safety history for each of the 
chemotherapy agents used both individually and as part of the chemotherapy doublets 
planned in Study B9991023.38,39,41,42  The combination of carboplatin with pemetrexed 
(Cohorts A1 and A3) and cisplatin with gemcitabine (Cohorts A2 and A4) are standard 
chemotherapy regimens for patients affected by non-squamous NSCLC and with 
cisplatin-eligible UC, respectively.  These regimens have a well characterized toxicity 
profile.  Overall, AEs frequently seen with these regimens include fatigue, hematologic 
toxicity, gastrointestinal toxicity (nausea, vomiting, diarrhea), neurotoxicity, and 
hypersensitivity reactions.  In order to minimize the occurrence of chemotherapy-related 
AEs, detailed dose modification guidelines to be followed in the event of 
chemotherapy-related toxicity are also provided.
Two studies in patients with advanced ovarian cancer are evaluating avelumab in 
combination with chemotherapy: Study B9991009 uses the combination of avelumab plus 
pegylated liposomal doxorubicin and Study B9991010 uses the combination of avelumab 
plus carboplatin/paclitaxel.  While results by treatment arm from both studies are blinded to 
the Pfizer teams, early data have been reviewed by external data monitoring committees and 
both studies have been deemed safe to continue. 
As mentioned above, combination of PD-1/ PD-L1 inhibitors with chemotherapy has resulted 
in increased clinical activity for the combination relative to chemotherapy alone.  In addition, 
the safety profile of each combination does not significantly differ from the one of each agent 
alone.  For example, in the KEYNOTE-021 study of carboplatin and pemetrexed with or 


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without pembrolizumab in patients with advanced non-squamous NSCLC, the frequency of 
Grade 3 AEs was 40% (23/59) in the chemotherapy plus pembrolizumab arm compared to 
25% (16/62) in the chemotherapy alone arm.  There was no increased risk of 
immune-mediated AEs in patients treated with chemotherapy plus pembrolizumab as 
compared to the known safety profile of single-agent pembrolizumab.  Further, there was no 
increased risk of AEs leading to permanent discontinuation or to death in the chemotherapy 
plus pembrolizumab combination arm.
Overall, given the distinct mechanisms of action and toxicity profiles of avelumab and the 
selected chemotherapy regimens, relevant safety concerns are not expected from these 
combinations.  The most frequently observed severe toxicities of avelumab are largely 
non-overlapping with the ones of the chemotherapy agents to be evaluated in the present 
study. 
Since the chemotherapy agents are small molecules, there is no expectation of any drug-drug 
interaction between these agents and avelumab, as it is a mAb.  To confirm, the PK of 
avelumab, the chemotherapy agents, and any other immunotherapies used in future portions 
of this study will be assessed in this study to evaluate the drug-drug interaction potential in 
an exploratory manner within each of the combinations. 
For the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be 
included.
In this study, each of the selected chemotherapy doublets is dosed on a Q3W schedule.  In an 
effort to mitigate unexpected hematologic toxicity and considering that the tolerability of 
avelumab in patients with severe myelosuppression is currently not well characterized, a 
Q3W schedule was adopted for avelumab in this study in order to avoid dosing of avelumab 
during the expected hematologic nadir period for the selected chemotherapy regimens. 
As previously described, the 2 tumor types selected for evaluation in this study are sensitive 
not only to chemotherapy, but also to inhibitors of the PD-1/PD-L1 axis.  Of particular 
importance to this study, avelumab has demonstrated antitumor activity in each tumor type.  
First-line treatment of patients with advanced non-squamous NSCLC with chemotherapy in 
combination with a PD-1 inhibitor, pembrolizumab, resulted in significantly improved 
median PFS and ORR compared to those seen with chemotherapy alone.27 Based on clinical 
data for each agent alone and, as available, in combination with other agents to be used in 
this study, and considering data from combinations including similar drugs, the conduct of 
this trial with the initial combination of avelumab plus chemotherapy is considered 
justifiable.  Given the different mechanisms of action of each of the agents to be used in this 
study, increases in the rate or severity of toxicities seen are not expected compared to when 
each agent is used independently.  Thus, the projected benefit/risk of avelumab given in 
combination with chemotherapy is anticipated to be favorable for investigation in these 
populations of patients with advanced solid tumors.  Any combination in this study shall be 
discontinued in the event of any new findings that indicate a significant deterioration of the 
risk-benefit relationship that would render continuation of the combination unjustifiable.


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1.4. Biomarker Rationale
This study intends to characterize the ability of chemotherapy in isolation or together with 
various immunotherapies to increase the clinical benefit seen with single-agent avelumab.  
As the immunotherapies may vary with respect to targets engaged, target modulation needed 
for optimal activity and amount of prior clinical experience, some customization of the 
biomarker strategy will be needed for each combination tested.  The following represents an 
overview of the planned strategy, followed by comments specific to each combination.  For 
the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be 
included.
The success of the combinations being tested will likely be contingent on identifying the 
specific tumor types and/or patients most likely to respond to the combination.  Successful 
response to immunotherapy relies upon recognition of a tumor by the immune system, which 
is impacted by 3 factors:
1. The cell intrinsic immunogenicity of any tumor cells, for example their expression of 
MHC or of surface molecules such as PD-L1, which will determine whether tumor 
reactive immune cells can effectively recognize and kill the tumor cells.
2. The cell extrinsic immunogenicity of the tumor microenvironment, for example the 
presence or absence of suppressive cells such as Tregs or MDSCs, which will 
significantly impact the ability of tumor reactive immune cells to function.
3. The antigenicity of the tumor, that is how many mutations are present within the 
tumor, and whether those mutations generate recognizable T cell epitopes that might 
lead to priming of the immune response and subsequent targeting and elimination of 
the tumor.
The collection of pre-treatment tumor tissue, archival and/or de novo biopsy is mandatory for 
this study in order to enable assessments that inform as to these 3 factors.  Parameters that 
may be studied include, but are not limited to, assessment of PD-L1 expression by tumor 
and/or immune cell types in the tumor using immunohistochemistry (IHC), 
 
 
 
 
 
As noted above, chemotherapy has the potential to alter both the tumor cell intrinsic and 
extrinsic immunogenicity of the tumor, and an additional component of the biomarker plan 
for this study is to assess and confirm such changes within the tumor following treatment.  
To this end, collection of on-treatment tumor biopsies is mandatory unless clinically 
contraindicated in order to enable the parameters listed above to be compared pre- and
post-treatment.  These paired measurements are performed with the aim of identifying PD or 
mechanistic biomarkers for the combinations being tested, which could help inform optimal 
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dose and schedule for the combinations, aid in confirming activity for the combinations and, 
in the event that clinical benefit is not observed or is transient, may help inform as to the 
reasons for lack of benefit. A comparison will be made between paired biopsy data from 
patients receiving the 800 mg dose of avelumab and from patients receiving the 1200 mg 
avelumab dose in order to assess any quantitative or qualitative differences in the 
pharmacodynamic responses observed at different dose levels.
Biopsies at end of treatment in the event of discontinuation due to progressive disease are 
also requested from patients unless clinically contraindicated.  Collection and analyses of 
these biopsies will enable exploration of the possible causes for lack of clinical benefit or for 
emerging resistance to therapy.
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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary Objectives
•
Phase 1b lead-in: To assess DLT rate of avelumab in combination with 
chemotherapy, as first-line treatment in patients with locally advanced or metastatic 
solid tumors.
•
To assess, per RECIST v1.1 (Appendix 3), the ORR of avelumab in combination with 
chemotherapy, as first-line treatment in patients with locally advanced or metastatic 
solid tumors.
Secondary Objectives
•
To assess the overall safety and tolerability of avelumab in combination with 
chemotherapy; 
•
To characterize the PK of avelumab and chemotherapy when given in combination;
•
To evaluate the immunogenicity of avelumab, when given in combination with 
chemotherapy;
•
To assess the antitumor activity, per RECIST v1.1, of avelumab in combination with 
chemotherapy;
•
To assess the correlation of antitumor activity, per RECIST v1.1, of avelumab in 
combination with chemotherapy, with mutational load in baseline tumor tissue; 
•
To assess the correlation of PD-L1 expression in baseline tissue and changes in this 
marker on-treatment, with antitumor activity, per RECIST v1.1, of avelumab in 
combination with chemotherapy.
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2.2. Endpoints
Primary Endpoints
•
Phase 1b lead-in: First 2 cycles DLT. 
•
Confirmed OR, as assessed by the Investigator using RECIST v1.1.
Secondary Endpoints
•
AEs as characterized by type, severity (as graded by National Cancer Institute [NCI] 
Common Terminology Criteria for Adverse Events [CTCAE] v.4.03), timing, 
seriousness, and relationship to study treatments;
•
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v.4.03) and timing;
•
PK parameters of avelumab; 
•
PK parameters of chemotherapies, as data permit;
•
ADA levels;
•
Time-to-event endpoints including PFS, duration of response (DR), and time to tumor 
response (TTR), as assessed by the Investigator using RECIST v1.1; and OS;
•
Mutational load within baseline tumor tissue;
•
PD-L1 expression in baseline and on-treatment tumor tissue.
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3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b/2, open-label, multi-center, safety, clinical activity, PK, and PD study of 
avelumab in combination with chemotherapy with or without other anti-cancer 
immunotherapies, as first-line treatment of adult patients with locally advanced or metastatic 
solid tumors.  Initially, avelumab will be evaluated in combination with standard-of-care 
chemotherapy in patients with advanced non-squamous NSCLC and cisplatin-eligible 
urothelial cancer (UC).  These two tumor types were selected for study because they are 
responsive to chemotherapy, which currently is first-line standard-of-care for these 
indications.  In addition, avelumab has shown preliminary evidence of clinical activity in 
both non-squamous NSCLC and UC.
Given the growing preclinical and clinical indications that combinations of anti-cancer 
immunotherapies potentially improve patient outcomes compared to results seen with single 
agents, in portions of the study to be added in the future, avelumab will be evaluated in 
combination with both standard-of-care chemotherapy and other anti-cancer 
immunotherapies in patients with advanced malignancies.  Addition of new therapy 
combinations will be based on emerging preclinical and clinical data supportive of the 
tolerability and potential clinical benefit of each agent to be combined (eg, chemotherapy, 
anti-cancer immunotherapy agents) with avelumab and will be accomplished by protocol 
amendment.  For the UK and the Czech Republic: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and chemotherapy, in up to 4 tumor-specific 
cohorts, will be included.

Group A: avelumab plus chemotherapy alone:

Cohort A1: avelumab 800 mg Q3W plus pemetrexed/carboplatin in patients with 
non-squamous NSCLC;

Cohort A2: avelumab 800 mg Q3W plus gemcitabine/cisplatin in patients with 
cisplatin-eligible UC;

Cohort A3: avelumab 1200 mg Q3W plus pemetrexed/carboplatin in patients with 
non-squamous NSCLC;

Cohort A4: avelumab 1200 mg Q3W plus gemcitabine/cisplatin in patients with 
cisplatin-eligible UC.
Each combination cohort will be studied in 2 phases: 1) a Phase 1b lead-in to evaluate 
preliminary safety of the combination, and 2) a Phase 2 cohort expansion to evaluate 
preliminary efficacy and further evaluate safety. Phase 2 cohort expansion may be initiated 
only for the highest dose of avelumab deemed safe in each combination.


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Phase 1b Lead-in
The safety of avelumab will be assessed independently in combination with each of the two 
different chemotherapy regimens.
The 1200 mg Q3W dosing regimen is being explored additionally in this Phase 1b/2 trial 
since it is projected to maintain the avelumab average exposures close to those observed with 
the approved dose of 10 mg/kg Q2W while extending the dosing interval for use in 
combination with Q3W chemotherapy regimens
Up to 12 patients will be enrolled into each cohort and evaluated for DLT (defined in 
Section 3.3) during the first 2 cycles of treatment as follows:
Cohorts A1 and A2: 

Enroll and treat up to 6 DLT-evaluable patients in each cohort:

If 1 of 6 patients experience DLT in Cohort A1 (or A2), enrollment will be  initiated 
in Phase 1b Cohort A3 (or A4);

If 3 of up to 6 patients experience DLT in Cohort A1 (or A2), enrollment in 
Cohort A1 (or A2) will be discontinued; there will be no further enrollment of 
patients with the combination;

If 2 of 6 patients experience DLT in Cohort A1 (or A2), the cohort will be expanded 
to enroll up to 6 additional DLT-evaluable patients in the Phase 1b Cohort A1 
(or A2);

If 3 of 12 patients experience DLT in Cohort A1 (or A2), enrollment may be 
initiated in Phase 1b Cohort A3 (or A4);

If 4 of up to 12 patients experience DLT in Cohort A1 (or A2), enrollment in the 
Cohort A1 (or A2) will be discontinued; there will be no further enrollment of 
patients with the combination.
Cohorts A3 and A4: 

Enroll and treat up to 6 DLT-evaluable patients in each cohort:

If 1 of 6 patients experience DLT in Cohort A3 (or A4), enrollment may be initiated 
in Phase 2 Cohort A3 (or A4) expansion with the study treatment of avelumab 
1200 mg Q3W in combination with chemotherapy; there will not be any enrollment 
in Phase 2 Cohort A1 (or A2) expansion with the study treatment of avelumab 
800 mg Q3W in combination with chemotherapy;


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
If 3 of up to 6 patients experience DLT in Cohort A3 (A4), enrollment in Cohort A3 
(or A4) will be discontinued; enrollment may be initiated in Phase 2 Cohort A1 
(or A2) expansion with the study treatment of avelumab 800 mg Q3W in combination 
with chemotherapy;

If 2 of 6 patients experience DLT in Cohort A3 (or A4), the Cohort A3 (or A4) will 
be expanded to enroll up to 6 additional DLT-evaluable patients;

If 3 of 12 patients experience DLT in Cohort A3 (or A4), enrollment may be 
initiated in Phase 2 Cohort A3 (or A4) expansion with the study treatment of 
avelumab 1200 mg Q3W in combination with chemotherapy; there will not be 
any enrollment in Phase 2 Cohort A1 (or A2) with the study treatment of 
avelumab 800 mg Q3W in combination with chemotherapy;

If 4 of up to 12 patients experience DLT in Cohort A3 (or A4), enrollment may
be initiated in Phase 2 Cohort A1 (or A2) expansion with the study treatment of 
avelumab 800 mg Q3W in combination with chemotherapy.
Phase 2 Cohort Expansion
If investigational products administration in the Phase 1b Lead-in portion of a given cohort is 
deemed safe based on the criteria described in “Phase 1b Lead-in” Section, then enrollment 
into that cohort may continue into the Phase 2 Cohort Expansion.  The dose of avelumab to 
be administered in the Phase 2 Cohort Expansion (800 mg Q3W for Cohorts A1 and A2 or 
1200 mg Q3W for Cohorts A3 and A4) will be determined based on the number of observed 
DLTs as described in “Phase 1b Lead-in” section.  The highest dose level of avelumab 
deemed safe for the combination will be advanced.
For the cohort of patients with cisplatin-eligible UC selected to expand to Phase 2, up to 
approximately 40 patients, including those enrolled in Phase 1b Lead-in and those enrolled in 
the Phase 2 Cohort Expansion, will be treated with the combination of avelumab and 
chemotherapy with or without other immunotherapies. For the cohort of patients with 
non-squamous NSCLC selected to expand to Phase 2, approximately 20 patients, including 
those enrolled in Phase 1b Lead-in and those enrolled in the Phase 2 Cohort Expansion, will 
be treated with the combination of avelumab and chemotherapy with or without other 
immunotherapies.  Up to approximately 80 patients in the Phase 1b lead-ins and 
Phase 2 cohort expansions combined for cisplatin-eligible UC and non-squamous NSCLC 
will be enrolled in Group A.
In future portions of the study, up to approximately 40 patients in each cohort (including 
those enrolled in Phase 1b lead-in and those enrolled in Phase 2) will be enrolled and treated
with avelumab plus chemotherapy in the initial portion of the study and, in future portions of 
the study, with avelumab plus chemotherapy with or without other anti-cancer 
immunotherapies.  For the UK and the Czech Republic: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and chemotherapy, in up to 4 tumor-specific 
cohorts, will be included. 


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For both Phase 1b lead-in and Phase 2 cohort expansion, all patients will initially receive 
either avelumab in combination with chemotherapy (Group A) or avelumab in combination 
with chemotherapy and other anti-cancer immunotherapies in portions of the study to be 
added in the future.  Patients will continue to receive study treatment until disease 
progression is confirmed by the Investigator, patient refusal, unacceptable toxicity, or until 
the study is terminated by the Sponsor, whichever occurs first.  In Cohorts A1 and A3, 
treatment with carboplatin and pemetrexed will continue for a maximum of 4-6 cycles; in 
addition, maintenance therapy with pemetrexed may be administered at the discretion of the 
Investigator.  In Cohorts A2 and A4, treatment with chemotherapy will continue until 
optimal response is achieved.
If discontinuation of chemotherapy is required for any reasons other than PD or 
protocol-specified limits, treatment with avelumab (Group A) or avelumab and/or the other 
anti-cancer immunotherapies in future portions of the study should be continued. 
Patients who stop avelumab or the other anti-cancer immunotherapies for unacceptable 
toxicity may continue treatment with the investigational product(s) (eg, chemotherapy) that 
is/are not considered to be responsible for the toxicity observed. 
3.1.1. Tumor Assessments
Antitumor activity will be assessed by radiological tumor assessments at 6-week intervals, 
using RECIST v1.1. In case PR or CR is observed according to RECIST v1.1, tumor 
assessment should be repeated at least 4 weeks after initial documentation.  After 1 year from 
the first dose of study treatment, tumor assessments will be conducted at 12-week intervals 
until PD per RECIST v1.1.  In addition, radiological tumor assessments will also be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration).  
Details of the treatment after initial evidence of radiological disease progression are provided 
in Section 5.4.5. 
Further specific guidance on tumor imaging is provided in Section 7.6.
3.1.2. Safety Assessments
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as reported in the Schedule of Activities and described in Section 7.1. 
3.1.3. Pharmacokinetic/Immunogenicity Assessments
PK and immunogenicity blood sampling will be collected for each combination as described 
in the Schedule of Activities and Section 7.2.
The proposed doses, schedule(s), and PK time points may be reconsidered and amended 
during the study based on the emerging safety and PK data. 


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3.1.4. Biomarker Assessments
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 the 
combination of avelumab and chemotherapy with or without other immunotherapies. 
 
 
 
For the UK and the Czech Republic: 
Only 1 additional anti-cancer immunotherapy, in combination with avelumab and 
chemotherapy, in up to 4 tumor-specific cohorts, will be included.  Biomarker assessments 
are described in Section 7.4.
3.2. Study Designs for Each Group
Each combination will be administered in 21-day cycles.  The DLT observation period for 
evaluation of each dose level during Phase 1b lead-in is the first 2 cycles of treatment. 
3.2.1. Group A (Avelumab plus Chemotherapy)
Group A (Cohorts A1, A2, A3 and A4) will evaluate the combination of avelumab with 
chemotherapy in patients with non-squamous NSCLC or cisplatin-eligible UC.  The study 
design is illustrated in Figure 1.
Figure 1.
Group A (Avelumab plus Chemotherapy)
Refer to Section 3.1- Phase 1b Lead-in and Phase 2 Cohort Expansion. 
C
CI


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3.3. Dose-Limiting Toxicity Definition
Severity of adverse events will be graded according to CTCAE version 4.03.  Any of the 
following AEs occurring in the first 2 cycles (cycle duration with no delays is 21 days) of 
treatment during the Phase 1b lead-in of each cohort that are attributable to one or more of 
the investigational products will be classified as DLTs:
Hematologic:

Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 109/L) 
lasting >7 days;

Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of
>38.3 degrees C (>101 degrees F) or a sustained temperature of 38 degrees C
(100.4 degrees F) for more than 1 hour;

Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection);

Grade 3 thrombocytopenia (platelet count <50,000 - 25,000/mm3 or 
<50.0 –25.0 × 109/L) with bleeding;

Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L);

Grade 4 anemia (life-threatening consequences; urgent intervention indicated).
Non-Hematologic:

Grade 4 toxicities;

Grade 3 toxicities persisting for >3 days despite adequate medical management 
(eg, nausea, vomiting, and diarrhea) except for endocrinopathies controlled with 
hormonal therapy;

Potential Hy’s law cases defined as: ALT or AST >3 x the upper limit of normal 
(ULN) if normal at baseline OR ALT or AST doubling the baseline (if > ULN at 
baseline) associated with total bilirubin >2 x ULN and an alkaline phosphatase 
<2 x ULN;

In an asymptomatic patient, Grade 3 QTcF prolongation (QTcF 501) will first 
require repeat testing, re-evaluation by a qualified person, and correction of reversible 
causes, such as electrolyte abnormalities or hypoxia, for confirmation.  If, after 
correction of any reversible causes, the Grade 3 QTcF prolongation persists, then the 
event should be considered a DLT.
Non-Adherence to Treatment Schedule:

Delay of 3 weeks in receiving the next scheduled administration due to persisting 
treatment-related toxicities;


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
Failure to deliver at least 75% of the planned doses of each of the investigational 
products during the first 2 cycles due to treatment-related toxicities.
Grade 3 laboratory abnormalities without a clinical correlate and not requiring medical 
intervention DO NOT constitute a DLT.  Grade 3 laboratory abnormalities also have to 
represent a clinically relevant shift from baseline to be considered a DLT.
While the rules for adjudicating DLTs are specified above, an AE not listed above, or an AE 
meeting the DLT criteria above but occurring outside of the DLT observation period may be 
defined as a DLT after consultation between Sponsor and Investigator, based on the 
emerging safety profile for the combinations.
During the Phase 1b lead-in, patients who did not receive at least 75% of the planned doses 
of investigational products during the first 2 treatment cycles for reasons other than 
investigational products-related toxicity are not evaluable for DLT.  Additional patients will 
be enrolled in the specific cohort to replace those patients who are not considered DLT 
evaluable.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol. 
Eligibility criteria specific to each unique combination of avelumab and chemotherapy with 
or without other immunotherapies are indicated. 
4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
1. Histological diagnosis of locally advanced (primary or recurrent) or metastatic solid 
tumor that is not amenable for treatment with curative intent as follows: 

For all groups: 

Measurable disease by RECIST v1.1 with at least 1 measurable lesion;

No prior systemic treatment for unresectable locally advanced or metastatic
disease for the tumor type under study.  If prior systemic chemotherapy 
treatment was given in the adjuvant or neo-adjuvant setting or as part of 
radiotherapy-chemotherapy treatment, disease free interval after stop of 
systemic treatment must be more than 6 months for non-squamous NSCLC 
and more than 12 months for UC;


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
Availability of tumor specimens: A mandatory archived formalin-fixed, 
paraffin-embedded (FFPE) tumor tissue block sufficient in size to allow for 
sectioning of at least 10 slides must be available from the most recent primary 
or metastatic tumor biopsy or resection prior to start of study therapy.  The 
archived sample must have been taken within 18 months prior to enrollment, 
with no intervening systemic anti-cancer therapy.  If such an archived sample 
is not available, a de novo (ie, fresh) tumor sample must be obtained prior to 
enrollment.  If blocks cannot be provided, then at least 10, but preferably 15, 
freshly prepared slides must be provided.  Core needle or excision biopsies are 
required. If a patient has only one measurable (target) lesion and no suitable 
archived tumor tissue to serve as a baseline sample, then that one measurable 
(target) lesion should not be biopsied and that patient is not eligible for 
enrollment.

For Group A:

Non-squamous NSCLC, with no activating EGFR mutations, ALK or 
ROS1 translocations/rearrangements.  If monotherapy pembrolizumab is 
available as a standard of care treatment option, patients must have a tumor 
proportion score (TPS) <50% for PD-L1 (via the 22C3 pharmDx or the 
Ventana (SP263) PD-L1 IHC assay);

Transitional cell carcinoma of the urothelium including the bladder, urethra, 
renal pelvis, and ureter.
2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
3. Age 18 years (20 years in Japan).
4. Estimated life expectancy of at least 90 days.
5. Adequate hepatic function defined by a total bilirubin level 1.5 × ULN, an AST 
level 2.5 × ULN, and an ALT level 2.5 × ULN.
6. Adequate renal function defined by an estimated creatinine clearance 50 mL/min 
according to the Cockcroft-Gault formula or by 24 hour urine collection for creatinine 
clearance or according to local institutional standard method. 
7. Adequate bone marrow function including: ANC 1,500/mm3 or 1.5 × 109/L; 
platelets 100,000/mm3 or 100 × 109/L; hemoglobin 9 g/dL (may have been 
transfused).
8. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study. 


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9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
10. Pregnancy test (for females of childbearing potential) negative at screening.  Female 
patients of non-childbearing potential must meet at least 1 of the following criteria:
a.
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 with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy 
and/or bilateral salpingectomy; 
c.
Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are considered to
be of childbearing potential.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
anti-OX-40, anti-glucocorticoid induced tumor necrosis factor (TNF) receptor 
(GITR), anti-lymphocyte activation gene-3 (LAG-3), anti-T cell immunoglobulin and 
mucin (TIM-3) domain, or anti-cytotoxic T lymphocyte-associated protein 
4 (CTLA-4) antibody (including ipilimumab), IDO1 inhibitor, or any other antibody 
or drug specifically targeting T cell co-stimulation or immune checkpoint pathways.
2. Patients with known symptomatic central nervous system (CNS) metastases requiring 
steroids.  Patients with previously diagnosed CNS metastases are eligible if they have 
completed their treatment and have recovered from the acute effects of radiation 
therapy or surgery prior to enrollment, have discontinued corticosteroid treatment for 
these metastases for at least 14 days, and are neurologically stable. 
3. Diagnosis of any other malignancy within 2 years prior to enrollment.  Adequately 
treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder, 
breast, or cervix, or low grade (Gleason 6) prostate cancer on surveillance without 
any plans for treatment intervention (eg, surgery, radiation, or castration) are allowed.
4. Current use of immunosuppressive medication at the time of enrollment, EXCEPT for 
the following: a. intranasal, inhaled, topical steroids, or local steroid injection 
(eg, intra-articular injection); b. systemic corticosteroids at physiologic doses 
10 mg/day of prednisone or equivalent; c. steroids as premedication for 
hypersensitivity reactions.


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5. Active or prior autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or 
hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible. 
6. Prior organ transplantation including allogenic stem-cell transplantation. 
7. Active infection requiring systemic therapy. 
8. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome.
9. 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).
10. Vaccination within 4 weeks of the first dose of investigational product is prohibited 
except for administration of inactivated vaccines. 
11. Known prior severe hypersensitivity to the investigational products or any component 
in their formulations, including known severe hypersensitivity reactions to 
monoclonal antibodies (NCI CTCAE v4.03 Grade 3).
12. Known prior severe hypersensitivity to platinum-related compounds for all cohorts, to 
pemetrexed for patients enrolled in Cohorts A1 and A3, and to gemcitabine for 
patients enrolled in Cohorts A2 and A4 (NCI CTCAE v4.03 Grade 3).
13. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however 
alopecia, sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a 
safety risk based on Investigator's judgment are acceptable.
14. Known history of colitis, inflammatory bowel disease, pneumonitis, pulmonary 
fibrosis.
15. Ongoing cardiac dysrhythmias of NCI CTCAE v4.03 Grade 2 or prolongation of the 
QTcF interval to >480 msec. 
16. Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months 
prior to enrollment), unstable angina, congestive heart failure (New York Heart 
Association Classification Class II), or serious cardiac arrhythmia requiring 
medication.
17. Major surgery 28 days or major radiation therapy 14 days prior to enrollment.  
Prior palliative radiotherapy (10 fractions) to metastatic lesion(s) is permitted, 
provided it has been completed at least 48 hours prior to enrollment.


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18. Participation in other studies involving investigational drug(s) within 28 days prior to 
study entry.
19. Concurrent treatment with a prohibited medication listed in protocol Section 5.7.
20. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the patient inappropriate for entry into this 
study.
21. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the Investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
22. Pregnant female patients; breastfeeding female patients; fertile male patients and 
female patients of childbearing potential who are unwilling or unable to use at least 
1 highly effective methods of contraception as outlined in this protocol for the 
duration of the study and for at least 90 days after the last dose of chemotherapy (for 
male and female patients) or at least 30 days after the last dose of avelumab (for 
female patients), whichever is longer.
4.3. Lifestyle Guidelines
In this study, fertile male patients and female patients who are of childbearing potential will 
receive chemotherapy, which has been associated with suspected or demonstrated 
teratogenicity/fetotoxicity.  Patients will also receive avelumab and, in portions of the study 
to be added in the future, other anti-cancer immunotherapy, for which the teratogenic risk is 
not known.  For the UK and the Czech Republic: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and chemotherapy, in up to 4 tumor-specific 
cohorts, will be included.  Patients who are, in the opinion of the Investigator, sexually active 
and at risk for pregnancy with their partner(s) must agree to use at least 1 method of highly 
effective (failure rate <1% per year) contraception, preferably with low user dependency, 
throughout the study and for at least 90 days after the last dose of chemotherapy (for male 
and female patients) or at least 30 days after the last dose of avelumab (for female patients), 
whichever is longer.  The Investigator or his or her designee, in consultation with the patient, 
will confirm that the patient has selected at least 1 highly effective method of contraception, 
preferably with low user dependency, for the individual patient and his/her partner(s) from
the list of permitted contraception methods (see below) and will confirm that the patient has 
been instructed in the consistent and correct use of this contraceptive method.  At time points 
indicated in the Schedule of Activities, the Investigator or designee will inform the patient of 
the need to use at least 1 highly effective method of contraception consistently and correctly 
and document the conversation, and the patient’s affirmation, in the patient’s chart.  In 
addition, the Investigator or designee will instruct the patient to call immediately if the 


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selected contraception method is discontinued or if pregnancy is known or suspected in the 
patient or partner. 
Highly effective methods of contraception are those that, result in a failure rate of less than 
1% per year when used consistently and correctly (ie, perfect use) and include the following:
Highly Effective Methods That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion.

Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the women of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional highly effective 
method of contraception should be used.  The spermatogenesis cycle is 
approximately 90 days.
Highly Effective Methods That Are User Dependent 

Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

oral;

intravaginal;

transdermal;

injectable.

Progestogen-only hormone contraception associated with inhibition of ovulation:

oral;

injectable.

Sexual abstinence:


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
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
All sexually active male patients must agree to prevent potential transfer of and exposure of 
partner(s) to chemotherapy through ejaculate by using a condom consistently and correctly, 
beginning with the first dose of study treatments and continuing for at least 90 days after the 
last dose of chemotherapy or longer as required by local regulations.
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 on study-related medical 
questions or problems, patients are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study. The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS 
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).  
This is a study of avelumab in combination with chemotherapy with or without other 
immunotherapies.  The investigational products to be evaluated in this study are described in 
Table 5.
Avelumab 800 mg (Cohorts A1 and A2) or 1200 mg (Cohorts A3 and A4) fixed dose will be 
administered as a 1-hour (hr) intravenous (IV) infusion on Day 1 of each 21-day cycle.
Each chemotherapy doublet will be administered IV as shown below per local guidelines.


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Table 5.
Investigational Products
Investigational Product
Dose(s) and Schedule 
(21-day cycle)a,b
Cohorts
Tumor Type
Avelumabc
800 mg or 1200 mg, Day 1
IV over 60 minutes
All
All
Pemetrexed/Carboplatinc
A1, A3
Non-squamous 
NSCLC
Pemetrexed
500 mg/m2, Day 1
IV over 10 minutes
Carboplatin
AUC 5, Day 1
IV over 60 minutes
Gemcitabine/Cisplatin
A2, A4
UC
Gemcitabine
1000 mg/m2, Day 1 and Day 8
IV over 30 minutes
Cisplatin
70 mg/m2, Day1
IV over 60 minutes
AUC=area under the curve; IV=intravenously; NSCLC=non-small cell lung cancer; UC=urothelial cancer
a
Order of administration for agents in each chemotherapy doublet is as appears in the table.  For example, for 
the pemetrexed/carboplatin doublet, pemetrexed is administered prior to carboplatin. 
b
Durations of chemotherapy infusions shown are recommended.  Sites are advised to follow their local 
guidelines.
c
Avelumab dosed at 800 mg Q3W in Cohorts A1 and A2 and at 1200 mg Q3W in Cohorts A3 and A4.
5.1. Allocation to Treatment
Each combination will be evaluated in 2 study phases: a Phase 1b lead-in and a 
Phase 2 cohort expansion.
At the time that a patient has signed informed consent and entered screening, the site should 
contact the interactive response technology (IRT) system to obtain the patient identification 
number.  Once a patient has met all eligibility criteria and has been assigned to the 
appropriate cohort by the Sponsor study team or designee, patient enrollment and allocation 
of investigational product will be managed by the IRT system.  The site will need to contact 
the IRT system to enroll the patient and to obtain the study drug allocation information.  
Study treatment must be initiated preferably on the day of enrollment, but no later than 
3 days after enrollment.  See Schedule of Activities.  At the time of enrollment, site 
personnel (study coordinator or specified designee) will be required to enter into or select 
information from the IRT system including, but not limited to, the user’s identification (ID) 
and password, the protocol number, and the patient number.  The IRT system will then 
provide a treatment assignment and dispensable unit (DU) or vial or bottle number for each 
investigational product to be dispensed.  The IRT system will also provide a confirmation 
report containing the patient number and DU or vial or bottle numbers assigned. The 
confirmation report must be stored in the site’s files. 
There is a 24 hour a day, 365 days a year IRT helpdesk available for any questions or issues.  
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT system. 


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Enrollment into Cohort A1, A2, A3 and A4 will follow the sequential steps below:

Enroll and assess safety of the A1 and A2 Phase 1b lead-in cohorts;

Enroll and assess safety of the A3 and A4 Phase 1b lead-in cohorts;

Enroll Phase 2 cohort expansions (A1 or A3 for non-squamous NSCLC; A2 or A4 for 
cisplatin-eligible UC) provided investigational products administration in a given 
cohort is deemed safe in Phase 1b-lead in according to the criteria described in 
Section 3.1.
Patients are not allowed to crossover between the different cohorts evaluated in this study. 
5.2. Treatment Duration
For both Phase 1b lead-in and the Phase 2 cohort expansion, all patients will initially receive 
either avelumab in combination with chemotherapy (Group A) or avelumab in combination 
with chemotherapy and other anti-cancer immunotherapies in portions of the study to be 
added in the future.  Patients will continue to receive study treatment until disease 
progression is confirmed by the Investigator, patient refusal, unacceptable toxicity, or until 
the study is terminated by the Sponsor, whichever occurs first.  In Cohorts A1 and A3, 
treatment with carboplatin and pemetrexed will continue for a maximum of 4-6 cycles; in 
addition, maintenance therapy with pemetrexed may be administered at the discretion of the 
Investigator.  In Cohorts A2 and A4, treatment with chemotherapy will continue until 
optimal response is achieved.
If discontinuation of chemotherapy is required for any reasons other than PD or 
protocol-specified limits, treatment with avelumab (Group A) and/or the other anti-cancer 
therapies in future portions of the study should be continued. 
Patients who stop avelumab or the other anti-cancer immunotherapies in future portions of 
the study for unacceptable toxicity may continue treatment with the investigational 
product(s) (eg, chemotherapy) that is/are not considered to be responsible for the toxicity 
observed. 
For the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be 
included.
5.3. Patient Compliance
5.3.1. Avelumab and Chemotherapy
For each administration of avelumab and chemotherapy, the site will complete the required 
dosage Preparation Record located in the Investigational Product Manual.  The use of the 
Preparation Record is preferred, but it does not preclude the use of an existing appropriate 
clinical site documentation system.  The existing clinical site's documentation system should 
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This may be used in place of the Preparation Record after approval from the sponsor and/or 
designee. 
All doses of investigational products (avelumab and chemotherapy) will be by the 
appropriately designated study staff at the investigator site.
The information related to each trial drug administration, including the date, time, and dose 
of study drug, will be recorded on the electronic case report form (eCRF).  The Investigator 
will ensure that the information entered into the eCRF regarding drug administration is 
accurate for each patient.  Any reason for noncompliance should be documented.
Non-compliance is defined as a patient missing >1 infusion of any investigational product 
(avelumab or chemotherapy) for non-medical reasons.  If 1 infusion is missed and the 
interval between the subsequent infusion and the last administered treatment is longer than 
4 weeks for nonmedical reasons, the criteria of insufficient compliance will have been met as 
well. 
5.4. Investigational Product Supplies and Administration
Investigational products must not be used for any purpose other than the trial.  The 
administration of trial drug to patients who have not been enrolled into the trial is not covered 
by the trial insurance.
5.4.1. Avelumab
Avelumab will be supplied for the study by Pfizer Global Clinical Supply, Worldwide 
Research and Development.  Drug supplies will be shipped to the study sites with a Drug 
Shipment and Proof of Receipt form.  This form will be completed, filed, and the shipment 
confirmed as directed on the bottom of the Drug Shipment and Proof of Receipt form.  The 
Investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of 
investigational products in accordance with the protocol and any applicable laws and 
regulations.
5.4.1.1. Dosage Form and Packaging
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  It is 
presented with a nominal volume of 10 mL at a concentration of 20 mg/mL in single-use 
glass vials closed with a rubber stopper and sealed with an aluminum polypropylene flip off 
seal.  The vial is intended for single use only. 
Packaging and labeling of avelumab will be in accordance with applicable local regulatory 
requirements and applicable Good Manufacturing Practice (GMP) guidelines.  Avelumab 
will be packed in boxes each containing one vial.  The information on the study treatment 
will be in accordance with approved submission documents.
Avelumab will be shipped under refrigerated conditions (2C to 8C) that are monitored with 
temperature control monitoring devices.


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5.4.1.2. Preparation
For avelumab, please see the Investigational Product (IP) Manual for instructions on how to 
prepare the investigational products for administration.  The IV investigational products 
should be prepared and dispensed by an appropriately qualified and experienced member of 
the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance, as 
well as trained in the procedures specified in this protocol. 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of hazardous agents.
Any spills that occur should be cleaned up using the facility’s standard cleanup procedures 
for biologic products.
Detailed information on infusion bags and medical devices to be used for the preparation of 
the dilutions and subsequent administration(s) for avelumab will be provided in the IP 
Manual. 
Any unused portion of the diluted avelumab solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and national standards of incineration.
5.4.1.3. Administration
Avelumab will be administered by IV infusion at the investigational site on an outpatient 
basis.
Avelumab will be administered as an 800 mg fixed dose via a 1-hour (-10/+20 minutes) 
IV infusion Q3W on Day 1 of each 3-week (21-day) cycle.  Following each infusion of 
avelumab, patients must be observed for 30 minutes post-infusion for potential infusion 
related reactions.  Patients should be instructed to report any delayed reactions to the 
Investigator immediately.
In order to mitigate avelumab infusion-related reactions, patients must be premedicated 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab.  Premedication 
should be administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity of prior infusion reactions.  Premedication will include an antihistamine 
(for example, 25-50 mg diphenhydramine IV or oral equivalent), and paracetamol 
(acetaminophen) (eg, 500-650 mg IV or oral equivalent).  This regimen may be modified 
based on local treatment standards and guidelines, as appropriate, provided it does not 
include systemic corticosteroids.  On visits when both chemotherapy and avelumab are 
infused, avelumab will be infused after chemotherapy.  If premedication for avelumab was 
administered prior to chemotherapy, the decision whether to repeat premedication prior to 
avelumab is at the discretion of the Investigator depending on the elapsed time and the 
half-life of corresponding premedication agent.


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5.4.2. Chemotherapies
All chemotherapy agents (carboplatin, cisplatin, gemcitabine, and pemetrexed) will be 
supplied for the study by Pfizer Global Clinical Supply, Worldwide Research and 
Development.  The use of drug(s) or combination of drugs in this protocol meets the criteria 
described under Title 21 Code of Federal Regulations (CFR) 312.2(b) for Investigational 
New Drug (IND) exemption.
5.4.2.1. Dosage and Administration
For both the Phase 1b lead-in and Phase 2 cohort expansion, all patients will initially receive 
chemotherapy in combination with avelumab (Group A) or, in future portions of the study,  
chemotherapy in combination with avelumab and other anti-cancer immunotherapies until 
discontinuation of chemotherapy is required for any reason other than PD or 
protocol-specified limits.  If discontinuation of chemotherapy is required for any reasons 
other than PD or protocol-specified limits, treatment with avelumab (Group A) or avelumab 
and/or the other anti-cancer immunotherapies in future portions of the study should be 
continued.  For the UK and the Czech Republic: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and chemotherapy, in up to 4 tumor-specific 
cohorts, will be included.
For each chemotherapeutic agent, refer to the IP manual for preparation and administration 
instructions.  Additional details for calculation of carboplatin dose based on the 
Calvert40 formula can be found in Appendix 4. 
For each chemotherapeutic agent, with the exception of pemetrexed, sites should follow local 
guidelines for specific pretreatments.  For pemetrexed, the following premedications should 
be administered, as noted in the United States Prescribing Information, unless differently 
required by local guidelines:41

Folic acid (400 – 1000 g) orally once daily beginning 7 days prior to the first dose of 
pemetrexed and continuing daily through and including 21 days after the last dose of 
pemetrexed.

Vitamin B12 (1 mg) intramuscularly beginning 1 week prior to the first dose of 
pemetrexed and every 3 cycles subsequently.

Dexamethasone (4 mg) orally twice daily on the day before, the day of, and the day 
after each pemetrexed infusion.
All patients receiving chemotherapy should be weighed within 3 days of Day 1 prior to 
dosing for every cycle to ensure they did not experience either a weight loss or gain of 
>10% from the weight used for the last dose calculation.  For weight change 10% the 
decision to recalculate the chemotherapy doses can be in accordance with institutional 
practice.  If the patient experienced either a weight loss or gain >10% compared to the weight 
used for the last dose calculation, the amount of study drug must be recalculated.


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5.4.3. Timing of Investigational Product Administrations
In Group A, chemotherapy is administered prior to avelumab. The avelumab infusion is to 
be administered after the end of the infusion of the last chemotherapy agent. 
For patients participating in the serial PK collection for chemotherapy on Cycle 2, 
chemotherapy and avelumab infusions are recommended to be performed as described in 
Table 2 and Table 4 on Cycle 2 Day 1, for ease of compliance with the protocol-defined PK 
blood and Electrocardiogram (ECG) collection times in relation to dosing of the three agents. 
Premedications for chemotherapy agents should be administered as described in 
Section 5.4.2.1.  When chemotherapy and avelumab are to be administered on the same day 
and premedication for avelumab was administered prior to chemotherapy, the decision 
whether to repeat premedication prior to avelumab infusion is at the discretion of the 
Investigator depending on the elapsed time and the half-life of corresponding premedication 
agent.
The infusion line should be flushed, according to local practice, between infusions, and a 
new administration set should be used for avelumab.
The exact duration of each infusion should be recorded in both source documents and case 
report forms (CRFs). Dose reduction for toxicity management for avelumab is not 
permitted; however, next cycle administration of avelumab may be omitted or delayed due to 
persisting toxicity as described in Table 7 and Section 5.4.4.4.
On days when PK samples are taken, samples for each respective agent will be taken at the 
time relative to dosing of that specific agent as described in the Schedule of Activities tables.
5.4.4. Recommended Dose Modifications 
Every effort should be made to administer study treatment on the planned dose and schedule. 
In the event of multiple toxicities, treatment/dose modifications should be based on the worst 
toxicity observed.  Patients are to be instructed to notify Investigators at the first occurrence 
of any adverse symptom.  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. 
Treatment/Dose modifications may occur independently for each drug in the combination 
based on the observed toxicity and the guidance provided below.  All dose modifications 
must be clearly documented in the patient's notes and in the CRF.
Dose reductions are only allowed for chemotherapy (carboplatin, cisplatin, gemcitabine, and 
pemetrexed).  No dose reductions are allowed for avelumab.  Intra-patient dose escalation is
not allowed for any of the study drugs at any time.


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In the event that it becomes necessary to stop dosing with one or both of the two 
chemotherapeutic drugs in the combination, the patient should remain in the study and 
avelumab (Group A) may be continued uninterrupted at the Investigator’s discretion.
In the event that it is necessary to permanently discontinue treatment with avelumab 
(Group A), the patient may continue to receive chemotherapy at Investigator’s discretion.
5.4.4.1. Guidelines for Chemotherapy Toxicity Management
Dose modification (dose delays and dose reductions) for chemotherapy (carboplatin, 
cisplatin, gemcitabine, and pemetrexed) due to adverse drug reactions should be made in 
accordance with the guidance provided below, product labeling, and institutional guidelines.
Starting doses for each chemotherapeutic agent and dose reduction levels are described in 
Table 6.
For any adverse event of NCI CTCAE v4.03 Grade 3 and Grade 4 severity not covered in the 
following sections and considered at least possibly related to chemotherapy, treatment should 
be withheld until recovery to Grade 1 and then, at Investigator’s discretion, the 
chemotherapy treatment should be permanently discontinued or dose should be reduced by 
one dose level as described in Table 6.  If more than 2 dose reductions for one chemotherapy 
agent are necessary, the patient should discontinue from that chemotherapy agent.  Treatment 
with avelumab (Group A) should be discontinued according to Section 5.4.4.4.
5.4.4.2. Dose Delays: All Investigational Products
Retreatment may not occur until all of the following parameters have been met:

ANC is 1.0 x 109/L; 

Platelet count is 75 x 109/L (when gemcitabine or cisplatin is used the platelet count 
is 100 x 109/L);  

Calculated creatinine clearance as determined prior to each administration of study 
drug is at least 50 mL/min according to institutional standard practices (when 
pemetrexed or cisplatin are included in the chemotherapy regimen). For patients 
receiving cisplatin, if calculated creatinine clearance is 40 and <50 mL/min, 
treatment with cisplatin may continue, but cisplatin dose must be reduced by 
50% from previous dose.  For a given patient, the same method of creatinine 
clearance calculation should be used at each assessment.
All study drugs (including avelumab) will be delayed until the above criteria are met. 


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5.4.4.3. Dose Reductions: Chemotherapy
For chemotherapy (carboplatin, cisplatin, gemcitabine, or pemetrexed) the dose may need to 
be reduced when treatment is resumed based on the worst toxicity experienced in the 
previous cycle.  Dose reductions may be independent for each drug in the combination based 
on the toxicity and the specific drug management recommendations.  Once a dose has been 
reduced for a given patient, all subsequent cycles should be administered at that dose level, 
unless further dose reduction is required.  Intra-patient dose escalation is not allowed for any 
of the study drugs at any time.  Dose reduction criteria are described below (Table 6) for each 
chemotherapy drug administered in this study. 
Table 6.
Dose Modification Levels for Chemotherapy (Cisplatin, Carboplatin, 
Pemetrexed, and Gemcitabine)
Drug
Starting Dose
Dose Level -1
Dose Level -2
Reduce to 75% of 
starting dose.
Reduce to 50% of starting 
dose.
Gemcitabine
1000 mg/m2
Pemetrexed
500 mg/m2
Carboplatin
AUC 5 
Cisplatin
70 mg/m2
5.4.4.4. Dose Modifications for Avelumab 
For avelumab, no dose reductions are permitted in this study, but the next avelumab infusion 
may be omitted or delayed based on persisting toxicity.
Recommended treatment modifications for avelumab due to drug-related toxicity are shown 
in Table 7. 


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Table 7.
Avelumab Treatment Modifications for Drug-Related Toxicity
NCI CTCAE 
Severity Grade
Avelumab 
Treatment Modification
Infusion-related Reaction / 
Hypersensitivity
Grade 1-4
See Section 5.4.4.5 and Table 8.
Immune-related AE (irAE)
Grade 1-4
See Section 5.4.4.6 and Table 9.
Drug-related adverse reactions
(excluding infusion-related reaction / 
hypersensitivity and immune-related 
AE)
Grade 1
Continue as per schedule.
Grade 2
Continue as per schedule.
Grade 3

Withhold. 

Re-initiate once toxicity is Grade 1 or baseline.

Permanently discontinue if toxicities do not resolve 
to Grade 1 or baseline within 12 weeks or if the 
same Grade 3 toxicity recurs (consider consult with 
the medical monitor before permanently 
discontinuing the treatment).
Exceptions are:

Laboratory values that do not have any clinical 
correlate.
Grade 4

Permanently discontinue avelumab. 
Exceptions are:

Laboratory values that do not have any clinical 
correlate.  
Avelumab infusion-related reactions, hypersensitivity reactions (Grades 1 to 4) and irAEs 
should be handled according to guidelines in Section 5.4.4.5 and Section 5.4.4.6.
5.4.4.5. Avelumab: Infusion-Related Reactions/Hypersensitivity Reactions
5.4.4.5.1. Special Precautions for Avelumab Administration
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.
In order to mitigate avelumab IRRs, patients have to be premedicated approximately 30 to 
60 minutes prior to the first 4 infusions of avelumab.  Premedication should be administered 
for subsequent avelumab doses based upon clinical judgment and presence/severity of prior 
infusion reactions.  Premedication will include an antihistamine (for example, 25-50 mg 
diphenhydramine IV or oral equivalent), and paracetamol (acetaminophen) (eg, 500-650 mg
paracetamol [acetaminophen] IV or oral equivalent).  This regimen may be modified based 
on local treatment standards and guidelines, as appropriate provided it does not include 
systemic corticosteroids. 


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On visits when both chemotherapy and avelumab are infused, avelumab will be infused after 
chemotherapy.  If premedication for avelumab was administered prior to chemotherapy, the 
decision whether to repeat pre medication prior to avelumab is at the discretion of the 
Investigator depending on the elapsed time and the half-life of corresponding premedication 
agent. 
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice 
Following the infusions of avelumab, patients must be observed for 30 minutes post- infusion 
for potential IRRs.  Patients should be instructed to report any delayed reactions to the 
Investigator immediately.
Symptoms of avelumab IRRs include but are not limited to fever, chills, flushing, 
hypotension, dyspnea wheezing, back pain, abdominal pain, and urticaria.  Management of 
avelumab infusion reactions is described in Table 8.


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Table 8.
Treatment Modification for Symptoms of Avelumab Infusion-Related 
Reactions
NCI CTCAE Grade 
Treatment Modifications
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.

Decrease the investigational product 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, IV fluids); prophylactic 
medications indicated for 24 hours.

Temporarily discontinue 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 recurrence or 
worsening.
Grade 3 or Grade 4 – severe or life-threatening

Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
clinical sequelae.

Grade 4: Life-threatening consequences; urgent 
intervention indicated.

Stop the avelumab infusion immediately and 
disconnect infusion tubing from the patient.

Patients must be withdrawn immediately 
from avelumab treatment and must not 
receive any further avelumab treatment.
* If avelumab infusion rate has been decreased by 50% or interrupted due to an infusion reaction, it must 
remain decreased for the next scheduled infusion.  If no infusion reaction is observed in the next scheduled 
infusion, the infusion rate may be returned to baseline at the subsequent infusions.
IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
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 8 (including reducing the infusion 
rate by 50%), the Investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed.  At the next dose, the Investigator may consider the addition of 
H2-blocker antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofen to the 
mandatory premedication.  Prophylactic steroids are NOT permitted. 
5.4.4.6. Avelumab: Immune-Related Adverse Events Toxicity Management 
Treatment of irAEs is mainly dependent upon severity (NCI CTCAE grade v4.03):

Grade 1 or 2: treat symptomatically or with moderate-dose steroids, more frequent 
monitoring;

Grade 1 or 2 (persistent): manage similar to Grade 3 to 4 AE;

Grade 3 or 4: treat with high-dose corticosteroids.


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For patients receiving avelumab, any AE suspected to be immune-related (irAE) should be 
managed according to the guidance for management of irAEs (Table 9).  For 
Grade 3 suspected immune-related toxicities, chemotherapy may also be placed on hold 
until the irAE resolved to Grade 1, based on the Investigator’s medical judgment. 
Table 9.
Management of Immune-Related Adverse Events 
Gastrointestinal irAEs
Grade 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 patient 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 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

Withhold  avelumab for 
Grade 3

Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3

1.0 to 2.0 mg/kg/day IV 
prednisone 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 following 
steroids taper (for initial Grade 3)

If worsens, persists >3 to 5 days, or 
recurs after improvement:

Add infliximab 5 mg/kg (if no 
contraindication).  Note: Infliximab 
should not be used in cases of 
perforation or sepsis


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Table 9.
Management of Immune-Related Adverse Events 
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 
(eg, antihistamines, topical 
steroids) 

If Grade 2 persists >1 to 2 weeks or 
recurs: 

Withhold avelumab therapy

Consider skin biopsy 

Consider 0.5 to 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 of 
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


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Table 9.
Management of Immune-Related Adverse Events 
prednisone or equivalent 

Add prophylactic antibiotics 
for opportunistic infections

Consider bronchoscopy, lung 
biopsy 

If not improving after 2 weeks or 
worsening: 

Treat as Grade 3 to 4
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4: Life-threatening 

Permanently discontinue 
avelumab therapy

Hospitalize 

Pulmonary and Infectious 
Disease consults

1.0 to 2.0 mg/kg/day 
prednisone or equivalent 

Add prophylactic antibiotics 
for opportunistic infections 

Consider bronchoscopy, lung 
biopsy 

If improves Grade 1: 

Taper steroids over at least 
1 month

If not improving after 48 hours or 
worsening: 

Add additional immunosuppression 
(eg, infliximab, cyclophosphamide, 
intravenous immunoglobulin, or 
mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Function Tests 
(LFT) 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 elevations persist >5 to 7 days or 
worsen: 

Treat as Grade 3 or Grade 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 returns to Grade 1: 

Taper steroids over at least 
1 month 

If does not improve in >3 to 5 days, 
worsens or rebounds: 

Add mycophenolate mofetil 1 gram 
(g) twice daily 

If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines 


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Table 9.
Management of Immune-Related Adverse Events 
if clinically warranted
Renal irAEs
Grade of Creatinine Increased
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased >ULN–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*

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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Table 9.
Management of Immune-Related Adverse Events 

Consider myocardial biopsy if 
recommended per cardiology 
consult
Immune-mediated myocarditis

Permanently discontinue 
avelumab therapy

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
Management
Follow-up
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 

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


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Table 9.
Management of Immune-Related Adverse Events 
appropriate 

Rule-out secondary 
endocrinopathies 
(ie, hypopituitarism / 
hypophysitis)
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)

If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (ie, subnormal 
serum FT4 with 
inappropriately low TSH 
and/or low serum cortisol with 
inappropriately low ACTH):

Refer to endocrinologist 
for dynamic testing as 
indicated and 
measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women) 

Hormone replacement/ 
suppressive therapy as 
appropriate 

Perform pituitary MRI 
and visual field 
examination as indicated

If hypophysitis confirmed:

Continue avelumab if 
mild or moderate 
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 prednisolone 
or equivalent) followed 
by corticosteroids taper 
during at least 1 month

Add prophylactic 
antibiotics for 
opportunistic infections

Resume avelumab once symptoms and 
hormone tests improve to Grade 1 
(with or without hormone replacement)

In addition, for hypophysitis with 
abnormal MRI, resume avelumab only 
once shrinkage of the pituitary gland on 
MRI/CT scan is documented 

Continue hormone 
replacement/suppression therapy as 
appropriate
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management


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Table 9.
Management of Immune-Related Adverse Events 
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 resuming avelumab 
therapy

If irAE is confirmed, treated 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 investigational 
products therapy following steroids 
taper
Recurrence of same Grade 3 irAE 

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 
immunosuppressants 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
ACTH=adrenocorticotropic hormone, ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate 
aminotransferase, BNP=B-type natriuretic peptide, CK-MB=creatine kinase muscle and brain units, 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=free 
thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of normal.


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5.4.4.7. Recommended Treatment Modifications for Pemetrexed, Carboplatin, 
Avelumab (Cohorts A1 and A3) 
5.4.4.7.1. Hematological Toxicities 
In the event of hematologic toxicities, treatment may be delayed to allow sufficient time for 
recovery, as described above. If patients develop hematologic toxicities Grade 3, therapy 
should be withheld until ANC is 1.0 x 109/L and platelet count is 75 x 109/L, or values 
returned to baseline levels.  Upon recovery, dose adjustments for the chemotherapy at the 
start of a subsequent cycle should be based on nadir hematologic counts from the preceding 
cycle of therapy. Dose modification (dose delays and dose change) for pemetrexed and 
carboplatin due to adverse drug reactions should be made in accordance with the guidance 
provided below (Table 10), product labeling, and institutional guidelines.
Table 10.
Pemetrexed, Carboplatin, Avelumab (Cohorts A1 and A3) Hematologic 
Toxicity Management
Hematologic Toxicity 
Pemetrexed
Carboplatin
Avelumab
Grade 1 and Grade 2
Continue at the same dose 
level.
Continue at the same dose 
level.
Continue as per schedule
Grade 3 and 4
Delay dosing until 

ANC 1.0 x 109/L 
and 

platelets 75 x 109/L.
Once blood counts have 
improved, pemetrexed can 
be reinitiated at the same 
dose level: 
Exception are:

Platelet Grade 3: 
Reduce to 75% of 
previous dose

Platelet Grade 3 with 
bleeding: Reduce to 
50% of previous dose

ANC Grade 4: 
Reduce to 75% of 
previous dose.
Delay dosing until 

ANC 1.0 x 109/L 
and 

platelets 75 x 109/L.
Once blood counts have 
improved, carboplatin can 
be reinitiated at the same 
dose level: 
Exception are:

Platelet Grade 3: 
Reduce to 75% of 
previous dose.

ANC Grade 4: 
Reduce to 75% of 
previous dose.
Delay dosing until 

ANC 1.0 x 109/L 
and 

platelets 75 x 
109/L.
then resume avelumab at 
the same dose level.
Note: hematological growth factors for neutropenia or anemia are allowed
5.4.4.7.2. Non-Hematological Toxicities 
In the event of non-hematologic toxicities, treatment may be delayed to allow sufficient time 
for recovery.  If patients develop non-hematologic toxicities Grade 3 (excluding 
neurotoxicity), therapy should be withheld until toxicity is Grade 1 or baseline.  Upon 
recovery, dose adjustments at the start of a subsequent cycle should be based on the 
maximum non-hematologic toxicity from the preceding cycle of therapy. Dose modification 
(dose delays and dose change) for pemetrexed and carboplatin due to adverse drug reactions
should be made in accordance with the guidance provided below (Table 11), product labeling 
and institutional guidelines.


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For patients receiving avelumab, any adverse event suspected to be immune-related (irAE) 
should be managed according to the guidance for management of irAEs (Section 5.4.4.6, 
Table 9).  For Grade 3 suspected immune-related toxicities or events requiring systemic 
corticosteroids/immunosuppressant, chemotherapy may also be placed on hold until the irAE 
resolved to Grade 1, based on Investigator’s medical judgment. 
Guidelines for the management of avelumab infusion-related reactions and hypersensitivity 
reaction are outlined in Section 5.4.4.5 and Table 8.
If there is a hypersensitivity reaction to carboplatin or pemetrexed, then this should be 
managed as per local institutional protocols.  In the case of recurrent hypersensitivity 
reactions, despite adequate premedication, the drug (carboplatin or pemetrexed) may be 
discontinued at the discretion of the treating physician, and the patient may continue on 
treatment with single chemotherapeutic agent (either carboplatin or pemetrexed) in 
combination with avelumab.
Table 11.
Pemetrexed, Carboplatin, Avelumab (Cohorts A1 and A3) Non-Hematologic 
Toxicity Management
Toxicity
Pemetrexed
Carboplatin
Avelumab
Adverse events with 
potential 
immune-related 
etiology (see 
Section 5.4.4.6) 
Continue for Grade 1/2 events
Pemetrexed may be placed on 
hold for events Grade 3 or 
events requiring corticosteroids / 
immunosuppressant, until the 
event resolves to Grade 1 based 
on Investigator’s medical 
judgment and after discussion
with the Sponsor
Continue for Grade 1/2 events
Carboplatin may be placed on 
hold for events Grade 3 or 
events requiring corticosteroids / 
immunosuppressant, until the 
event resolves to Grade 1 based 
on Investigator’s medical 
judgment and after discussion 
with the Sponsor
See Section 5.4.4.6
and Table 9
Neurotoxicity
Grade 1/2: continue at the same 
dose.
Grade 3: permanently 
discontinue
Grade 1: continue at the same 
dose
Grade 2: reduce to 50%
Grade 3/4: permanently 
discontinue 
See Section 5.4.4.4
and Table 7
Mucositis
Grade 1/2: continue at the same 
dose 
Grade 3: delay until recovery to 
Grade 1 and then resume at 
50%  of previous dose
Grade 1/2: continue at the same 
dose 
Grade 3: delay until recovery to 
Grade 1 and then resume at the 
same dose 
See Section 5.4.4.4
and Table 7
Diarrhea
Grade 1/2: continue at the same 
dose 
Grade 3 or any grade requiring 
hospitalization: delay until 
recovery to Grade 1 and then 
resume at 75% of previous dose
Grade 1/2: continue at the same 
dose 
Grade 3: delay until recovery to 
Grade 1 and then resume at 
75% of previous dose
See 
Section 5.4.4.6 and 
Table 9
IRR and 
Hypersensitivity
See Section 5.4.4.7.2.
See Section 5.4.4.7.2.
See Section 5.4.4.5
and Table 8


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Toxicity
Pemetrexed
Carboplatin
Avelumab
Other 
Non-hematologic 
Toxicity
Grade 1/2: continue at the same 
dose 
Grade 3: at Investigator 
discretion’s delay until recovery 
to Grade 1 and then resume at 
75% of the previous dose or 
permanently discontinue
Exceptions are:
Laboratory values that do not 
have any clinical correlate.  
Grade 1/2: continue at the same 
dose 
Grade 3: at Investigator 
discretion’s delay until recovery 
to Grade 1 and then resume at 
75% of the previous dose or 
permanently discontinue
Exceptions are:
Laboratory values that do not 
have any clinical correlate.  
See Section 5.4.4.4
and Table 7
5.4.4.8. Recommended Treatment Modifications for Cisplatin, Gemcitabine, Avelumab 
(Cohorts A2 and A4) 
5.4.4.8.1. Hematologic Toxicities
In the event of hematologic toxicities, treatment may be delayed to allow sufficient time for 
recovery, as described above.  If patients develop hematologic toxicities Grade 3, therapy 
should be withheld until ANC is 1.0 x 109/L and platelet count is 100 x 109/L for cisplatin 
dosing, or values returned to baseline levels.  Upon recovery, dose adjustments at the 
subsequent dose should be based on nadir hematologic counts from the preceding dose of 
therapy. Dose modification (dose delays and dose change) for cisplatin and gemcitabine due 
to adverse drug reactions should be made in accordance with the guidance provided below 
(Table 12), product labeling and institutional guidelines.
Table 12.
Cisplatin, Gemcitabine, Avelumab (Cohorts A2 and A4) Hematologic 
Toxicity Management
Hematologic Toxicity 
Cisplatin
Gemcitabine
Avelumab
Grade 1 and Grade 2 
Continue at the same dose 
level.
Exception is: 

Platelets <100 x 109/L: 
delay dosing until 
platelets 100 x 109/L 
and then resume 
cisplatin at 75% of the 
previous dose
Continue at the same dose.
Exception is:

Platelet <100 x 109/L: 
delay dosing until 
platelets 100 x 109/L 
and then resume 
gemcitabine at 75% of 
the previous dose.
Continue as per schedule
Grade 3 and 4
Delay dosing until 

ANC 1.0 x 109/L and

platelets 100 x 109/L.
Once blood counts have 
improved, cisplatin can be 
reinitiated at 75% of the 
previous dose level 
Delay dosing until 

ANC 1.0 x 109/L and

platelets 100 x 109/L.
Once blood counts have 
improved, gemcitabine can be 
reinitiated at the same dose 
level.
Delay until 

ANC is 1.0 x 109/L 
and 

Platelet count is 
75 x 109/L
Then resume avelumab at 
the same dose level.
Note: hematological growth factors for neutropenia or anemia are allowed.


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5.4.4.8.2. Non-Hematologic Toxicities 
In the event of non-hematologic toxicities, treatment may be delayed to allow sufficient time 
for recovery, as described above.  If patients develop non-hematologic toxicities 
Grade 3 therapy should be withheld until toxicity is Grade 1 or baseline.  Upon recovery, 
dose adjustments at the subsequent dose should be based on the maximum non-hematologic 
toxicity from the preceding dose of therapy. Dose modification (dose delays and dose 
change) for cisplatin and gemcitabine due to adverse drug reactions should be made in 
accordance with the guidance provided below (Table 13), product labeling and institutional 
guidelines.
For patients receiving avelumab, any adverse event suspected to be immune-related (irAE) 
should be managed according to the guidance for management of irAEs (Section 5.4.4.6, 
Table 9).  For Grade 3 suspected immune-related toxicities or events requiring 
corticosteroids/immunosuppressant, chemotherapy may also be placed on hold until the irAE 
resolved to Grade 1, based on Investigator’s medical judgment. 
Guidelines for the management of avelumab infusion-related reactions and hypersensitivity 
reaction are outlined in Section 5.4.4.5 and in Table 8.
If there is a hypersensitivity reaction to cisplatin or gemcitabine, then this should be managed 
as per local institutional protocols.  In the case of recurrent hypersensitivity reactions, despite 
adequate premedication, the drug (cisplatin or gemcitabine) may be discontinued at the 
discretion of the treating physician, and the patient may continue on treatment with single 
chemotherapeutic agent (either cisplatin or gemcitabine) in combination with avelumab. 


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Table 13.
Cisplatin, Gemcitabine, Avelumab (Cohorts A2 and A4) Non-Hematologic 
Toxicity Management
Toxicity
Cisplatin
Gemcitabine
Avelumab
Adverse events with 
potential immune-related 
etiology (see 
Section 5.4.4.6) 
Continue for Grade 
1/2 events
Cisplatin may be placed on 
hold for events Grade 3 or 
events requiring 
corticosteroids / 
immunosuppressant, until 
the event resolves to 
Grade 1 based on 
Investigator’s medical 
judgment and after 
discussion with the Sponsor
Continue for Grade 
1/2 events
Gemcitabine may be placed 
on hold for events Grade 3
or events requiring 
corticosteroids / 
immunosuppressant, until 
the event resolves to 
Grade 1 based on 
Investigator’s medical 
judgment and after 
discussion with the Sponsor
See Section 5.4.4.6. and 
Table 9
Neurotoxicity
Peripheralneurotoxicity

Grade 2: reduce to 
75% of the previous 
dose 

Grade 3: delay until 
recovery to Grade 1
and then resume at 
75% of the previous 
dose or permanently 
discontinue
Ototoxicitya

Grade 2 clinical 
hearing loss: reduce to 
75% of previous dose.

Grade 3: delay until 
recovery to Grade 
1 and then resume at 
75% of the previous 
dose or permanently 
discontinue
No dose reductions are 
needed. Dose reduction 
may be reduced at 
Investigator’s discretion. 
See Section 5.4.4.4 and 
Table 7


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Table 13
Cisplatin, Gemcitabine, Avelumab (Cohorts A2 and A4) Non-Hematologic 
Toxicity Management (continued)
Toxicity
Cisplatin
Gemcitabine
Avelumab
Gastrointestinal toxicity 
(nausea or vomiting)
Grade 3 nausea or vomiting
despite optimal antiemetic
prophylaxis and therapy: 
delay until recovery to 
Grade 1 and then resume at 
same dose or at 75% of the 
previous dose
Grade 4 vomiting despite 
optimal antiemetic 
prophylaxis and therapy:
delay until recovery to 
Grade 1 and then resume at 
50% of the previous dose
Grade 3 nausea or 
vomiting despite optimal 
antiemetic prophylaxis and 
therapy: delay until 
recovery to Grade 1 and 
then resume at same dose 
or at 75% of the previous 
dose
See Section 5.4.4.4 and 
Table 7
Hepatotoxicity 
Grade 3: delay until recovery 
to Grade 1 and then resume 
at 75% of the previous dose 
Grade 4: delay until recovery 
to Grade 1 and then resume 
at 75% of the previous dose 
or permanently discontinue
Grade 3: permanently 
discontinue 
See Section 5.4.4.6 and 
Table 9
IRR and Hypersensitivity
See Section 5.4.4.8.2.
See Section 5.4.4.8.2
See Section 5.4.4.5 and 
Table 8
Unexplained dyspnea or 
other evidence of severe 
pulmonary toxicity
Grade 3: delay until 
recovery to Grade 1 and 
then resume at 75% of the 
previous dose or 
permanently discontinue
Permanently discontinue
See Section 5.4.4.6 and 
Table 9
Renal toxicities
Serum creatinine >1.5 mg/dL 
AND creatinine clearance 
<40 mL/min, delay until:

Serum creatinine is 
<1.5 mg/dL OR

Creatinine clearance is 
50 mL/min and 
Then resume at 50% of the 
previous dose
Serum creatinine >1.5 mg/dL 
AND creatinine clearance 
40 mL/min to <50 mL/min, 
continue dosing but reduce 
dose to 50% of previous 
dose
Grade 3: delay until 
recovery to Grade 1 and 
then resume at same dose 
or at 75% of the previous 
dose
See Section 5.4.4.6. and 
Table 9


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Table 13
Cisplatin, Gemcitabine, Avelumab (Cohorts A2 and A4) Non-Hematologic 
Toxicity Management (continued)
Toxicity
Cisplatin
Gemcitabine
Avelumab
Other Non- hematologic 
Toxicity
Grade 1/2: continue at the 
same dose
Grade 3: at Investigator’s 
discretion delay until 
recovery to Grade 1 and 
then resume at 75% of the 
previous dose or 
permanently discontinue
Exceptions are:
Laboratory values that do not 
have any clinical correlate.  
Grade 1/2: continue at the 
same dose 
PermanentlyDiscontinue in 
case of: 

Hemolytic-uremic 
syndrome

Capillary leak 
syndrome

Posterior reversible 
encephalopathy 
syndrome
For other toxicity: 

Grade 3: at 
Investigator’s 
discretion delay until 
recovery to Grade 1 
and then resume at 
50% of the previous 
dose or permanently 
discontinue
Exceptions are:
Laboratory values that do 
not have any clinical 
correlate.  
See Section 5.4.4.4 and 
Table 7
a.
Audiograms should be performed before starting treatment with cisplatin and then repeated as per local 
practice.
5.4.5. Treatment after Initial Evidence of Radiological 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 cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiologic imaging shows disease progression, patients may continue to receive avelumab 
(Group A) or, in portions of the study to be added in the future, avelumab plus other
anti-cancer immunotherapies until the next scheduled tumor assessment if they are clinically 
stable. If chemotherapy dosing was ongoing at the time of PD determination, chemotherapy 
dosing should be discontinued until results of the next scheduled tumor assessment are 
available. Patients must meet the following criteria in order to be classified as clinically 
stable:

Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression; 


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
No decline in ECOG performance status; 

Absence of rapid progression of disease by radiographic imaging; 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention.
For the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be 
included.
Patients who are deemed clinically unstable should be withdrawn from study treatment and 
should enter the follow-up portion of the study. 
If repeat imaging no longer shows PD but rather CR, PR or SD compared to the baseline 
scan, treatment with avelumab may be continued in Group A or with avelumab and other 
anti-cancer immunotherapies in future versions of the study.  In addition, treatment with 
chemotherapy may be resumed if the patient was receiving chemotherapy at the time of the 
initial determination of PD. 
If the repeat imaging confirms PD, patients should be considered for discontinuation from all 
investigational products.  However, according to the Investigator’s clinical judgment and 
after discussion between the Investigator and the Sponsor, if a patient with evidence of PD is 
still experiencing clinical benefit, the patient may be eligible for continued treatment with the 
investigational products.  The Investigator’s judgment should be based on the overall 
benefit-risk assessment and the patient’s clinical condition, including performance status, 
clinical symptoms, adverse events, and laboratory data. 
Before continuation of treatment after confirmation of PD, the patient must be re-consented 
via informed consent addendum and informed that, in order to continue receiving the 
investigational products on study, the patient may be foregoing approved therapy with 
possible clinical benefit(s).
If the patient is subsequently found to have further disease progression either radiologically 
according to RECIST v 1.1 or clinically, then treatment with avelumab should be 
permanently discontinued.
Patients who stop treatment for reasons other than toxicity with any of the investigational 
products and then experience radiologic disease progression shortly thereafter will be eligible 
for re-treatment with the investigational products they were receiving at the time of treatment 
discontinuation at the discretion of the Investigator and after discussion with the Sponsor. 
5.4.6. Food Requirements
The IV investigational products (avelumab, chemotherapies) may be administered without 
regard to food.


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5.5. Investigational Product Storage
The Investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products (avelumab, chemotherapies) are stored in a secured area with 
controlled access under required storage conditions and in accordance with applicable 
regulatory requirements.
Investigational products should be stored in their original containers and in accordance with 
the labels.
For all investigational products, the storage conditions stated in the product’s SRSD (eg, 
IB) for avelumab or local guidelines for all chemotherapy agents will be superseded by the 
storage conditions stated in the labeling. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all nonworking days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the Pfizer provides permission to use the investigational product.  It will not be 
considered a protocol deviation Pfizer approves the use of the investigational product after 
the temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
5.6. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of all investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 


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5.6.1. Destruction of Investigational Product Supplies
The Sponsor or designee will provide guidance on the destruction of unused investigational 
products (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Medications
Medications or vaccinations specifically prohibited in the exclusion criteria are also not 
allowed during the active treatment period, except for administration of inactivated vaccines. 
If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy or 
medication/vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician.  However, the 
decision to continue the patient on study therapy or medication/vaccination schedule requires 
the mutual agreement of the Investigator, the Sponsor, and the patient.
Concomitant treatment considered necessary for the patient’s well-being may be given at 
discretion of the treating physician.
Concomitant medications and treatments will be recorded for all patients from 28 days prior 
to the start of study treatment and up to 90 days after the last dose of study treatment.  All 
concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic 
diseases, and non-drug supportive interventions (eg, transfusions).  Concomitant medications 
should be reviewed at each study visit, and any prohibited treatments (as described in 
Section 5.7) should be discussed with the patient and appropriately managed. Given that 
recording of non-serious AEs ends when a patient begins a new anti-cancer therapy 
(Section 8.1.4.2 Recording Non-serious AEs and SAEs on the CRF), recording of 
concomitant medications associated with these non-serious AEs should also end.  Reporting 
of concomitant medications associated with SAEs should continue to be reported for up to 
90 days after the last dose of study drug (Section 8.1.4.2), even if the patient begins a new 
anti-cancer therapy.
Concurrent anti-cancer therapy with agents other than study treatments is not allowed.  
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
Recommended medications to treat infusion-related reactions and hypersensitivity reactions 
and immune-related events are reported in Section 5.4.4.5, and Section 5.4.4.6, respectively.


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5.7.1. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is not permitted during 
the DLT observation period (eg, the first two cycles of treatment), but they may be used to 
treat emergent neutropenia as indicated by the current American Society of Clinical 
Oncology (ASCO) guidelines44 or as allowed per local guidance.
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. 
5.7.2. Concomitant Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study.  The 
appropriate interval of time between surgery and administration of investigational products
required to minimize the risk of impaired wound healing and bleeding has not been 
determined.  In case of a surgical procedure, investigational products should be delayed.  
Postoperatively, the decision to reinitiate investigational products should be discussed with 
the Sponsor. 
5.7.3. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain, the sites of bone disease should be present at baseline; otherwise, bone 
pain requiring radiotherapy will be considered as a sign of disease progression.  Study 
treatment should be withheld for the entire duration of palliative radiotherapy and can be 
restarted upon recovery from any radiotherapy-related toxicities, but no sooner than 48 hours 
after radiotherapy completion. 
5.7.4. Other Prohibited Concomitant Medicines and Therapies
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 investigational products. 

Radiation therapy (with the exception noted above in the Concomitant Radiotherapy
Section 5.7.3).

Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs (see 
Table 9).  See below Clarification Regarding Steroid Use.


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
Other experimental pharmaceutical products.

Any vaccine therapies for the prevention of infectious disease (eg, human papilloma 
virus vaccine) except for inactivated vaccines (eg, influenza vaccine).

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or those 
known to potentially interfere with major organ function (eg, hypericin).
Clarifications Regarding Steroid Use: Data indicate that corticosteroids have an adverse 
effect on T-cell function and that they inhibit and damage lymphocytes.45,46 Furthermore, as 
with all immunotherapies intended to augment T-cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit.  
However, studies with anti-CTLA-4 compounds indicate that short term use of steroids can 
be employed without compromising clinical outcomes.47 Therefore, the use of steroids 
during this trial is restricted as follows:

Premedication: steroid inclusion in the premedication regimen for chemotherapy as 
required per product label or local guidelines is allowed in all study arms.

Therapeutic use: for the treatment of infusion-related reactions and for the treatment 
of irAEs, steroids are permitted according to the modalities indicated in Table 9.

Physiologic use: replacement for adrenal insufficiency at doses equivalent to 10 mg 
prednisone daily are acceptable.

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) are permitted. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.8. Rescue Medications and Supportive Care
5.8.1. 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, 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. 


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
Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice, assuming there is no expected drug-drug interaction with study 
treatments (see Section 5.7.4).  Prophylactic administration should be considered for 
the cases outlined in Table 9.

Anti-inflammatory or narcotic analgesics may be offered as needed. 

Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed.
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see the Schedule of Activities and Assessments section (Section 7).
6.1.1. Tumor Biospecimens
A mandatory archived FFPE tumor tissue block sufficient in size to allow for sectioning of at 
least 10 slides must be available from the most recent primary or metastatic tumor biopsy or 
resection prior to start of study therapy.  The archived sample must have been taken within 
18 months prior to enrollment, with no intervening systemic anti-cancer therapy.  If such an 
archived sample is not available, a de novo (ie, fresh) tumor sample must be obtained prior to 
enrollment.  The lesion to be biopsied must not be the only measurable (the only target) 
lesion. 
FFPE tissue blocks should be provided if available and permitted by local laws and policies.  
If blocks cannot be provided for these reasons, then sections must be freshly cut (ie, cut no 
more than 30 days prior to shipment to the central laboratory), 5 µm thick and mounted on 
positively-charged microscope slides (SuperFrost Plus glass slides are recommended).  A 
minimum of 10, but preferably 15, slides should be provided. 
Subject to the availability of a biopsiable lesion that is not the only target lesion, collection of 
a biopsy on Cycle 2 Day 8 (-7 days to +2 days) (prior to dosing) and then as clinically 
indicated during treatment is mandatory unless clinically contraindicated.  These 
on-treatment biopsies are required except in instances where the procedure poses 
unacceptable risks per Investigator documentation. 
An optional biopsy at End of Treatment, if a patient discontinues due to disease progression, 
is requested except in instances where the procedure poses unacceptable risks per 
Investigator documentation.  The tumor sample collected at the End of Treatment should be 
performed before initiation of subsequent anti-cancer therapy, preferably no later than 7 days 
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See Schedule of Activities for timing of biopsies. 
A minimum 18 gauge core needle is requested for use in biopsies in order to maximize the 
quality and value of obtained tissue; a minimum of 3 separate cores are requested for each 
biopsy procedure.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material) is not adequate and should not be submitted. 
Guidance for Selection of Biopsy Site: If there are multiple measurable lesions that could 
serve as target lesions, one of these lesions may be the lesion that is biopsied. The biopsied 
lesion must not be assessed as a target lesion and must be distinct from the target lesions 
being followed for measurable disease.  Most importantly, the biopsied lesion must be one 
that can be accessed safely.  Biopsies from bone lesions should not be submitted.
If a patient has only one measurable lesion and, hence, only one target lesion and no suitable 
archived tumor tissue to serve as a baseline sample, then that one measurable lesion should 
not be biopsied and that patient is not eligible for enrollment.
6.2. Treatment Period
For treatment period procedures, see the Schedule of Activities and Assessments section 
(Section 7).
For the treatment period, where multiple procedures are scheduled at the same nominal time 
point(s) relative to dosing, the following prioritization of events should be adhered to, where 
possible:

Pharmacokinetic blood specimens – obtain at the scheduled time.

Electrocardiograms (ECGs) – obtain as close as possible to the scheduled time, but 
prior to blood specimen collection.

Blood pressure/pulse rate – may be obtained prior to or after ECG collection but must 
be obtained prior to blood specimen collection and within 60 minutes of the nominal 
time.

Clinical safety laboratory tests – obtain as close as possible to the scheduled time.

Other procedures – All other procedures should be obtained as close as possible to the 
scheduled time, but may be obtained before or after blood specimen collection, unless 
sampling is determined by the study personnel to potentially impact the results.
At the end of study, patients who are deriving clinical benefit from study treatment will be 
provided with an option of continuing study treatment (eg, rollover study).
6.3. Short-Term and Long-Term Follow-up
For follow-up procedures see the Schedule of Activities and Assessments section (Section 7).


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In Short-term Follow-up, patients should be evaluated up to 90 days (30 days, 60 days, and 
90 days) after last dose of investigational product(s) for safety.  Patients continuing to 
experience toxicity following discontinuation of investigational products will continue to be 
followed at least every 4 weeks regardless of initiation of new anti-cancer treatment until 
resolution or determination, in the clinical judgment of the Investigator, that no further 
improvement is expected.  Physical examination, ECOG status, vital signs, and safety 
laboratory measurements are not required for patients who initiate new anti-cancer treatment, 
unless the patient continues to experience toxicity following discontinuation of the 
investigational products.  Contraception check and serum/urine pregnancy tests are required 
for up to 90 days after last dose of chemotherapy or up to 30 days after last dose of avelumab 
whichever is longer for all patients who enter Short-term Follow-up regardless of initiation of 
subsequent anti-cancer therapy. 
Following completion of the Short-term Follow-up period, all patients will be followed for 
survival and subsequent anti-cancer treatments every 12 weeks (±14 days) until death, end of 
the study, or patient withdrawal of consent, whichever comes first.  These visits may be 
conducted in-clinic or by remote contact (eg, telephone). 
Patients whose disease has not progressed at the time of End of Treatment will continue to 
undergo disease assessments every 6 weeks (2 days) for 1 year from the start of study 
treatment and then every 12 weeks (14 days) thereafter until documented disease 
progression regardless of initiation of subsequent anti-cancer therapy.
6.4. 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 (see also 
Section 8.1.3) or behavioral reasons, or the inability of the patient to comply with the 
protocol-required schedule of study visits or procedures at a given investigator site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to 
continue study treatment, provided that the treating physician has determined that the 
benefit/risk for doing so is favorable (See Section 5.4.5 for details and exceptions); 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to 1 or more of the 
investigational products, the Investigator may continue treatment with the other 
investigational product(s);

Pregnancy;

Significant protocol violation;


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
Lost to follow-up;

Patient refused further treatment;

Study terminated by Sponsor;

Death.
Reasons for withdrawal from study follow-up may include:

Study terminated by Sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request that the patient return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival (if 
survival is a secondary endpoint) unless the patient withdraws consent for disclosure of 
future information or for further contact.  In this case, no further study specific evaluations 
should be performed, and no additional data should be collected.  The Sponsor may retain 
and continue to use any data collected before such withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to 
perform the test.  In these cases the Investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
Investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, shipment 
instructions and contact information will be provided to the investigator site prior to initiation 
of the study. 


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7.1. Safety Assessments
Safety assessments will include collection of AEs, SAEs, vital signs and physical 
examination, ECG (12-lead), laboratory assessments, including pregnancy tests, and 
verification of concomitant treatments.  See also Schedule of Activities. 
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, and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting study treatments; once at the start of screening and once at the 
baseline visit, immediately before study drugs 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 investigational products.  Additional pregnancy tests (serum or urine) will be 
repeated at every treatment cycle, prior to dosing, during the active treatment period, at the 
end of treatment, during follow-up (for at least 90 days after the last dose of chemotherapy or 
for at least 30 days after last dose of avelumab, whichever is longer), and additionally 
whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
In the case of a positive confirmed pregnancy, the patient will be withdrawn from 
administration of investigational product but may remain in the study. See also Schedule of 
Activities.
Additional pregnancy tests may also be undertaken if requested by institutional review 
boards (IRBs)/ECs or if required by local regulations.
7.1.2. Contraceptive Check
Fertile male patients and female patients who are of childbearing potential, who are, in the 
opinion of the Investigator, sexually active and at risk for pregnancy with their partner(s), 
will need to affirm that they meet the criteria for correct use of at least one method of highly 
effective contraception.  The Investigator or his or her designee will discuss with the patient 
the need to use at least 1 highly effective contraception method 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 the selected contraception method(s)
is discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner.  
Patients who are, in the opinion of the Investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use at least 1 method of highly effective contraception 
throughout the study or for at least 90 days after the last dose of chemotherapy (for male and 
female patients) or at least 30 days after the last dose of avelumab (for female patients), 
whichever is longer.  See also Schedule of Activities.
7.1.3. Adverse Events
Assessment of AEs will include the type, incidence, severity (graded by the NCI CTCAE 
v4.03) timing, seriousness, and relatedness.


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7.1.4. Laboratory Safety Assessments
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at local laboratories.  They may also be performed when clinically 
indicated.  The required laboratory tests are listed in Table 14.  See Schedule of Activities for 
details on sample timings. 
Full hematology and full clinical chemistry tests must be performed. Full hematology panel 
as well as AST, ALT, and creatinine results must be reviewed by medically-qualified study 
personnel prior to each administration of study drug.  Results from all other laboratory
assessments are not required to be reviewed prior to study drug dosing, unless there are signs 
or symptoms to suggest an underlying lab abnormality. However, all lab results should be 
reviewed as soon as they are available.


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Table 14.
Laboratory Tests
Hematology
Chemistry Panel
(* denotes core 
chemistry test)
Coagulation
Urinalysis
Pregnancy Test
Hemoglobin
ALT*
PT or INR
Proteinb
For female patients 
of childbearing 
potential, serum or 
urine 
Platelets
AST*
PTT
Glucose
WBC
Alk Phosphatase*
Blood
Absolute Neutrophils
Sodium*
Absolute Lymphocytes
Potassium*
Absolute Monocytes
Magnesium*
Absolute Eosinophils
Chloride*
Absolute Basophils
Total Calcium*
Total Bilirubin* a
BUN or Urea*
Creatinine*
Glucose (non-fasted)*
Albumin*
Thyroid Function Tests
Phosphorous or 
Phosphate*
TSH, Free T4
Total protein*
Uric acid
Amylase
Gamma glutamyl 
transferase
Cholesterol
Other Tests
Creatine kinase
ACTH
C-reactive protein
HBV surface antigen
Lactate dehydrogenase 
(LDH)
Anti-HCV antibody
Lipase
If Anti-HCV antibody 
positive, then HCV RNA 
testing
Triglycerides
Note: aFor potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin 
time (PT)/INR, alkaline phosphatase, total bile acids, and acetaminophen levels.
bDipstick is acceptable.  Microscopic analysis should be performed if dipstick result is abnormal.  Additional 
tests may be undertaken if needed, at Investigator’s discretion. 
Abbreviations: ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, PT=prothrombin time, 
PTT= activated partial thromboplastin time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, 
CRP=C-reactive protein, HBV= hepatitis B Virus, HCV= hepatitis C Virus, INR=international normalized 
ratio, LDH=lactate dehydrogenase, TSH=thyroid-stimulating hormone, WBC=white blood cell


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7.1.5. Vital Signs and Physical Examination
Patients will have a physical examination to include major body systems, sitting blood 
pressure, pulse rate, assessment of ECOG performance status, and height (height will be 
measured at screening only) at the time points described in the Schedule of Activities.  
Determination of ECOG Performance Status will continue through the 30-day Follow-Up 
visit unless the patient has started on a new anti-cancer therapy.
Vital signs include blood pressure and pulse rate and should be taken prior to receipt of study 
treatment pre-medication and all study treatment with the patient in the seated position after 
the patient has been sitting quietly for at least 5 minutes. 
Weight for the purposes of chemotherapy 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.
7.1.6. (12-Lead) Electrocardiogram
All patients require triplicate ECG measurements.  Triplicate 12-lead (with a 10-second 
rhythm strip) tracing will be used for all ECGs (screening and on-treatment).  On-treatment 
ECGs will be performed on Day 1 of Cycles 1 to 3, before administration of any study drug 
(including avelumab) and at the end of avelumab infusion for all patients (see Schedule of 
Activities).  All pre-dose ECGs are to be collected prior to administration of any study drug 
(chemotherapy, avelumab, or any other anti-cancer immunotherapies used in future portions 
of the study).  For the UK and the Czech Republic: Only 1 additional anti-cancer 
immunotherapy, in combination with avelumab and chemotherapy, in up to 4 tumor-specific 
cohorts, will be included. 
It is preferable that the machine used has a capacity to calculate the standard intervals 
automatically.  At each time point (see the Schedule of Activities), 3 consecutive 12-lead 
ECGs will be performed approximately 2 minutes apart to determine mean QTc interval.  If 
the mean QTc is prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs should be 
re-evaluated by a specialist at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate.  If manual reading verifies a QTc 
of >500 msec, immediate correction for reversible causes (including electrolyte 
abnormalities, hypoxia and concomitant medications for drugs with the potential to prolong 
the QTc interval) should be performed.  In addition, repeat ECGs should be immediately 
performed hourly for at least 3 hours until the QTc interval falls below 500 msec.  If QTc 
interval reverts to less than 500 msec, and in the judgment of the Investigator(s) and Sponsor 
is determined to be due to cause(s) other than investigational product, treatment may be 
continued with regular ECG monitoring as clinically indicated.  If in that timeframe the QTc 
intervals rise above 500 msec, the investigational product(s) will be held until the QTc 
interval decreases to 500 msec.  Patients will then restart the investigational product at the 
next lowest dose level or dose delayed as appropriate for specific investigational product.  If 
the QTc interval has still not decreased to <500 msec after 2-weeks, or if at any time a patient 
has a QTc interval >515 msec or becomes symptomatic, the patient will be removed from the 
study.  Additional triplicate ECGs may be performed as clinically indicated. 


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Each episode of prolongation of the QTc interval will be evaluated by a specialist to 
determine if due to the investigational product(s) or due to other potential precipitating 
factors (eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance).
If a patient experiences any cardiac or neurologic AEs (especially syncope, dizziness, 
seizures, or stroke), an ECG in triplicate should be obtained at the time of the event. 
ECG collections should be started within a 10% window relative to nominal time, except 
when coinciding with the end of avelumab infusion time, in which case ECG collection 
should be started within up to 10 minutes after the end of infusion.  Any pre-dose ECG 
should be performed up to one hour prior to the start of the first infusion.  ECG collections 
which are time-matched with PK blood samples (eg, pre-dose ECG matched with pre-dose 
avelumab PK blood draw) should be taken at the same time during the clinic visit. When the 
nominal time of an ECG coincides with a nominal time for a PK sample, the ECG must be 
completed before the PK sample is drawn.  The PK sample should be collected as close to the 
nominal time as possible.  If the infusion of avelumab is interrupted due to a non-cardiac or 
neurological AE, any ECG scheduled during the time the AE is occurring is not required. 
Clinically significant new findings seen on any ECGs taken after screening should be 
recorded as AEs.
7.2. Pharmacokinetics Assessments
Blood samples will be obtained from all patients for PK analysis of avelumab according to 
the Schedule of Activities. 
Blood samples for serial PK analysis of chemotherapy will be obtained as follows:

Cohorts A1 and A3: Serial PK for carboplatin and pemetrexed in at least 8 patients, 
according to Table 2.

Cohorts A2 and A4: Serial PK for cisplatin and gemcitabine in at least 8 patients, 
according to the Table 4.
The PK collection strategy, including nominal time points, serial versus sparse PK sampling 
and the number of patients, may be modified based on emerging data.
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, with the exception of samples where nominal time coincides with end of 
infusion, samples obtained within ±30% of the nominal time (eg, within 18 minutes of a 
60 minute sample) will not be captured as a protocol deviation, as long as the exact time of 
the sample collection is noted on the source document and data collection tool (eg, CRF). 
Pre-dose PK samples should be taken on that same visit day prior to receiving any study 
drug, and may be grouped together (eg, pre-dose PK samples for avelumab and 


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chemotherapy agents are collected together at the same time before administration of the first 
agent).
For avelumab samples where nominal time coincides with end of infusion, a sample collected 
within 30 minutes post end of infusion will not be captured as a protocol deviation, as long as 
the exact time of the sample collection is noted on the source document and data collection 
tool (eg, CRF).  If the infusion of avelumab is interrupted due to AE, any PK samples 
scheduled during the time the AE is occurring are not required. 
For other study drugs where nominal time coincides with end of infusion, a sample collected 
within 10 min post end of infusion will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF). 
All samples, regardless of protocol compliance, which contain actual time of collection will 
be used by the Sponsor in PK analyses.  If a scheduled blood sample collection cannot be 
completed for any reason, the missed sample time may be re-scheduled with agreement of 
clinical Investigators, patient and Sponsor.
•
Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the Investigator site prior to initiation of the trial.
•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
The samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the Sponsor.  On a case by case basis, the Sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulted in compromised 
sample integrity, will be considered a protocol deviation.
7.2.1. All Groups: Blood for PK Analysis of Avelumab
Blood samples (3.5 mL whole blood at each time point) will be collected for PK analysis of 
avelumab into appropriately labeled serum separator tube (SST) as outlined in the Schedule 
of Activities.  PK sampling schedule may be modified based on emerging PK data.  Blood 
for PK samples will be drawn from the arm contralateral to the drug infusion.
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7.2.2. All Groups: Blood for PK Analysis of Chemotherapies
PK sampling schedules may be modified based on emerging PK data.
7.2.2.1. Cohorts A1 and A3: Blood for PK Analysis of Carboplatin
Blood samples (3 mL whole blood at each time point) will be collected into appropriately 
labeled tubes containing K2 ethylenediaminetetraacetic acid (EDTA) for PK analysis of 
carboplatin (free and total platinum) as outlined in the Schedule of Activities.  Blood for PK 
samples will be drawn from the arm contralateral to the drug infusion.
7.2.2.2. Cohorts A1 and A3: Blood for PK Analysis of Pemetrexed
Blood samples (2 mL whole blood at each time point) will be collected into appropriately 
labeled tubes containing K2EDTA for PK analysis of pemetrexed as outlined in the Schedule 
of Activities.  Blood for PK samples will be drawn from the arm contralateral to the drug 
infusion.
7.2.2.3. Cohorts A2 and A4: Blood for PK Analysis of Gemcitabine
Blood samples (3 mL whole blood at each time point) will be collected into appropriately 
labeled tubes containing K2EDTA for PK analysis of gemcitabine (and its metabolite, 
2',2'-difluorodeoxyuridine [dFdU]) as outlined in the Schedule of Activities.  Blood samples 
will be pretreated with tetrahydrouridine (THU) to inhibit ex vivo conversion of gemcitabine 
to dFdU.  Detailed instructions on the preparation and use of THU will be provided in the lab 
manual.  Blood for PK samples will be drawn from the arm contralateral to the drug infusion.
7.2.2.4. Cohorts A2 and A4: Blood for PK Analysis of Cisplatin
Blood samples (3 mL whole blood at each time point) will be collected into appropriately 
labeled tubes containing K2EDTA for PK analysis of cisplatin (free and total platinum) as 
outlined in the Schedule of Activities.  Blood for PK samples will be drawn from the arm 
contralateral to the drug infusion.
7.3. Immunogenicity Assessments
Blood samples (3.5 mL whole blood) will be collected for assessment of avelumab ADAs 
into an appropriately labeled serum separator tube (SST).  Pre-dose ADA samples will be 
collected within 2 hours prior to the first drug administration of the day (when multiple 
agents are dosed on the same day).  Further details can be found in the Lab Manual.  This 
assessment will take place at regular intervals during the treatment and follow-up periods as 
described in the Schedule of Activities. 
A tiered ADA testing strategy will be used: all samples that are positive in the screening 
assay will be confirmed for antibody specificity.  Confirmed positive samples will be further 
characterized for titer and tested in the neutralizing antibody (nAb) assay, if appropriate.

Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the Investigator site prior to initiation of the trial.


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•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
The immunogenicity samples must be processed and shipped as indicated in the 
instructions provided to the investigator site to maintain sample integrity.  Any 
deviations from the immunogenicity sample handling procedure (eg, sample 
collection and processing steps, interim storage or shipping conditions), including any 
actions taken, must be documented and reported to the Sponsor.  On a case by case 
basis, the Sponsor may make a determination as to whether sample integrity has been 
compromised.  Any deviation from the specified sample handling procedure resulting 
in compromised sample integrity, will be considered a protocol deviation.
7.4. Biomarker and Pharmacodynamic Assessments
Information about the following tumor biomarkers of known prognostic significance will be 
collected at Screening. 
•
NSCLC:
•
EGFR and ALK required to be collected for patients with non-squamous NSCLC.
•
KRAS, ROS1, and PD-L1 collected if available for patients with non-squamous 
NSCLC. 
•
UC: PD-L1 collected if available.
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers in tissue and blood that may have predictive value in 
identifying those patients who are most likely to benefit from treatment with the combination 
of avelumab and chemotherapy with or without other immunotherapies.  In addition, analyses 
of biomarkers in paired pre- and post-treatment biopsies and of sequentially obtained blood 
samples will provide an opportunity to investigate pharmacodynamic effects.  Samples 
collected at the End of Treatment visit may help us understand potential acquired 
mechanisms of resistance to the drug combination. 
7.4.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies
Baseline tumor biospecimens (see Section 6.1.1) will be used to analyze candidate DNA, 
RNA, and/or protein markers, or relevant signatures of markers for their ability to identify 
those patients who are most likely to benefit from treatment with the study drugs. 
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These markers will also be analyzed in on-treatment biopsies in order to assess 
pharmacodynamic and mechanistic biomarkers that may inform dose selection and activity.
Candidate markers of interest include the mutational and neoantigen load of tumors as 
determined by DNA sequencing at baseline and PD-L1 expression on/in tumor and 
infiltrating immune cells measured by IHC at baseline and on-treatment.
Optional tumor biopsies obtained upon disease progression may be used to assess the same, 
or additional, markers with the aim of determining any acquired mechanisms of resistance.  
Additional information on tissue collection procedures can be found in Section 6.1.1 and the
Study Manual. 
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7.6. Tumor Response Assessments
Tumor assessments must include all known or suspected disease sites.  The minimum 
recommended body areas to be scanned depending upon malignancy are detailed in the 
Imaging Manual.  Imaging may include chest, abdomen and pelvis computed tomography 
(CT) or magnetic resonance imaging (MRI) scans.  For patients with NSCLC (Cohorts A1 
and A3), pelvic assessments will be conducted only if clinically indicated at baseline or at 
any subsequent point.  Patients with cisplatin-eligible UC (Cohorts A2 and A4) should have 
chest, abdomen, and pelvis CT or MRI scans.  Brain CT or MRI scans are required at 
baseline for all patients with stable brain lesions and for those for whom CNS involvement is 
suspected.  If stable brain metastases are present at baseline, brain imaging should be 
repeated at each tumor assessment.  Otherwise, brain imaging will be conducted 
post-baseline only when clinically indicated.
Whole body bone imaging using bone scan (bone scintigraphy) (preferred method) or other 
methods considered standard of care locally such as 18-fluorodeoxyglucose positron 
emission tomography (18F-FDG-PET), 18F-sodium fluoride-PET (18F- NaF-PET), PET/CT,
CT, or MRI is required at baseline.  Bone lesion(s) identified at baseline by bone 
scintigraphy, 18F-FDG-PET, 18F- NaF-PET, or PET/CT will be further assessed by 
correlative imaging, such as diagnostic CT or MRI as per local practice (where bone scans 
are not used as a routine restaging tool) and subsequently re-assessed by diagnostic CT or 
MRI as per the tumor assessment schedule.  Only for those patients with bone lesions present 
at baseline, whole body bone imaging should be repeated at every other tumor assessment 
visit (ie, every 12 weeks during the first 12 months of study treatment and every 24 weeks 
thereafter) and at the time of confirmation of CR.  For all patients, whole body bone imaging 
may be repeated during study as clinically indicated (ie, patient describes new or worsening 
bone pain, or has increasing alkaline phosphatase level or other signs and symptoms of 
new/progressing bone metastases). 
The schedule of tumor assessments should be fixed according to the calendar regardless of 
treatment schedule or treatment delays or interruptions due to toxicity. 
The CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons.  The same imaging technique used to characterize each identified and 
reported lesion at baseline will be employed in the following tumor assessments.
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Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline, then every 6 weeks (2 days) for 1 year from start of study treatment, and then 
every 12 weeks (14 days) thereafter until disease progression regardless of initiation of 
subsequent anti-cancer therapy, as specified in the Schedule of Activities. In addition, 
radiological tumor assessments will be conducted whenever disease progression is suspected 
(eg, symptomatic deterioration). 
Baseline scans must be performed within 28 days prior to first dose of study drug. 
Assessment of response will be made using RECIST v1.1 (Appendix 3). Measurable or 
evaluable lesions that have been previously irradiated will not be considered target lesions 
unless increase in size has been observed following completion of radiation therapy.
In case CR or PR is observed, tumor assessments must be confirmed on repeated imaging at 
least 4 weeks after initial documentation.  See Section 5.4.5 for treatment after initial 
evidence of disease progression. 
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.  All radiographic images will be collected and stored by an 
independent third-party imaging laboratory.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; (2) 
non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
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Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the Investigator are to be reported 
regardless of whether the event is determined by the Investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the Investigator does not become 
immediately aware of the occurrence of an event, the Investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the Investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the Investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
Investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The Investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.


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8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 90 calendar days after the last administration of investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the Investigator becomes aware of them; at a minimum, all SAEs that the 
Investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the Investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the Investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the Investigator may be required until the event or its sequelae resolve or 
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If a patient begins a new anti-cancer therapy, the recording period for non-serious AEs ends 
at the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5. Causality Assessment
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
Investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the Sponsor.  If the Investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the Investigator determines that an SAE is associated with study procedures, 
the Investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study patient administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  Examples of AEs include, but are not limited to: 

Abnormal test findings;

Clinically significant signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.


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Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the Investigator or Sponsor.
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 
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8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
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8.3. Severity Assessment
GRADE
Clinical Description of Severity
0
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the Investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 
8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.


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The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the Sponsor. 
The patient should return to the Investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a co-formulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 


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All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of Investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a patient or patient’s partner becomes or is found to be pregnant during the patient’s 
treatment with the investigational product, the Investigator must report this information to 
Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, regardless of 
whether an SAE has occurred.  In addition, the Investigator must submit information 
regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a patient 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24 hours of awareness of the exposure.  The 
information submitted should include the anticipated date of delivery (see below for 
information related to termination of pregnancy).


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Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The Investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
Investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the Investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the Sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
Investigator will provide the patient with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The Investigator must document in the source documents that the 
patient was given the Pregnant Partner Release of Information Form to provide to his partner.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the Investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.


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An occupational exposure is reported to Pfizer Safety within 24 hours of the Investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the Investigator site file.
8.4.4. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the Sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.


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9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the Sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
This section describes the data analysis and statistical methods for each of the combinations 
and cohorts evaluated in this study. 
9.1. Analysis Sets 
9.1.1. Full Analysis Set
For each cohort, the full analysis set includes all enrolled patients in the cohort who receive 
at least 1 dose of study drug.  Each patient will be classified according to the first treatment 
combination received.
9.1.2. Safety Analysis Set 
The safety analysis set includes all patients who receive at least 1 dose of study drug.  In this 
non-randomized study, the full analysis set and the safety analysis set are identical. 
9.1.3. Evaluable for DLT Analysis Set
The DLT analysis set is a subset of the safety analysis set and includes all enrolled patients in 
Phase 1b lead-in who are eligible for the study, receive at least one dose of the combination 
treatment, and either experience DLT during the first 2 cycles of treatment, or complete the 
DLT observation period for the first 2 cycles of treatment. 
Patients without DLTs who withdraw from study treatment before receiving, over 2 cycles, at 
least 75% of the prescribed doses of avelumab and each relevant chemotherapy for reasons 
other than treatment-related toxicity (eg, missed appointments or development of rapidly 
progressing disease) are not evaluable for DLT.
9.1.4. Pharmacokinetics Analysis Sets
The PK concentration analysis sets (one unique set for each individual agent used in study 
treatment) are subsets of the safety analysis set including all treated patients who have at 
least one post-dose concentration measurement above the limit of quantitation of avelumab 
or other study drugs which they were assigned to receive, based on the cohort. 
The PK parameter analysis sets (one unique set for each individual agent used in study 
treatment) are subsets of the safety analysis set including all treated patients who have at 
least one PK parameter of interest of avelumab or the other study drugs which they were 
assigned to receive, based on the cohort.


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9.1.5. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set including all treated 
patients who have at least one ADA sample collected.
9.1.6. Biomarker Analysis Set
For all combinations, the biomarker analysis set is a subset of the safety analysis set 
including all treated patients who have at least one screening biomarker assessment.  
Analysis sets will be defined separately for blood-based and tumor tissue-based biomarkers.
If mutational profiling is performed on samples derived from the biomarker analysis set, the 
analysis may be limited to screening samples only.
9.2. Statistical Methods and Properties
Phase 1b lead-in: Before expanding each cohort into the Phase 2 cohort expansion, the 
safety of the combination in a cohort must be confirmed in DLT-evaluable patients in the 
Phase 1b lead-in. 
Up to 12 patients will be enrolled into each cohort in the Phase 1b lead-in and evaluated for 
DLT during the first 2 cycles of treatment as follows.
Cohorts A1 and A2

Enroll and treat up to 6 DLT-evaluable patients in each cohort:

If 1 of 6 patients experience DLT in Cohort A1 (or A2), enrollment may be initiated 
in Phase 1b Cohorts A3 (or A4); 

If 3 of up to 6 patients experience DLT in Cohort A1 (or A2), enrollment in Cohort 
A1 (or A2) will be discontinued; there will be no further enrollment of patients with 
the combination; 

If 2 of 6 patients experience DLT in Cohort A1 (or A2), the cohort will be expanded 
to enroll up to 6 additional DLT-evaluable patients in the Phase 1b Cohort A1 
(or A2):

If 3 of 12 patients experience DLT in Cohort A1(or A2), enrollment may be 
initiated in Phase 1b Cohort A3 (or A4);

If 4 of up to 12 patients experience DLT in Cohort A1 (or A2), enrollment in 
Cohort A1 (or A2) will be discontinued; there will be no further enrollment of 
patients with the combination.


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Cohorts A3 and A4

Enroll and treat up to 6 DLT-evaluable patients in each cohort:

If 1 of 6 patients experience DLT in Cohort A3 (or A4), enrollment may be initiated 
in Phase 2 Cohort A3 (or A4) expansion with the study treatment of avelumab 
1200 mg Q3W in combination with chemotherapy; 

If 3 of up to 6 patients experience DLT in Cohort A3 (or A4), enrollment in the 
Cohort A3 (or A4) will be discontinued; enrollment may be initiated in Phase 2 
Cohort A1 (or A2) expansion with the study treatment of avelumab 800 mg Q3W in 
combination with chemotherapy;

If 2 of 6 patients experience DLT in Cohort A3 (or A4), the Cohort A3 (or A4) will 
be expanded to enroll up to 6 additional DLT-evaluable patients;

If 3 of 12 patients experience DLT in Cohort A3 (or A4), enrollment may be 
initiated in Phase 2 Cohort A3 (or A4) expansion with the study treatment of 
avelumab 1200 mg Q3W in combination with chemotherapy; there will not be 
any enrollment in Phase 2 Cohorts A1 (or A2) expansion with the study treatment 
of avelumab 800 mg Q3W in combination with chemotherapy;

If 4 of up to 12 patients experience DLT in Cohort A3 (or A4), enrollment may
be initiated in Phase 2 Cohort A1 (or A2) expansion with the study treatment of 
avelumab 800 mg Q3W in combination with chemotherapy. 
Table 15 shows the probability of meeting DLT requirements to escalate to dose level of 
avelumab 1200 mg Q3W in combination with chemotherapy. For example, for a DLT that 
occurs in 10% of patients, the probability of confirming safety and escalating to 
avelumab 1200 mg Q3W is approximately 0.97. 
As per the DLT criteria, if the dose level of avelumab is escalated to 1200 mg, Phase 2 cohort 
expansion may be initiated with the study treatment of avelumab, either 800 mg Q3W or 
1200 mg Q3W, in combination with chemotherapy.
Table 15.
Probability of Escalating Dose Level of Avelumab to 1200 mg Q3W after 
Phase 1b Lead-in of Each Cohort (A1 and A2)
True underlying DLT rate*
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose level 
of avelumab 
0.97
0.82
0.56
0.31
0.14
0.05
0.01
0.002
<0.0001
*True underlying DLT rate for the combination of avelumab 800 mg Q3W with chemotherapy.


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9.3. Sample Size Determination
The number of patients to be enrolled in the Phase 1b lead-in may depend upon the observed 
safety profile, which will determine the number of patients enrolled in each cohort.  The total 
number of patients in the Phase 1b lead-in is expected to be up to 48 (up to 12 patients per 
cohort). 
If investigational products administration the Phase 1b Lead-in portion of a given cohort is 
deemed safe based on the criteria described in “Phase 1b Lead-in” Section 3.1, then 
enrollment into that cohort may continue into the Phase 2 Cohort Expansion.  The dose of 
avelumab to be administered in the Phase 2 Cohort Expansion (800 mg Q3W for Cohorts A1 
and A2 or 1200 mg Q3W for Cohorts A3 and A4) will be determined based on the number of 
observed DLTs as described in “Phase 1b Lead-in” Section 3.1. The highest dose level of 
avelumab deemed safe for the combination will be advanced.
Based on safety data for patients with cisplatin-eligible UC, the Phase 1b lead-in from either 
Cohort A2 (800 mg avelumab plus chemotherapy) or cohort A4 (1200 mg avelumab plus 
chemotherapy) may be selected to continue enrollment into the Phase 2 cohort expansion. 
Up to approximately 40 patients with cisplatin-eligible UC, including Phase 1b lead-in and 
Phase 2 cohort expansion patients, may receive the selected avelumab dose plus 
chemotherapy.
Based on safety data for patients with non-squamous NSCLC, the Phase 1b lead-in from 
either Cohort A1 (800 mg avelumab plus chemotherapy) or Cohort A3 (1200 mg avelumab 
plus chemotherapy) may be selected to continue enrollment into the Phase 2 cohort 
expansion. Up to approximately 20 patients with non-squamous NSCLC, including Phase 1b 
lead-in and Phase 2 cohort expansion patients, may receive the selected avelumab dose plus 
chemotherapy.
In future portions of the study, up to approximately 40 patients in each cohort (including 
those enrolled in Phase 1b lead-in and those enrolled in Phase 2) will be enrolled and treated 
with avelumab plus chemotherapy with or without other anti-cancer immunotherapies. For 
the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be 
included.
With 40 patients with cisplatin-eligible UC and 20 patients with non-squamous NSCLC in 
Phase 1b and Phase 2 combined, ORR can be estimated with a maximum standard error of 
0.079 and 0.112, respectively. Within each cohort, ORR will be estimated and the two-sided 
exact 90% confidence interval will be calculated.  Table 16 provides the exact binomial 
90% confidence intervals for ORR based on different observed responses in a cohort.


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Table 16.
Sample Size and Exact 90% CI for ORR in each Cohort
N per Cohort
Number of Responders
Observed ORR
90% CI for ORR
20
1
5%
(0.3% – 21.6%)
2
10%
(1.8% – 28.3%)
3
15%
(4.2% – 34.4%)
4
20%
(7.1% – 40.1%)
5
25%
(10.4% – 45.6%)
6
30%
(14.0% – 50.8%)
7
35%
(17.7% – 55.8%)
8
40%
(21.7% – 60.6%)
9
45%
(25.9% – 65.3%)
10
50%
(30.2% – 69.8%)
12
60%
(39.4% – 78.3%)
15
75%
(54.4% – 89.6%)
40
2
5%
(0.9% – 14.9%)
4
10%
(3.5% – 21.4%)
6
15%
(6.7% – 27.5%)
8
20%
(10.4% – 33.2%)
10
25%
(14.2% – 38.7%)
12
30%
(18.3% – 44.0%)
14
35%
(22.6% – 49.2%)
16
40%
(26.9% – 54.2%)
18
45%
(31.5% – 59.1%)
20
50%
(36.1% – 63.9%)
24
60%
(45.8% – 73.1%)
30
75%
(61.3% – 85.8%)
35
87.5%
(75.5% – 94.9%)
CI=confidence interval; ORR=objective response rate
9.4. Efficacy Analysis
All efficacy analyses will be performed for each cohort separately including all patients in 
the full analysis set from the Phase 1b lead-in and the Phase 2 cohort expansion parts 
combined. 
9.4.1. Analysis of the Primary Endpoint
The primary endpoint for Phase 1b lead-in and the Phase 2 cohort expansion combined is the 
confirmed objective response (OR) as assessed by the Investigator using RECIST v1.1. 
OR is defined as a CR or PR per RECIST v1.1 from the first dose of study treatment until 
disease progression or death due to any cause.  Both CR and PR must be confirmed by repeat 
assessments performed no less than 4 weeks after the criteria for response are first met.  
Objective response rate (ORR) is defined as the proportion of patients with a confirmed CR 
or PR per Investigator’s assessment according to RECIST v.1.1.  Confirmed responses are 
those that persist on repeat tumor assessments for at least 4 weeks after initial documentation 
or response.  Otherwise, the patient will be counted as a non-responder in the assessment of 
ORR.  Additionally, patients with inadequate data for tumor assessment (eg, no baseline 
assessment or no follow up assessments) will be considered as non-responders in the 
assessment of ORR.  The two-sided exact 90% CI for ORR will be calculated.


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9.4.2. Analysis of the Secondary Endpoints
Time to Tumor Response (TTR) is defined for patients with confirmed objective response 
(CR or PR) as the time from the first dose of study treatment to the first documentation of 
objective tumor response.
Duration of Response (DR) is defined for patients with confirmed objective response (CR or 
PR) as the time from the first documentation of objective tumor response to the first 
documentation of objective tumor progression or to death due to any cause, whichever occurs 
first.  Censoring for DR will follow that described below for PFS.
Progression-Free Survival (PFS) is defined as the time from the first dose of study treatment 
to the date of disease progression by RECIST v1.1 or death due to any cause, whichever 
occurs first. PFS data will be censored on the date of the last adequate tumor assessment for 
patients who do not have an event (PD or death), for patients who start new anti-cancer 
treatment prior to an event, or for patients with an event after 2 or more missing tumor
assessments.  Patients who do not have a baseline tumor assessment or who do not have any 
post-baseline tumor assessments will be censored on the date of first dose of study treatment 
unless death occurred on or before the time of the second planned tumor assessment in which 
case the death will be considered an event.
Overall Survival (OS) is defined as the time from the first dose of study treatment to the date 
of death.  Patients without an event (death) will be censored at the date of last contact.
TTR will be summarized using simple descriptive statistics (eg median and range).  DR, PFS, 
and OS will be analysed using Kaplan-Meier methods and descriptive statistics.  Point 
estimates will be presented with their 90% and 95% confidence intervals.  In addition, 
progression date, death date, date of first response, and last tumor assessment date will be 
listed, together with best overall response (BOR), TTR, DR, and PFS.
9.5. Analysis of Pharmacokinetics and Pharmacodynamics 
9.5.1. Analysis of Pharmacokinetics of Study Drugs 
Serum pharmacokinetic parameters including the maximum serum concentration (Cmax), 
trough serum concentration (Ctrough), and area under the concentration versus time curve 
(AUClast, AUCτ) for avelumab will be estimated using non-compartmental analysis, if data 
permit. 
Plasma pharmacokinetic parameters including the maximum plasma concentration (Cmax), 
trough plasma concentrations (Ctrough), and area under the plasma concentration versus time 
curve (AUClast, AUCτ) for chemotherapy (carboplatin [free and total platinum], pemetrexed, 
gemcitabine [including metabolite dFdU], and cisplatin [free and total platinum]) will be 
estimated using non-compartmental analysis, if data permit.
The single-dose and/or multiple-dose/ steady-state PK parameters will be summarized 
descriptively by cycle, day (if applicable), and dose (if applicable).  Dose-normalized (DN) 
parameters (eg, DN-Cmax, DN-Ctrough, DN-AUC) will be reported as appropriate.


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Avelumab, chemotherapy (carboplatin [free and total platinum], pemetrexed, gemcitabine 
[including metabolite dFdU], and cisplatin [free and total platinum]) concentrations will be 
summarized descriptively (n, mean, standard deviation [SD], coefficient of variation [CV], 
median, minimum, maximum, geometric mean and its associated CV) by cycle, day, nominal 
time and dose (if applicable).  Individual patient and median profiles of the 
concentration-time data will be plotted by cycle, day (if applicable), and dose (if applicable) 
using nominal times.  Individual and median profiles will be presented on both linear-linear 
and log-linear scales.
The pharmacokinetic interaction potential of each drug will be evaluated in an exploratory 
manner based on overall assessment of the geometric mean ratios for exposure parameters 
(eg, Cmax, area under the curve to the end of the dosing period [AUCtau]) of each drug at 
single-dose and/or multiple-dose/steady-state in comparison to those PK parameters obtained 
from the monotherapy or appropriate combination settings.  Comparison will be made to 
historical PK data and presented descriptively, if data permit. 
9.5.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to further 
characterize the pharmacokinetics and/or to investigate any association between avelumab 
and chemotherapy exposure and biomarkers or significant safety or efficacy endpoints.  The 
results of these analyses, if performed, may be reported separately.
9.5.3. Analysis of Immunogenicity Data of Avelumab and Other Study Drugs
Anti-drug antibody (ADA) and neutralizing antibody (nAb) data will be listed and 
summarized for each dosing interval for avelumab.  The percentage of patients with positive 
ADA and neutralizing antibodies each will be summarized across the study and by cohort.  
For patients with positive ADA, the magnitude (titer), time of onset, and duration of ADA 
response will also be described, if data permit.  The effect of ADA on avelumab 
concentrations will be evaluated.
9.6. Biomarker Analyses for Secondary 
 Endpoints
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate.  
Appropriate change from baseline measurements will be provided. 
For discrete measurement biomarkers, frequencies and percentages of categorical biomarker 
measures will be determined at baseline and on-treatment/end of treatment time points. 
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics.  The statistical approaches will examine correlations of biomarker results with 
pharmacokinetic parameters and measures of efficacy, such as tumor response and 
progression free survival.
CCI


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9.7. Safety Analysis
Safety analysis will be performed on the safety analysis set in the study for each combination 
and cohort for Phase 1b lead-in and for all patients in the Phase 1b lead-in and Phase 2 cohort 
expansion parts combined. 
9.7.1. Analysis of the Primary Endpoint in the Phase 1b Lead-in
DLT is the primary endpoint of the Phase 1b lead-in part of the study for all cohorts 
evaluated. 
Analyses of DLT are based on the DLT-evaluable set.  The occurrence of DLTs and AEs 
constituting DLTs will be summarized and listed per cohort for patients in the Phase 1b 
lead-in.
9.7.2. Analysis of Secondary Safety Endpoints
9.7.2.1. Adverse Events
AEs will be graded by the Investigator according to the CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE summaries will 
be on TEAE, those with initial onset or increasing in severity after the first dose of study 
treatment.  The number and percentage of patients who experienced any AE, SAE, 
treatment-related AE, and treatment-related SAE will be summarized according to worst 
toxicity grades. 
9.7.2.2. Laboratory Test Abnormalities
The laboratory results will be graded according to the CTCAE v4.03 severity grade whenever 
applicable.  The number and percentage of patients who experienced laboratory test 
abnormalities will be summarized according to worst toxicity grade observed for each 
laboratory test. 
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done. 
Shift tables will be provided to examine the distribution of laboratory toxicities.
9.7.2.3. Electrocardiograms
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on-treatment ECG data. Baseline ECG is defined as the ECG performed on Day 1 of 
Cycle 1 prior to any study drug treatment.
ECG measurements (an average of the triplicate measurements, if applicable) will be used for 
the statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.


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QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS and QTc.  
Individual QT (all evaluated corrections) intervals will be listed by combination, cohort, time 
point and dose (if applicable).  The most appropriate correction factor will be selected and 
used for the following analyses of central tendency and outliers and used for the study 
conclusions. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment by combination, cohort, time point, and dose (if applicable).  The 
maximum change from baseline will be calculated as well as the maximum post-baseline 
interval across time points.  Categorical analysis will be conducted for the maximum change 
from baseline in corrected QT and the maximum post-baseline QT interval. 
Shift tables will be provided for baseline versus worst on-treatment corrected QT (one or 
more correction method will be used) using maximum CTCAE Grade.  Shift tables will also 
be provided for ECG abnormality at baseline versus on-treatment (yes, no, not done: (n, %)).  
Patients experiencing clinically-relevant morphological ECG changes will be summarized 
(including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration-corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
9.8. 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. 
9.9. Data Safety Monitoring Committee 
This study will not use an external Data Safety Monitoring Committee.  For the purpose of 
this protocol, Pfizer procedures for periodic safety review will be applied by an internal 
safety review team with medical and statistical capabilities to review individual and summary 
data collected in the safety and clinical databases, including surveillance for SAEs according 
to regulatory guidelines.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
Investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.


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


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11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
Investigator agrees to keep records, including the identity of all participating patients 
(sufficient information to link records, eg, CRFs and hospital records), all original signed 
informed consent documents, copies of all CRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the Investigator according to International Conference on Harmonization 
(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.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guideline for Good Clinical Practice, and the Declaration of 
Helsinki. 


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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 law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, address, birth date and other identifiable data will be replaced by numerical codes 
based on a numbering system provided by Pfizer in order to de-identify the study patients.  
The investigator site will maintain a confidential list of patients who participated in the study, 
linking each patient’s numerical code to his or her actual identity.  In case of data transfer, 
Pfizer will maintain high standards of confidentiality and protection of patient personal data 
consistent with applicable privacy laws.
The informed consent document and any patient recruitment materials must be in compliance 
with ICH GCP, local regulatory requirements, and legal requirements, including applicable 
privacy laws.
The informed consent document(s) used during the informed consent process and any patient 
recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/Independent Ethics Committee (IEC) before use, and available for inspection.
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The Investigator 
will retain the original of each patient's signed consent document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study drugs, 
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 (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 


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CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State. 
13.2. End of Trial in All Other Participating Countries
End of Trial in all other participating countries is defined as Last Subject Last Visit.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab or other anti-cancer immunotherapies used in future portions of the study at any 
time.  For the UK and the Czech Republic: Only 1 additional anti-cancer immunotherapy, in 
combination with avelumab and chemotherapy, in up to 4 tumor-specific cohorts, will be 
included. 
If a study is prematurely terminated, Pfizer will promptly notify the Investigator.  After 
notification, the Investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 1 month.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
Pfizer product, regardless of the geographical location in which the study is conducted.  US 
Basic Results are submitted for posting within 1 year of the primary completion date (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD is defined as the date that the final patient was examined or received an intervention for 
the purposes of final collection of data for the primary outcome, whether the clinical study 
concluded according to the pre-specified protocol or was terminated.


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


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Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Appendix 1. Abbreviations and Definitions of Terms
The following is a list of abbreviations that may be used in the protocol.
18F-FDG-PET
18-Fluorodeoxyglucose Positron Emission Tomography 
18F-NaF-PET
Fluorine 18 Sodium Fluoride Positron Emission Tomography
ADA
Anti-Drug Antibody
ADL
Activities of Daily Life
AE
Adverse Event
ALK
Anaplastic Lymphoma Kinase
ALT 
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BID
Twice-Daily
BNP
B-Type Natriuretic Peptide
BOR
Best Overall Response
BP
Blood Pressure
BUN
Blood Urea Nitrogen
C
Celsius
Cavg
Average plasma concentration
CFR
Code of Federal Regulations
CI
Confidence Interval
CK
Creatine Kinase
CK-MB
Creatine Kinase – Muscle and Brain Subunits
CL
Clearance
Cmax
Maximum Plasma Concentration
CNS
Central Nervous System
CPK
Creatine Phosphokinase
Ctrough
Lowest (trough) Concentration 
CR
Complete Response
CRF
Case Report Form
CSA
Clinical Study Agreement
ct
Circulating Tumor
CT
Clinical Trial
CT
Computerized Tomography 
CTA
Clinical Trial Application
CTLA-4
Cytotoxic T Lymphocyte-Associated Protein 4
CTCAE 
Common Terminology Criteria for Adverse Events (US NCI)
CV
Coefficient of Variation
CYP
Cytochrome P450
DAI
Dosage and Administration Instructions
DDI
Drug-Drug Interaction
dFdU
Difluorodeoxyuridine
DILI
Drug-Induced Liver Injury 
DLBCL
Diffuse Large B Cell Lymphoma
CCI


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DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DR
Duration of Response
DU
Dispensible Unit
EC
Ethics Committee 
ECG 
Electrocardiogram
ECOG
Easter Cooperative Oncology Group
eCRF
Electronic Case Report Form 
EDP
Exposure During Pregnancy
EDTA
Ethylenediaminetetraacetic Acid
EGFR
Epidermal Growth Factor Receptor
EU
European Union
EudraCT
European Clinical Trials Database
F
Farenheit
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose
FFPE
Formalin Fixed, Paraffin Embedded
FSH
Follicle Stimulating Hormone
GCP 
Good Clinical Practice
GFR
Glomerular filtration rate
GGT
Gamma-Glutamyl Transferase
GH
Growth Hormone
GITR
Glucocorticoid Induced TNF Receptor
GMP
Good Manufacturing Practice
GVHD
Graft versus Host Disease
HA
Hyaluronic Acid
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HDPE
High-Density Polyethylene 
HIV 
Human Immunodeficiency Virus
HR
Hazard Ratio
hr
hour
hrs
hours
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IC50
50% Inhibitory Concentration
ICH
International Conference on Harmonization
ID
Identification
IEC 
Independent Ethics Committee
IERC
Independent Endpoint Review Committee
IFN
Interferon
Ig
Immunoglobulin
IGF-1
Insulin-Like Growth Factor-1
IHC
Immunohistochemistry
IND
Investigational New Drug
INR 
International Normalized Ratio
IP
Investigational Product


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IRB 
Institutional Review Board
IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
IUD
Intra-Uterine Device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IWR
Interactive Web-Based Response
LAG3
Lymphocyte Activation Gene 3
LFT
Liver Function Test
LH
Luteninizing Hormone
mAb
Monoclonal Antibody
MCC
Merkel Cell Carcinoma
MDSC
Myeloid Derived Suppressor Cell
MedDRA
Medical Dictionary for Regulatory Activities
MHC
Major Histocompatibility Compex
MHRA
Medicines and Healthcare products Regulatory Agency
MOA
Monamine Oxidase
MRI 
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose 
mRNA
Messenger Ribonucleic Acid
MVAC
Methotrexate/Vinblastine/Doxorubicin/Cisplatin 
N/A
Not Applicable
nAb
Neutralizing Antibody
NE
Not Evaluable
NCI 
National Cancer Institute
NSAIDs
Nonsteroidal Anti-inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PBMC
Peripheral Blood Mononuclear Cell
PD
Pharmacodynamic
PD
Progressive Disease 
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression-Free Survival
PK
Pharmacokinetics
PO
By Mouth (Oral Administration)
PR
Partial Response
PRL
Prolactin
PS
Performance Status
PT
Preferred Term
PT
Prothrombin Time
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
QD
Once Daily
RCC
Renal Cell Carcinoma


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RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
sBLA
Supplemental Biologics Application
SC
Subcutaneous
SD
Stable Disease
SRSD
Single Reference Safety Document
SST
Serum Separator Tube
SUKL
Czech Republic State Institute for Drug Control
t½
Terminal Half-Life
T4
Free Thyuroxine
TBili
Total Bilirubin
TCR
T-cell Receptor
TEAE
Treatment Emergent Adverse Event
TGF
Tumor Growth Factor
TGI
Tumor Growth Inhibition
THU
Tetrahydrouridine 
TIL
Tumor Infiltrating Lymphocytes 
TIM3
T cell immunoglobulin and mucin
TKI
Tyrosine Kinase Inhibitor
TNF
Tumor Necrosis Factor
TO
Target Occupancy
TPS
Tumor Proportion Score
Treg
Regulatory T cell
TSH
Thyroid Stimulating Hormone
TTR
Time to Tumor Response
UC
Urothelial Cancer
UK
United Kingdom
ULN 
Upper Limit of Normal
US
United States
USPI
United States Prescribing Information
v
Version
WBC 
White Blood Cell
WHO
World Health Organization


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


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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 tumors: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.49
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray. 

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. 

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions. 
Non-measurable disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and <15 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline. 

Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.
Normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.


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


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


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


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Objective Response Status at Each Assessment for Patients with Measurable 
Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Objective status
CR
CR
No
CR
CR
Non-CR/Non-PD or not all evaluated
No
PR
PR
Non-PD* or not all evaluated
No
PR
SD
Non-PD* or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes**
PD
*Non-PD includes CR and Non-CR/Non-PD
** New lesions must be unequivocal 
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest sum on study).  
For CR and PR, the patient’s best response assignment will depend on the achievement of 
both measurement and confirmation criteria.  CR and PR must be confirmed by 
2 measurements at least 4 weeks apart.  In the case of SD, follow up measurements must 
have met the SD criteria at least once after start of the treatment at a minimum interval of 
6 weeks. 


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Appendix 4. Calculation of Carboplatin Dose Based on Calvert Formula
The carboplatin dose should be calculated according to the Calvert40 formula as follows: 

Carboplatin dose = Target AUC x (GFR + 25).

Maximum Carboplatin Dose (mg) = target AUC (mg·min/mL) x (150 mL/min).
The maximum dose is based on a glomerular filtration rate (GFR) estimate that is capped at 
125 mL/min for patients with normal renal function.  No higher estimated GFR values should 
be used.
The GFR should be calculated as per local practice. 
GFR Limitations

Isotopic GFR is inaccurate in patients with significant effusions, ascites or edema as 
the isotope distributes into third space fluid collections.

Patients who have had complicated or prolonged post-operative recovery and who 
have been maintained on prolonged IV fluids with poor nutrition will have a falsely 
low serum creatinine.

Formulae, such as the Cockroft-Gault formula, are inaccurate at the extremes of age 
and weight.  The calculated GFR may be falsely high in obese young women and 
falsely low in thin elderly women.

It is assumed that clinicians entering patients into this protocol will be aware of these 
issues and the clinical judgment of an experienced clinician should be applied to the 
calculation of the carboplatin dose.
The dose of carboplatin should be recalculated prior to each infusion unless the isotopic 
method is used, in which case, the dose should be recalculated if the creatinine rises above 
1.5 X ULN.

SAP_001.pdf: 
Avelumab
B9991023 (MSB0010718C) Statistical Analysis Plan    
PFIZER CONFIDENTIAL
Page 1
JAVELIN CHEMOTHERAPY MEDLEY
A MULTICENTER, OPEN-LABEL, PHASE 1B/2 STUDY TO EVALUATE SAFETY 
AND EFFICACY OF AVELUMAB (MSB0010718C) IN COMBINATION WITH 
CHEMOTHERAPY WITH OR WITHOUT OTHER ANTI-CANCER 
IMMUNOTHERAPIES AS FIRST-LINE TREATMENT IN PATIENTS WITH 
ADVANCED MALIGNANCIES
STATISTICAL ANALYSIS PLAN – B9991023
Compounds:
MSB0010718C
Compound Name:
Avelumab
Version:
2.0
Date:
10-Feb-2021
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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B9991023 (MSB0010718C) Statistical Analysis Plan    
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Page 2
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................6
APPENDICES ...........................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................9
2.1. Study Objectives .....................................................................................................10
2.2. Study Design ...........................................................................................................10
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................14
3.1. Primary Endpoints...................................................................................................14
3.2. Secondary Endpoints...............................................................................................16
3.2.1. Safety endpoints..........................................................................................16
3.2.2. Efficacy endpoints ......................................................................................16
3.2.3. Pharmacokinetic endpoints.........................................................................16
3.2.4. Immunogenicity endpoints .........................................................................17
3.2.5. Biomarker endpoints...................................................................................17
3.4. Baseline Variables...................................................................................................18
3.4.1. Study drug, study treatment and baseline definitions.................................18
3.4.2. Baseline characteristics...............................................................................19
3.5. Safety Endpoints .....................................................................................................19
3.5.1. Adverse events............................................................................................19
4. ANALYSIS SETS ...............................................................................................................20
4.1. Full Analysis Set .....................................................................................................20
4.2. Safety Analysis Set..................................................................................................20
4.3. Other Analysis Set...................................................................................................20
4.3.1. DLT-evaluable set ......................................................................................20
4.3.2. PK analysis sets ..........................................................................................20
4.3.3. Biomarker analysis sets ..............................................................................21
4.3.4. Immunogenicity analysis set.......................................................................21
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................21
5.1. Hypotheses and Decision Rules ..............................................................................21
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5.1.1. Hypotheses and sample size determination................................................21
5.1.2. Decision rules .............................................................................................23
5.2. General Methods .....................................................................................................23
5.2.1. Data handling after the cut-off date............................................................24
5.2.2. Pooling of centers .......................................................................................24
5.2.3. Presentation of continuous and qualitative variables..................................24
5.2.4. Definition of study day...............................................................................25
5.2.5. Definition of start of new anti-cancer drug therapy....................................25
5.2.6. Definition of start of new anti-cancer therapy............................................25
5.2.7. Definition of on-treatment period...............................................................26
5.2.8. Standard derivations and reporting conventions.........................................26
5.2.9. Unscheduled visits......................................................................................26
5.2.10. Adequate baseline tumor assessment........................................................27
5.2.11. Adequate post-baseline tumor assessment................................................27
5.3. Methods to Manage Missing Data ..........................................................................27
5.3.1. Missing data................................................................................................27
5.3.1.1. Pharmacokinetic concentrations................................................27
5.3.1.2. Pharmacokinetic parameters .....................................................28
5.3.2. Handling of incomplete dates .....................................................................28
5.3.2.1. Disease history ..........................................................................28
5.3.2.2. Adverse events ..........................................................................28
5.3.2.3. Prior and concomitant medications...........................................29
5.3.2.4. Exposure....................................................................................30
5.3.3. Imputation rules for date of last contact and efficacy assessments ............30
5.3.3.1. Date of last contact....................................................................30
5.3.3.2. Death date..................................................................................30
5.3.3.3. Tumor assessments....................................................................31
5.3.3.4. Date of start of new anti-cancer therapy ...................................31
6. ANALYSES AND SUMMARIES ......................................................................................33
6.1. Primary Endpoints...................................................................................................33
6.1.1. DLT for Phase 1b........................................................................................33
6.1.1.1. Primary analysis ........................................................................33
6.1.2. Objective response as assessed by the Investigator per RECIST v1.1.......33


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6.1.2.1. Primary analysis ........................................................................33
6.2. Secondary Endpoint(s) ............................................................................................35
6.2.1. Safety endpoints..........................................................................................35
6.2.2. Efficacy endpoints ......................................................................................35
6.2.2.1. Tumor shrinkage from baseline.................................................35
6.2.2.2. Duration of response .................................................................35
6.2.2.3. Time to response .......................................................................37
6.2.2.4. Progression-free survival...........................................................37
6.2.2.5. Overall Survival ........................................................................39
6.2.3. Pharmacokinetic endpoints.........................................................................40
6.2.4. Population pharmacokinetic endpoints.......................................................41
6.2.5. Biomarker endpoints...................................................................................42
6.2.6. Endpoints for immunogenicity data of avelumab.......................................42
6.4. Subset Analyses.......................................................................................................45
6.5. Baseline and Other Summaries and Analyses.........................................................45
6.5.1. Baseline summaries ....................................................................................45
6.5.1.1. Demographic characteristics .....................................................45
6.5.1.2. Medical history..........................................................................46
6.5.1.3. Disease characteristics...............................................................47
6.5.1.4. Prior anti-cancer therapies.........................................................47
6.5.2. Study conduct and patient disposition........................................................48
6.5.2.1. Patient disposition .....................................................................48
6.5.2.2. Protocol deviations....................................................................48
6.5.3. Study treatment compliance and exposure .................................................49
6.5.3.1. Exposure to Avelumab..............................................................50
6.5.3.2. Exposure to Pemetrexed............................................................50
6.5.3.3. Exposure to Carboplatin............................................................51
6.5.3.4. Exposure to Gemcitabine ..........................................................52
6.5.3.5. Exposure to Cisplatin ................................................................53
6.5.3.6. Dose reductions.........................................................................53
6.5.3.7. Dose delays ...............................................................................53
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6.5.3.8. Infusion rate reductions.............................................................54
6.5.3.9. Infusion interruptions ................................................................55
6.5.4. Concomitant medications and non-drug treatments ...................................55
6.5.5. Subsequent anti-cancer therapies................................................................55
6.6. Safety Summaries and Analyses .............................................................................55
6.6.1. Adverse events............................................................................................55
6.6.1.1. All adverse events .....................................................................57
6.6.1.2. Adverse events leading to dose reduction.................................58
6.6.1.3. Adverse events leading to interruption of study treatment .......58
6.6.1.4. Adverse events leading to discontinuation of study 
treatment............................................................................................59
6.6.2. Deaths .........................................................................................................59
6.6.3. Serious adverse events................................................................................60
6.6.4. Other significant adverse events.................................................................60
6.6.5. Laboratory data...........................................................................................60
6.6.5.1. Hematology and chemistry parameters.....................................60
6.6.5.2. Other laboratory parameters......................................................62
6.6.6. Vital signs...................................................................................................63
6.6.7. Electrocardiogram.......................................................................................63
7. INTERIM ANALYSES.......................................................................................................64
7.1. Introduction .............................................................................................................64
7.2. Interim Analyses and Summaries............................................................................64
8. REFERENCES ....................................................................................................................64
9. APPENDICES .....................................................................................................................65
LIST OF TABLES
Table 1.
Summary of Major Changes in SAP Amendments ....................................7
Table 2.
PK Parameters to be Determined for Avelumab and Chemotherapya......17
Table 3.
Biomarker Definition and Determination.................................................17
Table 4.
Sample Size and Exact 90% CI for ORR in each treatment group ..........22


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Table 5.
Probability of Escalating Dose Level of Avelumab to 1200 mg 
Q3W after Phase 1b Lead-in of Each Cohort (from A1 to A3 and 
from A2 to A4) .........................................................................................23
Table 6.
Chemotherapy Doublets (IV) ...................................................................23
Table 7.
Outcome and Event Dates for DR Analyses.............................................36
Table 8. 
DR Censoring Reasons and Hierarchy .....................................................37
Table 9.
Outcome and Event Dates for PFS Analyses ...........................................38
Table 10.
PFS Censoring Reasons and Hierarchy....................................................39
Table 11.
OS Censoring Reasons and Hierarchy......................................................40
Table 12. 
Patients Characterized Based on Anti-Drug Antibody Results 
(ADA Status) ............................................................................................43
Table 13. 
Patients Characterized Based on Neutralizing Antibody Results 
(nAb Status)..............................................................................................44
Table 14.
Case Definition for irAEs .........................................................................65
Table 15.
Case Definition for IRRs – IV Study Drugs Administered in 
Combination (eg, Doublets or Triplets)....................................................68
LIST OF FIGURES
Figure 1
Study Design Schema...............................................................................14
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................65
Appendix 2. Infusion Related Reactions .................................................................................67
Appendix 3. Abbreviations and Definitions of Terms.............................................................69


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991023 is based on the protocol amendment 
04 dated 02OCT2018.  
Table 1.
Summary of Major Changes in SAP Amendments
Version
Version 
Date
Summary of Changes
1
09 Aug
2017
Not applicable (N/A)
2
10 Feb 2021
The following changes in the SAP were implemented in accordance to 
protocol amendment 4. 
•
Section 2.2 “Study Design”, Section 3.4.1 “Study drug, study treatment 
and baseline definitions”, Section 5.1.1 “Hypotheses and sample size 
determination” and Section 5.2 “General Methods” - introduction of the 
evaluation of 1200 mg fixed dose avelumab administered Q3W in 
combination with chemotherapy in both the NSCLC (Cohort A3) and 
UC (Cohort A4) cohorts.
•
Section 5.1.1 “Hypotheses and sample size determination” – added the 
rows for 20 patients in Table 4 “Sample Size and Exact 90% CI for 
ORR in each treatment group” to account for the reduction of the target 
number of patients with non-squamous NSCLC in Phase 1b + Phase 2 
combined.
•
Section 0 “Decision rules” – updated the Table 5 to show the 
probability of escalating dose level of avelumab to 1200 mg Q3W in 
Cohorts A3 and A4 after the Phase 1b lead-in (Cohorts A1 and A2), 
instead of the probability of expanding Phase 1b lead-in.
In addition, the following changes were implemented.
•
Section 3.2.3. “Pharmacokinetic endpoints” – Table 2 of the PK
parameters was simplified.
•
Section 3.4.2. “Baseline characteristics”, Section 5.2.8. “Standard 
derivations and reporting conventions”, Section 6.5.1.1. “Demographic 
characteristics” – the summary of physical measurements (BMI, height 
and weight) was deleted.
•
Section 3.5.1 and Section 6.6.1 “Adverse events” – updated definition 
of treatment-emergent adverse events to include only adverse events 
with onset dates during the on-treatment period.
•
Section 4.3.1 “DLT-evaluable set” – clarified the definition of DLT-
evaluable set using the number of doses as criteria of “at least 75% 
intended dose”.
•
Section 4.3.2 “PK analysis sets” – updated the definition of PK analysis 
sets. 
•
Section 5.1.1. “Hypotheses and sample size determination” – the Phase 
1b Lead-in dose escalation rules were removed and a reference to 
Section 2.2. was added.
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•
Section 5.3.2 "Handling of incomplete dates" for PK and 
Immunogenicity data was removed because no imputation will be done
for unknown or partially unknown dates.
•
Section 5.3.2.5 “Date of last contact” – added withdrawal of consent 
date in the derivation of date of last contact.
•
Section 5.3.2.8 “Date of start of new anti-cancer therapy” – added 
details of imputation rules for incomplete dates for start date of new 
anti-cancer therapy (drug therapy, radiation, surgery). 
•
Section 6.1.2.1. “Primary analysis” – removed 2-sided 90% CI for 
ORR.
•
Section 6.2.2.2 “Duration of response” – added details regarding 
censoring for duration of response since “no adequate baseline 
assessment” and “no adequate post-baseline assessment” which is used 
in censoring for PFS analyses is not applicable to analyses of duration 
of response for patients with objective response. The listing of duration 
of response time was deleted.
•
Section 6.2.2.2 “Duration of response”, Section 6.2.2.4 “Progression-
free survival” and Section 6.2.2.5 “Overall survival” – added additional 
landmark analyses of probability of being event-free “every 3 months 
as appropriate” to represent longer responses.
•
Section 6.2.2.4. “Progression-free survival” - the summary of time of 
follow-up for PFS was simplified.
•
Section 6.2.2.5. “Overall survival” - the summary of time of follow-up 
for OS was simplified.
•
Section 6.2.5 “Biomarker endpoints” – removed the descriptive 
summary statistics because only the categorical data are available; 
removed the summary for OS for each biomarker category. 
•
Section 6.2.6 “Endpoints for immunogenicity data of avelumab” –
added details for the analysis of ADA and nAB.
•
Section 6.4 “Subset Analyses” – removed subset analyses for the 
following variables based on clinical importance and number of 
patients expected in the subgroups: duration of response, ECOG 
performance score, adenocarcinoma type in NSCLC cohorts.
•
Section 6.5.1.3 “Disease characteristics” – removed summary of 
substance use.
•
Section 6.5.1.4 “Prior anti-cancer therapies” – removed summary by 
drug class. The data will be included in the listing of anti-cancer 
therapies with a flag to identify prior therapies.
•
Section 6.5.1.4. “Prior anti-cancer therapies”, Section 6.5.5. 
“Subsequent anti-cancer therapies” - the listings of anti-cancer 
radiation therapy and anti-cancer surgeries were deleted.
•
Section 6.5.2.2. “Protocol deviations” – Incorrect dose was removed.
•
Section 6.5.3 “Study treatment compliance and exposure” - removed 
by-cycle summaries.
•
Section 6.5.4 “Concomitant medications and non-drug treatments” –
removed summary tables of prior medications, pre-medications and 
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non-drug treatments. The listings of prior medications, concomitant 
medications, pre-medications and non-drug treatments were deleted.

Section 6.5.5 “Subsequent anti-cancer therapies” - removed summary 
by type of therapy. The data will be included in the listing of anti-
cancer therapies.

Section 6.6.1 “Adverse events” and subsections – added summaries of 
adverse events leading to dose reduction of each chemotherapy, and 
summaries of adverse events leading to interruption of each study drug. 
The following summaries were removed: all immune-related AEs 
(irAEs), irAEs leading to death, irAEs of Grade ≥ 3, all infusion related 
reactions (IRRs), IRRs leading to death, IRRs of Grade ≥ 3, time 
related to first onset of an IRR, treatment-related AEs leading to 
discontinuation of each study drug, any and all study drugs. 

Section 6.6.5 “Laboratory data” and subsections – removed descriptive 
summaries by visit as data will be summarized based on newly 
occurring or worsening laboratory abnormalities.  Laboratory test 
results with no CTCAE criteria will not be summarized.

Section 6.6.5.2. “Other laboratory parameters” - the listing of abnormal 
values of laboratory results was removed.

Section 6.6.6 “Vital Signs” – removed summary and listing.

Section 6.6.7 “Electrocardiogram” – removed by-cycle summaries and 
listings. The study-specific QT correction for heart rate (QTcP) has 
been deleted from the SAP.

Section 6.6.8 “Physical Examination” was removed as data not 
collected in the eCRF

Section 6.6.9 “ECOG performance status” – removed the ECOG shift 
table.

Appendix 1 “Immune-Related Adverse Events” – updated the 
definition of irAEs in Table 14 with steps 3 and 4 of the algorithm to be 
checked concurrently. 
Redundant listings or listings that do not provide meaningful information 
were removed. Minor editorial and consistency changes throughout the 
document.
2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991023.  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 (i.e.,
pharmacokinetics [PK] data, immunogenicity data, biomarker data). The primary analysis 
will include all data up to a clinical cut-off date corresponding to 18 months after the last 
patient receives the first dose of study drug.  The final analysis of the data will be performed 
after last patient last visit (LPLV). 
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes.


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2.1. Study Objectives
Primary Objectives
•
Phase 1b lead-in: To assess dose limiting toxicity (DLT) rate of avelumab in 
combination with chemotherapy, as first-line treatment in patients with locally advanced 
or metastatic solid tumors;
•
To assess, per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, 
the objective response rate (ORR) of avelumab in combination with chemotherapy as 
first-line treatment in patients with locally advanced or metastatic solid tumors.
Secondary Objectives
•
To assess the overall safety and tolerability of avelumab in combination with 
chemotherapy; 
•
To characterize the pharmacokinetics (PK) of avelumab and chemotherapy when given in 
combination;
•
To evaluate the immunogenicity of avelumab, when given in combination with 
chemotherapy;
•
To assess the antitumor activity, per RECIST v1.1, of avelumab in combination with 
chemotherapy;
•
To assess the correlation of antitumor activity, per RECIST v1.1, of avelumab in 
combination with chemotherapy, with mutational load in baseline tumor tissue;
•
To assess the correlation of PD-L1 expression in baseline tissue and changes in this 
marker on-treatment, with antitumor activity, per RECIST v1.1, of avelumab in 
combination with chemotherapy.
2.2. Study Design
This is a Phase 1b/2, open-label, multi-center, safety, clinical activity, PK, and 
pharmacodynamics study of avelumab in combination with chemotherapy, as first-line 
treatment of adult patients with locally advanced or metastatic solid tumors.   Initially, 
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avelumab will be evaluated in combination with standard-of-care chemotherapy in patients 
with advanced non-squamous non-small cell lung cancer (NSCLC) and cisplatin-eligible 
urothelial cancer (UC).  These two tumor types were selected for study because they are 
responsive to chemotherapy, which currently is first-line standard-of-care for these 
indications.  In addition, avelumab has shown preliminary evidence of clinical activity in 
both non-squamous NSCLC and UC.
Given the growing preclinical and clinical indications that combinations of anti-cancer 
immunotherapies potentially improve patient outcomes compared to results seen with single 
agents, in portions of the study to be added in the future, avelumab will be evaluated in 
combination with both standard-of-care chemotherapy and other anti-cancer 
immunotherapies in patients with advanced malignancies.  Addition of new therapy 
combinations will be based on emerging preclinical and clinical data supportive of the 
tolerability and potential clinical benefit of each agent to be combined (eg, chemotherapy, 
anti-cancer immunotherapy agents) with avelumab and will be accomplished by protocol 
amendment.
Avelumab in combination with chemotherapy (Group A) will be evaluated as follows:

Cohort A1: avelumab 800 mg Q3W plus pemetrexed/carboplatin in patients with non-
squamous NSCLC;

Cohort A2: avelumab 800 mg Q3W plus gemcitabine/cisplatin in patients with cisplatin-
eligible UC;

Cohort A3: avelumab 1200 mg Q3W plus pemetrexed/carboplatin in patients with 
non-squamous NSCLC;

Cohort A4: avelumab 1200 mg Q3W plus gemcitabine/cisplatin in patients with 
cisplatin-eligible UC.
Patients are not allowed to cross over between the different combinations evaluated in this 
study.
Each combination will be studied in 2 phases: 

a Phase 1b lead-in to evaluate preliminary safety of the combination;

a Phase 2 cohort expansion to evaluate preliminary efficacy and further evaluate safety.  
Phase 1b Lead-in
The safety of avelumab will be assessed independently in combination with each of the two 
different chemotherapy regimens.
The 1200 mg Q3W dosing regimen is being explored additionally in this Phase 1b/2 trial 
since it is projected to maintain the avelumab average exposures close to those observed with 


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the approved dose of 10 mg/kg Q2W while extending the dosing interval for use in 
combination with Q3W chemotherapy regimens.
Up to 12 patients will be enrolled into each cohort defined above and evaluated for DLT 
during the first 2 cycles of treatment as follows:
Cohorts A1 and A2: 

Enroll and treat up to 6 DLT-evaluable patients in each cohort:
-
If 1 of 6 patients experiences DLT in Cohort A1 (or A2), enrollment may be 
initiated in Phase 1b Cohort A3 (or A4);
-
If 3 of up to 6 patients experience DLT in Cohort A1 (or A2), enrollment in 
Cohort A1 (or A2) will be discontinued; there will be no further enrollment of 
patients with the combination;
-
If 2 of 6 patients experience DLT in Cohort A1 (or A2), the cohort will be expanded 
to enroll up to 6 additional DLT-evaluable patients in the Phase 1b Cohort A1 
(or A2);

If 3 of 12 patients experience DLT in Cohort A1 (or A2), enrollment may be 
initiated in Phase 1b Cohort A3 (or A4);

If 4 of up to 12 patients experience DLT in Cohort A1 (or A2), enrollment in 
the Cohort A1 (or A2) will be discontinued; there will be no further enrollment of 
patients with the combination. 
Cohorts A3 and A4: 

Enroll and treat up to 6 DLT-evaluable patients in each cohort:
-
If 1 of 6 patients experience DLT in Cohort A3 (or A4), enrollment may be initiated
in Phase 2 Cohort A3 (or A4) expansion with the study treatment of avelumab 
1200 mg Q3W in combination with chemotherapy; there will not be any enrollment 
in Phase 2 Cohort A1 (or A2) expansion with the study treatment of avelumab 
800 mg Q3W in combination with chemotherapy;
-
If 3 of up to 6 patients experience DLT in Cohort A3 (A4), enrollment in Cohort A3 
(or A4) will be discontinued; enrollment may be initiated in Phase 2 Cohort A1 
(or A2) expansion with the study treatment of avelumab 800 mg Q3W in combination 
with chemotherapy;
-
If 2 of 6 patients experience DLT in Cohort A3 (or A4), the Cohort A3 (or A4) will 
be expanded to enroll up to 6 additional DLT-evaluable patients;

If 3 of 12 patients experience DLT in Cohort A3 (or A4), enrollment may be 
initiated in Phase 2 Cohort A3 (or A4) expansion with the study treatment of 


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avelumab 1200 mg Q3W in combination with chemotherapy; there will not be 
any enrollment in Phase 2 Cohort A1 (or A2) with the study treatment of 
avelumab 800 mg Q3W in combination with chemotherapy;

If 4 of up to 12 patients experience DLT in Cohort A3 (or A4), enrollment may 
be initiated in Phase 2 Cohort A1 (or A2) expansion with the study treatment of 
avelumab 800 mg Q3W in combination with chemotherapy.
Phase 2 Cohort Expansion
If investigational products administration in the Phase 1b Lead-in portion of a given cohort is 
deemed safe based on the criteria described in “Phase 1b lead-in” Section, then enrollment 
into that cohort may continue into the Phase 2 Cohort Expansion.  
The dose of avelumab to be administered in the Phase 2 Cohort Expansion (800 mg Q3W for 
Cohorts A1 and A2 or 1200 mg Q3W for Cohorts A3 and A4) will be determined based on 
the number of observed DLTs as described in “Phase 1b Lead-in” section.  The highest dose 
level of avelumab deemed safe for the combination will be advanced.
For the cohort of patients with cisplatin-eligible UC selected to expand to Phase 2, up to 
approximately 40 patients, including those enrolled in Phase 1b Lead-in and those enrolled in 
the Phase 2 Cohort Expansion, will be treated with the combination of avelumab and 
chemotherapy with or without other immunotherapies. For the cohort of patients with 
non-squamous NSCLC selected to expand to Phase 2, approximately 20 patients, including 
those enrolled in Phase 1b Lead-in and those enrolled in the Phase 2 Cohort Expansion, will 
be treated with the combination of avelumab and chemotherapy with or without other 
immunotherapies.  Up to approximately 80 patients in the Phase 1b lead-ins and 
Phase 2 cohort expansions combined for cisplatin-eligible UC and non-squamous NSCLC 
will be enrolled in Group A.
For both Phase 1b lead-in and Phase 2 cohort expansion, all patients will initially receive 
either avelumab in combination with chemotherapy (Group A) or avelumab in combination 
with chemotherapy and other anti-cancer immunotherapies in portions of the study to be 
added in the future.  Patients will continue to receive study treatment until disease 
progression is confirmed by the Investigator, patient refusal, unacceptable toxicity, or until 
the study is terminated by the Sponsor, whichever occurs first.  In Cohorts A1 and A3, 
treatment with carboplatin and pemetrexed will continue for a maximum of 4-6 cycles; in
addition, maintenance therapy with pemetrexed may be administered at the discretion of the 
Investigator.  In Cohorts A2 and A4, treatment with chemotherapy will continue until 
optimal response is achieved.
If discontinuation of chemotherapy is required for any reasons other than progressive disease 
or protocol-specified limits, treatment with avelumab (Group A) or avelumab and/or the 
other anti-cancer immunotherapies in future portions of the study should be continued. 


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Patients who stop avelumab or the other anti-cancer immunotherapies for unacceptable 
toxicity may continue treatment with the investigational product(s) (eg, chemotherapy) that 
is/are not considered to be responsible for the toxicity observed.
Figure 1
Study Design Schema 
  
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND
CONVENTIONS
3.1. Primary Endpoints

Phase 1b lead-in: First 2 cycles DLT.
Severity of adverse events will be graded according to Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.  Any of the following adverse events (AEs)
occurring in the first 2 cycles (cycle duration with no delays is 21 days) of treatment 
during the Phase 1b lead-in of each cohort that are attributable to one or more of the 
investigational products will be classified as DLTs:
Hematologic:
-
Grade 4 neutropenia (absolute neutrophil count [ANC] <500/mm3 or <0.5 x 109/L) 
lasting >7 days;


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-
Febrile neutropenia, defined as ANC <1000/mm3 with a single temperature of
>38.3 degrees C (>101 degrees F) or a sustained temperature of ≥38 degrees C
(100.4 degrees F) for more than 1 hour;
-
Neutropenic infection (ANC <1,000/mm3 or <1.0 x 109/L, and Grade >3 infection);
-
Grade ≥3 thrombocytopenia (platelet count <50,000 - 25,000/mm3 or <50.0 ̢
25.0 × 109/L) with bleeding;
-
Grade 4 thrombocytopenia (platelet count <25,000/mm3 or <25.0 x 109/L);
-
Grade 4 anemia (life-threatening consequences; urgent intervention indicated).
Non-Hematologic:
-
Grade 4 toxicities;
-
Grade 3 toxicities persisting for > 3 days despite adequate medical management (eg, 
nausea, vomiting, and diarrhea) except for endocrinopathies controlled with hormonal 
therapy;
-
Potential Hy’s law cases defined as: ALT or AST > 3 x the upper limit of normal 
(ULN) if normal at baseline OR ALT or AST doubling the baseline (if > ULN at 
baseline) associated with total bilirubin > 2 x ULN and an alkaline phosphatase < 2 x 
ULN.
-
In an asymptomatic patient, Grade 3 QTcF prolongation (QTcF ≥501) will first 
require repeat testing, re-evaluation by a qualified person, and correction of reversible 
causes, such as electrolyte abnormalities or hypoxia, for confirmation.  If, after 
correction of any reversible causes, the Grade 3 QTcF prolongation persists, then the 
event should be considered a DLT.
Non-Adherence to Treatment Schedule:
-
Delay of ı3 weeks in receiving the next scheduled administration due to persisting
treatment-related toxicities;
-
Failure to deliver at least 75% of the planned doses each of the investigational 
products during the first 2 cycles due to treatment-related toxicities.
Grade ≥3 laboratory abnormalities without a clinical correlate and not requiring medical 
intervention do not constitute a DLT.  Grade≥ 3 laboratory abnormalities also have to 
represent a clinically relevant shift from baseline to be considered a DLT.
While the rules for adjudicating DLTs are specified above, an AE not listed above, or an 
AE meeting the DLT criteria above but occurring outside of the DLT observation period 
may be defined as a DLT after consultation between Sponsor and Investigator, based on 
the emerging safety profile for the combinations.


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
Confirmed objective response (OR), as assessed by the Investigator using RECIST v1.1.
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the date of first dose of study treatment until the date of the first documentation 
of progressive disease (PD). Both CR and PR must be confirmed by repeat assessments 
performed no less than 4 weeks after the criteria for response are first met.
3.2. Secondary Endpoints
3.2.1. Safety endpoints

AEs as characterized by type, severity (as graded by National Cancer Institute [NCI] 
CTCAE v.4.03), timing, seriousness, and relationship to study treatments;
AEs will be graded by the investigator according to the NCI CTCAE version 4.03 and 
coded using the Medical Dictionary for Regulatory Activities (MedDRA)

Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v.4.03) and timing.
3.2.2. Efficacy endpoints

Time-to-event endpoints including progression-free survival (PFS), duration of response 
(DR), time to tumor response (TTR), as assessed by the Investigator using RECIST v1.1; 
and overall survival (OS);
DR is defined, for patients with OR, as the time from the first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.  
TTR is defined, for patients with an OR, as the time from the date of first dose of study 
treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
PFS is defined as the time from the date of first dose of study treatment to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.
OS is defined as the time from the date of first dose of study treatment to the date of 
death due to any cause.
3.2.3. Pharmacokinetic endpoints

PK parameters of avelumab; 

PK parameters of chemotherapies, as data permit.
Serum PK parameters of avelumab will be reported including but not limited to Cmax and 
Ctrough after single dose and at multiple dose/steady state. PK parameters of 
chemotherapies will be reported as data permit, including but not limited to Cmax,  Ctrough, 
Tmax, AUCss,, and AUClast following multiple dosing.


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Dose-normalized (dn) parameters will be reported as appropriate.
Table 2.
PK Parameters to be Determined for Avelumab and Chemotherapya
Parameter
Definition
Method of Determination
AUClast b
Area under the plasma concentration-time 
profile from time zero to the time of the last 
quantifiable concentration (Clast) for 
chemotherapy
Linear/Log trapezoidal method
AUCss, τ b
Area under the plasma concentration-time 
profile from time zero to the next dose (after 
multiple doses)
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
Ctrough
Predose concentration during multiple dosing
Observed directly from data
AUCss, τ(dn)b
Dose normalized AUCss, τ
AUCss, τ / Dose
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
Ctrough(dn)
Dose normalized Ctrough
Ctrough / Dose
a Chemotherapy includes carboplatin, cisplatin, gemcitabine, pemetrexed (including any bioanalytically-quantified 
analytes associated with the drug as applicable, e.g. metabolites, or free and total forms of drug)
b if data permit.
3.2.4. Immunogenicity endpoints

Anti-drug antibody (ADA) levels;
The presence of ADA / Neutralizing antibodies (nAb) for avelumab when used in 
combination with chemotherapy (in Cohorts A1 and A2).
3.2.5. Biomarker endpoints

Mutational load within baseline tumor tissue.

PD-L1 expression in baseline and on-treatment tumor tissue.
Table 3.
Biomarker Definition and Determination
Parameter
Definition
Method of Determination
Mutational load within 
baseline tumor tissue
The total number or number per megabase of 
the genome, coding, base substitution, and 
indel mutations present in the sample.
Next generation sequencing 
followed by computational 
analysis.
PD-L1 expression at 
baseline and on 
treatment
The number of PD-L1 positive cells and/or 
qualitative assessment of PD-L1 staining on 
tumor and inflammatory cells in regions of 
interest
Pathologist, assisted by 
image analysis.


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3.4. Baseline Variables
3.4.1. Study drug, study treatment and baseline definitions
In this study, ‘study drug’ refers to avelumab, and chemotherapies (carboplatin, cisplatin, 
gemcitabine, pemetrexed), and ‘study treatment’ (or ‘treatment group’) refers to one of 
the following:
•
Cohort A1: avelumab 800 mg Q3W plus pemetrexed/carboplatin in patients with non-
squamous NSCLC;
•
Cohort A2: avelumab 800 mg Q3W plus gemcitabine/cisplatin in patients with cisplatin-
eligible UC;
•
Cohort A3: avelumab 1200 mg Q3W plus pemetrexed/carboplatin in patients with non-
squamous NSCLC;
•
Cohort A4: avelumab 1200 mg Q3W plus gemcitabine/cisplatin in patients with cisplatin-
eligible UC.
Start and end dates of study treatment:
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination. 
The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination.
Definition of baseline: 
Definition of baseline for efficacy analyses and for safety analyses
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for safety and efficacy analyses.  If an assessment is planned 
to be performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
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is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of
Treatment (EOT) visit). Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
3.4.2. Baseline characteristics
Baseline characteristics (including demographics, disease history and prior anti-cancer 
therapies) are described in Section 6.5.1.  These baseline characteristics are not planned to be 
included as stratification variables or covariates in statistical models unless otherwise 
specified in Section 6.  
3.5. Safety Endpoints
3.5.1. Adverse events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs)
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendix 1 and 0, 
respectively.


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4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
The full analysis set (FAS) will include all patients who receive at least one dose of study 
drug.  Patients will be classified according to the study treatment actually received.  If a 
patient receives more than one treatment the patient will be classified according to the first 
study treatment received.
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug.  
Patients will be classified according to the study treatment actually received.  If a patient 
receives more than one study treatment, the patient will be classified according to the first 
study treatment received. In this non-randomized study, the FAS and the safety analysis set 
are identical.
4.3. Other Analysis Set
4.3.1. DLT-evaluable set
The DLT analysis set is a subset of the safety analysis set and includes all enrolled patients in 
the Phase 1b lead-in who are eligible for the study, receive at least one dose of the 
combination treatment, and either experience DLT during the first 2 cycles (6 weeks) of 
treatment, or complete the DLT observation period for the first 2 cycles of treatment.  
Patients without DLTs who withdraw from study treatment before receiving at least 75% of 
the prescribed doses for 2 cycles for all investigational products in the combination for 
reasons other than treatment-related toxicity (eg, missed appointments or development of 
rapidly progressing disease, consent withdrawal) are not evaluable for DLT. To meet the 
criteria of “at least 75% intended dose”, the patient must have received at least 2 of the 2 
intended doses for each study drug except gemcitabine, or 3 of the 4 intended doses for 
gemcitabine during the DLT observation period.
4.3.2. PK analysis sets
The PK concentration analysis sets (one unique set for each study drug used in the 
combination treatment) are subsets of the safety analysis set including patients who have at 
least one concentration measurement for avelumab or other study drugs (including any 
bioanalytically-quantified analytes associated with the drug, e.g. metabolites, free and total 
forms of drug, or enantiomers) which they were assigned to receive, based on the treatment 
group. 
The PK parameter analysis sets (one unique set for each study drug used in the combination 
treatment) are subsets of the safety analysis set including patients who have at least one PK 


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parameters of interest for avelumab or the other study drugs (including any bioanalytically-
quantified analytes associated with the drug, e.g. metabolites, free and total forms of drug, or 
enantiomers) which they were assigned to receive, based on the treatment group.
4.3.3. Biomarker analysis sets
The biomarker analysis set is a subset of the safety analysis set including patients who have 
at least one baseline biomarker assessment.  Analysis sets will be defined separately for 
blood-based and tumor tissue-based biomarkers.
For the analysis of tumor tissue-based biomarkers in paired biopsies, the analysis set is a 
subset of the safety analysis set including patients who have at least one baseline and one on-
treatment biomarker assessment for the same biomarker.
4.3.4. Immunogenicity analysis set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample collected for avelumab.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and sample size determination
Phase 1b lead-in
There is no formal hypothesis testing in this phase. However, before expanding each cohort 
into the Phase 2 cohort expansion, the safety of the combination in a cohort must be 
confirmed in DLT-evaluable patients in the Phase 1b lead-in. 
Up to 12 patients will be enrolled into each treatment group in the Phase 1b lead-in and 
evaluated for DLT during the first 2 cycles of treatment as follows (see Section 2.2 Phase 1b 
Lead-in).
Phase 2
In Phase 2 enrollment in each treatment group will be expanded to a total of up to 
approximately 40 patients (including those enrolled in Phase 1b lead-in and those enrolled in 
Phase 2). 
Phase 1b and 2 combined
Based on safety data for patients with cisplatin-eligible UC, the Phase 1b lead-in from either 
Cohort A2 (800 mg avelumab plus chemotherapy) or cohort A4 (1200 mg avelumab plus 
chemotherapy) may be selected to continue enrollment into the Phase 2 cohort expansion. 
Up to approximately 40 patients with cisplatin-eligible UC, including Phase 1b lead-in and 
Phase 2 cohort expansion patients, may receive the selected avelumab dose plus 
chemotherapy.


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Based on safety data for patients with non-squamous NSCLC, the Phase 1b lead-in from 
either Cohort A1 (800 mg avelumab plus chemotherapy) or Cohort A3 (1200 mg avelumab 
plus chemotherapy) may be selected to continue enrollment into the Phase 2 cohort 
expansion. Up to approximately 20 patients with non-squamous NSCLC, including Phase 1b 
lead-in and Phase 2 cohort expansion patients, may receive the selected avelumab dose plus 
chemotherapy.
With 40 patients with cisplatin-eligible UC and 20 patients with non-squamous NSCLC in 
Phase 1b and Phase 2 combined, ORR can be estimated with a maximum standard error of 
0.079 and 0.112, respectively. Table 4 provides the exact binomial 90% confidence intervals 
(CIs) for ORR based on different observed responses in a treatment group.
Table 4.
Sample Size and Exact 90% CI for ORR in each treatment group
N per treatment 
group
Number of 
responders
Observed ORR
90% CI for ORR
20
1
5%
(0.3% – 21.6%)
2
10%
(1.8% – 28.3%)
3
15%
(4.2% – 34.4%)
4
20%
(7.1% – 40.1%)
5
25%
(10.4% – 45.6%)
6
30%
(14.0% – 50.8%)
7
35%
(17.7% – 55.8%)
8
40%
(21.7% – 60.6%)
9
45%
(25.9% – 65.3%)
10
50%
(30.2% – 69.8%)
12
60%
(39.4% – 78.3%)
15
75%
(54.4% – 89.6%)
40
2
5%
(0.9% – 14.9%)
4
10%
(3.5% – 21.4%)
6
15%
(6.7% – 27.5%)
8
20%
(10.4% – 33.2%)
10
25%
(14.2% – 38.7%)
12
30%
(18.3% – 44.0%)
14
35%
(22.6% – 49.2%)
16
40%
(26.9% – 54.2%)
18
45%
(31.5% – 59.1%)
20
50%
(36.1% – 63.9%)
24
60%
(45.8% – 73.1%)
30
75%
(61.3% – 85.8%)
35
87.5%
(75.5% – 94.9%)
CI=confidence interval; ORR=objective response rate


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5.1.2. Decision rules
Phase 1b lead-in
The Table 5 below shows the probability of meeting DLT requirements to escalate to dose 
level of avelumab 1200 mg Q3W in combination with chemotherapy.  For example, for a 
DLT that occurs in 10% of patients, there is a greater than 97% probability of confirming 
safety and escalating to avelumab 1200 mg Q3W. Conversely, for a DLT that occurs with a 
rate of 60%, the probability of escalating is 5%.
Table 5.
Probability of Escalating Dose Level of Avelumab to 1200 mg Q3W after 
Phase 1b Lead-in of Each Cohort (from A1 to A3 and from A2 to A4)
True underlying DLT rate*
10%
20%
30%
40%
50%
60%
70%
80%
90%
Probability of escalating dose 
level of avelumab
0.97
0.82
0.56
0.31
0.14
0.05
0.01
0.002
<0.0001
*True underlying DLT rate for the combination of avelumab 800 mg Q3W with chemotherapy.
Phase 2
There are no formal decision rules in this phase of the study. 
5.2. General Methods
As described in Section 3.4, in this study ‘treatment group’ refers to one of the following:

Cohort A1: avelumab 800 mg Q3W plus pemetrexed/carboplatin in patients with non-
squamous NSCLC;

Cohort A2: avelumab 800 mg Q3W plus gemcitabine/cisplatin in patients with cisplatin-
eligible UC;

Cohort A3: avelumab 1200 mg Q3W plus pemetrexed/carboplatin in patients with non-
squamous NSCLC;

Cohort A4: avelumab 1200 mg Q3W plus gemcitabine/cisplatin in patients with cisplatin-
eligible UC.
Each chemotherapy doublet will be administered IV as shown in Table 6.
Table 6.
Chemotherapy Doublets (IV) 
Chemotherapy Doublet
Dose(s) and Schedule 
(21-day cycle)a
Cohort
Tumor Type
Pemetrexed/Carboplatin
A1, A3
Non-squamous NSCLC
    Pemetrexed
500 mg/m2, Day 1
    Carboplatin
AUC 5, Day 1
Gemcitabine/Cisplatin
A2, A4
UC
    Gemcitabine
1000 mg/m2, Day 1 and Day 8
    Cisplatin
70 mg/m2, Day 1
a Order of administration is as appears in the table.  For example, for the pemetrexed/carboplatin doublet, pemetrexed is 
administered prior to carboplatin.  


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Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment group including the data from the combined Phase 1b lead-in and Phase 2. 
DLTs will be summarized based on the DLT-evaluable set by treatment group including data 
from Phase 1b lead-in only.
Other safety data, exposure data, concomitant medications and non-drug treatments will be 
summarized based on the safety analysis set by treatment group including the data from the 
combined Phase 1b lead-in and Phase 2.
PK data will be summarized based on the PK analysis sets by treatment group including the 
data from the combined Phase 1b lead-in and Phase 2.
Biomarker data will be summarized based on the biomarker analysis sets by treatment group
including the data from the combined Phase 1b lead-in and Phase 2.
Immunogenicity data will be summarized based on the immunogenicity analysis set by 
treatment group including the data from the combined Phase 1b lead-in and Phase 2.
5.2.1. Data handling after the cut-off date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients treated at each center.
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.


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5.2.4. Definition of study day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment (eg, 
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. Definition of start of new anti-cancer drug therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.2.8 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of start of new anti-cancer therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.2 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment amongst the following:

Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages

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 ‘On-Study Cancer Surgery’, and ‘Follow-up Surgery’ eCRF 
pages when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially Resected’.  
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.2.8 should be applied using ‘Follow-up Cancer Therapy’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘On-Study Cancer 
Surgery’, and ‘Follow-up Surgery’ eCRF pages.


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5.2.7. Definition of on-treatment period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard derivations and reporting conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

Age [years]: 
-
(date of given informed consent - date of birth + 1) / 365.25
-
In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth)
-
In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth)
The integer part of the calculated age will be used for reporting purposes. 
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits
(if such analyses are performed).


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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 first dose of 
study treatment.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions).
5.2.11. Adequate post-baseline tumor assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.1.2.1).  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. If this is performed, a footnote 
or other documentation in the clinical study report (CSR) detailing the exclusions will 
be provided. 
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 at the discretion of the clinical pharmacologist.  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 or flagged 
in the listings and will not be included in the calculation of summary statistics or statistical 
analyses.
5.3.2. Handling of incomplete dates
5.3.2.1. Disease history
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows:

If the day is missing, it will be imputed to the 15th day of the month. 

If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st.

If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st. 

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.


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
If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015.

If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 
treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014.

In all other cases the missing onset day or missing onset month will be replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off outcome of AE is ongoing at cut-off. 
5.3.2.3. Prior and concomitant medications
Incomplete prior/concomitant medication dates will be imputed as follows:

If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment.

If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015. 

If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014.

In all other cases the missing medication day or missing medication month will be 
replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete medication stop date will not be imputed. 


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5.3.2.4. Exposure
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows:

If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date

If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date) 
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date)
= min (EOT date, death date), for all other cases.
Imputation rules for date of last contact and efficacy assessments
5.3.2.5. 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 (eg. 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 where “Subject Remains in Follow-up” or “Subject No Longer Being 
Followed for Survival” collected on the “Survival Follow-up” eCRF

Study drug start and end dates

Withdrawal of consent date

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up or death).
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.
5.3.2.6. Death date
Missing or partial death dates will be imputed based on the last contact date:

If the date is missing it will be imputed as the day after the date of last contact 


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
If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following:
-
Missing day:
1st day of the month and year of death
-
Missing day and month:
January 1st of the year of death
5.3.2.7. 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.
5.3.2.8. 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. If the imputation results in an end date prior to the imputed 
start date then the imputed start date should be set to the end date.

The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is
o
completely missing then it will be ignored in the imputations below
o
partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy
o
partially missing with only month and year available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy

For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below. 


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
If the start date of new anti-cancer therapy is completely or partially missing, then the 
imputed start date of new anti-cancer therapy is derived as follows:
o
Start date of new anti-cancer therapy is completely missing
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy]
o
Only year (YYYY) for start of anti-cancer therapy is available
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY; 
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = 01JANYYYY
o
Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available
IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]);
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 


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THEN 
imputed start date = 01 MMM YYYY;
ELSE IF
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
THEN 
imputed start date = 01 MMM YYYY.
6. ANALYSES AND SUMMARIES 
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.
6.1. Primary Endpoints 
6.1.1. DLT for Phase 1b
6.1.1.1. Primary analysis
The following analyses will be based on the DLT-evaluable set for patients in the Phase 1b 
lead-in.  DLTs will be listed and summarized by treatment group.
6.1.2. Objective response as assessed by the Investigator per RECIST v1.1 
6.1.2.1. Primary analysis
The following analyses will be based on the FAS by treatment group using the data from the 
combined Phase 1b lead-in and Phase 2.  Assessment of response will be made using 
RECIST v1.1. Assessments below refer to investigator assessment.   
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the date of first dose of study treatment until the first 
documentation of PD, according to the following rules. Only tumor assessments performed 
on or before the start date of any further anti-cancer therapies will be considered in the 
assessment of BOR.  Clinical deterioration will not be considered as documentation of 
disease progression.

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) 


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
SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of first dose of study treatment and before 
first documentation of PD (and not qualifying for CR or PR). 

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the date of first dose 
of study treatment and before first documentation of PD (and not qualifying for CR or 
PR).

PD = first documentation of PD ≤ 12 weeks after the date of first dose of study treatment 
(and not qualifying for CR, PR, SD or non-CR/non-PD).  

NE:  all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the rare 
case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-
SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met.
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set.
ORR by treatment group will also be calculated along with the 2-sided 95% CI using the 
Clopper-Pearson method 2 (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option). 
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 first dose of study treatment 
without further evaluable tumor assessments)


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
PD too late (>12 weeks after the date of first dose of study treatment)
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD too early’ (ie, SD of insufficient duration).
6.2. Secondary Endpoint(s)
6.2.1. Safety endpoints
Refer to Section 1.1.
6.2.2. Efficacy endpoints
The following analyses will be based on the FAS by treatment group using the data from the 
combined Phase 1b lead-in and Phase 2.  Assessment of response will be made using 
RECIST v1.1.  Tumor-related endpoints will be analyzed based on investigator assessment.  
6.2.2.1. Tumor shrinkage from baseline
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:

((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment group. 
These plots will display the best percentage change from baseline in the sum of the diameters
of all target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment.
6.2.2.2. Duration of response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are described in Table 7.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375


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Table 7.
Outcome and Event Dates for DR Analyses
Scenario
Date of event/censoring
Outcome
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 12 weeks after the date of first dose of 
study treatment
Date of PD or death
Event
PD or death 
-
After 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored
No PD and no death
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived 
based on documented 
progression only.
New anti-cancer therapy given prior to PD or 
death
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with 2-sided 
95% CIs.  In particular, the DR rates at 3, 6, 9, 12 months and every 6 months after as 
appropriate will be estimated with corresponding 2-sided 95% CIs.  The CIs for the median 
will be calculated according to Brookmeyer and Crowley (1982)1 and the CIs for the survival 
function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 8 following the hierarchy shown.


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Table 8.
DR Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
Start of new anti-cancer therapy before event  
Start of new anti-cancer therapy
2 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization
Event after 2 or more missing 
assessments a
3
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment]
Withdrawal of consent
4
No event and lost to follow-up in any disposition page 
Lost to follow-up
5
No event and [disposition page for any epoch after 
screening says patient will not continue into any 
subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
6 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
6.2.2.3. Time to response
Time to response (TTR) is defined, for patients with OR, as the time from the date of first 
dose of study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
TTR (in months) = [first date of OR – date of first dose of study treatment 
+1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.4. Progression-free survival
Progression-Free Survival (PFS) is defined as the time from the date of first dose of study 
treatment to the date of the first documentation of PD or death due to any cause, whichever 
occurs first.   
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.  Patients who do not have an adequate baseline tumor assessment or who do not 
have an adequate post-baseline tumor assessment will be censored on the date of first dose of 
study treatment unless death occurred on or before the time of the second planned tumor 
assessment (ie ≤ 12 weeks after the date of first dose of study treatment) in which case the 
death will be considered an event. 
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every 6 weeks until PD regardless of initiation of subsequent 
anti-cancer therapy.  After 8 time (one year) from the date of first dose of study treatment, 
tumor assessments will be conducted less frequently, ie, at 12-week intervals.


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The censoring and event date options to be considered for the PFS analysis are presented in 
Table 9.  
PFS (months) = [date of event or censoring– date of first dose of study treatment 
+1]/30.4375
Table 9.
Outcome and Event Dates for PFS Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
date of first dose of study 
treatment a
Censored a
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤12 weeks after the date of first dose of 
study treatment
Date of PD or death
Event
PD or death 
-
After 2 or more missing or inadequate 
post-baseline tumor assessments 
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
No PD and no death
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived 
based on documented 
progression only.
New anti-cancer therapy given prior to PD or 
death
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 ≤12 weeks after the date of first dose of study treatment and did not initiate new anti-
cancer therapy, the death is an event with date on death date
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided 
95% CIs.  In particular, the PFS rates at 3, 6, 9, 12, 15 months and every 6 months after as 
appropriate will be estimated with corresponding 2-sided 95% CIs.  The CIs for the median 
will be calculated according to Brookmeyer and Crowley (1982)1 and the CIs for the survival 
function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 


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estimate of the standard error will be computed using Greenwood’s formula. PFS will be 
displayed graphically and analyzed using Kaplan-Meier methodology. 
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 10 following the hierarchy shown.
Table 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 before event
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of first dose of study treatment
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [disposition page for any epoch after 
screening says patient will not continue into any 
subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A Kaplan-Meier plot for PFS follow-up duration will also be generated to assess the follow-
up time in the treatment groups reversing the PFS censoring and event indicators, including 
the median time of follow-up for PFS with 2-sided 95% CIs.  
6.2.2.5. Overall Survival
Overall survival (OS) is defined as the time from the date of first dose of study treatment to 
the date of death due to any cause. Patients last known to be alive will be censored at date of 
last contact.
OS (months) = [date of death or censoring– date of first dose of study treatment 
+1]/30.4375
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rates at 3, 6, 9, 12, 15, 18 months and every 6 months after as 
appropriate will be estimated with corresponding 2-sided 95% CIs.  The CIs for the median 
will be calculated according to Brookmeyer and Crowley (1982)1 and the CIs for the survival 


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function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)3 (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.  OS will be 
displayed graphically and analyzed using Kaplan-Meier methodology.  
Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 11 following the hierarchy shown.
Table 11.
OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 14 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators, including the 
median time of follow-up for OS with 2-sided 95% CIs.  
6.2.3. Pharmacokinetic endpoints
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
group.  
Cmax and Ctrough for avelumab, and Cmax, Ctrough, Tmax, and AUCss,, as data permit for each 
chemotherapy agent, will be summarized descriptively (n, mean, SD, CV, median, minimum,
maximum, geometric mean, its associated CV, and 95% CI) by treatment group, cycle, and 
day (as applicable).
Dose normalized parameters (eg, Cmax(dn), Ctrough(dn)) will be reported as appropriate. 
Pharmacokinetic parameters for avelumab and each chemotherapy (carboplatin, cisplatin, 
gemcitabine, pemetrexed) will be taken from observed values or derived from plasma 
concentration-time data as described in Section 3.2.2.


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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 group, dose level, cycle, 
day and nominal time. Additionally, similar descriptive statistics may also be 
generated for dose-normalized avelumab pharmacokinetic parameters.

Linear-linear and/or log-linear plots of mean, median and/or individual plasma 
concentrations by nominal time for chemotherapy (carboplatin, cisplatin, 
gemcitabine, pemetrexed), including individual bioanalytically-quantified analytes 
associated with each study drug as applicable, may be presented for PK sampling 
days by treatment group, cycle, and study day. Patients who have undergone 
intrapatient dose reduction or escalation will be excluded from the median plasma 
concentration-time plots.

Pharmacokinetic parameters for avelumab and each chemotherapy (carboplatin, 
cisplatin, gemcitabine, pemetrexed) will be listed and summarized by treatment 
group/dose level, cycle and study day (as applicable) using descriptive statistics (n, 
mean, SD, %CV, median, minimum, maximum, geometric mean and its associated 
%CV, and 95% CI). For Tmax, the range (min, max) will also be provided. PK 
parameters with zero values will be excluded from the calculation of geometric means 
and its associated %CV. If an intrapatient dose escalation or reduction occurs, dose-
dependent PK parameters (AUC, Cmax and Ctrough, as applicable) 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 Ctrough parameters for avelumab will be 
summarized (as described above) using data pooled across treatment groups in which 
different avelumab doses were administered.

Box plots for selected PK parameters (ie. Cmax and/or Ctrough for avelumab) will be 
generated for each treatment group. Individual data points, the geometric mean and 
the median of the parameter in each treatment will be overlaid on the box plots. If a 
treatment group has limited evaluable PK data (n<4), matchstick plots showing the 
PK parameter 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. In 
addition, box plots for dose-normalized avelumab Cmax and Ctrough parameters will be 
created using either data pooled across treatment groups in which different avelumab 
doses were administered (if needed to increase sample size in summary figures) or 
separated by treatment group (to illustrate dose linearity considerations).

Ctrough for avelumab will be plotted for each treatment group using a box-whisker plot 
by cycle and day within cycle in order to assess the attainment of steady-state.
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 


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association between avelumab and chemotherapy (carboplatin, cisplatin, gemcitabine, 
pemetrexed) exposure and biomarkers or significant safety/efficacy endpoints. The results of 
these analyses, if performed, may be reported separately.
6.2.5. Biomarker endpoints
Secondary endpoints in the study are candidate predictive biomarkers in tumor tissue 
including PD-L1 expression and mutational load at baseline and change in PD-L1 expression 
upon treatment.
Biomarker data will be analyzed based on the full analysis sets as defined in Section 4.3.3. 
Data will be presented by treatment group including the data from the combined Phase 1b 
lead-in and Phase 2.
Biomarkers will be listed and summarized at all timepoints described below: 

Tumor based biomarkers from archival FFPE tumor tissue block at screening 

Tumor based biomarkers from de novo tumor biopsy at screening, on treatment and 
end of treatment. 
Where patients provide both archival and de novo samples at screening, data from the de 
novo sample will be used in the summary analysis.
For both biomarkers, patients may be classified as positive, negative, unknown, or some 
other category according to scoring algorithms and cut-offs established from external 
sources.  If no external standards exist, biomarkers may be stratified using the median, 
quartiles and tertiles. The number and percentage of patients in each category will be 
tabulated.
BOR and OR will be summarized by treatment group and for each category following the 
methodology outlined in Section 6.1.2.1. Tumor shrinkage will be plotted by treatment group 
and by biomarker category following the methodology outlined in 6.2.2.1. 
DR and PFS (if meaningful) will be summarized for the cohort of UC patients that is 
expanded to Phase 2 (A2 or A4) for each biomarker category following the methodology 
outlined in Sections 6.2.2.2 and 6.2.2.4. The censoring rules for DR and PFS are as described 
in Table 7 and Table 9.
6.2.6. Endpoints for immunogenicity data of avelumab 
ADA and Nab data will be listed and summarized for avelumab by treatment group including 
data from the combined Phase 1b lead-in and Phase 2. 
The percentage of patients with positive ADA and neutralizing antibodies each will be 
summarized. For patients with positive ADA, the magnitude (titer), time of onset, and 
duration of ADA response will also be described, if data permit. A comparison of the safety, 
efficacy, and avelumab PK endpoints between avelumab ADA and nAb positive vs. negative 
patients may be performed, if data permit.


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Blood samples for avelumab immunogenicity testing will be collected from all patient’s pre-
dose on Day 1 of Cycles 1, 2, 3, 6, 10, and 14, and at End of Treatment. 
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.  Analyses 
of nAb data described in the following sections will 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 12.  
Table 12.
Patients Characterized Based on Anti-Drug Antibody Results (ADA Status)
Category
Definition
Patients at Risk (Denominator for 
Incidence)
ADA never-positive
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint)
Number of patients with at least one 
valid ADA result at any time point
ADA ever-positive 
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint)
Number of patients with at least one 
valid ADA result at any time point
Baseline ADA 
positive
A positive ADA result at baseline
Number of patients with valid baseline 
ADA result
Treatment-boosted 
ADA*
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result
Treatment-induced 
ADA
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive post-baseline 
ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Transient ADA 
response*
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Persistent ADA 
response*
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
ADA: anti-drug antibody, NR = not reportable. * ADA category may be reported if necessary.
Patients will be characterized into different nAb categories based on the criteria in Table 13. 
For nAb, treatment-boosted is not applicable since no titer result is available.


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Table 13. Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Patients at Risk (Denominator for 
Incidence)
nAb never-positive 
No positive nAb results at any time point
(including no positive ADA results at any 
time point and no nAb results)
Number of patients with at least one 
valid ADA result at any time point
nAb ever-positive 
At least one positive nAb result at any time 
point
Number of patients with at least one 
valid ADA result at any time point
Baseline nAb 
positive
A positive nAb result at baseline
Number of patients with valid baseline 
ADA result
Treatment-induced 
nAb
Patient is not nAb positive at baseline and has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive post-
baseline ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
Transient nAb 
response*
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive.
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR)
Persistent nAb 
response*
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
ADA = antidrug antibody, nAb = neutralizing antibody, NR = not reportable. * May be reported if necessary.
The number and percentage of patients in each ADA and nAb category (as appropriate) will 
be summarized. 
In order to derive and interpret persistent and transient ADA responses, 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. 
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

the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (end of treatment) is after the cut-off date.


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Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result. 
Based on the results observed, additional analyses may be performed for ADA including PK, 
safety and/or efficacy relationships.
6.4. Subset Analyses
ORR for the UC patients (Cohort A2 and A4) including the data from the combined Phase 1b 
lead-in and Phase 2 in the following subsets: patients with visceral disease (Yes, No). Subset 
analyses will be performed only if there are at least 10 patients in the associated cohorts and 
each subset.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline summaries
The following analyses will be based on the FAS separately by treatment group including the 
data from the combined Phase 1b lead-in and Phase 2.
6.5.1.1. Demographic characteristics
Demographic characteristics will be summarized by treatment group using the following 
information from the ‘Screening/Baseline Visit’ eCRF pages.
•
Demographic characteristics 
-
Gender: Male, Female 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Unknown
-
Ethnic origin: 

Hispanic or Latino 

Not Hispanic or Latino
-
Age (years): summary statistics 
CCI


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-
Age categories: 

< 65 years, ≥ 65 years 

< 65, 65-<75, 75-<85, ≥ 85 years
-
Pooled Geographical Region (as applicable): 

North America 

Europe

Asia

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the overall 
treated population)
-
Geographic Region (as applicable):

North America

Latin America

Western Europe

Eastern Europe

Middle East

Australasia

Asia

Africa
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4 
Center codes will be used for the determination of the patient’s geographic region.
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity and ECOG 
performance status.
6.5.1.2. Medical history
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’ 
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.


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6.5.1.3. Disease characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’ and RECIST eCRF 
pages will be summarized by treatment group. Summary statistics will be presented for the 
following.
From the ‘Primary Diagnosis’ eCRF page:

Site of primary tumor

Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page)

Time since initial diagnosis to date of first dose of study treatment (months), defined as 
(date of first dose of study treatment – date of initial diagnosis)/30.4375
From the RECIST eCRF page:

Measurable disease (lesions) at baseline (Yes, No)

Involved tumor sites at baseline
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ eCRF page) and derived variables as above.
6.5.1.4. Prior anti-cancer therapies
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Anti-Cancer 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, 0, 1, 2, 3, ≥4

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.


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Prior anti-cancer drug therapies will be included in the listing that follow with a flag to 
identify prior therapies. These will include the patient identification number, and all the 
relevant collected data-fields on the corresponding eCRF pages.

Listing of anti-cancer drug therapies 
6.5.2. Study conduct and patient disposition
The following analyses will be performed based on the FAS separately by treatment group 
including the data from the combined Phase 1b lead-in and Phase 2.
6.5.2.1. Patient disposition
The percentages below will be calculated based on the number of patients in the FAS in each 
treatment group.

Total number of patients screened overall

Number of patients who discontinued from the study prior to treatment with study drug 
overall and by the main reason for discontinuation

Number and percentage of treated patients in each of the analysis sets defined in Section 4

Number and percentage of patients  with study drug ongoing (separately for each study 
drug administered in combination)

Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug (separately for each study drug administered in 
combination)

Number and percentage of patients who entered follow-up

Number and percentage of patients who discontinued follow-up overall and by the main
reason for discontinuation

Number and percentage of patients who entered long-term follow-up

Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation
In addition, the following will be summarized:

Number and percentage of treated patients overall, by region (Europe, EEA (required by 
EudraCT), North America, Latin America, Middle East, Asia, Australasia, Africa), by 
country within region 

Number and percentage of treated patients by center
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


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
Patients who receive the wrong treatment 

Patients who receive an excluded concomitant medication

Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study treatment compliance and exposure
The following analyses will be based on the safety analysis set by treatment group.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  
For Cycle X, actual cycle start date for each patient is

the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the patient 
received study treatment on that visit (ie, any study drug with dose>0 at that visit)

the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 

for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day;

for the last cycle, actual cycle end date = actual cycle start date + 21 – 1 day.
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included.   
Exposure may be summarized as dose received (cumulative dose, actual dose intensity) and 
as dose received relative to intended dose (relative dose intensity [RDI]).  
The information that will be summarized depends on how the study drug is dosed (infusion 
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 fixed dose of 800 mg once every 3 
weeks in 3-week cycles.


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
Pemetrexed administered as a 10-minute IV infusion at a dose of 500 mg/m2 once every 3 
weeks in 3-week cycles

Carboplatin administered as a 60-minute IV infusion at a dose of AUC 5 mg/mL/min 
once every 3 weeks in 3-week cycles

Gemcitabine administered as a 30-minute IV infusion at a dose of 1000 mg/m2 at Day 1 
and Day 8 in 3-week cycles

Cisplatin administered as a 60-minute IV infusion at a dose of 70 mg/m2 once every 3 
weeks in 3-week cycles
Note: The Intended Cumulative Dose and the Intended DI remain constant for all cycles; the 
intended dose level is fixed at the start of treatment and the intended treatment cycle duration 
is the same for the entire dosing period, including the last cycle.
6.5.3.1. Exposure to Avelumab 
The dose level for avelumab is calculated as actual dose administered (mg).
Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle with non-zero dose of study drug + 21 – 1
Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab – first dose date of avelumab + 21)/7  
Cumulative dose (mg) is the sum of the actual doses of avelumab received.  
Actual Dose Intensity (DI)

Overall actual DI (mg/3-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/3].  
Relative Dose Intensity (RDI)  

Intended DI (mg/3-week cycle) 
= [intended cumulative dose per cycle] / [intended number of 3-weeks in a cycle] 
= [800 (mg)] / [1 (3-week cycle)]  
= 800 (mg/3-week cycle)

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [800 (mg/3-week cycle)]
6.5.3.2. Exposure to Pemetrexed   
The dose level for pemetrexed is calculated as actual dose administered/m2 (mg/m2). The 
BSA (m2) is calculated based on the weight and the height (Section 5.2.8). The last available 
weight of the patient within 3 days pre-dose Day 1 of each cycle will be used.


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Intended duration of treatment with pemetrexed (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 + 21 – 1
Duration of exposure to pemetrexed (weeks) = 
(last dose date of pemetrexed – first dose date of pemetrexed + 21)/7  
Cumulative dose (mg/m2) is the sum of the actual doses of pemetrexed received on study.
Actual Dose Intensity (DI)

Overall actual DI (mg/m2/3-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with pemetrexed (weeks)/3].  
Relative Dose Intensity (RDI)  

Intended DI (mg/m2/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [500 (mg/m2)] / [1 (3-week cycle)]  
= 500 (mg/m2/3-week cycle)

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]  
= 100 × [overall actual DI] / [500 (mg/m2/3-week cycle)]
6.5.3.3. Exposure to Carboplatin
The dose level for carboplatin is calculated as actual dose administered AUC 
(AUC mg/mL/min).  Carboplatin dose is calculated based on the Calvert formula.
Intended duration of treatment with carboplatin (weeks) = 
(end date–date of first dose of study drug +1)/7, 
where end date = start date of last cycle with non-zero dose of study drug + 21 – 1
Duration of exposure to carboplatin (weeks) = 
(last dose date of carboplatin – first dose date of carboplatin + 21)/7  
Cumulative dose (AUC) is the sum of the actual doses of carboplatin received.  


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Actual Dose Intensity (DI)

Overall actual DI (AUC/3-week cycle) = [overall cumulative dose (AUC)] / [intended 
duration of treatment with carboplatin (weeks)/3].  
Relative Dose Intensity (RDI)  

Intended DI (AUC/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [5 AUC] / [1 (3-week cycle)]  
= 5 AUC/3-week cycle

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]   
= 100 × [overall actual DI (AUC/3-week cycle)] / [5 AUC /3-week cycle] 
6.5.3.4. Exposure to Gemcitabine
The dose level for gemcitabine is calculated as actual dose administered/m2 (mg/m2). The 
BSA (m2) is calculated based on the weight and the height (Section 5.2.8). The last available 
weight of the patient within 3 days pre-dose Day 1 of each cycle will be used. 
Intended duration of treatment with gemcitabine (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 + 21 – 1
Duration of exposure to gemcitabine (weeks) = 
(last dose date of gemcitabine – first dose date of gemcitabine + n)/7  
with n = 7 if the last dose is at Day 1 of the cycle, and n=14 if the last dose is at Day 8 of the 
cycle.
Cumulative dose (mg/m2) is the sum of the actual doses of gemcitabine received.  
Actual Dose Intensity (DI)

Overall actual DI (mg/m2/3-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with gemcitabine (weeks)/3].  
Relative Dose Intensity (RDI)  

Intended DI (mg/m2/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [2 × 1000 (mg/m2)] / [1 (3-week cycle)] = 2000 
(mg/m2/3-week cycle)

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]    
= 100 × [overall actual DI] / [2 × 1000 (mg/m2/3-week cycle)]


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6.5.3.5. Exposure to Cisplatin 
The dose level for cisplatin is calculated as actual dose administered/ m2 (mg/m2). The BSA 
(m2) is calculated based on the weight and the height (Section 5.2.8).  The last available 
weight of the patient within 3 days pre-dose Day 1 of each cycle will be used.
Intended duration of treatment with Cisplatin (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 + 21 – 1
Duration of exposure to Cisplatin (weeks) = 
(last dose date of cisplatin – first dose date of cisplatin + 21)/7  
Cumulative dose (mg/m2) is the sum of the actual doses of cisplatin received.  
Actual Dose Intensity (DI)

Overall actual DI (mg/m2/3-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with cisplatin (weeks)/3].  
Relative Dose Intensity (RDI)  

Intended DI (mg/m2/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [70 (mg/m2)] / [1 (3-week cycle)] = 70 (mg/m2/3-week 
cycle)

Overall RDI (%) = 100 × [overall actual DI] / [intended DI] = 100 × [overall actual DI] / 
[70 (mg/m2/3-week cycle)]
6.5.3.6. Dose reductions 
Applicable to avelumab, carboplatin, cisplatin, gemcitabine and pemetrexed. 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. 
6.5.3.7. Dose delays 
Applicable to avelumab, carboplatin, cisplatin, gemcitabine and pemetrexed.
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses. 
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – Planned days between 
two consecutive doses. 


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Avelumab, carboplatin, cisplatin and pemetrexed
For Cycle 1:
     Dose Delay (days) = day of the first day of study drug -1
After Cycle 1:
     Dose Delay (days) = Date of dose x of study drug – Date of dose (x-1) of study drug – 21
Gemcitabine
For the first dose of Cycle 1:
      Dose Delay (days) = day of the first dose of gemcitabine -1
After the first dose of Cycle 1:
Dose Delay (days) = Date of dose x – Date of dose (x–1) – d, 
where d = 7 if Dose x and Dose (x–1) belong to the same cycle, and d = 14 if Dose x is the 
first dose of a cycle and Dose (x–1) is the last dose of the previous cycle.
Dose delays will be grouped into the following categories: 

No delay 

1-2 days delay

3-6 days delay

7 or more days delay
For example, for avelumab, administered on a 3-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 22; however, 
if the patient receives avelumab at Day 23 or 24, this is considered as 1-2 days delay.  
No delay and 1-2 days delay will also be summarized together. 
The number and percentage of 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. 
6.5.3.8. Infusion rate reductions
Applicable to avelumab.
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized.


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6.5.3.9. Infusion interruptions
Applicable to avelumab, carboplatin, cisplatin, gemcitabine, and pemetrexed.
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant medications and non-drug treatments
The following analyses will be based on the safety analysis set by treatment group.
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study drugs and pre-medications for study drug, which are started before the first dose of 
study treatment. 
Concomitant medications will be summarized from the ‘General Concomitant Medications’ 
eCRF page. 
Summary of concomitant medications will include the number and percentage of patients by 
Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred term. A patient 
will be counted only once within a given drug class and within a given drug name, even if 
he/she received the same medication at different times. If any concomitant medication is 
classified into multiple ATC classes, the medication will be summarized separately under 
each of these ATC classes. The summary tables will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used. In 
case any specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category. 
6.5.5. Subsequent anti-cancer therapies
The following analyses will be based on the FAS by treatment group.
Anti-cancer drug treatment will be provided in a data listing with data retrieved from 
‘Follow-up Cancer Therapy’ eCRF page. 
6.6. Safety Summaries and Analyses
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of 
AEs and other safety parameters will be based on the safety analysis set by treatment group.  
6.6.1. Adverse events
TEAEs are those events with onset dates occurring during the on-treatment period as defined 
in Section 3.5.1.


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All analyses described in what follows will be based on TEAEs (started during the on-
treatment period) if not otherwise specified. The AE listings will include all AEs (whether 
treatment-emergent or not). AEs outside the on-treatment period will be flagged in the 
listings.

Related Adverse Events: adverse events with relationship to study treatment (as recorded 
on the AE eCRF page, Relationship with study treatment = Related) reported by the 
investigator and those of unknown relationship (ie, no answer to the question ‘Relationship 
with study treatment’).  Related AEs are those related to any study drug (ie, at least one of 
the study drugs). 

Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).

Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction of 
study treatment (as recorded on the AE eCRF page, Action taken with study treatment = 
Dose reduced).

Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).  IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.

Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).  

Adverse Events Leading to Death: adverse event leading to death (as recorded on the AE 
eCRF page, Outcome = Fatal, as well as AEs of Grade 5).

Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan [SRP] and finalized for analysis of the current study
data prior to DB lock)

Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in 0 for a pre-specified search list of MedDRA PTs documented in the SRP and 
finalized for analysis of the current study data prior to DB lock.
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment group, primary SOC 
and PT in decreasing frequency based on the frequencies observed for each treatment group. 
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.


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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 PT as event category and MedDRA 
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 group:
-
TEAEs
-
TEAEs, Grade ≥ 3
-
Related TEAEs
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to dose reduction of carboplatin 
-
TEAEs leading to dose reduction of cisplatin
-
TEAEs leading to dose reduction of gemcitabine
-
TEAEs leading to dose reduction of pemetrexed
-
TEAEs leading to interruption of avelumab
-
TEAEs leading to interruption of carboplatin
-
TEAEs leading to interruption of cisplatin
-
TEAEs leading to interruption of gemcitabine
-
TEAEs leading to interruption of pemetrexed
-
TEAEs leading to discontinuation of avelumab
-
TEAEs leading to discontinuation of carboplatin
-
TEAEs leading to discontinuation of cisplatin
-
TEAEs leading to discontinuation of gemcitabine
-
TEAEs leading to discontinuation of pemetrexed
-
TEAEs leading to discontinuation of any study drug
-
Serious TEAEs
-
Related Serious TEAEs 
-
TEAEs leading to death
-
Related TEAEs leading to death


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-
irAEs
-
IRRs 

TEAEs by SOC and PT and worst grade

TEAEs related to any drug by SOC and PT and worst grade

TEAEs leading to death by SOC and PT

Related TEAEs leading to death by SOC and PT
6.6.1.2. Adverse events leading to dose reduction
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment group:

TEAEs leading to dose reduction of avelumab by SOC and PT

TEAEs leading to dose reduction of carboplatin by SOC and PT

TEAEs leading to dose reduction of cisplatin by SOC and PT

TEAEs leading to dose reduction of gemcitabine by SOC and PT

TEAEs leading to dose reduction of pemetrexed by SOC and PT
6.6.1.3. Adverse events leading to interruption of study treatment
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).  IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay). 
As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding 

IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.7). These IRRs will be considered as IRRs leading to 
interruption of infusion.

IRRs occurring on the day after infusion and subsequent dose administration had no delay
(as defined in Section 6.5.3.7).
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment group:

TEAEs leading to interruption of avelumab by SOC and PT

TEAEs leading to interruption of carboplatin by SOC and PT

TEAEs leading to interruption of cisplatin by SOC and PT


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
TEAEs leading to interruption of gemcitabine by SOC and PT

TEAEs leading to interruption of pemetrexed by SOC and PT
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 group:

TEAEs leading to discontinuation of avelumab by SOC and PT

TEAEs leading to discontinuation of carboplatin by SOC and PT

TEAEs leading to discontinuation of cisplatin by SOC and PT

TEAEs leading to discontinuation of gemcitabine by SOC and PT

TEAEs leading to discontinuation of pemetrexed by SOC and PT

TEAEs leading to discontinuation of any study drug by SOC and PT
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’ 
eCRFs, by treatment group.  

All deaths 

Deaths within 30 days after last dose of study treatment

Reason for Death 
-
Disease progression
-
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.


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6.6.3. Serious adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group:

SAEs by SOC and PT

Related SAEs by SOC and PT
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other significant adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group:

irAEs by Cluster and PT and Maximum CTCAE Grade

irAEs leading to discontinuation of any study drug, by Cluster and PT

Serious irAEs, by Cluster and PT.
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group:

IRRs by PT and Maximum CTCAE Grade

IRRs leading to discontinuation of any study drug, by PT 

Serious IRRs, by PT.
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
6.6.5. Laboratory data
6.6.5.1. Hematology and chemistry parameters
Laboratory results will be classified according to the NCI-CTCAE criteria v4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 
Abnormalities classified according to NCI-CTCAE toxicity grading v4.03 will be described 
using the worst grade. For those parameters which are graded with two toxicities, the 
toxicities will be summarized separately. Low direction toxicity grades at baseline and post 
baseline will be set to 0 when the variables are derived for summarizing high direction 
toxicity, and vice versa.  


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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 group:

ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN

AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN

(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN

TBILI ≥ 2×ULN

Concurrent  ALT ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN 


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
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 groups, by graphically displaying

peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin =2×ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at
AST=3×ULN and total bilirubin =2×ULN . 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with concurrent 
(ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing) will be 
provided.
Parameters with NCI-CTCAE 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 shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered as 
the worst grade for the summary. 

The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)).
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE.
6.6.5.2. Other laboratory parameters
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests. 


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6.6.6. 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.
6.6.7. Electrocardiogram
QTcB and QTcF will be derived based on RR and QT (see below).  The average of the 
replicate measurements should be determined after the derivation of the individual parameter 
at each time point.
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB 
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF 
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions. 
ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category.

Pearson correlation between QT and HR, QTc (QTcB, QTcF) and HR using individual 
(non-averaged) baseline assessments 

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 
7. INTERIM ANALYSES
There is no formal interim analysis planned for this study.
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Not applicable.
8. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
2.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413, 1934.
3.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience. 2002.  
4.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.


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9. APPENDICES
Appendix 1. Immune-Related Adverse Events
The MedDRA PTs and clusters for irAEs are defined in the SRP for avelumab.
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 14.  
Unless otherwise noted, this case definition is hierarchical, ie, each step is only checked for 
patients and events that have already met the prior step.  
Table 14.
Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list, then it is in for the next 
step
2
AE onset during 1st study drug 
administration or anytime thereafter through 
90 days after last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
Steps 3 and 4 will be checked concurrently.  Step 5 
will be checked if the criteria in Step 4 is met, 
irrespective of whether the Criteria in Step 3 is met.
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs 
if A) OR B) OR C) below are met then the AE is in 
for the next step
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA, L04AB, 
L04AC, L04AD, L04AX, A07EA) and AE PT 
is in any of the irAE clusters.
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters associated 
with “Immune-mediated endocrinopathies”
C) conmed ATC code is A10A and AE PT is in 
the irAE cluster associated with “Immune-
mediated endocrinopathies: Type I Diabetes 
Mellitus”


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


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Appendix 2. Infusion Related Reactions
For defining an AE as IRR, the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered. 

All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
infusion) and the event resolved with end date within 2 days after onset. 

All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
the infusion) or the day after the study drug infusion (irrespective of resolution date).
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab. 
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 15
and will be identified for IV drugs only.     


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Table 15.
Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets)
Condition
Selection criterion
IRR can be associated with the first IV drug and/or subsequent IV drugs that are administered in 
combination.  Without loss of generality assume triplet IV with D1 administered first then D2 then D3.  The 
IV study drug or drugs associated with the IRR need to be identified in the analysis data set to enable 
subsequent analysis.
The following are not sequential and an AE can be classified as an IRR associated with multiple DJ from 
one or more of I, II, III, IV, V below:
I - If the AE meets [1 AND 2A1] for a DJ then the AE is classified as an IRR associated with the DJ
that meets the 2A1 criterion 
II - If the AE meets [1 AND 2A2] for a DJ then the AE is classified as an IRR associated with the DJ
and associated with DJ+1 that meets the 2A2 criterion 
III - If the AE meets [3 AND 4B] for any DJ then the AE is classified as an IRR associated with all DJ
that meet the 4B criterion.
IV- If the AE meets [3 AND 4A1] for a DJ then the AE is classified as an IRR associated with the DJ
that meets the 4A1 criterion 
V- If the AE meets [3 AND 4A2] for a DJ then the AE is classified as an IRR associated with the DJ
and associated with DJ+1 that meets the 4A2 criterion 
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list 
2A1

AE onset date = date of infusion of study drug DJ AND

AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND

[AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion 
of study drug DJ+1] AND

AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND

AE end date – AE onset date ≤2 
2A2

AE onset date = date of infusion of study drug DJ AND

AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND

AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) AND

AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND

AE end date – AE onset date ≤2 
3
PT is included in the ‘IRRs CORE’ list 
4A1

AE onset date = date of infusion of study drug DJ AND

AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND

[AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of infusion 
of study drug DJ+1]
4A2

AE onset date = date of infusion of study drug DJ AND

AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND

AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion of study drug D J


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Appendix 3. Abbreviations and Definitions of Terms
The following is a list of abbreviations that may be used in the Statistical Analysis Plan.
ADA
Anti-Drug Antibody
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT 
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BOR
Best Overall Response
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
Ctrough
Lowest (trough) Concentration 
CR
Complete Response
CRF
Case Report Form
CSR
Clinical Study Report
CTCAE 
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DLT
Dose-Limiting Toxicity
DR
Duration of response
ECG 
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
End of Treatment
irAE
Immune-Related Adverse Event
IRR
Infusion related reaction
IV
Intravenous
MedDRA
Medical Dictionary for Regulatory Activities
N/A
Not Applicable
nAb
Neutralizing Antibody
NCI 
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate
OS 
Overall Survival
PD
Progressive Disease 
PD-L1
Programmed Death-Ligand 1
PFS
Progression-Free Survival
PR
Partial Response
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
RECIST v1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
TBILI
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
Tmax
Time to Maximum Plasma Concentration


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TTR
Time-to-Tumor Response
UC
Urothelial Cancer
ULN 
Upper Limit of Normal
WBC
White Blood Cell