Clinical trial NCT01772004
Conditions: Solid Tumors
Keywords: Solid Tumors MSB0010718C Phase 1 Pharmacokinetic anti PD-L1 Non-small cell lung cancer (NSCLC) Metastatic breast cancer (MBC) Gastric and gastroesophageal junction (GEJ) cancer Ovarian cancer Colorectal cancer (CRC) Castrate-resistant prostate cancer (CRPC) Melanoma Urothelial carcinoma Bladder cancer Head and neck squamous cell carcinoma (HNSCC) Renal cell carcinoma (RCC) Adrenocortical carcinoma (ACC)
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2013-01-31; Completion date: 2019-12-16
Enrollment: 1756 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1, open-label, dose-escalation trial of avelumab \[antibody targeting programmed death ligand 1 (anti PD-L1)\] with consecutive parallel group expansion in participants with selected tumor indications. New recruitment is open for all active cohorts.

Active cohorts: Escalation revised dosing regimen cohort.

Closed cohorts: Non-small cell lung cancer (NSCLC, first line), NSCLC (post-platinum), metastatic breast cancer (MBC), colorectal cancer (CRC), urothelial carcinoma (secondary), mesothelioma, gastric/GEJ cancer (first line switch maintenance and second line), and ovarian cancer (secondary and platinum refractory + liposomal doxorubicin), renal cell carcinoma (second line) melanoma and head, neck squamous cell carcinoma (HNSCC), castrate-resistant prostate cancer (CRPC), adrenocortical carcinoma (ACC) urothelial carcinoma (efficacy), gastric/gastroesophageal junction (GEJ) cancer (third line), renal cell carcinoma (RCC, first line) and escalation phase .

Detailed description:

Arms: arm 1: Participants with metastatic or locally advanced solid tumors received intravenous infusion of Avelumab at a dose of 1.0 milligrams per kilogram (mg/kg) once every 2 weeks in dose escalation cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or investigational medicinal product (IMP) occurs. arm 2: Participants with metastatic or locally advanced solid tumors received intravenous infusion of Avelumab at a dose of 3.0 mg/kg once every 2 weeks in dose escalation cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 3: Participants with metastatic or locally advanced solid tumors received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in dose escalation cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 4: Participants with metastatic or locally advanced solid tumors received intravenous infusion of Avelumab at a dose of 20.0 mg/kg once every 2 weeks in dose escalation cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 5: Participants with metastatic or locally advanced solid tumors received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once weekly for the first 12 weeks and once every 2 weeks starting Week 13 in dose escalation cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 6: Participants with non-small cell lung cancer (NSCLC), who had progressed after 1 line of platinum-containing doublet chemotherapy received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in primary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 7: Participants with non-small cell lung cancer (NSCLC), first line received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in primary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 8: Participants with metastatic breast cancer received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in primary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 9: Participants with gastric (GC) and gastroesophageal junction cancer (GEJC) who progressed on or after first line chemotherapy received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in primary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 10: Participants with gastric (GC) and gastroesophageal junction cancer (GEJC) who non-progressed on or after first-line chemotherapy received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in primary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 11: Participants with colorectal cancer received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 12: Participants with castrate-resistant prostate cancer received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 13: Participants with adrenocortical carcinoma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 14: Participants with melanoma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 15: Participants with mesothelioma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 16: Participants with urothelial carcinoma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 17: Participants with ovarian carcinoma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 18: Participants with Renal cell carcinoma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks as a first-line therapy in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 19: Participants with Renal cell carcinoma who failed 1 prior systemic first-line regimen received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks as a second line treatment in secondary expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 20: Participants with ovarian carcinoma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in efficacy expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 21: Participants with urothelial carcinoma received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in efficacy expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 22: Participants with gastric (GC) and gastroesophageal junction cancer (GEJC) who have failed both a first-line chemotherapy regimen and subsequent ramucirumab therapy, received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks as a third-line treatment in efficacy expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs. arm 23: Participants with head and neck squamous cell carcinoma (HNSCC) received intravenous infusion of Avelumab at a dose of 10.0 mg/kg once every 2 weeks in efficacy expansion cohort until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs.
Interventions: intervention 1: Avelumab
Intervention descriptions: intervention 1: Participants received intravenous infusion of Avelumab in dose escalation and expansion cohorts until confirmed progression, unacceptable toxicity, or any reason for withdrawal from the trial or IMP occurs.

Protocol documents:
Prot_000.pdf: 
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Clinical Trial Protocol
Clinical Trial Protocol Number
EMR100070-001
Title
A Phase I, open-label, multiple-ascending dose 
trial to investigate the safety, tolerability, 
pharmacokinetics, biological and clinical activity 
of avelumab (MSB0010718C) in subjects with 
metastatic or locally advanced solid tumors and 
expansion to selected indications.
Short Trial Name
JAVELIN Solid Tumor
Trial Phase
Phase I/Ib
IND Number
EudraCT Number
2013-002834-19
Coordinating Investigator
 
 
Sponsor
For all countries except the USA:
Merck KGaA, Frankfurter Str. 250, 
Darmstadt, Germany
For sites in the USA:
EMD Serono, Inc
One Technology Place, 
Rockland, MA 02370, USA
Medical Responsible: 
45A Middlesex Turnpike
Billerica, MA 01821, USA
Tel:  
Fax: 
Clinical Trial Protocol Version
06 August 2018 / Version 19.0
Replaces Clinical Trial Protocol Version
02 March 2017 / Version 18.0
Current Clinical Trial Protocol 
Amendment
Amendment No. 18.0 / 06 August 2018
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This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2018 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights 
reserved.
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Table of Contents
Table of Contents
..............................................................................................................3
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................8
List of Abbreviations ...........................................................................................................9
1
Synopsis..............................................................................................15
2
Sponsor, Investigators and Trial Administrative Structure ................40
2.1
Investigational Sites............................................................................40
2.2
Trial Coordination / Monitoring.........................................................40
2.2.1
Safety Monitoring Committee............................................................40
2.2.2
Central Reader and Independent Endpoint Review Committee.........41
3
Background Information.....................................................................41
3.1
Investigational Medicinal Product......................................................41
3.2
Non-Clinical Findings for Avelumab.................................................42
3.2.1
In vitro and in vivo Pharmacology Findings ......................................42
3.2.2
Toxicology..........................................................................................43
3.3
Pharmacokinetics / Immunogenicity Findings ...................................44
3.4
Safety..................................................................................................45
3.4.1
Clinical Pharmacodynamics ...............................................................52
3.5
Rationale for the Clinical Trial...........................................................52
3.5.1
Rationale for 10 mg/kg Once Weekly Dose-Escalation Cohort.........54
3.5.2
Rationale for Expansion Cohorts........................................................56
3.5.3
Rationale for New Expansion Cohorts / Expanding Initial 
Expansion Secondary Cohorts............................................................56
3.5.4
Rationale for Adding First-Line NSCLC Cohort ...............................59
3.5.5
Rationale for Additional Efficacy Expansion Cohorts.......................61
3.6
Rationale for Expanding Inclusion Criteria for Gastric / GEJ 
Cohort .................................................................................................64
3.7
Summary of the Overall Benefit and Risk..........................................64
4
Trial Objectives ..................................................................................67
5
Investigational Plan ............................................................................68
5.1
Overall Trial Design and Plan ............................................................68
5.1.1
Overall Design....................................................................................68
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5.1.2
Trial Endpoints ...................................................................................72
5.1.3
Trial Medication Administration and Schedule..................................73
5.1.4
Avelumab Dose Escalation.................................................................74
5.1.5
Planned Number of Subjects ..............................................................80
5.1.6
Planned Treatment Duration...............................................................80
5.1.7
Dose Modification and ADRs Requiring Treatment 
Discontinuation...................................................................................81
5.1.8
Analysis Cut-Off Dates.......................................................................82
5.2
Discussion of Trial Design .................................................................83
5.2.1
Inclusion of Special Populations ........................................................84
5.3
Selection of Trial Population..............................................................84
5.3.1
Inclusion Criteria ................................................................................84
5.3.2
Exclusion Criteria (applicable to all subjects, including all 
expansion cohorts)..............................................................................89
5.4
Criteria for Initiation of Treatment with the Investigational 
Medicinal Product...............................................................................90
5.5
Criteria for Subject Withdrawal..........................................................91
5.5.1
Withdrawal From the Trial .................................................................91
5.5.2
Withdrawal From the Investigational Medicinal Product ..................91
5.6
Premature Discontinuation of the Trial ..............................................92
5.7
Definition of End of Trial...................................................................92
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................92
6.1
Description of Investigational Medicinal Product(s)..........................93
6.2
Dosage and Administration ................................................................93
6.3
Assignment to Treatment Cohorts......................................................94
6.4
Other Drugs to be Used in the Trial....................................................94
6.5
Concomitant Medications and Therapies ...........................................95
6.5.1
Permitted Medicines and Therapies....................................................95
6.5.2
Non-Permitted Medicines and Therapies ...........................................95
6.5.3
Other Trial Considerations .................................................................96
6.5.4
Special Precautions.............................................................................96
6.6
Packaging and Labeling....................................................................105
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6.7
Preparation, Handling and Storage...................................................105
6.8
Investigational Medicinal Product Accountability...........................106
6.9
Assessment of Investigational Medicinal Product Compliance .......107
6.10
Method of Blinding...........................................................................107
6.11
Emergency Unblinding.....................................................................108
6.12
Treatment of Overdose .....................................................................108
6.13
Medical Care of Subjects After End of Trial....................................108
7
Trial Procedures and Assessments....................................................108
7.1
Schedule of Assessments..................................................................108
7.1.1
Screening and Baseline Procedures and Assessments......................108
7.1.2
Treatment Period ..............................................................................110
7.1.3
End of Treatment ..............................................................................115
7.1.4
Post-Treatment Safety Follow-Up....................................................116
7.1.5
Blood Consumption for Clinical Assessments .................................116
7.2
Demographic and Other Baseline Characteristics ............................117
7.2.1
Demographic Data............................................................................117
7.2.2
Diagnosis of Tumor..........................................................................117
7.2.3
Medical History ................................................................................117
7.2.4
Vital Signs and Physical Examination..............................................118
7.2.5
CT or MRI Scans for Tumor Assessment at Baseline......................118
7.2.6
Cardiac Assessments ........................................................................118
7.2.7
Clinical Laboratory Tests .................................................................119
7.3
Assessment of Efficacy.....................................................................119
7.4
Assessment of Safety........................................................................123
7.4.1
Adverse Events .................................................................................123
7.4.2
Pregnancy and In Utero Drug Exposure...........................................128
7.4.3
Laboratory Assessments ...................................................................129
7.4.4
Vital Signs, Physical Examinations, and Other Assessments...........131
7.5
Pharmacokinetics..............................................................................131
7.5.1
Dose Escalation Phase ......................................................................131
7.5.2
Expansion Phase...............................................................................132
7.5.3
Body Fluid ........................................................................................133
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7.6
Biomarkers and 
........................................133
7.6.1
Biomarker Investigation in Dose Escalation Cohorts.......................134
7.6.2
Biomarkers Investigation in Expansion Cohorts..............................134
7.7
Other Assessments............................................................................138
7.7.1
ADA Analysis...................................................................................138
8
Statistics............................................................................................138
8.1
Sample Size ......................................................................................138
8.2
Randomization..................................................................................141
8.3
Endpoints..........................................................................................141
8.3.1
Primary Endpoints ............................................................................141
8.3.2
Secondary Endpoints ........................................................................141
8.3.3
Safety Endpoints...............................................................................142
8.4
Analysis Sets.....................................................................................142
8.5
Description of Statistical Analyses...................................................143
8.5.1
General Considerations.....................................................................143
8.5.2
Analysis of Primary Endpoints.........................................................144
8.5.3
Analysis of Secondary Endpoints.....................................................145
8.5.4
Safety Analyses ................................................................................147
8.6
Interim Analysis................................................................................148
9
Ethical and Regulatory Aspects........................................................150
9.1
Responsibilities of the Investigator ..................................................150
9.2
Subject Information and Informed Consent .....................................151
9.3
Subject Identification and Privacy....................................................151
9.4
Emergency Medical Support and Subject Card................................152
9.5
Clinical Trial Insurance and Compensation to Subjects...................152
9.6
Independent Ethics Committee or Institutional Review Board........152
9.7
Health Authorities.............................................................................153
10
Trial Management.............................................................................153
10.1
Case Report Form Handling.............................................................153
10.2
Source Data and Subject Files..........................................................153
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10.3
Investigator Site File and Archiving.................................................154
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................155
10.5
Changes to the Clinical Trial Protocol..............................................155
10.6
Clinical Trial Report and Publication Policy....................................155
10.6.1
Clinical Trial Report.........................................................................155
10.6.2
Publication........................................................................................155
11
References.........................................................................................157
12
Appendices .......................................................................................163
Appendix I
Schedule of Assessments..................................................................164
Appendix II
ECOG Performance Status ...............................................................180
Appendix III
Guidance on Contraception ..............................................................181
Appendix IV
Protocol Amendments and List of Changes .....................................182
Appendix V
Signature Pages and Responsible Persons for the Trial....................186
Signature Page – Protocol Lead.......................................................................................187
Signature Page – Coordinating Investigator ....................................................................188
Signature Page – Principal Investigator...........................................................................189
Table of In-Text Tables
Table 3.1
Most Frequently Reported TEAEs During Dose Expansion 
(≥10% of Subjects) ............................................................................46
Table 3.2
Most Frequently Reported TEAEs ≥ Grade 3 During Dose 
Expansion (> 1.5% of Subjects) .........................................................47
Table 3.3
Most Frequently Reported Treatment-related TEAEs During Dose 
Expansion (≥ 5% of Subjects) ............................................................48
Table 5.1
Modification of Dose Escalation Based on DLT Observations at 
Dose Levels Below 10.0 mg/kg..........................................................76
Table 6.1
Treatment Modification for Symptoms of Infusion-related 
Reactions Caused by Avelumab.........................................................98
Table 6.2
Management of Immune-Related Adverse Events...........................101
Table 7.1
Overall Responses Derived from Changes in Index, Non-Index, 
and New Lesions...............................................................................122
Table 7.2
Required Laboratory Panel Tests......................................................130
Table 8.1
95% Confidence Intervals of Estimated Response Rates.................140
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Table 8.2
Probability of Observing a Response Rate of Less Than 5% in 
Interim Analysis................................................................................149
Table of In-Text Figures
Figure 5.1
Schematic of Trial Design ..................................................................72
Figure 5.2
Dose Escalation Algorithm for Doses up to 10 mg/kg.......................75
Figure 5.3
Dose Escalation Algorithm for 15 and 20 mg/kg...............................78
Figure 6.1
Assessment and Initial Management of Tumor Lysis Syndrome 
(TLS).................................................................................................100
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List of Abbreviations
5-FU
5-fluorouracil
ACC
adrenocortical carcinomas
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANA
anti-nuclear antibody
ANC
absolute neutrophil count
ANCA
anti-neutrophil cytoplasmic antibody
AST
aspartate aminotransferase
aPTT
activated partial thromboplastin time
AUC0-∞
area under the curve from the time of dosing extrapolated to infinity
AUC0-t
area under the concentration-time curve from the time of dosing to the 
time of the last observation
AUCtau
area under the concentration-time curve 
β-HCG
β-human chorionic gonadotropin
BOR
best overall response
bpm
beats per minute
BSC
best supportive care
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CA-125
cancer antigen 125
CI
confidence interval
Cmax
maximum plasma concentration observed post-dose
Cmin
trough concentration
CNS
central nervous system
CPT
Cell Preparation Tube™
CR
complete response
CRC
colorectal cancer
CRF
Case Report Form
CRO
Contract Research Organization
CRPC
castrate-resistant prostate cancer
CT 
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte antigen-4
DBP
diastolic blood pressure
DLT
dose-limiting toxicity
DQA
Development Quality Assurance
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
ELISPOT
enzyme-linked immunosorbent spot
EMA
European Medicines Agency
FACS
fluorescence-activated cell sorter
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FAS
full analysis set
FDA
Food and Drug Administration
FFPE
formalin fixed, paraffin embedded
FIGO
International Federation of Gynecology and Obstetrics
FOLFOX
Oxaliplatin, 5-FU, and folinic acid 
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GEJ
gastroesophageal junction
GGT
gamma-glutamyl transferase
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
H1
histamine H1 receptor
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papillomavirus
IASLC
International Association for the Study of Lung Cancer
ICF
Informed Consent Form
ICH
International Conference for Harmonization
IEC
Independent Ethics Committee
IERC
Independent Endpoint Review Committee
IHC
immunohistochemistry
IMP
Investigational Medicinal Product
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irAE
immune-related adverse event
irBOR
immune-related best overall response
irPFS
immune-related progression-free survival
irRC
Immune-Related Response Criteria
IRB
Institutional Review Board
i.v.
intravenous
LDH
lactate dehydrogenase
MBC
metastatic breast cancer
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mIU/mL
milli international units per milliliter 
MoA
mechanism of action
MOP
Manual of Operations
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NBF
neutral-buffered formalin
NCI
National Cancer Institute 
NK
natural killer
NOAEL
no observed adverse effect level
NSAID
nonsteroidal anti-inflammatory drugs
NSCLC
non-small cell lung cancer 
OS
overall survival 
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PAD
pharmacologically active dose
PBL
peripheral blood leukocytes
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PD
pharmacodynamic(s)
PD-1
programmed death 1
PD-L1
programmed death ligand 1
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
QS
quantum satis
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RF
rheumatoid factor
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
stable disease
SMC
Safety Monitoring Committee
SUSAR
suspected unexpected serious adverse reaction
t1/2
half-life
T4
free thyroxine
tmax
time to reach maximum concentration
TEAE
treatment-emergent adverse event
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TNM
Tumor Node Metastasis Classification of Malignant Tumors (UICC)
TO
total occupancy
TSH
thyroid-stimulating hormone
TGF
transforming growth factor
UICC
Union Internationale Contre le Cancer
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
VEGFR-2
vascular endothelial growth factor receptor-2
WBC
white blood cell
λz
terminal elimination rate constant
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1
Synopsis
Trial title
A Phase I, open-label, multiple ascending dose trial to 
investigate the safety, tolerability, pharmacokinetics, 
biological 
and 
clinical 
activity 
of 
avelumab
(MSB0010718C) in subjects with metastatic or locally 
advanced solid tumors and expansion to selected 
indications.
Trial number
EMR 100070-001
EudraCT number
2013-002834-19
Sponsor
For all countries except the United States:
Merck KGaA, Frankfurter Str. 250, Darmstadt,
Germany
For sites in the United States:
EMD Serono, Inc
One Technology Place, Rockland, MA 02730, USA
Phase
I/Ib
IND Number
FDA "covered trial"
Yes
Trial centers/country
Up to 8 enrolling centers for dose escalation and up to 
approximately 
160 enrolling 
centers 
for 
treatment 
expansion. 
The trial will be performed in the USA, Asia, and Europe.
Planned trial period
(first enrollment-last subject 
out)
First subject in: Q1, 2013.
Last subject out (dose escalation): Q2, 2018.
Last subject out (after expansion and follow-up): 
Q2, 2019.
Trial objectives
Primary objective
!
To assess the safety and tolerability of avelumab and to 
determine the maximum tolerated dose (MTD) of 
avelumab in subjects with metastatic or locally advanced 
solid tumors.
!
To assess the best overall response (BOR) according to 
Response 
Evaluation 
Criteria 
in 
Solid 
Tumors 
version 1.1 (RECIST 1.1) in the efficacy expansion
cohorts (ovarian cancer, platinum refractory and prior 
liposomal doxorubicin; urothelial carcinoma, platinum 
ineligible or progressed after at least 1 line of platinum-
based therapy; gastric and gastroesophageal junction
[GEJ] cancer, third-line; head and neck squamous cell 
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carcinoma [HNSCC], platinum ineligible or progressed 
after at least 1 line of platinum-based therapy).
Secondary objectives
! To characterize the pharmacokinetic (PK) profile of 
avelumab
and to correlate exposure with target 
occupancy.
! To evaluate the immunogenicity of avelumab and to 
correlate it to exposure and biological activity.
! To assess the best overall response (BOR) and 
progression-free survival time (PFS) according to 
RECIST 1.1. 
! To assess the immune-related BOR (irBOR) and 
immune-related PFS (irPFS) using the modified 
Immune-Related Response Criteria (irRC), derived from 
RECIST 1.1.
! To assess overall survival time (OS).
! To evaluate biological responses to avelumab in blood/
serum.
! To evaluate the association between tumor programmed 
death ligand 1 (PD-L1) expression and BOR. 
! To characterize changes in soluble factors (e.g., cytokine 
profiles, soluble programmed death 1 [PD-1] and soluble 
PD-L1) and immune cell profiling (e.g., natural killer 
[NK] cells, neutrophils, lymphocytes).  
Exploratory objectives (efficacy expansion cohort only)
!
 
Trial design and plan
This is a Phase I, open-label, dose-escalation trial with 
consecutive parallel group expansion in non-small cell lung 
cancer (NSCLC), gastric and GEJ cancer, metastatic breast 
cancer (MBC), colorectal cancer (CRC), castrate-resistant 
prostate cancer (CRPC), melanoma, ovarian cancer,
HNSCC, adrenocortical carcinoma (ACC), mesothelioma, 
and urothelial carcinoma. Subjects in the 10mg/kg once 
weekly cohort, NSCLC (post platinum doublet), CRC and
CRPC cohorts will be enrolled in the USA only.
Dose escalation phase
Cohorts of 3 subjects with metastatic or locally advanced 
solid tumors will receive avelumab at escalating dose levels. 
At each dose level, subjects will receive avelumab
intravenously as a 1-hour intravenous infusion once every 
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2 weeks until confirmed progression, unacceptable toxicity, 
or any criterion for withdrawal from the trial or the 
investigational medicinal product
(IMP) occurs (see 
Section 5.5). An additional cohort of 6 subjects will receive 
avelumab once weekly at a dose of 10 mg/kg for 
12 consecutive weeks (10 mg/kg once weekly cohort) and 
then once every 2 weeks thereafter (this cohort will not be 
subject to DLT as a primary endpoint and will not be subject 
to SMC review after the first 3 subjects). Subjects who have 
experienced a confirmed complete response (CR) should be 
treated for a maximum of 24 months after confirmation, at 
the discretion of the investigator. If the investigator believes 
that a subject may benefit from treatment beyond 24 months, 
it may be permissible after discussion with the sponsor.  
Subjects who experienced a CR and have already stopped 
treatment can resume treatment with avelumab at the same 
dose and schedule. Subjects re-initiating treatment should be 
assessed according to the Schedule of Assessments 
(Appendix I).
Dose escalation (3+3 design) will be performed at the 
following dose levels
! 1.0 mg/kg, once every 2 weeks
! 3.0 mg/kg, once every 2 weeks
! 10.0 mg/kg, once every 2 weeks
Once 1 subject has experienced dose-limiting toxicity (DLT) 
at a dose below 10.0 mg/kg, dose escalation will be reduced 
as described in Section 5.1.4.2.
The first subject of each cohort should be observed for 
16 days (i.e., 48 hours after the second dose) for the 
occurrence of DLT before the second subject is administered 
the trial medication. Thereafter, within each cohort of the 
dose escalation phase, subjects may only be consecutively 
dosed with an interval of at least 48 hours. However, after 
3 subjects have been treated at 10 mg/kg and no DLT has 
been observed, the other 3 subjects required to complete this 
cohort can be enrolled without sequential dosing (i.e., not 
required to wait until 48 hours). If no more than 1 DLT has 
been observed in these 6 subjects, the safety of 10 mg/kg 
will have been established. 
Each subject will stay on the dose level assigned at trial entry 
(only adaptations for weight changes are needed as 
described in Section 5.1.7.1).
The decision to escalate to the next dose level will be based 
on safety assessments after all subjects of a cohort have 
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reached Day 21 (DLT evaluation period). In order to assess 
the safety of avelumab, a safety monitoring committee 
(SMC), responsible for dose escalation decisions, will be 
established.
Once the MTD (see Section 5.1.4.2) or maximum dose to be 
investigated is reached, the respective dose level cohort will 
be filled to a total of 6 subjects. Once the dose of 10 mg/kg 
is established as safe, 10 additional subjects at 3 mg/kg and 
10 mg/kg each may be enrolled, for the purpose of 
generating additional safety, PK and receptor occupancy 
data, if agreed with the SMC.
Once 6 subjects treated at 10 mg/kg have completed the DLT 
observation period and the safety of 10 mg/kg is established, 
a dose level of 15 mg/kg (if 1 DLT was observed) or 
20 mg/kg (if no DLT was observed) dosing every 2 weeks 
will be initiated. In this 20 mg/kg dose level, the safety, PK, 
receptor occupancy, and PD activity of the IMP will be 
evaluated using the methodology that was used for the other 
cohorts. Accrual in these dose levels will be completed using 
a “3+3” method, the same methodology that was used for 
the completion of the previous dose levels. Once the safety 
of the 15 and/or 20 mg dose level has been established (i.e., 
no more than 1 DLT out of 6 subjects treated), up to 
15 additional subjects will be enrolled at 15 or 20 mg/kg 
without sequential dosing (i.e., not required to wait until 
48 hours between 2 subjects). This additional cohort will 
have the purpose of generating safety data, PK data and 
receptor occupancy data at a dose of the respective dose.
With the safety of the 10 mg/kg and 20 mg/kg once every 
2 weeks established, a new cohort of 10 mg/kg administered 
once weekly is being initiated in 6 evaluable subjects to 
assess safety of a more frequent dosing at 10 mg/kg every 
week for 12 weeks followed by 10 mg/kg every 2 weeks.  
Subjects in this cohort of 6 evaluable subjects will receive 
avelumab at 10 mg/kg once weekly for the first 12 weeks.  
Starting Week 13, dosing with 10 mg/kg will be once every 
2 weeks. Subjects in this cohort will be enrolled in selected 
sites in the USA only.
Definition of DLT
With some exceptions discussed in Section 5.1.4.2.2, a DLT 
is defined as a Grade ≥ 3 adverse drug reaction (ADR) 
according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0, 
occurring in the DLT evaluation period confirmed by the 
SMC to be relevant for the study drug treatment. Any DLT 
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will immediately lead to permanent withdrawal of 
avelumab. ADRs requiring treatment discontinuation are 
defined in Section 5.1.7.2.
Expansion phase
After determination of the avelumab dose and regimen for 
further investigation, enrollment in several expansion 
cohorts will be opened in selected tumor indications to 
determine the safety and clinical activity of avelumab. 
Subject eligibility will need to be confirmed by the contract 
research organization (CRO) / Sponsor before the first 
administration of the study drug during the expansion phase.
Based on data generated in the dose escalation phase, the 
dose of avelumab to be used in the expansion phase was 
determined to be 10 mg/kg. In addition, with the emergence 
of promising efficacy data, expansion cohorts have been 
expanded and divided into:
! 4 primary cohorts (N=150 subjects each) of:
1. NSCLC, post platinum doublet; 
2. NSCLC, first-line, does not carry an epidermal 
growth factor receptor (EGFR) activating mutation 
or 
anaplastic 
lymphoma 
kinase
(ALK) 
re-arrangements
(non-squamous cell histologies 
require testing if status is unknown);
3. Gastric and GEJ junction cancer; and 
4. MBC.
! 8 secondary cohorts:
1. CRC (N=20), 
2. CRPC (N=20), 
3. ACC (N=50), 
4. Melanoma (N=50), 
5. Mesothelioma (N=50), 
6. Urothelial carcinoma (N=50; note: enrollment is 
being stopped [N=44] due to the opening of a
urothelial efficacy expansion cohort), 
7. Ovarian cancer (N=120), and
8. Renal 
cell 
carcinoma 
(RCC), 
second-line, 
(N=20 with expansion of 60 first-line).
! 4 efficacy expansion cohorts with the primary objective 
to assess BOR according to RECIST 1.1:
1. Ovarian cancer, platinum refractory, prior liposomal 
doxorubicin (N=100); 
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2. Urothelial 
carcinoma, 
platinum 
ineligible 
or 
progressed after at least 1 line of platinum-based 
therapy (N=200); 
3. Gastric and GEJ cancer, third line (N=150); 
4. HNSCC, platinum ineligible or progressed after at 
least 1 line of platinum-based therapy (N=150);
Subjects in the NSCLC (post platinum doublet), CRC, and 
CRPC cohorts will be enrolled in the USA only.
During enrollment of the expansion part, the SMC will 
monitor all safety information of the participating subjects 
on an ongoing basis (i.e., when 40, 120, 200, 290, 380, 480, 
600, 740, 900, 1080, and 1300 subjects have been enrolled 
and treated for at least 4 weeks and on a quarterly basis 
thereafter until end of enrolment). The SMC may modify the 
frequency of meetings as deemed appropriate by the SMC 
during the course of the trial.  
For subjects enrolled in the efficacy expansion cohorts and 
the secondary urothelial carcinoma cohort, an Independent 
Endpoint Review Committee (IERC) will perform a blinded 
determination as to whether the criteria for tumor response 
or progression according to RECIST 1.1 have been met.
Subjects will receive avelumab intravenously as a 1-hour 
infusion once every 2 weeks until confirmed progression, 
unacceptable toxicity, or any reason for withdrawal from the 
trial or IMP occurs (see Section 5.5). Subjects who have 
experienced a confirmed CR should be treated for a 
maximum of 24 months after confirmation, at the discretion 
of the investigator. If the investigator believes that a subject 
may benefit from treatment beyond 24 months, it may be 
permissible after discussion with the sponsor. Subjects who 
experienced a CR and have already stopped can resume 
treatment with avelumab at the same dose and schedule.
Subjects re-initiating treatment should be assessed 
according to the Schedule of Assessments (Appendix I).  
For subjects who achieve a CR on avelumab therapy and 
then subsequently develop disease progression after 
stopping therapy, but prior to the end of the trial, one 
re-initiation of treatment at the same dose and schedule is 
allowed at the discretion of the investigator and agreement 
of the trial Medical Monitor. In order to be eligible for 
retreatment, the subject must not have experienced any 
toxicity that led to treatment discontinuation of the initial 
avelumab therapy.
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Prior to re-initiation of the study treatment, malignant 
disease needs to be radiologically re-staged to assess all 
known sites of the disease and to establish a new baseline 
for subsequent tumor measurements. Relevant safety 
laboratory results must be available and verified prior to 
re-initiating of treatment.
Subjects who re-initiate treatment will stay on study and will 
be treated and monitored according to the protocol and the 
“until 
progression” 
schedule 
in 
the 
Schedule 
of 
Assessments.
In the case of study termination, subjects continuing to 
benefit from study treatment may still have access to study 
treatment via enrollment in a rollover study if not available 
through some other mechanism (eg, expanded access, 
marketed product).
Planned number of subjects
Dose escalation phase: 18 up to 66 subjects.
Expansion phase: Up to approximately 1640 subjects.
The final sample size, however, may vary, depending on the 
total number of dose levels to be tested, subject replacement 
for DLT evaluation if applicable, and the number of 
expanded cohorts.
Schedule of visits and 
assessments for dose escalation 
cohorts 
Washout (Day -28 to first treatment)/Screening/
Baseline Assessments (Day -18 to first treatment)
Screening will include the informed consent, recording of 
the demographic information, the complete medical history, 
and baseline medical condition; a complete physical 
examination including vital signs, body weight, and height, 
12-lead electrocardiogram (ECG) and a determination of the 
Eastern Cooperative Oncology Group (ECOG) performance 
status; AE and concomitant medication assessments; safety 
laboratory assessments; the tumor evaluation by computed 
tomography (CT) scan or magnetic resonance imaging 
(MRI) as well as tumor markers; tumor tissue (biopsy or 
surgical specimen prepared as blocks or slides [optional]); 
bone scan (as clinically indicated); serum β-human 
chorionic gonadotropin (β-HCG) pregnancy test for women 
of child bearing potential; blood hepatitis B virus (HBV), 
hepatitis C virus (HCV), and human immunodeficiency 
virus (HIV) testing. Adrenocorticotropic hormone, anti-
nuclear antibody, anti-neutrophil cytoplasmic antibody, 
rheumatoid factor, free thyroxine, and thyroid-stimulating 
hormone will also be assessed at screening.
Following completion of the above screening assessments, 
baseline samples for human anti-drug antibody (ADA), 
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 assessments will be collected prior to the first 
administration of avelumab, i.e., either during the screening 
period or pre-dose on Day 1.
Treatment phase
Visits will take place on Days 1, 2, 3, 15, 29, 43, and every 
2 weeks thereafter.
For the 10 mg/kg once weekly cohort only, visits will take 
place every week up to and including Week 12 and then 
every 2 weeks thereafter starting at Week 13.
Safety (including AEs and concomitant medications, 
laboratory values, ECOG performance status, physical 
examinations, vital signs, and 12-lead ECGs), PK, 
immunogenicity, and tumor response assessments will be 
conducted as outlined in Appendix I.
The schedule of the biological response assessment 
comprising immunomonitoring on tumor biopsies and 
blood, measurement of soluble factors, and tumor tissue 
evaluation are displayed in Appendix I.
Discontinuation visit, end-of-treatment visit, safety 
follow-up visit, and survival follow-up
All subjects who discontinue trial treatment prematurely for 
an AE should have a full safety evaluation at the time of 
discontinuation of trial treatment (discontinuation visit). The 
discontinuation visit will consist of documentation of AEs 
and 
concomitant 
medication, 
physical 
examination 
(including vital signs and body weight), 12-lead ECG,
laboratory evaluations (hematology, hemostaseology, full 
serum chemistry, and full urinalysis) and ECOG 
performance status.
In addition, all subjects will have an end-of-treatment visit 
scheduled 4 weeks after the last administration of avelumab.
The end-of-treatment visit is scheduled 4 weeks after the last 
administration of avelumab but before any new therapy is 
started, if possible. The visit will comprise a full assessment 
of safety parameters, immunogenicity assessment, and 
tumor response assessment as appropriate.
Post-treatment Follow-up
All subjects will have a subsequent visit scheduled 10 weeks 
after the last administration of avelumab. The visit will 
include a full assessment of safety parameters.
Adverse events will be documented until the end of 
treatment visit. After the end of treatment visit only 
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treatment related AEs have to be documented until the post-
treatment safety follow-up visit. Subjects with a serious AE
ongoing at the post-treatment safety follow-up must be 
monitored and followed up by the investigator until 
stabilization or until the outcome is known, unless the 
subject is documented as “lost to follow-up”.
Subjects without progressive disease at the end-of-treatment 
visit will be followed up for disease progression (CT / MRI 
scans every 12 weeks) up to 1 year. In addition, subjects will 
be followed for any AE suspected to be related to trial 
treatment, especially for the occurrence of new autoimmune 
events up to 3 months after the last dose of avelumab.
After the end-of-treatment visit, subjects will be followed 
quarterly for survival (including assessment of any further 
tumor therapy). The survival follow-up will continue until 
1 year after the last subject receives the last dose of 
avelumab. 
Schedule of visits and 
assessments for expansion 
cohorts
Washout (Day -28 to first treatment)/Screening/ Baseline 
Assessments (Day -18 to first treatment)
Subjects in all expansion cohorts will be enrolled after the 
dose and regimen of avelumab has been determined. Visits 
will be conducted every 2 weeks and the main assessments 
are the same as those for dose escalation cohorts with the 
following exceptions:
! Subjects with liver metastases at baseline will have visits 
every week, up to Week 7.
! PK samples will be collected prior to each IMP 
administration in all subjects in the expansion phase. In 
addition, expanded PK sampling will be collected in all 
expansion subjects in the CRC and CRPC secondary 
cohorts (20 subjects in each).  For subjects in the first-line 
NSCLC cohort, samples for PK analysis will be collected 
within 2 hours prior to each study drug administration on 
Days 1, 15, 29, 43, 57, 71, 85, 99, and 169. Post-study 
drug administration samples will also be collected at the 
end of the infusion and also 2 to 8 hours after the end of 
infusion (later is better depending on how long the 
subject will stay in the clinic), on Days 1, 43, 85, and 169. 
Samples will also be collected at the 10-week safety 
follow-up visit. For subjects enrolled in the efficacy 
expansion cohorts and the RCC secondary cohort, 
samples for PK determination will be collected prior to 
each administration of study drug on Days 1, 15, 29, 43, 
57, 71, 85, and 169. Post-study drug administration 
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samples will be collected at the end of infusion and 2 to 
8 hours after the end of infusion (later is better, depending 
on how long the subject will stay in the clinic) at Days 1, 
43, 85, and 169.  Exact sampling times will be recorded.  
Samples will be collected at the 10-week Safety 
Follow-up visit.
! Samples for ADA analysis will be collected before start 
of infusion on Days 1, 15, 29, 43, 57, 71, 85 (every 
2 weeks) and on Days 127, and 169 (every 6 weeks), and 
at the end-of-treatment visit.
! Immunomonitoring samples will be collected before start 
of infusion on Days 1, 15, 43, 85 and at the end-of-
treatment visit in all subjects enrolled in secondary 
expansion cohorts, except for the RCC cohort. In addition 
a sample may be collected at Day 3, but is optional.
! Soluble factors samples will be collected for all subjects
in the primary and secondary expansion cohorts, except 
for the RCC cohort, before start of first infusion (Day 1), 
Day 43, and at the end-of-treatment visit. In addition, 
except for the RCC cohort, subjects in the secondary
expansion cohorts will have samples collected on Day 3
(optional). For subjects enrolled in the efficacy expansion
cohorts and the RCC secondary cohort, 
 
 
 
 
! For subjects enrolled in the efficacy expansion cohorts
and the RCC secondary cohort, blood samples for 
 profiling will be collected 
before the start of infusion on Days 1, 15, 29, and 43 and 
the end-of-treatment visit.
! Samples will be collected for receptor occupancy in the 
CRC and CRPC cohorts only.
! For subjects in the HNSCC cohort only, human 
papillomavirus status should be determined. 
! Collection of tumor tissue (the most recent biopsy or 
surgical specimen provided as block or slides) is required 
for all subjects. 
o For subjects in the MBC cohort, the biopsy or surgical 
specimen must have been collected within 90 days 
prior to the first IMP administration.
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o For subjects in the melanoma and mesothelioma 
cohorts only, if an optional fresh biopsy is obtained 
prior to the first dose of trial treatment, archival tumor 
material is not required. Fresh biopsies may also be 
collected on Day 43 and at the end-of-treatment visit.
These biopsies are optional.
o For subjects in the efficacy expansion cohorts and the 
first-line NSCLC primary expansion cohort, fresh 
biopsies may also be collected on Days 43 and at the 
end-of-treatment visit. These biopsies are optional.
Diagnosis and inclusion and 
exclusion criteria 
Inclusion criteria for dose escalation, including the 
10 mg/kg once weekly cohort:
1.
Signed written informed consent.
2.
Male or female subjects aged ≥ 18 years.
3.
Histologically or cytologically proven metastatic or 
locally advanced solid tumors, for which no standard 
therapy exists or standard therapy has failed.
Availability of tumor archival material or fresh biopsies 
is optional for subjects in dose escalation.
4.
ECOG performance status of 0 to 1 at trial entry and an 
estimated life expectancy of at least 3 months.
5.
Disease 
must 
be 
measurable 
with 
at 
least 
1 unidimensional measurable lesion by RECIST 1.1, 
except for subjects with metastatic CRPC or MBC who 
may be enrolled with objective evidence of disease 
without a measureable lesion.
6.
Adequate hematological function defined by white 
blood cell (WBC) count ≥ 3 × 109/L with absolute 
neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte 
count ≥ 0.5 × 109/L, platelet count ≥100 × 109/L, and 
hemoglobin ≥9 g/dL (may have been transfused). For 
subjects with gastric cancer only, the acceptable 
parameters for WBC, ANC, and lymphocytes are as 
follows: WBC ≥ 2 × 109/L, ANC ≥ 1.0 × 109/L, and 
lymphocyte count ≥ 0.5 × 109/L.
7.
Adequate hepatic function defined by a total bilirubin 
level ≤ 1.5 × the upper limit of normal range (ULN), an 
aspartate aminotransferase (AST), level ≤ 2.5 × ULN, 
and 
an 
alanine 
aminotransferase 
(ALT)
level 
≤2.5 × ULN or, for subjects with documented 
metastatic disease to the liver, AST and ALT levels 
≤5 × ULN.
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8.
Adequate renal function defined by an estimated 
creatinine clearance > 50 mL/min according to the 
Cockcroft-Gault formula.
9.
Highly effective contraception (that is, methods with a 
failure rate of less than 1% per year) for both male and 
female subjects if the risk of conception exists (Note:  
The effects of the study treatment on the developing 
human fetus are unknown; thus, women of childbearing 
potential and men must agree to use highly effective 
contraception, defined in Appendix III or as stipulated 
in national or local guidelines.  Highly effective 
contraception must be used 28 days prior to first study 
treatment administration, for the duration of study 
treatment, and at least for 60 days after stopping study 
treatment.  Should a woman become pregnant or suspect 
she is pregnant while she or her partner is participating 
in this study, the treating physician should be informed 
immediately.)
Inclusion criteria for expansion phase:
1.
Signed written informed consent.
2.
Male or female subjects aged ≥ 18 years.
3.
Subjects must have relapsed, refractory, or progressive 
disease following last line of treatment (with the 
exception of the NSCLC first-line and gastric and GEJ 
cancer primary cohorts,
which do not require 
progression). Availability of tumor archival material or 
fresh biopsies (excluding bone biopsies) is mandatory 
for eligibility in the expansion cohorts. For subjects in 
the MBC cohort, the biopsy or surgical specimen must 
have been collected within 90 days prior to the first IMP 
administration. Specifically, the following will be 
required:
Primary expansion cohorts
o
NSCLC post platinum doublet: Histologically or 
cytologically confirmed stage IIIB or stage IV 
NSCLC that has progressed after 1 line of platinum-
containing doublet chemotherapy. Subjects should 
have received only 1 line of platinum-containing 
treatment for metastatic disease (i.e., adjuvant 
treatment with a platinum-containing regimen is not 
sufficient for eligibility because not received in the 
context of a metastatic disease). Subjects in the 
NSCLC cohort will only be enrolled in the USA.
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o
NSCLC first line: Stage IV (per 7th International 
Association for the Study of Lung Cancer [IASLC]
classification) 
or 
recurrent 
NSCLC 
that 
is 
histologically proven.  Subjects must not have 
received treatment for their metastatic or recurrent 
disease.  No activating EGFR mutation nor ALK
translocation / re-arrangement (non-squamous cell 
histologies require testing if status is unknown).
o
Gastric and GEJ cancer: Histologically confirmed, 
unresectable 
locally 
advanced 
or 
metastatic 
adenocarcinoma of the gastric and GEJ, treated with 
first-line chemotherapy combination in metastatic 
setting with or without disease progression. Subjects 
should have received no more than 1 line of 
treatment for metastatic disease. Subjects should not 
have been treated with trastuzumab (but can be 
Human Epidermal growth factor Receptor 2 [HER2] 
positive). Subjects who received any platinum 
containing doublet or triplet as a neoadjuvant 
chemotherapy strategy, but are not ultimately 
candidates for surgery will also be eligible. In 
addition, subjects with gastric cancer can enter in the 
study if their WBC is ≥2 × 109/L with ANC ≥1.0 
× 109/L and lymphocyte count ≥0.5 × 109/L. 
o
MBC: Subjects must have histologically confirmed 
locally advanced or MBC and have tumor that is 
refractory to or progressive after standard of care 
therapy. Subjects must have received no more than 
3 prior lines of cytotoxic therapy for metastatic 
disease. Subjects must have received a taxane and an 
anthracycline, unless contra-indicated. 
Secondary expansion cohorts
o
CRC: Histologically or cytologically confirmed 
recurrent or refractory metastatic CRC (according to 
AJCC/UICC TNM Staging System seventh edition) 
after failure of prior therapy containing oxaliplatin/
fluoropyrimidine 
and/or 
irinotecan/
fluoropyrimidine 
and, 
if 
eligible, 
cetuximab 
(Erbitux®) and bevacizumab (Avastin®). These 
subjects will be enrolled in sites located in the USA 
only.
o
CRPC: Histologically or cytologically confirmed 
asymptomatic or minimally symptomatic metastatic 
CRPC (according to AJCC/UICC TNM Staging 
System seventh edition) with objective evidence of 
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disease (non measureable or measurable lesion) with 
stable, ongoing adequate testosterone suppression 
proven 
by 
castrate 
levels 
of 
testosterone 
(≤50 ng/dL), except for subjects with prior 
orchiectomy. Minimally symptomatic is defined as 
patients who do not require consistent treatment with 
opiates over the last month (less than 7 days of 
opiates in the last 28 days, and no opiates 
administered 3 days in a row), for the treatment of 
their prostate cancer. Additional androgen blockade 
or treatment with an anti-androgen receptor is 
acceptable. These subjects will be enrolled in sites 
located in the USA only.
o
Melanoma: 
Histologically 
or 
cytologically 
confirmed stage IIIc or IV unresectable melanoma, 
(according to AJCC/UICC TNM Staging System 
seventh edition) after failure of at least 1 prior 
standard therapy for metastatic disease. All subjects
with metastatic melanoma will be required to 
undergo screening with a MRI or CT scan (either,
with contrast preferred) to rule out brain metastases, 
unless imaging has previously been performed 
within 28 days prior to screening.
o
Ovarian cancer: Histologically or cytologically 
confirmed recurrent or refractory (progression 
within 6 months of platinum-based therapy or 
progression after subsequent therapy in previously 
relapsed subjects), stage III-IV epithelial ovarian, 
fallopian tube or peritoneal cancer subjects 
(according to AJCC/UICC TNM and International 
Federation of Gynecology and Obstetrics (FIGO) 
Staging System seventh edition) who have 
progressed following adjuvant therapy or therapy for 
metastatic disease. 
o
ACC: Histologically or cytologically confirmed 
metastatic ACC. Subjects must have previously 
received at least 1 line of systemic therapy for 
metastatic disease, of which at least 1 must be 
platinum-based. Subjects receiving mitotane may 
continue to receive mitotane at enrolment and on 
study.
o
Mesothelioma:
Histologically or cytologically 
confirmed mesothelioma (pleural or peritoneal) with 
unresectable disease. Subjects must have received 
and progressed after either a platinum-pemetrexed 
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containing regimen or a platinum-containing 
regimen followed by pemetrexed (or vice versa) after 
disease progression. Subjects must present with at 
least 1 measurable lesion that has not been irradiated.
o
Urothelial 
carcinoma:
Histologically 
or 
cytologically documented locally advanced or 
metastatic transitional cell carcinoma of the 
urothelium (including renal pelvis, ureters, urinary 
bladder, urethra). A tumor sample (1 tumor block or 
at least 7 unstained slides) must be available.  
Subjects can be either: ineligible for cisplatin-based 
chemotherapy or have progressed after treatment 
with at least one platinum-containing regimen (e.g., 
platinum plus another agent such as gemcitabine,
methotrexate, vinblastine, doxorubicin, etc.) for 
inoperable locally advanced or metastatic urothelial 
carcinoma or disease recurrence. Ineligibility to 
treatment with a platinum salt is defined by the 
existing of any (at least 1) of impaired renal function, 
a hearing loss of 25 decibels at 2 contiguous 
frequencies, or Grade ≥2 peripheral neuropathy. 
o Renal cell carcinoma, second-line with first-line 
expansion:
Histologically 
or 
cytologically 
documented RCC with a component of clear cell 
subtype, with metastasis. A tumor sample (1 tumor 
block or at least 7 unstained slides) must be 
available. Eligible subjects must have measureable 
disease. Subjects must have failed 1 prior systemic 
first-line regimen for metastatic RCC (except for 
subjects enrolled in first-line expansion).
Efficacy expansion cohorts:
o
Gastric and GEJ cancer, third line: Histologically 
confirmed, 
unresectable 
locally 
advanced 
or 
metastatic adenocarcinoma of the gastric and GEJ, 
treated with both a first-line chemotherapy 
combination and followed by ramucirumab (alone or 
in combination). Subjects must have progressed 
during or after ramucirumab therapy. Subjects with 
gastric cancer can enter into the study if their WBC 
is ≥ 2 × 109/L with ANC ≥ 1.0 × 109/L and 
lymphocyte count ≥ 0.5 × 109/L.
o
Ovarian cancer, platinum refractory and prior 
liposomal 
doxorubicin:
Histologically 
or 
cytologically 
confirmed, 
platinum-refractory 
(progression within 6 months of platinum-based 
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therapy), Stage III-IV epithelial ovarian, fallopian 
tube, or peritoneal cancer subjects (according to 
AJCC/UICC TNM and FIGO Staging System, 
7th edition). Subjects must have received at least 
1 line of prior platinum-based chemotherapy 
regimen, as well as prior liposomal doxorubicin 
(monotherapy or combination), in order to be 
considered eligible for this study. Subjects may have 
received any additional number of prior systemic 
therapies for metastatic disease. 
o
Urothelial carcinoma, platinum ineligible or 
progressed after at least 1 line of platinum-based 
therapy:
Histologically 
or 
cytologically 
documented 
locally 
advanced 
or 
metastatic 
transitional cell carcinoma of the urothelium 
(including renal pelvis, ureters, urinary bladder, 
urethra). A tumor sample (1 tumor block or at least 
7 unstained slides) must be available. Subjects can 
be either: ineligible for cisplatin based chemotherapy 
or have progressed after treatment with at least 
1 platinum-containing regimen (e.g., platinum plus 
another agent such as gemcitabine, methotrexate, 
vinblastine, doxorubicin, etc.) for inoperable locally 
advanced or metastatic urothelial carcinoma or 
disease recurrence. Ineligibility to treatment with a 
platinum salt is defined by the existing of any (at 
least 1) of impaired renal function, a hearing loss of 
25 decibels at 2 contiguous frequencies, or Grade ≥2 
peripheral neuropathy. Subjects may have received 
any number of prior systemic therapies for metastatic 
disease. 
o
Head and neck, platinum ineligible or progressed 
after at least 1 line of platinum-based therapy:
Histologically 
or 
cytologically 
documented 
recurrent or metastatic HNSCC of the oral cavity, 
oropharynx, hypopharynx, or larynx. Subjects must 
have experienced tumor progression or recurrence 
within 6 months of the last dose of any number of 
platinum-based chemotherapy regimens given in the 
adjuvant, primary, recurrent, or metastatic setting. 
Ineligibility to treatment with a platinum salt is 
defined by the existing of any (at least 1) of impaired 
renal function, a hearing loss of 25 decibels at 
2 contiguous frequencies, or Grade ≥2 peripheral 
neuropathy. A tumor sample (1 tumor block or at 
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least 7 unstained slides) must be available. Subjects 
may have received any number of prior systemic 
therapies for metastatic disease. Except for subjects 
who are platinum ineligible, subjects must have 
received at least 1
line of platinum-based 
chemotherapy.
4.
ECOG performance status of 0 to 1 at trial entry and an 
estimated life expectancy of at least 3 months. 
5.
Disease 
must 
be 
measurable 
with 
at 
least 
1 unidimensional measurable lesion by RECIST 1.1, 
except for subjects with metastatic CRPC who may be 
enrolled with objective evidence of disease without a 
measureable lesion.
6.
Adequate hematological function defined by WBC 
≥3 × 109/L with ANC ≥ 1.5 × 109/L, lymphocyte count 
≥0.5 × 109/L, platelet count ≥100 × 109/L, and 
hemoglobin ≥9 g/dL (may have been transfused). For 
subjects with gastric cancer only the acceptable 
parameters for WBC, ANC, and lymphocytes are as 
follows: WBC ≥2 × 109/L, ANC ≥ 1.0 × 109/L, and 
lymphocyte count ≥ 0.5 × 109/L.
7.
Adequate hepatic function defined by a total bilirubin 
level ≤ 1.5 × ULN and an AST level ≤2.5 × ULN and 
an ALT level ≤2.5 × ULN for all subjects.
8.
Adequate renal function defined by an estimated 
creatinine clearance > 30 mL/min according to the 
Cockcroft-Gault 
formula
or 
measured 
24-hour 
creatinine clearance (or local institutional standard 
method).
9.
Highly effective contraception for both male and female 
subjects if the risk of conception exists. (See Section 
5.3.1 for additional details.)
Exclusion criteria (applicable to all subjects, including 
all expansion cohorts):
1.
Concurrent treatment with a non-permitted drug (see 
Section 6.5.2).
2.
Prior therapy with any antibody/drug targeting T cell 
co-regulatory proteins (immune checkpoints) such as 
anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte 
antigen-4 (CTLA-4) antibody. For subjects with 
metastatic melanoma, prior treatment with a CTLA-4 
antibody is not an exclusion.
3.
Concurrent anticancer treatment within 28 days before 
the start of trial treatment (e.g., cytoreductive therapy, 
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radiotherapy [with the exception of palliative bone 
directed radiotherapy], immune therapy, or cytokine 
therapy except for erythropoietin); major surgery within 
28 days before the start of trial treatment (excluding 
prior diagnostic biopsy); use of hormonal agents within 
7 days before the start of trial treatment, except for 
subjects in the CRPC cohort who may remain on 
treatment with luteinizing hormone-releasing hormone 
agonists or antagonists; or use of any investigational 
drug within 28 days before the start of trial treatment. 
Subjects in the gastric and GEJ cohort who have not 
progressed on first-line chemotherapy may be enrolled 
within the 28-day period following prior treatment 
provided all toxicity from prior therapy has resolved to 
Grade ≤1.
Subjects receiving immunosuppressive agents (such as 
steroids) for any reason should be tapered off these
drugs before initiation of the study treatment (with the 
exception of patients with adrenal insufficiency, who 
may continue corticosteroids at physiologic replacement 
dose, equivalent to ≤10 mg prednisone daily). Steroids 
with no or minimal systemic effect (topical, inhalation) 
are allowed.
4.
Previous malignant disease other than the target 
malignancy to be investigated in this trial within the last 
5 years with the exception of basal or squamous cell 
carcinoma of the skin or cervical carcinoma in situ.
5.
Rapidly progressive 
disease (e.g., tumor lysis 
syndrome).
6.
Active or history of central nervous system (CNS) 
metastases.
7.
Receipt of any organ transplantation including 
allogeneic stem-cell transplantation. 
8.
Significant acute or chronic infections including, among 
others:
!
Known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS)
!
Positive test for HBV surface antigen and / or 
confirmatory HCV RNA (if anti-HCV antibody 
tested positive).
9.
Active or history of any autoimmune disease (subjects 
with diabetes Type I, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunosuppressive 
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treatment are eligible) or immunodeficiencies.
10. Known severe hypersensitivity reactions to monoclonal 
antibodies (Grade ≥3 NCI-CTCAE v4.0), any history 
of anaphylaxis, or uncontrolled asthma (i.e., 3 or more 
features of partly controlled asthma).
11. Persisting toxicity related to prior therapy Grade > 1 
NCI-CTCAE v4.0, however sensory neuropathy 
≤Grade 2 is acceptable.
12. Pregnancy or breast feeding.
13. Known alcohol or drug abuse.
14. Clinically significant (i.e., 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 uncontrolled cardiac arrhythmia 
requiring medication. 
15. All other significant diseases (e.g., inflammatory bowel 
disease), which, in the opinion of the investigator, might 
impair the subject’s tolerance of trial treatment.
16. Any psychiatric condition that would prohibit the 
understanding or rendering of informed consent.
17. Legal incapacity or limited legal capacity.
18. Vaccination within 4 weeks of the first dose of 
avelumab and while on study is prohibited except for 
administration of inactivated vaccines (e.g. inactivated 
influenza vaccines).
Investigational Medicinal 
Product: dose/mode of 
administration/ dosing schedule
Avelumab will be administered as a 1-hour (-10 minutes / 
+20 minutes, i.e., 50-80 minutes) intravenous (i.v.) infusion. 
Subjects will receive avelumab once every 2 weeks until 
confirmed progression, unacceptable toxicity, or any 
criterion for withdrawal from the trial or IMP occurs (see 
Section 5.5). For the 10 mg/kg once weekly cohort only, 
subjects 
will 
receive 
avelumab 
once 
weekly 
for 
12 consecutive weeks and then starting at Week 13, once 
every 2 weeks thereafter.
The dose of avelumab will be calculated based on the weight 
of the subject determined within 72 hours prior to 
administration.  The dose of avelumab used for the previous
administration can be repeated if the change in the subject’s 
weight is 10% or less than the weight used for the last dose 
calculation.
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Premedication with an antihistamine and with paracetamol 
(acetaminophen) approximately 30 to 60 minutes prior to 
each dose of avelumab is mandatory (for example, 25-50 mg 
diphenhydramine 
and 
500-650 
mg 
paracetamol 
[acetaminophen] i.v. or oral equivalent). This regimen may 
be modified based on local treatment standards and 
guidelines, as appropriate.
Immediate access to intensive care unit or equivalent 
environment and appropriate medical therapy (including i.v.
epinephrine, 
corticosteroids, 
antihistamines, 
bronchodilators, and oxygen) must be in place for use in the 
treatment of potential infusion-related reactions. Infusion of 
avelumab will be stopped in case of Grade ≥2 infusion-
related, allergic, or anaphylactic reactions (according to 
NCI-CTCAE v4.0). Following avelumab infusions, subjects 
must be observed for 2 hours post infusion for potential 
infusion-related reactions. 
Relevant clinical laboratory results essential for patient 
management decisions (hematology, biochemistry, liver 
function tests) must be available and reviewed before 
administration of avelumab.
Reference therapy: dose/mode 
of administration/dosing 
schedule
Not applicable.
Planned treatment duration per 
subject
The planned treatment duration is until unacceptable 
toxicity, or any criterion for withdrawal from the trial or IMP 
occurs. Subjects who have experienced a confirmed CR 
should be treated for a maximum of 24 months after 
confirmation, at the discretion of the investigator. If the 
investigator believes that a subject may benefit from 
treatment beyond 24 months, it may be permissible after 
discussion with the sponsor. Subjects who experienced a CR 
and have already stopped treatment can resume treatment 
with avelumab at the same dose and schedule. 
For subjects who achieve a CR on avelumab therapy and
then subsequently develop disease progression
after 
stopping therapy, but prior to the end of the trial, one 
re-initiation of treatment at the same dose and schedule is 
allowed at the discretion of the investigator and agreement 
of the trial Medical Monitor. In order to be eligible for 
retreatment, the subject must not have experienced any 
toxicity that led to treatment discontinuation of the initial 
avelumab therapy. Subjects who re-initiate treatment will 
stay on study and will be treated and monitored according to 
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the protocol and the “until progression” schedule in the 
Schedule of Assessments.
Primary endpoints
Occurrence of DLTs during the first 3 weeks of treatment in 
the dose escalation part (excluding 10 mg/kg once weekly 
cohort).
The confirmed BOR, per RECIST 1.1, as adjudicated by an 
Independent Endpoint Review Committee (IERC) for 
subjects enrolled in the efficacy expansion cohorts only.
Secondary endpoints
! Number, severity, and duration of treatment-emergent 
adverse events (TEAEs) for all dose groups / indications 
according to the NCI-CTCAE v4.0.
! Number, severity, and duration of treatment-related AEs 
according to NCI-CTCAE v4.0.
! PK profile.
! irBOR and BOR according to modified irRC and to 
RECIST 1.1, respectively, per investigator assessment.
! The confirmed BOR, per RECIST 1.1, as adjudicated by 
an IERC, for subjects enrolled in the secondary urothelial 
carcinoma cohort.
! irPFS time and PFS time according to modified irRC and 
to RECIST 1.1, respectively, per investigator assessment.
! OS time.
! Pharmacodynamic (PD) profile
! Serum titers of ADAs.
! Expression of PD-L1 on tumor tissue.
! For the primary expansion cohorts only: Unconfirmed 
response at Week 13 according to RECIST 1.1.
! Duration of response according to modified irRC and to 
RECIST 1.1, respectively, per investigator assessment.
! For the efficacy expansion cohorts only: 
o PFS time, according to RECIST 1.1, per IERC
o Duration of response according to RECIST 1.1, per 
IERC.
Pharmacokinetics/Receptor 
occupancy 
PK parameters are described in Section 7.5.
Receptor 
occupancy 
(Pharmacodynamics):
avelumab
binding to PD-L1 molecules on circulating peripheral blood 
leukocytes (PBLs) will be investigated by flow cytometry on 
serially 
collected 
blood 
samples 
as 
described 
in 
Section 7.6.1.1.
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Biomarkers
 
In the dose escalation part, biological activities such as 
circulating cellular markers monitoring (e.g., lymphocyte, 
NK cells activation and regulatory markers by flow 
cytometry), soluble factors (e.g., cytokines profile, soluble 
PD-1, soluble PD-L1), predictive biomarker candidates (i.e., 
level of PD-L1 tumor expression), and optionally 
mechanisms related to antibody-dependent cell-mediated 
cytotoxicity (ADCC) (e.g., in vitro ADCC assay) and 
cellular composition of tumor microenvironment will be 
investigated on blood and plasma / serum samples as 
described in Section 7.6.1.2. 
In the expansion part (including efficacy expansion
cohorts), 
a 
similar 
immunomonitoring
approach 
(e.g., cellular and soluble markers monitoring and optional 
intratumoral cellular monitoring) to the escalation part will 
be considered as follow-up in all subjects in the secondary 
expansion cohorts. Additional analyses such as antigen 
specific 
immune 
responses 
(e.g., 
enzyme-linked 
immunosorbent spot, profile of tumor infiltrated cells, intra-
tumoral immune response profiling) may be investigated as 
retrospective analyses according to indication. For the RCC 
secondary cohort, the primary cohorts, and the efficacy 
expansion cohorts, immunomonitoring will be limited to 
soluble factors analyses. Predictive biomarker candidates 
will be investigated in all indications (for example, level of 
PD-L1 tumor expression).
 
 
 
Statistical methods (includes 
sample size calculation)
The total sample size at the end of the trial (based on the 
dose escalation part and all expansion cohorts) is expected 
to be approximately 1706 treated subjects.
The dose escalation part of the trial follows a 
well established current methodology (3 + 3 cohort design) 
of dose-finding studies in oncology.
The sample size of 150 for expansion in the primary cohorts 
(NSCLC [first-line and post platinum doublet cohorts], 
gastric and GEJ cancer, and MBC) and 2 efficacy expansion
cohorts (gastric and GEJ cancer [third-line] and HNSCC) 
has been chosen based on knowledge that PD-L1 is 
clinically active in NSCLC and that PD-L1 is also expressed 
in MBC, gastric cancer, and HNSCC microenvironment. 
Published data have linked the expression of PD-L1 by 
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tumor cells and clinical activity of agents blocking the PD-1
/ PD-L1 pathway. Enrollment of 150 subjects will allow for 
a robust assessment of safety and efficacy endpoints in these 
indications, including a precise determination of response 
rates. In addition, data from these cohorts will be used to 
investigate the association between the pattern of expression 
of membrane PD-L1 and clinical response to PD-L1 
blockade, and to determine whether accrual in future studies 
should be restricted based on PD-L1 expression status. 
The sample size of 20 for each of the 4 original secondary 
expansion cohorts (CRC, CRPC, ovarian, and melanoma) 
was chosen primarily to further explore the safety and 
efficacy of avelumab in specific indications and to provide 
preliminary data to aid in future study design. Following 
completion of dose escalation in this trial and in the broader 
context of ongoing research with PD-L1 inhibition, it is 
considered appropriate to add 4 new secondary cohorts 
(ACC, mesothelioma, urothelial carcinoma, and RCC) to the 
expansion phase of this trial and to increase subject 
enrollment in 2 of the initial secondary cohorts (melanoma 
and ovarian cancer). 
The primary endpoint of the efficacy expansion cohorts is 
the confirmed BOR according to RECIST 1.1, as 
adjudicated by an IERC. For each of these cohorts, the
primary analysis will aim to reject the null hypothesis of an 
ORR ≤10% by means of an exact binomial test at the 1-sided 
alpha level of 0.025. Analyses are considered positive if the 
lower limit of the 95% confidence interval of the confirmed 
BOR exceed 10%. Confidence intervals will be constructed 
using the Clopper-Pearson method.
For the gastric, ovarian, and head and neck cancer cohorts, 
the  primary analysis is planned 6 months after start of 
treatment of the last subject in the given cohort. Interim 
analyses will be conducted after 60% of the subjects in the 
given cohort have been followed up for 13 weeks. 
The sample size of 150 (or 100) in these efficacy expansion 
cohorts will provide approximately 91% (or 80%) power 
under an assumed response rate of 20% to reject the null 
hypothesis of a response rate ≤10% at a 1-sided significance 
level of 0.025. 
For the urothelial carcinoma efficacy expansion cohort, the 
primary analysis of confirmed BOR will be performed in 
subjects with PD-L1 positive tumors followed by all treated 
subjects. Interim analyses will be conducted for the 
109 subjects enrolled in the urothelial carcinoma efficacy 
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expansion cohort prior to Protocol Amendment 13. Subjects 
will be considered PD-L1 positive (negative) if at least (less 
than) 5% of the tumor cells show PD-L1 membrane staining, 
respectively. If during assay development (based on generic 
samples) a different cut-off is determined to be more 
appropriate, this cut-off may be adapted in the SAP prior to 
analysis of subject samples from this trial.  
Descriptive statistics and graphical representations will be 
the main analysis tools. For all analyses, results and 
graphical representation of data will be presented by dose 
level (cohort) / expansion cohorts.
An interim analysis of response will be conducted in each of 
the primary expansion cohorts after the first 75 subjects have 
reached the time point of their second post-baseline tumor 
assessment scheduled in Week 13, i.e., 13 weeks after start 
of treatment of the 75th subject. 
In the NSCLC (post platinum doublet) cohort only, 
2 additional interim analyses of efficacy will be conducted, 
13 weeks after the start of treatment of the 60th and the last 
subject, respectively.
In the first-line NSCLC primary expansion cohort, an 
interim analysis of response will be conducted 13 weeks 
after start of treatment of the 30th subject.
For each primary or secondary expansion cohort, an 
additional interim analysis may be conducted 13 weeks after 
the start of treatment of the last subject in that cohort.
In the secondary cohorts that plan to enroll more than 
20 subjects, i.e., the ACC, melanoma, mesothelioma, 
ovarian cancer, and urothelial carcinoma cohorts, an interim 
analysis of response will be performed 13 weeks after the 
start of treatment of the 20th subject. Accrual in each cohort 
may be paused
during the interim analysis. If no 
unconfirmed response according to RECIST 1.1 is observed 
in a given cohort in the interim analysis, accrual in that 
cohort will be stopped. In addition, for the ovarian cancer 
secondary expansion cohort, an interim analysis of response 
will be performed for internal planning purposes 13 weeks 
after the start of treatment of the 75th subject.
In the efficacy expansion cohorts, interim analyses for 
efficacy are planned 13 weeks after the start of treatment of 
the 30th subject in all cohorts, 13 weeks after start of 
treatment of the 60th subject in the ovarian cohort, and 
13 weeks after start of treatment of the 90th subject in the 
gastric / GEJ and HNSCC cohorts. No futility rule is 
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foreseen because the clinical activity of anti-PD-1 / 
anti-PD-L1 agents in these tumor types is established, and
the patient populations are characterized by a high unmet 
medical need. If efficacy criteria are met at the second 
interim analysis, enrollment will continue to the planned full 
number of subjects in order to collect further data on the 
primary and secondary endpoints, especially on the 
association between PD-L1 expression and efficacy 
endpoints. 
Statistics for continuous variables may include means, 
medians, ranges and appropriate measures of variability. 
Qualitative variables will be summarized by counts and 
percentages. The uncertainty of estimates will be assessed 
by confidence intervals. The results of the safety evaluations 
will be tabulated and displayed by dose level/expansion 
cohorts. With the exception of the hypothesis test for the 
ORR in the efficacy expansion cohorts, only exploratory 
statistical analysis will be performed. Descriptive statistics 
will be examined for indications of dose-related toxicity.
Listings will be produced upon completion of each dose 
escalation cohort of subjects and the decision as to whether 
to proceed with dose-escalation, dose-reduction or to enroll 
another cohort at the same dose level will be determined by 
reviewing these data. Full details of the planned analyses 
will be described in the trial statistical analysis plan, 
separately for the dose escalation and the expansion part.
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2
Sponsor, Investigators and Trial Administrative Structure
The Sponsor of this clinical trial with avelumab is EMD Serono Inc, Rockland, MA, in the USA 
and Merck KGaA, Darmstadt, Germany in rest of world.
This trial requires a significant logistic and administrative structure for its efficient execution. 
Details of such structures and associated procedures will be defined in a separate Manual of 
Operations (MOP). This will be prepared under the supervision of the clinical trial leader in close 
collaboration with the responsible units at the Sponsor.
2.1
Investigational Sites
The trial will be conducted in up to 8 enrolling centers in the USA for the dose escalation part of 
the trial and up to approximately 160 enrolling centers for the treatment expansion part of the trial 
(approximately 100 of which are anticipated to be in the USA). The trial will be performed in the 
USA, Asia, and Europe.
2.2
Trial Coordination / Monitoring
The Sponsor will coordinate the trial and will provide the support of contract research 
organizations (CRO) for some activities of the trial. Sponsor Global Clinical Operations will 
perform oversight of the activities performed by the CROs.
The Clinical Trial Supplies department of the Sponsor will supply the trial medication of 
avelumab, which will be distributed to the sites by the CRO.
Safety laboratory assessments will be performed locally by investigational sites. Pharmacokinetic 
(PK), pharmacodynamic (PD), 
 and 
 
assessments will be performed under the responsibility of the Sponsor. 
The Global Drug Safety Department, Merck KGaA, Darmstadt, Germany or their designated 
representatives will supervise drug safety and the timely reporting of adverse events (AEs) and 
serious adverse events (SAEs).
Quality assurance of the trial conduct will be performed by the Development Quality Assurance 
(DQA) Department, Merck KGaA, Darmstadt, Germany.
The department of Global Biostatistics will supervise the statistical analyses (with the exception 
of the PK data analyses), which will be outsourced to a CRO.
2.2.1
Safety Monitoring Committee
To ensure subjects’ safety during the escalation part as well as the expansion part, a safety 
monitoring committee (SMC) will review the safety data on a regular basis. The SMC consists of 
permanent members from the Sponsor and/or CRO (Early clinical development lead, medical lead, 
biostatistician [in the expansion part], global drug safety representative), the coordinating 
investigator, and external experts with expertise in the management of cancer patients. During the 
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escalation part, the SMC will evaluate the safety data and will decide on dose-limiting toxicities 
(DLTs) relevant for the treatment and will advise on dose escalation or suspension of enrollment, 
with the final adjudication being a Sponsor prerogative. In 10 mg/kg once weekly cohort the SMC
will evaluate overall safety data when all 6 subjects have completed minimum 4 week-treatment 
period, and after 12 weeks of observation have been completed for all subjects enrolled in this 
cohort. During the enrollment phase of the expansion part, the SMC will monitor on an ongoing 
basis (i.e., when 40, 120, 200, 290, 380, 480, 600, 740, 900, 1080, and 1300 subjects have been 
enrolled and treated for at least 4 weeks and on a quarterly basis thereafter until end of enrolment), 
all safety information of the participating subjects and will decide by consensus on continuation, 
modification, or suspension of the trial or of a particular expansion cohort. The SMC may modify 
the frequency of meetings as deemed appropriate by the SMC during the course of the trial.  The 
specific working procedures will be described in an SMC charter, which will be established prior 
to the start of recruitment.
2.2.2
Central 
Reader 
and 
Independent 
Endpoint 
Review 
Committee
A central facility will read and interpret all radiographic scans for subjects enrolled in the efficacy 
expansion cohorts and the secondary urothelial carcinoma cohort. The data for all images will be 
transferred from trial sites to the central reading center for evaluation. Scans will be evaluated at 
the central facility in accordance with Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1). The imaging data will be transferred to the Sponsor or designee at regular intervals. 
A manual from the vendor will be provided to each trial site. 
For subjects enrolled in the efficacy expansion cohorts and the secondary urothelial carcinoma 
cohort, the Independent Endpoint Review Committee (IERC) will perform a blinded determination 
as to whether the criteria for tumor response or progression according to RECIST 1.1 have been 
met. The IERC will be composed of a minimum of 3 members, including 1 oncologist. The role 
of the IERC will be to review radiographic image findings and physical findings for the 
determination of the time point overall response and date of disease progression according to 
RECIST 1.1 for each subject. The full membership, mandate, and processes of the IERC will be 
detailed in the IERC charter.
3
Background Information
3.1
Investigational Medicinal Product
The investigational medicinal product (IMP) for the present trial is avelumab (MSB0010718C), a 
fully human monoclonal antibody of the IgG1 isotype. This anti-PD-L1 therapeutic antibody 
concept is intended to be developed in oncological settings by Merck KGaA, Darmstadt, Germany 
and by its affiliate EMD Serono Inc, Rockland MA, USA.
Avelumab drug product is a sterile liquid formulation intended for intravenous injection (i.v.). It 
is presented at a concentration of 10 mg/mL (process A formulation) and 20 mg/mL (process B 
formulation) in vials of nominal volume of 8 and 10 mL, respectively (see Section 6.1 and the 
latest Investigator’s Brochure for additional details).
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The drug product is presented in type 1 glass vials closed with a rubber stopper and sealed with an 
aluminum / yellow polypropylene flip off seal. Both of the primary packaging materials are of 
European Pharmacopeia and United States Pharmacopeia quality.
3.2
Non-Clinical Findings for Avelumab
3.2.1
In vitro and in vivo Pharmacology Findings
Programmed death ligand 1 (PD-L1) is a transmembrane protein that was first identified for its 
role in the maintenance of self-tolerance and prevention of autoimmunity (1). Engagement of PD-
L1 on dendritic cells with the programmed death 1 (PD-1) receptor on T cells delivers an inhibitory 
signal that promotes T cell anergy or apoptosis (2). This immunoinhibitory checkpoint is often 
subverted by tumor cells that over-express PD-L1 in order to escape immunosurveillance in the 
tumor microenvironment. Indeed, there is a strong correlation between PD-L1 expression and 
prognosis in cancer. Blockade of the interaction between PD-L1 on tumor cells and PD-1 on T 
cells is expected to reverse T cell suppression within tumors, thereby promoting effective 
anti-tumor immune responses. 
Several antibodies directed against the PD-L1 / PD-1 pathway are in clinical development for 
cancer treatment (3). Compared with anti-PD-1 antibodies that target T-cells, anti-PD-L1 
antibodies that target tumor cells are expected to have less side effects, including a lower risk of 
autoimmune-related safety issues, as blockade of PD-L1 leaves the PD-L2 / PD-1 pathway intact 
to promote peripheral self-tolerance (4). To this end, a fully human IgG1 anti-PD-L1 antibody 
(avelumab; drug code MSB0010718C) has been produced. Avelumab selectively binds to PD-L1 
and competitively blocks its interaction with PD-1. Furthermore, this antibody is cross-reactive 
with murine PD-L1, thus allowing in vivo pharmacology studies to be conducted in normal 
laboratory mice. However, due to immunogenicity directed against the fully human avelumab
molecule, the dosing regimen was limited to 3 doses given within a week. The key preclinical 
pharmacology findings for avelumab are summarized below.
!
Functional enhancement of primary T cell activation in vitro in response to antigen-specific 
and antigen non-specific stimuli.
!
Significant inhibition of in vivo tumor growth (PD-L1 expressing MC38 colon carcinoma) as 
a monotherapy.
!
In vivo efficacy is driven by CD8+ T cells, as evidenced by complete abrogation of anti-tumor 
activity when this cell type was systemically depleted.
!
Combination with localized, fractionated radiotherapy resulted in complete regression of 
established tumors with generation of anti-tumor immune memory.
!
Chemotherapy combinations also showed promising activity:
oAdditive combination effect when partnered with oxaliplatin and 5-fluorouracil (5-FU) (core 
components of FOLFOX [oxaliplatin, 5-FU, and folinic acid]) against MC38 colon tumors.
oSignificant increase in survival when partnered with gemcitabine against PANC02 
pancreatic tumors.
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!
Antibody-dependent cell-mediated cytotoxicity (ADCC) was demonstrated against human 
tumor cells in vitro; furthermore, studies in ADCC deficient settings in vivo support a 
contribution of ADCC to anti-tumor efficacy.
!
No complement-dependent cytotoxicity was observed in vitro.
!
Immunomonitoring assays with translational relevance for the clinic further support an 
immunological mechanism of action:
oConsistent increases in CD8+PD-1+ T cells and CD8+ effector memory T cells as measured 
by fluorescence-activated cell sorter (FACS).
oEnhanced tumor-antigen specific CD8+ T cell responses as measured by pentamer staining 
and enzyme-linked immunosorbent spot (ELISPOT) assays.
3.2.2
Toxicology
The toxicological profile of avelumab was investigated in vivo in mice, rats, and cynomolgus 
monkeys. In addition, in vitro cytokine release assays in human and cynomolgus whole blood and 
peripheral blood mononuclear cells (PBMCs) as well as a tissue cross reactivity study in normal 
human and cynomolgus monkey tissues (experimental part ongoing) were initiated. Repeat-dose 
toxicity studies with 4-week duration were performed in mice, rats, and cynomolgus monkeys, 
receiving a once weekly i.v. bolus injection / infusion. An additional pivotal and good laboratory 
practice (GLP)-compliant repeat-dose toxicity study with intermittent once weekly i.v. infusion 
(1.5 hours) over 13 weeks followed by an 8-week recovery period was performed in cynomolgus 
monkeys and included the investigation of safety pharmacologically relevant parameters 
(electrocardiogram [ECG], arterial blood pressure measurement, central nervous system [CNS] 
evaluation, respiratory frequency), TK, and immunogenicity (study RF4990, preliminary data).
The available results are summarized as follows:
In a pilot 4-week repeat-dose i.v. toxicity study in Wistar rats, avelumab was tested at dose levels 
of 20, 40, and 140 mg/kg. Avelumab was systemically and locally tolerated up to 140 mg/kg in 
rats. However, based on the binding affinity data (see Investigator’s Brochure for avelumab, 
Version 2, February 2014), the rat is not considered to be an appropriate rodent species for non-
clinical safety testing.
In the pilot 4-week repeat-dose i.v. toxicity study in CD-1 mice, mortalities occurred at all dose 
levels, i.e., 20, 40, and 140 mg/kg, within 30 minutes after treatment, mainly after the third 
administration. Overall, the maximum tolerated dose (MTD) could not be established in this study 
since mortality was observed at all dose levels. The observed clinical symptoms as well as the 
histopathological findings (vascular immune complex deposition) are considered to be indicative 
of hypersensitivity reactions in mice.
A second 4-week repeat-dose i.v. toxicity study in CD-1 mice at a dose level of 20 mg/kg 
confirmed the hypersensitivity reactions including the clinical findings and the mortality observed 
in the initial study. Results from an additional study in CD-1 mice suggest that the observed 
mortality after few repeated treatments with avelumab was due to an immune-mediated 
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hypersensitivity reaction in this species, the mechanism of which is highly likely to be anaphylaxis 
(immunoglobulin E [IgE] / immunoglobulin G [IgG] mediated reaction).
In primates (cynomolgus monkeys), neither in the pilot 4-week i.v. repeat-dose toxicity study nor 
in the pivotal 13-week i.v. infusion repeat-dose toxicity study followed by an 8-week recovery 
period, clinical signs of hypersensitivity have been seen at the tested dose levels of 20, 60, and 140 
mg/kg, respectively. In both studies, avelumab induced, locally at the injection sites, an increased 
severity in subcutaneous fibroplasia and mononuclear cell infiltrates without dose dependency. In 
the pivotal 13-week i.v. infusion repeat-dose toxicity study an increase in the hyalinization of the 
germinal centers of the spleen was observed in a few animals of the 60 and 140 mg/kg dose groups 
compared to the control group, with this finding being of unclear toxicological significance. All 
histological changes were completely reversible after an 8-week treatment-free period. In the pilot 
4-week as well as in the pivotal 13-week i.v. repeat-dose toxicity study a no observed adverse 
effect level (NOAEL) of 140 mg/kg was established for systemic toxicity. 
The cytokine release assays in male and female whole blood and PBMCs revealed no clear-cut 
evidence for release of pro-inflammatory cytokines.
As only limited information on potential effects of avelumab on the reproductive and 
developmental system is available, it is mandatory that women of child-bearing potential apply 
effective contraception during therapy with avelumab and 8 weeks thereafter. Pregnant women 
must not be included into the trial. No data on the transfer of avelumab into milk is available; thus 
lactating women should be excluded.
3.3
Pharmacokinetics / Immunogenicity Findings
Preliminary PK assessments have been collected and analyzed in the current ongoing
EMR100070-001 trial. The preliminary results based on the data available as of 19 December 2014 
are presented under the individual trial headings.
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab have 
been characterized in 57 Caucasian subjects treated in the dose escalation and expansion cohort of 
the Phase I Trial EMR100070-001 by standard non-compartmental analysis based on rich serum 
concentration-time data obtained over a complete dosing interval of 2 weeks (= tau). The analysis 
of these data revealed that the exposure parameters maximum concentration observed post-dose 
(Cmax) and area under the concentration-time curve (AUCtau) increased with the doses in a linear 
fashion.
The apparent terminal half-life (t1/2) was 69 hours (mean) ± 21 hours (standard deviation) for 
1 mg/kg, 84 ± 22 hours for the 3 mg/kg, 106 ± 29 hours for 10 mg/kg, and 134 ± 74 hours for the 
20 mg/kg dose.  Taking into account the variability, the t1/2 of the 10 and 20 mg/kg doses can be 
regarded as similar, indicating that target mediated elimination does not increase at these doses. 
This implies that target occupancy is likely to be high at these 2 doses throughout the dosing 
interval. 
Trough concentrations (Cmin) were obtained for the majority of subjects enrolled in the trial. The 
median Cmin at the end of the first cycle after administration of the 10 mg/kg dose was 20 μg/mL 
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(n=256).  This median Cmin increased during the subsequent cycles to 24 μg/mL (second cycle; 
n=233), 26 μg/mL (third cycle; n=167), and remained between 24 and 37 μg/mL during the 
subsequent cycles (n=22 to 114) indicative for no significant accumulation with the biweekly 
dosing scheme.  Median Cmin after the 3 mg/kg dose were 3.7 μg/mL after the first dose, 3.9 μg/mL 
after the second dose and 8.3 μg/mL after the third dose (n=7 to 12), though some trough values 
below 1 μg/mL were observed, as well as antidrug antibodies in at least 1 subject in this dose group 
on Day 85 of the treatment period, accompanied by loss of quantifiable exposure.  Median trough 
concentrations after the 20 mg/kg dose were 44, 70, and 77 μg/mL after the first, second, and third 
dose, respectively (n=14 to 19).
For the 10 mg/kg dose, the volume of distribution was 55 mL/kg (mean) ± 12 mL/kg (standard 
deviation) and total systemic clearance was low (0.38 mL/h/kg ± 0.11 mL/h/kg).
3.4
Safety
The available safety data for current EMR100070-001 trial are summarized below based on the 
safety data cut-off date, 05 November 2014.  In addition to subjects treated during dose escalation, 
a total of 480 subjects were enrolled during the dose expansion (NSCLC:  184; metastatic breast 
cancer:  169; gastric cancer:  47; colorectal cancer:  22; castrate-resistant prostate cancer:  11; 
ovarian cancer:  37, melanoma: 5; mesothelioma: 1; adrenocortical carcinoma: 1; and urothelial 
carcinoma: 3), treated with the recommended dose of 10 mg/kg avelumab once every 2 weeks and 
followed up for at least 4 weeks up to the cut-off date.  Further information about the events 
described below is available in the latest version of the Investigator’s Brochure.
All Treatment-emergent Adverse Events
For all subjects treated during the dose expansion, the most frequently affected System Organ 
Classes (with an incidence > 30%) were general disorders and administration site conditions 
(59.6%), gastrointestinal disorders (57.3%), respiratory, thoracic and mediastinal disorders 
(39.8%), musculoskeletal and connective tissue disorders (38.8%), and metabolic and nutrition 
disorders (32.3%). 
Table 3.1, shows the most frequently reported treatment-emergent adverse events (TEAEs)
observed in ≥ 10% of subjects during the dose expansion portion of the trial. 
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Table 3.1
Most Frequently Reported TEAEs During Dose Expansion (≥10% of 
Subjects)
Treatment-emergent Adverse Eventsa
Preferred Term (MedDRA)
Subjects (Safety Population, N = 480)
N (%)
Fatigue
148 (30.8)
Nausea
127 (26.5)
Vomiting
78 (16.3)
Diarrhoea
70 (14.6)
Constipation
69 (14.4)
Decreased appetite 
68 (14.2)
Cough 
65 (13.5)
Anaemia 
61 (12.7)
Dyspnoea
57 (11.9)
Back pain
52 (10.8)
Dyspnoea exertional 
52 (10.8)
Pyrexia 
50 (10.4)
Arthralgia
49 (10.2)
MedDRA = Medical Dictionary for Regulatory Activities.
a Only treatment-emergent adverse events started during the on-treatment period are summarized.
TEAEs Grade ≥3
Of the 480 subjects treated during dose expansion, 218 (45.4%) experienced at least 1 TEAE that 
was National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
Grade ≥ 3.  Of these, 148 (30.8%), 30 (6.3%), and 40 (8.3%) were Grade 3, Grade 4, and Grade 5 
TEAEs, respectively.  Of the Grade ≥ 3 TEAEs, the most frequent was dyspnea, reported in 
28 subjects (5.8%), followed by anemia reported in 25 subjects (5.2%), disease progression 
reported in 17 subjects (3.5%), pneumonia reported in 12 subjects (2.5%), hyponatremia and 
pleural effusion each reported in 10 subjects (2.1%), aspartate aminotransferase increased and back 
pain each reported in 9 subjects (1.9%), respiratory failure reported in 8 subjects (1.7%); and 
abdominal pain, arthralgia, gamma-glutamyltransferase (GGT) increased, hyperglycemia, 
non-cardiac chest pain, and vomiting were each reported in 7 subjects (1.5%; Table 3.2).  All of 
the other Grade ≥3 TEAEs were observed in less than 1.5% of subjects. 
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Table 3.2
Most Frequently Reported TEAEs ≥ Grade 3 During Dose Expansion (> 
1.5% of Subjects)
Treatment-emergent Adverse Eventsa
Preferred Term (MedDRA)
Subjects (Safety Population, N = 480)
N (%)
Dyspnea
28 (5.8)
Anaemia
25 (5.2)
Disease progression
17 (3.5)
Pneumonia
12 (2.5)
Hyponatraemia 
10 (2.1)
Pleural effusion
10 (2.1)
Aspartate aminotransferase increased
9 (1.9)
Back pain
9 (1.9)
Respiratory failure
8 (1.7)
Abdominal pain
7 (1.5)
Arthralgia
7 (1.5)
Gamma glutamyltransferase increased
7 (1.5)
Hyperglycaemia
7 (1.5)
Non-cardiac chest pain
7 (1.5)
Vomiting
7 (1.5)
MedDRA = Medical Dictionary for Regulatory Activities; TEAE – treatment-emergent adverse event.
a  Only treatment-emergent adverse events started during the on-treatment period are summarized.
Treatment-related TEAEs
Treatment-related TEAEs occurred in 330 of 480 subjects (68.8%) during the dose expansion, of 
which 59 (12.3%) were reported as Grade ≥ 3 treatment-related TEAEs. As shown in Table 3.3, 
the most frequently observed treatment-related TEAE (incidence ≥ 5%) was fatigue (20.2%), 
followed by nausea (12.9%), infusion-related reaction (9.8%), chills (6.9%), diarrhea (6.9%), 
decreased appetite (6.3%), pyrexia (5.6%), influenza like illness (5.2%), and arthralgia (5.0%).
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Table 3.3
Most Frequently Reported Treatment-related TEAEs During Dose 
Expansion (≥ 5% of Subjects)
Treatment-emergent Adverse Eventsa
Preferred Term (MedDRA)
Subjects (Safety Population, N = 480)
N (%)
Fatigue
97 (20.2%)
Nausea
62 (12.9%)
Infusion-related reaction
47 (9.8%)
Chills
33 (6.9%)
Diarrhoea
33 (6.9%)
Decreased appetite
30 (6.3%)
Pyrexia
27 (5.6%)
Influenza like illness
25 (5.2%)
Arthralgia
24 (5.0%)
MedDRA = Medical Dictionary for Regulatory Activities; TEAE – treatment-emergent adverse event.
a  Only treatment-emergent adverse events started during the on-treatment period are summarized.
Treatment-related TEAEs Grade ≥ 3 
Of the Grade ≥ 3 treatment-related TEAEs (59 subjects; 12.3%), the following occurred in more 
than 2 subjects: fatigue (5 subjects, 1.0%), anemia (5 subjects, 1.0%), infusion-related reaction, 
lipase increased, and GGT increased (each in 4 subjects, 0.8%).
Of the 59 subjects who had Grade ≥ 3 treatment-related TEAEs, 44 (9.2%) had Grade 3 treatment-
related TEAEs, 11 (2.3%) had Grade 4 treatment-related TEAEs, and 4 (0.8%) had Grade 5 
treatment-related TEAEs.  One Grade 3 event of encephalopathy (Subject 101-0032), which was 
initially considered as posterior reversible encephalopathy syndrome, was assessed as related to 
trial medication with an alternative explanation of hypertension.
Serious Adverse Events 
Overall, 176 of the 480 subjects (36.7%) treated during the dose expansion had serious TEAEs.  
Of these, 22 (4.6%) subjects reported dyspnea, which was the most frequent serious TEAE in this 
group, followed by 19 subjects (4.0%) reporting disease progression, 12 subjects (2.5%) reporting 
pleural effusion, 11 subjects (2.3%) reporting pneumonia, and 7 subjects (1.5%) reporting anemia.  
All other serious TEAEs were each reported in less than 1.5% of subjects. 
Of the serious TEAEs considered treatment-related by the investigator (31 subjects; 6.5%), the 
following were reported for 2 or more subjects:  infusion-related reaction (4 subjects, 0.8%), 
pneumonitis (3 subjects, 0.6%), and disease progression, dyspnea, and hypercalcemia (each in 
2 subjects, 0.4%).
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Deaths
In total, 134 subjects (27.9%) treated during the dose expansion died up to the cut-off date 
(05 November 2014).  Of these, the majority of deaths (101 deaths; 21.0%) were due to disease 
progression.  An additional 8 deaths (1.7%) were due to TEAEs unrelated to trial treatment, 
4 deaths (0.8%) were due to TEAEs related to trial treatment, and the reason for 8 deaths (1.7%) 
was labeled as other.  The reason for 13 deaths (2.7%) was unknown at the time of the data cut-off. 
Of the 134 subjects who died, 53 subjects (11.0%) died within 30 days of the last administration 
of trial treatment. Among these deaths, 39 (8.1%) were due to disease progression, 7 (1.5%) were 
due to TEAEs unrelated to trial treatment, 4 (0.8%) were due to TEAEs related to trial treatment, 
and 3 (0.6%) were due to other reasons.  No death of unknown reason was reported in the 30-day 
period.
Treatment-emergent AEs Leading to Permanent Discontinuation of Avelumab
A total of 80 subjects (16.7%) treated during the dose expansion withdrew permanently from trial 
treatment due to 1 or more TEAE.  In 25 (6.6%) of these subjects, the TEAEs leading to treatment 
discontinuation were considered related to trial treatment by the investigator.  These TEAEs were 
infusion-related reaction (6 withdrawals; 1.6%), GGT increased (3 withdrawals, 0.8%), dyspnea 
(3 withdrawals; 0.8%), and radiation pneumonitis, aspartate aminotransferase (AST) increased, 
hepatocellular injury, blood creatine phosphokinase increased, blood pressure increased, 
pneumonitis, anaphylactic reaction, food allergy, adrenal insufficiency, anemia, hypercalcemia, 
hyperglycemia, arthralgia, arthritis, myositis, pain, abdominal pain lower, chest discomfort, 
cramps and ache on back and all over body (not yet coded), encephalopathy, syncope, and flushing 
(1 withdrawal each; 0.3%).
Most of the events of infusion-related reaction and anaphylactic reaction that led to permanent 
discontinuation of trial treatment (as described above) occurred before implementation of 
mandatory premedication on 28 January 2014. 
Immune-related Adverse Events
As of 05 November 2014, a cumulative review revealed 56 cases of potential immune-related AEs 
out of 480 subjects (11.7%) treated in the dose expansion part of trial EMR 100070-001 and 4 
cases out of 50 subjects (8.0%) treated in the dose escalation part of trial EMR 100070-001. A 
customized Medical Dictionary for Regulatory Activities (MedDRA) query was used for data 
retrieval from the clinical database with predefined Preferred Terms of potential immune-related 
AEs (irAEs).
Of 69 potential irAEs reported, 13 were SAEs (18.8%) and 56 were non-serious AEs (81.1%). In 
the majority of the cases, there was a plausible temporal association between the event onset and 
the drug administration. Of these 69 events, 46 events (66.7%) were assessed as treatment-related 
by the investigator and 23 events (33.3%) were assessed as not treatment-related by the 
investigator.
Twenty-six events were assessed as Grade 1, 29 events as Grade 2, 11 events as Grade 3, 2 events
as Grade 4, and 1 event (pneumonitis) as Grade 5 (Please note: 2 more events of autoimmune 
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hepatitis had a fatal outcome; however, they were assessed as Grade 3 with a consequent fatal liver 
failure).
Based on the irAE cases that have been observed, all trial investigators have been trained to be 
made aware of the frequency and severity of the observed events and to proactively administer 
steroid treatment for any suspicion of irAEs. Of note, irAEs are considered as an identified risk 
by the Sponsor.
Infusion-related Reactions
Two suspected unexpected serious adverse reactions (SUSARs; anaphylactic reaction and 
infusion-related reaction) involving 2 subjects were reported in December 2013 and triggered a
cumulative review of serious and non-serious cases of infusion-related reactions / hypersensitivity 
across the avelumab program. Following evaluation of safety signals, infusion-related reactions /
hypersensitivity have been classified as a newly identified risk (previously classified as a potential 
risk) and a mandatory premedication regimen of histamine H1 receptor (H1) blockers plus 
acetaminophen was implemented for all trial subjects as of 28 January 2014.
As of 05 November 2014, 49 (10.2%) of the 480 subjects in the expansion cohort experienced at 
least 1 episode of an infusion-related reaction when receiving avelumab monotherapy. Most of the 
events were Grade 1 (8 subjects, 1.7%) or Grade 2 (36 subjects, 7.5%) in intensity, and Grade 3 (3 
subjects, 0.6%) or Grade 4 events (2 subjects, 0.4%) were less frequent.  No Grade 5 events were 
reported.  Most of the infusion-related reaction events had an onset after the first (30 subjects, 
6.3%) or second (16 subjects, 3.3%) avelumab infusion.  In 8 subjects (1.7%), avelumab treatment 
was discontinued because of infusion-related reaction events.
In addition, 1 subject (2.0%) in the dose escalation cohort reported an infusion-related reaction 
event (Grade 2).
In addition to the aforementioned 49 subjects, 1 case of Grade 4 cardiac arrest occurred 1.5 hours 
after the third infusion of avelumab (10 mg/kg). The subject died due to an anoxic brain injury 
7 days later; no autopsy was performed. 
Starting from 29 January 2014, the Sponsor has implemented a mandatory premedication with H1 
blockers plus acetaminophen for all subjects who are to receive avelumab.  This premedication 
procedure was applied to 28 and 440 subjects in the dose escalation and the pooled treatment 
expansion cohort, respectively. Under this premedication procedure, 33 of 440 subjects (7.5%) in 
the expansion cohort experienced infusion-related reaction events, with 6 subjects (1.4%) having 
Grade 1, 26 subjects (5.9%) having Grade 2, and 1 subject (0.2%) having Grade 3 events.  No 
infusion-related reaction events were reported in the 28 subjects in the dose escalation cohort.
Guidelines for the management of infusion-related reactions and severe hypersensitivity reaction 
according to the National Cancer Institute (NCI) are found in Sections 6.5.4.1 and 6.5.4.2, 
respectively. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) and can be found 
at https://www.resus.org.uk/pages/reaction.pdf.
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Laboratory Abnormalities
Preliminary data relating to laboratory abnormalities observed during dose expansion (cut-off 
05 November 2014) are summarized below. Interpretation of these data should reflect the fact that 
for approximately 40% of subjects laboratory data were unavailable at the time of the safety data 
cut-off.
Hematology
Various hematology abnormalities were reported in up to approximately 60% of subjects, 
however, Grade 3 or 4 abnormalities were usually much less frequent. In all subjects treated during 
dose expansion, the most frequent Grade 3 or 4 abnormality was lymphocyte count decreased, 
which occurred in 55 subjects (11.5%), all of which were Grade 3. Other less frequent Grade 3 or 
4 abnormalities included anemia (all Grade 3) in 25 subjects (5.2%), platelet count decreased in 
14 subjects (2.9%), neutrophil count decreased and white blood cell count decreased each in 5 
subjects (1.0%).
Blood Chemistry
A considerable proportion of subjects (up to over 60% for some measurements) in the dose 
expansion cohort experienced abnormalities of blood chemistry; however, most of these 
abnormalities were mild (Grade 1 or 2). Grade 3 or 4 blood chemistry abnormalities occurred less 
frequently. The following Grade 3 or 4 abnormalities were observed in > 5% of subjects: GGT
increased, which was reported in 87 subjects (18.1%) treated in the dose expansion phase, 
hyponatremia (32 subjects, 6.7%), and AST increased (30 subjects, 6.3%).
Vital Signs and Body Weight
Data relating to vital signs and body weight observed during dose expansion (cut-off 
05 November 2014) are summarized below. Abnormalities of vital signs were defined as:
! Systolic blood pressure (SBP): SBP ≤95 mmHg as well as a decrease from baseline 
≥20 mmHg, or SBP ≥160 mmHg as well as an increase from baseline ≥20 mmHg
! Diastolic blood pressure (DBP): DBP ≤45 mmHg as well as a decrease from baseline 
≥10 mmHg or DBP ≥110 mmHg as well as an increase from baseline ≥10 mmHg
! Pulse rate: ≤50 beats per minute (bpm) as well as a decrease from baseline ≥ 20 bpm or pulse 
rate ≥ 120 bpm as well as an increase from baseline ≥ 20 bpm
! Body weight: increase or decrease in body weight from baseline ≥ 10%.
A small fraction of all subjects experienced vital sign abnormalities as defined above during trial 
treatment, with pulse rate ≥ 120 bpm and increase from baseline ≥ 20 bpm (41 subjects, 8.5%)
representing the most notable change.
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3.4.1
Clinical Pharmacodynamics
Receptor occupancy was measured in vitro by flow cytometry on peripheral blood CD3+ T-cells 
after spiking of human whole blood samples from 8 healthy volunteers with avelumab over a 
concentration range of 0.003 to 10 μg/mL. In this assay, free receptors were measured in samples 
spiked over this range and compared with the amount of free receptors in the unspiked sample. A 
50% receptor occupancy was observed at a drug concentration of 0.122 μg/mL ± 0.042 μg/mL 
(standard deviation) and a plateau indicating at least 95% receptor occupancy was reached in all 
donor blood samples at 1 μg/mL.
These in vitro data combined with PK data were confirmed in ex-vivo samples taken at Cmin after 
the first dose (Day 15) in a small number of subjects during the initial dose escalation part of the 
Phase Ib Trial EMR100070-001 (n=9). For doses of 10 mg/kg, target occupancy (TO) was greater 
than 90% for these 4 subjects, at trough serum levels ranging between 12.69 to 26.87 μg/mL. Also,
for doses of 3 mg/kg, available TO data for 2 subjects with trough levels ranging from 4.56 to 6.99 
μg/mL, showed greater than 90% TO at trough exposure levels. At dose level 1 mg/kg, 2 out of 3 
subjects displayed less than 90% TO at trough serum concentrations. 
Avelumab serum 
concentrations were below the quantification limit of 0.2 μg/mL in these 2 subjects.
Based on the observed avelumab serum concentrations in the EMR100070-001 Phase I clinical 
trial and the in vitro receptor occupancy data, trough concentrations were sufficient to achieve full 
target occupancy throughout the entire dosing interval in all of the subjects receiving the 10 mg/kg 
dose. After the 3 mg/kg dose, Cmin were insufficient in 3 of the 13 subjects to assure full target 
occupancy; therefore, in order to achieve target saturation during the whole treatment period in all 
subjects, the dose of 10 mg/kg every 2 weeks was selected as the dose for further investigation in 
the Phase Ib expansion cohorts and for the subsequent clinical studies.
3.5
Rationale for the Clinical Trial
The administration of avelumab to subjects with advanced malignancies for which no approved / 
established treatment option exist is justified by the following:
! Avelumab is capable of inhibiting tumor growth in vivo when applied as a monotherapy and its 
efficacy can be further enhanced via combination with standard-of-care therapies, though the 
treatment was limited for only 3 doses in the first weeks due to immunogenicity of the 
humanized antibody in mice.
! The relevance of PD-L1 blockade has been demonstrated in Phase I studies performed with 
antibodies targeting either PD-L1 or PD-1. One Phase I trial has been reported for BMS-936559 
targeting PD-L1 (5). At the time of data cut-off, a total of 160 subjects could be evaluated for 
clinical efficacy, which was demonstrated in the range of 1-10 mg/kg. Objective clinical 
responses up to > 1 year were observed in 9 out of 52 subjects with melanoma, 5 out of 49 
subjects with non-small cell lung cancer (NSCLC), 2 out of 17 subjects with renal cell 
carcinoma, and 1 out of 17 subjects with ovarian cancer. No response could be observed in 
7 subjects with pancreatic cancer and 18 subjects with colorectal cancer (CRC). Overall, these 
results are suggestive of relevant clinical efficacy through inhibition of PD-L1, which is further 
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supported by reported clinical efficacy of the anti-PD-1 monoclonal antibodies, BMS-936558 
and CT-011 (6,7).
The starting dose of 1.0 mg/kg has been selected based on the results of 2 complementary 
approaches reflected in the respective guidelines:
! Data from the pivotal 13-week i.v. infusion repeat-dose toxicity study in cynomolgus monkeys 
revealed a NOAEL of 140 mg/kg for systemic toxicity. Applying the algorithm given in the 
Food and Drug Administration (FDA) guideline on "Estimating the Maximum Safe Starting 
Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers" this would imply 
a “Maximum Recommended Starting Dose” of approximately 4.5 mg/kg.
! The International Conference for Harmonization (ICH) guideline S9 (8) states that the primary 
goal of selecting the clinical start dose is to administer a pharmacologically active dose (PAD) 
that is reasonably safe to use. This PAD approach is also recommended by the FDA guideline 
on "Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers" (9). The lowest PAD level can be estimated from xenograft tumor 
models and from posology of clinical surrogates. The PAD approach for the proposed avelumab
first-in-man study is based on the finding that PD-L1 antagonism resulted in tumor growth 
inhibition for example in a MC38 colorectal syngeneic mouse model, and on the assumption 
that anti-neoplastic activity is a function of target occupancy. In the MC38 xenograft tumor 
model, avelumab demonstrated biological activity at doses of 400 μg per mouse i.v., observed 
7 to 10 days after the third dose. The regimen was restricted to 3 administrations due to lethal 
anaphylaxis resulting from the administration of a humanized antibody to mice. Based on these 
data and our PK model, a human dose of 10 mg/kg would allow a serum concentration above 
the assumed minimum required trough concentration of 50 μg/mL for a period of approximately 
2 weeks. An initial dose of 1 mg/kg is 10-fold lower than this dose, conservatively 
acknowledging the model´s limitations. In order to supplement and improve the PAD approach 
for initial dose estimation and dose escalation, PD-L1 target occupancy was assumed as 
appropriate surrogate: In principle, 100% saturation is expected to generate maximum efficacy. 
For BMS-936559, it was demonstrated that early indications of anti-neoplastic activity already 
occur at trough occupancy levels of 65% as measured on CD3 T cells positive cells within a 
2-week cycle (5). Using PK and PD data from mice and monkeys, a 2-compartment model with 
mixed linear and Michaelis-Menten elimination pathways was employed to predict the human 
PK and corresponding target occupancy for avelumab. Allometric scaled human simulation 
aiming for at least 95% target occupancy supports the dosing of once every 2 weeks at a human 
dose level of approximately 7 mg/kg, while the proposed initial dose of 1.0 mg/kg is expected 
to result in at least 50% target occupancy, which may be sufficient to induce beneficial clinical 
effects.
The dose escalation scheme was designed based on the following:
! Three dose levels, i.e., 1, 3, and 10 mg/kg, are expected to be sufficient for evaluation of the 
safety, PK profile, and early indications of efficacy. The PK and extent of target binding will 
be closely monitored during the dose escalation phase of the clinical study (PD-L1 saturation 
on T cells as function of exposure). 
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The dose rationale for the avelumab first-in-man study is supported by the excellent clinical safety 
profile of BMS-936559 (5). Although it is acknowledged that avelumab and BMS-936559 are 
different with respect to some features like isotype, terminal half-life, and capability to induce 
effector functions, they are similar regarding specificity and mode of action. Non-clinical safety 
evaluation of BMS-936559 (5) resulted in the first-in-man study NCT00729664, the design of 
which is highly comparable to the concept presented here. Our strategy is further supported by 
positive safety results from a number of Phase I clinical studies with anti-PD-1 monoclonal 
antibody BMS-936558, which shares some crucial aspects of the mechanism of action (MoA) with 
avelumab and MDX-1105 (6,10).
3.5.1
Rationale for 10 mg/kg Once Weekly Dose-Escalation Cohort
With the completion of the dose expansion phase of the study, completion of the safety and PK 
analysis for the dose-escalation phase, and preliminary safety and PK from the expansion phase 
(EMR100070-001 interim CSR 2016), a decision has been made to add a cohort of 6 evaluable 
patients who will be treated with avelumab 10 mg/kg once weekly to this trial. This cohort (N=6) 
is being added to the dose-escalation phase of the study to provide preliminary PK and safety data 
with this regimen. This regimen is planned to be further explored in a first-line NSCLC Phase III 
study; therefore, the preliminary analyses described below are more detailed for this cohort. 
Subjects in this cohort will receive avelumab at 10 mg/kg once weekly for the first 12 weeks 
followed by 10 mg/kg once every 2 weeks starting at Week 13. This decision is based on the 
following: 
! An exposure-efficacy response relationship was observed in NSCLC subjects treated with 
10 mg/kg once every 2 weeks, based on preliminary analysis.  For the first-line NSCLC cohort 
(n=156), a relationship between steady state trough concentrations and best overall response 
(BOR) was observed and supported by logistic regression (univariate analysis; p=0.0001): the 
response rate was higher in subjects with higher PK exposure (approximately 5, 10, 23, and 
36% objective response rate in 1st, 2nd, 3rd, and 4th exposure quartile, respectively) regardless of 
PD-L1 expression.  Similarly, for progression-free survival (PFS) and overall survival (OS)
endpoints in NSCLC subjects, an exposure-efficacy relationship was suggested by Cox models, 
though high uncertainty exists in these analyses. 
! Population PK analysis and simulation showed that a 10 mg/kg once every week regimen may
increase the exposure, such that more than 90% of the subjects dosed with 10 mg/kg once every 
week will have predicted steady state trough concentrations higher than the observed lower 
bound of the 4th exposure quartile for the 10 mg/kg once every 2 weeks.  Specifically, the 
median steady state trough concentration is predicted to increase from 22.9 μg/mL (range: 
4.2-74.5 μg/mL) in the once every 2 weeks regimen to 83.3 μg/mL (range: 28.6-204 μg/mL) in 
the once weekly regimen (data on file), potentially enhancing efficacy as suggested by the 
preliminary exposure-efficacy analyses.
! A significant exposure-efficacy relationship was also observed for the second-line NSCLC 
cohort of subjects (p=0.005 for BOR correlation with steady state trough concentrations), based 
on preliminary analysis.
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! Similar trends for higher response rates in subjects with higher exposure were observed in 
urothelial cancer and gastric cancer cohorts, though not significant due to the low number of 
responders in these data sets.
! Kaplan-Meier plots for preliminary PFS and OS data separated by exposure quartiles showed 
trends of prolonged PFS and OS for subjects in the higher exposure quartiles based on steady 
state trough concentration, compared with subjects with lower exposure, for the following 
cohorts: post-platinum doublet NSCLC, first-line NSCLC, urothelial cancer - secondary and 
efficacy cohorts, gastric cancer - second-line and switch-maintenance cohorts, metastatic breast 
cancer, ovarian cancer, mesothelioma, malignant melanoma.
! In both first-line and post-platinum doublet NSCLC cohorts, a trend of higher ORR was 
observed with increasing PD-L1 expression cut-offs (1, 5, 50, and 80% of cells stained) in 
subjects in the upper half of the exposure range, but not in subjects in the lower half of the 
exposure range, suggesting that predictivity of PD-L1 status improves at higher exposure.  
The 12-week duration for avelumab once a week administration, followed by once every 2 weeks
starting at Week 13 was selected based on preliminary observations from the first-line NSCLC 
cohort of this study dosed with 10 mg/kg once every 2 weeks, that suggest:
! Majority of responses occurred within 12 weeks of treatment initiation, and
! Majority of responses appeared to be durable.
It is not expected that the exposure at 10 mg/kg once every week for the first 12 weeks would 
substantially impact the manageable safety profile currently observed with 10 mg/kg once every 
2 weeks dosing:
! The exposure-irAE relationship curve appeared to be flat or shallow for shorter treatment 
durations (≤18 weeks) based on dataset that included > 1450 subjects from studies 
EMR100070-001, EMR100070-002, and EMR100070-003 (refer to exposure-safety report).  
For all other AEs analyzed, AE incidence appeared to not increase with increasing exposure. 
! Based on population PK modeling, median exposures are not expected to exceed those for 
previously administered regimens; the steady state maximum concentration is similar to that 
for 10 mg/kg once every 2 weeks regimen, while steady state AUC is similar to that for 
20 mg/kg once every 2 weeks regimen (data on file). 
! Avelumab has shown an adequate safety profile in 27 subjects treated with 20 mg/kg once every 
2 weeks and more than 1450 subjects treated with 10 mg/kg once every 2 weeks.  The MTD 
was not reached in dose escalation phase of this study.  
In summary, the dosing regimen of 10 mg/kg once a week for 12 weeks followed by 10 mg/kg 
once every 2 weeks starting at Week 13 is supported by the exposure-efficacy relationship, 
time-to-response analyses, and an acceptable benefit-risk profile, as described above. This regimen 
may also allow the evaluation of clinical outcomes in subjects with higher exposure and high 
expression of PD-L1 in subsequent studies with avelumab.
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3.5.2
Rationale for Expansion Cohorts
The indications for the initial expansion cohorts have been selected based on several factors:
! PD-L1 over-expression in tumors.
! Clinical activity demonstrated for PD-1 / PD-L1 blocking monoclonal antibodies in solid 
tumors in the case of NSCLC.
! Unmet medical need.
! Evidence for susceptibility to cancer immunotherapy.
Over-expression of PD-L1 has been described for NSCLC, metastatic breast cancer (MBC), CRC, 
castrate-resistant prostate cancer (CRPC), melanoma, renal cell carcinoma, hepatocellular 
carcinoma, head and neck squamous cell carcinoma (HNSCC), ovarian, breast, pancreatic, 
gastro-esophageal and bladder urothelial carcinomas as well as glioblastoma multiforme and
certain type of hematopoietic malignancies (11-25).
Recently, the expression of PD-L1 in immune infiltrating cells of gastric cancer micro-
environment has been demonstrated (internal data produced by the Sponsor’s Biomarker group).
Blockade of PD-L1 led to objective clinical responses in NSCLC, melanoma, and ovarian cancer 
(5), while blockade of its counterpart PD-1 led to objective clinical responses in NSCLC and 
melanoma (6). A limited number of subjects with CRC or CRPC, which do not allow to drawing 
final conclusions on the potential clinical activity of PD-1 / PD-L1 checkpoint inhibitors in these 
indications, have been treated up to date. However, it should be noted that avelumab is an IgG1 
isotype based antibody that potentially exerts ADCC, which differentiates it from the other 
therapeutic antibodies already being explored for their use in solid tumors (5,6) but lacking such 
effector functions.
In general, the anti-tumor immunotherapy via blockade of the PD-1 / PD-L1 axis seems not to be 
limited to any specific tumor types, but there is recent evidence that PD-L1 tumor expression is a 
pre-requisite to achieve an objective response upon blockade of the PD-1 / PD-L1 axis (6). Seven 
tumor types, i.e., NSCLC, gastric and gastroesophageal junction (GEJ) cancer, MBC, CRC, CRPC, 
melanoma, and ovarian cancer, for which a high medical need and evidence for susceptibility to 
cancer immunotherapy is given, were selected to be explored in the expansion phase of this trial. 
3.5.3
Rationale for New Expansion Cohorts / Expanding Initial 
Expansion Secondary Cohorts
The expansion phase of the trial provides for further exploration of signals in 4 new secondary 
cohorts and in the expanded melanoma and ovarian cancer secondary cohorts. The rationale is 
provided below.
Melanoma: The clinical activity of PD-1/PD-L1 blockade in metastatic melanoma has been 
clearly established (26,27). It is therefore considered appropriate to expand the sample size of the 
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metastatic melanoma cohort from 20 to 50 subjects in order to obtain more precise estimates of 
response rate for avelumab and to evaluate its association with PD-L1 expression in this indication.
Ovarian cancer: Initial data from the ovarian cancer expansion cohort include unconfirmed 
partial responses (PRs). By expanding the cohort from 20 to 75 subjects, these preliminary signals 
can be further evaluated, and a precise evaluation of the response rate and the association of 
response and PD-L1 expression can be conducted. A further expansion to 120 subjects is necessary 
for the development of a potential companion diagnostic for PD-L1 expression in ovarian cancer.
Adrenocortical carcinoma (ACC): Although ACC is a rare malignancy, metastases are common, 
prognosis is poor and available systemic therapies are toxic with limited benefits (28,29). The First 
International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma 
Treatment (FIRM-ACT) established that first line standard of care with the combination of 
mitotane, etoposide, doxorubicin and cisplatin demonstrates a response rate of 23.3%, with a 
progression-free survival of 5.0 months and an OS of 14.8 months (30). However, it is of note that 
58% of these patients experienced SAEs. In spite of this trial, mitotane remains the only approved 
treatment for ACC. Defining effective therapies directed at defined molecular targets has not yet 
yielded results (28). Although immunotherapy has not been extensively explored there is evidence 
that inactivation of TLR4 and decreased expression of CD14 may be mediated by immune 
mechanisms that are not yet fully characterized in this disease (31). There is agreement within the 
oncology community that the dire nature of advanced ACC warrants more aggressive clinical trial 
involvement (29).
Mesothelioma: Malignant mesothelioma is an uncommon malignancy, with 2,500 cases per year 
diagnosed in the USA. For patients with unresectable disease, OS is only around 12 months. 
First-line chemotherapy with cisplatin and pemetrexed is standard with response rates of 41.3% 
and median survival 12 months (32). Second-line therapies remain inadequate with OS collectively 
around 9 months with most of that benefit in patients who could be rechallenged with the standard 
first line agents (33).
PD-L1 is expressed at the surface of mesothelioma tumor cells. In a series of 224 cases of 
malignant pleural mesothelioma, PD-L1 expression (defined as more than 5% of tumor cells 
positive by immunohistochemistry [IHC]) was detected in 89 subjects (40%) (34). When compared 
with other parameters, there were no significant differences in gender, age, decade of diagnosis,
or lymphocytic infiltration between PD-L1 positive and negative subjects. Survival was 
significantly worse for subjects with PD-L1 expression (6 months median, range 4-9 months) 
compared to those without PD-L1 expression (14 months median, range 11-16 months; p<0.0001). 
Furthermore, PD-L1 expression remained significantly associated with worse survival after 
adjusting for age, gender, lymphocytic infiltration, and therapeutic surgical intervention 
(p=0.0002).
In a recently published smaller study, 6 of 8 mesothelioma samples were positive for PD-L1 as 
well as for tumor infiltrating CD68+ macrophages (35). This pattern of inflammation was 
remarkable for its similarity to T cell inflamed patterns seen with other tumor types such as 
melanoma. Checkpoint inhibition with the anti-CTLA4 monoclonal antibody trametinib 
preliminarily has shown a disease control rate of 31% and a 1-year survival of 48.3% in 21 subjects 
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who had failed first-line therapy with platinum and pemetrexed (36). An updated analysis 
continues to show clinical benefit with a median OS of 11.3 months (37).
When considered together, the above data suggest that checkpoint inhibition is an important and 
underexplored therapeutic strategy in mesothelioma. Thus, there is a strong rationale to evaluate 
an anti-PD-L1 in subjects with mesothelioma who have progressed after a platinum/pemetrexed 
containing regimen, particularly as there is no established treatment for the management of 
mesothelioma patients who have progressed after 1 platinum/pemetrexed containing regimen (38).
Urothelial carcinoma: Metastatic urothelial carcinoma (bladder, ureter, renal pelvis, urethra) is 
considered a chemosensitive tumor with first-line cisplatin-based regimens achieving response 
rates of approximately 50% and median survival of around 14 months (39,40). However, complete 
response (CR) is rare and most patients develop resistant disease. Success with second-line agents 
has been modest, with response rates ranging from 9-33% and progression-free survival around 
3 months (41,42). After failure of platinum therapies effective options are limited.
A growing body of evidence suggests that the acquired cell-mediated immune dysfunction 
observed in urothelial carcinoma may be related to expression of PD-L1 and PD-1 (43). In one 
study (43) 12.4% of urothelial tumors expressed PD-L1, which was associated with more advanced 
stage at cystectomy. PD-1 expression was observed on 95.5% of tumor-infiltrating lymphocytes, 
which was also correlated with more aggressive pathology and PD-L1 expression. Moreover, for 
the subset of subjects with organ-confined disease (n=167), B7-H1 expression independently 
predicted all-cause mortality after cystectomy (p<0.001). In their sample of 65 subjects with 
urothelial cancer, Nakanishi et al (44) showed an association between PD-L1 expression and post-
operative recurrence and survival. PD-L1 expression has also been observed to be associated with 
increasingly aggressive pathology and may contribute to failure of local therapies to prevent local 
progression and muscle invasion (45). Conversely, in subjects who develop metastatic disease, 
PD-L1 expression in infiltrating mononuclear cells was significantly associated with longer 
survival (46).
The first demonstration of activity of anti-PD-L1 antibodies was described by Powles et al (47). 
In a Phase I study, subjects with urothelial bladder cancer received MPDL3280A (an anti-PD-L1 
monoclonal antibody) at a dose 15 mg/kg i.v. q3w for up to 1 year. Overall response rate (ORR)
(including unconfirmed responses) was assessed by RECIST v1.1 (48). In parallel, tumor and 
circulating biomarkers were evaluated to study MPDL3280A immune correlates. Efficacy data on 
20 PD-L1+ subjects were reported. Subjects were 84% male, median age was 66 years
(42-86 years), 57% were Eastern Cooperative Oncology Group (ECOG) performance status 1 and 
68% had visceral metastases. Most of the subjects had received prior platinum-based 
chemotherapy. Subjects evaluable for efficacy at the time of analysis had a median follow up of 
2.8 months (1.4 to 5 months). The ORR was 50% (1 CR and 9 PR) with a median time to response 
of 43 days (39 to 82 days), corresponding to the first radiographic assessment. Subjects who had 
visceral metastases at baseline also responded, and all responders were still responding at the time 
of clinical cut-off. 
The treatment of patients with advanced urothelial carcinoma appears to have reached a plateau 
using cytotoxic chemotherapy regimens. An approach that holds promise is immune modulation 
by targeting the patient’s immune system to generate a response that can control the tumor given 
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that CD8+ T cell activation and infiltration may be associated with better outcomes (49). The 
absence of satisfactory therapeutic options after failure of first line platinum-based combinations, 
the association of PD-L1 expression data with outcomes and now evidence of clinical activity of 
anti-PD-L1 directed therapy, all support further evaluation of these agents for metastatic urothelial 
carcinoma.
Further details on the trial design and its rationale are provided in Sections 5.1 and 5.2.
The data obtained from this study will form the basis for the dose and regimen selection for further 
clinical studies involving avelumab and will also be supportive to provide a basis for combination 
with standard-of-care therapies to be explored in the future.
Renal Cell Carcinoma: The rationale to add a new cohort of subjects with advanced renal cell 
carcinoma (RCC; n=20 second-line subjects, with expansion of 60 first-line subjects) is supported 
by the recent clinical data demonstrating single-agent efficacy with an antibody blocking the PD-1/ 
PD-L1 pathway in RCC patients whose disease has progressed following vascular endothelial 
growth factor (VEGF) pathway inhibitor therapy. In particular, nivolumab, a fully human 
anti-PD-1 monoclonal antibody, has shown durable tumor responses with an ORR of 
approximately 20% and median PFS of approximately 16 weeks in heavily pretreated advanced 
RCC patients (50).  In addition, MPDL3280A, another human monoclonal antibody that targets 
PD-L1, has shown an ORR of 13% and stable disease ≥24 weeks in 32% of patients with 
pretreated RCC (51).  Although preliminary, these data demonstrate the potential clinical activity 
of an anti-PD-1 or PD-L1 antibody in advanced RCC patients. Data from this cohort will provide 
essential data on the potential clinical activity of avelumab in advanced RCC, and will help inform 
future development and clinical trials in RCC.
Enrollment of first-line RCC subjects was opened after 2 documented objective responses among 
the 20 subjects enrolled in the second-line RCC cohort were observed by RECIST 1.1 (2 PRs), 
and justified further evaluation in this patient population.
3.5.4
Rationale for Adding First-Line NSCLC Cohort
The rationale to enroll NSCLC subjects who have not received a systemic treatment for their 
metastatic disease and to administer them avelumab is supported by 2 different sets of data:
!
The results coming from a study that used an anti-PD-1 to block the interaction between 
PD-L1 and PD-1 (52).
!
The interim analysis of the first 75 subjects with NSCLC (post platinum doublet) that have 
been enrolled in the current Phase I study and have being followed up for at least 13 weeks.
Gettinger et al (52) have presented the results of an ad hoc analysis of the safety data from a cohort 
of chemotherapy-naïve patients with Stage IIIB or IV NSCLC and ECOG performance status 0 or 
1 who received nivolumab 3 mg/kg i.v. every 2 weeks until progressive disease or unacceptable 
toxicity. Efficacy was evaluated using RECIST 1.1 at Week 11, Week 17, Week 23, and every 
3 months thereafter until disease progression. 
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The overall median follow-up time was 66.1 weeks (range 13.3 to 89.1 weeks). 
An ORR of 30% was reported; 5 of 6 responders (83%) achieved response by first scan (Week 11). 
Two patients had > 80% target lesion reduction at 18 weeks. Of 15 evaluable tumor samples, 
9 were PD-L1+. The ORR was 67% in PD-L1+ patients; no responses were observed in the 
6 PD-L1- patients. The ORR was 36% for patients with NSCLC (4 of 11 patients) and 22% in 
patients with squamous cell lung cancer (2 of 9 patients). Responses were durable (median duration 
of response not reached, with 5 ongoing responses).
In terms of safety, a total of 17 patients (85%) experienced any-grade treatment-related AEs. Most 
patients only reported Grade 1 or 2 AEs (13/17 patients, 76%). Five treatment-related Grade 3/4 
AEs were reported in 4 patients (20%): 1 case each of increased aspartate aminotransferase (AST), 
increased alanine aminotransferase (ALT), hyperglycemia, rash, and cardiac failure. All resolved 
with treatment discontinuation and/or management per guidelines. Treatment-related AEs leading 
to discontinuation of study medication occurred in 2 patients: Grade 3/4 increased ALT and 
increased AST (n = 1 each; occurred in the same patient) and cardiac failure (n = 1). 
Overall, these preliminary data obtained on a small number of patients suggest that the blockade 
of the PD-1/PD-L1 axis results in a response rate that compares favorably with the existing 
standard of care, i.e., platinum based doublets; indeed, it is generally considered that the 
administration of platinum doublets as a treatment of first-line NSCLC results in a response rate 
ranging between 15 and 25% that is accompanied with an incidence of Grade 3/4 drug-related 
adverse events in the range of 20 to 30%.
As specified in the Phase I Study EMR100070-001 protocol, an interim analysis of response was 
conducted for the NSCLC post platinum doublet expansion cohort 13 weeks after start of treatment 
of the 75th subject.  
Entry to Study EMR100070-001 for subjects with NSCLC was restricted to subjects with 
measurable disease, defined as at least 1 unidimensional measurable lesion by RECIST 1.1.  Tumor 
burden at baseline was evaluated using a computed tomography (CT) scan or magnetic resonance 
imaging (MRI; if MRI was used, then CT of chest was mandatory) of the chest, abdomen, and 
pelvis within 18 days of the start of treatment using RECIST 1.1 for target and non-target lesions. 
During the study, tumor assessments are performed every 6 weeks for the first 12 months then 
every 12 weeks until end of treatment, and subjects without progressive disease at the end-of-
treatment visit are followed up for disease progression (CT / MRI scans every 12 weeks) up to 
1 year.
The protocol-specified interim analysis for tumor response was conducted using RECIST 1.1. The 
BOR according to RECIST 1.1 was determined for each subject as the best response reported by 
the investigator from the start of treatment until disease progression. No confirmation of response 
(CR or PR) in a subsequent tumor assessment was required for the interim analysis.
The interim analysis population consisted of all treated subjects (n=75) who started treatment at 
least 13 weeks prior to the cut-off date of June 24, 2014. The ORR evaluated during the interim 
analysis was 13.3% (10 of 75 subjects; 95% confidence interval [CI]: 6.6%, 23.2%), including 
1 subject with CR, 9 subjects with PR.  There were also 25 subjects with stable disease (SD), 
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29 subjects with progressive disease, 11 subjects who were not evaluable. Subsequently, a further 
interim analysis of the first 90 treated NSCLC subjects was conducted (cut-off date July 17, 2014; 
13 weeks after start of study treatment of the 90th subject, with a median follow-up of 6 months; 
range: 3 to 10 months). The ORR evaluated during this analysis was 13.3% (12 of 90 subjects; 
95% CI: 7.1%, 22.1%), including 1 CR, 11 PR, 30 SD, 35 progressive disease, and 13 not 
evaluable. Ten out of the 12 responses were still on-going at the cut-off date for this analysis. The 
onset of response was rapid, with most subjects (7 of 12 [58%]) having their first documented 
response at Week 7.  
Overall, these data support proceeding with an expansion cohort of subjects with Stage IV or 
recurrent NSCLC who have not received systemic treatment for their metastatic or recurrent 
disease. 
3.5.5
Rationale for Additional Efficacy Expansion Cohorts
The expansion phase of the trial provides for further exploration of signals in 4 new efficacy 
expansion cohorts. The rationale is provided below.
3.5.5.1
Ovarian Cancer, Platinum Refractory and Prior Liposomal 
Doxorubicin
An additional expansion cohort of subjects with ovarian cancer (N=100) has been added to enroll 
specifically subjects with advanced ovarian cancer who are considered refractory to 
platinum-based chemotherapy and have received prior treatment with liposomal doxorubicin (for 
example, may be in combination with a platinum regimen, or as monotherapy, or in combination 
with other therapies) for advanced ovarian cancer. Subjects who have received treatment with 
platinum-based chemotherapy AND who have progressed during treatment within 6 months from 
the last dose of chemotherapy are considered refractory to platinum-based therapy. Refractory 
ovarian cancer is associated with a poor prognosis with few effective therapeutic options. 
Platinum-based chemotherapy and liposomal doxorubicin have established clinical benefit in 
advanced ovarian cancer. This expansion cohort seeks to enroll a specific patient population with 
advanced ovarian cancer that has exhausted all established therapeutic options (for example, 
platinum-based chemotherapy and liposomal doxorubicin) and thus represent a patient population 
with a high unmet need for new effective therapies. Data from this cohort may provide important 
efficacy data that may allow for further development with Phase III clinical trials.
3.5.5.2
Urothelial Carcinoma, Platinum Ineligible or Progressed after 
at Least 1 Line of Platinum-based Therapy: 
An additional expansion cohort of subjects with urothelial carcinoma (N=200) has been added so 
that a more precise evaluation of response rate and the potential association of response to PD-L1 
expression can be conducted. The target population for this cohort is subjects with advanced 
bladder cancer who have progressed after at least 1 line of platinum-based therapy or who are 
considered ineligible to receive platinum-based therapy. Ineligibility to treatment with a platinum 
salt is defined by the presence of any 1 of the following criteria: 
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! Impaired renal function 
! Hearing loss of 25 decibels at 2 contiguous frequencies
! Grade ≥2 peripheral neuropathy 
Subjects may have received any number of prior systemic therapies for metastatic disease. Subjects 
must have received at least 1 line of platinum-based chemotherapy. Platinum refractory bladder 
cancer is associated with a poor prognosis with few effective therapeutic options. Data from this 
cohort may provide important efficacy data that may allow for further development with Phase III 
clinical trials.
3.5.5.3
Rationale for Further Expansion of the Urothelial Carcinoma 
Cohort 
The urothelial carcinoma secondary expansion cohort in study EMR100070-001 included 
44 subjects with metastatic or locally advanced urothelial carcinoma who progressed after 
treatment with at least 1 platinum-containing regimen or were platinum ineligible. Subjects 
included in this cohort were treated with avelumab and followed up for at least 3 months. At a data 
cut-off date of 19 March 2015, among the 44 subjects in this cohort, there were 7 responders 
(15.9%), including 1 CR and 6 PR. Six of the 7 responders had responses that were still ongoing 
at the time of this analysis. The disease control rate was 59.1%, based on 7 responses and 
19 subjects with stable disease. 
Preliminary results of the role of PD-L1 expression to predict response to avelumab therapy in this 
initial cohort of subjects with urothelial cancer suggest a potential correlation with PD-L1 tumor 
expression and response (unpublished data). These early data appear to be consistent with Phase I 
data from other antibodies that block the anti-PD-1 or PD-L1 pathway (47). As a result, the 
Sponsor has decided to further expand enrollment in the urothelial carcinoma efficacy expansion 
cohort (N=200, see Section 8.1), in order to obtain a sufficient number of subjects to better 
understand the clinical activity of avelumab in this disease and to validate the potential correlation 
between PD-L1 expression and clinical outcomes. Specifications for a confirmatory analysis based 
on PD-L1 expression status will be made in the Statistical Analysis Plan (SAP) for study 
EMR100070-001 prior to any statistical analysis of PD-L1 expression data from the urothelial 
carcinoma efficacy expansion cohort.
3.5.5.4
Gastric / GEJ Cancer, Third Line:
The rationale to add a new cohort of subjects with metastatic gastric and GEJ cancer (N=150) who 
have failed both a first-line chemotherapy regimen and subsequent ramucirumab therapy, is 
supported by the recent data and subsequent regulatory approval of ramucirumab in patients with 
metastatic gastric cancer. Of note, ramucirumab is a recombinant monoclonal antibody of the IgG1 
class that binds to vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks the 
activation of the receptor. 
On 21 April 2014, the U. S. Food and Drug Administration approved ramucirumab for use as a 
single agent for the treatment of patients with advanced or metastatic gastric or GEJ 
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adenocarcinoma with disease progression on or after prior treatment with fluoropyrimidine- or 
platinum-containing chemotherapy. This approval was based on the demonstration of improved 
OS in a multinational, randomized (2:1), double-blind, multicenter study enrolling 355 patients 
with previously treated advanced or metastatic, gastric or GEJ adenocarcinoma. Patients were 
randomized to receive either ramucirumab plus best supportive care (BSC) or placebo plus BSC. 
The median OS was 5.2 months in the ramucirumab plus BSC arm and 3.8 months in the placebo 
plus BSC arm (hazard ratio [HR]=0.78; 95% CI: 0.60, 0.998; p =0.047). Median PFS was longer 
in the ramucirumab arm compared to the placebo arm (HR=0.48; 95% CI: 0.38, 0.62; p <0.001).
The safety of ramucirumab as a single agent was evaluated in 570 patients, including 236 patients 
with locally advanced or metastatic gastric or GEJ adenocarcinoma, with an ECOG performance 
status of less than or equal to 1, who received ramucirumab. The most common adverse reactions 
(all grades) observed in ramucirumab-treated patients at a rate of greater than or equal to 10% and 
greater than or equal to 2% higher than placebo were hypertension and diarrhea. The Grade 3 to 4 
adverse reactions reported at a higher incidence in the ramucirumab arm (greater than or equal to
2% difference between arms) included hypertension and hyponatremia. The most common SAEs
with ramucirumab were intestinal obstruction (2.1%) and anemia (3.8%). Other important risks 
described in labeling include hemorrhage, arterial thrombotic events, infusion-related reactions, 
gastrointestinal perforation, impaired wound healing, clinical deterioration in patients with 
cirrhosis, and reversible posterior leukoencephalopathy. 
The availability and use of ramucirumab in second-line metastatic gastric cancer has subsequently 
led to the emergence of a subpopulation of patients who have progressed on both chemotherapy 
and ramucirumab and now have few, if any, effective therapeutic options. Data from this cohort 
may provide important insight on the potential role of anti-PD-L1 therapy in these patients.
3.5.5.5
Head and Neck Cancer, Platinum Ineligible or Progressed 
After at Least 1 Line of Platinum-based Therapy:
The rationale to add a new cohort of subjects with HNSCC (N=150) is the observation that immune 
escape may play a prominent role in HNSCC, as both human papillomavirus (HPV) positive and 
HPV-negative HNSCC display a T-cell-inflamed phenotype characterized by the presence of 
tumor-infiltrating lymphocytes and PD-L1 expression (53). 
Recently, promising clinical data has emerged suggesting that antibodies that block the 
PD-1 / PD-L1 pathway may be an effective therapy for metastatic HNSCC (54). These data 
demonstrated a 19.6% best overall response rate (11 of 56 responses), with 7 of 11 responders still 
on treatment. Furthermore, 51% of patients experienced no change or a decrease from baseline in 
the size of their target lesions. PD-L1 expression appeared to be correlated with response with a 
50% ORR in the 12 patients with PD-L1 expression above the cutpoint and 11.4% ORR in the 
44 patients with PD-L1 expression below the cutpoint. These data demonstrate promising 
antitumor activity with an acceptable safety profile in patients with recurrent or metastatic HNSCC 
and who were treated with an anti-PD-1 agent. 
In addition, these data support proceeding with an expansion cohort of subjects with HNSCC who 
have progressed after at least 1 line of platinum-based therapy or who are considered ineligible to 
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receive platinum-based therapy. Ineligibility to platinum treatment is defined by the presence of 
any 1 of the following criteria: 
! Impaired renal function 
! Hearing loss of 25 decibels at 2 contiguous frequencies
! Grade ≥2 peripheral neuropathy 
Subjects may have received any number of prior systemic therapies for metastatic disease. Subjects 
must have received at least 1 line of platinum-based chemotherapy. Platinum refractory HNSCC 
is associated with a poor prognosis with few effective therapeutic options. Data from this cohort 
may provide important efficacy data which may allow for further development with Phase III 
clinical trials.
3.6
Rationale for Expanding Inclusion Criteria for Gastric / GEJ 
Cohort
Recent data provide evidence of clinical activity of anti-PD-L1 therapy in metastatic gastric cancer 
patients, which supports the expanded inclusion in this trial of subjects who have progressed on 
first-line chemotherapy for metastatic disease. The evidence includes:
! Data presented at the American Society for Clinical Oncology Annual Meeting 2014 from a 
Phase I expansion cohort of 16 subjects with gastroesophageal cancer treated with MEDI4736 
(anti-PD-L1), which reported 4 out of 16 responders (55).
! Preliminary data from the gastric and GEJ cancer expansion cohort in the current trial 
(EMR100070-001), which includes 2 unconfirmed PRs out of 6 subjects who have completed 
7 weeks of follow-up (as of 17 July 2014).
Based on the above data, eligibility for this cohort will be expanded to allow subjects who have 
progressed on first-line chemotherapy for metastatic disease to be enrolled, in addition to subjects 
who have not progressed. 
3.7
Summary of the Overall Benefit and Risk
The risk-benefit relationship has been carefully considered in the planning of the trial. Based on 
the pre-clinical and clinical data available to date, the conduct of the trial is considered justifiable 
using the dose(s) and dosage regimen(s) of the avelumab as specified in this clinical trial protocol. 
A SMC is planned for the ongoing assessment of the risk-benefit ratio. The trial shall be 
discontinued in the event of any new findings that indicate a relevant deterioration of the 
risk-benefit relationship and would render continuation of the trial unjustifiable. The risks of 
exposure to avelumab include: 
! Infusion-related reactions
! irAEs.
! Infusion-related reactions are a risk inherent to the administration of any recombinant protein 
to humans. 
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Incidence of immunogenicity and character or severity of immunogenicity-induced side effects 
cannot be predicted by animal models because humanized or fully human proteins usually provoke 
a much stronger immune-response in rodents or non-human primates than in humans. Avelumab
caused lethal immune-mediated anaphylactic hypersensitivity reactions in mice after repeated 
application, while a control antibody lacking pharmacological activity only triggered a moderate 
immune reaction. However, in primates (cynomolgus monkeys), as a species closer to human, 
neither in the pilot 4-week i.v. repeat-dose toxicity study nor in the pivotal 13-week i.v. infusion 
repeat-dose toxicity study, clinical signs of hypersensitivity have been seen at dose levels of 20, 
60, and 140 mg/kg, respectively.
Immune-related AEs are events that are drug-related and can be explained by an 
immune-phenomenon after other etiologies have been ruled out. Relevant clinical safety 
experience has been generated with several PD-1/PD-L1 pathway blocking monoclonal antibodies. 
For the anti-PD-L1 monoclonal antibody MDX-1105, an MTD could not be reached and the most 
common drug-related AEs were fatigue, infusion reactions, diarrhea, arthralgia, rash, nausea, 
pruritus, and headache. Most events were low grade, with treatment-related Grade 3 or 4 events 
noted in 19 of 207 subjects (9%) (5). Drug-related AEs of special interest, with potential immune-
related causes, were observed in 81 of 207 subjects (39%) and included rash, hypothyroidism, 
hepatitis, and 1 case each of sarcoidosis, endophthalmitis, diabetes mellitus, and myasthenia 
gravis. These AEs were predominantly Grade 1 or 2 and were managed with treatment interruption 
or discontinuation. Nine subjects were treated with glucocorticoids for the management of AEs, 
with improvement or resolution of events in all subjects. Overall, the safety profile for this 
compound, blocking the PD-1 / PD-L1 axis at the same level as avelumab, is acceptable in the 
context of the treatment of subjects with advanced malignancies. Nevertheless, especially the 
occurrence of irAE will be carefully monitored.
In addition, since the drug can induce ADCC, there is a potential risk of tumor lysis syndrome. 
Should this occur, subjects should be treated per the local guidelines and the management 
algorithm published by Howard et al (56). See Figure 6.1, Section 6.5.4.3.
At the time of preparation of this Amendment, safety data from 53 subjects treated with avelumab
at doses ranging from 1 to 20 mg/kg during dose escalation and > 1400 subjects at a dose of 
10 mg/kg in dose expansion were available (refer to current IB). 
As one can deduce from the clinical experience with ipilimumab, which blocks cytotoxic T 
lymphocyte antigen-4 (CTLA-4), a negative regulator of T-cell activation like PD-L1, potential 
side effects of PD-L1 antagonism include immune-related adverse reactions, which can be severe 
and may involve the gastrointestinal, liver, skin, endocrine, or other organ systems (57-61). 
Skin-related AEs can be expected after 2 to 3 weeks, gastrointestinal and hepatic AEs after 6 to 
7 weeks, and endocrinologic AEs only after an average of 9 weeks (62) and constitute the clinically 
most relevant safety concern apart from acute severe infusion reactions. The kinetics of the 
occurrence of such irAEs have not been reported for either BMS-936559 targeting PD-L1 (5) nor 
for the anti-PD-1 monoclonal antibody BMS-936558 (6). However, their toxic effects seem to be 
less common and of lower grade compared with ipilimumab. Nevertheless, careful monitoring of 
such AEs of special interest (AESI) is implemented in this protocol throughout the complete 
treatment period and up to 3 months post-treatment for follow-up (see Sections 7.1.4 and 7.4.1.1).
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A direct benefit is considered unlikely for participants in this Phase I trial, at least in the low doses 
of the dose escalation part. However, durable partial responses have been reported with another 
anti-PD-L1 monoclonal antibody (6). Therefore, only subjects with malignancies for which no 
standard therapy exists or subjects having experienced a failure of standard therapy are eligible for 
this part of the study (i.e., 1 and 3 mg/kg). However, allometric scaled human simulations suggests 
that the proposed initial dose of 1.0 mg/kg is expected to result in at least 50% target occupancy, 
which may be sufficient to induce beneficial clinical effects. Moreover, expansion on a dose level 
displaying pharmacological and/or clinical activity, to enrich for subjects in selected indications 
will be done. 
The sample size of 150 for expansion in the primary cohorts (NSCLC [both post platinum doublet 
and first-line], gastric and GEJ cancer, and MBC) and 2 efficacy expansion cohorts (gastric and 
GEJ cancer and HNSCC) has been chosen based on knowledge that PD-L1 is clinically active in 
NSCLC and that PD-L1 is also expressed in MBC, gastric cancer, and HNSCC microenvironment. 
Data published by Topalian et al, have linked the expression of PD-L1 by tumor cells and clinical 
activity of agents blocking the PD-1/ PD-L1 pathway (6), but additional results presented at ASCO 
in 2013 suggest that the response to agents that block the PD-1/PD-L1 pathway does not require 
the expression of PD-L1 by tumor cells. It might be speculated that PD-L1 has to be involved in 
the phenomenons that drive the escape from the immune response for an anti-PD-L1 agent to have 
clinical activity (63,64). Enrollment of 150 subjects will allow for a robust assessment of safety 
and efficacy endpoints in these indications, including a precise determination of response rates. In 
addition, data from these cohorts will be used to investigate the association between the pattern of 
expression of membrane PD-L1 and clinical response to PD-L1 blockade, and to determine 
whether accrual in future studies should be restricted based on PD-L1 expression status. 
The sample size of 20 for each of the 4 original secondary disease specific expansion cohorts was 
chosen primarily to further explore the safety and efficacy of avelumab in specific indications and 
to provide preliminary data to aid in future study design. However, following completion of dose 
escalation in this trial and in the broader context of ongoing research with PD-L1 inhibition, it is 
considered appropriate to add 4 new secondary cohorts (ACC, mesothelioma, urothelial 
carcinoma, and RCC) to the expansion phase of this trial and to increase subject enrollment in 2 of 
the 4 initial secondary cohorts (melanoma and ovarian cancer).
An interim analysis will take place after 75 subjects treated in the primary expansion cohorts have 
been followed for 3 months or until discontinuation if earlier. This interim analysis will enable a 
first assessment of the association between PD-L1 expression and tumor response, to support the 
planning of subsequent studies and the possible development of a companion diagnostic assay. A 
futility rule will be applied that will imply a stop of enrollment in the given cohort in case of 
insufficient clinical activity.  
In the first-line NSCLC primary expansion cohort, an interim analysis of response will be 
conducted 13 weeks after start of treatment of the 30th subject.
For the efficacy expansion cohorts, interim analyses for efficacy are planned 13 weeks after the 
start of treatment of the 30th subject in all cohorts, 13 weeks after start of treatment of the 60th 
subject in the ovarian cohort, and 13 weeks after start of treatment of the 90th subject in the gastric 
/ GEJ and HNSCC cohorts. No futility rule is foreseen because the clinical activity of Anti-PPD-1 
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/ Anti-PD-L1 agents in these tumor types is established, and the patient populations are 
characterized by a high unmet medical need. If efficacy criteria are met at the second interim 
analysis, enrollment will continue to the planned full number of subjects in order to collect further 
data on the primary and secondary endpoints, especially on the association between PD-L1 
expression and efficacy endpoints. 
In addition, in the NSCLC post platinum doublet cohort only, 2 additional interim analyses of 
efficacy will be conducted, 13 weeks after the start of treatment of the 60th and the last subject, 
respectively.
For each expansion cohort, an additional interim analysis may be conducted 13 weeks after the 
start of treatment of the last subject in that cohort.
Also, in the secondary cohorts that plan to enroll more than 20 subjects, i.e., the ACC, melanoma, 
mesothelioma, ovarian cancer, and urothelial carcinoma cohorts, an interim analysis of response 
will be performed 13 weeks after the start of treatment of the 20th subject. Accrual in each cohort 
may be paused during the interim analysis. If no unconfirmed response according to RECIST 1.1 
is observed in a given cohort in the interim analysis, accrual in that cohort will be stopped. In 
addition, for the ovarian cancer secondary expansion cohort, an interim analysis of response will 
be performed for internal planning purposes 13 weeks after the start of treatment of the 75th subject.
Enrollment of first-line RCC subjects was opened after 2 documented objective responses among 
the 20 subjects enrolled in the second-line RCC cohort were observed by RECIST 1.1 (2 PRs), 
and justified further evaluation in this patient population.
In conclusion, the risk-benefit ratio of treatment with avelumab in the targeted trial population is 
considered positive given the poor prognosis of subjects with advanced malignancies.
This clinical trial will be conducted in compliance with the clinical trial protocol, Good Clinical 
Practice (ICH Topic E6, Good Clinical Practice [GCP]) and the applicable national regulatory 
requirements.
4
Trial Objectives
Primary objective
! To assess the safety and tolerability of avelumab and to determine the MTD of avelumab in 
subjects with metastatic or locally advanced solid tumors.
! To assess the BOR according to RECIST 1.1 in the efficacy expansion cohorts (ovarian cancer, 
platinum refractory, prior liposomal doxorubicin; urothelial carcinoma, platinum ineligible or 
progressed after at least 1 line of platinum-based therapy; gastric and GEJ cancer, third line; 
HNSCC, platinum ineligible or progressed after at least 1 line of platinum-based therapy).
Secondary objectives
! To characterize the PK profile of avelumab and to correlate exposure with target occupancy.
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! To evaluate the immunogenicity of avelumab and to correlate it to exposure and biological 
activity.
! To assess the BOR and PFS according to RECIST 1.1.
! To assess the immune-related BOR (irBOR) and immune-related PFS (irPFS) using the 
modified Immune-Related Response Criteria (irRC), derived from RECIST 1.1.
! To assess OS.
! To evaluate biological responses to avelumab in blood/serum.
! To evaluate the association between tumor PD-L1 expression and BOR.
! To characterize changes in soluble factors (e.g., cytokine profiles, soluble PD-1 and soluble 
PD-L1) and immune cell profiling (e.g., natural killer [NK] cells, neutrophils, lymphocytes).
Exploratory objectives (efficacy expansion cohort only)
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase I, open-label, dose-escalation trial with consecutive parallel-group expansion in 
selected solid tumor indications. 
5.1.1
Overall Design
The current trial is a standard dose escalation “3 + 3” cohort design, for which 3 to 6 subjects will 
be enrolled at each dose level depending on the occurrence of DLTs (see Section 5.1.4.2.2). This 
dose escalation phase of the trial is currently being conducted in the USA only.
Cohorts of 3 subjects with metastatic or locally advanced solid tumors, for which no standard 
therapy exists or a standard therapy has failed, will receive avelumab at escalating dose levels with 
3 to 3.3 times of increase in dose (see Section 5.1.4.2). The starting avelumab dose is 1.0 mg/kg; 
the maximally envisaged dose is 10 mg/kg. At each dose level, subjects will receive avelumab
once every 2 weeks until confirmed progression, unacceptable toxicity, or any reason for 
withdrawal from the trial or IMP occurs (see Section 5.5). Subjects who have experienced a 
confirmed CR should be treated for a maximum of 24 months after confirmation, at the discretion 
of the investigator. If the investigator believes that a subject may benefit from treatment beyond 
24 months, it may be permissible after discussion with the sponsor.
Subjects who experienced a CR and have already stopped treatment can resume treatment with 
avelumab at the same dose and schedule. For subjects who achieve a CR on avelumab therapy and 
then subsequently develop disease progression after stopping therapy, but prior to the end of the 
trial, one re-initiation of treatment at the same dose and schedule is allowed at the discretion of the 
investigator and agreement of the trial Medical Monitor. In order to be eligible for retreatment, the 
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subject must not have experienced any toxicity that led to treatment discontinuation of the initial 
avelumab therapy. Subjects who re-initiate treatment will stay on study and will be treated and 
monitored according to the protocol and the “until progression” schedule in the Schedule of 
Assessments (see Appendix I).
The dose range and schedule for this trial was developed based on safety considerations as well as 
on preclinical PK / PD modeling. Because peripheral blood T cells express PD-L1, it is possible 
to assess in vivo receptor occupancy by anti-PD-L1 antibody as a PD measure and potential 
surrogate for clinical activity. From mouse tumor models, it was concluded that a stable avelumab
blood concentration of at least 50 μg/mL has to be realized in order to induce clinically relevant 
effects. Such an exposure level was corresponding to approximately 95% target occupancy and 
could be kept over time in the clinical setting by an avelumab dose of 7 mg/kg administered every 
2 weeks. Close monitoring of exposure as well as of target saturation on lymphocytes during the 
clinical trial will enable to modify the protocol, in case the finally aimed target occupancy would 
not be achieved. The clinical design is nearly identical to study NCT00729664 investigating BMS-
936559, hence supported by the excellent safety and very positive efficacy data gained from this 
trial.
Besides determination of the MTD / maximum feasible dose, it is the intention to establish PK / PD 
correlations based on PD-L1 receptor occupancy to provide guidance for the dose and regimen to 
be used in expansion cohorts covering selected tumor indications. The MoA of avelumab in 
humans will be investigated through monitoring the activation status of the immune system (i.e., 
leukocyte subsets phenotypes, PD-1 signaling pathway, ADCC, cytokines profiling). Furthermore, 
explorations of specific anti-tumor immune responses and evaluations of potential 
predictive/prognostic biomarker candidates are planned in this trial. 
Assessment of safety parameters will focus on potential acute side effects like cytokine release 
syndrome caused by potential exaggerated pharmacological activity of avelumab i.e., 
overstimulation of cytokine-releasing hematological cells or damage of cytokine containing cells 
by ADCC. Potential acute side effects also include allergic reactions / hypersensitivities, in the 
worst case anaphylaxis (65), which could develop as consequence of an immunogenicity response 
and might be pronounced due to the immunostimulatory properties of avelumab, promoting an 
immune response against itself.
Evaluation of middle-term safety will cover incidence and severity of potential irAE, which may 
become manifest earliest after weeks of treatment (57-61,66). Such events may consist of 
persistent rash, diarrhea and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, 
cardiomyopathy, or uveitis and other inflammatory eye conditions. The spectrum of hypothetical 
irAEs also includes formation of auto-antibodies like anti-nuclear antibodies (ANAs) or 
antineutrophil cytoplasmic antibodies (ANCAs).
DLTs will be monitored centrally, and the decision to escalate to the next dose level will be 
proposed by the SMC as outlined in Section 2.2.1. 
Once the dose of 10 mg/kg is established as safe (see Section 5.1.4.2), 10 additional subjects at 
3 mg/kg and 10 mg/kg each may be enrolled, for the purpose of generating additional safety, PK 
and receptor occupancy data, if agreed with the SMC.
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Once 6 subjects treated at 10 mg/kg have completed the DLT observation period and the safety of 
10 mg/kg is established, a dose level of 15 mg/kg (if 1 DLT was observed) or 20 mg/kg (if no DLT 
was observed) dosing every 2 weeks will be initiated. In this 20 mg/kg dose level, the safety, PK, 
receptor occupancy, and PD activity of the IMP will be evaluated using the methodology that was 
used for the other cohorts. Accrual in these dose levels will be completed using a “3+3” method, 
the same methodology that was used for the completion of the previous dose levels. Once the 
safety of the 15 and/or 20 mg dose level has been established (i.e., no more than one DLT out of 
6 subjects treated), up to 15 additional subjects will be enrolled at 15 or 20 mg/kg without 
sequential dosing (i.e., not required to wait until 48 hours between 2 subjects). This additional 
cohort will have the purpose of generating safety data, PK data and receptor occupancy data at a 
dose of the respective dose.
With the safety of the 10 mg/kg and 20mg/kg once every 2 weeks established, a new cohort of 
10 mg/kg administered once weekly for the first 12 weeks is being initiated to assess safety of 
higher intensity of already established dose.  Six evaluable subjects are planned to be included in 
this cohort. Subjects in this cohort will receive avelumab at 10 mg/kg once weekly for the first 
12 weeks. Starting Week 13, dosing with 10 mg/kg will be once every 2 weeks.
Subjects who do not complete 4 weeks of treatment for reasons other than treatment-related AE 
will be replaced. Subjects in this cohort will be enrolled in selected sites in the USA only.
In 10 mg/kg once weekly cohort the SMC will evaluate overall safety data when all 6 evaluable 
subjects have completed a minimum 4-week treatment period, and after 12 weeks of observation 
have been completed for all subjects enrolled in this cohort (see Section 2.2.1).
Expansion cohorts
After an avelumab dose and regimen for further investigation are established, enrollment 
in expansion cohorts will be opened in up selected tumor indications to determine the safety and 
clinical activity of avelumab. Subjects will be divided into:
! 4 primary cohorts (N=150 subjects each) of:
1. NSCLC, post platinum doublet; 
2. NSCLC, first line, does not carry an epidermal growth factor receptor (EGFR) activating 
mutation or anaplastic lymphoma kinase (ALK) re-arrangements (non-squamous cell 
histologies require testing if status is unknown);
3. Gastric and GEJ junction cancer; and 
4. MBC
! 8 secondary cohorts: 
1. CRC (N=20), 
2. CRPC (N=20), 
3. ACC (N=50), 
4. Melanoma (N=50), 
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5. Mesothelioma (N=50), 
6. Urothelial carcinoma (N=50; note: enrollment is being stopped [N=44] due to the opening 
of a urothelial efficacy expansion cohort), 
7. Ovarian cancer (N=120), and
8. Renal cell carcinoma (RCC), second line, (N=20 with expansion of 60 first-line).
! 4 efficacy expansion cohorts with the primary objective to assess BOR according to 
RECIST 1.1:
1. Ovarian cancer, platinum refractory, prior liposomal doxorubicin (N=100); 
2. Urothelial carcinoma, platinum ineligible or progressed after at least 1 line of 
platinum-based therapy (N=200); 
3. Gastric and GEJ cancer, third line (N=150); 
4. HNSCC, platinum ineligible or progressed after at least 1 line of platinum-based therapy 
(N=150).
Subjects in the NSCLC (post platinum doublet), CRC, and CRPC cohorts will be enrolled in the 
USA only.
A schematic illustration of the trial design is shown in Figure 5.1.
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Figure 5.1
Schematic of Trial Design
* Subjects in the NSCLC (post-platinum doublet), CRC and CRPC cohorts will be enrolled in the USA only.
Abbreviations: ACC: adrenocortical carcinoma; DLT: dose-limiting toxicity; CRC: colorectal cancer, CRPC: castrate-resistant 
prostate cancer; GEJ: gastroesophageal junction; HNSCC: head and neck squamous cell carcinoma; MBC: metastatic breast cancer; 
MTD: maximum tolerated dose; NSCLC: non-small cell lung cancer, RCC: renal cell carcinoma.
5.1.2
Trial Endpoints
5.1.2.1
Primary Endpoints
! Occurrence of DLTs during the first 3 weeks of treatment in the dose escalation part (excluding 
the once weekly 10 mg/kg cohort).
! The confirmed BOR, per RECIST 1.1, as adjudicated by an IERC (see Section 7.3) for subjects 
enrolled in the efficacy expansion cohorts only.
5.1.2.2
Secondary Endpoints
! Number, severity, and duration of TEAEs for all dose groups / indications according to the 
NCI-Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
! Number, severity, and duration of treatment-related AEs according to NCI-CTCAE v4.0.
! PK profile.
Dose escalation (Standard “3 + 3” Design) up to 10 mg/kg 
Expansion cohorts in 16 different indications
  Dose and regimen will be defined based on dose escalation part
  Parallel enrollment
  150 subjects per indication in primary cohorts
3 subjects
3 subjects
3 subjects
* if DLT: +3 subjects
*
*
20.0
10.0
3.0
1.0
  20-120 subjects per indication in secondary cohorts
  100-200 subjects per efficacy cohort
MTD: no more than 1/6
subjects with DLT
DLT observation period
3 weeks
Dose 
Levels 
(mg/kg)
Primary: NSCLC (post platinum doublet)*, 
NSCLC (first-line)*, gastric / GEJ cancer, and 
MBC
Secondary: CRC*, CRPC*, melanoma, 
ovarian cancer, ACC, mesothelioma, and 
urothelial carcinoma, RCC 
Efficacy expansion: Ovarian (platinum 
refractory, liposomal doxorubicin), urothelial 
carcinoma (platinum ineligible, or 
progressed), gastric / GEJ (third-line), HNSCC 
(platinum ineligible, or progressed), 
10 mg/kg once weekly safety evaluation cohort (N = 6)
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! irBOR and BOR according to modified irRC and to RECIST 1.1, respectively, per investigator 
assessment.
! The confirmed BOR, per RECIST 1.1, as adjudicated by an IERC, for subjects enrolled in the 
secondary urothelial carcinoma cohort.
! irPFS time and PFS time according to modified irRC and to RECIST 1.1, respectively, per 
investigator assessment.
! OS time.
! Pharmacodynamic profile.
! Serum titers of anti-drug antibodies (ADA).
! Expression of PD-L1 on tumor tissue.
! For the primary expansion cohorts only: Unconfirmed response at Week 13 according to 
RECIST 1.1, per investigator assessment.
! Duration of response according to modified irRC and to RECIST 1.1, respectively, per 
investigator assessment.
! For the efficacy expansion cohorts only: 
o
PFS time, according to RECIST 1.1, per IERC
o
Duration of response according to RECIST 1.1, per IERC.
5.1.3
Trial Medication Administration and Schedule
Subjects will receive i.v. infusion of avelumab (over 1 hour [-10 minutes / +20 minutes, i.e., 50 to 
80 minutes]) once every 2 weeks. Premedication with an antihistamine and with paracetamol 
(acetaminophen) approximately 30 to 60 minutes prior to each dose of avelumab is mandatory (for 
example, 25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] i.v. or oral 
equivalent). This regimen may be modified based on local treatment standards and guidelines, as 
appropriate.
For subjects in the 10 mg/kg once weekly cohort, subjects will receive i.v. infusion of avelumab
(over 1 hour [-10 minutes / +20 minutes, i.e., 50 to 80 minutes]) once every week for the first 
12 weeks, then starting with Week 13, once every 2 weeks thereafter.  Premedication will be 
administered as above. 
The trial treatment schedule is illustrated in Appendix I.
The formulation and packaging information of avelumab is provided in Sections 6.1 and 6.6.
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5.1.4
Avelumab Dose Escalation
5.1.4.1
Starting Dose
The starting dose of avelumab will be 1.0 mg/kg.
5.1.4.2
Dose Escalation Scheme
The avelumab dose escalation will be performed in cohorts of 3 subjects each according to the 
following dose levels with a 3 or 3.3 times of dose increase at each escalation:
! 1.0 mg/kg
! 3.0 mg/kg
! 10.0 mg/kg
The dose escalation criteria are as follows:
For each dose level, DLTs are assessed during the first 3 weeks. The criteria for moving from one 
dose level to another do not allow escalation to the next cohort in cases where ≥2 of 3 or 6 subjects 
in a cohort experience a DLT. If 1 of 3 subjects in a cohort experiences a DLT, this cohort will be 
expanded to 6 subjects. The MTD is defined as the highest dose where fewer than 2 of 6 subjects 
experience a DLT. Thus, the MTD cohort should accrue at a total of 6 subjects.
Once the MTD or maximum dose to be investigated is reached, the respective dose level cohort 
will be filled to a total of 6 subjects. Once the dose of 10 mg/kg is established as safe, 10 additional 
subjects at 3 mg/kg and 10 mg/kg each may be enrolled, for the purpose of generating additional 
safety, PK and receptor occupancy data, if agreed with the SMC.
A schematic of dose escalation is presented in Figure 5.2.
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Figure 5.2
Dose Escalation Algorithm for Doses up to 10 mg/kg
Abbreviations: IMP: investigational medicinal product; DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
Each subject will stay on the dose level assigned at trial entry. The first subject of each cohort 
should be observed for 16 days (i.e., 48 hours after the second dose) for DLT occurrence before 
the second subject is to be administered the trial medication. Thereafter, within each cohort of the 
dose escalation phase, subjects may only be consecutively dosed with an interval of at least 
48 hours. However, after 3 subjects have been treated at 10 mg/kg and no DLT has been observed, 
the other 3 subjects required to complete this cohort can be enrolled without sequential dosing (i.e., 
not required to wait until 48 hours). If no more than 1 DLT has been observed in these 6 subjects, 
the safety of 10 mg/kg will have been established.
At the conclusion of the DLT observation period of each cohort, a data review will be conducted.
The SMC that includes all principal investigators is responsible for making dose escalation 
decisions. This committee will make the decision whether or not to escalate the avelumab dose to 
the next level by reviewing the safety data after all subjects of a cohort have completed Day 21 
observation (the DLT evaluation period). 
Once 1 subject has experienced DLT at a dose level below 10.0 mg/kg, dose escalation will be 
reduced as described in Table 5.1:
No
Yes
0 of 3
1 of 6
∀2 of 6
∀2 of 3
Determine MTD 
Number of 
DLTs
Max. dose per 
protocol?
MTD / max. dose to be confirmed
based on total of 6 patients
Determine MTD
Start
1.0 mg/kg IMP
Treat 3 additional patients
Treat 3 patients
(assess DLT after 3 weeks)
Escalate to next 
dosing cohort
Number of 
DLTs
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Table 5.1
Modification of Dose Escalation Based on DLT Observations at Dose 
Levels Below 10.0 mg/kg
Dose Escalation Schedule 
Scenarios
Dose of Avelumab (mg/kg)
Dose Levels
No DLT
DLT at Level 2
DLT at Level 1
Level 1
1.0
1.0
1.0
Level 2
3.0
3.0
1.5
Level 3
10.0
4.5
2.5
Level 4
7.0
3.5
Level 5
10.0
5.0
Level 6
7.5
Level 7
10.0
DLT: dose-limiting toxicity.
If > 1 out of 6 subjects experiences DLT at the first dose level, the SMC will discuss if an avelumab
dose lower than the starting dose of 1.0 mg/kg will be tested. Other dose modifications (i.e., 
de-escalation) may also be considered by the SMC, if deemed necessary. 
5.1.4.2.1
Dosing After 6 Subjects Treated at 10 mg/kg
Once the safety of the administration of the IMP at 10 mg/kg has been established in 6 subjects 
treated at 10 mg/kg and observed during the DLT observation period, subsequent dosing will be 
determined by the SMC after review of the safety and PK data generated for those 6 subjects. 
If 1 DLT was observed in the 6 subjects treated at 10 mg/kg during the DLT observation period, a 
dose level of 15 mg/kg will be initiated. The safety, PK, receptor occupancy, and PD activity of 
the drug administered at a dose of 15 mg/kg will be evaluated using the methodology that was 
used for the other dose levels. If no subjects dosed at 15 mg/kg experience a DLT the next cohort 
can be dosed at 20 mg/kg. If 1 of 3 subjects dosed at 15 mg/kg experiences a DLT, this cohort will 
be expanded to 6 subjects. 
Once the safety of PD-L1 has been established at 15 mg/kg (defined as no DLT observed in the 
3 subjects or up to 1 DLT observed in 6 subjects treated at 15 mg/kg during the DLT observation 
period), the 20 mg/kg dose level will be initiated.
If there was no DLT observed in the first 6 subjects treated at a dose of 10 mg/kg, the dose 
escalation will proceed from 10 to 20 mg/kg. In this 20 mg/kg cohort, the safety, PK, receptor 
occupancy, and PD activity of the drug will also be evaluated using the methodology that was used 
for the other cohorts. Accrual in the 20 mg/kg cohort will be completed using a “3+3” method that 
was used for the completion of the previous cohorts. 
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After 3 subjects have been enrolled at a dose of 20 mg/kg and followed up during the DLT period, 
after the SMC has reviewed the safety data available and has concluded that no DLT occurred, 
3 additional subjects will be enrolled at a dose of 20 mg/kg in an unstaggered fashion (i.e., 
3 subjects the same day). If ≥2 (of 3 or 6) subjects experiences a DLT, the 15 mg/kg dose will 
have to be explored before the MTD can be determined.
Once the safety of a dose of 15 mg/kg or 20 mg/kg has been established (i.e., no more than 1 DLT 
out of 6 subjects treated at that dose), the SMC will have the possibility to allow enrollment of up
to 15 additional subjects at that dose, without sequential dosing (i.e., not required to wait until 
48 hours between 2 subjects). This additional cohort will have the purpose of generating safety, 
PK, and receptor occupancy data at a dose of 15 or 20 mg/kg. 
Based on their review of the safety and PK data, the SMC will have the possibility to enroll an 
additional 10 subjects at 3 mg/kg and 10 mg/kg each. 
A schematic of the dose escalation for 15 and 20 mg/kg is presented in Figure 5.3.
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Figure 5.3
Dose Escalation Algorithm for 15 and 20 mg/kg
Abbreviations: IMP: investigational medicinal product; DLT: dose-limiting toxicity; MTD: maximum tolerated dose.
5.1.4.2.2
10 mg/kg Once Weekly Cohort
With the safety of the 10 mg/kg and 20 mg/kg once every 2 weeks established, a new cohort of 
10 mg/kg administered once weekly is being initiated in 6 evaluable subjects to assess safety of a 
more frequent dosing at 10 mg/kg every week for 12 weeks followed by 10 mg/kg every 2 weeks.   
Subjects in this cohort of 6 evaluable subjects will receive avelumab at 10 mg/kg once weekly for 
the first 12 weeks. Starting Week 13, dosing with 10 mg/kg will be once every 2 weeks. Overall 
safety of subjects in this cohort will be monitored by the SMC (see Section 2.2.1).
Dose
20 mg/kg IMP
Safety of
15 mg/kg
established
  Treat 3 subjects
  (assess DLT after 3 weeks)   
≥2 of 3
Number of 
DLTS
Treat 3 additional 
subjects at 20 mg/kg
≥2 of 6
Number of 
DLTS
≤1 of 6
6 subjects treated at 
10 mg/kg IMP
No DLTs
1 DLT
Dose
15 mg/kg IMP
  Treat 3 subjects
  (assess DLT after 
   3 weeks)   
≤1 of 6
≥2 of 6
≥2 of 3
Safety of
10 mg/kg
established
Safety of
10 mg/kg
established
Number of 
DLTS
Treat 3 additional 
subjects at 15 mg/kg
Number of 
DLTS
0 DLT
1 DLT
15 mg previously 
tested
15 mg not 
previously tested
Safety of
15 mg/kg
established
15 mg previously 
tested
15 mg not 
previously tested
Safety of 20 mg/kg
established
1 DLT
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5.1.4.3
Dose-Limiting Toxicity
A DLT is defined as a ≥ Grade 3 adverse drug reaction (ADR) according to the NCI-CTCAE v4.0, 
occurring in the DLT evaluation period of the dose escalation cohorts. ADRs are defined in this 
trial as any AEs suspected to be related to avelumab by the investigator and / or Sponsor.
The observation period for DLTs refers to the first 3 weeks of trial drug treatment in the dose 
escalation part for all dose cohorts for all subjects with data used for implementing the 
dose-escalation algorithm for determination of the MTD. Additional subjects enrolled in the dose 
escalation phase will have AEs collected but will not have a specific DLT observation period. A 
DLT is defined as any ≥ Grade 3 treatment-related toxicity confirmed by the SMC to be relevant 
for the study drug treatment. The SMC recognizes that in the absence of prior human experience 
with avelumab, a conservative approach will be adopted in ascribing the relevance of the 
treatment-related toxicity to drug. Treatment-related SAE will be ascribed as related to drug except 
where a clear relationship to the underlying disease or recognized co-morbidities is evident. For 
this trial, the MTD is defined as the highest dose where < 2 of 6 subjects experience a DLT. 
A DLT is specifically defined as any one of the following: 
Any Grade ≥ 3 toxicity that is possibly, probably, or definitely related to avelumab, occurring 
during the DLT evaluation period (21 days after administration of avelumab), except for any of 
the following: 
! Grade 3 infusion-related reaction resolving within 6 hours and controlled with medical 
management.
! Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management.
! Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to ≤ Grade 1. 
! Grade 3 diarrhea, Grade 3 skin toxicity, or Grade 3 liver function test (ALT, AST, or GGT) 
increase that resolves to ≤ Grade 1 in less than 7 days after medical management 
(e.g., immunosuppressant treatment) has been initiated.
! Single laboratory values out of normal range that are unlikely related to trial treatment according 
to the investigator, do not have any clinical correlate, and resolve to ≤ Grade 1 within 7 days 
with adequate medical management.
! Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor.
DLTs requiring treatment discontinuation are described in Section 5.1.7.2.
Subjects who do not complete the DLT observation period for reasons other than a DLT will be 
replaced.
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5.1.5
Planned Number of Subjects
The planned number of the evaluable subjects for this trial is derived from the dose escalation 
“3+3” design and the expansion cohort sizes:
Dose escalation phase (including the 10 mg/kg once weekly cohort): 18 up to 66 subjects.
Primary and secondary expansion phase: 1040 subjects; 4 cohorts with 150 subjects each, 1 cohort 
with 120 subjects, 4 cohorts with 50 subjects, and 2 cohorts with 20 subjects each, and 1 cohort 
with 80 subjects (20 with expansion of an additional 60 subjects).
Efficacy expansion cohorts: 600 subjects; 2 cohorts with 150 subjects each and 1 cohort with 
200 subjects and 1 cohort with 100 subjects.
The final sample size, however, may vary depending on the total number of dose levels to be 
escalated and tested, the subject replacement for DLT evaluations if applicable, and the number of 
expanded cohorts. At each dose level, 3 or 6 subjects will be treated depending on toxicities 
observed. A small number of additional subjects might be enrolled to replace the drop-out subjects.
In the event that rapid recruitment in the expansion phase impacts supply of IMP, the screening of 
new subjects for any cohort may be temporarily paused with 24 hours’ notice to investigators.
5.1.6
Planned Treatment Duration
The trial duration for a subject is estimated to be up to 30 weeks. This includes an 18-day screening 
period (decision will be made in this period for subjects’ trial inclusion if all eligibility criteria are 
met), a treatment duration until confirmed progression, unacceptable toxicity, or any criterion for 
withdrawal from the trial or IMP occurs (see Section 5.5) and an end-of-treatment visit 4 weeks 
after the last dose of avelumab administration. 
For subjects who achieve a CR on avelumab therapy and then subsequently develop disease 
progression after stopping therapy, but prior to the end of the trial, one re-initiation of treatment at 
the same dose and schedule is allowed at the discretion of the investigator and agreement of the 
trial Medical Monitor. In order to be eligible for retreatment, the subject must not have experienced 
any toxicity that led to treatment discontinuation of the initial avelumab therapy. Prior to 
re-initiation of the study treatment, malignant disease needs to be radiologically re-staged to assess 
all known sites of the disease and to establish a new baseline for subsequent tumor measurements. 
Relevant safety laboratory results must be available and verified prior to re-initiating of treatment.
Subjects who re-initiate treatment will stay on study and will be treated and monitored according 
to the protocol and the “until progression” schedule in the Schedule of Assessments (see Appendix 
I).
Moreover, any ADRs should be followed until they resolve, return to baseline, or are irreversible 
(see Section 7.1.4 for details). 
Planned first subject in: Q1, 2013.
Planned date last subject out (dose escalation): Q2, 2018.
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Planned date last subject out (after expansion and follow-up): Q2, 2019.
In the case of study termination (see Section 5.6), subjects continuing to benefit from study 
treatment may still have access to study treatment via enrollment in a rollover study if not available 
through some other mechanism (eg, expanded access, marketed product).
5.1.7
Dose 
Modification 
and 
ADRs 
Requiring 
Treatment 
Discontinuation
5.1.7.1
Dose Modification
In general, each subject will stay on the avelumab dose level assigned in the trial unless treatment 
needs to be stopped.
The dose of avelumab will be calculated based on the weight of the subject determined on the day 
prior to or the day of each drug administration.
5.1.7.2
ADRs Requiring Treatment Discontinuation or Modifications
The following ADRs require permanent treatment discontinuation of avelumab:
Any Grade 4 ADRs require treatment discontinuation except for single laboratory values out 
of normal range that are unlikely related to trial treatment as assessed by the investigator, do not 
have any clinical correlate, and resolve within 7 days with adequate medical management.
Any Grade 3 ADRs require treatment discontinuation except for any of the following:
!
Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management.
!
Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to ≤ Grade 1. 
!
Single laboratory values out of normal range (excluding ≥ Grade 3 liver function test increase) 
that are unlikely related to trial treatment according to the investigator, do not have any clinical 
correlate, and resolve to ≤ Grade 1 within 7 days with adequate medical management.
!
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor.
!
Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay. The Study 
Medical Monitor should be consulted for such Grade ≥ 3 amylase or lipase abnormalities.
!
Increases in ECOG performance status ≥ 3, which do not resolve to # 2 by cycle Day 14 of 
the following cycle (infusions should not be given on the following cycle, if the ECOG 
performance status is ≥ 3 on the day of study drug administration).
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Any Grade 2 ADR should be managed as follows:
! Infusion should not be given in case of ongoing Grade 2 ADR on the day of trial treatment 
administration.
! Treatment can be resumed according to original schedule once ADR resolved to Grade ≤1. Up 
to 2 subsequent study drug doses may be omitted. If more than two doses are skipped, treatment 
may be resumed after consultation with study Medical Monitor.
!
Infusion-related reactions, hypersensitivity reactions (Grades 1 to 4), tumor lysis syndrome, 
and irAEs should be handled according to the guidelines provided in Sections 6.5.4.1, 6.5.4.2
6.5.4.3, 6.5.4.4, respectively.
5.1.8
Analysis Cut-Off Dates
After the end of the dose escalation part of the trial, a full analysis for safety and PK / PD data will 
be made and a full clinical trial report will be prepared. The cut-off date will be the time point 
when all subjects complete at least their first three 2-week treatment cycle, i.e., 6 weeks after the 
last subject of the escalation part has received its first administration of avelumab.
The primary data cut-off for the once weekly 10 mg/kg cohort is 4 weeks after the last evaluable 
subject in this cohort started treatment.
The primary data cut-off for the expansion cohorts is 6 months after the last subject started 
treatment. 
An interim analysis of response will be conducted for each of the primary expansion cohorts after 
the first 75 subjects have reached the time point of their second post-baseline tumor assessment 
scheduled in Week 13, i.e., 13 weeks after start of treatment of the 75th subject. In addition, for the 
ovarian cancer secondary expansion cohort, an interim analysis of response will be performed for 
internal planning purposes 13 weeks after the start of treatment of the 75th subject.
In the first-line NSCLC primary expansion cohort, an interim analysis of response will be 
conducted 13 weeks after start of treatment of the 30th subject.
In the efficacy expansion cohorts, interim analyses for efficacy are planned 13 weeks after the start 
of treatment of the 30th subject in all cohorts, 13 weeks after start of treatment of the  60th subject 
in the ovarian cohort, and 13 weeks after start of treatment of the 90th subject in the gastric / GEJ
and HNSCC cohorts. No futility rule is foreseen because the clinical activity of anti-PD-1 / 
anti-PD-L1 agents in these tumor types is established, and the patient populations are characterized 
by a high unmet medical need. If efficacy criteria are met at the interim analysis, enrollment will 
continue to the planned full number of subjects in order to collect further data on the primary and 
secondary endpoints, especially on the association between PD-L1 expression and efficacy 
endpoints. 
An interim analysis will be conducted at 6 months after the last subject’s first dose of study 
treatment for the 109 subjects enrolled in the urothelial carcinoma efficacy expansion cohort prior 
to Protocol Amendment 13.
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In addition, in the NSCLC post platinum doublet cohort only, 2 additional interim analyses of 
efficacy will be conducted, 13 weeks after the start of treatment of the 60th and the last subject, 
respectively.
For each primary or secondary expansion cohort, an additional interim analysis may be conducted
13 weeks after the start of treatment of the last subject in that cohort.
Interim analyses for 6 of the 8 secondary cohorts are planned as described in Section 8.6.
Final data cut-off will be 1 year after the last dose of avelumab has been administered.
5.2
Discussion of Trial Design
This is a Phase I, open-label, dose-escalation trial with a planned consecutive expansion part in 
selected tumor indications. An open-label, unblinded design is appropriate for a dose-escalation 
trial with consecutive expansion cohorts in cancer subjects.
In this trial, the assessment of the safety and tolerability of the IMP with the determination of the 
MTD (in the dose escalation part only) is set to be the primary objective. The determination of the 
MTD is one of the first major steps in the development of a compound entering early clinical 
development because it is expected to use a dose close to the highest tolerable dose in future 
clinical development in order to achieve the best efficacy to risk ratio for subjects. The MTD will 
be determined using a standard “3 + 3 subjects” dose escalation design based on DLT assessments, 
which is commonly used in first-in-man oncology trials (67). The aim of this design is to maximize 
the protection to subjects and reduce the chances of more subjects to be exposed to possible drug 
toxicities. However, at the end of the dose-escalation part, it is intended to fill cohorts as described 
in Section 5.1.1 to identify a reasonable dose and schedule for the expansion part. All these 
assessments will be correlated to PK / PD parameters to identify the most meaningful dose for 
expansion cohorts in selected tumor indications. 
The enrichment of dose-escalation cohorts below the MTD is reasonable for immunotherapeutic 
anticancer compounds (which is in contrast to most chemotherapies, that are typically given at the 
MTD), as the optimal biological effects are often not exclusively observed at the MTD level but 
already significantly below (6,68).
A reasonably safe starting dose of 1.0 mg/kg has been identified both via a NOAEL based or a 
PAD driven approach taking also into account the available information on clinical experience 
with BMS-936559, an anti-PD-L1 monoclonal antibody, which can be considered as clinical 
surrogate and gives an estimate of the irAEs to be expected at various dose levels (5). Initial dose 
setting follows the principle that the start dose should be pharmacologically active but also 
reasonably safe to use. This initial dose estimation algorithm is proposed in Guideline ICH S9 (8)
and applicable for an end-stage cancer population.
In addition to determining the MTD, the study will serve to explore biologic and clinical 
parameters after exposure to avelumab. Due to a limited understanding of the interaction of the 
immune system and tumors in cancer subjects, there can be no certainty that the doses to be 
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examined will be associated with relevant anti-tumor activity. The selection of the dose to be used 
for further clinical evaluation will be based on the best current scientific knowledge.
The target population for the dose-escalation part comprises subjects with metastatic or locally 
advanced solid tumors. Based on the literature, tumor indications with an over-expression of 
PD-L1 are selected. These include NSCLC, gastric / GEJ cancer, MBC, CRC, CRPC, melanoma, 
ovarian cancer, HNSCC, and RCC. In order to obtain a trend of biological / clinical activity in 
these and in other relevant indications (ACC, mesothelioma, and urothelial carcinoma) and to 
collect further safety data, a treatment expansion at a meaningful dose level and regimen to be 
identified during the dose-escalation part to ensure further development in selected settings is 
justified. Furthermore, data from the expansion cohorts will allow to explore whether the 
expression of membrane PD-L1 is associated with clinical response to PD-L1 blockade and 
whether PD-L1 expression might serve as a marker for patient selection in the future development 
program of avelumab.
The tests and analyses to examine the biologic effects of the avelumab regimen will be the 
assessment of general markers of immune activation known to show typical changes after 
treatment with therapies blocking immune checkpoints. These details are specified in Section 7.6.
5.2.1
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
Inclusion criteria for dose escalation, including the 10 mg/kg once weekly cohort:
1.
Signed written informed consent.
2.
Male or female subjects aged ≥ 18 years.
3.
Histologically or cytologically proven metastatic or locally advanced solid tumors, for which 
no standard therapy exists or standard therapy has failed. Availability of tumor archival 
material or fresh biopsies is optional for subjects in dose escalation.
4.
ECOG performance status of 0 to 1 at trial entry and an estimated life expectancy of at least 
3 months. 
5.
Disease must be measurable with at least 1 unidimensional measurable lesion by 
RECIST 1.1, except for subjects with metastatic CRPC or MBC who may be enrolled with 
objective evidence of disease without a measureable lesion.
6.
Adequate hematological function defined by white blood cell (WBC) count ≥ 3 × 109/L with 
absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet 
count ≥100 × 109/L, and hemoglobin ≥9 g/dL (may have been transfused). For subjects with 
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gastric cancer only, the acceptable parameters for WBC, ANC, and lymphocytes are as 
follows: WBC ≥ 2 × 109/L, ANC ≥ 1.0 × 109/L, and lymphocyte count ≥ 0.5 × 109/L.
7.
Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal 
range (ULN), an AST level ≤ 2.5 × ULN, and an ALT level ≤2.5 × ULN or, for subjects 
with documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN.
8.
Adequate renal function defined by an estimated creatinine clearance > 50 mL/min according 
to the Cockcroft-Gault formula.
9.
Highly effective contraception (that is, methods with a failure rate of less than 1% per year) 
for both male and female subjects if the risk of conception exists (Note:  The effects of the 
study treatment on the developing human fetus are unknown; thus, women of childbearing 
potential and men must agree to use highly effective contraception, defined in Appendix III
or as stipulated in national or local guidelines.  Highly effective contraception must be used 
28 days prior to first study treatment administration, for the duration of study treatment, and 
at least for 60 days after stopping study treatment.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, the treating 
physician should be informed immediately.)
Inclusion criteria for expansion phase:
1.
Signed written informed consent.
2.
Male or female subjects aged ≥ 18 years.
3.
Subjects must have relapsed, refractory, or progressive disease following last line of 
treatment (with the exception of the NSCLC first-line and gastric and GEJ cancer primary 
cohorts, which do not require progression). Availability of tumor archival material or fresh 
biopsies (excluding bone biopsies) is mandatory for eligibility in the expansion cohorts. For 
subjects in the MBC cohort, the biopsy or surgical specimen must have been collected within 
90 days prior to the first IMP administration. Specifically, the following will be required:
Primary expansion cohorts
! NSCLC post platinum doublet: Histologically or cytologically confirmed stage IIIB 
or stage IV NSCLC that has progressed after 1 line of platinum-containing doublet 
chemotherapy. Subjects should have received only 1 line of platinum-containing 
treatment for metastatic disease (i.e., adjuvant treatment with a platinum-containing 
regimen is not sufficient for eligibility because not received in the context of a metastatic 
disease). Subjects in the NSCLC cohort will only be enrolled in the USA. 
! NSCLC first line: Stage IV (per 7th International Association for the Study of Lung 
Cancer [IASLC] classification) or recurrent NSCLC that is histologically proven.
Subjects must not have received treatment for their metastatic or recurrent disease. No 
activating EGFR mutation nor ALK translocation / re-arrangement (non-squamous cell 
histologies require testing if status is unknown).
! Gastric and GEJ cancer, first-line maintenance or second-line: Histologically 
confirmed, unresectable locally advanced or metastatic adenocarcinoma of the gastric 
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and GEJ, treated with first-line chemotherapy combination in metastatic setting with or 
without disease progression. Subjects should have received no more than 1 line of 
treatment for metastatic disease. Subjects should not have been treated with trastuzumab 
(but can be Human Epidermal growth factor Receptor 2 [HER2] positive). Subjects who 
received any platinum containing doublet or triplet as a neoadjuvant chemotherapy 
strategy, but are not ultimately candidates for surgery will also be eligible. In addition, 
subjects with gastric cancer can enter in the study if their WBC is ≥2 × 109/L with ANC 
≥1.0 × 109/L and lymphocyte count ≥0.5 × 109/L.
! MBC: Subjects must have histologically confirmed locally advanced or MBC and have 
tumor that is refractory to or progressive after standard of care therapy. Subjects must 
have received no more than 3 prior lines of cytotoxic therapy for metastatic disease. 
Subjects must have received a taxane and an anthracycline, unless contra-indicated. 
Secondary expansion cohorts
! CRC: Histologically or cytologically confirmed recurrent or refractory metastatic CRC 
(according to AJCC/UICC TNM Staging System seventh edition) after failure of prior 
therapy containing oxaliplatin/fluoropyrimidine and/or irinotecan/fluoropyrimidine 
and, if eligible, cetuximab (Erbitux®) and bevacizumab (Avastin®). These subjects will 
be enrolled in sites located in the USA only.
! CRPC: Histologically or cytologically confirmed asymptomatic metastatic CRPC or 
minimally symptomatic (according to AJCC/UICC TNM Staging System seventh 
edition) with objective evidence of disease (non measureable or measurable lesion) with 
stable, ongoing adequate testosterone suppression proven by castrate levels of 
testosterone (≤50 ng/dL), except for subjects with prior orchiectomy. Minimally 
symptomatic is defined as patients who do not require consistent treatment with opiates 
over the last month (less than 7 days of opiates in the last 28 days, and no opiates 
administered 3 days in a row), for the treatment of their prostate cancer. Additional 
androgen blockade or treatment with an anti-androgen receptor is acceptable. These 
subjects will be enrolled in sites located in the USA only.
! Melanoma: Histologically or cytologically confirmed stage IIIc or IV unresectable 
melanoma (according to AJCC/UICC TNM Staging System seventh edition) after 
failure of at least 1 prior standard therapy for metastatic disease. All subjects with 
metastatic melanoma will be required to undergo screening with a MRI or CT scan 
(either, with contrast preferred) to rule out brain metastases, unless imaging has 
previously been performed within 28 days prior to screening.
! Ovarian cancer: Histologically or cytologically confirmed recurrent or refractory 
(progression within 6 months of platinum-based therapy or progression after subsequent 
therapy in previously relapsed subjects), stage III-IV epithelial ovarian, fallopian tube 
or peritoneal cancer subjects (according to AJCC/UICC TNM and International 
Federation of Gynecology and Obstetrics (FIGO) Staging System seventh edition) who 
have progressed following adjuvant therapy or therapy for metastatic disease. 
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! ACC: Histologically or cytologically confirmed metastatic ACC. Subjects must have 
previously received at least 1 line of systemic therapy for metastatic disease, of which 
at least 1 must be platinum-based. Subjects receiving mitotane may continue to receive 
mitotane at enrolment and on study.
! Mesothelioma: Histologically or cytologically confirmed mesothelioma (pleural or 
peritoneal) with unresectable disease. Subjects must have received and progressed after 
either a platinum-pemetrexed containing regimen or a platinum-containing regimen 
followed by pemetrexed (or vice versa) after disease progression. Subjects must present 
with at least 1 measurable lesion that has not been irradiated.
! Urothelial carcinoma: Histologically or cytologically documented locally advanced or 
metastatic transitional cell carcinoma of the urothelium (including renal pelvis, ureters, 
urinary bladder, urethra). A tumor sample (1 tumor block or at least 7 unstained slides) 
must be available.  Subjects can be either: ineligible for cisplatin-based chemotherapy 
or have progressed after treatment with at least 1 platinum-containing regimen (e.g., 
platinum plus another agent such as gemcitabine,
methotrexate, vinblastine, 
doxorubicin, etc.) for inoperable locally advanced or metastatic urothelial carcinoma or 
disease recurrence. Ineligibility to treatment with a platinum salt is defined by the 
existing of any (at least 1) of impaired renal function, a hearing loss of 25 decibels at 
2 contiguous frequencies, or Grade ≥2 peripheral neuropathy. Subjects may have 
received any number of prior systemic therapies for metastatic disease.
! Renal cell carcinoma, second-line with first-line expansion: Histologically or 
cytologically documented RCC with a component of clear cell subtype, with metastasis. 
A tumor sample (1 tumor block or at least 7 unstained slides) must be available. Eligible 
subjects must have measureable disease. Subjects must have failed 1 prior systemic 
first-line regimen for metastatic RCC (except for subjects enrolled in first-line 
expansion).
Efficacy expansion cohorts:
! Gastric and GEJ cancer, third line: Histologically confirmed, unresectable locally 
advanced or metastatic adenocarcinoma of the gastric and GEJ, treated with both a 
first-line chemotherapy combination and followed by ramucirumab (alone or in 
combination). Subjects must have progressed during or after ramucirumab therapy. 
Subjects with gastric cancer can enter into the study if their WBC is ≥2 × 109/L with 
ANC ≥1.0 × 109/L and lymphocyte count ≥0.5 × 109/L.
! Ovarian cancer, platinum refractory and prior liposomal doxorubicin:
Histologically or cytologically confirmed, platinum-refractory (progression within 
6 months of platinum-based therapy), Stage III-IV epithelial ovarian, fallopian tube, or 
peritoneal cancer subjects (according to AJCC/UICC TNM and FIGO Staging System, 
7th edition). Subjects must have received at least 1 line of prior platinum-based 
chemotherapy regimen, as well as prior liposomal doxorubicin (monotherapy or 
combination), in order to be considered eligible for this study. Subjects may have 
received any additional number of prior systemic therapies for metastatic disease.
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! Urothelial carcinoma, platinum ineligible or progressed after at least 1 line of 
platinum-based therapy: Histologically or cytologically documented locally advanced 
or metastatic transitional cell carcinoma of the urothelium (including renal pelvis, 
ureters, urinary bladder, urethra). A tumor sample (1 tumor block or at least 7 unstained 
slides) must be available. Subjects can be either: ineligible for cisplatin based 
chemotherapy or have progressed after treatment with at least 1 platinum-containing 
regimen (e.g., platinum plus another agent such as gemcitabine, methotrexate, 
vinblastine, doxorubicin, etc.) for inoperable locally advanced or metastatic urothelial 
carcinoma or disease recurrence. Ineligibility to treatment with a platinum salt is defined 
by the existing of any (at least 1) of impaired renal function, a hearing loss of 25 decibels 
at 2 contiguous frequencies, or Grade ≥2 peripheral neuropathy. Subjects may have 
received any number of prior systemic therapies for metastatic disease. 
! Head and neck, platinum ineligible or progressed after at least 1 line of platinum-
based therapy: Histologically or cytologically documented recurrent or metastatic 
HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx. Subjects must have 
experienced tumor progression or recurrence within 6 months of the last dose of any 
number of platinum-based chemotherapy regimens given in the adjuvant, primary, 
recurrent, or metastatic setting. Ineligibility to treatment with a platinum salt is defined 
by the existing of any (at least 1) of impaired renal function, a hearing loss of 25 decibels 
at 2 contiguous frequencies, or Grade ≥2 peripheral neuropathy. A tumor sample 
(1 tumor block or at least 7 unstained slides) must be available. Subjects may have 
received any number of prior systemic therapies for metastatic disease. Except for 
subjects who are platinum ineligible, subjects must have received at least 1 line of 
platinum-based chemotherapy.
4.
ECOG performance status of 0 to 1 at trial entry and an estimated life expectancy of at least 
3 months. 
5.
Disease must be measurable with at least 1 unidimensional measurable lesion by 
RECIST 1.1, except for subjects with metastatic CRPC who may be enrolled with objective 
evidence of disease without a measureable lesion. 
6.
Adequate hematological function defined by WBC ≥ 3 × 109/L with ANC ≥ 1.5 × 109/L, 
lymphocyte count ≥ 0.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥9 g/dL (may 
have been transfused). For subjects with gastric cancer only, the acceptable parameters for 
WBC, ANC, and lymphocytes are as follows: WBC ≥ 2 × 109/L, ANC ≥1.0 × 109/L, and 
lymphocyte count ≥ 0.5 × 109/L.
7.
Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × ULN and an AST level 
≤2.5 × ULN and an ALT level ≤2.5 × ULN for all subjects.
8.
Adequate renal function defined by an estimated creatinine clearance > 30 mL/min according 
to the Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local 
institutional standard method).
9.
Highly effective contraception (that is, methods with a failure rate of less than 1% per year) 
for both male and female subjects if the risk of conception exists (Note:  The effects of the 
study treatment on the developing human fetus are unknown; thus, women of childbearing 
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potential and men must agree to use highly effective contraception, defined in Appendix III
or as stipulated in national or local guidelines.  Highly effective contraception must be used 
28 days prior to first study treatment administration, for the duration of study treatment, and 
at least for 60 days after stopping study treatment.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, the treating 
physician should be informed immediately.)
5.3.2
Exclusion Criteria (applicable to all subjects, including all 
expansion cohorts)
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1.
Concurrent treatment with a non-permitted drug (see Section 6.5.2).
2.
Prior therapy with any antibody/drug targeting T cell co-regulatory proteins (immune 
checkpoints) such as anti-programmed death 1 (PD-1), anti-PD-L1, or CTLA-4 antibody. 
For subjects with metastatic melanoma, prior treatment with a CTLA-4 antibody is not an 
exclusion.
3.
Concurrent anticancer treatment within 28 days before the start of trial treatment 
(e.g., cytoreductive therapy, radiotherapy [with the exception of palliative bone directed 
radiotherapy], immune therapy, or cytokine therapy except for erythropoietin); major surgery 
within 28 days before the start of trial treatment (excluding prior diagnostic biopsy); use of 
hormonal agents within 7 days before the start of trial treatment, except for subjects in the 
CRPC cohort who may remain on treatment with luteinizing hormone-releasing hormone 
agonists or antagonists; or use of any investigational drug within 28 days before the start of 
trial treatment. Subjects in the gastric and GEJ cohort who have not progressed on first-line 
chemotherapy may be enrolled within the 28-day period following prior treatment provided 
all toxicity from prior therapy has resolved to Grade ≤1.
Subjects receiving immunosuppressive agents (such as steroids) for any reason should be 
tapered off these drugs before initiation of the study treatment (with the exception of patients 
with adrenal insufficiency, who may continue corticosteroids at physiologic replacement 
dose, equivalent to ≤ 10 mg prednisone daily). Steroids with no or minimal systemic effect 
(topical, inhalation) are allowed.
4.
Previous malignant disease other than the target malignancy to be investigated in this trial 
within the last 5 years with the exception of basal or squamous cell carcinoma of the skin or 
cervical carcinoma in situ.
5.
Rapidly progressive disease (e.g., tumor lysis syndrome).
6.
Active or history of CNS metastases.
7.
Receipt of any organ transplantation including allogeneic stem-cell transplantation. 
8.
Significant acute or chronic infections including, among others:
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!
Known history of testing positive test for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome (AIDS)
!
Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV 
antibody tested positive).
9.
Active or history of any autoimmune disease (subjects with diabetes Type I, vitiligo, 
psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible) or immunodeficiencies.
10.
Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE 
v4.0), any history of anaphylaxis, or uncontrolled asthma (i.e., 3 or more features of partly 
controlled asthma) (71).
11.
Persisting toxicity related to prior therapy > Grade 1 NCI-CTCAE v4.0, however sensory 
neuropathy ≤ Grade 2 is acceptable.
12.
Pregnancy or lactation period. Note: a negative pregnancy test is required for women of 
childbearing potential. Women who are postmenopausal (age-related amenorrhea 
≥12 consecutive months or follicle-stimulating hormone (FSH) > 40 milli international units 
per milliliter [mIU/mL]), or who had undergone hysterectomy or bilateral oophorectomy are 
exempt from pregnancy testing. If necessary to confirm postmenopausal status a FSH level 
will be included at screening. 
13.
Known alcohol or drug abuse.
14.
Clinically significant (i.e., 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 uncontrolled cardiac arrhythmia requiring medication. 
15.
All other significant diseases (e.g., inflammatory bowel disease), which, in the opinion of the 
investigator, might impair the subject’s tolerance of trial treatment.
16.
Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent.
17.
Legal incapacity or limited legal capacity.
18.
Vaccination within 4 weeks of the first dose of avelumab and while on study is prohibited 
except for administration of inactivated vaccines (e.g. inactivated influenza vaccines).
5.4
Criteria for Initiation of Treatment with the Investigational 
Medicinal Product
The inclusion and exclusion criteria will be checked at the screening visit. Eligible subjects will 
be enrolled before treatment start after verification of fulfilling all inclusion criteria without 
matching any exclusion criterion. 
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5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal From the Trial
Subjects are free to discontinue the trial at any time without giving their reasons.
A subject must be withdrawn in the event of any of the following:
!
Withdrawal of the subject’s consent.
!
Participation in any other therapeutic trial during the treatment duration of this trial. 
If a subject has failed to attend scheduled trial assessments, the investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
In case of premature withdrawal from the trial, the investigations scheduled for the last visit should 
be performed (see Section 7.1.3 for end-of-treatment visit), if possible, with focus on the most 
relevant assessments. In any case, the appropriate case report form (CRF) section must be 
completed.
In the dose escalation part of the trial, only subjects who do not complete the DLT observation 
period (3 weeks) for reasons other than a DLT will be replaced. Subjects who require 
discontinuation of avelumab due to a DLT will not be replaced. In the expansion part of the trial, 
if a subject is withdrawn prior to progression for any reason, they will not be replaced except for 
the rule described above.
5.5.2
Withdrawal From the Investigational Medicinal Product
The subject must be withdrawn in the event of any of the following:
! Occurrence of an exclusion criterion, which is clinically relevant and affects the subject’s 
safety, if discontinuation is considered necessary by the investigator and/or Sponsor.
! Therapeutic failure requiring urgent additional drug (if applicable).
! Occurrence of any Grade ≥ 3 ADRs as defined in Section 5.1.7.
! Occurrence of AEs, resulting in the discontinuation of trial drug being desired or considered 
necessary by the investigator and/or the subject (if applicable).
! Occurrence of pregnancy (if applicable).
! Use of a non-permitted concomitant drug, as defined in Section 6.5.2, where the predefined 
consequence is withdrawal from the IMP (the Sponsor may be contacted to discuss whether the 
trial treatment must be discontinued).
! Non-compliance (see Section 6.9).
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5.6
Premature Discontinuation of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
! New information leading to unfavorable risk-benefit judgment of the IMP, e.g., due to:
! Evidence of inefficacy of the IMP.
! Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions.
! Other unfavorable safety findings (Note: evidence of inefficacy may arise from this trial or 
from other trials; unfavorable safety findings may arise from clinical or non-clinical 
examinations, e.g., toxicology).
! Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons.
! Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely.
! Discontinuation of development of the Sponsor’s IMP.
! Withdrawal of IMP(s) from the market for safety reasons (applicable to trials with marketed 
products only).
Health authorities and independent ethics committees (IECs) / institutional review boards (IRBs)
will be informed about the discontinuation of the trial in accordance with applicable regulations.
The whole trial may be terminated or suspended upon request of health authorities.
The Sponsor may terminate the study at any time once access to study treatment for subjects still 
benefitting is provisioned via a rollover study, expanded access, marketed product, or another 
mechanism of access as appropriate.
5.7
Definition of End of Trial
The end of the trial will be defined as 1 year after the last subject completes his /her 
end-of-treatment visit.
If the trial is not terminated for a reason given in Section 5.6, the end of the trial is defined as 
1 year after the last subject has received the last dose of avelumab.
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term IMP refers to the investigational drug undergoing a clinical trial, as well as to any 
comparator drug or placebo (as applicable). In this trial, the IMP is avelumab and no comparator 
drug or placebo is involved.
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6.1
Description of Investigational Medicinal Product(s)
Avelumab is a sterile, clear, and colorless solution intended for intravenous administration. It is 
presented at a concentration of 10 or 20 mg/mL in single-use glass vials closed with a rubber 
stopper and sealed with an aluminum / yellow polypropylene flip off seal.
Each single-use 10 mg/mL vial contains 80 mg of avelumab as preservative-free acetate buffered 
solution (pH 5.5) containing mannitol, methionine, and polysorbate 20 (Tween 20), as stabilizers. 
Each single-use 20 mg/mL vial contains 200 mg of avelumab as preservative-free acetate buffered 
solution (pH 5.2) containing mannitol and polysorbate 20 (Tween 20), as stabilizers.
For avelumab drug product, only excipients that conform to the current European Pharmacopeia
and / or the current United States Pharmacopeia are used (see the latest Investigator’s Brochure
for additional details).
6.2
Dosage and Administration
Subjects will receive intravenous infusion of avelumab over 1 hour (-10 minutes / +20 minutes, 
i.e., 50 to 80 minutes) once every 2 weeks (for subjects in the 10 mg/kg once weekly cohort, once 
weekly for 12 weeks, then starting with Week 13, once every 2 weeks thereafter) (refer to 
Appendix I). Premedication with an antihistamine and with paracetamol (acetaminophen) 
approximately 30 to 60 minutes prior to each dose of avelumab is mandatory (for example, 
25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] i.v. or oral equivalent). 
This regimen may be modified based on local treatment standards and guidelines, as appropriate. 
Modifications of the infusion rate due to infusion-related reactions are described in Section 6.5.4.
The starting dose of avelumab in the dose escalation phase is 1.0 mg/kg (dose-escalation according 
to 3 + 3 design up to 10.0 mg/kg is intended) and the treatment cycle will be 2 weeks (14 days). 
The dose of avelumab in the expansion phases is 10 mg/kg. 
The dose of avelumab will be calculated based on the weight of the subject determined within 
72 hours prior to administration. The dose of avelumab used for the previous administration can 
be repeated if the change in the subject’s weight is 10% or less than the weight used for the last 
dose calculation.  Subjects will receive avelumab until confirmed progression, unacceptable 
toxicity, or any criterion for withdrawal from the trial or IMP occurs (see Section 5.5). Subjects 
who have experienced a confirmed CR should be treated for a maximum of 24 months after 
confirmation, at the discretion of the investigator. If the investigator believes that a subject may 
benefit from treatment beyond 24 months, it may be permissible after discussion with the sponsor.
Subjects who experienced a CR and have already stopped treatment can resume treatment with 
avelumab at the same dose and schedule. Subjects re-initiating treatment should be assessed 
according to the Schedule of Assessments (Appendix I).
In the case of study termination (see Section 5.6), subjects continuing to benefit from study 
treatment may still have access to study treatment via enrollment in a rollover study if not available 
through some other mechanism (eg, expanded access, marketed product).
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Relevant clinical laboratory results essential for patient management decisions (hematology, 
biochemistry, liver function tests) must be available and reviewed before administration of 
avelumab.
6.3
Assignment to Treatment Cohorts
The investigator or delegate will assign a unique subject identifier number to eligible subjects in 
chronological order at the time of informed consent signature. Subject identifiers will comprise 
17 digits, the first 10 digits representing the trial number, the following 3 digits representing the 
site number, and the last 4 digits representing the subject number, which is allocated sequentially 
starting with 0001.
The Sponsor’s / CRO’s medical responsible must confirm enrollment and dose level after receipt 
of the appropriate information relating to subject entry criteria.
This trial is not randomized. Therefore, no central treatment allocation is planned.
6.4
Other Drugs to be Used in the Trial
Premedication with an antihistamine and with paracetamol (acetaminophen) approximately 30 to 
60 minutes prior to each dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine 
and 500-650 mg paracetamol [acetaminophen] i.v. or oral equivalent). This regimen may be 
modified based on local treatment standards and guidelines, as appropriate.
As with all monoclonal antibody therapies, there is a risk of allergic reaction 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 (i.v. antihistamines), bronchodilators, 
or equivalents and oxygen should be available for immediate access. Infusion of avelumab will be 
stopped in case of Grade ≥2 infusion-related, allergic, or anaphylactic reactions. Following 
avelumab infusions, subjects must be observed for 2 hours post infusion for potential infusion-
related reactions. Please refer to the guidelines for handling of infusion-related reaction in 
Section 6.5.4.1.
If an allergic reaction occurs, the subject must be treated according to the best available medical 
practice. Guidelines for management of infusion-related reactions and severe hypersensitivity 
reaction according to the National Cancer Institute are found in Section 6.5.4. A complete
guideline for the emergency treatment of anaphylactic reactions according to the Working Group 
of 
the 
Resuscitation 
Council 
(United 
Kingdom) 
and 
can 
be 
found 
at 
https://www.resus.org.uk/pages/reaction.pdf. Subjects should be instructed to report any delayed 
reactions to the investigator immediately.
Further precautions are provided in Section 6.5.4. For prophylaxis of flu-like symptoms, 25 mg of 
indomethacin or comparable non-steroidal anti-inflammatory drug (NSAID) dose (e.g., ibuprofen 
600 mg, naproxen sodium 500 mg) may be administered 2 hours before and 8 hours after the start 
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of each dose of avelumab intravenous infusion. Alternative treatments for fever (e.g., paracetamol) 
may be given to subjects at the discretion of the investigator.
6.5
Concomitant Medications and Therapies
6.5.1
Permitted Medicines and Therapies
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary for the subjects’ welfare and will not interfere with the trial medication may be given at 
the investigator’s discretion.
Other drugs to be used for prophylaxis, treatment of anaphylactic reactions, infusion-related 
reactions, severe hypersensitivity reactions / flu-like symptoms and tumor lysis syndrome are 
described in Sections 5.1.7.2, 6.4 and 6.5.4.
The investigator will record all concomitant medications taken by the subject during the trial, from 
the date of signature of informed consent, in the appropriate section of the CRF.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the CRF, noting the name, 
dose, duration and indication of each drug.
Palliative bone directed radiotherapy may be administered during the trial. The assessment of PD 
will be made according to RECIST 1.1 (48) and not based on the necessity for palliative bone 
directed radiotherapy. 
6.5.2
Non-Permitted Medicines and Therapies
As stated for the exclusion criteria in Section 5.3.2, subjects must not have had chemotherapy, 
radiotherapy (other than palliative bone directed radiotherapy as described in Section 6.5.1), major 
surgery, or received another investigational agent within 28 days before the start of study 
treatment.
The following treatments must not be administered during the study:
! Immunotherapy, immunosuppressive drugs (i.e., chemotherapy or systemic corticosteroids 
except for short term treatment of allergic reactions or for the treatment of irAEs), or other 
experimental pharmaceutical products. Short term administration of systemic steroid (i.e., for 
allergic reactions or the management of irAEs) is allowed. Steroids with no or minimal systemic 
effect (topical, inhalation) are allowed.
! Any vaccine therapies for the prevention of infectious disease, except administration of
inactivated vaccines (for example, inactivated influenza vaccine).
! Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony 
stimulating factor). Exception: Erythropoietin and darbepoietin alpha may be prescribed at the 
investigator’s discretion.
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Clarification of Steroid Use:
Data indicate that corticosteroids have an adverse effect on T cell function (68) and that they inhibit 
and damage lymphocytes (69). Furthermore, as with all immunotherapies intended to augment 
cell-mediated immunity, there is a risk that concomitant immunosuppressives such as steroids will 
counteract the intended benefit. However, studies with anti-CTLA4 compounds indicate that short 
term use of steroids can be employed without compromising clinical outcomes (62). Therefore, 
the use of steroids during this trial is restricted as follows:
! Therapeutic use: limited to the treatment of infusion-related reactions and short term treatment 
of ir-AEs. The course of steroid treatment should be completed as soon as clinically feasible.
! Physiologic use: replacement for adrenal insufficiency at doses equivalent to ≤10 mg 
prednisone daily are acceptable.
! Prophylactic use: prophylactic use, e.g., for the prevention of acute infusion-related reactions,
constitutes concomitant use and is prohibited.
If the administration of a non-permitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment (the Sponsor may be contacted to discuss whether 
the trial treatment must be discontinued).
Medications others than those specifically excluded in this study (see above) may be administered 
for the management of symptoms associated with the administration of avelumab as required. 
These might include analgesics, anti-nausea medications, antihistamines, diuretics, anti-anxiety 
medications, and medication for pain management, including narcotic agents.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the CRF, noting the name, 
dose, duration and indication of each drug.
6.5.3
Other Trial Considerations
The following non-drug therapies must not be administered during the study (and within 28 days 
before the start of trial treatment):
! Major surgery (excluding prior diagnostic biopsy).
! Herbal remedies with immunostimulating properties (e.g., mistle toe extract) or known to 
potentially interfere with major organ function (e.g., hypericin)
! Subjects should not abuse alcohol or other drugs during the study.
6.5.4
Special Precautions
As a routine precaution, subjects enrolled in this trial must be observed for 2 hours post infusion, 
in an area with resuscitation equipment and emergency agents. At all times during avelumab
treatment, immediate emergency treatment of an infusion-related reaction or a severe 
hypersensitivity reaction according to institutional standards must be assured. In order to treat 
possible anaphylactic reactions, for instance, dexamethasone 10 mg and epinephrine in a 
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1:1000 dilution or equivalents should always be available along with equipment for assisted 
ventilation. 
Infusion of avelumab will be stopped in case of ≥ Grade 2 hypersensitivity, inflammatory response, 
or anaphylactic reaction. The treatment recommendations for infusion-related reactions, severe 
hypersensitivity reactions, and tumor lysis syndrome according to the NCI are outlined in Sections
6.5.4.1, 6.5.4.2 and 6.5.4.3, respectively. All infusion-related reactions, occurring during study 
drug infusion or after completion of the study drug administration, should be reported as AESIs or 
SAEs in case any serious criterion is met (see Section 7.4.1.4).
Investigators should also monitor subjects closely for potential irAEs, which may become manifest 
at the earliest after weeks of treatment. Such events may consist of persistent rash, diarrhea and 
colitis, autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other 
inflammatory eye conditions. The spectrum of hypothetical irAEs also includes formation of 
auto-antibodies like ANAs or ANCAs.
6.5.4.1
Infusion-related Reactions
Premedication with an antihistamine and with paracetamol (acetaminophen) approximately 30 to 
60 minutes prior to each dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine 
and 500-650 mg paracetamol [acetaminophen] i.v. or oral equivalent). This regimen may be 
modified based on local treatment standards and guidelines, as appropriate. Avelumab will be 
administered by i.v. infusion over a 1-hour period (-10 minutes / +20 minutes, that is, 50 to 
80 minutes).
A. Symptoms:
!
Fever
!
Chills
!
Rigors
!
Diaphoresis
!
Headache
B. Management (see Table 6.1)
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Table 6.1
Treatment Modification for Symptoms of Infusion-related Reactions 
Caused by Avelumab
NCI-CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
The recommended total infusion time for avelumab
should not exceed 120 minutes.
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (e.g., antihistamines, 
NSAIDs, narcotics, i.v. fluids); prophylactic medications 
indicated for # 24 hours.
Stop avelumab infusion.
Resume infusion at 50% of previous rate once infusion-
related reaction has resolved or decreased to at least 
Grade 1 in severity, and monitor closely for any 
worsening.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
Stop the avelumab infusion immediately and disconnect 
infusion tubing from the subject.
Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any further 
avelumab treatment.
i.v.=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an infusion 
related reaction, it must remain decreased for all subsequent infusions. If a subject experiences a 
Grade 3 or 4 infusion-related reaction at any time, the subject must discontinue avelumab. If an 
infusion reaction occurs, all details about drug preparation and infusion must be recorded.
6.5.4.2
Severe Hypersensitivity Reactions and Flu-like Symptoms
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf. Subjects should be instructed to report any delayed 
reactions to the Investigator immediately.
A. Symptoms
!
Impaired airway
!
decreased oxygen saturation (< 92%)
!
confusion
!
lethargy
!
hypotension
!
pale/clammy skin
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!
cyanosis
B. Management
1. Epinephrine injection and dexamethasone infusion
2. Patient should be placed on monitor immediately 
3. Alert intensive care unit (ICU) for possible transfer if required
For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable NSAID dose 
(e.g., ibuprofen 600 mg, naproxen sodium 500 mg) may be administered 2 hours before and 
8 hours after the start of each dose of avelumab i.v. infusion. Alternative treatments for fever (e.g., 
paracetamol) may be given to subjects at the discretion of the investigator.
6.5.4.3
Tumor Lysis Syndrome
In addition, since avelumab can induce ADCC, there is a potential risk of tumor lysis syndrome. 
Should this occur, subjects should be treated as per local guidelines and the management algorithm 
(Figure 6.1) published by Howard et al (56).
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Figure 6.1
Assessment and Initial Management of Tumor Lysis Syndrome (TLS)
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia
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6.5.4.4
Immune-Related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of irAEs 
is mainly dependent upon severity (NCI-CTCAE grade):
! Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring
! Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4)
! Grade 3 to 4:  treat with high dose corticosteroids
Treatment of irAEs should follow guidelines set forth in Table 6.2.
Table 6.2
Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea / Colitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Diarrhea: < 4 stools/day over Baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment 
(e.g., loperamide)
Close monitoring for worsening symptoms
Educate subject to report worsening immediately
If worsens:
Treat as Grade 2 or 3/4 
Grade 2
Diarrhea: 4 to 6 stools per day over 
Baseline; i.v. fluids indicated < 24 
hours; not interfering with ADL
Colitis: abdominal pain; blood in stool 
Delay avelumab therapy
Symptomatic treatment
If improves to Grade 1: 
Resume avelumab therapy
If persists > 5 to 7 days or recur:
0.5 to 1.0 mg/kg/day methylprednisolone or 
equivalent 
When symptoms improve to Grade 1, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy per 
protocol.
If worsens or persists > 3 to 5 days with oral 
steroids:
Treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per day 
over Baseline; incontinence; i.v. fluids 
≥24 hrs; interfering with ADL
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Discontinue avelumab therapy 
per protocol
1.0 to 2.0 mg/kg/day 
methylprednisolone i.v. or  
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade 1, then taper over at 
least 1 month
If persists > 3 to 5 days, or recurs after 
improvement:
Add infliximab 5 mg/kg (if no contraindication), 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
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Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Management
Follow-up
Grade 1 to 2 
Covering ≤ 30% body surface area 
Symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
Continue avelumab therapy
If persists > 1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay avelumab therapy
Consider 0.5 to 1.0 mg/kg/day methylprednisolone 
i.v. or oral equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4
Covering > 30% body surface area; life 
threatening consequences 
Delay or discontinue  avelumab  
therapy
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
methylprednisolone i.v. or i.v.
equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic 
infections 
Resume avelumab therapy
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Radiographic changes only 
Consider delay of avelumab
therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-image at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2
Mild to moderate new symptoms 
Delay avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily, 
consider hospitalization 
1.0 mg/kg/day methyl-
prednisolone i.v. or oral 
equivalent 
Consider bronchoscopy, lung 
biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to near baseline, taper 
steroids over at least 1 month and then resume 
avelumab  therapy and consider prophylactic 
antibiotics
If not improving after 2 weeks or worsening: 
Treat as Grade 3 to 4 
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Grade of Pneumonitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 3 to 4
Severe new symptoms; New / worsening 
hypoxia; life-threatening 
Discontinue avelumab therapy
Hospitalize 
Pulmonary and Infectious 
Disease consults
2 to 4 mg/kg/day 
methylprednisolone i.v. or i.v.
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to baseline: 
Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
Add additional immunosuppression (for example,
infliximab, cyclophosphamide, 
i.v. immunoglobulin, or mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and / or total bilirubin > ULN to
1.5 x ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as 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 
Delay avelumab therapy
Increase frequency of 
monitoring to every 3 days 
If returns to baseline: 
Resume routine monitoring, resume avelumab
therapy
If elevations persist > 5 to 7 days or worsen: 
0.5 to 1 mg/kg/day methylprednisolone or oral 
equivalent and when LFT returns to Grade 1 or 
Baseline, taper steroids over at least 1 month, 
consider prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy
Grade 3 to 4
AST or ALT > 5 x ULN and / or total 
bilirubin > 3 x ULN 
Discontinue avelumab therapy 
Increase frequency of 
monitoring to every 1 to 2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone i.v. or i.v.
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult gastroenterologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy if 
clinically warranted
If returns to Grade 2: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, worsens or 
rebounds: 
Add mycophenolate mofetil 1 gram (g) twice daily 
If no response within an additional 3 to 5 days, 
consider other immunosuppressants per local 
guidelines 
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Cardiac irAEs
Myocarditis
Management
Follow-up
New onset of cardiac signs or symptoms 
and / or new laboratory cardiac 
biomarker elevations (e.g. 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.a
Consider myocardial biopsy if 
recommended per cardiology 
consult.
If symptoms improve and immune-mediated 
etiology is ruled out, re-start avelumab therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-mediated 
etiology is suspected or confirmed following 
cardiology consult, manage as immune-mediated 
myocarditis.
Immune-mediated myocarditis 
Permanently discontinue 
avelumab.
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.a
Methylprednisolone 1 to 
2 mg/kg/day.
Once improving, taper steroids over at least 1 
month and add prophylactic antibiotics for 
opportunistic infections.
If no improvement or worsening, consider 
additional immunosuppressants (e.g. azathioprine, 
cyclosporine A)
a Local guidelines, or eg. European Society of Cardiology or American Heart Association guidelines
European Society of Cardiology guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
American Heart Association guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Management
Follow-up
Asymptomatic TSH abnormality
Continue avelumab therapy  
If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 
2 subsequent measurements: include T4 at subsequent cycles as clinically indicated; 
consider endocrinology consult 
Symptomatic endocrinopathy 
Evaluate endocrine function 
Consider pituitary scan 
Symptomatic with abnormal lab
/ pituitary scan: 
If improves (with or without hormone 
replacement): 
Taper steroids over at least 1 month and consider 
prophylactic antibiotics for opportunistic 
infections 
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Delay avelumab therapy
1 to 2 mg/kg/day 
methylprednisolone iv or by 
mouth equivalent 
Initiate appropriate hormone 
therapy 
Endocrinology consult to 
distinguish (differentiate) 
between primary from 
secondary dysfunction. No 
abnormal lab/pituitary MRI 
scan but symptoms persist: 
Repeat labs in 1 to 3 
weeks/MRI in 1 month
Resume avelumab therapy 
Subjects with adrenal insufficiency may need to 
continue steroids with mineralocorticoid 
component 
Suspicion of adrenal crisis (for example,
severe dehydration, hypotension, shock 
out of proportion to current illness)
Delay or discontinue avelumab therapy 
Rule out sepsis 
Stress dose of i.v. steroids with mineralocorticoid activity 
i.v. fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic endocrinopathy 
ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computerized tomography; 
irAE=immune-related adverse event, iv=intravenous, LFT=liver function test, LLN=lower limit of normal, MRI=magnetic 
resonance imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event, NSAID=non-
steroidal anti-inflammatory drugs, T4=free thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of normal.
6.6
Packaging and Labeling
Avelumab is formulated as a 10.0 mg/mL or 20 mg/mL solution in single-use glass vials, with a 
rubber stopper. The Clinical Trial Supplies department of the Sponsor will supply the trial 
medication of avelumab, which will be distributed to the sites by the CRO.
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable Good Manufacturing Practice (GMP) guidelines. Avelumab will be packed in boxes 
containing a suitable number of vials. The information on the medication will be in accordance 
with approved submission documents. 
Avelumab will be shipped in transport cool containers (2°C to 8°C) that are monitored with 
temperature control devices.
6.7
Preparation, Handling and Storage
For application in this trial, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection) supplied in an infusion bag. Detailed information on infusion bags and 
medical devices to be used for the preparation of the dilutions and subsequent administration will 
be provided in the MOP.
Document No. 
 
Object No. 
 
0900babe810325b3v1.0
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Avelumab drug product must be stored at 2°C to 8°C until use, with a temperature log maintained 
daily. All medication boxes supplied to each study center must be stored carefully, safely, and 
separately from other drugs.
Avelumab drug product stored at room temperature (23°C to 27°C) or at elevated temperatures 
(38°C to 42°C) for extended periods is subject to degradation. Avelumab must not be frozen. 
Rough shaking of avelumab must be avoided.
Avelumab must not be used for any purpose other than the study. The administration of IMPs to 
subjects who have not been enrolled into the study is not covered by the study insurance.
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain bacteriostatic 
preservatives. Any spills that occur should be cleaned up using the facility’s standard cleanup 
procedures for biologic products.
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration.
6.8
Investigational Medicinal Product Accountability
The investigator is responsible for ensuring accountability for IMP, including reconciliation of 
drugs and maintenance of drug records.
! Upon receipt of IMP, the investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the 
Sponsor and returning it to the Sponsor. A copy will be retained for the Investigator File.
! The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
forms provided by the Sponsor and an accurate accounting will be available for verification by 
the Sponsor monitor at each monitoring visit.
! IMP accountability records will include:
o Confirmation of IMP delivery to the trial site.
o The inventory at the site of IMP provided by the Sponsor and prepared at the site.
o The use of each dose by each subject.
o Destruction of unused treatment product (unused product will not be returned to the 
Sponsor).
o Dates, quantities, batch numbers, expiry dates and (for IMP prepared at the site) formulation, 
as well as the subjects’ trial numbers.
! The investigator should maintain records that adequately document:
o That the subjects were provided the doses specified by the clinical trial 
protocol/amendment(s).
o That all IMP provided by the Sponsor was fully reconciled.
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Unused IMP must not be discarded or used for any purpose other than the present trial. IMP that 
has been dispensed to a subject must not be re-dispensed to a different subject.
The Sponsor monitor will periodically collect the IMP accountability forms and will check all 
returns (both unused and used containers) before authorizing their destruction by the trial site.
At the conclusion or termination of this study, site study personnel and the clinical study monitor 
will conduct a final product supply inventory on the Investigational Drug Accountability Forms 
and all unused containers will be destroyed. Instructions for destruction of product will be provided 
to the site. The clinical study monitor will be supplied with a copy for filing of the Investigational 
Drug Accountability Forms. This documentation must contain a record of clinical supplies used, 
unused and destroyed and shall include information on:
! All administered units.
! All unused units
! All destroyed units (during the study).
! All destroyed units at the end of the study.
! Date of destruction(s).
! Name and signature of the investigator/pharmacist.
In addition, it must be ensured at each study site that the study drug is not used:
! After the expiry date.
! After the retest date unless the study drug is reanalyzed and its retest date extended.
This is to be closely monitored by the study monitor.
6.9
Assessment of Investigational Medicinal Product Compliance
In this trial, subjects will receive trial treatment (avelumab intravenous infusions) at the 
investigational site. Well trained medical staffs will monitor and perform the trial drug 
administration. The information of each trial drug administration including the date, time, and dose 
of trial drug will be recorded on the eCRF. The investigator will make sure that the information 
entered into the eCRF regarding drug administration is accurate for each subject. Any reason for 
non-compliance should be documented.
Non-compliance is defined as a subject missing > 1 cycle of study treatment for non-medical 
reasons. If 1 cycle was missed and the interval between the subsequent treatment cycle and the last 
administered treatment cycle is longer than 4 weeks for non-medical reasons, the criteria of 
insufficient compliance are met as well.
6.10
Method of Blinding
Not applicable.
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6.11
Emergency Unblinding
Not applicable.
6.12
Treatment of Overdose
An overdose is defined as any dose 10% greater than the calculated dose for that particular 
administration. Any overdose must be recorded in the trial medication section of the CRF.
For monitoring purposes, any case of overdose, whether or not associated with an AE (serious or 
non-serious), must be reported to the Sponsor’s Global Drug Safety department in an expedited 
manner using the Serious Adverse Event Report Form (see Section 7.4.1.4).
There are no known symptoms of avelumab overdose to date. The investigator should use his or 
her clinical judgment when treating an overdose of the investigational drug.
6.13
Medical Care of Subjects After End of Trial
After a subject has completed the trial or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the trial site’s standard of care and generally accepted 
medical practice and depending on the subject’s individual medical needs.
Upon withdrawal from trial treatment, subjects may receive whatever care they and their 
physicians agree upon. Subjects will be followed for survival and AEs as specified in Section 7.1.4.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
A complete schedule of assessments is provided in Appendix I.
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent according to the procedure described in Section 9.2.
7.1.1
Screening and Baseline Procedures and Assessments
There is a 28-day washout / recovery period for prior anticancer treatment (e.g., cytoreductive 
therapy, radiotherapy [with the exception of palliative bone directed radiotherapy], immune 
therapy, or cytokine therapy except for erythropoietin) and major surgery before the start of trial 
treatment (Section 5.3.2). The screening procedures and baseline assessments will be completed 
within 18 days before trial treatment starts.
During the screening period and before any trial related investigations and assessments are started, 
the subjects will be asked to sign the relevant informed consent form(s) (ICFs). The subjects’ 
information that will be documented during screening includes the demographic information (birth 
date, sex, and race) and the complete medical history including the history of the tumor disease, 
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previous and concomitant medications, and baseline medical condition (the information of 
concomitant medications and AEs will be monitored throughout the trial treatment period). 
Moreover, an Emergency Medical Support card will be handed out at the baseline assessments 
visit.
During screening, subjects will undergo a complete physical examination including recording 
body height, vital signs including body weight, 12-lead ECG, and a determination of the ECOG 
performance status (Appendix II).
The screening laboratory examination includes hematology, hemostaseology, full serum 
chemistry, serum electrophoresis, and full urinalysis. Free thyroxine (T4), and thyroid-stimulating 
hormone (TSH) will also be assessed at screening. 
During screening, a serum β-human chorionic gonadotropin (β-HCG) pregnancy test will be 
performed for women of child bearing potential and blood hepatitis B virus (HBV), hepatitis C 
virus (HCV), and HIV testing will be performed for all screening subjects because these conditions 
are trial entry exclusion criteria (see Section 5.3.2). Women who are postmenopausal (age-related 
amenorrhea ≥12 consecutive months or increased FSH > 40 mIU/ml), or who had undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status an FSH will be drawn at screening.
The tumor evaluation (type / staging, etc.) will be performed using CT scan or MRI (if MRI is 
used, CT of chest is mandatory) as well as tumor markers or any other established methods (see 
Section 7.2.5 for details). For expansion subjects, an MRI or CT scan (either, with contrast 
preferred) must be performed at screening in order to rule out brain metastases, unless imaging has 
previously been performed within 6 weeks  prior to screening (within 28 days for melanoma cohort 
subjects). In subjects with gastric/GEJ cancer, HNSCC, ovarian cancer, CRPC, mesothelioma, or 
urothelial carcinoma this scan is only necessary if clinically indicated.
Collection of tumor biopsies or archived surgical specimen will also be done during this period, if 
applicable (optional for the dose escalation phase). Subjects in the expansion phase are required to 
provide tumor tissue samples (the most recent biopsy or surgical specimen provided as block or 
slides), see Section 7.6.2.4 for details. In addition:
! For expansion subjects in the MBC cohort, the biopsy or surgical specimen must have been 
collected within 90 days prior to the first IMP administration.
! For expansion subjects in the melanoma and mesothelioma cohorts, if an optional fresh biopsy 
is obtained prior to the first dose of trial treatment, there is no requirement to collect archive 
tissue for trial entry.
Subject eligibility will need to be confirmed by the CRO / Sponsor before the first administration 
of the study drug during the expansion phase only.
Following completion of the above screening assessments, baseline samples for ADA, 
and 
 assessments should be collected prior to the first administration of avelumab, i.e., either 
during the screening period or pre-dose on Day 1. The term for ADA on CRF is human-antihuman 
antibodies (HAHA).
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For expansion subjects in the ovarian cancer cohort only, blood sampling for cancer antigen 125 
(CA-125) will be performed prior to the first administration of avelumab, i.e., either during the 
screening period or pre-dose on Day 1. 
Subjects in the first-line NSCLC cohort with non-squamous cell histology and unknown EGFR 
and ALK status will have to be tested and found to be negative for EGFR-activating mutations and
ALK rearrangements (see Section 7.6.2.4).
For subjects in the HNSCC cohort only, HPV status will be determined (see Section 7.6.2.4).
7.1.2
Treatment Period
In this trial, the treatment will be given until confirmed progression, unacceptable toxicity, or any 
criterion for withdrawal from the trial or IMP occurs (see Section 5.5). Subjects who have 
experienced a confirmed CR should be treated for a maximum of 24 months after confirmation, at 
the discretion of the investigator. If the investigator believes that a subject may benefit from 
treatment beyond 24 months, it may be permissible after discussion with the sponsor. In the case 
of study termination (see Section 5.6), subjects continuing to benefit from study treatment may 
still have access to study treatment via enrollment in a rollover study if not available through some 
other mechanism (eg, expanded access, marketed product).
Subjects who experienced a CR and have already stopped treatment can resume treatment with 
avelumab at the same dose and schedule. For subjects who achieve a CR on avelumab therapy and 
then subsequently develop disease progression after stopping therapy, but prior to the end of the 
trial, one re-initiation of treatment at the same dose and schedule is allowed at the discretion of the 
investigator and agreement of the trial Medical Monitor. In order to be eligible for retreatment, the 
subject must not have experienced any toxicity that led to treatment discontinuation of the initial 
avelumab therapy. Prior to re-initiation of the study treatment, malignant disease needs to be 
radiologically re-staged to assess all known sites of the disease and to establish a new baseline for 
subsequent tumor measurements. Relevant safety laboratory results must be available and verified 
prior to re-initiating of treatment. Subjects who re-initiate treatment will stay on study and will be 
treated and monitored according to the protocol and the “until progression” schedule in the 
Schedule of Assessments (see Appendix I).
Subjects will be asked to visit the investigational site every 2 weeks. A time window of up to 
3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all study 
procedures (except optional PK sampling visits on Days 2 and 3; see Section 7.5 for details). In
addition, the tumor evaluation (see Section 7.3) has a tumor assessment visiting time window of 
5 days prior to dosing (-5 days). Furthermore, if any screening procedures are conducted within 
3 days prior to Day 1 of trial treatment (Week 1, Day 1), the assessments scheduled on Week 1, 
Day 1 do not need to be repeated except for the evaluation of AEs and concomitant medications.
Subjects in the 10 mg/kg once weekly cohort will be asked to visit the investigational site once 
weekly (± 1 day) for the first 12 weeks then once every 2 weeks (-3/+1 days) starting on Week 13.
Subjects will receive avelumab i.v. infusion once every 2 weeks (subjects in the 10 mg/kg once 
weekly cohort will receive avelumab i.v. infusion once every week for the first 12 weeks, then 
once every 2 weeks starting on Week 13). Premedication with an antihistamine and with 
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paracetamol (acetaminophen) approximately 30 to 60 minutes prior to each dose of avelumab is 
mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol 
[acetaminophen] i.v. or oral equivalent). This regimen may be modified based on local treatment 
standards and guidelines, as appropriate. Avelumab will be administered by i.v. infusion over a 1-
hour period (-10 minutes / +20 minutes, i.e., 50 to 80 minutes).
7.1.2.1
Dose Escalation Phase
During the treatment period, the following assessments will be performed (see Appendix I for the 
detailed schedule):
! Except for the 10 mg/kg once weekly cohort (see Section 2.2.1), DLTs will be assessed during 
the first 3 weeks of trial treatment for each dose level of the dose escalation part (see Section 
5.1.4.2).
! AEs and concomitant medications will be documented in each study visit.
! ECOG performance status will be assessed prior to trial treatment on Day 1 (unless the 
screening ECOG was performed within 3 days prior to Day 1) and every 2 weeks thereafter and 
documented in each study visit and at each weekly visit for the 10 mg/kg once weekly cohort.
! Physical examinations will be performed prior to trial treatment in each visit until Week 13 
(except Days 2 and 3), and every 6 weeks thereafter.
! Vital signs will be assessed prior to trial treatment in each visit until Week 13 (except Days 2
and 3), and every 2 weeks thereafter.
! Body weight will be assessed prior to trial treatment every 2 weeks and at each weekly visit for 
the 10 mg/kg once weekly cohort.
! The 12-lead ECGs (assessed prior to infusion and 2 hours ± 20 minutes after infusion) will be 
assessed every 2 weeks until Visit 13, and every 6 weeks thereafter. 
! The laboratory hematology and hemostaseology tests will be assessed prior to trial treatment 
and every 2 weeks thereafter and at each weekly visit for the 10 mg/kg once weekly cohort. 
! Full serum chemistry will be assessed prior to trial treatment at Week 7 and Week 13 and every 
6 weeks thereafter. Core serum chemistry will be performed at Week 3, Week 5, Week 9 and 
Week 11 and then every 2 weeks thereafter (and at each weekly visit for the 10 mg/kg once 
weekly cohort); if a full and core chemistry are scheduled at the same visit only the full 
chemistry will be performed. Full urinalysis will be performed at screening and a basic
urinalysis will be performed prior to trial treatment every 2 weeks.
! Except for the 10 mg/kg once weekly cohort, a urine β-HCG pregnancy test will be performed
prior to each administration of the study drug (if applicable).  For the 10 mg/kg once weekly 
cohort, a pregnancy test should be performed every 4 weeks.
! Except for the 10 mg/kg once weekly cohort, the tumor evaluation (see Section 7.3) will be 
performed at Week 7, and then once every 6 weeks, with a tumor assessment visiting time 
window of 5 days prior to dosing.  For the 10 mg/kg once weekly cohort, tumor assessments 
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will be once every 6 weeks for the first 12 months from the first dose (until Week 55), then 
every 12 weeks thereafter.
! Except for the 10 mg/kg once weekly cohort, PK samples will be drawn on Days 1, 2, 3, 15, 
29, 43, 85, 127, and 169 (see Section 7.5 for details). PK sampling on Days 2 and 3 is optional.
For the 10 mg/kg once weekly cohort, blood samples for PK determinations will be collected 
from all subjects within 2 hours prior to each infusion at Weeks 1, 2, 3, 5, and 7 (every 2 weeks), 
at Weeks 13, 15, 19, and 25, and then at 12-week intervals while on treatment. A sample at the 
end of infusion (within 15 minutes) will be collected at Weeks 1, 7, 13, and 25. 
! ACTH, ANA, ANCA, RF, free T4, and TSH will be measured prior to trial treatment every 
6 weeks during the treatment period, from Week 7 onwards.  For the 10 mg/kg once weekly 
cohort, samples for ACTH, ANA, and RF as indicted in the Schedule of Assessments and as 
clinically indicated.  Samples for free T4 and TSH will be 6-weekly.
! ADA samples will be drawn on Days 1, 15, 29, 43, 57, 71, 85, 127, and 169 (see Section 7.7.1).
For the 10 mg/kg once weekly cohort, samples for ADA determination will be collected Days 
1 (baseline), 15, 29, 43, 57, 71, 85, Week 19, and on Week 25 and every 12 weeks thereafter. 
The baseline sample should be collected prior to the first administration of trial treatment, i.e., 
either during the screening period or pre-dose on Day 1. The term for ADA on CRF is human-
antihuman antibodies (HAHA).
! Except for the 10 mg/kg once weekly cohort, receptor occupancy test will be performed on 
Days 1, 3, 15, 29, 43, and 85 (see Section 7.6.1).  Receptor occupancy will not be determined 
for the 10 mg/kg once weekly cohort.
! The immunomonitoring and soluble factors will be performed as described in Section 7.6.1.2
and Appendix I. Immune monitoring will not be performed for the 10 mg/kg once weekly 
cohort.
7.1.2.2
Expansion Phase
During the treatment period, the following assessments will be performed (see Appendix I for the 
detailed schedule):
! AEs and concomitant medications will be documented in each study visit.
! ECOG performance status will be assessed prior to trial treatment at Day 1 (unless the screening 
ECOG was performed within 3 days prior to Day 1) and every 2 weeks thereafter.
! Physical examinations will be performed prior to trial treatment in each visit until Week 13 
(except Day 2 and Day 3), and every 6 weeks thereafter.
! Vital signs and body weight will be assessed prior to trial treatment in each visit until Week 13 
(except Day 2 and Day 3), and every 2 weeks thereafter.
! The 12-lead ECGs (assessed prior to infusion and 2 hours ± 20 minutes after infusion) will be 
assessed every 2 weeks until Visit 13, and every 6 weeks thereafter.
! The laboratory hematology and hemostaseology tests will be assessed prior to trial treatment 
and every 2 weeks thereafter. 
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! Full serum chemistry will be assessed prior to trial treatment, at Week 7 and Week 13 and then 
every 6 weeks thereafter. Core serum chemistry will be performed at Week 3, Week 5, Week 9 
and Week 11 and every 2 weeks thereafter; if a full and core chemistry are scheduled at the 
same visit only the full chemistry will be performed. In addition, for subjects with liver 
metastases at baseline, samples for ALT, AST, total bilirubin, and alkaline phosphatase 
determination will be collected at Weeks 2, 4, and 6. Full urinalysis will be performed at 
screening and a basic urinalysis will be performed prior to trial treatment as defined in Appendix 
I (except for subjects with urothelial cancers, whose urine is usually unfit for analytical 
purposes).
! The urine β-HCG pregnancy test will be performed every 4 weeks in premenopausal women 
(before administration of the study drug).
! The tumor evaluation (see Section 7.3) will be performed at Week 7, and then once every 
6 weeks for the first 12 months then every 12 weeks thereafter, with a tumor assessment visiting 
time window of 5 days prior to dosing.
Melanoma and mesothelioma: For subjects in the melanoma and mesothelioma cohorts only, 
fresh biopsies may be obtained on Day 43. These biopsies are optional.
Mesothelioma: For subjects in the mesothelioma cohort only, tumor biopsies (core needle 
biopsies) may be performed between Cycles 2 and 3, and in the case of disease progression, to 
differentiate between actual disease progression and a tumor flare resulting from intratumor 
inflammation. These biopsies are optional. See Section 7.3.
Efficacy expansion cohorts and first-line NSCLC primary expansion cohort: For subjects 
in the efficacy expansion cohorts and the first-line NSCLC primary expansion cohort, fresh 
biopsies may also be collected on Days 43 and at the end-of-treatment visit. These biopsies are 
optional.
! Ovarian cancer: For subjects in the ovarian cancer cohorts only, blood sampling for CA-125 
will be performed at Week 7, and then once every 6 weeks.
! PK samples 
o Will be drawn prior to each administration of study drug on Days 1, 15, 29, 43, 57, 71, 85,
127, and 169 for all subjects in the primary NCSLC (post platinum doublet cohort), gastric
/ GEJ cancer, and MBC cohorts. 
o Will be drawn prior to each administration of study drug on Days 1, 15, 29, 43, 57, 71, 85,
127, and 169 for all subjects in the secondary ACC, melanoma, mesothelioma, ovarian 
cancer, and urothelial carcinoma cohorts.
o Will be drawn prior to each administration of study drug on Days 1, 2, 3, 15, 29, 43, 85, 127, 
and 169 (see Section 7.5 for details) for all subjects in the secondary CRC and CRPC cohorts.
PK sampling on Days 2 and 3 is optional.  Additionally, samples will be drawn on Day 1 at 
the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours post infusion.
o Will be drawn prior to each study drug administration on Days 1, 15, 29, 43, 57, 71, 85, 99, 
and 169 for subjects in the first-line NSCLC cohort. Post-study drug administration samples 
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will also be collected immediately after the end of the infusion and also 2 to 8 hours after 
the end of infusion (later is better depending on how long the subject will stay in the clinic), 
on Days 1, 43, 85, and 169 while on treatment. Samples will also be collected at the 10-week 
safety follow-up visit.
o Will be drawn prior to each study drug administration on Days 1, 15, 29, 43, 57, 71, 85, and 
169 for subjects in the efficacy expansion cohorts and the RCC secondary cohort. Post-study 
drug administration samples will be collected immediately after the end of infusion and 2 to 
8 hours after the end of infusion (later is better, depending on how long the subject will stay 
in the clinic) at Days 1, 43, 85, and 169.  Exact sampling times will be recorded. Samples 
will be collected at the 10-week Safety Follow-up visit.
o For subjects who achieve a CR on avelumab therapy and then subsequently develop disease 
progression after stopping therapy, PK samples will be drawn prior to the second retreatment 
infusion, then 2 weeks later, and then every 6 weeks until 6 months after treatment 
re-initiation.
! Free T4 and TSH will be measured prior to trial treatment at Week 13, Week 25,
end-of-treatment, and if clinically indicated.
! ADA samples will be drawn on Days 1, 15, 29, 43, 57, 71, 85, 127, and 169 (see Section 7.7.1).
The term on CRF is human-antihuman antibodies (HAHA).
o For subjects who achieve a CR on avelumab therapy and then subsequently develop disease 
progression after stopping therapy, ADA samples will be drawn prior to the second 
retreatment infusion, then 2 weeks later, and then every 6 weeks until 6 months after 
treatment re-initiation.
! Receptor occupancy test will be performed for subjects in the CRC and CRPC cohorts only on 
Days 1, 15, 29, 43, and 85 (see Section 7.6.2.1).
! The immunomonitoring samples will be collected for all subjects enrolled in the secondary 
expansion cohorts, except for the RCC cohort, as described in Section 7.6.2.2 and Appendix I.
! The soluble factors will be performed on all subjects in the primary and secondary expansion 
cohorts, except for the RCC cohort, before start of first infusion (Day 1) and on Day 43. In 
addition, except for the RCC cohort, all subjects enrolled in the secondary expansion cohorts 
will also have samples drawn 48 hours (±6 hours) after start of first infusion (Day 3, optional).
See Section 7.6.2.2 and Appendix I for details.
 
 
! For subjects enrolled in the efficacy expansion cohorts and the RCC secondary cohort, blood 
samples for 
 will be collected before the start of infusion 
on Days 1, 15, 29, and 43.
PK sampling on Days 2 and 3 are optional and only applicable for subjects in the secondary CRC 
and CRPC cohorts (expanded PK sampling). Therefore, the visit at Day 2 is optional; however
should a subject attend, blood draws for PK sampling and soluble factors (as applicable) are 
strongly encouraged. 
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7.1.3
End of Treatment
Discontinuation visit 
Any subject who experiences an AE that mandates discontinuation of trial treatment should have 
a Discontinuation visit as soon as possible after the decision to discontinue trial treatment (at least 
within 7 days). For all these subjects, the discontinuation visit consists of:
! Documentation of AEs and concomitant medication.
! Physical examination including vital signs and body weight.
! The 12-lead ECGs.
! Laboratory hematology, hemostaseology, full serum chemistry, and basic urinalysis.
! ECOG performance status will be assessed.
End-of-treatment visit
The end-of-treatment visit is scheduled 4 weeks (28 days) after the last administration of avelumab
but before any new therapy is started, if possible, whichever occurs earlier. The end-of-treatment 
visit will comprise a full assessment for safety, immunogenicity, and tumor response as 
appropriate, which will include the following (refer to Appendix I):
! AEs, and concomitant medications, and vital signs and body weight.
! Physical examinations.
! The 12-lead ECGs.
! The laboratory hematology, hemostaseology, full serum chemistry, serum electrophoresis tests 
and full urinalysis.
! ECOG performance status will be assessed. 
! The urine β-HCG pregnancy test (in women of child bearing potential).
! The tumor evaluation (only to be performed, if no disease progression was documented 
previously).
! ADA sample (any remaining sample may be used for PK determination) (see Section 7.7.1).
The term on CRF is human-antihuman antibodies (HAHA).  For the 10 mg/kg once weekly 
cohort, a blood sample for PK determination will be collected.
! The immunomonitoring and soluble factors will be performed as described in Section 7.6.1.2
and Appendix I.
For subjects enrolled in the efficacy expansion cohorts and the RCC secondary cohort, blood 
samples for 
Melanoma and mesothelioma: For subjects in the melanoma and mesothelioma cohorts only, 
fresh biopsies may be obtained at the end-of-treatment visit. These biopsies are optional.
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Ovarian cancer: For subjects in the ovarian cancer cohort only, blood sampling for CA-125.
! T4 and TSH levels.
! ADA sampling.
! Immunomonitoring for all subjects.
! Soluble factors assessments.
7.1.4
Post-Treatment Safety Follow-Up
All subjects will have a subsequent visit scheduled 10 weeks after the last administration of 
avelumab. The visit will include the following full assessment of safety parameters (refer to 
Appendix I):
! Any treatment related AEs and concomitant medications will be documented, including further 
anti-cancer therapy.
! Vital signs and body weight will be measured.
! Physical examination will be performed.
! ECOG performance status will be assessed. 
! 12-lead ECG will be assessed.
! Laboratory testing consisting of the following will be assessed:
o hematology, hemostaseology, full serum chemistry, and full urinalysis
o T4 and TSH levels
o PK sample (any remaining sample may be used for ADA determination)
! A urine β-HCG pregnancy test (in women of child bearing potential) will be conducted.
After the End-of-Treatment visit only treatment-related AEs have to be documented until the 
Post-treatment Safety Follow-up visit. Subjects with a SAE ongoing at the post-treatment safety 
follow-up visit must be monitored and followed up by the investigator until stabilization or until 
the outcome is known, unless the subject is documented as “lost to follow up.”
Subjects without progressive disease according to RECIST 1.1 at the end-of-treatment visit will 
be followed up for radiographic disease progression (CT / MRI scans) every 12 weeks up to 1 year.
After the end-of-treatment visit, subjects will be followed quarterly (± 14 days) for survival 
(including assessment of any further tumor therapy). The survival follow-up will continue until 
1 year after the last subject receives the last dose of avelumab.
7.1.5
Blood Consumption for Clinical Assessments
The overall amount of blood to be drawn from a single subject with a body weight ≥ 70 kg (154 lbs) 
must not exceed 120 mL/day and 550 mL in an 8-week period for safety laboratory testing, 
pregnancy testing, PK analyses, exploratory biomarker investigation, and antibody evaluation.
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7.2
Demographic and Other Baseline Characteristics
The assessments and procedures described in this section must be performed during the screening 
period.
7.2.1
Demographic Data
The following demographic data will be recoded:
! Subject identifier
! Date of birth
! Sex
! Race
7.2.2
Diagnosis of Tumor
The tumor disease information that will be documented and verified at the screening visit for each 
subject includes:
! Detailed history of the tumor including histopathological diagnosis, grading and staging in 
accordance with the International Union Against Cancer Tumor Node Metastasis Classification 
at diagnosis (UICC TNM).
! All therapy used for prior treatment of the tumor (including surgery, radiotherapy and 
chemotherapy, immunotherapy).
! Any other conditions that were treated with chemotherapy, radiation therapy, or 
immunotherapy.
! Current cancer signs and symptoms and side effects from current and / or previous anticancer 
treatments.
! Current cancer disease status.
! HER2 status if available (gastric / GEJ cancer only)
! Smoking history.
! EGFR-activating mutation or ALK re-arrangement status (NSCLC non-squamous cell 
histology only).
! HPV status (HNSCC only).
7.2.3
Medical History
In order to determine the subject’s eligibility to the trial, a complete medical history of each subject 
will be collected and documented during screening, which will include, but may not be limited to, 
the following:
! Past and concomitant non-malignant diseases and treatments.
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! All medications taken and procedures carried out within 30 days prior to screening.
For the trial entry, all the subjects must fulfill all inclusion criteria described in Section 5.3.1, and 
none of the subjects should have any exclusion criterion from the list described in Section 5.3.2.
7.2.4
Vital Signs and Physical Examination
Vital signs including body temperature, respiratory rate, heart rate (after 5-minute rest), and arterial 
blood pressure (after 5-minute rest) will be recorded at study entry. 
A complete physical examination (including, in general, appearance, dermatological, head/neck, 
pulmonary, cardiovascular, gastrointestinal, genitourinary, lymphatic, musculoskeletal system, 
extremities, eyes [inspection and vision control], nose, throat, and neurologic status) will be 
performed and the results documented.
The ECOG performance status will be documented during the screening phase.
Body weight and height will be recorded.
7.2.5
CT or MRI Scans for Tumor Assessment at Baseline
A CT scan or MRI (if MRI is used, CT of chest is mandatory) of the chest, abdomen, and pelvis 
(at a minimum and other established assessments of tumor burden if CT / MRI imaging is not 
sufficient for the individual subject; other regions as specifically required for specific tumor 
indications) will be performed within 18 days prior to trial treatment start in order to document the 
baseline status of the tumor disease using RECIST 1.1 target and non-target lesions. However, if 
the results of a CT scan or MRI performed within 4 weeks prior to first treatment are available, the 
screening CT / MRI does not need to be performed. 
A brain CT / MRI scan (either, contrast preferred) is required at screening if not performed within 
the previous 6 weeks (within 28 days for subjects in the melanoma cohort). In subjects with 
gastric/GEJ cancer, HNSCC, ovarian cancer, CRPC, mesothelioma, or urothelial carcinoma this 
scan is only necessary if clinically indicated. Thereafter, brain CT/MRI scan should be done if 
clinically indicated by development of new specific symptoms.
A bone scan should be done at screening as clinically indicated.
7.2.6
Cardiac Assessments
A 12-lead ECG will be recorded at screening, at regular intervals during treatment, at the end of 
treatment and at the post-treatment follow-up visit. ECGs will be recorded after the subject has 
been in a supine position breathing quietly for 5 minutes. The ECG results will be used to evaluate 
the heart rate, atrial-ventricular conduction, QR and QT intervals, and possible arrhythmias.
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7.2.7
Clinical Laboratory Tests
Blood samples will be collected at screening for clinical laboratory parameter evaluations. These 
clinical laboratory test results will serve not only as the baseline values for subsequent safety 
clinical laboratory evaluations during the trial, but also help to make sure that each enrolled subject 
fulfills all the trial entry criteria and does not meet any of the trial exclusion criteria for laboratory 
parameters as listed in Section 5.3. Detailed description of laboratory assessments is provided in 
Section 7.4.3.
7.3
Assessment of Efficacy
For the efficacy expansion cohorts and the secondary urothelial carcinoma cohort, radiographic 
images and physical findings (physical assessments) used for the local determination of disease 
progression will be read centrally and reviewed by a blinded IERC.  The IERC will make a 
determination as to whether the criteria for tumor response or progression according to RECIST 
1.1 have been met.
For all subjects in all cohorts, tumor response assessment will be performed by CT scan or MRI 
(if MRI is used, CT of chest is mandatory) imaging of the chest/abdomen/pelvis (plus other regions 
as specifically required for specific tumor types) and other established assessments of tumor
burden if CT / MRI imaging is insufficient for the individual subject. All the scans performed at 
baseline and other imaging performed as clinically required (other supportive imaging) need to be 
repeated at subsequent visits. In general, lesions detected at baseline need to be followed using the 
same imaging methodology and preferably the same imaging equipment at subsequent tumor 
evaluation visits.
A brain CT / MRI scan (either, with contrast preferred) is required at screening if not performed 
within the previous 6 weeks (within 28 days for subjects in the melanoma cohort). In subjects with 
gastric/GEJ cancer, HNSCC, ovarian cancer, CRPC, mesothelioma, or urothelial carcinoma this 
scan is only necessary if clinically indicated. Thereafter brain CT / MRI scan should be performed, 
if clinically indicated by development of new specific symptoms. A bone scan should be done at 
screening and beyond as clinically indicated. Skin metastasis can be used as target lesions 
according to RECIST 1.1 using measurements by caliper, if they fulfill RECIST 1.1 for target 
lesions as described below. The presence of new cutaneous lesions will be considered diagnostic 
of progression for RECIST 1.1, even if not imaged. For each subject, the investigator will 
designate 1 or more of the following measures of tumor status to follow for determining response: 
CT or MRI images of primary and/or metastatic tumor masses, physical examination findings, and 
the results of other assessments. All available images collected during the trial period will be 
considered. The most appropriate measures to evaluate the tumor status of a subject should be 
used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to 
the measures used to document the progressive tumor status that qualifies the subject for 
enrollment. The tumor response assessment will be assessed and listed according to the schedule 
of assessments (refer to Appendix I).
The foreseen treatment duration is until confirmed progression, unacceptable toxicity, or any 
criterion for withdrawal from the trial or IMP occurs (see Section 5.5). Before stopping the 
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treatment, progressive disease should be confirmed by imaging preferably 6 weeks (but not 
later) after progression has been diagnosed according to RECIST 1.1. Evidence of progression 
of prostate cancer within the first 3 months on bone scan only should be interpreted with extreme 
caution due to risk of tumor flare. If progression is based on the occurrence of a new lesion in an 
area not scanned at baseline, a further on-study scan 6 weeks later should be considered before 
performing the end-of-treatment visit. Treatment may be continued despite progression according 
to RECIST 1.1 at any time if:
!
There are no new symptoms or worsening of existing symptoms.
!
There is no decrease in ECOG performance status.
!
The investigator does not consider it necessary to administer a salvage therapy. 
The treatment should be stopped immediately, if the subject does not tolerate avelumab anymore 
or if therapeutic failure occurs, which requires urgent treatment with an additional drug or results 
in clinically significant progression/deterioration. 
Tumor responses to treatment will be assigned based on the evaluation of the response of target, 
non-target, and new lesions according to RECIST 1.1 (all measurements should be recorded in 
metric notation, see reference 48).
! To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized in 
target and non-target lesions as described in reference 48.
Results for these evaluations will be recorded with as much specificity as possible so that pre- and 
post-treatment results will provide the best opportunity for evaluating tumor response. 
Any CR or partial response (PR) should be confirmed as described in reference 48. In the case of 
a PR or CR, a confirmatory CT or MRI scan must be done no sooner than 28 days 
(preferably at the scheduled 6-week interval). 
The investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the investigator suspects progressive disease. 
As outlined in Section 5.1, treatment may continue with the investigational drug(s) and the subject 
may remain on study according to the investigator’s decision and in agreement with the subject in 
case of progressive disease according to RECIST 1.1. Following PD on RECIST 1.1, modified 
“immune related response criteria” (irRC; see below and reference 48) should be used as guidance 
for further clinical care.
Subjects who have experienced a confirmed CR should be treated for a maximum of 24 months 
after confirmation, at the discretion of the investigator. If the investigator believes that a subject 
may benefit from treatment beyond 24 months, it may be permissible after discussion with the 
sponsor. Subjects who experienced a CR and have already stopped treatment can resume treatment 
with avelumab at the same dose and schedule. Subjects re-initiating treatment should be assessed 
according to the Schedule of Assessments (Appendix I).
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Melanoma and mesothelioma: For subjects in the melanoma and mesothelioma cohorts only, 
fresh biopsies may be obtained on Day 43 and at the end-of-treatment visit. These biopsies are 
optional.
Mesothelioma: For subjects in the mesothelioma cohort only, tumor biopsies (core needle 
biopsies) may be performed between Cycles 2 and 3, and in the case of disease progression, to 
differentiate between actual disease progression and a tumor flare resulting from intratumor 
inflammation. These biopsies are optional. Should the histology of the biopsy performed be 
consistent with tumor progression, treatment with avelumab may continue at the discretion of the 
investigator provided there is no significant clinical deterioration.
Efficacy expansion cohorts and first-line NSCLC primary expansion cohort: For subjects in 
the efficacy expansion cohorts and the first-line NSCLC primary expansion cohort, fresh biopsies 
may also be collected on Days 43 and at the end-of-treatment visit. These biopsies are optional.
Modified immune-related response criteria (irRC), derived from RECIST 1.1
This new classification is based on the recent learning from clinical studies with cancer 
immunotherapies that even if some new lesions appear at the beginning of a treatment or if the 
total tumor burden does not increase substantially, tumor regressions or stabilizations might still 
occur later. For this trial, the concepts of the irRC (72) are combined with RECIST 1.1 to come up 
with the modified irRC, which uses unidimensional measurements. 
For modified irRC, only target and measurable lesions are taken into account. In contrast to the 
RECIST 1.1, the modified irRC criteria (a) require confirmation of both progression and response 
by imaging at 6 weeks after initial imaging (evidence of progression of prostate cancer within the 
first 3 months on bone scan only should be interpreted with extreme caution due to risk of tumor 
flare) and (b) do not necessarily score the appearance of new lesions as progressive disease if the 
sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target 
lesions, maximum of 2 per organ) and measurable new lesions does not increase by ≥20%.
The same method of assessment and the same technique should be used to characterize each 
identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All 
measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are 
displayed below. 
Modified immune-related response criteria are defined as follows:
New measurable lesions: Incorporated into tumor burden.
New non-measurable lesions: Do not define progression but precludes (irCR).
Overall irCR:
Complete disappearance of all lesions (whether measurable or not) and no new 
lesions. All measurable lymph nodes also must have a reduction in short axis to 
10 mm or less.
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Overall irPR:
Sum of the longest diameters of target and new measurable lesions decreases 
≥30%. 
Overall irSD:
Sum of the longest diameters of target and new measurable lesions neither irCR, 
irPR, (compared to baseline) or irPD (compared to nadir).
Overall irPD:
Sum of the longest diameters of target and new measurable lesions increases 
≥20% (compared to nadir), confirmed by a repeat, consecutive observations at 
least 4 weeks (normally it should be done at 6 weeks) from the date first 
documented.
Documentation of immune-related PD (based on modified irRC), does not mandate 
discontinuation of the study treatment even after irPD is confirmed with CT scan 6 weeks 
after the initial observation of irPD. Please refer to Section 5.5.2 (Withdrawal from the 
Investigational Medicinal Product) to determine when it is appropriate to discontinue 
treatment with the study drug.
Overall responses derived from changes in index, non-index, and new lesions as demonstrated in 
Table 7.1.
Table 7.1
Overall Responses Derived from Changes in Index, Non-Index, and New 
Lesions
Measurable Response
Non-Measurable Response
Overall Response 
Using Modified irRC
Index and New, Measurable 
Lesions (Tumor Burden) 
Non-Index Lesions
New, Non-
Measurable Lesions
Decrease 100%
Absent
Absent
irCR1
Decrease 100%
Stable
Any
irPR1
Decrease 100%
Unequivocal progression
Any
irPR1
Decrease ≥ 30%
Absent / Stable
Any
irPR1
Decrease ≥ 30%
Unequivocal progression
Any
irPR1
Decrease < 30% increase 
< 20%
Absent / Stable
Any
irSD
Decrease < 30% to increase 
< 20%
Unequivocal progression
Any
irSD
Increase ≥ 20%
Any
Any
irPD
1  Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive
assessment at least 4 weeks apart (normally it should be done 6 weeks apart).
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7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analyzing of 
baseline medical conditions, AEs, physical examination findings including vital signs and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the trial, from the time of the subject’s signature of informed consent. 
Trial site personnel will report any AE, whether observed by the investigator or reported by the 
subject (see Section 7.4.1.2, “Methods of Recording and Assessing Adverse Events”). Given the 
intended MoA, particular attention will be given to AEs that may follow the enhanced T-cell 
activation such as dermatitis, colitis, hepatitis, uveitis, or other immune-related reactions. 
Ophthalmologic examinations should be considered, when clinically indicated, for signs or 
symptoms of uveitis. 
The reporting period for AEs is described in Section 7.4.1.3.
The safety assessments will be performed according to the schedule of assessment (refer to 
Appendix I).
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The investigator is required to Grade the severity/intensity of each AE.
Investigators will reference the NCI-CTCAE, v4.0 (publication date: 28 May 2009). This is a 
descriptive terminology that can be used for AE reporting.
A general grading (severity / intensity) scale is provided at the beginning of the referenced 
document, and specific event Grades are also provided.
If a particular AE’s severity/intensity is not specifically graded by the guidance document, the 
investigator is to revert to the general definitions of Grade 1 through Grade 5 and use his or her 
best medical judgment.
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The 5 general grades are:
Grade 1:
Mild
Grade 2:
Moderate
Grade 3:
Severe
Grade 4:
Life-threatening or disabling
Grade 5:
Death related to AE
According to the Sponsor’s convention, if a severity/intensity of Grade 4 or 5 is applied to an AE, 
then the investigator must also report the event as an SAE as per Section 7.4.1.4. However, a 
laboratory abnormality with a severity/intensity of Grade 4, such as anemia or neutropenia, is 
considered serious only if the condition meets 1 of the serious criteria described below.
In the case of death, the primary cause of death or the event leading to death should be recorded 
and reported as an SAE. “Fatal” will be recorded as the outcome of this respective event; death 
will not be recorded as separate event. Only if no cause of death can be reported (e.g., sudden 
death, unexplained death), the death per se might be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to the IMP using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to 
avelumab include, but may not be limited to, temporal relationship between the AE and avelumab, 
known side effects of avelumab, medical history, concomitant medication, course of the 
underlying disease, trial procedures.
Not related: Not suspected to be reasonably related to the IMP. AE could not medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. A reasonable alternative explanation must be available.
Related:
Suspected to be reasonably related to the IMP. AE could medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation or are considered otherwise medically important by the investigator. If 
an abnormality fulfills these criteria, the identified medical condition (e.g., anemia, increased 
ALT) must be reported as the AE rather than the abnormal value itself.
Adverse Drug Reaction (ADR)
ADRs are defined in this trial as any AEs suspected to be related to avelumab by the investigator 
and / or Sponsor.
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Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence that at any dose:
! Results in death.
! Is life-threatening.
NOTE: The term “life-threatening” in this definition refers to an event in which the subject is at 
risk of death at the time of the event; it does not refer to an event that hypothetically might cause 
death if it were more severe.
! Requires inpatient hospitalization or prolongation of existing hospitalization.
! Results in persistent or significant disability/incapacity.
! Is a congenital anomaly/birth defect.
! Is otherwise considered as medically important.
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered as SAEs when, based upon appropriate medical judgment, they may jeopardize 
the subject or may require medical or surgical intervention to prevent 1 of the outcomes listed in 
this definition. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered a serious adverse reaction and all such cases should be reported in an expedited manner 
as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g., an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered as SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs.
AE/SAEs Observed in Association with Disease Progression
Disease progression recorded in the course of efficacy assessments only, but without any adverse 
signs or symptoms should not be reported as an AE.
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However, if adverse signs or symptoms occur in association with disease progression then these 
should be recorded as AEs and as SAEs if they meet any seriousness criteria.
Pre-defined Potential AEs of Special Interest (AESI) for Safety Monitoring
Any infusion reaction, regardless of grade, must be reported in an expeditious manner and will be 
considered an AE of special interest (AESI).
The reporting of AESI is defined in Section 7.4.1.4.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his/her condition. During the reporting 
period of the trial any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the CRF. 
Among these AEs, all SAEs and all nonserious AEs of special interest must be additionally 
documented and reported using the appropriate Report Form as described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and times to be completed when it is important to assess the time of AE onset 
relative to the recorded treatment administration time), its severity, its causal relationship with the 
trial treatment, any other potential causal factors, any treatment given or other action taken 
(including dose modification or discontinuation of the IMP) and its outcome. In addition, serious 
cases should be identified and the appropriate seriousness criteria documented.
Specific guidance can be found in the CRF Completion and Monitoring Conventions.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is included into the trial 
(date of first signature of informed consent) and continues through the trial’s End-of-Treatment 
visit, 28 days after last trial drug administration. After the End-of-Treatment visit only 
treatment-related AEs have to be documented through the post-treatment safety follow-up period, 
defined as 10 weeks after the last trial drug administration.
Any SAE suspected to be related to the trial treatment must be reported whenever it occurs, 
irrespective of the time elapsed since the last administration.
7.4.1.4
Procedure for Reporting Serious Adverse Events / Adverse 
Events of Special Interest
Serious Adverse Events
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In the event of any new SAE (of any Grade) occurring during the reporting period, the investigator 
must immediately (i.e., within a maximum 24 hours after becoming aware of the event) inform the 
Sponsor or designee by telephone, by fax or by e-mail.
When an event (or follow-up information) is reported by telephone, a written report must be sent 
immediately thereafter by fax or e-mail.
Reporting procedures and timelines are the same for any new information on a previously reported 
SAE (= follow-up).
For names, addresses, telephone and fax numbers for SAE reporting, see information included in 
the SAE Report Form.
All written reports should be transmitted using the SAE Report Form, which must be completed 
by the investigator following specific completion instructions. The AE section of the CRF must be 
completed. Relevant pages from the CRF may be provided in parallel (e.g., medical history,
concomitant drugs). 
In all cases, the information provided in the SAE Report Form must be consistent with the data on 
the event that is recorded in the corresponding sections of the CRF.
The investigator/reporter must respond to any request for follow-up information (e.g., additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor or designee may have on the AE within the same timelines as described for initial reports. 
This is necessary to permit a prompt assessment of the event by the Sponsor or designee and (as 
applicable) to allow the company to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made by the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department of the Sponsor may contact the investigator 
directly to obtain clarification or to discuss a particularly critical event.
Adverse Events of Special Interest
In the event of a non-serious immune-related reaction, the investigator must complete the AESI 
Report Form and send it to the Sponsor/designee immediately within 24 hours. Names, addresses, 
and telephone and fax numbers for AESI reporting will be included on the Report Form. Serious 
AESIs must be reported in an expedited manner as SAEs, as outlined above.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to health authorities in accordance with 
applicable laws and regulations.
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The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (and in particular deaths) involving his/her subjects to the IEC / IRB that 
approved the trial.
In accordance with ICH GCP guidelines, the Sponsor or designee will inform the investigator of 
“findings that could adversely affect the safety of subjects, impact the conduct of the trial, or alter 
the IEC’s/IRB’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor or designee will inform the investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (suspected 
unexpected serious adverse reactions [SUSARs]). The investigator should place copies of safety 
reports in the Investigator Site File. National regulations with regard to safety report notifications 
to investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor or designee will provide 
appropriate Safety reports directly to the concerned health authority and lead IEC / IRB and will 
maintain records of these notifications. When direct reporting by the Sponsor or designee is not 
clearly defined by national or site-specific regulations, the investigator will be responsible for 
promptly notifying the concerned IEC / IRB of any safety reports provided by the Sponsor or 
designee and of filing copies of all related correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs / SUSARs / Safety Issues will be carried out in accordance with that 
Directive and with the related detailed guidance.
7.4.1.6
Monitoring of Subjects with Adverse Events
Adverse events are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) 
and are assessed for final outcome at the End-of-Treatment visit. After the End-of-Treatment visit, 
only treatment-related AEs have to be documented until the Post-treatment Safety Follow-up visit, 
defined as 10 weeks after the last trial drug administration. All SAEs ongoing at the post-treatment 
safety follow-up visit must be monitored and followed up by the investigator until stabilization or 
until the outcome is known, unless the subject is documented as “lost to follow-up.” Reasonable 
attempts to obtain this information must be made and documented. It is also the responsibility of 
the investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed.
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the investigator as related to trial treatment (e.g., resulting from a 
drug interaction with a contraceptive medication) are considered as AEs. However, all pregnancies 
with an estimated conception date during the period defined in Section 7.4.1.3 must be recorded 
by convention in the AE page/section of the CRF. The same rule applies to pregnancies in female 
subjects and in female partners of male subjects. The investigator must notify the Sponsor or 
designee in an expedited manner of any pregnancy using the Pregnancy Report Form, which must 
be transmitted according to the same process as described for SAE reporting in Section 7.4.1.4. 
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Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The investigator must notify the Sponsor or designee of these outcomes using the Pregnancy 
Report Form, and in case of abnormal outcome, the SAE Report Form when the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form when the child/fetus sustains an 
event).
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days from delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor or designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Laboratory Assessments
It is essential that the Sponsor be provided with a list of laboratory normal ranges before shipment 
of trial drug. Any change in laboratory normal ranges during the trial will additionally be 
forwarded to the CRO and the Sponsor.
Blood samples will be taken from non-fasted subjects. All routine laboratory analyses will be 
performed at a laboratory facility local to the investigational site.
Relevant results essential for patient management decisions (hematology, biochemistry, liver 
function tests) must be available and reviewed before administration of avelumab.
The report of the results must be retained as a part of the subject’s medical record or source 
documents. Blood samples for the tests listed in Table 7.2 will be taken from non-fasted subjects 
during the screening phase (within 18 days prior to the first treatment administration), at the 
end-of-treatment visit, and during the treatment phase as specified in Appendix I. Serum 
electrophoresis, T4, TSH and urinalysis will be assessed at the time points defined in Appendix I. 
If confirmation of a subject’s postmenopausal status is necessary, a FSH level will also be 
performed at screening, see Section 7.1.1.
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Table 7.2
Required Laboratory Panel Tests
Full Chemistry
Hematology
Albumin
Absolute lymphocyte count
Alkaline phosphatase*
Absolute neutrophil count
ALT (SGPT)*
Hematocrit
Amylase
Hemoglobin
AST (SGOT)*
Platelet count
Gamma glutamyltransferase (GGT)
Red blood cells (RBC)
Blood urea nitrogen (BUN)/Total urea*
WBC and differential count
Calcium*
RBC morphology#
Chloride*
Reticulocytes#
Cholesterol
Mean corpuscular hemoglobin (MCH)
Creatine kinase
Mean corpuscular volume (MCV)
Creatinine*
Mean corpuscular hemoglobin concentration 
(MCHC)
C-reactive protein (CRP)
Glucose*
Hemostaseology
Lactate dehydrogenase (LDH)
Activated partial thromboplastin time (aPTT)
Lipase
Prothrombin time (INR)
Phosphorus/Phosphates*
Magnesium*
Urinalysis***
Full: protein content**, albumin 
Basic (dipstick): protein content only**
Potassium*
Serum electrophoresis#
Sodium*
Total bilirubin*
Total protein
Totality of binding ADA
Uric acid
Triglycerides
ACTH (10 mg/kg once weekly cohort), ANA 
(10 mg/kg once weekly cohort), RF (10 mg/kg once 
weekly cohort), TSH, and T4.
Hormone
Follicle-stimulating hormone (if applicable)
ACTH: adrenocorticotropic hormone; ADA: anti-drug antibody; ALT: alanine aminotransferase; 
ANA: anti-nuclear antibody; AST: aspartate aminotransferase; RF: rheumatoid factor; SGOT: serum glutamic 
oxaloacetic transaminase; SGPT: serum glutamic pyruvic transaminase; T4: Free thyroxine; TSH: Thyroid-
stimulating hormone.
*Core serum chemistries.
**If urinalysis is positive for protein, sediment will also be evaluated.
*** Urinalysis does not have to be performed on subjects with urothelial cancers.  
#  Only if clinically indicated.
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If a subject has a clinically significant abnormal laboratory test value that is not present at baseline, 
the test will be repeated weekly and the subject will be followed until the test value has returned 
to the normal range or the investigator has determined that the abnormality is chronic or stable.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
The ECOG performance status will be assessed at screening and at subsequent visits as indicated 
in the schedule of assessments and documented in the CRF.
Body weight will be measured at screening and at subsequent visits as indicated in the schedule of 
assessments and documented in the CRF. Body height will be measured at screening only.
A physical examination will be conducted at screening and at subsequent visits as indicated in the 
schedule of assessments (Appendix I) and documented in the CRF (detailed description in Section 
7.1). Results of the physical examination including any abnormalities will be documented in the 
CRF. Abnormal findings are to be reassessed at subsequent visits.
A 12-lead ECG will be recorded at screening and at study visits as indicated in the schedule of 
assessment.
All newly diagnosed or worsening conditions, signs and symptoms observed since screening, 
whether related to trial treatment or not, are to be reported as AEs.
For female subjects of childbearing potential, serum β-HCG pregnancy test will be carried out 
during the screening phase. A urine β-HCG test will be performed before administration of IMP 
during the treatment phase according to schedules of assessments (Appendix I), at the 
end-of-treatment visit and at the post-treatment follow-up visit. Results of the most recent 
pregnancy test should be available prior to the next dosing of IMP. Subjects that are 
postmenopausal (age-related amenorrhea ≥ 12 consecutive months or FSH > 40 mIU/ml), or who 
had undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing.
7.5
Pharmacokinetics
7.5.1
Dose Escalation Phase
Pharmacokinetic parameters include AUC0-t, AUC0-∞, λz, Cmax, tmax, and t½ (for definitions, see 
Section 8.5.3.2). Blood samples for the analysis of serum concentrations of avelumab will be 
drawn in all subjects according to the schedule listed below and the Schedule of Assessments (see 
Appendix I).
! Day 1: prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after 
infusion.
! Day 2: 24 and 36 hours after infusion (optional).
! Day 3: 48 hours after infusion (±6 hours) (optional).
! Days 15, 29, 43, 85, 127, and 169: prior to infusion (trough value) and immediately after 
infusion is completed (peak value).
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!
For the 10 mg/kg of avelumab once weekly cohort, blood samples for PK determinations 
will be collected from all subjects within 2 hours prior to each infusion at Weeks 1, 2, 3, 5, 
and 7 (every 2 weeks), at Weeks 13, 15, 19, and 25, and then at 12-week intervals while 
on treatment. A sample at the end of infusion (within 15 minutes) will be collected at 
Weeks 1, 7, 13, and 25. Samples will be collected at the End-of-Treatment visit and the 
Safety Follow-up visit.
7.5.2
Expansion Phase
! PK samples will be obtained prior to each administration of study drug on Days 1, 15, 29, 43, 
57, 71, 85, 127, and 169 for all subjects in the primary cohorts (NCSLC post platinum doublet, 
gastric / GEJ cancer, and MBC).
! PK samples will be obtained prior to each administration of study drug on Days 1, 15, 29, 43, 
57, 71, 85, 127, and 169 for all subjects in the ACC, melanoma, mesothelioma, ovarian cancer, 
and urothelial carcinoma secondary cohorts.
! Expanded PK sampling will be performed for all subjects in the CRC and CRPC secondary 
cohorts as follows:
o
Day 1: prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours 
after infusion.
o
Day 2: 24 and 36 hours after infusion (optional).
o
Day 3: 48 hours after infusion (±6 hours) (optional).
o
Days 15, 29, 43, 85, 127, and 169: prior to infusion (trough value) and immediately after 
infusion is completed (peak value).
! Expanded PK sampling will be performed for all subjects in the first-line NSCLC cohort as 
follows:
o
Within 2 hours prior to each study drug administration on Days 1, 15, 29, 43, 57, 71, 85, 
99, and 169. 
o
Post-study drug administration samples will be collected at the end of the infusion and 
also 2 to 8 hours after the end of infusion (later is better depending on how long the 
subject will stay in the clinic), on Days 1, 43, 85, and 169. 
o
Samples will also be collected at the 10-week safety follow-up visit (any remaining 
sample may be used for ADA determination).
! For subjects enrolled in the efficacy expansion cohorts and the RCC secondary cohort, samples 
for PK determination will be collected as follows:
o
Within 2 hours prior to each study drug administration on Days 1, 15, 29, 43, 57, 71, 85, 
and 169. 
o
Post-study drug administration samples will be collected at the end of infusion and 2 to 
8 hours after the end of infusion (later is better, depending on how long the subject will 
stay in the clinic) at Days 1, 43, 85, and 169.  Exact sampling times will be recorded.  
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o
Samples will be collected at the 10-week Safety Follow-up visit (any remaining sample 
may be used for ADA determination).
! For subjects who achieve a CR on avelumab therapy and then subsequently develop disease 
progression after stopping therapy, PK samples will be drawn as follows:
o
Within 2 hours prior to the second retreatment infusion, then prior to infusion 2 weeks 
later, and then every 6 weeks until 6 months after treatment re-initiation (e.g., pre-dose 
at Weeks 3, 5, 11, 17, and 23).
7.5.3
Body Fluid
Whole blood sufficient to provide 2 mL of plasma/serum will be collected for PK assessments. 
Post-infusion samples should be drawn from a site other than the infusion site (i.e., contralateral 
arm) on the days of infusion. If the infusion is interrupted, the reason for interruption will be 
documented on the CRF.
Further details will be summarized in the Laboratory Manual.
7.6
Biomarkers and 
Due to limited understanding of the biological activities induced by avelumab in cancer subjects, 
there can be no certainty that the doses examined will be associated with relevant anti-tumor 
immune activities. As the consequence, in addition to determining the MTD, the study will serve 
to 1) evaluate receptor occupancy at different levels, 2) investigate the mechanism of action of the 
drug by monitoring the activation status of the immune system (e.g., leukocyte subsets, PD-1 
signaling pathway, ADCC-related activities, cytokines profile, soluble PD-1, and soluble PD-L1) 
in order to establish the optimal biological dose, 3) investigate safety markers (see Section 7.4), 
4) explore anti-tumor specific immune responses induced by the exposure to avelumab, and 
5) evaluate potential predictive / prognostic biomarker candidates related to the drug and/or the 
cancer (e.g., level of PD-L1 tumor expression, profile of tumor infiltrating cells). 
Details of time points and sampling are provided in Appendix I. Time points and markers proposed 
in the expansion part may change based on biological activities to be observed in the escalation 
part and /or indications.
In order to complete all the assessments on tumor materials, blood (plasma and serum samples), 
the Sponsor or the designated CRO will provide instructions and necessary supplies to the site, 
including shipping materials and prepaid mailers. Please refer to the Laboratory Manual for 
detailed information.
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7.6.1
Biomarker Investigation in Dose Escalation Cohorts
7.6.1.1
Receptor Occupancy – Dose Escalation Phase
Eight mL of blood will be collected in heparinized tube (one 8 mL Cell Preparation Tube™[CPT]) 
to analyze receptor occupancy on Day 1 before start of the infusion, at 4 and 48 hours (±6 hours; 
Day 3) after the start of infusion, and before the start of each infusion on Days 15, 29, 43, and 85
for subjects in dose escalation phase.  Note: no samples will be obtained for receptor occupancy 
from the 10 mg/kg once weekly cohort.
7.6.1.2
Immunomonitoring 
As biomarker research is constantly evolving, the selection of markers with the highest specificity 
and relevance to treatment effect may change.
Leukocyte subpopulations and immune activation status will be assessed by flow cytometry 
(FACS) on PBMC from heparinized blood samples (16 mL, two 8 mL CPTs) drawn before start 
of each infusion, and 48 hours (±6 hours) after start of each infusion on Days 1, 43, 85, and before 
start of infusion only on Days 15, 127, and 169. Supplementary 16 mL (two 8 mL CPTs) of blood 
will be collected at the end-of-treatment visit (within 28 days after the last treatment) for biological 
follow-up. A complete differential blood count will be provided for each time point for calculations 
of the absolute count of leukocyte subpopulations. From these samples, plasma (3 to 5 mL) will 
be collected for retrospective analyses, if technically feasible. Note: no samples will be obtained 
for immune monitoring from the 10 mg/kg once weekly cohort.
Soluble factors (e.g., cytokines profile, soluble PD-1, and soluble PD-L1) will be assessed on
blood (plasma/serum) samples collected before start of each infusion and 48 hours (±6 hours) after 
start of each infusion on Days 1 (baseline value, if not collected at screening), 43, 85, and before 
start of infusion only on Days 15, 127, and 169. One additional blood sample for soluble factors
will be collected at the end-of-treatment visit (within 28 days after the last treatment) for biological 
follow-up. In addition, any remaining backup PK and ADA serum samples may be used for 
assessment of soluble factors if needed.  For the 10 mg/kg once weekly cohort, blood samples for 
soluble factors will be collected before start of each infusion on Days 1 (baseline), 8, 15, 29, 43, 
and 85.
7.6.2
Biomarkers Investigation in Expansion Cohorts
Of note, time points and markers in this section may change on the basis of the results to be 
observed in the escalation part and /or indication.
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7.6.2.1
Receptor Occupancy – CRPC and CRC Cohorts
Eight mL of blood will be collected in heparinized tube (one 8 mL CPT) to analyze receptor 
occupancy on Day 1 before start of the infusion, at 4 hours (±6 hours) after the start of infusion, 
and before the start of each infusion on Days 15, 29, 43, and 85 for subjects in the CRPC and CRC 
cohorts.
7.6.2.2
Immunomonitoring
Primary Cohorts (NSCLC post platinum doublet and first-line, Gastric / GEJ Cancer,
MBC):
Soluble factors (e.g., cytokines profile) will be assessed on blood samples collected before start 
of infusion (Day 1), Day 43, and at the end-of-treatment visit (within 28 days after the last 
treatment). In addition, any remaining backup PK and ADA serum samples may be used for 
assessment of soluble factors if needed.
Secondary Cohorts (except for the RCC Cohort):
Leukocyte subpopulations and immune activation status will be assessed by flow cytometry 
using heparinized blood. All expansion subjects in the secondary cohorts will have 40 mL of blood 
(five 8 mL CPTs) collected before start of infusion at Days 1 (if not collected at screening), 15, 
43, and 85, and at the end-of-treatment visit. Additionally, 40 mL of blood will be collected 
48 hours (±6 hours; Day 3) after the start of the first infusion only of IMP in these subjects (this 
sample is optional). Until completion of the escalation part, it is planned to consider similar 
markers (see Section 7.6.1.2).
Soluble factors (e.g. cytokines profile) will be assessed on blood samples at the same times as 
the primary cohorts (Day 1, Day 43, and at the end-of-treatment visit [within 28 days after the last 
treatment]). In addition, subjects in the secondary expansion cohorts will have blood drawn 
48 hours after start of first infusion only (±6 hours; Day 3; this sample is optional). In addition, 
any remaining backup PK and ADA serum samples may be used for assessment of soluble factors 
if needed.
Efficacy Expansion Cohorts and the RCC Secondary Cohort:
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7.6.2.4
Predictive/Prognostic Biomarkers
It is important to identify biomarkers that help to predict and/or evaluate the efficacy of the therapy, 
in order to achieve the optimal benefit from targeted therapies. No thoroughly validated biomarkers 
are available to date for anti-PD-1 / PD-L1 therapies. Therefore, this trial plans to evaluate 
biomarkers from archived tumor and/or biopsies (excluding bone biopsies) and blood samples that 
might be predictive of therapy outcome for all indications. Of note, availability of tumor archival 
material and/or fresh biopsies will be a prerequisite for all subjects to be enrolled in the expansion 
part.
The following requirements apply to the archived and fresh tissue samples collected during the 
trial: 
Tissue collection: Endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies 
and surgical specimens are suited. Fine needle aspiration biopsies are not suited. The most recent 
biopsy or surgical specimen is required. For expansion subjects in the MBC cohort, the biopsy or 
surgical specimen must have been collected within 90 days prior to the first IMP administration.
Tissue processing: The cancer tissues should be fixed in 10% neutral buffered formalin (NBF), 
paraffin-embedded and routinely processed for histological evaluation. Formalin substitutes are 
not suited as fixative. 
Tissue storage: Fresh tumor tissue obtained from subjects in the melanoma and mesothelioma 
cohorts for the evaluation of efficacy should be stored in defined cryopreservation medium 
containing 10% dimethyl sulfoxide [CryoStor® CS10]. (This additional tumor biopsy is optional).
Provision of samples: 1. priority: tumor containing formalin fixed, paraffin embedded (FFPE) 
tissue block; 2. priority: if the tumor containing FFPE tissue block cannot be provided in total, 
sections from this block should be provided which are freshly cut, 4 μm thick and mounted on 
positively-charged microscope slides. SuperFrost Plus glass slides are recommended. Preferably, 
25 slides should be provided; if not possible a minimum of 7 slides is required. 
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For subjects in the first-line NSCLC primary expansion cohort with non-squamous cell histology 
and unknown EGFR and ALK status, additional slides may be necessary for determination if 
EGFR and ALK status prior enrollment.  Please refer to the Laboratory Manual for detailed 
information.
For subjects in the HNSCC cohort additional slides may be necessary for determination of tumor 
HPV status. Please refer to the Laboratory Manual for detailed information.
Sample shipment: The tumor blocks and freshly prepared slides should be sent with next shipment 
to the central lab at room temperature. 
Sample storage: At the central laboratory the FFPE tissue blocks shall be stored at room 
temperature and the tumor slides shall be frozen in sealed containers at -20°C.
A panel of putative markers including molecular, soluble and cellular markers may be analyzed at 
baseline from archived tumor tissue (or fresh tumor biopsy, if available), whole blood, and serum 
samples to investigate a possible correlation between clinical efficacy and analyzed markers. 
The following assessment will be considered:
Mandatory (for all indications in the expansion cohorts, including efficacy expansion
cohorts):
! Level of PD-L1 expression in archived tumor and/or fresh biopsy by immunohistochemistry 
staining (IHC). Of note, further techniques to evaluate the expression of PD-L1 and/or marker 
candidates impacting the targeting or contributing to improve its expression may be also 
investigated if needed.
! Mandatory for ovarian cancer cohorts only:
o Blood levels of CA-125, at screening, Week 7 and every 6 weeks thereafter.
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7.7
Other Assessments
7.7.1
ADA Analysis
The blood sample for baseline ADA analysis will be collected before trial treatment start. Further 
serum samples for ADA analysis will be collected on Days 15, 29, 43, 57, 71, 85 (every 2 weeks), 
on Days 127 and 169 (every 6 weeks) prior administration of study drug, and at the 
End-of-Treatment visit (any remaining sample from this visit may be used for PK determination).  
For the 10 mg/kg once weekly cohort, samples for ADA determination will be collected Days 1 
(baseline), 15, 29, 43, 57, 71, 85, Week 19, and on Week 25 and every 12 weeks thereafter. The 
baseline sample should be collected prior to the first administration of trial treatment, i.e., either 
during the screening period or pre-dose on Day 1. The term for ADA on CRF is human-antihuman 
antibodies (HAHA).
For subjects who achieve a CR on avelumab therapy and then subsequently develop disease 
progression after stopping therapy, ADA samples will be drawn prior to the second retreatment 
infusion, then 2 weeks later, and then every 6 weeks until 6 months after treatment re-initiation
(e.g. pre-dose at Weeks 3, 5, 11, 17, and 23).
Samples positive for ADA will be re-analyzed to determine the titer and characterized for the 
presence of neutralizing antibodies that block binding to PD-L1.
8
Statistics
8.1
Sample Size
The sample size for the dose-escalation part of the trial is not based on any statistical assumptions. 
Rather, it follows the “3 + 3 rule”, a well-established methodology in the design of dose-finding 
trials in oncology.
This trial plans for cohorts of 3 subjects to be treated at each escalating dose level. After the 
appearance of a single DLT, the cohort for that dose level will be expanded to 6 subjects.
Therefore, the number of subjects enrolled in the dose-escalation phase of the trial will depend on 
the number of dose escalation steps needed to reach the MTD. Once the dose of 10 mg/kg is 
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established as safe, accrual of 10 additional subjects at 3 mg/kg and 10 mg/kg each may be 
enrolled, for the purpose of generating additional safety, PK and receptor occupancy data, if agreed 
with the SMC. Once the safety of a dose of 15 mg/kg or 20 mg/kg has been established, the SMC 
will have the possibility to allow enrollment of up to 15 additional subjects at that dose. 
Together with the 6 subjects in the once weekly 10 mg/kg cohort, the expected total sample size 
in the dose escalation phase of the trial will be up to 66 subjects.
The primary endpoint of the efficacy expansion cohorts is the confirmed BOR according to 
RECIST 1.1, as adjudicated by an IERC. The ORR will be determined as the proportion of subjects 
with a confirmed BOR of PR or CR. For each of these cohorts, the trial aims at demonstrating an 
ORR greater than 10% by means of an exact binomial test with an overall 1-sided alpha level of 
0.025.   
Based on an assumed ORR of 20% in an unselected population, the sample size of 150 subjects 
(gastric / GEJ cancer, HNSCC) will provide approximately 91% power, and the sample size of 
100 subjects (ovarian cancer) will provide approximately 80% power to reject the null hypothesis 
of ORR ≤ 10% at the primary analysis.
The sample size of 200 subjects in the urothelial carcinoma efficacy expansion cohort is expected 
to result in 50-60 PD-L1 positive subjects (based on an expected proportion of 85% PD-L1-
evaluable subjects and a proportion of 30 to 35% PD-L1 positive subjects among those that are 
evaluable). Under the assumption of an ORR of 27% in PD-L1 positive subjects, the sample size 
of 50 to 60 PD-L1 positive subjects will provide at least 90% power to reject the null hypothesis 
of ORR ≤ 10%.
The assumption of an ORR of 27% in PD-L1 positive subjects in the urothelial carcinoma efficacy 
expansion cohort is supported by preliminary results of the urothelial carcinoma secondary 
expansion cohort.  
In the given populations of refractory metastatic cancer patients, it is considered that superiority 
compared with an ORR of 10% may indicate clinical benefit if the observed responses are durable. 
The assumption of an ORR of 20% in an unselected population in gastric / GEJ cancer, HNSCC, 
and ovarian cancer is supported by results from clinical studies with anti-PD-1 / anti-PD-L1 agents.
The sample size of 150 for each of the 4 primary disease specific expansion cohorts has been 
chosen primarily to further explore the safety and efficacy of avelumab in specific indications, as 
well as in subgroups defined by PD-L1 tumor expression status, and to provide data to aid in future 
study design. 
From an efficacy perspective, the sample size of 150 in each of the primary expansion cohorts will 
provide estimates and 95% Clopper-Pearson CIs for response rate of 10% (5.7%, 16.0%) in the 
case of 15 responders out of 150 subjects, and of 20% (13.9%, 27.3%) in the case of 30 responders 
out of 150 subjects. 
Furthermore, the following can be said regarding the precision of estimated response rates in 
subjects that are positive for PD-L1 expression: For given proportions of PD-L1 positive subjects 
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in an expected range of 30 to 70% and given response rates in the subgroup of PD-L1 positive 
subjects in an expected range from 20 to 33%, the subgroup analysis 95% Clopper-Pearson CIs 
based on a total sample size of 150 will be as shown in Table 8.1.
Table 8.1
95% Confidence Intervals of Estimated Response Rates
Response rate in PD-L1 positive subjects
20%
33.3%
Proportion and absolute number of PD-L1 
positive subjects (N=150)
95% CI
95% CI
30% (45)
(9.6%, 34.6%)
(20.0%, 49.0%)
50% (75)
(11.6%, 30.8%)
(22.9%, 45.2%)
70% (105)
(12.8%, 28.9%)
(24.4%, 43.2%)
CI: confidence interval; PD-L1: Programmed death ligand 1.
The sample size of 120 in the ovarian cancer secondary expansion cohort will provide estimates 
and 95% Clopper-Pearson CIs for response rate of 10% (5.3%, 16.8%) in the case of 12 responders 
out of 120 subjects, and of 20% (13.3%, 28.3%) in the case of 24 responders out of 120 subjects.
The sample size of 50 in the secondary expansion cohorts of ACC, melanoma, mesothelioma, and 
urothelial carcinoma will provide estimates and 95% Clopper-Pearson CIs for response rate of 
10% (3.3%, 21.8%) in the case of 5 responders out of 50 subjects, and of 20% (10.0%, 33.7%) in 
the case of 10 responders out of 50 subjects. 
For the secondary expansion RCC cohort, the 20 subjects of second-line RCC and 60 subjects of 
first-line RCC will be analyzed separately. The sample size of 20 second-line RCC subjects will 
enable observation of at least 2 responders with a probability of at least 89.8% if the true response 
rate is at least 18%, which is considered an effect of interest. The sample size of 60 first-line RCC 
subjects will provide estimates and 95% Clopper-Pearson CIs for response rate of 20% (10.8%, 
32.3%) in the case of 12 responders out of 60 subjects, and of 25% (14.7%, 37.9%) in the case of 
15 responders out of 60 subjects.
The sample size of 20 subjects for the interim evaluation of clinical activity in each of the ACC, 
melanoma, mesothelioma, ovarian cancer, and urothelial carcinoma secondary cohorts will enable 
observation of at least 1 responder with a probability of at least 93% (79%, 98%) if the true 
response rate in PD-L1 positive subjects is at least 25%, which is considered as an effect of interest, 
and the prevalence of PD-L1 positivity is 50% (30%, 70%), respectively. Thus, the failure to detect 
at least 1 response among the first 20 subjects is seen as an indicator of insufficient clinical activity 
in a given cohort. See also Section 8.6.
The sample size of 109 subjects for the interim evaluation of tumor activity in urothelial carcinoma 
efficacy cohort will provide estimates and 95% Clopper-Pearson CIs for response rate of 23% 
(9.9%, 42.3%) in the case of 7 responders of 30 PD-L1 positive subjects, of 27% (12.2%, 45.9%) 
in the case of 8 responders of 30 PD-L1 positive subjects, and of 33% (17.2%, 52.8%)  in the case 
of 10 responders of 30 PD-L1 positive subjects.
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From a safety assessment perspective, the total sample size of 1640 from all 16 cohorts will provide 
sufficient data to detect safety signals. Specifically, for toxicities with an incidence rate of 0.5%, 
the probability of observing at least 1 event will be >99%.
The total sample size at the end of the trial (based on the dose escalation part and the expansion 
cohorts) is expected to be up to approximately 1706 treated subjects.
8.2
Randomization
Not applicable.
8.3
Endpoints
8.3.1
Primary Endpoints
! Occurrence of DLTs during the first 3 weeks of treatment in the dose escalation part (excluding 
the once weekly 10 mg/kg cohort).
! The confirmed BOR, per RECIST 1.1, as adjudicated by an IERC (see Section 7.3) for subjects 
enrolled in the efficacy expansion cohorts.
8.3.2
Secondary Endpoints
! Number, severity, and duration of TEAEs for all dose groups / indications according to the 
NCI-CTCAE) v4.0.
! Number, severity, and duration of treatment-related AEs according to NCI-CTCAE v4.0.
PK profile.
! irBOR and BOR according to modified irRC and to RECIST 1.1, respectively, per investigator 
assessment.
! The confirmed BOR, per RECIST 1.1, as adjudicated by an IERC (see Section 7.3) for subjects 
enrolled in the secondary urothelial carcinoma cohort
! irPFS time and PFS time, according to modified irRC and to RECIST 1.1, respectively, per 
investigator assessment, defined from first administration of trial treatment until first 
observation of progressive disease or death when death occurs within 12 weeks of the last tumor 
assessment or first administration of trial treatment (whichever is later). Any subject with 
neither assessment of tumor progression, nor death date within 12 weeks after last tumor 
assessment will be censored on the date of last tumor assessment or first administration of trial 
treatment.
! OS time defined as the time from first administration of trial treatment to death. For subjects 
who are still alive at the time of data cut-off for the trial analysis or who are lost to follow-up, 
survival will be censored at the last recorded date that the subject is known to be alive, as of the 
cut-off date for the analysis.
! Pharmacodynamic profile.
! Serum titers of ADA.
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! Expression of PD-L1 on tumor tissue.
! For the primary expansion cohorts only: Unconfirmed response at Week 13 according to 
RECIST 1.1, per investigator assessment.
! Duration of response, according to modified irRC and to RECIST 1.1, per investigator 
assessment, defined as the time from the first observation of response to the first observation of 
documented disease progression (or death within 12 weeks of the last tumor assessment). 
Subjects without an event at the analysis cut-off date will be censored on the date of the last 
tumor assessment.
! For the efficacy expansion cohorts only: 
o
PFS time, according to RECIST 1.1, per IERC
o
Duration of response according to RECIST 1.1, per IERC.
8.3.3
Safety Endpoints
Besides the endpoints specified as primary and secondary variables the following endpoints will 
be evaluated:
! Laboratory parameters
8.4
Analysis Sets
The following analysis sets will be defined separately for the dose escalation part and the 
expansion cohorts in this trial, as applicable:
! DLT population (dose escalation part): all subjects with data used for implementing the dose-
escalation schedule. These subjects should have received all study treatment administrations in 
the DLT evaluation period or should have stopped treatment because of DLTs in the DLT 
evaluation period.
! Safety population: all subjects who have received at least 1 dose of trial treatment.
! Full analysis set (FAS): all subjects who have received at least 1 dose of trial treatment.
! PD-L1 positive FAS (urothelial carcinoma efficacy expansion cohort): all PD-L1+ subjects 
who have received at least 1 dose of trial treatment. 
! PK population: All subjects who have completed at least 1 infusion of study drug, and who 
have provided sufficient concentration measurements.
! Efficacy population (efficacy expansion cohorts): all subjects who have received at least 
1 dose of trial treatment and have measurable disease at baseline according to IERC assessment.
! PD-L1 positive efficacy population (urothelial carcinoma efficacy expansion cohort): all 
PD-L1+ subjects who have received at least 1 dose of trial treatment and have measurable 
disease at baseline according to IERC assessment.  
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! Efficacy population (primary and secondary expansion cohorts): all subjects who have 
received at least 1 dose of trial treatment and have measurable disease at baseline according to 
investigator assessment.
The definition of the Safety Population and the FAS are identical in this non-randomized study; 
the Safety population will be used for the safety analysis and the FAS will be used for efficacy 
analysis. The PD-L1 positive FAS will be the primary analysis population for the primary endpoint 
of BOR by IERC in the urothelial carcinoma efficacy expansion cohort.
PD-L1 status is assessed by immunohistochemistry. Subjects will be considered PD-L1 positive 
(negative) for the urothelial carcinoma efficacy expansion cohort if at least (less than) 5% of the 
tumor cells show PD-L1 membrane staining, respectively. If during assay development (based on 
generic samples) a different cut-off is determined to be more appropriate, this cut-off may be 
adapted in the SAP prior to analysis of subject samples from this trial. 
8.5
Description of Statistical Analyses
8.5.1
General Considerations
All data recorded during the study will be presented in individual data listings performed on the 
safety population. All data will be evaluated as observed, and no imputation method for missing 
values will be used unless otherwise specified. All data will be presented in a descriptive manner. 
Confirmatory analyses will be conducted for the primary endpoint of the efficacy expansion 
cohorts. Each cohort will be analyzed separately, and no multiplicity adjustment across cohorts 
will be performed. All other analyses are considered as exploratory, even if statistical tests are 
used.
Descriptive statistics will be used to summarize the trial results, i.e., statistics for continuous 
variables may include means, medians, ranges and appropriate measures of variability. Qualitative 
variables will be summarized by counts and percentages. The uncertainty of estimates will be 
assessed by CIs. Unless otherwise specified, the calculation of proportions will be based on the 
sample size of the population of interest. Counts of missing observations will be included in the 
denominator and presented as a separate category if not otherwise specified in the SAP.
The DLT population is the underlying data set for the MTD determination. Safety analyses will be 
performed on the safety population and efficacy analyses will be performed on the FAS. Sensitivity 
analysis of the BOR on the efficacy population will be conducted according to further 
specifications in the SAP. Analyses of PK variables will be performed on the PK population.
The estimation of PK parameters will be performed using WinNonlin® Version 5.0 or higher. All 
other statistical analyses will be performed using SAS® Version 9.1.3 or higher, or R, Version 
2.10.1 or higher.
Full details of the planned analyses will be described in the trial statistical analysis plan (SAP), 
separately for the dose escalation and the expansion part of the trial.
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Unless otherwise specified, the endpoint analyses described in the following will be performed 
separately for both the dose escalation part and the expansion cohorts of the trial. The primary 
analysis of the once weekly 10 mg/kg cohort is a safety analysis, which will be done in the 
framework of the first SMC meeting in this cohort.
8.5.2
Analysis of Primary Endpoints
8.5.2.1
Maximum Tolerated Dose Determination
For determination of the MTD, individual subject data from the dose escalation part will be 
reported. 
In addition, for the final statistical analysis, the following will be analyzed:
! At each dose level, the number and proportion of subjects in the DLT population who 
experience a DLT during the first DLT evaluation period.
! At each dose level, the number and proportion of TEAEs experienced by subjects in the DLT 
population during the first DLT evaluation period.
The MTD will be determined according to the dose-escalation plan described in Section 5.1.4.2.
The MTD is defined as the highest dose level at which no more than 1 subject out of 6 subjects 
treated in a cohort and evaluable for DLT determination experiences a DLT.
8.5.2.2
Confirmed Best Overall Response per RECIST 1.1 by IERC 
The primary endpoint in the efficacy expansion cohorts is the BOR according to RECIST 1.1 and 
as adjudicated by an IERC (see Section 2.2.2), defined as the best response obtained among all 
tumor assessment visits after start of trial treatment until documented disease progression, taking 
into account the following requirement for confirmation.  For a BOR of PR or CR, confirmation 
of the response according to RECIST 1.1 (48) will be required, preferably at the regularly 
scheduled 6-week assessment interval, but no sooner than 4 weeks after the initial documentation 
of CR or PR. Confirmation of PR can be confirmed at an assessment later than the next assessment 
after the initial documentation of PR. A BOR of SD requires that a time point overall response of 
SD has been determined at a time point at least 37 days after start of study treatment. The response 
at each scheduled tumor assessment and the BOR will be listed for each subject. 
For the gastric / GEJ cancer, HNSCC, and ovarian cancer efficacy expansion cohorts, the primary 
analysis of the BOR by IERC will be conducted in the FAS, defined as all treated subjects. The 
number and proportion of BOR (defined as CR + PR) will be tabulated. The ORR will be 
determined as the proportion of subjects with a confirmed BOR of PR or CR. An exact binomial 
test will be performed at a 1-sided alpha level of 0.025. The primary analysis is planned 6 months 
after start of treatment of the last subject in the given cohort. Interim analyses will be conducted 
after 60% of the subjects in the given cohort have been followed up for 13 weeks. Analyses are 
considered positive if the lower limit of the 95% confidence interval exceed 10%. Confidence 
intervals will be constructed using the Clopper-Pearson method.
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For the urothelial carcinoma efficacy expansion cohort, the analysis of the BOR by IERC will be 
conducted in the PD-L1 positive FAS (see Section 8.5.3.1) followed by the FAS. The number and 
proportion of BOR (defined as CR + PR) will be tabulated. The ORR will be determined as the 
proportion of subjects with a confirmed BOR of PR or CR. An exact binomial test will be 
performed in the PD-L1 positive FAS and in the FAS to determine whether the null hypothesis of 
an ORR ≤ 10% can be rejected at the 1-sided alpha level of 0.025. Interim analyses will be 
conducted  for the 109 subjects enrolled in the urothelial carcinoma efficacy expansion cohort prior 
to Protocol Amendment 13.  Analyses are considered positive if the lower limit of the 95% CI of 
the confirmed BOR exceeds 10%. Confidence intervals will be constructed using the 
Clopper-Pearson method.
8.5.3
Analysis of Secondary Endpoints
8.5.3.1
Efficacy Parameters
Clinical efficacy parameters will be analyzed descriptively in the FAS, and, in addition, for the 
urothelial carcinoma efficacy expansion cohort, in the PD-L1 positive FAS. Response rates will in 
addition be calculated in the efficacy population according to further specifications in the SAP.
Pooling of data from secondary and efficacy expansion cohorts may be considered to enhance 
precision of estimates. Further details will be specified in the SAP.
The primary efficacy parameter in the expansion part is the Best Overall Response according to 
RECIST 1.1.
The BOR per investigator assessment will be determined according to RECIST 1.1 and modified 
irRC, respectively. The BOR will be evaluated over the whole trial period. For a BOR of PR or 
CR, confirmation of the response according to RECIST 1.1 (48) will be required. The response at 
each scheduled tumor assessment and the BOR will be listed for each subject. The number and 
proportion of BOR (defined as CR+PR) will be tabulated by cohort.
Duration of response, according to modified irRC and to RECIST 1.1, will be calculated for each 
subject with a confirmed response in the expansion cohorts and will be analyzed using the 
Kaplan-Meier method in the primary expansion cohorts. 
PFS time, irPFS time, and OS time will be presented in subject listings and analyzed using the 
Kaplan-Meier method in the FAS analysis set of the expansion cohorts that enrolled the full 
planned number of subjects.
In the expansion cohorts, subgroup analyses of efficacy parameters will be performed according 
to tumor PD-L1 expression status (positive, negative). Subjects will be considered PD-L1 positive 
(negative) if at least (less than) 5% of the tumor cells show PD-L1 membrane staining, 
respectively. If during assay development (based on generic samples) a different cut-off is 
determined to be more appropriate, this cut-off may be adapted in the SAP prior to analysis of 
subject samples from this trial. The association between PD-L1 expression status (positive, 
negative) and response (according to RECIST 1.1 as well as according to modified irRC) will be 
assessed using Fisher’s exact test. 
 
 
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8.5.3.2
Pharmacokinetic Profile
Plasma concentrations of avelumab will be determined by a validated method at the times listed in 
Schedule of Assessments (Appendix I).
The following PK parameters will be estimated and reported:
! AUC0→t: Area under the concentration-time curve from the time of dosing to the time of the 
last observation (calculated by linear trapezoidal summation).
! AUC0→∞: Area under the curve from the time of dosing extrapolated to infinity (calculated by 
the linear trapezoidal summation and extrapolated to infinity using Clast/λz).
! λz: Terminal elimination rate constant. The value of λz is determined from the slope of the 
regression line of log (concentration) vs. time with the following constraints: (i) there must be 
at least 3 consecutive measurable concentrations, (ii) all concentrations must be declining with 
time, and (iii) the correlation coefficient (r) of regression must be ≥ 0.95.
! Cmax: Maximum plasma concentration observed post-dose.
! tmax: Time at which the Cmax occurs.
! t½: Elimination half-life, determined as 0.693/ λz.
The PK parameters will be summarized using descriptive statistics. Individual as well as mean 
concentration-time plots will be depicted.
Unresolved missing data may be imputed when the analysis integrity is affected. The conservative 
principle will be used for data imputation.
8.5.3.3
Serum Titers of Anti-Avelumab Antibodies (ADA)
Immunogenicity testing strategy will be implemented and conducted in line with:
! Immunogenicity 
Assessment 
of 
Biotechnology-Derived 
Therapeutic 
Proteins 
(EMEA/CHMP/BMWP/14327/2006) (73).
! Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use 
(EMA/CHMP/BMWP/86289/2010) (74).
! FDA (2009, draft) Guidance for Industry: Assay Development for Immunogenicity Testing of 
Therapeutic Proteins (75).
A qualified method that uses an acid dissociation step to detect ADA in the presence of excess 
drug in human serum will be applied. Removal of drug after acid treatment is not required. ADA
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titers of positive samples will be determined and characterized for the presence of neutralizing 
antibodies that block binding to PD-L1.
In case anaphylactic reactions occur, the ADA samples from these subjects will be investigated 
for the presence of drug-specific IgE using a novel Phadia® ImmunoCAP® method, developed for 
this purpose. The analysis will also be performed in 50 randomly selected subjects enrolled in the 
expansion cohort that have not presented with anaphylactic reactions to serve as a control. 
8.5.4
Safety Analyses
The extent of exposure to avelumab will be characterized by duration (weeks), number of 
administrations, cumulative dose (mg/kg), dose intensity (mg/kg/week), relative dose intensity 
(actual dose given/planned dose), number of dose reductions, and number of dose delays.
Safety analyses will be performed on the safety population. The safety endpoints will be tabulated 
by dose-level and cohort, using descriptive statistics.
Safety assessments will be based on review of the incidence of AEs including AEs of special 
interest, ADRs, and changes in vital signs, ECGs, body weight, and laboratory values (hematology 
and serum chemistry).
The on-treatment period is defined as the time from the first dose of study treatment to the last 
dose of study treatment + 30 days, or the earliest date of new anticancer therapy – 1 day, whichever 
occurs first.
Adverse events
AEs will be coded according to Medical Dictionary for Regulatory Activities (MedDRA). Severity 
of AEs will be graded using the NCI-CTCAE v4.0 toxicity grading scale. 
Treatment emergent adverse events (TEAEs) are those adverse events with onset dates during the 
on-treatment period, or if the worsening of an event is during the on-treatment period. The 
incidence of TEAEs regardless of attribution and AEs defined as possibly related to avelumab will 
be summarized by preferred term and system organ class, and described in terms of intensity and 
relationship to avelumab. All premature terminations will be summarized by primary reason for 
study withdrawal.
Descriptive statistics will be examined for indications of dose-related ADRs.
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Laboratory variables 
Laboratory results will be classified by Grade according to NCI-CTCAE. The worst on-trial 
Grades after the first trial treatment will be summarized. Shifts in toxicity grading from first 
treatment to highest Grade will be displayed. Results for variables that are not part of NCI-CTCAE 
will be presented as below, within, or above normal limits. Only subjects with post-baseline 
laboratory values will be included in these analyses. 
Physical examination (including vital signs and 12-lead ECGs)
Physical examination data, including vital signs (body temperature, respiratory rate, heart rate, and 
blood pressure) and 12-lead ECG recorded according to the Schedule of Assessments (Appendix 
I) will be presented. 
Further details will be provided in the SAP based on current safety experience applying the latest 
MedDRA version.
8.6
Interim Analysis
In the dose escalation part, the trial data will be evaluated before decision is made to go to the next 
dose level or to start with treatment in expansion cohorts.
For the NSCLC (post platinum doublet and first-line), gastric / GEJ cancer, and MBC expansion 
cohorts, an interim analysis will be performed after the first 75 subjects have reached the time
point of the second post-baseline tumor assessment scheduled in Week 13, i.e. 13 weeks after start 
of treatment of the 75th subject. Efficacy in this 75 subject subset of the cohort will be analyzed 
in terms of the unconfirmed response at Week 13. If the rate of unconfirmed response at Week 13 
(according to RECIST 1.1) in the efficacy population defined as all treated subjects with 
measurable disease at baseline is less than 5%, enrollment in the given cohort will be stopped.
Other efficacy and safety endpoints will be analyzed as well, as detailed in the SAP.
Based on a comprehensive review of the efficacy and safety data it may be considered whether 
recruitment in a subgroup of the study population of the given indication, defined by PD-L1 
expression status, might be resumed by means of a substantial Protocol Amendment.
Statistical considerations related to this futility rule:
Under different assumptions on the true response rate in the overall population, the probabilities 
of observing a response rate of less than 5% in this analysis (i.e., 3 or less responders out of 
75 subjects) are noted in Table 8.2.
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Table 8.2
Probability of Observing a Response Rate of Less Than 5% in Interim 
Analysis
True response rate in overall population
Probability of 3 or less responders in 75 patients
0.03
0.81
0.05
0.48
0.10
0.05
0.15
0.002
In the NSCLC cohort only, 2 additional interim analyses of efficacy parameters are planned for 
internal planning purposes at the following time points: 
! 13 weeks after start of treatment of the 60th subject 
! 13 weeks after start of treatment of the last subject.
In the first-line NSCLC primary expansion cohort, an interim analysis of response will be 
conducted 13 weeks after start of treatment of the 30th subject.
In the efficacy expansion cohorts, interim analyses for efficacy are planned 13 weeks after the start 
of treatment of the 30th subject in all cohorts, 13 weeks after start of treatment of the  60th subject 
in the ovarian cohort, and 13 weeks after start of treatment of the 90th subject in the gastric / GEJ
and HNSCC cohorts. The interim analyses after 60/90 subjects aim to demonstrate efficacy as 
specified in Section 8.5.2.2. No futility rule is foreseen because the clinical activity of 
anti-PD-1 / anti-PD-L1 agents in these tumor types is established, and the patient populations are 
characterized by a high unmet medical need. If efficacy criteria are met at the interim analysis, 
enrollment will continue to the planned full number of subjects in order to collect further data on 
the primary and secondary endpoints, especially on the association between PD-L1 expression and 
efficacy endpoints.  
In the RCC cohort, one interim analysis of response will be performed 13 weeks after the start of 
treatment of the 20th subject of second line RCC.
In addition, in the other secondary cohorts that plan to enroll more than 20 subjects, i.e., the ACC, 
melanoma, mesothelioma, ovarian cancer and urothelial carcinoma cohorts, an interim analysis of 
response will be performed 13 weeks after the start of treatment of the 20th subject. Accrual in each 
cohort may be paused during the interim analysis. If no unconfirmed response according to 
RECIST 1.1 is observed in a given cohort in the interim analysis, accrual in that cohort will be 
stopped.  In addition, for the ovarian cancer secondary expansion cohort, an interim analysis of 
response will be performed for internal planning purposes 13 weeks after the start of treatment of 
the 75th subject.
For the purpose of internal planning and for reporting to regulatory authorities, the primary 
analysis results of the secondary urothelial carcinoma cohort will be updated. The efficacy 
endpoints such as BOR, PFS, OS, and safety endpoints such as the occurrence of TEAE will be 
included for these additional analyses. Interim analyses will be conducted for the 109 subjects 
enrolled in the urothelial carcinoma efficacy expansion cohort prior to Protocol Amendment 13.  
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The results of this analysis may be subject to reporting to regulatory authorities. The interim 
analysis is considered positive if the lower limit of the 95% CI of the confirmed BOR exceeds 
10%. Results will be presented for PD-L1 positive FAS and FAS.  Further details will be provided 
in the SAP.
The sequence of statistical analyses planned for urothelical cancer subjects will consider the 
objective to evaluate the association between tumor PD-L1 expression and BOR prospectively. In 
a first step, the secondary urothelial carcinoma cohort served as a “training set” for the 
identification of a PD-L1 expression cut-off that is most likely to identify a subset of the subject 
population with enhanced clinical benefit.  The PD-L1 expression cut-off was specified prior to 
any statistical analysis of the PD-L1 expression data from the urothelial carcinoma efficacy 
expansion cohort.  In the next step, the cut-off will be verified by conducting an interim evaluation 
with data from subjects of the efficacy expansion cohort at 6 months after the last subject’s first 
dose of study treatment for the 109 subjects enrolled in the urothelial carcinoma efficacy expansion 
cohort prior to Protocol Amendment 13. In case the cut-offs are not mutually supportive in terms 
of clinical efficacy endpoints the cut-off could be refined and the remainder of approximately 
100 subjects of the efficacy expansion cohort will serve as the “validation set” to qualify the tumor 
PD-L1 expression cut-off. Otherwise, data from subjects of the urothelial carcinoma expansion 
cohort will be pooled for the final efficacy analyses of the expansion cohort.
For each primary and secondary expansion cohort, an additional interim analysis may be conducted 
13 weeks after the start of treatment of the last subject in that cohort. In general, interim analyses 
at time points that are not specified in the protocol may be performed for internal planning 
purposes.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The investigator is responsible for the conduct of the trial at his/her site. He/she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on 
Good Clinical Practice (ICH Topic E6, 1996) and applicable regulatory requirements. In particular, 
the investigator must ensure that only subjects who have given their informed consent are included 
into the trial.
In 1998, the FDA introduced a regulation (21 CFR, Part 54) entitled “Financial Disclosure by 
Clinical Investigators”. For trials conducted in any country that could result in a product 
submission to the FDA for marketing approval and could contribute significantly to the 
demonstration of efficacy and safety of the IMP (named “covered trials” by the FDA), the 
investigator and all sub-investigators are obliged to disclose any financial interest which they, their 
spouses or their dependent children may have in the Sponsor or the Sponsor’s product under study. 
This information is required during the trial and for 12 months following completion of the trial.
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9.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the trial is his / her written informed 
consent. The subject’s written informed consent to participate in the trial must be given before any 
trial-related activities are carried out. A separate specific 
 ICF will be provided to subjects 
who are willing to participate in this optional procedure, which refers to the extraction and analysis 
of DNA from blood and / or tumor biopsy in order to better understand how 
) may affect 
the efficacy of avelumab.
Adequate information must therefore be given to the subject by the investigator before informed 
consent is obtained (a person designated by the investigator may give the information, if permitted 
by local regulations). A subject information sheet in the local language and prepared in accordance 
with the Note for Guidance on Good Clinical Practice (ICH Topic E6, 1996) will be provided by 
the Sponsor for the purpose of obtaining informed consent. In addition to providing this written 
information to a potential subject, the investigator or his/her designate will inform the subject 
verbally of all pertinent aspects of the trial. The language used in doing so must be chosen so that 
the information can be fully and readily understood by lay persons. 
Depending on national regulations, a person other than the investigator may inform the subject and 
sign the ICF, as above.
Where the information is provided by the investigator, the ICF must be signed and personally dated 
by the subject and the investigator. 
The signed and dated declaration of informed consent will remain at the investigator’s site, and 
must be safely archived by the investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information and ICF 
should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor or designee and be submitted again to the IEC / IRB for 
review and favorable opinion. The agreed, revised information will be provided to each subject in 
the trial for signing and dating. The investigator will explain the changes to the previous version.
9.3
Subject Identification and Privacy
A unique subject number will be assigned to each subject at inclusion, immediately after informed 
consent has been obtained. This number will serve as the subject’s identifier in the trial as well as 
in the clinical trial database.
The subject’s data collected in the trial will be stored under this number. The subject’s original 
medical data that are reviewed at the site during source data verification by the Monitor, audits 
and Health Authority inspections will be kept strictly confidential.
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Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor or designee. The Emergency 
Medical Support card is based on the need to provide clinical trial subjects with a way of 
identifying themselves as participating in a clinical trial, and subsequently to give health care 
providers access to the information about this participation that may be needed to determine the
course of the subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical trial; and this may include the possibility of emergency unblinding if needed, in case of 
blinded trials.
Clinical trial investigators, who are already aware of the clinical trial protocol and treatment, have 
other means of accessing the necessary medical information for the management of emergencies 
occurring in their subjects.
The first point of contact for all emergencies will be the clinical trial investigator caring for the 
affected subject. The investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the investigator is available when an event occurs, s/he will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard processes 
established for the investigators.
In cases where the investigator is not available, the Phase I facility will provide the appropriate 
means to contact a physician. This includes the provision of a 24-hour contact number at the 
facility, whereby the health care providers will be given access to an appropriate physician to assist 
with the medical emergency and to provide support for the potential unblinding of the subject 
concerned.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage shall be provided for each country participating to the trial. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents (such as the ICF) to the responsible IEC / IRB for its 
favorable opinion/approval. The written favorable opinion/approval of the IEC / IRB will be filed 
in the Investigator Site File, and a copy will be filed with the CRO.
The trial must not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC / IRB. The IEC / IRB will be asked to provide 
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documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained.
Amendments to the clinical trial will also be submitted to the concerned IEC / IRB, before 
implementation in case of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC / IRB during the course of the trial in accordance with national regulations 
and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (e.g., Investigational Medicinal 
Product Dossier, Subject Information, and ICF) will be submitted or notified to the Health 
Authorities in accordance with the regulations of the countries involved in the trial.
10
Trial Management
10.1
Case Report Form Handling
The investigator or designee will be responsible for entering trial data in the electronic CRF 
(eCRF) provided by the CRO and follow the data standards of the Sponsor. It is the investigator’s 
responsibility to ensure the accuracy of the data entered in the eCRFs.
The data will be entered into a validated database. The CRO will be responsible for data review 
and processing, in accordance with the Sponsor’s data management procedures. Database lock will 
occur once quality control procedure, and quality assurance procedures (if applicable) have been 
completed. PDF files of the eCRFs will be provided to the investigators at the completion of the 
trial.
10.2
Source Data and Subject Files
The investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible. In 
particular, the following data should be available in this file: 
! Subject’s full name,
! Date of birth,
! Sex,
! Race,
! Height,
! Weight,
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! Medical history and concomitant diseases,
! Prior and concomitant therapies (including changes during the trial),
! Tumor disease information,
! Trial identification (EMR 100070-001),
! Date of subject’s inclusion into the trial (i.e., date of giving informed consent),
! Subject number in the trial,
! Dates of the subject’s visits to the site,
! Any medical examinations and clinical findings predefined in the clinical trial protocol,
! All AEs observed in the subject,
! Date of subject’s end of trial, and
! Date of and reason for early withdrawal of the subject from the trial or from IMP, if applicable.
It must be possible to identify each subject by using this subject file.
Additionally, any other documents containing source data must be filed. This includes original 
printouts of data recorded or generated by automated instruments, photographic negatives, X-rays, 
CT or MRI scan images, ECG recordings, laboratory value listings, etc. Such documents must bear 
at least the subject number and the date when the procedure was performed. Information should 
be printed by the instrument used to perform the assessment or measurement, if possible. 
Information that cannot be printed by an automated instrument will be entered manually. Medical 
evaluation of such records should be documented as necessary and the documentation signed and 
dated by the investigator.
10.3
Investigator Site File and Archiving
The investigator will be provided with an investigator Site File upon initiation of the trial. This file 
will contain all documents necessary for the conduct of the trial and will be updated and completed 
throughout the trial. It must be available for review by the Monitor, and must be ready for Sponsor 
audit as well as for inspection by Health Authorities during and after the trial, and must be safely 
archived for at least 15 years (or per local requirements or as otherwise notified by the Sponsor) 
after the end of the trial. The documents to be thus archived include the Subject Identification List 
and the signed subject ICFs. If archiving of the Investigator Site File is no longer possible at the 
site, the investigator must notify the Sponsor.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the investigator should ensure that no destruction 
of medical records is performed without the written approval of the Sponsor.
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH Note for Guidance on Good Clinical 
Practice (ICH Topic E6, 1996). The site Monitor will perform visits to the trial site at regular 
intervals.
Representatives of the Sponsor’s Quality Assurance unit or a designated organization, as well as 
Health Authorities, must be permitted to inspect all trial-related documents and other materials at 
the site, including the Investigator Site File, the completed CRFs, the IMP(s), and the subjects’ 
original medical records/files.
The clinical trial protocol, each step of the data capture procedures, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the health authorities and 
to the relevant IEC / IRB for approval or favorable opinion. In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC / IRB or to Health 
Authorities only where requested by pertinent regulations.
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the subject’s informed consent prior to implementation (see Section 9.2).
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, or completion of a particular cohort or cohorts if applicable, a clinical 
trial report according to ICH Topic E3 will be written by the Sponsor or the designated CRO in 
consultation with the principal investigator.
10.6.2
Publication
The first publication will be a publication of the results of the analysis of the primary endpoint(s) 
that will include data from all trial sites that participated in the dose escalation phase of the trial.
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial. Any publications and presentations of the results (abstracts in journals or 
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newspapers, oral presentations, etc.), either in whole or in part, by investigators or their 
representatives will require pre-submission review by the Sponsor.
The Sponsor will not suppress or veto publications, but maintains the right to delay publication in 
order to protect intellectual property rights.
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11
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Latchman Y, Wood CR, Chernova T, et al. PD-L1 is a second ligand for PD-1 and inhibits T 
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Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients 
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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-
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12
Appendices
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Appendix I
Schedule of Assessments
Dose Escalation Phase (excepting 10 mg/kg once weekly cohort)
Measure
Screening/
Baseline 
Assessments
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Post 
Treatment
Safety 
Follow-up 
Visit
Post-
Treatment 
Survival 
Follow-up 
(18)
Day -18 to
First 
Treatment
V1
V2
V3
V4#
V5
V6#
V7
V8
V9
V10 V11
Until 
Progression
Up to ≤7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (18)
W1
W1
W1
W3
W5
W7
W9 W11 W13
d1
d2*
d3*
d15
d29
d43
d57
d71
d85
Written informed consent
X
In- and exclusion criteria
X
X 
(23)
Medical history
X
Demographic data
X
HBV, HCV, and HIV testing 
X
Physical examination
(including height at screening)
X
X
X
X
X
X
X
X
6∃weekly
x/X
X
Vital signs 
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
Weight
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
ECOG performance status
X (19)
X
X
X
X
X
X
X
2∃weekly
x/X
X
Enrollment (if eligible) (3)
X
IMP administration 
X
X
X
X
X
X
X
2∃weekly
DLT Assessment (20)
X
X
12-lead ECG (4)
X
X
X
X
X
X
X
X
6∃weekly
x/X
X
Hematology and hemostaseology 
X
X
X
X
X
X
X
2∃weekly
x/X
X
Core serum chemistry (5)
X
X
X
X
2∃weekly
Full serum chemistry (21)
X
X
X
6∃weekly
x/X
X
Urinalysis (22)
X
X
X
X
X
X
X
2∃weekly
x/X
X
β-HCG pregnancy test (if 
applicable) (6)
X
X
X
X
X
X
X
X
2∃weekly
- /X
X
Tumor evaluation / staging (CT 
Scan/ MRI/ Tumor markers / other 
established methods) (7,8,9,10)
X
X
X
6∃weekly
- /X
X
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Measure
Screening/
Baseline 
Assessments
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Post 
Treatment
Safety 
Follow-up 
Visit
Post-
Treatment 
Survival 
Follow-up 
(18)
Day -18 to
First 
Treatment
V1
V2
V3
V4#
V5
V6#
V7
V8
V9
V10 V11
Until 
Progression
Up to ≤7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (18)
W1
W1
W1
W3
W5
W7
W9 W11 W13
d1
d2*
d3*
d15
d29
d43
d57
d71
d85
Documentation of AEs and 
concomitant medication
X
X
X*
X*
X
X
X
X
X
X
2∃weekly
x/X
X (18)
X (18)
ACTH, ANA, ANCA, RF, free T4,
and TSH 
X
X
X
6∃weekly
- /X
X
PK sampling (11) 
X 
X*
X*
X
X
X
X
6∃weekly
up to incl. 
week 25
X
ADA sampling (12)
X
X
X
X
X
X
X
6∃weekly
up to incl. 
week 25
- /X
Receptor occupancy (13)
X
X*
X
X
X
X
Immunomonitoring (14)
X
X*
X
X
X
6∃weekly
up to incl. 
week 25
- /X
Soluble factors (14)
X
X*
X
X
X
6∃weekly
up to incl. 
week 25
- /X
Tumor biopsy or archived surgical 
X 
X
- /X
ACTH: adrenocorticotropic hormone; ADA: anti-drug antibody; AE: adverse events; ANA: anti-nuclear antibody; ANCA: anti-neutrophil cytoplasmic antibody;  
β-HCG: β-human chorionic gonadotropin; CT: computer tomography; DLT: dose-limiting toxicity; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; HBV: 
hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; IMP: investigational medicinal product; MRI: magnetic resonance imaging; PK: 
pharmacokinetics; RF: rheumatoid factor; SAE: serious adverse event; TSH: Thyroid-stimulating hormone, T4: Free thyroxine.
#Following approval of Protocol Amendment 7, the visits at Weeks 2 and 4 (Visit 4/Day 8 and Visit 6/Day 22) are no longer required and subjects will not 
be required to attend these visits. 
*Sampling on Days 2 and 3 is optional. As a result, the visit at Day 2 is optional. However, the visit at Day 3 is required for all dose escalation subjects in order 
that relevant biomarker samples can be collected as described in the corresponding footnotes.
A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all study procedures (except Days 2 and 3), except 
for body weight, which should be obtained on the same day as study drug administration. In addition, the tumor evaluation (see Section 7.3) has a tumor assessment 
visiting time window of 5 days prior to dosing (-5 days).
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1.
Tumor evaluation at the end-of-treatment visit should only be performed if no disease progression was documented previously.
2.
If another antineoplastic therapy is administered before the end of this 28 day-period, the end-of-treatment visit should be conducted if possible prior to the 
start of this new therapy.
3.
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion 
(Section 5.3.2). 
4.
12-lead ECG should be assessed before infusion and 2 hours (± 20 minutes) after infusion.
5.
Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin), acute 
chemistry panel (sodium, potassium, chloride, blood urea nitrogen (BUN)/total urea, creatinine, glucose), and mineral panel (magnesium, phosphorus, 
calcium). If full and core chemistry are scheduled at the same visit, the full chemistry will be performed.
6.
In serum at screening; in urine thereafter. Results of the most recent pregnancy test should be available prior to next dosing of IMP.
7.
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST 1.1 is documented during the course of the 
study confirmation of the response should be performed according to RECIST 1.1 after 6 weeks. CT scan or MRI (if MRI is used, CT of chest is mandatory) 
should always be used.
8.
A CT scan or MRI (if MRI is used, CT of chest is mandatory) of the chest, abdomen, and pelvis will be performed within 18 days prior to trial treatment start 
in order to document the baseline status of the tumor disease using RECIST 1.1 target and non-target lesions. However, if the results of a CT scan or MRI 
performed within 4 weeks prior to first treatment are available, the screening CT / MRI does not need to be performed. 
9.
Brain CT/MRI scan (either, with contrast preferred) is required at screening if not performed within the previous 6 weeks. In subjects with ovarian cancer, 
castrate-resistant prostate cancer (CRPC), mesothelioma, or urothelial carcinoma this scan is only necessary if clinically indicated. Thereafter, brain CT/MRI 
scan should be done if clinically indicated by development of new specific symptoms.
10. A bone scan should be done at screening and beyond as clinically indicated. Bone metastases detected at screening need to be followed at the tumor evaluation 
visits.
11. PK serum samples will be drawn on Day 1 before and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours post infusion. PK sampling on Days 
2 and 3 is optional. Where performed, on Day 2, samples will be collected 24 and 36 hours post infusion and on Day 3, a single sample will be drawn 48 hours 
post infusion (± 6 hours). On Days 15, 29, 43, 85, 127, and 169, samples will be collected prior to infusion (trough value) and immediately after infusion is 
completed (peak value).
12. ADA serum samples will be collected prior to trial treatment on Days 1 (baseline), 15, 29, 43, 57, 71, 85 (every 2 weeks) and on Days 127, and 169 (every 6 
weeks). The baseline sample should be collected prior to the first administration of trial treatment, i.e., either during the screening period or pre-dose on Day 1.
13. Blood samples for receptor occupancy will be collected on Day 1 before start of the infusion, 4 and 48 hours (Day 3, ± 6 hours) after the start of infusion, and 
before the start of each infusion on Days 15, 29, 43, and 85.
14. Blood samples for immunomonitoring will be collected before start of each infusion and 48 hours (± 6 hours) after start of each infusion on Days 1 (baseline), 
43, 85, and only before start of infusion on Days 15, 127, and 169. One additional blood sample will be collected at the end-of-treatment visit (within 28 days 
after the last treatment). A complete differential blood count will be provided for each time point for calculations of the absolute count of leukocyte 
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subpopulations. From these samples, plasma (3 to 5 mL) will be collected for retrospective analyses. The baseline sample should be collected prior to the first 
administration of trial treatment, i.e., either during the screening period or pre-dose on Day 1.
15. Blood samples for soluble factors will be collected before start of each infusion and 48 hours (± 6 hours) after start of each infusion on Days 1 (baseline), 43, 
85, and only before start of infusion on Days 15, 127 and 169. One additional sample will be collected at the end-of-treatment visit (within 28 days after the 
last treatment) for biological follow-up. The baseline sample should be collected prior to the first administration of trial treatment, i.e., either during the 
screening period or pre-dose on Day 1.
16. Endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies and surgical specimens are suited. Fine needle aspiration biopsies are not suited. 
Samples can be provided as block or slides (see Section 7.6.2.4 for details).
 
18. Adverse events will be documented at each trial visit until the End-of-Treatment visit. After the End-of-Treatment visit only treatment-related AEs have to be 
documented until the Post-treatment Safety Follow-up visit. Subjects with a SAE ongoing at the post-treatment safety follow-up must be monitored and 
followed up by the investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up”. Any SAE assessed 
as related to IMP must be reported whenever it occurs, irrespective of the time elapsed since the last administration of IMP. Subjects without progressive 
disease at the end-of-treatment visit will be followed up for disease progression (CT / MRI scans every 12 weeks) up to 1 year. In addition, subjects will be 
followed quarterly (± 14 days) for survival (including assessment of any further tumor therapy). The survival follow-up will continue until 1 year after the last 
subject receives the last dose of avelumab. See Section 7.1.4 for details.
19. If the screening ECOG was performed within 3 days prior to Day 1 it does not have to be repeated at Visit 2.
20. The observation period for DLTs refers to the first 3 weeks of trial drug treatment in the dose escalation part for all subjects with data used for implementing 
the dose-escalation algorithm for determination of the MTD. Additional subjects enrolled in the dose escalation phase will have AEs collected but will not 
have a specific DLT observation period.
21. Full chemistry panel and other laboratory studies are detailed in Table 7.2. Serum electrophoresis only at screening and end-of-treatment. Follicle-stimulation 
hormone at screening, if applicable (Section 7.1.1).
22. Full urinalysis at screening and end-of-treatment and basic urinalysis (protein content only) at each visit indicated prior to administration of study drug. If 
urinalysis (full or basic) is positive for protein, sediment will be evaluated.
23. Prior to the first administration of trial treatment, subject eligibility should be re-confirmed with respect to data collected on Day 1.
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Avelumab in Metastatic or Locally Advanced Solid Tumors
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Dose Escalation Phase – 10 mg/kg once weekly cohort
Measure
Screening/
Baseline 
Assessments
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Post 
Treatment
Safety 
Follow-up 
Visit
Post-
Treatment 
Survival 
Follow-up 
(16)
Day -18 to
First 
Treatment
V1
V2 V3 V4 V5 V6 V7 V8 V9 V10 V11
V12
V13
Until 
Progression
Up to ≤ 7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (16)
W1
W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12 W13
d1
d8 d15 d22 d29 d36 d43 d50 d57 d63
d71
d78
d85
Written informed consent
X
In- and exclusion criteria
X
Medical history
X
Demographic data
X
HBV, HCV, and HIV testing 
X
Physical examination
(including height at screening)
X
X
X
X
X
X
X
X
6∃weekly
x/X
X
Vital signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
ECOG performance status
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
Enrollment (if eligible) (3)
X
IMP administration 
X
X
X
X
X
X
X
X
X
X
X
X
X
2∃weekly
12-lead ECG (4)
X
X
X
X
X
X
X
X
6∃weekly
x/X
X
Hematology and hemostaseology 
X
X
X
X
X
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
Core serum chemistry (5)
X
X
X
X
X
X
X
X
X
X
2∃weekly
Full serum chemistry (17)
X
X
X
6∃weekly
x/X
X
Urinalysis (18)
X
X
X
X
X
X
X
2∃weekly
x/X
X
β-HCG pregnancy test (if 
applicable) (6)
X
X
X
X
X
4∃weekly
- /X
X
Tumor evaluation / staging (CT 
Scan/ MRI/ Tumor markers / other 
established methods) (7,8,9,10)
X
X
X
6-weekly 
for first 
12 months, 
then 
12-weekly
- /X
X (16)
Documentation of AEs and 
concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2∃weekly
x/X
X (16)
X (16)
ACTH, ANA, RF
X
As clinically indicated
6∃weekly
- /X
X
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Measure
Screening/
Baseline 
Assessments
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Post 
Treatment
Safety 
Follow-up 
Visit
Post-
Treatment 
Survival 
Follow-up 
(16)
Day -18 to
First 
Treatment
V1
V2 V3 V4 V5 V6 V7 V8 V9 V10 V11
V12
V13
Until 
Progression
Up to ≤ 7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (16)
W1
W2 W3 W4 W5 W6 W7 W8 W9 W10 W11 W12 W13
d1
d8 d15 d22 d29 d36 d43 d50 d57 d63
d71
d78
d85
Free T4 and TSH
X
X
X
6-weekly
- /X
X
PK sampling (11) 
X
X
X
X
X
X
W15, W19, 
W25 then 
12∃weekly
-/X
X
ADA sampling (12)
X
X
X
X
X
X
X
W19, W25 
then 
12∃weekly
- /X
X
Soluble factors (13)
X
X
X
X
X
X
Tumor biopsy or archived surgical 
specimen (optional) (14)
X 
X
- /X
ACTH: adrenocorticotropic hormone; ADA: anti-drug antibody; AE: adverse events; ANA: anti-nuclear antibody; β-HCG: β-human chorionic gonadotropin; CT: computer 
tomography; DLT: dose-limiting toxicity; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human 
immunodeficiency virus; IMP: investigational medicinal product; MRI: magnetic resonance imaging; PK: pharmacokinetics; RF: rheumatoid factor; SAE: serious adverse event; 
TSH: Thyroid-stimulating hormone, T4: Free thyroxine.
A time window of 1 day before or 1 day after the scheduled visit day (±1 day) will be permitted for all study procedures for the first 12 weeks and then up to 3 days 
before or 1 day after the scheduled visit day (-3/+1 days) starting at Week 13. In addition, the tumor evaluation (see Section 7.3) has a tumor assessment visiting 
time window of 5 days prior to dosing (-5 days).
1.
Tumor evaluation at the end-of-treatment visit should only be performed if no disease progression was documented previously.
2.
If another antineoplastic therapy is administered before the end of this 28 day-period, the end-of-treatment visit should be conducted if possible prior to the 
start of this new therapy.
3.
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion 
(Section 5.3.2). 
4.
12-lead ECG should be assessed before infusion and 2 hours (± 20 minutes) after infusion.
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5.
Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin), acute 
chemistry panel (sodium, potassium, chloride, blood urea nitrogen (BUN)/total urea, creatinine, glucose), and mineral panel (magnesium, phosphorus, 
calcium). If full and core chemistry are scheduled at the same visit, the full chemistry will be performed.
6.
In serum at screening; in urine thereafter. Results of the most recent pregnancy test should be available prior to next dosing of IMP.
7.
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST 1.1 is documented during the course of the 
study confirmation of the response should be performed according to RECIST 1.1 after 6 weeks. CT scan or MRI (if MRI is used, CT of chest is mandatory) 
should always be used.
8.
A CT scan or MRI (if MRI is used, CT of chest is mandatory) of the chest, abdomen, and pelvis will be performed within 18 days prior to trial treatment start 
in order to document the baseline status of the tumor disease using RECIST 1.1 target and non-target lesions. However, if the results of a CT scan or MRI 
performed within 4 weeks prior to first treatment are available, the screening CT / MRI does not need to be performed. 
9.
Brain CT/MRI scan (either, with contrast preferred) is required at screening if not performed within the previous 6 weeks. In subjects with ovarian cancer, 
castrate-resistant prostate cancer (CRPC), mesothelioma, or urothelial carcinoma this scan is only necessary if clinically indicated. Thereafter, brain CT/MRI 
scan should be done if clinically indicated by development of new specific symptoms.
10. A bone scan should be done at screening and beyond as clinically indicated. Bone metastases detected at screening need to be followed at the tumor evaluation 
visits.
11. Blood samples for PK determinations will be collected from all subjects within 2 hours prior to each infusion at Weeks 1, 2, 3, 5, and 7 (every 2 weeks), at 
Weeks 13, 15, 19, and 25, and then at 12-week intervals while on treatment. A sample at the end of infusion (within 15 minutes) will be collected at Weeks 1, 
7, 13, and 25. Samples will be collected at the EoT visit and the Safety Follow-up visit.
12. ADA serum samples will be collected prior to trial treatment on Days 1 (baseline), 15, 29, 43, 57, 71, 85, and on Week 19 and Week 25, then every 12 weeks 
thereafter. Samples will be collected at the EoT visit and the Safety Follow-up visit.  The baseline sample should be collected prior to the first administration 
of trial treatment, i.e., either during the screening period or pre-dose on Day 1. The term for ADA on CRF is human-antihuman antibodies (HAHA).
13. Blood samples for soluble factors will be collected before start of each infusion on Days 1 (baseline), 8, 15, 29, 43, and 85.
14. Endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies and surgical specimens are suited. Fine needle aspiration biopsies are not suited. 
Samples can be provided as block or slides (see Section 7.6.2.4 for details). Optional tumor biopsies will be collected prior to infusion on Day 1, Day 43, and 
at the end-of-treatment visit (see Section 7.6.2.4 for details).
16. Adverse events will be documented at each trial visit until the End-of-Treatment visit. After the End-of-Treatment visit only treatment-related AEs have to be 
documented until the Post-treatment Safety Follow-up visit. Subjects with a SAE ongoing at the post-treatment safety follow-up must be monitored and 
followed up by the investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up”. Any SAE assessed 
as related to IMP must be reported whenever it occurs, irrespective of the time elapsed since the last administration of IMP. Subjects without progressive 
disease at the end-of-treatment visit will be followed up for disease progression (CT / MRI scans every 12 weeks) up to 1 year or until disease progression, 
whichever is first. In addition, subjects will be followed quarterly (± 14 days) for survival (including assessment of any further tumor therapy). The survival 
follow-up will continue until 1 year after the last subject receives the last dose of avelumab. See Section 7.1.4 for details. 
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17. Full chemistry panel and other laboratory studies are detailed in Table 7.2. Follicle-stimulation hormone at screening, if applicable (Section 7.1.1).
18. Full urinalysis at screening, the end-of-treatment, and the 10-week safety follow-up and basic urinalysis (protein content only) at each visit indicated prior to 
administration of study drug and at the discontinuation visit. If urinalysis (full or basic) is positive for protein, sediment will be evaluated.
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Expansion Phase
Measure
Washout$/ 
Screening/
Baseline 
Assessments
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Post 
Treatment 
Safety Follow-
up Visit
Post-
Treatment 
Survival 
Follow-up 
(18)
Day -28$/   
-18 to First 
Treatment
V1
V2
V3 V4# V5 V6# V7 V8# V9 V10 V11
V12
Until 
Progression
Up to ≤7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (18)
W1 W1 W1 W2 W3 W4 W5 W6 W7 W9 W11 W13
d1
d2* d3*
d8
d15 d22 d29 d36 d43 d57
d71
d85
Written informed consent
X
In- and exclusion criteria
X
Medical history
X
Demographic data
X
HBV, HCV, and HIV testing 
X
Physical examination
(including height at screening)
X
X
X
X
X
X
X
X
6∃weekly
x/X
X
Vital signs 
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
Weight
X
X
X
X
X
X
X
X
2∃weekly
x/X
X
ECOG performance status
X (19)
X
X
X
X
X
X
X
2∃weekly
x/X
X
Enrollment (if eligible) (3)
X
IMP administration 
X
X
X
X
X
X
X
2∃weekly
12-lead ECG (4)
X
X
X
X
X
X
X
X
6 weekly
x/X
X
Hematology and hemostaseology
X
X
X
X
X
X
X
2 weekly
x/X
X
Core serum chemistry (5) 
X
X
X
X
X
X
X
2 weekly
Full serum chemistry (20)
X
X
X
6 weekly
x/X
X
Urinalysis (6)
X
X
X
X
X
X
X
2∃weekly
x/X
X
β-HCG pregnancy test (if 
applicable) (7)
X
X
X
X
X
4∃weekly
- /X
X
Tumor evaluation / staging (CT 
Scan/ MRI/ Tumor markers / 
other established methods) 
(8,9,10,11, 24)
X
X
X
6∃weekly for 
first 
12 months, 
then 
12-weekly
- /X
X
Optional fresh biopsies 
(melanoma and mesothelioma 
cohorts, fist-line NSCLC, and 
efficacy expansion cohorts) (23)
X
X
- /X
Documentation of AEs and 
concomitant medication
X
X
X*
X*
X
X
X
X
X
X
2∃weekly
x/X
X (18)
X (18)
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Avelumab in Metastatic or Locally Advanced Solid Tumors
EMR100070-001
173/190
Measure
Washout$/ 
Screening/
Baseline 
Assessments
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Post 
Treatment 
Safety Follow-
up Visit
Post-
Treatment 
Survival 
Follow-up 
(18)
Day -28$/   
-18 to First 
Treatment
V1
V2
V3 V4# V5 V6# V7 V8# V9 V10 V11
V12
Until 
Progression
Up to ≤7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (18)
W1 W1 W1 W2 W3 W4 W5 W6 W7 W9 W11 W13
d1
d2* d3*
d8
d15 d22 d29 d36 d43 d57
d71
d85
Free T4, and TSH 
X
X
Week 25 and 
as indicated
- /X
X
CA-125 sampling (22)
X
X
X
6-weekly
- /X
PK sampling (12) 
X 
X*
X* 
X
X
X
X
X
X
6∃weekly or 
12-weekly up 
to incl. week 
25 (see 
footnote 12
for specifics)
-13
X
ADA sampling (13)
X 
X
X
X
X
X
X
6∃weekly
up to incl. 
week 25
- /X
-12
Receptor occupancy (21)
X
X
X
X
X
Immunomonitoring (14)
X
X* 
X
X
X
- /X
Soluble factors (15)
X
X*
X
(15)
X
(15)
X
- /X
Tumor tissue (biopsy or archived 
surgical specimen); HPV 
determination for subjects in 
HNSCC cohort only (16)
X
AE: adverse events; ADA: anti-drug antibody (ADA); β-HCG: β-human chorionic gonadotropin; CA-125: cancer antigen 125; CT: computer tomography; CRPC: castrate-resistant 
prostate cancer; DLT: dose-limiting toxicity; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; GEJ: Gastro-esophageal junction; HBV: hepatitis B virus; 
HCV: hepatitis C virus; HIV: human immunodeficiency virus; HNSCC: head and neck squamous cell carcinoma; HPV: human papilloma virus; IMP: investigational medicinal 
product; MRI: magnetic resonance imaging; PK: pharmacokinetics; SAE: serious adverse event; TSH: thyroid-stimulating hormone, T4: Free thyroxine.
$ There is a 28-day washout / recovery period for prior anticancer treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative 
bone directed radiotherapy], immune therapy, or cytokine therapy except for erythropoietin) and major surgery before the start of trial treatment 
(Section 5.3.2).  The screening procedures and baseline assessments will be completed within 18 days before trial treatment starts. 
# Following approval of Protocol Amendment 9, the visits at Weeks 2, 4, and 6 (Visit 4/Day 8, Visit 6/Day 22 and Visit 8/Day 36) have been restored for 
subjects with liver metastases at baseline for the collection of blood samples for ALT, AST, total bilirubin, and alkaline phosphatase determination. 
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* PK and ADA sampling on Days 2 and 3 are optional and only applicable for subjects in the secondary CRC and CRPC cohorts (expanded PK sampling) and the 
efficacy expansion cohorts (ADA sampling). Therefore, the visit at Day 2 is optional; however should a subject attend, blood draws for PK sampling and soluble 
factors (as applicable) are strongly encouraged.
A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all study procedures (except Days 2 and 3), except 
for body weight, which should be obtained on the same day as study drug administration. In addition, the tumor evaluation (see Section 7.3) has a tumor assessment 
visiting time window of 5 days prior to dosing (-5 days).
1.
Tumor evaluation at the end-of-treatment visit should only be performed if no disease progression was documented previously.
2.
If another antineoplastic therapy is administered before the end of this 28 day-period, the end-of-treatment visit should be conducted if possible prior to the 
start of this new therapy.
3.
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion 
(Section 5.3.2). 
4.
12-lead ECG should be assessed before infusion and 2 hours (± 20 minutes) after infusion.
5.
Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin), acute 
chemistry panel (sodium, potassium, chloride, blood urea nitrogen (BUN)/total urea, creatinine, glucose), and mineral panel (magnesium, phosphorus, 
calcium). If full and core chemistry are scheduled at the same visit, the full chemistry will be performed. Subjects with liver metastases at baseline will have 
visits every week, up to Week 7 for collection of blood samples for ALT, AST, total bilirubin, and alkaline phosphatase determination.
6.
Full urinalysis at screening and end-of-treatment and basic urinalysis (protein content only) at each visit as indicated prior to administration of study drug. If 
urinalysis (full or basic) is positive for protein (dipstick), sediment will be evaluated. Urinalysis does not have to be performed in subjects with urothelial 
cancers.
7.
In serum at screening; in urine thereafter. Results of the most recent pregnancy test should be available prior to next dosing of IMP.
8.
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST 1.1 is documented during the course of the 
study confirmation of the response should be performed according to RECIST 1.1 after 6 weeks. CT scan or MRI (if MRI is used, CT of chest is mandatory) 
should always be used.
9.
A CT scan or MRI (if MRI is used, CT of chest is mandatory) of the chest, abdomen, and pelvis will be performed within 18 days prior to trial treatment start 
in order to document the baseline status of the tumor disease using RECIST 1.1 target and non-target lesions. However, if the results of a CT scan or MRI 
performed within 4 weeks prior to first treatment are available, the screening CT / MRI does not need to be performed. 
10. Brain CT/MRI scan (either, with contrast preferred) is required at screening if not performed within the previous 6 weeks. In subjects with gastric/GEJ cancer, 
HNSCC, ovarian cancer, CRPC, mesothelioma, or urothelial carcinoma this scan is only necessary if clinically indicated. For expansion subjects in the 
melanoma cohort, an MRI or CT scan (either, with contrast preferred) must be performed at screening in order to rule out brain metastases, unless imaging has 
previously been performed within 28 days prior to screening. Thereafter, brain CT/MRI scan should be done if clinically indicated by development of new 
specific symptoms.
11. A bone scan should be done at screening and beyond as clinically indicated. Bone metastases detected at screening need to be followed at the tumor evaluation 
visits.
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12. PK samples will be obtained prior to each administration of study drug on Days 1, 15, 29, 43, 57, 71, 85, 127, and 169 for all subjects in the primary cohorts 
(NCSLC post platinum doublet, gastric / GEJ cancer, and MBC) and the ACC, melanoma, mesothelioma, ovarian, and urothelial secondary cohorts. All 
expansion subjects in the CRC and CRPC secondary cohorts will have PK serum samples collected on Day 1 before and at the end of the 1-hour infusion, and 
at 0.5, 1, 2, 4, 6, and 12 hours post infusion. PK sampling on Days 2 and 3 is optional. Where performed, on Day 2, samples will be collected 24 and 36 hours 
post infusion and, on Day 3, a single sample will be drawn 48 hours post infusion (± 6 hours). On Days 15, 29, 43, 85, 127, and 169, samples will be collected 
prior to infusion (trough value) and immediately after infusion is completed (peak value). For subjects in the first-line NSCLC cohort, samples for PK analysis 
will be collected prior to each study drug administration on Days 1, 15, 29, 43, 57, 71, 85, 99, and 169. Post-study drug administration samples will also be 
collected immediately after the end of the infusion and also 2 to 8 hours after the end of infusion (later is better depending on how long the subject will stay in 
the clinic), on Days 1, 43, 85, and 169. Samples will also be collected at the 10-week safety follow-up visit, and remaining sample from this visit may be used 
to test for ADA. For subjects enrolled in the efficacy expansion cohorts and the RCC secondary cohort, samples for PK determination will be collected prior 
to each administration of study drug on Days 1, 15, 29, 43, 57, 71, 85, and 169. Post-study drug administration samples will be collected immediately after the 
end of infusion and 2 to 8 hours after the end of infusion (later is better, depending on how long the subject will stay in the clinic) at Days 1, 43, 85, and 169.  
Exact sampling times will be recorded.  Samples will be collected at the 10-week Safety Follow-up visit, and remaining sample from this visit may be used to 
test for ADA.
13. ADA serum samples will be collected on Days 1 (baseline), 15, 29, 43, 57, 71, 85 (every 2 weeks) on Days 127, and 169 (every 6 weeks), and at the end-of-
treatment visit (within 28 days after the last treatment). Remaining sample from the end-of-treatment visit may be used to test for PK. The baseline sample 
should be collected prior to the first administration of trial treatment, i.e., either during the screening period or pre-dose on Day 1. The term for ADA on CRF 
is human-antihuman antibodies (HAHA).
14. All subjects in the secondary expansion cohorts, except for the RCC cohort, will have 40 mL of blood (five 8 mL CTPs) collected before start of infusion at 
Days 1 (baseline), 15, 43, and 85 and at the end-of treatment visit for immunomonitoring. Additionally, 40 mL of blood will be collected 48 hours (Day 3, 
± 6 hours) after the start of the first infusion only of IMP in these subjects (this sample is optional). A complete differential blood count will be provided for 
each time point for calculations of the absolute count of leukocyte subpopulations. From these samples, plasma (3 to 5 mL) will be collected for retrospective 
analyses. The baseline sample should be collected prior to the first administration of trial treatment, i.e., either during the screening period or pre-dose on 
Day 1.
15. Soluble factors samples will be collected for all subjects in the primary and secondary expansion cohorts, except for the RCC cohort, before start of infusion 
on Days 1 (baseline) and 43, and at the end-of-treatment visit (within 28 days after the last treatment). In addition, except for the RCC cohort, a serum sample 
will be collected from subjects in the secondary expansion cohorts 48 hours after the start of the first infusion only (Day 3, ± 6 hours; this sample is optional).
The baseline sample should be collected prior to the first administration of trial treatment, i.e., either during the screening period or pre-dose on Day 1. For 
subjects enrolled in the efficacy expansion cohorts and the RCC secondary cohort, 
 
16. Endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies and surgical specimens are suited. Fine needle aspiration biopsies are not suited.
The most recent biopsy or surgical specimen is required. For subjects in the MBC cohort, the biopsy or surgical specimen must have been collected within 
90 days prior to the first IMP administration. Samples can be provided as block or slides (see Section 7.6.2.4 for details). In the melanoma and mesothelioma 
cohorts, optional tumor biopsies will be collected prior to infusion on Day 1, Day 43, and at the end-of-treatment visit (see Section 7.6.2.2 for details). For 
subjects in the HNSCC cohort additional slides may be necessary for determination of tumor HPV status.  Please refer to the Laboratory Manual for detailed 
information.
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18. Adverse events will be documented at each trial visit until the End-of-Treatment visit. After the End-of-Treatment visit only treatment-related AEs have to be 
documented until the Post-treatment Safety Follow-up visit. Subjects with a SAE ongoing at the post-treatment safety follow-up must be monitored and 
followed up by the investigator until stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up”. Any SAE assessed 
as related to IMP must be reported whenever it occurs, irrespective of the time elapsed since the last administration of IMP. Subjects without progressive 
disease at the end-of-treatment visit will be followed up for disease progression (CT / MRI scans every 12 weeks) up to 1 year or until disease progression, 
whichever is first. In addition, subjects will be followed quarterly (± 14 days) for survival (including assessment of any further tumor therapy). The survival 
follow-up will continue until 1 year after the last subject receives the last dose of avelumab. See Section 7.1.4 for details.
19. If the screening ECOG was performed within 3 days prior to Day 1 it does not have to be repeated at Visit 2.
20. Full chemistry panel and other laboratory studies are detailed in Table 7.2. Serum electrophoresis only at screening and end-of-treatment. Follicle-stimulation 
hormone at screening, if applicable (Section 7.1.1).
21. The blood sample for receptor occupancy will be collected on Day 1 before start of the infusion, 4 hours after the start of infusion, and before the start of each 
infusion on Days 15, 29, 43, and 85 for expansion subjects in the CRC and CRPC cohorts.
22. Ovarian cancer cohort only: Blood samples for CA-125 will be collected prior to trial treatment on Days 1, 43, 85, 127, and 169 (every 6 weeks), and at the 
end-of-treatment visit.
23. Melanoma and mesothelioma cohorts only: If optional fresh biopsy is taken prior to first dose of trial treatment, archive tumor material is not required for trial 
entry. Fresh biopsies may also be collected on Day 43 and at the end-of-treatment visit. These biopsies are optional. For subjects in the efficacy expansion 
cohorts and the first-line NSCLC primary expansion cohort, fresh biopsies may also be collected on Days 43 and at the end of treatment visit. These biopsies 
are optional.
24. Mesothelioma cohort only: Tumor biopsies (core needle biopsies) may be performed between Cycles 2 and 3, and in the case of disease progression, to 
differentiate between actual disease progression and a tumor flare resulting from intratumor inflammation. These biopsies are optional. See Section 7.3.
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Subjects with Complete Response who Subsequently Progress After Stopping Therapy Then Re-initiate Therapy 
Measure
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Safety Follow-
up Visit
Post-
Treatment 
Follow-up (3)
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Up to ≤ 7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (3)
W1
W3
W5
W7
W9
W11
W13
d1
d15
d29
d43
d57
d71
d85
Physical examination
X
X
X
6∃weekly
x/X
X
Vital signs 
X
X
X
X
X
X
X
2∃weekly
x/X
X
Weight
X
X
X
X
X
X
X
2∃weekly
x/X
X
ECOG performance status
X
X
X
X
X
X
X
2∃weekly
x/X
X
IMP administration 
X
X
X
X
X
X
X
2∃weekly
12-lead ECG (4)
X
X
X
6 weekly
x/X
X
Hematology and hemostaseology
X
X
X
X
X
X
X
2 weekly
x/X
X
Core serum chemistry (5) 
X
X
X
X
2 weekly
Full serum chemistry (6)
X
X
X
6 weekly
x/X
X
Urinalysis (7)
X
X
X
X
X
X
X
2∃weekly
x/X
X
β-HCG pregnancy test (if applicable) (8)
X
X
X
X
4∃weekly
- /X
X
Tumor evaluation / staging (CT Scan/ MRI/ 
Tumor markers / other established methods) 
(9,10,11,12)
X
X
X
6∃weekly for 
first 12 months, 
then 12-weekly
- /X
X
Optional fresh biopsies (melanoma and 
mesothelioma cohorts only) (13)
X
- /X
Documentation of AEs and concomitant 
medication
X
X
X
X
X
X
X
2∃weekly
x/X
X
X (3)
Free T4, and TSH 
Week 25 and as 
indicated
- /X
X
CA-125 sampling (14)
X
X
X
6-weekly
- /X
PK sampling (15) 
X
X
X
6∃weekly until 
6 months
X
ADA sampling (16)
X
X
X
6∃weekly until 
6 months
- /X
Soluble factors (18)
X
- /X
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Measure
Treatment Phase
Discontinuation/ 
End-of-
Treatment
Visits
Safety Follow-
up Visit
Post-
Treatment 
Follow-up (3)
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Up to ≤ 7/28 
Days after Last 
Treatment (1,2)
10 Weeks 
after Last 
Treatment
Every 3 
months (3)
W1
W3
W5
W7
W9
W11
W13
d1
d15
d29
d43
d57
d71
d85
AE: adverse events; ADA: anti-drug antibody; β-HCG: β-human chorionic gonadotropin; CA-125: cancer antigen 125; CT: computer tomography; DLT: dose-limiting toxicity; 
ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; IMP: investigational 
medicinal product; MRI: magnetic resonance imaging; PK: pharmacokinetics; TSH: Thyroid-stimulating hormone, T4: Free thyroxine.
For subjects who achieve a CR on avelumab therapy and then subsequently develop disease progression after stopping therapy, but prior to the end of 
the trial, one re-initiation of treatment at the same dose and schedule is allowed at the discretion of the investigator and agreement of the trial Medical 
Monitor. In order to be eligible for retreatment, the subject must not have experienced any toxicity that led to treatment discontinuation of the initial 
avelumab therapy. Prior to re-initiation of the study treatment, malignant disease needs to be radiologically re-staged to assess all known sites of the 
disease and to establish a new baseline for subsequent tumor measurements. Relevant safety laboratory results must be available and verified prior to re-
initiating of treatment.
A time window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted for all study procedures (except Days 2 and 3), except 
for body weight, which should be obtained on the same day as study drug administration. In addition, the tumor evaluation (see Section 7.3) has a tumor assessment 
visiting time window of 5 days prior to dosing (-5 days).
1.
Tumor evaluation at the end-of-treatment visit should only be performed if no disease progression was documented previously.
2.
If another antineoplastic therapy is administered before the end of this 28 day-period, the end-of-treatment visit should be conducted if possible prior to the 
start of this new therapy.
3.
Subjects with an ADR ongoing at the end of the treatment visit and for any AE suspected to be related to trial treatment occurring up to 3 months after the last 
dose of avelumab will continue to be followed. Subjects without progressive disease at the end-of-treatment visit will be followed up for disease progression 
(CT / MRI scans every 12 weeks) up to 1 year or until disease progression, whichever is first. In addition, subjects will be followed quarterly (± 14 days) for 
survival (including assessment of any further tumor therapy). The survival follow-up will continue until 1 year after the last subject receives the last dose of 
avelumab. See Section 7.1.4 for details.
4.
12-lead ECG should be assessed before infusion and 2 hours (± 20 minutes) after infusion.
5.
Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin), acute 
chemistry panel (sodium, potassium, chloride, blood urea nitrogen (BUN)/total urea, creatinine, glucose), and mineral panel (magnesium, phosphorus, 
calcium). If full and core chemistry are scheduled at the same visit, the full chemistry will be performed.
6.
Full chemistry panel and other laboratory studies are detailed in Table 7.2. Serum electrophoresis only at end-of-treatment. 
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7.
Full urinalysis at Week 1/Day 1 and end-of-treatment and basic urinalysis (protein content only) at each visit as indicated prior to administration of study drug. 
If urinalysis (full or basic) is positive for protein (dipstick), sediment will be evaluated. Urinalysis does not have to be performed in subjects with urothelial 
cancers.
8.
Results of the most recent pregnancy test (urine β-HCG) should be available prior to next dosing of IMP.
9.
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST 1.1 is documented during the course of the 
study confirmation of the response should be performed according to RECIST 1.1 after 6 weeks. CT scan or MRI (if MRI is used, CT of chest is mandatory) 
should always be used.
10. Brain CT/MRI scan should be done if clinically indicated by development of new specific symptoms.
11. A bone scan should be done as clinically indicated. Bone metastases that had been detected at screening need to be followed at the tumor evaluation visits.
12. Mesothelioma cohort only: Tumor biopsies (core needle biopsies) may be performed between Cycles 2 and 3, and in the case of disease progression, to 
differentiate between actual disease progression and a tumor flare resulting from intratumor inflammation. These biopsies are optional. See Section 7.3.
13. Melanoma and mesothelioma cohorts only: Optional fresh biopsy is taken prior to first dose of trial treatment. These biopsies are optional.
14. Ovarian cancer cohort only: Blood samples for CA-125 will be collected prior to trial treatment on Days 1, 43, 85, 127, and 169 (every 6 weeks), and at the 
end-of-treatment visit.
15. PK samples will be obtained within 2 hours prior to the second retreatment infusion, then 2 weeks later, and then every 6 weeks until 6 months after treatment 
re-initiation (e.g., pre-dose at Weeks 3, 5, 11, 17, and 23).
16. ADA samples will be drawn prior to the second retreatment infusion, then 2 weeks later, and then every 6 weeks until 6 months after treatment re-initiation 
(e.g., pre-dose at Weeks 3, 5, 11, 17, and 23).
18. Soluble factors samples will be collected before start of the first infusion on Days 1 and at the end-of-treatment visit (within 28 days after the last treatment). 
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Appendix II
ECOG Performance Status
ECOG Performance Status1
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
> 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair > 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
1 Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, and Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-55.
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Appendix III Guidance on Contraception
Birth control methods considered as highly effective
According to the CTFG “Recommendations related to contraception and pregnancy testing in 
clinical trials” methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods, such as:
! combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation1 (oral, intravaginal, transdermal)
! progesterone-only hormonal contraception associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
! intrauterine device (IUD)2
! intrauterine hormone-releasing system (IUS)2
! bilateral tubal occlusion2
! vasectomized partner2,3
! sexual abstinence4
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method
2 Contraception methods in the context of this guidance are considered to have low user dependency
3 Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner 
of the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success
4 In the context of this guidance 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 treatments. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject.
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Appendix IV Protocol Amendments and List of Changes
Table of Previous Protocol Amendments
Amendment 
Number
Submission to 
Health Authority
(Yes/No/
Notification only)
Date
Region or Country
Included in the 
current document    
(Y/N)
Amendment 1
Yes
13 December 2012
Global
Yes
Amendment 2
Yes
29 May 2013
Global
Yes
Amendment 3
Yes
12 August 2013
Global
Yes
Amendment 4
Yes
20 September 2013
Local: EU
Yes
Amendment 5
Yes
08 October 2013
Local: EU
Yes
Amendment 6
Yes
28 October 2013
Global
Yes
Amendment 7
Yes
30 July 2014
Global
Yes
Amendment 8
Yes
19 November 2014
Global
Yes
Amendment 9
Yes
22 December 2014
Global
Yes
Amendment 10
Yes
04 March 2015
Global
Yes
Amendment 11
Yes
16 April 2015
Global
Yes
Amendment 12
Yes
10 July 2015
Global 
Yes
Amendment 13
Yes
20 October 2015
Global 
Yes
Amendment 14
Yes
11 March 2016
Global
Yes
Amendment 15
Yes
25 April 2016
Global
Yes
Amendment 16
Notification only
28 October 2016
Global
Yes
Amendment 17
Notification only
02 March 2017
Global
Yes
The purpose of this protocol amendment (Amendment 18, 06 August 2018) is provide language 
regarding continued access to study treatment for subjects who may continue to benefit from 
continued treatment if the study is terminated.
This amendment is not considered substantial.
List of Changes
Additions and amended text are shown in bold. If the original clinical trial protocol text was 
already bold, changes are shown in bold and underlined, deletions are marked using strike through.
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Comparison with Clinical Trial Protocol Version 18.0 / Amendment 17.0, 02 March 2017
Change
Section
Pages
Previous Wording
New Wording
Rationale
Updated Medical 
Responsible
Cover page
1
Medical Responsible: 
Merck KGaA, Frankfurter Str. 250 
64293 Darmstadt, Germany 
Tel:  
Fax: 
45A Middlesex Turnpike
Billerica, MA 01821, USA
Tel:  
Fax: 
Medical Responsible: 
45A Middlesex Turnpike
Billerica, MA 01821, USA
Tel:  
Fax: 
New 
Medical 
Responsible 
assigned
Updated 
projected last 
subject out date
Synopsis – Planned 
trial period
(first enrollment-last 
subject out)
5.1.6  Planned 
Treatment Duration
15
81
Last subject out (after expansion and 
follow-up): 
Q2, 2018 2019.
Last subject out (after expansion and 
follow-up): 
Q2, 2019.
Subjects 
staying 
on therapy longer 
than expected
Added language 
regarding 
availability of 
study drug 
through rollover 
study for 
subjects 
continuing to 
benefit from 
study treatment
Synopsis – Trial 
design and plan
21
Subjects who re initiate treatment will 
stay on study and will be treated and 
monitored according to the protocol and 
the “until progression” schedule in the 
Schedule of Assessments.
In the case of study termination, 
subjects continuing to benefit from 
study treatment may still have access to 
study treatment via enrollment in a 
rollover study if not available through 
some other mechanism (eg, expanded 
access, marketed product).
Subjects who re initiate treatment will 
stay on study and will be treated and 
monitored according to the protocol and 
the “until progression” schedule in the 
Schedule of Assessments.
In the case of study termination, subjects 
continuing 
to 
benefit
from 
study 
treatment may still have access to study 
treatment via enrollment in a rollover 
study if not available through some other 
mechanism 
(eg, 
expanded 
access, 
marketed product).
In order to not 
deny 
access 
to 
study 
treatment 
for subjects who 
continue to benefit 
after termination 
of the study 
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Change
Section
Pages
Previous Wording
New Wording
Rationale
Added language 
regarding 
availability of 
study drug 
through rollover 
study for 
subjects 
continuing to 
benefit from 
study treatment
5.1.6  Planned 
Treatment Duration
6.2  Dosage and 
Administration
7.1.2  Treatment 
Period
81
93 
110
…
In the case of study termination (see 
Section 5.6), subjects continuing to 
benefit from study treatment may still 
have access to study treatment via 
enrollment in a rollover study if not 
available 
through 
some 
other 
mechanism 
(eg, 
expanded 
access, 
marketed product).
…
In the case of study termination (see 
Section 5.6), subjects continuing to 
benefit from study treatment may still 
have access to study treatment via 
enrollment in a rollover study if not 
available through some other mechanism 
(eg, expanded access, marketed product).
In order to not 
deny 
access 
to 
study 
treatment 
for subjects who 
continue to benefit 
after termination 
of the study 
Added language 
regarding 
availability of 
study drug 
through rollover 
study for 
subjects 
continuing to 
benefit from 
study treatment
5.6  Premature 
Discontinuation of 
the Trial
81
The whole trial may be terminated or 
suspended 
upon 
request 
of 
health 
authorities.
The Sponsor may terminate the study 
at any time once access to study 
treatment for subjects still benefitting 
is provisioned via a rollover study, 
expanded access, marketed product, 
or another mechanism of access as 
appropriate.
The whole trial may be terminated or 
suspended 
upon 
request 
of 
health 
authorities.
The Sponsor may terminate the study at 
any time once access to study treatment 
for subjects still benefitting is 
provisioned via a rollover study, 
expanded access, marketed product, or 
another mechanism of access as 
appropriate.
In order to not 
deny 
access 
to 
study 
treatment 
for subjects who 
continue to benefit 
after termination 
of the study 
Updated Medical 
Responsible
Signature page –
Protocol lead
186
 
 
 
 
Merck KGaA, Frankfurter Str. 250 
64293 Darmstadt, Germany 
Tel:  
Fax: 
Merck Serono SIA
45A Middlesex Turnpike
Billerica, MA 01821, USA
Merck Serono SIA
45A Middlesex Turnpike
Billerica, MA 01821, USA
Tel:  
Fax: 
New Medical 
Responsible 
assigned
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Change
Section
Pages
Previous Wording
New Wording
Rationale
Tel:  
Fax: 
Updated Clinical 
Trial Leader 
information
Further Sponsor 
Responsible Persons
189
EMD Serono Research & Development, 
Inc.
45 Middlesex Turnpike, Billerica, MA 
01821, USA
EMD 
Serono 
Research 
& 
Development, Inc. 
45 Middlesex Turnpike, Billerica, MA 
01821, USA
 
 
EMD Serono Research & Development, 
Inc. 
45 Middlesex Turnpike, Billerica, MA 
01821, USA
 
New Leader 
assigned
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Appendix V
Signature Pages and Responsible Persons for the Trial
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Signature Page – Principal Investigator
Trial Title
A Phase I, open-label, multiple-ascending dose trial 
to 
investigate 
the 
safety, 
tolerability, 
pharmacokinetics, biological and clinical activity of 
avelumab
(MSB0010718C)
in subjects with 
metastatic or locally advanced solid tumors and 
expansion to selected indications.
IND Number
EudraCT Number
2013-002834-19
Clinical 
Trial 
Protocol 
Date 
/ 
Version:
06 August 2018 / Version 19.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that:
! I understand and will conduct the trial according to the clinical trial protocol, the approved 
protocol amendments, ICH Good Clinical Practice (ICH Topic E6 GCP) and all applicable 
Health Authority requirements and national laws.
! I will not deviate from the clinical trial protocol without prior written permission from the 
Sponsor and prior review and written approval from the Institutional Review Board or 
Independent Ethics Committee, except where necessary to prevent immediate danger to the 
subject.
I understand that some regulatory Health Authorities require the Sponsors of clinical trials to obtain 
and supply, when required, details about the investigators’ ownership interests in the Sponsor or 
Investigational Medicinal Product and information regarding any financial ties with the Sponsor. 
The Sponsor will use any such information that is collected solely for the purpose of complying 
with the regulatory requirements. I therefore agree to supply the Sponsor with any necessary 
information regarding ownership interest and financial ties (including those of my spouse and 
dependent children), and to provide updates as necessary.
Signature
Date of Signature
Name, academic qualifications
Position (job title)
Address of Institution
Phone, fax, e-mail
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Further Sponsor Responsible Persons
Name, academic degree
Function
Institution
Merck KGaA
Address
Frankfurter Str. 250 
64293 Darmstadt, Germany
Telephone number
Fax number
E-mail address
Name
Function
Institution
EMD Serono Research & Development, Inc.
Address
45 Middlesex Turnpike, Billerica, MA 01821, USA
Telephone number
Fax number
E-mail address
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SAP_001.pdf: 
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Statistical Analysis Plan for End of Dose Escalation Phase
Clinical Trial Protocol 
Identification No.
EMR 100070-001
Title:
A Phase I, open-label, multiple-ascending dose trial to 
investigate 
the 
safety, 
tolerability, 
pharmacokinetics, 
biological and clinical activity of avelumab (MSB0010718C)
in subjects with metastatic or locally advanced solid tumor and 
expansion to selected indications
Trial Phase
Phase I
Investigational Medicinal 
Product(s)
Avelumab
Clinical Trial Protocol 
Version
23 July 2015/Version 13.0 (Amendment 12)
Statistical Analysis Plan 
Author
Jiali Tang
Statistical Analysis Plan
Date and Version
12 October 2015/Final Version 1.0
Statistical Analysis Plan 
Reviewers
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany or its affiliate. 
Copyright © 2015 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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Statistical Analysis Plan 
Reviewers
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1
Signature Page
Statistical Analysis Plan: EMR 100070-001
A Phase I, open-label, multiple-ascending dose trial to investigate the safety, tolerability, 
pharmacokinetics, biological and clinical activity of avelumab (MSB0010718C) in subjects with 
metastatic or locally advanced solid tumor and expansion to selected indications
___________________________                                        ___________________
Signature                                                                                         Date of Signature
Trial Biostatistician
______________________________                                          ___________________
Signature                                                                                         Date of Signature
Senior Biostatistics Review
_______________                                                                         ___________________
Signature                                                                                         Date of Signature
Programming Team Lead
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____________________________                                          ___________________
Signature                                                                                         Date of Signature
Project Statistician
Merck KGaA
Frankfurter Str. 250
64293 Darmstadt, Germany
_____________________________                                          ___________________
Signature                                                                                         Date of Signature
Medical Responsible 
EMD Serono, Inc.
45 Middlesex Turnpike
Billerica, MA 01821, USA
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PPD
PPD


Avelumab
                    Avelumab in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
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2
Table of Contents
1
Signature Page ......................................................................................3
2
Table of Contents..................................................................................5
3
List of Abbreviations and Definition of Terms ....................................7
4
Modification History ..........................................................................11
5
Purpose of the Statistical Analysis Plan .............................................11
6
Summary of Clinical Trial Features ...................................................11
8
Overview of Planned Analyses...........................................................17
9
Changes to the Planned Analyses in the Clinical Trial Protocol........17
10
Analysis Sets.......................................................................................17
11
General Specifications for Statistical Analyses..................................17
12
Trial Subjects......................................................................................20
12.1
Disposition of Subjects and Discontinuations....................................20
12.2
Protocol Deviations ............................................................................22
12.2.1
Minor Protocol Deviation...................................................................22
12.2.2
Major Protocol Deviation ...................................................................22
13
Demographics and Other Baseline Characteristics.............................22
13.1
Demographics.....................................................................................22
13.2
Medical History ..................................................................................23
13.3
Disease History...................................................................................24
14
Prior and Concomitant Medications/Procedures ................................25
14.1
Prior Anti-Cancer Therapies/Procedures............................................25
14.2
Prior and Concomitant Medications/Procedures ................................26
14.3
Subsequent Anti-Cancer Therapies/Procedures .................................27
15
Treatment Compliance and Exposure.................................................27
16
Endpoint Evaluation ...........................................................................28
16.1
Primary Endpoint Analysis.................................................................28
16.2
Secondary Endpoint Analyses ............................................................29
16.3
Cytokine Profile..................................................................................31
16.4
Receptor Occupancy...........................................................................32
16.5
Pharmacokinetic Profile......................................................................32
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16.5.1
Missing PK Data.................................................................................32
16.5.2
Descriptive PK Analysis.....................................................................33
16.5.3
Pharmacokinetic Non-Compartment Analysis ...................................33
16.5.4
Figures ................................................................................................35
17
Safety Evaluation................................................................................36
17.1
Adverse Events ...................................................................................37
17.1.1
All Adverse Events.............................................................................37
17.1.2
Adverse Events Leading to Treatment Discontinuation.....................38
17.1.3
Serious Adverse Events......................................................................39
17.1.4
Infusion Related Reactions.................................................................39
17.1.5
Immune Related Adverse Events........................................................39
17.1.6
Subgroup Analysis of Adverse Events ...............................................40
17.2
Deaths .................................................................................................40
17.3
Clinical Laboratory Evaluation...........................................................41
17.3.1
Hematology, Chemistry, and Hormone Parameters ...........................43
17.3.2
Other laboratory parameters ...............................................................44
17.4
Vital Signs ..........................................................................................44
17.5
Other Safety or Tolerability Evaluations............................................45
18
Reporting Conventions .......................................................................46
18.1
Incomplete dates .................................................................................46
19
References...........................................................................................47
20
Appendices .........................................................................................47
20.1
Programmed Major Protocol Deviations............................................48
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Avelumab
                    Avelumab in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
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3
List of Abbreviations and Definition of Terms
ACC
Adrenocortical Carcinoma
ACTH
Adrenocorticotropic Hormone
ADR
Adverse Drug Reaction
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANA
Anti-Nuclear Antibody
ANC
Absolute Neutrophils Count
ANCA
Anti-Neutrophil Cytoplasmic Antibody
AST
Aspartate Aminotransferase
aPTT
Activated Partial Thromboplastin Time
ATC
Anatomical Therapeutic Chemical
BMI
Body Mass Index
BOR
Best Overall Response
CALCIO
Corrected Calcium and Ionized Calcium
CI
Confidence Interval
Cmin
Trough Concentration
CPK
Creatine Kinase
CR
Complete Response
CRC
Colorectal Cancer
CRPC
Castrate Resistant Prostate Cancer
CTCAE
Common Terminology Criteria for Adverse Events
CTR
Clinical Trial Report
CV
Coefficient of Variation
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DLT
Dose Limiting Toxicity
DRM
Database Review Meeting
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
eCcr
Estimated Creatinine Clearance Rate
eCRF
Electronic Case Report Form
eDISH
Evaluation of Drug-Induced Serious Hepatotoxicity
Free T4
Free Thyroxine
GEJ
Gastroesophageal Junction
GeoCV
Geometric Coefficient of Variation
GeoMean
Geometric Mean
GGT
Gamma Glutamyl Transferase
HB
Hemoglobin
HNSCC
Head and Neck Squamous Cell Carcinoma
HR
Heart Rate
ICF
Informed Consent Form
IERC
Independent Endpoint Review Committee
IMP
Investigational Medical Product
irAE
Immune Related Adverse Event
irBOR
immune-related BOR
irCR
immune-related Complete Response
irPD
immune-related Progressive Disease
irPR
immune-related Partial Response
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IRR
Infusion Related Reaction
irRC
immune-related Response Criteria
irSD
immune-related Stable Disease
i.v.
Intravenous
LDH
Lactate Dehydrogenase
LLOQ
Lower Limit of Quantification
LogFC
Log Fold Change from Baseline
MBC
Metastatic Breast Cancer
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum Tolerated Dose
NCA
Non-Compartment Analysis
NCI
National Cancer Institute 
NE
Not Assessable
NOS
Not Otherwise Specified
NSCLC
Non-Small Cell Lung Cancer
PBMC
Peripheral Blood Mononuclear Cell
PCSA
Potentially Clinically Significant Abnormalities
PD
Progressive Disease 
PD-1
Programmed Death 1
PD-L1
Programmed Death Ligand 1
RF
Rheumatoid Factor
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PK
Pharmacokinetics
PLT
Platelet Count
PR
Partial Response
PT
Preferred Term
QTc
Corrected QT
QTcB
QT Interval Correction based on Bazett's Formula
QTcF
QT Interval Correction based on Fridericia's Formula
RBC
Red Blood Cell
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SAF
Safety
SAP
Statistical Analysis Plan
SD
Stable Disease
SEM
Standard Error of Mean
SMC
Safety Monitoring Committee
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
TNM
Tumor Node Metastasis Classification of Malignant Tumors
TSH
Thyroid-Stimulating Hormone
ULN
Upper Limit of Normal
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4
Modification History
Unique Identifier for SAP 
Version
Date of SAP Version
Author
Changes from the 
Previous Version
Final v1.0
12Oct2015
Jiali Tang
NA
5
Purpose of the Statistical Analysis Plan
The purpose of this statistical analysis plan (SAP) is to document technical and detailed 
specifications for the final analysis of data collected for the Dose Escalation phase under protocol 
EMR 100070-001. Results of the analyses described in this SAP will be included in the Clinical 
Trial Report (CTR). Additionally, the planned analyses identified in this SAP will be included in 
regulatory submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to 
provide results for inclusion in a CTR but not identified in this prospective SAP will be clearly 
identified in the CTR. 
6
Summary of Clinical Trial Features
Trial 
Objectives
Primary
! To assess the safety and tolerability of avelumab and to determine the 
maximum tolerated dose (MTD) of avelumab in subjects with metastatic 
or locally advanced solid tumors.
Secondary
! To characterize the pharmacokinetic (PK) profile of avelumab and to 
correlate exposure with target occupancy. 
! To evaluate the immunogenicity of avelumab and to correlate it to 
exposure and biological activity.
! To assess the best overall response (BOR) according to Response 
Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1, 1).
! To assess the immune-related BOR (irBOR) using the modified Immune-
Related Response Criteria (irRC, 2), derived from RECIST 1.1.
! To evaluate biological responses to avelumab in blood/serum.
! To characterize changes in soluble factors (e.g., cytokine profiles, soluble 
programmed death 1 [PD-1], and soluble PD-L1) and immune cell 
profiling (e.g., natural killer cells, neutrophils, lymphocytes).
The objectives associated with expansion phase were included into the 
expansion SAP.
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Trial 
Endpoints
Primary
! Occurrence of dose limiting toxicities (DLTs) during the first 3 weeks of 
treatment in the dose escalation part. 
Secondary
! Number, severity, and duration of treatment-emergent adverse events 
(TEAEs) according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v4.0.
! Number, severity, and duration of treatment-related adverse events (AEs)
according to NCI-CTCAE v4.0.
! PK profile.
! irBOR and BOR according to modified irRC and to RECIST 1.1 criteria, 
respectively, per investigator assessment.
! Pharmacodynamic profile
! Serum titers of anti-avelumab antibodies.
The endpoints associated with expansion phase were included into the 
expansion SAP.
Trial Design
This is a Phase I, open-label, dose-escalation trial with consecutive parallel 
group expansion in non-small cell lung cancer (NSCLC), metastatic breast
cancer (MBC), gastric and GEJ cancer, colorectal cancer (CRC), castrate 
resistant prostate cancer (CRPC), melanoma, ovarian cancer, head and neck 
squamous cell carcinoma (HNSCC), adrenocortical carcinoma (ACC), renal 
cell carcinoma (RCC), mesothelioma, and urothelial carcinoma. 
Dose escalation phase
Cohorts of 3 subjects with metastatic or locally advanced solid tumors will 
receive avelumab at escalating dose levels. At each dose level, subjects will 
receive avelumab as a 1-hour intravenous (i.v.) infusion once every 2 weeks 
until confirmed progression, unacceptable toxicity, or any criterion for 
withdrawal from the trial or the investigational medicinal product (IMP) 
occurs. Subjects who have experienced a confirmed complete response (CR) 
should be treated for a maximum of 24 months after confirmation, at the 
discretion of the investigator. If the investigator believes that a subject may
benefit from treatment beyond 24 months, it may be permissible after 
discussion with the sponsor. Subjects who experienced a CR and have 
already stopped treatment can resume treatment with avelumab at the same 
dose and schedule. Subjects re-initiating treatment should be assessed 
according to the Schedule of Assessments.
Dose escalation (3+3 design) will be performed at the following dose
levels
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! 1.0 mg/kg
! 3.0 mg/kg
! 10.0 mg/kg
Once 1 subject has experienced a DLT at a dose below 10.0 mg/kg, dose 
escalation will be reduced as described in Section 5.1.4.2 of Protocol 
Amendment 12.
The first subject of each cohort should be observed for 16 days (i.e., 48 hours 
after the second dose) for the occurrence of DLT before the second subject 
is administered the trial medication. Thereafter, within each cohort of the 
dose escalation phase, subjects may only be consecutively dosed with an 
interval of at least 48 hours. However, after 3 subjects have been treated at 
10 mg/kg and no DLT has been observed, the other 3 subjects required to 
complete this cohort can be enrolled without sequential dosing (i.e., not 
required to wait until 48 hours). If no more than one DLT has been observed 
in these 6 subjects, the safety of 10 mg/kg will have been established. 
Each subject will stay on the dose level assigned at trial entry (only 
adaptations for weight changes are needed as described in Section 5.1.7.1 of 
Protocol Amendment 12).
The decision to escalate to the next dose level will be based on safety 
assessments after all subjects of a cohort have reached Day 21 (DLT 
evaluation period). In order to assess the safety of avelumab, a safety 
monitoring committee (SMC), responsible for dose escalation decisions, 
will be established.
Once the MTD or maximum dose to be investigated is reached, the 
respective dose level cohort will be filled to a total of 6 subjects. Once the 
dose of 10 mg/kg is established as safe, 10 additional subjects at 3 mg/kg 
and 10 mg/kg each may be enrolled, for the purpose of generating additional 
safety, PK and receptor occupancy data, if agreed with the SMC.
Once 6 subjects treated at 10 mg/kg have completed the DLT observation 
period and the safety of 10 mg/kg is established, a dose level of 15 mg/kg 
(if 1 DLT was observed) or 20 mg/kg (if no DLT was observed) dosing every 
2 weeks will be initiated. In this 20 mg/kg dose level, the safety, PK, receptor 
occupancy, and pharmacodynamic activity of the IMP will be evaluated 
using the methodology that was used for the other cohorts. Accrual in these 
dose levels will be completed using a “3+3” method, the same methodology
that was used for the completion of the previous dose levels. Once the safety 
of the 15 and/or 20 mg dose level has been established (i.e., no more than 1 
DLT out of 6 subjects treated), up to 15 additional subjects will be enrolled 
at 15 or 20 mg/kg without sequential dosing (i.e., not required to wait until 
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48 hours between 2 subjects). This additional cohort will have the purpose 
of generating safety data, PK data and receptor occupancy data at the 
respective dose.
Definition of DLT
A DLT is specifically defined as any Grade ≥ 3 toxicity that is possibly, 
probably, or definitely related to avelumab, occurring during the DLT 
evaluation period (21 days after administration of avelumab), except for any 
of the following: 
! Grade 3 infusion-related reaction resolving within 6 hours and controlled 
with medical management.
! Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is 
controlled with medical management.
! Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, 
emesis that resolves to ≤ Grade 1. 
! Grade 3 diarrhea, Grade 3 skin toxicity, or Grade 3 liver function test 
(ALT, AST, or GGT) increase that resolves to ≤ Grade 1 in less than 7 
days after medical management (e.g., immunosuppressant treatment) has 
been initiated.
! Single laboratory values out of normal range that are unlikely related to 
trial treatment according to the investigator, do not have any clinical 
correlate, and resolve to ≤ Grade 1 within 7 days with adequate medical 
management.
! Tumor flare phenomenon defined as local pain, irritation, or rash 
localized at sites of known or suspected tumor.
DLTs requiring treatment discontinuation are described in Section 5.1.7.2
of Protocol Amendment 12.
Subjects who do not complete the DLT observation period for reasons other 
than a DLT will be replaced.
Expansion phase
This section was included into the Expansion SAP.
Number of 
Subjects
Dose escalation phase: 18 up to 60 subjects.
The final sample size, however, will depend on the total number of dose 
levels to be tested, and subject replacement for DLT evaluation if applicable.
Trial Product
Avelumab will be administered as a 1-hour (-10 minutes /+20 minutes, i.e., 
50-80 minutes) i.v. infusion. Subjects will receive avelumab once every 2 
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weeks until confirmed progression, unacceptable toxicity, or any criterion 
for withdrawal from the trial or IMP occurs.
The dose of avelumab will be calculated based on the weight of the subject 
determined on the day prior to or the day of each drug administration.
Premedication with an antihistamine and with paracetamol (acetaminophen) 
approximately 30 to 60 minutes prior to each dose of avelumab is mandatory 
(for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol
[acetaminophen] i.v. or oral equivalent). This regimen may be modified 
based on local treatment standards and guidelines, as appropriate.
Immediate access to intensive care unit or equivalent environment and 
appropriate medical therapy (including i.v. epinephrine, corticosteroids, 
antihistamines, bronchodilators, and oxygen) must be in place for use in the 
treatment of potential infusion-related reactions. Infusion of avelumab will 
be stopped in case of Grade ≥2 infusion-related, allergic, or anaphylactic 
reactions (according to NCI-CTCAE v4.0). Following avelumab infusions, 
subjects must be observed for 2 hours post infusion for potential infusion-
related reactions.
Relevant clinical laboratory results essential for patient management 
decisions (hematology, biochemistry, liver function tests) must be available 
and reviewed before administration of avelumab.
Treatment and 
Trial Duration
The planned treatment duration is until unacceptable toxicity, or any 
criterion for withdrawal from the trial or IMP occurs.
Schedule of 
Visits
For dose escalation cohorts
1. Screening (days -18 to first treatment)
2. Treatment phase
Visits will take place on Days 1, 2, 3, 15, 29, 43, and every 2 weeks 
thereafter.
3. Discontinuation visit and end-of-treatment visit
All subjects who discontinue trial treatment prematurely for an AE should 
have a full safety evaluation at the time of discontinuation of trial treatment 
(discontinuation visit). In addition, all subjects will have an end-of-treatment 
visit scheduled 4 weeks after the last administration of avelumab but before 
any new therapy is started, if possible. 
4. Post-treatment follow-up
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All subjects will have a subsequent visit scheduled 10 weeks after the last 
administration of avelumab. The visit will include a full assessment of safety 
parameters.
AEs will be documented until the end of treatment visit. After the end of 
treatment visit only treatment related AEs have to be documented until the
post-treatment safety follow-up visit. Subjects with a serious AE ongoing at 
the post-treatment safety follow-up must be monitored and followed up by 
the investigator until stabilization or until the outcome is known, unless the
subject is documented as “lost to follow-up”.
Subjects without progressive disease at the end-of-treatment visit will be 
followed up for disease progression (CT / MRI scans every 12 weeks) up to 
1 year. In addition, subjects will be followed for any AE suspected to be 
related to trial treatment, especially for the occurrence of new autoimmune 
events up to 3 months after the last dose of avelumab.
After the end-of-treatment visit, subjects will be followed quarterly for 
survival (including assessment of any further tumor therapy). The survival 
follow-up will continue until 1 year after the last subject receives the last 
dose of avelumab.
For dose expansion cohorts
This section was included into the Expansion SAP.
Randomization 
and Blinding
Not applicable.
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8
Overview of Planned Analyses
There will be one planned analysis after the end of dose escalation phase. This SAP will only 
address the analysis for the dose escalation phase. Additional SAPs for SMC analyses and for all 
other analyses (interim, primary, and final) for expansion cohorts have been developed separately.
9
Changes to the Planned Analyses in the Clinical Trial 
Protocol
The data cut-off date was changed to Nov 20, 2015 from 6 weeks after the last subject of the dose 
escalation part has received its first administration of avelumab in order to provide a more 
comprehensive evaluation of the dose escalation phase in the first interim CTR for this study.
10
Analysis Sets
The following analysis sets will be defined for the dose escalation part:
! Screening analysis set: all subjects who signed the informed consent form (ICF).
! DLT analysis set: all subjects with data used for implementing the dose-escalation schedule.
These subjects should:
o Have received all study treatment administrations during the DLT evaluation period (first 21 
days of treatment) or 
o Have stopped treatment because of DLTs during the DLT evaluation period.
! Safety (SAF) analysis set: all subjects who have received at least 1 dose of trial treatment.
! PK analysis set: all subjects who receive at least one dose of avelumab, and provide at least one 
measurable post-dose concentration. 
Unless otherwise stated, DLT analysis set will be used for the summary of the incidence of DLT, 
and PK analysis set will be used for the PK analysis, other analyses including safety analyses will 
be based on SAF analysis set.
11
General Specifications for Statistical Analyses
! The endpoint data will be summarized by dose level and overall, unless otherwise specified. 
! All data recorded during the study will be presented in individual data listings. Data collected 
after re-initiation of treatment will not be included for safety summaries except for disposition, 
but will be included in the data listings.
! All data will be evaluated as observed, and no imputation method for missing values will be 
used, unless otherwise specified.
! Duration will be calculated as stop date – start date + 1, unless otherwise specified.
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! The first day (Day 1) of study treatment is defined as the day of the first administration of 
avelumab, unless otherwise stated. The last dose date of study treatment is defined as the day of 
the last administration of avelumab, prior to the re-initiation of study treatment if applicable.
! Baseline is defined as the last non-missing observation prior to the administration of first dose 
of trial treatment. Additionally, baseline for HR and QT/corrected QT (QTc) assessments will 
be derived from the visit where both HR and QT are not missing. If duplicate or triplicate 
electrocardiograms (ECGs) are collected, baseline for each ECG measurement is the average of 
the pre-dose replicate measurements on the baseline day. QT interval correction based 
Fridericia’s or Bazett's formula (QTcF/QTcB) will be derived based on HR and QT. The average 
of the replicate measurements should be determined after the derivation of the individual 
parameter at each time point.
! If the laboratory assessments are not done for scheduled visit but they are available for 
unscheduled visit on Day 1 from a different laboratory, the unscheduled visit will be included 
for the derivation of baseline; if there are multiple non-missing assessments on Day 1, the 
assessment from scheduled visit will be used for the derivation of baseline.
! On-treatment period is defined as the time from the first dose of study treatment to the last dose
date + 30 days, or the earliest date of subsequent anti-cancer drug therapy – 1 day, whichever 
occurs first. If the earliest date of subsequent anti-cancer drug therapy is a partial date and only 
day is missing, it will be imputed as the last day of the month. If both day and month are missing, 
no imputation should be performed. The imputed date will be used for defining on-treatment 
period as well as confirming immune-related progressive disease (irPD).
! All statistical analyses will be performed using SAS® Version 9.1.3 or higher.
! There will be no difference between scheduled and un-scheduled visits except for by-visit 
analysis of safety data and baseline derivation.
! The assignments of visit windows are described in Table 1 for the purpose of by-visit analyses
of safety data:
o Baseline will be derived as described above.
o No visit windowing will be performed at discontinuation, end of treatment, or safety follow-
up visits for laboratory, vital sign, and ECG data, and 2hr post dose assessment on Week 1 
Day 1 for ECG data. Instead, the earliest non-missing observation among the unscheduled or 
scheduled assessments for each visit (discontinuation, end of treatment, or safety follow-up) 
will be used for the analysis. For 2hr post dose assessment on Week 1 Day 1 ECG data, the 
earliest non-missing observation on Week 1 Day 1 will be used for the analysis.
o Scheduled and unscheduled assessments are included for visit windowing. Assessments on 
or after re-initiation of treatment are not be included for visit windowing.
o If there are multiple assessments for any specified visit and some of them are from scheduled 
visits, the assessment from scheduled visit with the closest distance to the planned study day 
will be used for analysis. 
o If there are multiple assessments for any specified visit and none of them are from scheduled 
visits, the assessment with the closest distance to the planned study day will be used for 
analysis. 
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o
If there are two or more unscheduled assessments with same distance to the planned study 
day such as (-1/+1 day), the assessment prior to the planned study day such as -1 day will be 
used for windowing. 
o There is no difference for visit windowing between tests from core serum chemistry panel 
and tests from full serum chemistry panel. Some subjects had non-core serum chemistry tests 
assessed at the scheduled visits only intended for core serum chemistry. Multiple protocol 
amendments is also taken into the consideration, as the full serum chemistry and hematology 
panels were assessed weekly until week 7 and bi-weekly thereafter prior to the approval of 
Protocol Amendment 7.
o For ECG assessment associated with study drug dose, only assessments where time point 
(prior to infusion or 2 hr after infusion) are not missing will be considered for the analysis.
Table 1. Visit Window Definition for Safety Assessment
Assigned 
Study 
Day 
(Inclusive)
Planned Study 
Day
(AWTARGE
T)
Analysis 
Visit 
(N) 
(AVISITN)
Analysis 
Visit
(AVISIT)
Assessment
From
(AWLO)
To
(AWHI)
~
1
1
Baseline
Lab, Vital Sign, ECG
1
1
1
2
Week 1 Day 1* 
ECG
5
11
8
3
Week 2 Day 5-11
Lab, Vital Sign
12
18
15
4
Week 3 Day 12-18
Lab, Vital Sign
5
18
15
4
Week 3 Day 5-18
ECG
19
25
22
5
Week 4 Day 19-25
Lab, Vital Sign
19
25
22
5
Week 4 Day 19-25
ECG
26
32
29
6
Week 5 Day 26-32
Lab, Vital Sign
26
36
29
6
Week 5 Day 26-36
ECG
33
39
36
7
Week 6 Day 33-39
Lab, Vital Sign
40
50
43
8
Week 7 Day 40-50
Lab, Vital Sign
37
50
43
8
Week 7 Day 37-50
ECG
51
64
57
10
Week 9 Day 51-64
Lab, Vital Sign, ECG
65
78
71
12
Week 11 Day 65-78
Lab, Vital Sign, ECG
79
92
85
14
Week 13 Day 79-92
Lab, Vital Sign
79
106
85
14
Week 13 Day 79-106
ECG
93
106
99
16
Week 15 Day 93-106
Lab, Vital Sign
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107
120
113
18
Week 17 Day 107-120
Lab, Vital Sign
121
134
127
20
Week 19 Day 121-134
Lab, Vital Sign
107
148
127
20
Week 19 Day 107-148
ECG
135
148
141
22
Week 21 Day 135-148
Lab, Vital Sign
149
162
155
24
Week 23 Day 149-162
Lab, Vital Sign
163
176
169
26
Week 25 Day 163-176
Lab, Vital Sign
149
190
169
26
Week 25 Day 149-190
ECG
177
190
183
28
Week 27 Day 177-190
Lab, Vital Sign
191
204
197
30
Week 29 Day 191-204
Lab, Vital Sign
205
218
211
32
Week 31 Day 205-218
Lab, Vital Sign
191
232
211
32
Week 31 Day 191-232
ECG
* only applies to 2 hr post dose.
! Presentation of continuous and qualitative variables:
o Continuous variables will be summarized using descriptive statistics i.e., number of non-
missing values and number of missing values, [i.e. n (missing)], mean, median, standard 
deviation, minimum, maximum and first and third quartile (Q1 and Q3). Confidence interval 
(CI) may be estimated for some of the endpoints, if appropriate.
o Qualitative variables will be summarized by counts and percentages. Unless otherwise stated,
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.
12
Trial Subjects
The subsections in this section include specifications for reporting subject disposition and 
treatment/trial discontinuations. Additionally procedures for reporting protocol deviations are 
provided.
12.1
Disposition of Subjects and Discontinuations
Summary of analysis sets will be tabulated using frequency and percentage by dose level (if 
applicable) and overall based on all the subjects who signed ICF, the number of subjects in SAF 
analysis set will be used as the denominator:
! All subjects who signed ICF
! Number of subjects in the SAF analysis set
! Number of subjects in the DLT analysis set
One table will provide the reasons for permanent discontinuation of study treatment and for end of 
study as collected on the Treatment Termination, and End of Study (if data is available) electric 
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Case Report Forms (eCRFs), respectively. The number and percentage of subjects in each 
disposition category will be presented in the table based on the SAF analysis set:
! Number of subjects in the SAF analysis set
! Number of subjects still on treatment
! Number of subjects off-treatment
! Reasons off-treatment
o Adverse event
o Lost to follow-up
o Protocol non-compliance
o Death
o Disease progression
o Withdrew consent
o Other
! Number of subjects in follow-up
! Number of subjects off-study
! Reasons off-study
o Study reached predefined end
o Lost to follow-up
o Death
o Withdrew consent
o Other
The listing of subject disposition will include all subjects who signed ICF (i.e. including screening 
failures). The listing will include the following information (if applicable): subject identifier, date 
of informed consent, included in the trial, reason for inclusion/exclusion, first/last dosing date, 
reason off-treatment, date and reason off-study, flags for SAF and DLT analysis sets, and be sorted 
by dose level and subject identifier.
A secondary listing for reason for end of treatment due to AEs will also be provided. The listing 
will be restricted to the SAF analysis set subjects who discontinued study treatment for the primary 
reason of an AE, and will include the following information: subject identifier, first/last dosing date, 
date off-treatment, and the relevant AE system organ classes (SOCs), preferred terms (PTs) and AE 
relationship to the study treatment.
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12.2
Protocol Deviations
12.2.1
Minor Protocol Deviation
A minor protocol deviation can be defined as any deviation from the study protocol that does not 
materially affect the safety of the subjects and/or the conduct of the study and/or its evaluation. An 
example of a minor protocol deviation would include a missed PK blood sample.
12.2.2
Major Protocol Deviation
A major and/or serious protocol deviation (otherwise known as a protocol violation) is one that 
materially affects the safety of the subjects and/or the evaluation of primary or key secondary 
endpoints of the study. 
Current ICH and EU GCP guidelines list the major protocol deviations that must be listed in the 
clinical report. These include:
! subjects that are dosed on the study despite not satisfying the inclusion criteria;
! subjects that develop withdrawal criteria whilst on the study but are not withdrawn;
! subjects that receive the wrong treatment or an incorrect dose;
! subjects that receive an excluded concomitant medication.
Major protocol deviations will be based upon clinical database and determined for all subjects by 
either medical review processes or programming based on the inclusion/exclusion criteria or other 
criteria presented in the protocol. The results will be included into SDTM, if identified by means 
of medical review. The ADAM datasets will include both, those identified by medical review and 
those identified by programming.
Major protocol deviations are specified in Appendix 20.1, and will be reported in a data listing.
13
Demographics and Other Baseline Characteristics
The demographics and other baseline characteristics will be summarized on the SAF analysis set.
13.1
Demographics
The demographics and baseline characteristics table will include descriptive statistics for the 
following variables:
! Age (in years)
! Age category (<65/≥65 years)
o 65-74, 
o 75-84, 
o ≥ 85
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! Sex
! Race
! Height (cm)
! Weight (kg)
! Body Mass Index (BMI) (kg/m2)
! Eastern Cooperative Oncology Group (ECOG) Performance Status
! Nicotine use status (Never used/ Regular user/ Occasional user/ Former user)
Baseline weight and height will be the last non-missing values prior to the first dose of study 
treatment from the Vital Signs eCRF page while baseline ECOG will be derived from the data 
collected on the ECOG eCRF page. Nicotine use status will be extracted from Nicotine 
Consumption eCRF page.
Age and BMI will be derived as:
! Age(year) = (Date of Informed Consent – Date of Birth + 1)/365.25.
o In case of missing day only: Age (years) = (year/month of given informed consent –
year/month of birth)/12
o In case only year of birth is given: Age (years) = (year of given informed consent - year of 
birth)
! BMI(kg/m2) = Weight(kg)/[Height(m)]2. 
The integer part of the calculated age will be used for report purpose. The above table will be
generated by dose level and overall.
The listing of demographics and baseline characteristics will include the following information: 
dose level, subject identifier, age, sex, race, height (cm), weight (kg), BMI (kg/m2), and ECOG.
The listing of nicotine consumption will be produced with the following data: nicotine use status, 
frequency of nicotine use, start/end date of nicotine consumption, nicotine consumption habit, and 
duration of consumption (years).
13.2
Medical History
Medical history will be coded using the latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA). Medical history will be summarized as the numbers and 
percentages of subjects by MedDRA PT as event category and MedDRA SOC as summary 
category, and sorted by SOC and PT in alphabetical order. Each subject will be counted only once 
within each PT or SOC.
Listing of medical history data by subject will include coded terms and all the relevant data fields 
as collected on the Medical History eCRF page.
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13.3
Disease History 
Disease histories are collected on Disease History eCRF page. Partial date will be imputed as 
described in the Section 18.1. 
The disease history table will include descriptive statistics for the following variables:
! Site of primary tumor
o Lung, not otherwise specified (NOS)
o Breast, NOS
o ….
! Tumor histopathologic/ cytologic type of interest
o Adrenocortical
o Anal
o Bladder
o ………
o Other
! Time since first diagnosis (years), defined as (the first dosing date – the date of first 
diagnosis)/365.25
! Time since metastatic or locally advanced disease (months), defined as (the first dosing date –
the date of first occurrence of metastatic or locally advanced disease)/30.4375
! Time since last disease progression (months), defined as (the first dosing date - the date of last 
progression of disease)/30.4375
! Tumor Node Metastasis Classification of Malignant Tumors (TNM) at initial diagnosis 
o TX
o T0
o N1 
o ….
! TNM at study entry
o TX
o T0
o N1
o …
Listing of disease history will be provided with all relevant data (primary site of tumor, sub-site, 
initial diagnosis date, first occurrence of metastatic or locally advanced disease, date of last disease 
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progression, TNM classification, tumor histopathologic/ cytologic type of interest etc.) and derived 
variables used in the above table.
14
Prior and Concomitant Medications/Procedures
Prior and concomitant anti-cancer therapy / other medications will be coded using the latest 
available version of WHO Drug Dictionary, and summarized by dose level and overall based on 
SAF analysis set.
14.1
Prior Anti-Cancer Therapies/Procedures
The prior anti-cancer treatments and procedures are collected under the Prior Anti-Cancer Drug 
Therapies Details, Prior Anti-Cancer Radiotherapies Details and Prior Anti-Cancer Surgeries 
Details eCRF pages.
The overall summary of presence of prior anti-cancer treatments table will include: the number and 
percentage of subjects by type of treatment, i.e. 
! Number of subjects with at least one type of prior anti-cancer treatment
! Number of subjects with at least one prior anti-cancer drug therapy
! Number of subjects with at least one prior anti-cancer radiotherapy
! Number of subjects with at least one prior anti-cancer surgery
Summary of prior anti-cancer drug therapy will include the following variables:
! Number of subjects with at least one prior anti-cancer drug therapy
! Number of any prior anti-cancer therapy lines: missing / 1 / 2 / 3 / ≥4
! Number of any prior anti-cancer therapy lines as continuous variable
! Number of prior anti-cancer therapy lines for metastatic or locally advanced disease: missing /
0 / 1 / 2 / 3 / ≥4. If the intent of therapy is metastatic, locally advanced, or palliative, it will be 
counted into therapy lines for metastatic or locally advanced disease.
! Number of prior anti-cancer therapy lines for metastatic or locally advanced disease as 
continuous variable
! Type of prior anti-cancer therapy: chemotherapy / antibody therapy / kinase inhibitors /
hormonal therapy / vaccines / bone marrow transplant / lymphocyte infusion / other
! Intent of therapy: adjuvant / neo-adjuvant / metastatic / locally advanced / palliative
! Best response: CR / partial response (PR) / progressive disease (PD) / stable disease (SD) / 
unknown / not assessable (NE) / not applicable. Best response is derived from the last treatment 
regimen. 
The prior anti-cancer drugs will also be extensively detailed with the number and percentage of 
subjects by ATC classification level 2 and PT in a table. A subject 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 
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different times. If any prior anti-cancer medication is classified into multiple Anatomical 
Therapeutic Chemical (ATC) classes, the medication will be summarized separately under each of 
these ATC classes. In case any specific medication does not have ATC classification level 2 coded 
term, it will be summarized under “Unavailable ATC classification” category. The summary will 
be sorted on decreasing frequency of drug class and decreasing frequency of drug name in a given 
drug class, based on the incidence in the “Overall” column. In case of equal frequency regarding 
drug class (respectively drug name), alphabetical order will be used.
The listings of prior anti-cancer treatments and procedures will also be provided: a) listing of prior 
anti-cancer drug therapies, b) listing of prior anti-cancer radiotherapies, and c) listing of prior anti-
cancer surgeries. These will include subject identifier and all the relevant collected data-fields on 
the corresponding eCRF pages.
14.2
Prior and Concomitant Medications/Procedures
Prior and concomitant procedures are collected on the Concomitant Procedures Details eCRF page. 
Prior and concomitant medications are collected on the Concomitant Medications Details eCRF 
page.
Medications started prior to first dose date of study treatment and continued into the on-treatment 
period as well as those started during on-treatment period are referred to as concomitant 
medications. Prior medications are defined as the medications started and stopped prior to the first 
dose date of trial treatment. Post medications are defined as any medications started after on-
treatment period.
Summary of concomitant medications will include the number and percentage of subjects by ATC 
classification level 2 and PT. A subject 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 summarize 
separately under each of these ATC classes. In case any specific medication does not have ATC 
classification level 2 coded term, it will be summarized under “Unavailable ATC classification” 
category. The summary of concomitant medications will be sorted on decreasing frequency of drug 
class and decreasing frequency of drug name in a given drug class, based on the incidence in the 
“Overall” column. In case of equal frequency regarding drug class (respectively drug name), 
alphabetical order will be used.
Prior and concomitant medication data will be listed from the Concomitant Medications eCRF page. 
The following variables will be included in the prior and concomitant medication listing: subject 
identifier, prior/ concomitant/ post medication, and all corresponding data fields on the 
corresponding eCRF page.
Prior and concomitant procedures data will be listed from the Concomitant Procedures Details 
eCRF page. Subject identifier and all collected data-fields on the corresponding eCRF page will be 
included in the listing.
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14.3
Subsequent Anti-Cancer Therapies/Procedures
Anti-cancer treatment after discontinuation of treatment with avelumab will be provided in a data 
listing with data retrieved from Anti-Cancer Treatment After Discontinuation, Radiotherapy After 
Discontinuation, and Surgery After Discontinuation eCRF pages.
15
Treatment Compliance and Exposure
Analysis of exposure will be based on the calculated actual dose levels (total dose 
administered/weight, mg/kg). The last available weight of the subject on or prior to the day of 
dosing will be used for the calculation. 
The summary of treatment exposure and compliance based on the SAF analysis set will include the 
following variables per subject (a cycle refers to the planned dosing interval of two weeks):
! Treatment duration (in weeks), defined as (the last dose date – the first dose date + 14)/7 
! Number of administrations as continuous variable
! Cumulative dose (mg/kg), defined as sum of actual dose levels 
! Dose intensity (mg/kg/cycle), defined as cumulative dose (mg/kg) / (0.5 * treatment duration 
(week)) 
! Relative dose intensity (%), defined as actual dose intensity (mg/kg/cycle) * 100/ planned dose 
level (mg/kg/cycle).
! Relative dose intensity by the following categories:
o >0.9
o >0.8-0.9
o <=0.8
Individual relative dose intensity (%) is calculated as actual dose (kg)/ planned dose (kg) × 100 for 
each infusion of study medication. A dose reduction is defined as actual non-zero dose < 90% of 
planned dose, or individual relative dose intensity < 90%. A table based on SAF analysis set will 
be prepared to summarize the number and percentage of subjects with at least one dose reduction, 
and a breakdown by the number of dose reductions (1/2/3/≥4).
Per protocol, avelumab will be administered as 1-hour i.v. infusion. Subjects will receive the study 
treatment once every 2 weeks. Dose delays will be grouped into the following categories based on 
the deviation of the actual to the planned treatment administration day (relative to the previous non-
zero dose date): no delay (including 1-2 days delays), 3-6 days delay, 7 or more days delay. For 
example, if one subject receives the study drug on day 1, then the next study drug administration 
date will be on day 15; however, if the subject receives the study drug at day 16 or 17, this is 
considered as ‘no delay’. Any zero dose prior to the last treatment administration is considered as 
a dose interruption.
The summary of dose delays will be based on the SAF analysis set and include the following 
categories:
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! No delay
! 3-6 days delay
! 7 or more days delay
The categorization is based on the maximum length of delay, i.e. the worst case of delay if subjects
have multiple dose delays. 
A listing of study drug administration will include subject identifier, study day, # of days relative 
to prior treatment, infusion rate, most recent body weight prior to infusion, actual/planned dose, 
batch ID, dose reduction/ dose delay or interruption, and other relevant information collected on 
the Cohort Treatment MSB0010718C Administration Details eCRF page.
A listing of treatment exposure and compliance will include subject identifier, assigned dose level,
and above derived variables summarized in the tables.
In order to mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg 
diphenhydramine and 650 mg acetaminophen (i.v. or oral equivalent) is mandatory 30 to 60 minutes 
prior to each dose of study drug starting on January 29, 2014. The use of premedication will be 
summarized as numbers of subjects with 0, 1, 2, 3, 4 doses among the first 4 treatment 
administrations that were administered without pre-medication. For example: if a subject 
discontinued after 3 doses, and 2 of them were administered with premedication, the number for 
that subject would be 1.
A listing of premedication will include subject identifier, reported medication term, date/time of 
premedication, and dose (unit). A listing containing subject identifier, visit, and unique study drug 
batch ID will also be created. 
16
Endpoint Evaluation
The subsections in this section include specifications for analyzing clinical trial endpoints specified 
in the Clinical Trial Protocol to meet the trial objectives for dose escalation, as well as any endpoints 
not identified in the Clinical Trial Protocol. Endpoints identified for expansion part in the Clinical 
Trial Protocol are included into other SAPs.
16.1
Primary Endpoint Analysis
The primary endpoint in the dose escalation part of this trial is the occurrence of DLTs during the 
DLT evaluation period.
A DLT is defined as a Grade >=3 adverse drug reaction according to the NCI-CTCAE v4.0, 
occurring during the DLT evaluation period confirmed by the SMC to be relevant for the study 
drug treatment based on the criteria specified in Protocol. 
The summary of DLTs will include the following variables by dose level and overall for the DLT 
analysis set:
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! the number and percentage of subjects who experienced a DLT during the DLT evaluation period
! number of DLT per subject, 1 /2 /≥3
! DLT by SOC and PT
The number and percentage of subjects who experienced a TEAE by SOC and PT during the DLT 
evaluation period will also be summarized by dose level and overall for the DLT analysis set. A 
listing of DLT AEs will include dose level, subject identifier, SOC/PT, and all relevant variables,
such as start/stop date, toxicity grade, relationship to the study treatment, outcome etc., from AE 
eCRF page.
The MTD or maximum dose will be determined according to the dose-escalation plan described in 
section 5.1.4.2 of trial protocol. The MTD or maximum dose is defined as the highest dose level at 
which no more than one out of 6 subjects treated in a cohort and evaluable for DLT determination 
experiences a DLT.
16.2
Secondary Endpoint Analyses
The Secondary endpoints for dose escalation are:
! Number, severity, and duration of TEAEs according to the NCI-Common Terminology Criteria 
for Adverse Events (CTCAE) v4.0.
! Number, severity, and duration of treatment-related AEs according to NCI-CTCAE v4.0.
! PK profile.
! irBOR and BOR according to modified irRC and to RECIST 1.1, respectively, per investigator 
assessment.
! Pharmacodynamic profile.
! Serum titers of anti-avelumab antibodies.
TEAE related endpoints will be discussed in the Section 17.1. Other secondary endpoints such as 
cytokine profile, receptor occupancy, PK profile, immunogenicity will be addressed in Sections
16.3, 16.4, 16.5, or 16.6, respectively. No efficacy summary will be performed due to small sample 
size and heterogeneous population in dose escalation part, but the endpoints at subject level will be 
derived as described in this section and displayed in the listings.
Efficacy evaluations include lesion assessments for target, non-target, and new lesions, tumor 
response according to RECIST 1.1 (1) and irRC (2). The confirmed BOR is defined as the best 
response obtained among all tumor assessment visits after first dose of study treatment until 
documented disease progression, taking into account the following requirements for confirmation:  
! CR or PR needs to be confirmed at a subsequent tumor assessment, preferably at the regularly 
scheduled 6-week assessment interval, but no sooner than 4 weeks after the initial documentation 
of CR or PR. 
! PR can be confirmed at an assessment later than the next assessment after the initial 
documentation of PR. 
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! The minimum duration for a BOR of SD is defined as at least 37 days after start of study 
treatment accounting for permitted deviations from the tumor assessment visit schedule. 
Table 2 summarized the derivation rules for the BOR when confirmation from subsequent 
assessment is needed (1). It is reasonable to consider a subject with time point response of PR-SD-
PR, PR-NE-PR or CR-NE-CR as a confirmed response as long as the second CR or PR is at least 
28 days away from the first time point.
Table 2
Best Overall Response when Confirmation of CR/PR Required
Initial overall response
Subsequent overall response
Confirmed time point overall response
CR
CR
CR provided subsequent CR is >=28 days away from the first 
time point
CR
PR
SD provided minimum criteria for SD duration met; otherwise, 
PD
CR
SD
SD provided minimum criteria for SD duration met; otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met; otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR provided subsequent CR is >=28 days away from the first 
time point
PR
PR
PR provided subsequent PR is >=28 days away from the first 
time point
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
SD
Any
SD provided minimum criteria for SD duration met, otherwise, 
NE
PD
Any
PD
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = Not assessable.
If a subject only has a response value of NE or the only response value is SD and is within 36 days of the first dose date, the 
best response will be NE.  
For irBOR, immune-related complete response (irCR), immune-related partial response (irPR), and 
irPD need to be confirmed by a second, consecutive assessment at least 4 weeks apart as described 
in Table 3 (1, 2). It is reasonable to consider a subject with time point response of irPR-irSD-irPR, 
irPR-NE-irPR or irCR-NE-irCR as a confirmed response as long as the second irCR or irPR is at 
least 28 days away from the first time point. irPD is also considered to be confirmed if the following 
event occurs:
! If subject is assessed with time point response of irPD-NE-irPD as long as the second irPD is at 
least 28 days away from the first time point; or
! If subject dies within 84 days after the initial observation of irPD; or
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! If subject receives subsequent anti-cancer drug therapy within 84 days after the initial 
observation of irPD; or
! If subject experiences clinical deterioration as assessed by investigator and recorded as reason 
for treatment discontinuation prior to or within 84 days after the assessment of irPD. 
In case a subject with a confirmed CR relapses within 1 year after stopping treatment, one re-
initiation of treatment is allowed according to Protocol. If the subject has irPD assessed at the same 
visit as the PD prior to the initiation of treatment, the irPD will be considered as confirmed. The 
minimum duration of immune-related stable disease (irSD) is defined as at least 37 days from Day 
1. 
Table 3
Immune-related BOR when Confirmation of irCR, irPR, irPD Required
Initial overall 
response
Subsequent overall 
response
Confirmed time point overall response
irCR
irCR
irCR provided subsequent irCR is >=28 days away from the first time point
irCR
irPR
irSD provided minimum criteria for irSD duration met; otherwise, irPD
irCR
irSD
irSD provided minimum criteria for irSD duration met; otherwise, irPD
irCR
irPD
irSD provided minimum criteria for irSD duration met; otherwise, irPD
irCR
NE
irSD provided minimum criteria for irSD duration met, otherwise, NE
irPR
irCR
irPR provided subsequent irCR is >=28 days away from the first time point
irPR
irPR
irPR provided subsequent irPR is >=28 days away from the first time point
irPR
irSD
irSD
irPR
irPD
irSD provided minimum criteria for irSD duration met, otherwise, irPD
irPR
NE
irSD provided minimum criteria for irSD duration met, otherwise, NE
irSD
Any
irSD provided minimum criteria for irSD duration met, otherwise, NE
irPD
irPD
irPD provided subsequent irPD is >=28 days away from the first time point,  death  
or take subsequent anti-cancer drug therapy within 84 days  after the first time 
point, or clinical deterioration.
irPD
Missing
irPD if subject dies or takes subsequent anti-cancer drug therapy within 84 days 
after the initial observation of irPD, or clinical deterioration, otherwise, NE
NE
NE
NE
irCR = immune-related complete response, irPR = immune-related partial response, irSD = immune-related stable disease, irPD 
= immune-related progressive disease, and NE = Not evaluable.
If a subject only has a response value of NE or the only response value is irSD and is within 36 days of the first dose date, the 
best response will be NE  
These evaluations will be presented in data listings with detailed information, such as lesion type, 
site, size, time point tumor response by type collected per eCRF pages as well as BOR and irBOR,
for all the subjects from SAF analysis set.
16.3
Cytokine Profile
The following parameters are assessed for the cytokines profile based on SAF analysis set:
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! Rantes, Interleukin-17, IL-6, MCP-1, IL-1beta, IL-2, IL-4, IL-5, IL-10, IL-12p70, IL-13, TNF-
Alpha, IFN-Gamma.
These parameters will be summarized by visit and dose level using the following variables:
! Absolute value
! Log fold change from baseline
If values are indicated to be below the lower limit of quantification (LLOQ), they will be imputed 
as 0.5* LLOQ for summary analysis. If multiple measurements per time point per subject exist, a 
single signal value will be derived by averaging.
Log fold change from baseline (logFC) is defined as 
! logFC (cytokine at time t) = log(cytokine signal at time t) – log(cytokine signal at baseline):
The cytokine data will be displayed graphically by dose level for each parameter:
! Boxplot of absolute value by visit (logarithmic and raw scale)
! Boxplot of log fold change from baseline by visit
! Line plot of per-subject data
The cytokine listing will be produced with relevant variables such as dose level, subject identifier, 
visit, parameter names and results. 
16.4
Receptor Occupancy
The receptor occupancy was assessed by flow cytometry on PBMC (peripheral blood mononuclear 
cell) samples collected on Day 1 before start of the infusion, at 4 and 48 hrs after the start of 
infusion, and before the start of each infusion on Days 15, 29, 43, and 85, if applicable. Quality of 
PBMCs such as cell viability was determined after thawing, ≥85% cell viability is required for 
reliable receptor occupancy assessment. Additional or alternative criteria might be used if a review 
of the data indicates that this is necessary. Data generated from samples with inadequate quality 
will be excluded from the analysis. 
This data will be summarized using descriptive statistics (n, mean, standard deviation, etc.) by visit 
and by dose level and overall based on SAF analysis set.  Line plots will be created to display the 
data graphically across visit per subject by dose level, or to display the mean and standard deviation 
across visit by dose level.
A listing of receptor occupancy will include variables such as subject identifier, visit, date of 
assessment, test parameter, and values etc.
16.5
Pharmacokinetic Profile
16.5.1
Missing PK Data
All PK analyses will be based on the PK analysis set.
! Concentrations below the limit of assay quantitation
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PK concentrations below LLOQ are taken as zero for descriptive statistics.
PK concentrations below LLOQ, which are before the last quantifiable data point, will be taken as 
zero for calculating the AUC of single dose profiles. Concentration below LLOQ, which occur after 
the last quantifiable data point, will not be considered in the calculation of the terminal first order 
rate constant (
z
∀).
! Deviations, missing concentrations and anomalous values
Concentrations will be set to missing in summary tables if the value is reported as no result. 
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will be 
coded as NC (not calculated).  (Note that NC values will not be generated beyond the day that a 
subject discontinues the treatment). For statistical analyses (i.e. analysis of variance), PK 
parameters coded as NC will be set to missing.
If an individual subject has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this subject/value will be excluded from the descriptive 
statistics and instead the result will be listed in a separate table. 
Relevant decisions on subject inclusion in the PK analysis set will be made before database lock in 
the Database Review Meeting (DRM).
16.5.2
Descriptive PK Analysis
Avelumab concentrations in serum will be displayed in listing and descriptively summarized by 
treatment, cohort, day and nominal time using the number of non-missing observations, number of 
missing observations, arithmetic mean, standard deviation, coefficient of variation (CV%), standard 
error of the mean (SEM), minimum, median and maximum. The pre-dose samples will be 
considered as if they had been taken simultaneously with the administration. Additional tables 
listing trough concentrations (Cmin) per cohort/day/administration will also be provided, and 
summarized descriptively using the aforementioned statistics.
Descriptive statistics of PK parameters will additionally show the geometric mean (GeoMean), the 
geometric coefficient of variation (GeoCV) and the 95% confidence interval for the GeoMean. 
For the calculation of descriptive statistics, values as presented in the data listings will be used.  
Minimum and maximum will be presented to the same decimal precision as collected.  Mean, 
median and GeoMean will be presented to one decimal place more than the precision of the data 
collected.  SD and SEM will be presented to two decimal places more than the precision of the data 
collected. The coefficient of variation (CV%), GeoCV and the 95% CI will be reported to 1 decimal 
place.  
16.5.3
Pharmacokinetic Non-Compartment Analysis
Pharmacokinetic parameters for avelumab will be evaluated according to standard non-
compartmental analysis (NCA) by the PK/pharmacodynamic data processing group of QPD, Merck 
Serono, Darmstadt, Germany, using the validated software tool Phoenix®/WinNonlin 6.3® (or 
later). 
The PK parameters listed below will be calculated for avelumab using the actual time elapsed from 
dosing (or using scheduled time if actual time is not available).
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Cmax
Maximum observed concentration in serum
tmax
Time to reach Cmax
AUC0-t
Area under the serum concentration-time curve from time zero to the last 
quantifiable concentration
Cmin
The minimum observed concentration during a complete dosing interval 
(serum trough concentration)   
When applicable the following parameters will also be calculated: 
AUC0-∞
Area under the serum concentration-time curve from time zero extrapolated 
to infinity.
#
-
0
AUC
= 
t-
0
AUC
+ 
extra
AUC
, where 
extra
AUC
= 
pred
last  
C
/
z
∀
AUCextra
The AUC from time tlast extrapolated to infinity given as a percentage of 
AUC0-∞ 
t1/2
Apparent terminal half-life, calculated by ln2/ λz
λz
Apparent terminal elimination rate constant determined by log-linear 
regression analysis of the measured serum concentrations of the terminal log-
linear phase.  
CL
Apparent total body clearance of drug from serum. CL = Dose i.v /
#
-
0
AUC
Vz
Apparent volume of distribution during terminal phase. VZ = Dose/(
#
-
0
AUC
*
z
∀)
AUC0-t/Dose
Dose-Normalized AUC0-t. Normalized using actual dose.
Cmax/Dose
Dose-Normalized Cmax, Normalized using actual dose.
The following PK parameters will be calculated for diagnostic purposes and listed, but will not be 
summarized:
! The time interval (h) of the log-linear regression to determine λz (t½, Interval).
! Number of data points (t½, N) included in the log-linear regression analysis to determine λz.
! Goodness of fit statistic (Rsq) for calculation of λz.  
! Percentage of AUC0-# obtained by extrapolation (%AUCextra), calculated by (1－
[AUC0-t/AUC0-#])×100.  If %AUCextra is greater than 20%, AUC0-#, CL/f, and Vz/f will be 
included in the Phoenix® WinNonlin® parameter outputs but will be flagged. 
The regression analysis (determination of ∀z) should contain as many data points as possible (but 
excluding Cmax) and has to include concentration data from at least 3 different time points, 
consistent with the assessment of a straight line (the terminal elimination phase) on the log-
transformed scale.  The observation period over which the regression line is estimated should be at 
least twofold the resulting t½ itself.
The calculation of the AUCs will be performed using the mixed log-linear trapezoidal method 
(linear up, log down). Extrapolated areas will always be computed using the predicted last 
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concentration that is estimated using the linear regression from terminal rate constant 
determination. 
If AUCextra>20% then AUC0-∞and all related parameters will be excluded from descriptive 
statistics.
16.5.4
Figures
Individual serum concentration-time profiles (linear and semi-logarithmic scales) will be plotted by 
dose level. Mean serum concentrations per administration will also be plotted on linear (±SD) and 
semi-logarithmic scales using schedule time points.
Dose proportionality will be evaluated for avelumab using data from subjects with a full PK profile, 
and will be presented graphically as follows:
! Boxplots of dose-normalized PK parameters (AUC0-t/Dose, AUC0-#/Dose and Cmax/Dose) 
by dose level.
! Scatterplots with regression lines for individual AUC0-t, AUC0-# and Cmax values (where 
applicable) and dose normalized AUC0-t, AUC0-# and Cmax versus dose on a linear scale. 
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17
Safety Evaluation
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs.
All safety analyses will be performed using the SAF analysis set, unless otherwise specified.
All safety parameters will be summarized by dose level and overall, unless otherwise stated.
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17.1
Adverse Events
The severity of adverse events will be graded using the NCI-CTCAE, version 4.0 except where 
CTCAE grades are missing. No imputation of missing grades will be performed. Adverse events 
will be coded according to the latest available version of MedDRA.
! Treatment Emergent Adverse Event: TEAEs are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the on-
treatment period as defined in Section 11.
! Related Adverse Event: adverse events with relationship to study treatment (relationship with 
study treatment = related) reported by the investigator and those of unknown relationship (i.e. 
no answer to the question “Relationship with study treatment”).
! Serious Adverse Event (SAE): serious adverse events (as recorded on the AE eCRF page, 
serious adverse event = yes).
! Adverse Event Leading to 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 Event Leading to Death: adverse event leading to death (as recorded on the AE eCRF 
page, outcome = fatal or toxicity grade = 5).
! Infusion Related Reaction (IRR): IRRs are identified by 3 PTs (infusion related reaction, drug 
hypersensitivity, anaphylactic reaction) with onset on study drug dosing date (not prior to 
infusion of study drug) or the day following study drug infusion. 
! Immune Related Adverse Event (irAE): irAEs are identified according to a pre-specified 
search list of MedDRA PTs, documented in a version-controlled repository maintained by the 
Sponsor and finalized for analysis prior to database lock.
AEs will be summarized using the MedDRA PT as event category and MedDRA primary SOC as 
summary category. All AE tables will be restricted to TEAEs unless otherwise specified.
Each subject will be counted only once within each PT or SOC and recording period. If a subject 
experiences more than one AE within a PT or SOC for the same recording period, only the AE with 
the strongest relationship or the worst severity, as appropriate, will be included in the summaries of 
relationship and severity. AEs with missing classifications regarding relationship to study treatment 
and start date greater or equal to start of study treatment will be considered as related to study 
treatment. AEs with missing toxicity grade will be counted into ‘any grade’ in the summarization 
by toxicity grade.
The AE tables will include the number and percentage of subjects with at least one TEAE, by 
MedDRA primary SOC (sorted by decreasing SOC frequencies in the overall column) and by PT 
(sorted by decreasing PT frequencies in overall column within SOC), unless otherwise stated.
17.1.1
All Adverse Events
All adverse events will be tabulated in the following tables by dose level and overall.
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! The overall summary of AEs table will include the following variables:
o
TEAEs
o
TEAEs, grade ≥ 3
o
Related TEAEs
o
Related TEAEs, grade ≥ 3
o
TEAEs leading to permanent treatment discontinuation
o
Related TEAEs leading to permanent treatment discontinuation
o
Serious TEAEs 
o
Related serious TEAEs
o
TEAEs leading to death
o
Related TEAEs leading to death
o
Treatment emergent irAEs
o
Related treatment emergent irAEs
o
Treatment emergent IRRs
o
Related treatment emergent IRRs 
! Incidence of TEAEs by SOC, PT, and worst grade
! Incidence of related TEAEs by SOC, PT, and worst grade
! Incidence of TEAEs by SOC and PT: displaying in separate columns All TEAEs / Related 
TEAEs / Grade ≥3 TEAEs / Related Grade ≥3 TEAEs
! Incidence of TEAEs leading to death by SOC and PT
! Incidence of related TEAEs leading to death by SOC and PT
! Incidence of non-serious TEAEs by SOC and PT
Listing of AEs including all relevant information such as AE SOC/PT, start/stop date, toxicity 
grade, relationship to the study treatment, action taken with study treatment, and outcome etc., will 
be provided. A separate listing of TEAEs started or worsened after on-treatment period will also be 
provided.
17.1.2
Adverse Events Leading to Treatment Discontinuation
Following summary tables will be produced:
! Incidence of TEAEs leading to permanent treatment discontinuation by SOC and PT
! Incidence of related TEAEs leading to permanent treatment discontinuation by SOC and PT 
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The listing of AEs leading to permanent treatment discontinuation will also be provided with the 
relevant information such as AE SOC/PT, start/stop date, toxicity grade, relationship to the study 
treatment, and outcome etc. 
17.1.3
Serious Adverse Events
Following summary tables will be produced:
! Incidence of serious TEAEs by SOC and PT
! Incidence of related serious TEAEs by SOC and PT
The listings of SAEs will also be provided with the relevant information such as AE SOC/PT, 
start/stop date, toxicity grade, relationship to the study treatment, action taken with study treatment, 
and outcome etc.
17.1.4
Infusion Related Reactions
IRRs will be summarized by the follow variables:
! Number of subjects with at least one event by the worst toxicity grade (grade 1/ grade 2/ grade 
3/ grade 4/ grade 5/ missing grade)
! Number of subjects with IRR leading to permanent treatment discontinuation
! Time related to first onset (infusion 1/ infusion 2/ infusion 3/ infusion 4 or later).  The events 
should be assigned to the actual drug infusions that the subject received, not to the planned dates. 
An IRR is assigned to a drug infusion if its onset is at the same date (but not before dosing) or 
the following day of drug infusion.  
! Number of subjects with at least one event by the worst toxicity grade that occurred in the 
presence of premedication (grade 1/ grade 2/ grade 3/ grade 4/ grade 5/ missing grade). The 
denominator will be the number of subjects with at least one dose administered in the presence 
of premedication. The maximum toxicity will be derived among those IRRs that occurred in the 
presence of premedication.
! Number of subjects with at least one event by the worst toxicity grade that occurred in the 
absence of premedication (grade 1/ grade 2/ grade 3/ grade 4/ grade 5/ missing grade). The 
denominator will be the number of subjects with at least one dose administered in the absence 
of premedication. The maximum toxicity will be derived among those IRRs that occurred in the 
absence of premedication.        
The listing of IRRs will be provided with the relevant information such as AE SOC/PT, start/stop 
date, toxicity grade, relationship to the study treatment, action taken with study treatment, outcome, 
premedication, and study medication batch ID etc.
17.1.5
Immune Related Adverse Events
irAEs will be summarized using the following variables:
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! The overall summary of treatment emergent irAEs will include the following categories:
o
irAEs
o
Related irAEs
o
Grade ≥ 3 irAE
o
Related grade ≥ 3 irAE
o
irAEs leading to permanent treatment discontinuation
o
Related irAEs leading to permanent treatment discontinuation
o
Serious irAEs 
o
Related serious irAEs
o
irAEs leading to death 
o
Related irAEs leading to death
! Incidence of treatment emergent irAEs by SOC and PT.
A listing containing all the PTs used to identify irAEs and a listing containing all the irAEs in the 
study will be generated as well.
17.1.6
Subgroup Analysis of Adverse Events
Subgroup analyses of AEs (TEAEs, irAEs, SAEs, IRRs) based on immunogenicity responses will 
be performed using summary statistics for qualitative comparison only. The number and percentage 
of subjects with at least one TEAE, irAE, SAE, or IRR will be compared between HAHA ever 
positive versus HAHA never positive subjects, and between subjects with treatment emergent 
immunogenicity response and the rest of the subjects.
17.2
Deaths
All deaths will be tabulated and listed for SAF analysis set by dose level and overall. The deaths 
table will include the following information:
! Number of subjects who died
o Primary reason for death 

Disease progression

Adverse event related to study treatment 

Adverse event not related to study treatment 

Other

Unknown
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! Number of subjects who died within 30 days of the last study treatment administration
o Primary reason for death 

Disease progression

Adverse event related to study treatment 

Adverse event not related to study treatment 

Other

Unknown
The listing of deaths will be provided with all the relevant information such as death date and reason 
for death. The death data will be ascertained from the dedicated Report of Death eCRF form.
17.3
Clinical Laboratory Evaluation
Laboratory abnormalities are classified according to NCI-CTCAE toxicity grading version 4.0 or 
based on normal ranges collected from laboratories. The toxicity grading is only related to the lab 
values itself and does not respect the non-numeric information as described in the CTC grading 
definition. CTCAE gradable parameters and associated toxicities are listed in Table 6. 
Table 6 CTCAE Gradable Parameters and Associated Toxicities
Panel
Parameter (test)
Low direction toxicity
High direction toxicity
Hematology
Hemoglobin (HB)
anemia
hemoglobin increased
Leukocytes
white blood cell decreased
Lymphocytes
lymphocyte count decreased
lymphocyte count increased
Neutrophils/ 
absolute 
neutrophils 
count (ANC)
neutrophil count decreased
Platelet count (PLT)
platelet count decreased
Chemistry
Albumin
hypoalbuminemia
Alkaline phosphatase (ALP)
alkaline phosphatase increased
Alanine aminotransferase (ALT)
ALT increased
Amylase
serum amylase increased
Aspartate aminotransferase (AST)
AST increased
Bilirubin (total)
blood bilirubin increased
Cholesterol
cholesterol high
Creatinine
creatinine increased
Creatinine clearance
chronic kidney disease
Creatine kinase (CPK)
CPK increased
Potassium
hypokalemia
hyperkalemia
Sodium
hyponatremia
hypernatremia
Magnesium 
hypomagnesemia
hypermagnesemia
Calcium
hypocalcemia
hypercalcemia
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Glucose
hypoglycemia
hyperglycemia
Gamma glutamyl transferase (GGT) 
GGT increased
Lipase
lipase increased
Phosphates
hypophosphatemia
Triglycerides
hypertriglyceridemia
Coagulation
Prothrombin time INR
INR increased
Activated Partial thromboplastin time
(aPTT)
aPTT prolonged
Grade 1 and 2 hypoglycemia/ hyperglycemia are based on fasting glucose, they will not be graded 
for this study because blood samples are taken from non-fasted subjects.
For calcium, CTCAE grading is based on corrected calcium and ionized calcium (CALCIO), if 
available. Corrected calcium is calculated from albumin and calcium as follows
Corrected calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL) - 4].
Chronic kidney disease will be graded based on estimated creatinine clearance rate (eCcr, ml/min), 
which is derived using Cockcroft-Gault formula:
 = (140 −) × ℎ() × 
  (μ/!)
where the constant is 1.23 for men and 1.04 for women.
The following are non-CTCAE gradable parameters collected in this study, their abnormalities are 
assessed as low, high, normal based on the comparison of observed values with normal ranges.
! Hematology: hematocrit, red blood cell (RBC), reticulocytes, mean corpuscular hemoglobin 
(MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration 
(MCHC).
! Serum Chemistry: chlorine, C-reactive protein, lactate dehydrogenase (LDH), total protein, total 
urea, uric acid. 
! Hormone: adrenocorticotropic hormone (ACTH), anti-nuclear antibody (ANA), anti-neutrophil 
cytoplasmic antibody (ANCA), rheumatoid factor (RF), free thyroxine (Free T4), thyroid-
stimulating hormone (TSH).
Laboratory abnormalities will be summarized using the worst grade during the on-treatment period. 
For these parameters which are graded with two toxicities such as potassium (hypokalemia/ 
hyperkalemia), the toxicities will be summarized separately. Low direction toxicity (eg. 
hypokalemia) grades at baseline and post-baseline will be set to 0 when the variables are derived 
for summarizing high direction toxicity (e.g. hyperkalemia), and vice versa.
The change and percent change from baseline will be derived for parameters with numeric results.
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17.3.1
Hematology, Chemistry, and Hormone Parameters 
CTCAE gradable parameters
The laboratory toxicities will be tabulated by the worst on-treatment CTCAE grade or the shift of 
CTCAE grade from baseline to worst grade during on-treatment period using descriptive statistics 
(count and percentage). The highest CTCAE grade during the on-treatment period is considered as 
the worst grade for the summary.
! The worst grade during the on-treatment period will be summarized considering only patients 
with post baseline laboratory samples: Laboratory tests by NCI-CTCAE grade (0, 1, 2, 3, 4, and
missing).
! The shift table will summarize baseline CTCAE grade vs. the worst on-treatment CTCAE grade
(grade = 0, 1, 2, 3, 4, missing). 
Non-CTCAE gradable parameters
Hematology, chemistry, and hormone evaluations which can’t be graded per CTCAE will be 
summarized as: 
! Shift from baseline value (low, normal, high) to above normal during on-treatment period
! Shift from baseline value (low, normal, high) to below normal during on-treatment period
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean, 
SD, median, Q1, Q3, minimum, and maximum) of actual values, absolute changes and percent 
changes from baseline to each visit over time. This summarization will apply to hematology and 
chemistry parameters with numeric results assessed at baseline, post-baseline, discontinuation, end 
of treatment, and/or safety follow-up visits based on visit windows specified in Section 11.
The listings (hematology, chemistry, and hormone) will include all the laboratory parameters as 
available in the database with the relevant information such as visit, assessment date, parameter, 
value, normal ranges etc. Listings will be sorted by subject identifier, group variable, parameter, 
assessment date or visit.
Liver function parameters
ALT, AST, ALP, and total bilirubin are used individually or together to assess possible drug 
induced liver toxicity. The ratio of test result over upper limit of normal (ULN) for individual test 
or combined tests will be calculated and classified for these parameters during the on-treatment 
period. 
Summary of liver function tests will include the following categories.  The number and percentage 
of subjects with each of the following during the on-treatment period will be summarized by dose 
level and overall:
! AST ≥3*ULN / ≥5*ULN / ≥10*ULN / ≥20*ULN.
! ALT ≥3*ULN / ≥5*ULN / ≥10*ULN / ≥20*ULN.
! (ALT or AST)  ≥3×ULN/ ≥5×ULN/ ≥10×ULN/ ≥20×ULN
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! Total bilirubin ≥2*ULN.
! Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN
! Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN
! (ALT or AST) ≥3*ULN concurrently with total bilirubin ≥2*ULN.
! (ALT or AST) ≥3*ULN concurrently with total bilirubin ≥2*ULN and ALP >2*ULN.
! (ALT or AST) ≥3*ULN concurrently with total bilirubin ≥2*ULN and (ALP ≤2*ULN or 
missing).
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, i.e. a subject 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 and percentage by dose level and overall. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created to 
graphically display
!
peak serum ALT(/ULN) vs. concurrent total bilirubin (/ULN) including reference lines at ALT 
>3×ULN and total bilirubin >2×ULN.
!
peak serum AST(/ULN) vs. concurrent total bilirubin (/ULN). 
Listing of subjects with ALT or AST ≥3*ULN or total bilirubin ≥2*ULN will include variables 
subject identifier, visit, date of collection, study day, parameter (ALT, AST, ALP, total bilirubin), 
result, unit, result/ULN, CTCAE grade.
17.3.2
Other laboratory parameters 
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected data-fields on the eCRF. 
!
Coagulation: aPTT, prothrombin time INR
!
Urinalysis: all urinalysis parameters
!
Other parameters: such as immunology, soluble factor
!
Pregnancy test
!
Serology
17.4
Vital Signs
Summary of vital signs will be based on the SAF analysis set. The potentially clinically significant 
changes from baseline as below in vital signs will be derived and summarized with subject 
incidence and percentage during the on-treatment period:
! ≥ 10% weight increase
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! ≥ 10% weight decreases
! ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg in systolic blood pressure
! ≥ 160 mmHg and increased from baseline ≥ 20 mmHg in systolic blood pressure
! ≤ 45 mmHg and decrease from baseline ≥ 10 mmHg in diastolic blood pressure
! ≥ 110 mmHg and increased from baseline ≥ 10 mmHg in diastolic blood pressure
! ≤ 50 bpm and decrease from baseline ≥ 20 bpm in pulse rate
! ≥ 120 bpm and increase from baseline ≥ 20 bpm in pulse rate
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean, 
SD, median, Q1, Q3, minimum, and maximum) of actual values, absolute changes and percent 
changes from baseline to each visit based on visit windows specified in Section 11. This 
summarization will apply to weight, blood pressure, respiratory rate, pulse, and temperature 
assessed at baseline, post-baseline, discontinuation, end of treatment, and/or safety follow-up visits.
Data listing of all vital signs will be provided with all relevant information such as visit, assessment 
date, parameter, and results.
17.5
Other Safety or Tolerability Evaluations
The incidence and percentage of subjects with potentially clinically significant abnormalities 
(PCSA) for 12-lead ECG parameters will be summarized during the on-treatment period based on 
SAF analysis set. The PCSA criteria are provided in the Table 7.
Table 7
Potentially Clinically Significant Abnormalities Criteria for ECG
Test
Potentially Clinically Significant Abnormalities (PCSA) Criteria
Heart Rate (HR)
≤ 50 bpm and decrease from baseline ≥ 20 bpm
≥ 120 bpm and increased from baseline ≥ 20 bpm
PR Interval
≥ 220 ms and increase from baseline ≥ 20 ms
QRS
≥ 120 ms
QTcF, QTcB absolute
interval >450 - ≤ 480 ms
interval >480 - ≤ 500 ms
interval >500 ms
QTcF, QTcB change 
from baseline
Increase from baseline > 30 - ≤ 60 ms
Increase from baseline > 60 ms
QT will be corrected based on Fridericia’s formula (QTcF= QT/ √##
$
) and RR=60/HR, and Bazett's 
formula (QTcB= QT/ √RR) and RR=60/HR, if possible. Baseline QTcF/QTcB will be derived from 
the visit that QT and HR are flagged as baseline. If there are multiple assessments at the same visit 
and time point, the average will be calculated for each parameter and used for the analysis.
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean, 
SD, median, Q1, Q3, minimum, and maximum) of actual values (with 95% CI of the mean), 
absolute changes from baseline (with 90% CI of the mean) to each visit based on visit windows 
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specified in Section 11. This summarization will apply to heart rate, QRS interval, QT interval, PR 
interval, QTcB, and QTcF assessed at baseline, post-baseline, discontinuation, end of treatment, 
and/or safety follow-up visits.
Listings of 12-lead ECGs will be provided with all relevant information such as visit, date/time of 
assessment, parameter, and results.
The ECOG shift from baseline to highest on-treatment score will be summarized by dose level and 
overall based on SAF analysis set. Missing category will be included and the number of subjects in 
each dose level will be used as the denominator.
ECOG performance status will also be presented in a data listing.
18
Reporting Conventions
! Reporting will require placement of decimals, and this will depend on the raw data collected. 
Generally, mean and median should be displayed one more decimal place than the raw data and 
standard deviation should be displayed two more decimal place than the raw data. Percentages 
will be reported as one decimal place.
! The rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. e.g. 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.
! The following conversion factors will be used to convert days to months or years, where 
applicable: 1 month = 30.4375 days and 1 year = 365.25 days.
! Data listings will be sorted by dose level, subject identifier, visit or date (if applicable), or 
parameters, as appropriate.
18.1
Incomplete dates
Missing or partial start dates for adverse events will be imputed as following:
! When the start Date of the AE is missing (but Month & Year is available), then the AE date will 
be imputed to the "1st Date of the reported Month" (e.g. if reported date is --/JAN/09, imputed 
date will be 01/JAN/09).  If the reported AE Month = the Month of the First Dosing date,  then 
the AE date will be imputed to the "1st Dosing date" (e.g. if AE reported date is --/JAN/09, and 
the First doing date is 13/JAN/09, then the AE imputed date will be 13/JAN/09). 
! When the Date & the Month of the AE is missing (but Year is available), then the AE date will 
be imputed to the "1st Date of the 1st Month of the reported Year" (e.g. if reported date is --/--
/09, imputed date will be 01/JAN/09). If the reported AE Year = the Year of the First Dosing 
date,  then the AE date & month will be imputed to the "1st Dosing date" (e.g. if AE reported 
date is --/--/09, and the First doing date is 13/APR/09, then the AE imputed date will be 
13/APR/09). 
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Avelumab
                    Avelumab in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
47/52
! When the date is completely missing, no imputation will be performed and the AE will be 
considered as treatment emergent, unless there is rational to clarify otherwise, e.g. AE stop date 
is prior to the first dose date.
Missing or partial dates for concomitant medications will be imputed as following:
! If the start day of medication is missing, it will be imputed to the first day of the month; if the 
stop day is missing, it will be imputed to the last day of the month. If both day and month are 
missing, the start date will be imputed as the first day of the year and stop date will be imputed 
as the last day of the year. If the start or stop date is completely missing, no imputation will be 
performed and the determination of prior medication or post medication will be based on non-
missing stop or start date, respectively; otherwise, the medication will be considered as 
concomitant. 
Missing or partial dates for disease history (initial diagnosis date, first occurrence of metastatic or 
locally advanced disease, date of last progression of disease) will be imputed as following:
! 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.
Partial dates for prior anti-cancer drug therapies will be imputed as following:
! If the day is missing, it will be imputed to the first day of the month; if both day and month are 
missing, no imputation will be performed.
No other dates will be imputed.
19
References
1. Eisenhauer EA. New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). Eur J Cancer 2009;45:228-47.
2. Wolchok et al. Guidelines for the evaluation of immune therapy activity in solid tumors: 
immune-related response criteria. Clin Cancer Res 2009;15(23):7412-20.
20
Appendices
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                                                                    MSB0010718C in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
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20.1
Programmed Major Protocol Deviations
Category of 
Protocol 
Deviation
Description of 
Protocol 
Deviation
Deviation 
Code
Protocol 
Section 
Variable [dataset] 
Proposed check / comment 
Inclusion criteria: 
For the subject to 
be eligible for 
inclusion, each 
criterion must be 
checked ‘YES’:
Criterion1: Signed 
written informed 
consent.
Eligibility and 
Entry Criteria
Subject did not 
meet inclusion 
criterion 1 (signed 
inform consent 
form).
PDEV01
Section 
5.3.1
DM. RFICDTC
list if DM. RFICDTC is missing or if 
DM.RFICDTC<Earliest date of SV.SVSTDTC.
Medical Review Required.
Criterion2: Male or 
female subjects 
aged >=18 years.
Eligibility and 
Entry Criteria
Subject did not 
meet inclusion 
criterion 2 (age >= 
18 years).
PDEV02
Section 
5.3.1
DM.AGE
List if DM.AGE<18.
Criterion3: 
Histologically or 
cytologically 
proven metastatic 
or locally advanced 
solid tumor or 
related prior anti-
cancer therapy. 
Eligibility and 
Entry Criteria
Subject did not 
meet inclusion 
criterion 3
(histologically or 
cytologically 
proven metastatic 
or locally 
advanced solid 
tumor).
PDEV03
Section 
5.3.1
Medical review required
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                                                                    MSB0010718C in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
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Category of 
Protocol 
Deviation
Description of 
Protocol 
Deviation
Deviation 
Code
Protocol 
Section 
Variable [dataset] 
Proposed check / comment 
Criterion5: Disease 
must be 
measurable at 
least 1 dimension 
except for CRPC 
or MBC (dose 
escalation). 
Eligibility and 
Entry Criteria
Subject did not 
meet inclusion 
criterion 5
(measurable 
disease at least 
one dimension 
except for CRPC 
and escalation 
MBC subjects).
PDEV04
Section 
5.3.1
TR.TRORRES, 
TRTESTCD;
SUPPTR.QNAM, 
QVAL.
list if TR.TRORRES is missing or not assessable 
where TRTESTCD=’ SUMDIAM' and TRCAT=
'RECIST' and SUPPTR.QVAL=’SCREENING’ 
where QNAM=’ASMNTVIS’. Do not check this for 
subjects where SUPPDM.QVAL = ’ CASTRATE-
RESISTANT PROSTATE CANCER’ where 
QNAM=’COHORT’ or SUPPDM.QVAL=’ DOSE 
ESCALATION AND DLT/MTD COHORTS’ where 
QNAM=’COHORT’ and MHLOC in (‘NIPPLE’ 
‘CENTRAL PORTION OF BREAST’ ‘UPPER-
INNER QUADRANT OF BREAST (UIQ)’ ‘LOWER-
INNER QUADRANT OF BREAST (LIQ)’ ‘UPPER-
OUTER QUADRANT OF BREAST (UOQ)’ 
‘LOWER-OUTER QUADRANT OF BREAST (LOQ)’ 
‘AXILLARY TAIL OF BREAST’ ‘OVERLAPPING 
LESION OF BREAST ‘BREAST, NOS’)
Criterion9: 
Effective 
contraception for 
both male and 
female subjects if 
the risk of 
conception exists.
Eligibility and 
Entry Criteria
Subject did not 
meet inclusion 
criterion 9
(effective 
contraception).
PDEV05
Section 
5.3.1
Medical review required
Exclusion criteria: 
For the subject to 
be eligible for 
inclusion, each 
criterion must be 
checked ‘NO’:
1. Concurrent 
treatment with a 
non-permitted 
drug.
Eligibility and 
Entry Criteria
Subject met 
exclusion criterion 
1 (non-permitted 
drug).
PDEV06
Section 
5.3.2
Medical review required
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                                                                    MSB0010718C in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
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Category of 
Protocol 
Deviation
Description of 
Protocol 
Deviation
Deviation 
Code
Protocol 
Section 
Variable [dataset] 
Proposed check / comment 
2. Prior therapy 
with any 
antibody/drug 
targeting T cell co-
regulatory proteins. 
Eligibility and 
Entry Criteria
Subject met 
exclusion criterion 
2 (prior therapy 
with any 
antibody/drug 
targeting T cell co-
regulatory 
proteins).
PDEV07
Section 
5.3.2
Medical review required
3. Concurrent 
anticancer 
treatment, major 
surgery, concurrent 
systemic therapy 
with steroids or 
other 
immunosuppressiv
e agents, or use of 
any investigational 
drug within 28 days 
before the start of 
trial treatment.
Eligibility and 
Entry Criteria
Subject met 
exclusion criterion 
3 (concurrent anti-
cancer therapy or 
surgery, 
concurrent 
systemic therapy 
with steroids or 
other), 
PDEV08
Section 
5.3.2
Medical review required
4. Previous 
malignant disease 
other than the 
target malignancy 
to be investigated 
in this trial within 
the last 5 years 
with the exception 
of basal or 
squamous cell 
carcinoma of the 
skin or cervical 
carcinoma in situ
Eligibility and 
Entry Criteria
Subject met 
exclusion criterion 
4 (previous 
malignant disease 
other than the 
target malignancy 
to be investigated 
in this trial within 
the last 5 years).
PDEV09
Section 
5.3.2
Medical review required
12. Pregnancy or 
lactation period.
Eligibility and 
Entry Criteria
Subject met 
exclusion criterion 
12 (pregnancy or 
lactation period).
PDEV10
Section 
5.3.2
PREG.PRRLTCD
Medical review required.
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MSB0010718C
                                                                    MSB0010718C in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
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Category of 
Protocol 
Deviation
Description of 
Protocol 
Deviation
Deviation 
Code
Protocol 
Section 
Variable [dataset] 
Proposed check / comment 
Non-permitted 
concomitant 
medication during 
the study
Concomitant 
Medication 
Criteria
Subject took 
prohibited 
medication during 
the study.
PDEV11
Section 
6.5.2
CMED.CMTERM
Medical review required
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn;
Other Criteria
Subject became 
pregnant, but 
continued on the 
study.
PDEV12
Section 
5.5.2
LB.LBORRES, 
BTESTCD;
DS.DSSTDTC,  
DSSCATE;
Medical review required.
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn;
Other Criteria
Subjects had 
ECOG>=3, did not 
resolved to <=2 by 
day 14 of next 
cycle, and 
continued on the 
study.
PDEV13
Section 
5.1.7.2 
and 5.5.2
XP.XPORRES, 
XPDY;
DS.DSSTDTC,  
DSSCATE;
Medical review required.
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn;
Other Criteria
Subject developed 
grade 4 AE, but 
continued on the 
study.
PDEV14
Section 
5.1.7.2 
and 5.5.2
ADAE.ATOXGRN, 
TRTEMFL, AREL; 
SDTM.AE.AEACNOT
H; SUPPAE.QVAL, 
QNAM
List if TOXGRN=4 and AREL=’Related’ and 
TRTEMFL=’Y’ and (SUPPAE.QVAL^=’Drug 
Withdrawn’ where QNAM in (ACNMSB, 
ACNMSB3) and SDTM.AEACNOTH^=’LED TO 
STUDY TERMINATION’)
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn;
Other Criteria
Subject developed 
grade 3 AE, but 
continued on the 
study.
PDEV15
Section 
5.1.7.2 
and 5.5.2
ADAE.ASEVN, 
TRTEMFL, 
AEDECOD, 
AEDUR.
DS.DSSTDTC,  
DSSCATE;
Medical review required.
Subjects 
overdosed
(>=110%  of 
assigned dose) 
IP Compliance 
Subject was 
overdosed.
PDEV16
Medical 
defined.
ADEXSUM.AVAL 
where 
PARAMACD=’ 
RDOSINT’
list if 
cumulative relative dose intensity or individual 
relative dose intensity >=110
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MSB0010718C
                                                                    MSB0010718C in Metastatic or Locally Advanced Solid Tumors
EMR 100070-001
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Category of 
Protocol 
Deviation
Description of 
Protocol 
Deviation
Deviation 
Code
Protocol 
Section 
Variable [dataset] 
Proposed check / comment 
NA
Other Criteria
Other protocol 
deviation
PDEV99
Medical 
defined
Medical review required.
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Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
 
 
4/89 
 
2 
Table of Contents 
1 
Signature Page ......................................................................................3 
2 
Table of Contents ..................................................................................4 
3 
List of Abbreviations and Definition of Terms ....................................7 
4 
Modification History ..........................................................................12 
5 
Purpose of the Statistical Analysis Plan .............................................14 
6 
Summary of Clinical Trial Features ...................................................15 
7 
Sample Size/Randomization ...............................................................21 
8 
Overview of Planned Analyses ...........................................................23 
8.1 
Interim Analysis ..................................................................................24 
8.2 
Safety Analysis for Interim CSR ........................................................27 
8.3 
Primary and Final Analyses ................................................................27 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol ........27 
10 
Analysis Sets .......................................................................................29 
11 
General Specifications for Statistical Analyses ..................................30 
12 
Trial Subjects ......................................................................................33 
12.1 
Disposition of Subjects and Discontinuations ....................................34 
12.2 
Protocol Deviations ............................................................................35 
12.2.1 
Minor Protocol Deviation ...................................................................35 
12.2.2 
Important Protocol Deviation .............................................................35 
13 
Demographics and Other Baseline Characteristics .............................36 
13.1 
Demographics .....................................................................................36 
13.2 
Medical History ..................................................................................38 
13.3 
Disease History ...................................................................................38 
13.4 
PD-L1 Expression Status and Biomarker ...........................................39 
14 
Prior and Concomitant Medications/Procedures ................................43 
14.1 
Prior Anti-Cancer Therapies/Procedures ............................................43 
14.2 
Prior and Concomitant Medications/Procedures ................................44 
14.3 
Subsequent Anti-Cancer Therapies/Procedures .................................45 
15 
Treatment Compliance and Exposure .................................................45 
16 
Endpoint Evaluation ...........................................................................47 
16.1 
Primary Endpoint Analyses ................................................................48 


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Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
 
 
6/89 
 
17.1.6 
Subgroup Analysis of Adverse Events ...............................................72 
17.2 
Deaths .................................................................................................72 
17.3 
Clinical Laboratory Evaluation ...........................................................73 
17.3.1 
Hematology and Clinical Chemistry Parameters ................................75 
17.3.2 
Other Laboratory Parameters ..............................................................77 
17.4 
Vital Signs ..........................................................................................77 
17.5 
Other Safety or Tolerability Evaluations ............................................77 
18 
Reporting Conventions .......................................................................79 
18.1 
Date of Last Contact ...........................................................................79 
18.2 
Incomplete Dates ................................................................................79 
19 
References ...........................................................................................81 
20 
Appendices .........................................................................................82 


Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
7/89 
 
3 
List of Abbreviations and Definition of Terms 
ACC 
Adrenocortical Carcinoma 
ACTH 
Adrenocorticotropic Hormone 
ADA 
Anti-Drug Antibody (referred to as HAHA on CRF and SDTM) 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALK 
Anaplastic Lymphoma Kinase  
ALT 
Alanine Aminotransferase 
ANA 
Anti-nuclear Antibody 
ANCA 
Anti-neutrophil Cytoplasmic Antibody 
ANC 
Absolute Neutrophils Count 
AST 
Aspartate Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BRCA1/2 
Breast Cancer 1 or 2 
BSA 
Body Surface Area 
CA125 
Cancer Antigen 125 
CALCIO 
Corrected Calcium and Ionized Calcium 
CI 
Confidence Interval 
Cmin 
Trough Concentration 
CPK 
Creatine Kinase 
CR 
Complete Response 


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Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
 
 
10/89 
 
LLOQ 
Lower Limit of Quantification 
MBC 
Metastatic Breast Cancer 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI 
Microsatellite Instability 
nAb 
Neutralizing Antibodies  
NCI 
National Cancer Institute  
NE 
Not Assessable 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCSA 
Potentially Clinically Significant Abnormalities 
PFS 
Progression Free Survival 
PLT 
Platelet Count 
PD 
Progressive Disease  
PD-1 
Programmed Death 1 
PD-L1 
Programmed Death Ligand 1 
PK 
Pharmacokinetics 
PKAS 
PK Analysis Set 
PO 
Per Oral 
PR 
Partial Response 
PRF 
Pathology Report Form 


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Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
13/89 
 
Unique Identifier 
for SAP Version 
Date of SAP 
Version 
Author 
Changes from the Previous Version 
10) Updated language to apply to most recent ICH E3 
guideline for important protocol deviations 
Final 8.0 
 
 
16.4.4 
Relation of Pharmacokinetics to Efficacy in 
Urothelial Carcinoma Cohorts 
Exposure response analyses supplemented 
Additional PD-L1 cut-offs supplemented 
Wording for presence of metastases at baseline 
updated. 
RCC cohort updates. 
PFS and OS Reasons for Censoring alignment with 
Avelumab Harmonized SAP. 
Final 9.0 
10Feb2017 
Jie Wang 
1) 
Section 8.1 added the subgroup for RCC first-line. 
2) 
Section 10, added PD-L1 positive (1% cut-off) 
FAS for NSCLC cohorts. 
3) 
Section 11, added an algorithm on how to 
calculate time since an event. 
4) 
Section 13.1, added Baseline Bellmunt Score, 
Baseline eCcr, and Time Since Last Prior Anti-
Cancer Chemotherapy. 
5) 
Section 13.4, added the definition of ‘negative’ for 
PD-L1 expression status based on the secondary 
cut-off for tumor cells. Added PD-L1 scoring for 
gastric. 
6) 
Section 16.1, updated BOR derivation. 
7) 
Section 16.2, updated BOR reasons for NE to 
align with the Harmonized SAP. Updated BOR 
and irBOR derivation. 
8) 
Section 16.2.3, updated the censoring reasons to 
be consistent with PFS censoring scenarios. 
9) 
Section 16.2.6, added subgroup analysis by 
Baseline Bellmunt Score, Time Since Last Prior 
Anti-cancer Chemotherapy, Gastric specific PD-
L1, and Region (Asia, Non-Asia). 
10) Section 16.5, added nAb TLFs 
11) Section 17.1 added the new process on how to 
identify and produce irAEs and clarified original 
and updated definitions. 
12) Section 17.1.6, added nAb categorization and 
expanded safety tables for ADA subgroup analysis 
13) Section 17.3, Added the calculation of corrected 
eCcr. 
14) Updated the terminology HAHA to the more 
accurate terminology: ADA 
15) Added Appendix II for irAEs and IRRs. 
 
 


Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
 
 
14/89 
 
5 
Purpose of the Statistical Analysis Plan 
The purpose of this statistical analysis plan (SAP) is to document technical and detailed 
specifications for the interim, primary, and final analyses of data collected for the expansion phase 
under protocol EMR 100070-001. Results of interim, primary, and final analyses described in this 
SAP will be included in the interim or final Clinical Study Reports (CSRs) or addenda thereto. 
Additionally, the planned interim, primary, and final analyses identified in this SAP will be 
included in regulatory submissions or future manuscripts. Any post-hoc, or unplanned analyses 
performed to provide results for inclusion in a CSR or report, but not identified in this prospective 
SAP, will be clearly identified in the CSR or report.  


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Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
16/89 
 
Primary  
• The confirmed BOR, per RECIST 1.1, as adjudicated by an Independent 
Endpoint Review Committee (IERC) for subjects enrolled in the efficacy 
expansion cohorts only. 
Secondary 
• Number, severity, and duration of treatment-emergent adverse events 
(TEAEs) for all cohorts according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0. 
• Number, severity, and duration of treatment-related adverse events 
(AEs) according to NCI-CTCAE v4.0. 
• PK profile. 
• irBOR and BOR according to modified irRC and to RECIST 1.1, 
respectively, per investigator assessment. 
• The confirmed BOR, per RECIST 1.1, as adjudicated by an IERC, for 
subjects enrolled in the secondary urothelial carcinoma cohort. 
• irPFS time and PFS time according to modified irRC and to RECIST 
1.1, respectively, per investigator assessment. 
• OS time. 
• Pharmacodynamic (PD) profile 
• Serum titers of anti-avelumab antibodies (ADA). 
• Expression of PD-L1 on tumor tissue. 
• For the primary expansion cohorts only: Unconfirmed response at Week 
13 according to RECIST 1.1. 
• Duration of response (DR) according to modified irRC and to RECIST 
1.1, respectively. 
• For the efficacy expansion cohorts and secondary urothelial carcinoma 
cohort:  
o PFS time, according to RECIST 1.1, per IERC 
o DR according to RECIST 1.1, per IERC. 
Trial Design 
This is a Phase I, open-label, dose-escalation trial with consecutive parallel 
group expansion in non-small cell lung cancer (NSCLC), metastatic breast 
cancer (MBC), gastric and GEJ cancer, colorectal cancer (CRC), castrate 
resistant prostate cancer (CRPC), melanoma, ovarian cancer, HNSCC, 
adrenocortical carcinoma (ACC), renal cell carcinoma (RCC), mesothelioma, 
and urothelial carcinoma.  
Dose escalation phase 
This section was included into the Dose Escalation SAP. 


Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
17/89 
 
Expansion phase 
After determination of the avelumab dose and regimen for further 
investigation, enrolment in several expansion cohorts will be opened in 
selected tumor indications to determine the safety and clinical activity of 
avelumab. Subject eligibility will be confirmed by the contract research 
organization (CRO) / Sponsor for each subject before the first 
administration of the study treatment during the expansion phase. 
Based on data generated in the dose escalation phase, the dose of avelumab 
to be used in the expansion phase was determined to be 10 mg/kg. In 
addition, with the emergence of promising efficacy data, expansion cohorts 
have been expanded and divided into: 
• 4 primary cohorts of:  
1. NSCLC, post platinum doublet (N=150);  
2. NSCLC, first-line, does not carry an epidermal growth factor 
receptor (EGFR) activating mutation or anaplastic lymphoma 
kinase (ALK) re-arrangements (N=150); 
3. Gastric and GEJ cancer (N=150); and  
4. MBC (N=150) 
• 8 secondary cohorts of:  
1. CRC (N=20),  
2. CRPC (N=20),  
3. ACC (N=50),  
4. Melanoma (N=50),  
5. Mesothelioma (N=50),  
6. Urothelial carcinoma (N=50; note: enrollment is being stopped 
[N=44] due to the opening of a urothelial efficacy expansion 
cohort),  
7. Ovarian cancer (N=120), and 
8. RCC, second-line, (N=20 with expansion of 60 first-line). 
• 4 efficacy expansion cohorts of: 
1. Ovarian cancer, platinum refractory, prior liposomal doxorubicin 
(N=100);  
2. Urothelial carcinoma, platinum ineligible or progressed after at least 
1 line of platinum-based therapy (N=200);  
3. Gastric and GEJ cancer, third line (N=150);  
4. HNSCC, platinum ineligible or progressed after at least 1 line of 
platinum-based therapy (N=150); 
Subjects in the NSCLC (post platinum doublet), CRC, and CRPC cohorts 
will be enrolled in the USA only.  


Avelumab 
Avelumab in Metastatic or Locally Advanced Solid Tumors 
EMR 100070-001 
 
 
18/89 
 
For subjects enrolled in the efficacy expansion cohorts and the secondary 
urothelial carcinoma cohort, an IERC will perform a blinded determination 
as to whether the criteria for tumor response or progression according to 
RECIST 1.1 have been met. 
Subjects will receive avelumab intravenously as a 1-hour infusion once 
every 2 weeks until confirmed progression, unacceptable toxicity, or any 
reason for withdrawal from the trial or Investigational Medical Product 
(IMP) occurs. Subjects who have experienced a confirmed complete 
response (CR) should be treated for a maximum of 24 months after 
confirmation, at the discretion of the investigator. If the investigator 
believes that a subject may benefit from treatment beyond 24 months, it 
may be permissible after discussion with the sponsor. Subjects who 
experienced a CR and have already stopped treatment can resume treatment 
with avelumab at the same dose and schedule. Subjects re-initiating 
treatment should be assessed according to the Schedule of Assessments.   
For subjects who achieve a CR on avelumab therapy and then subsequently 
develop disease progression after stopping therapy, but prior to the end of 
the trial, one re-initiation of treatment at the same dose and schedule is 
allowed at the discretion of the investigator and agreement of the trial 
Medical Monitor. In order to be eligible for retreatment, the subject must 
not have experienced any toxicity that led to treatment discontinuation of 
the initial avelumab therapy.  
Prior to re-initiation of the study treatment, malignant disease needs to be 
radiologically re-staged to assess all known sites of the disease and to 
establish a new baseline for subsequent tumor measurements. Relevant 
safety laboratory results must be available and verified prior to re-initiating 
of treatment. 
Subjects who re-initiate treatment will stay on study and will be treated and 
monitored according to the protocol and the “until progression” schedule in 
the Schedule of Assessments. 
Number of 
Subjects 
Expansion phase: 1610 subjects. 
Trial Product 
Avelumab will be administered as 1-hour intravenous (i.v.) infusion. 
Subjects will receive avelumab once every 2 weeks until confirmed 
progression, unacceptable toxicity, or any criterion for withdrawal from the 
trial or IMP occurs. 
The dose of avelumab will be calculated based on the weight of the subject 
determined on the day of each drug administration.  
Premedication 
with 
an 
antihistamine 
and 
with 
paracetamol 
(acetaminophen) approximately 30 to 60 minutes prior to each dose of 


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avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-
650 mg paracetamol [acetaminophen] i.v. or oral equivalent). This regimen 
may be modified based on local treatment standards and guidelines, as 
appropriate. 
Immediate access to intensive care unit or equivalent environment and 
appropriate 
medical 
therapy 
(including 
intravenous 
epinephrine, 
corticosteroids, antihistamines, bronchodilators, and oxygen) must be in 
place for use in the treatment of potential infusion reactions. Infusion of 
avelumab will be stopped in case of ≥ Grade 2 infusion-related, allergic, or 
anaphylactic reactions (according to NCI-CTCAE v4.0). Following 
avelumab infusion, subjects must be observed for 2 hours post infusion for 
potential infusion-related reactions (IRRs).  
Treatment 
and 
Trial Duration 
The planned treatment duration is until unacceptable toxicity, or any 
criterion for withdrawal from the trial or IMP occurs.  
Schedule of Visits 
1. Screening/Baseline assessment (day -18 to first treatment) 
2. Treatment phase 
Visits will be conducted weekly until week 7 and every 2 weeks thereafter 
prior to the approval of Protocol Amendment 7. For subjects participating 
in the expanded PK sampling, visits at Days 2 and 3 will be required. 
Following the approval of Protocol Amendment 7, the visits at Week 2, 4, 
and 6 are no longer required and subjects will not be required to attend these 
visits. 
3. Discontinuation visit and end-of-treatment visit  
All subjects who discontinue study treatment prematurely for an AE should 
have a full safety evaluation at the time of discontinuation (discontinuation 
visit). For all subjects who have completed treatment, an end-of-treatment 
visit should be scheduled 4 weeks after the last administration of avelumab. 
The end-of-treatment visit is scheduled 4 weeks after the last administration 
of avelumab but before any new therapy is started, if possible. The visit will 
comprise a full assessment of safety parameters, immunogenicity 
assessment, and tumor response assessment as appropriate. 
4. Post-treatment follow-up (safety follow-up visit and survival follow-up) 
All subjects will have a subsequent visit scheduled 10 weeks after the last 
administration of avelumab. The visit will include a full assessment of 
safety parameters. 
AEs will be documented until the end of treatment visit. After the end of 
treatment visit only treatment related AEs have to be documented until the 
post-treatment safety follow-up visit. Subjects with a serious AE ongoing 


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at the post treatment safety follow-up must be monitored and followed up 
by the investigator until stabilization or until the outcome is known, unless 
the subject is documented as “lost to follow-up”. 
Subjects without progressive disease (PD) at the end-of-treatment visit will 
be followed up for disease progression (CT / MRI scans every 12 weeks) 
up to 1 year. In addition, subjects will be followed for any AE suspected to 
be related to study treatment, especially for the occurrence of new 
autoimmune events up to 3 months after the last dose of avelumab. 
After the end-of-treatment visit, subjects will be followed quarterly for 
survival (including assessment of any further tumor therapy). The survival 
follow-up will continue until 1 year after the last subject receives the last 
dose of avelumab. 
Schedule of Assessments can be found in Section 12, Appendix I, of the 
protocol. 
Randomization 
and Blinding 
Not applicable.  


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8 
Overview of Planned Analyses 
This SAP will only address analyses for the expansion phase. Additional SAPs for Safety 
Monitoring Committee (SMC) analyses and for the final analysis of dose escalation phase have 
been developed separately. Trial endpoints specifically for dose escalation have been included into 
the dose escalation SAP. 
The planned analyses for the expansion phase are summarized in Table 2. An additional interim 
analysis may be conducted 13 weeks after the start of treatment of the last subject in that cohort 
for selected primary and secondary expansion cohorts. Depending on subject enrollment or 
planning of future study, a separate primary analysis may be performed for selected secondary 
cohorts. Those analyses, as well as an interim safety analysis for interim CSR, are also included 
into Table 2. 


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Table 2 
Planned Analyses for Expansion Cohorts 
Cohort 
Interim Analysis 
Primary Analysis 
Interim CSR and Final Analysis 
NSCLC post platinum doublet 
60 subjects 
75 subjects 
all subjects 
X 
Pooled expansion cohorts for interim 
CSR and all expansion cohorts together 
for final analysis 
NSCLC first-line 
30 subjects 
75 subjects 
all subjects 
X 
MBC 
75 subjects 
X 
Gastric and GEJ cancer primary  
75 subjects 
all subjects 
X 
CRPC 
 
X 
CRC 
 
X 
2nd Ovarian cancer cohort 
20 subjects 
75 subjects 
all subjects 
X 
ACC 
20 subjects 
all subjects 
X 
Melanoma 
20 subjects 
all subjects 
X 
Mesothelioma 
20 subjects 
all subjects 
X 
2nd Urothelial carcinoma cohort  
20 subjects 
all subjects 
X* 
RCC second-line 
20 subjects 
X 
RCC first-line 
30 subjects 
X 
Ovarian cancer efficacy 
30 subjects 
60 subjects 
X 
Urothelial carcinoma efficacy  
30 subjects 
109 subjects* 
X 
Gastric and GEJ cancer efficacy  
30 subjects 
90 subjects 
X 
HNSCC  
30 subjects 
90 subjects 
X 
X = Primary analysis to be conducted with a data cut-off date of the last subject first dose date + 6 months for each cohort. 
* = Interim analysis will be performed after the 109th dosed subject from efficacy urothelial carcinoma cohort has reached 6 months follow-
up period. 
8.1 
Interim Analysis 
For the NSCLC (post platinum doublet and first-line), gastric/GEJ cancer, and MBC expansion 
cohorts, an interim analysis will be performed after the 75th subject in each cohort has reached the 


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time point of the second post-baseline tumor assessment scheduled in Week 13, i.e. 13 weeks after 
start of treatment of the 75th subject. Efficacy in this 75 subject subset of the cohort will be 
analyzed in terms of the unconfirmed response at Week 13. If the rate of unconfirmed response at 
Week 13 (according to RECIST 1.1) in the efficacy population defined as all treated subjects with 
measurable disease at baseline is less than 5%, enrollment in the given cohort may be stopped. 
Based on a comprehensive review of the efficacy and safety data it may be considered whether 
recruitment in a subgroup of the study population of the given indication, defined by PD-L1 
expression status, might be resumed by means of a substantial Protocol Amendment. 
Statistical considerations related to this futility rule: 
Under different assumptions on the true response rate in the overall population, the probabilities 
of observing a response rate of less than 5% in this analysis (i.e., 3 or less responders out of 75 
subjects) are noted in Table 3. 
Table 3 
Probability of Observing a Response Rate of Less Than 5% in Interim 
Analysis 
True response rate in overall population 
Probability of 3 or less responders in 75 patients 
0.03 
0.81 
0.05 
0.48 
0.10 
0.05 
0.15 
0.002 
Interim analyses on the first 75 NSCLC post platinum doublet or MBC subjects included the 
baseline characteristics, efficacy (excluding DR, TTR and OS), and safety evaluations. Interim 
analyses on the first 75 gastric/GEJ cancer or NSCLC first-line subjects will include the baseline 
characteristics and efficacy (excluding DR, TTR and OS). 
In the NSCLC post platinum doublet cohort only, 2 additional interim analyses of efficacy 
parameters are planned for internal planning purposes at the following time points:  
• 13 weeks after start of treatment of the 60th subject. This interim analysis was performed on 
demographic, disease history, and efficacy endpoints. 
• 13 weeks after start of treatment of the last subject. This interim analysis will be performed on 
disposition, demographic and baseline characteristics, treatment exposure, and efficacy 
endpoints. The subgroup analyses on efficacy endpoints will be performed on all dosed subjects 
and on PD-L1 positive subjects based on tertiary cut-off as defined in Section 13.4. 
In the first-line NSCLC primary expansion cohort, an interim analysis of response will be 
conducted 13 weeks after start of treatment of the 30th subject. 
In the efficacy expansion cohorts, interim analyses for efficacy are planned 13 weeks after the start 
of treatment of the 30th subject in all cohorts, 13 weeks after start of treatment of the 60th subject 
in the ovarian cohort, and 13 weeks after the start of treatment of 90th subject in the gastric / GEJ  


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and HNSCC cohorts. The interim analyses after 60/90 subjects aim to demonstrate efficacy as 
specified in Section 16.1. No futility rule is foreseen because the clinical activity of 
anti-PD-1 / anti-PD-L1 agents in these tumor types is established, and the patient populations are 
characterized by a high unmet medical need. If efficacy criteria are met at the interim analysis, 
enrollment will continue to the planned full number of subjects in order to collect further data on 
the primary and secondary endpoints, especially on the association between PD-L1 expression and 
efficacy endpoints.    
In addition, in the secondary cohorts that plan to enroll more than 20 subjects, i.e., the ACC, 
melanoma, mesothelioma, ovarian cancer, and urothelial carcinoma cohorts, an interim analysis 
of response will be performed 13 weeks after the start of treatment of the 20th subject. Accrual in 
each cohort may be paused during the interim analysis. If no unconfirmed response according to 
RECIST 1.1 is observed in a given cohort in the interim analysis, accrual in that cohort will be 
stopped. The data included into the interim analysis are demographic, disease history, prior anti-
cancer therapy, PD-L1 expression status, lesion assessment, BOR, ORR by PD-L1 expression 
status, and PFS overall and by PD-L1 expression status. In addition, for the ovarian cancer 
secondary expansion cohort, an interim analysis of response will be performed for internal 
planning purposes 13 weeks after the start of treatment of the 75th subject. 
Enrollment of first-line RCC subjects was opened after 2 documented objective responses among 
the 20 subjects enrolled in the second-line RCC cohort were observed by RECIST 1.1 (2 PRs), 
and justified further evaluation in this patient population.   In the RCC cohort, interim analyses of 
response will be performed 13 weeks after the start of treatment of the 20th subject of second-line 
RCC; and after the 30th subject of the first-line RCC.  
The sequence of statistical analyses planned for urothelial cancer subjects will consider the 
objective to evaluate the association between tumor PD-L1 expression and BOR prospectively.  In 
a first step, the secondary urothelial carcinoma cohort served as a “training set” for the 
identification of a PD-L1 expression cut-off (5%) that is most likely to identify a subset of the 
subject population with enhanced clinical benefit.  The PD-L1 expression cut-off (5%) was 
specified prior to any statistical analysis of the PD-L1 expression data from the urothelial 
carcinoma efficacy expansion cohort (cut-off determined 11Mar2016).  In the next step, the cut-
off will be verified by conducting an interim evaluation with data from subjects of the efficacy 
expansion cohort at 6 months after the last subject’s first dose of study treatment for the 109 
subjects enrolled in the urothelial carcinoma efficacy expansion cohort prior to Protocol 
Amendment 13. The cut-off date for this analyses was 19Mar2016.  In case the cut-offs are not 
mutually supportive in terms of clinical efficacy endpoints, the cut-off could be refined and the 
remainder of approximately 100 subjects of the efficacy expansion cohort will serve as the 
“validation set” to qualify the tumor PD-L1 expression cut-off.  Otherwise, data from subjects of 
the urothelial carcinoma expansion cohorts will be pooled for the final efficacy analyses of the 
expansion cohorts at 6 months after start of treatment of the last subject enrolled in the efficacy 
expansion cohort.  
For each primary and secondary expansion cohort, an additional interim analysis may be 
conducted 13 weeks after the start of treatment of the last subject in that cohort. In general, interim 


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analyses at time points that are not specified in the protocol may be performed for internal planning 
purposes.  
8.2 
Safety Analysis for Interim CSR 
The purpose of analysis is to support comprehensive safety review of avelumab in the ongoing 
trials, the results will be included into an interim CSR.  
• The analysis for the interim CSR will be based on a data cut-off date of 20Nov2015. 
• The data to be included into the first interim CSR are demographics and baseline characteristics, 
prior anti-cancer therapy, concomitant medication and procedure, drug exposure and 
compliance, premedication, safety parameters (AEs, lab, vital signs, electrocardiograms 
[ECGs], and Eastern Cooperative Oncology Group [ECOG]), immunogenicity, and PK.  
• The data will be pooled across all the expansion cohorts for the analysis. 
• The safety analysis set (SAF) used for the analysis will contain all the expansion subjects who 
receive at least one dose of study treatment by the data cut-off date. 
8.3 
Primary and Final Analyses 
Primary analyses will include all the baseline characteristics, efficacy, and safety evaluations. Final 
analysis will contain efficacy evaluations and AEs. PK, pharmacodynamics, biomarker, and 
immunogenicity data may also be included for the primary or final analyses depending upon the 
purpose of reporting. 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol 
• Interim analysis for ovarian cancer cohort was performed on the first 23 dosed subjects because 
of the over-enrollment in the first stage of this cohort, with a data cut-off date on 17Jul2014 for 
the purpose of internal planning. 
• Addition of a combined interim analysis performed on the first 90 NSCLC and 75 MBC dosed 
subjects with a data cut-off date on 17Jul2014 for the purpose of internal planning. 
• The first interim analysis for secondary urothelial carcinoma cohort was performed on the first 
26 subjects due to using the same cut-off date as 75 subject interim analysis for primary 
gastric/GEJ cancer cohort. This was an acceptable deviation from the planned interim analysis 
on the first 20 subjects. A second interim analysis will be performed on 44 subjects from 
secondary urothelial carcinoma cohort due to addition of efficacy urothelial carcinoma cohort 
in Protocol Amendment 10. 
• Addition of analyses to explore the association between PD-L1 expression status and histology 
in NSCLC cohorts. 
• Addition of analysis related to premedication. 
• Addition of CD8+ and associated exploratory analyses in Section 16.3. 
• The cut-off date for the interim analysis for the HNSCC cohort is September 09, 2015, defined 
as the date at which 20 subjects have been followed-up for at least 13 weeks (instead of 30 


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subjects as planned in the protocol). This analysis will include summary of baseline 
characteristics, efficacy and safety data. All dosed subjects until the data cut-off date will be 
included for baseline and safety analyses.  
• Addition of an analysis on all the safety data including PK and immunogenicity to be included 
into an interim CSR.  
• For the purpose of internal planning and for reporting to regulatory authorities, the primary 
analysis results of the urothelial carcinoma secondary cohort will be updated based on a data 
cut-off date on Oct 7, 2015, as well as on the cut-off dates for the urothelial carcinoma efficacy 
expansion cohort, i.e. i) 4 months after start of treatment of the 109th subject (Jan 18, 2016); ii) 
6 months after start of treatment of the 109th subject (Mar 19, 2016), and iii) 6 months after 
start of treatment of the last subject enrolled in the efficacy expansion cohort.  The efficacy 
endpoints such as BOR, PFS, OS, and safety endpoints such as the occurrence of TEAE will be 
included for these additional analyses.  
• The interim analysis 13 weeks after the start of treatment of the 30th subject in the urothelial 
carcinoma efficacy cohort was not performed. Interim analyses will be conducted at 4 and 6 
months after the last subject’s first dose of study treatment for the 109 subjects enrolled in the 
urothelial carcinoma efficacy expansion cohort prior to Protocol Amendment 13. The results of 
these analyses may be subject to reporting to regulatory authorities. The interim analysis is 
considered positive if the lower limit of the 95% CI of the confirmed BOR exceeds 10%. The 
following subsets of the cohort are used for the interim analysis when 109th subject has been 
followed up for 4 months: 
o All subjects first dosed prior to or up to the cut-off date (analysis of safety) 
o All dosed subjects with at least 4 months follow-up as of the cut-off date (analysis 
of BOR, PFS, OS) 
• The following subsets of the cohort will be used for the interim analysis when 109th subject has 
been followed up for 6 months:  
o All subjects first dosed prior to or up to the cut-off date (analysis of safety) 
o All dosed subjects with at least 13 weeks follow-up as of the cut-off date (BOR, 
PFS, OS, DR, TTR) 
o All dosed subjects with at least 6 months follow-up as of the cut-off date (BOR, 
PFS, OS, DR, TTR) 
• Analyses on the corresponding PD-L1 positive subsets will be performed depending on PD-L1 
data availability at the time of the analysis.  
• CTCAE version 4.03 was utilized for laboratory toxicity grading in place of version 4.0 for 
outputs relating to the Interim Escalation and Expansion CSR. 
• Addition of TTR according to modified irRC and to RECIST 1.1 criteria, respectively, per 
investigator assessment. 
• For the efficacy expansion cohorts and the urothelial carcinoma secondary cohort:  
o TTR according to RECIST 1.1, per IERC 


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10 
Analysis Sets 
The following analysis sets are defined for the dose expansion phase and summarized in Table 4: 
• Screening analysis set (SCRN): all subjects who signed informed consent form (ICF). 
• PK analysis set (PKAS):  a subset of the safety analysis set and will include patients who have 
at least one post-dose concentration measurement above the lower limit of quantitation 
(LLOQ) for avelumab. 
• Safety analysis set (SAF): all subjects who have received at least 1 dose of study treatment. 
• Full analysis set (FAS): all subjects who have received at least 1 dose of study treatment. 
o PD-L1 positive (5% cut-off) FAS (urothelial carcinoma efficacy expansion cohort): all 
PD-L1+ subjects (defined as those with at least 5% of the tumor cells showing PD-L1 
membrane staining ≥1+ assessed by immunohistochemistry) who have received at least 1 
dose of study treatment.  
o PD-L1 positive (1% cut-off) FAS (NSCLC cohorts): all PD-L1+ subjects (defined as those 
with at least 1% of the tumor cells showing PD-L1 membrane staining ≥1+ assessed by 
immunohistochemistry) who have received at least 1 dose of study treatment.  
• Efficacy analysis set (EFF, efficacy expansion cohorts): all subjects who have received at least 
1 dose of study treatment and have measurable disease at baseline according to IERC 
assessment. 
o PD-L1 positive EFF (urothelial carcinoma efficacy expansion cohort): all PD-L1+ subjects 
(defined as those with at least 5% of the tumor cells showing PD-L1 staining ≥1+ assessed 
by immunohistochemistry) who have received at least 1 dose of study treatment and have 
measurable disease at baseline according to IERC assessment.   
• Efficacy analysis set (primary and secondary expansion cohorts): all subjects who have 
received at least 1 dose of study treatment and have measurable disease at baseline according 
to investigator assessment. 
The definition of the SAF and the FAS are identical in this non-randomized study; the SAF will 
be used for the safety analysis and the FAS will be used for efficacy analysis. The PD-L1 positive 
FAS will be the primary analysis population for the primary endpoint of BOR by IERC in the 
urothelial carcinoma efficacy expansion cohort, whereas for the other efficacy expansion cohorts 
the primary analysis population will be the FAS. 


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Table 4 
Summary of Analysis Sets and Associated Analyses 
Analysis Set 
Data/Endpoints 
Cohorts 
SAF 
Disposition, baseline, safety, PD-L1 and 
biomarker, CD8, exposure, immunogenicity 
All expansion cohorts 
PKAS 
PK data 
All expansion cohorts 
FAS 
Efficacy (BOR, PFS, TTR, OS, subgroup 
analysis, lesion assessment) 
All expansion cohorts  
PD-L1 positive (5% cut-off) FAS 
Efficacy (BOR, PFS, TTR, DR, OS, 
subgroup analysis, lesion assessment) 
Urothelial carcinoma efficacy cohort 
PD-L1 positive (1% cut-off) FAS 
Efficacy (BOR, PFS, TTR, DR, OS, 
subgroup analysis, lesion assessment) 
NSCLC cohorts 
EFF 
Efficacy (sensitivity analysis) 
All expansion cohorts  
PD-L1 positive EFF 
Efficacy (sensitivity analysis) 
Urothelial carcinoma efficacy cohort 
EFF 
BOR at 13 weeks (75 subjects interim 
analysis) 
Primary cohorts 
For interim analysis, all dosed subjects up to and including the data cut-off date will be included 
for the analysis. Additionally, two subsets of the population will be defined for interim analysis, 
dosed subjects with ≥ 6 or ≥ 13 weeks follow-up period up to the data cut-off date. The follow-up 
period is calculated from the first dose date to the data cut-off date. The analysis of BOR or 
associated subgroup analysis by PD-L1 status will be based on the two subset populations. The 
subset populations may also be used for the summary of demographic or other baseline data.  
11 
General Specifications for Statistical Analyses 
• Statistical analyses will be performed using electronic case report form (eCRF) data obtained 
until a clinical cut-off date.  
o The primary data cut-off for expansion cohorts is 6 months after the last subject started the 
treatment.  
o The interim data cut-off is 13 weeks after the pre-specified number of subjects started the 
treatment. For example, an interim analysis will be conducted after the first 75 subjects in 
each primary cohort have reached the time point of the second post-baseline tumor 
assessment scheduled in Week 13, i.e. 13 weeks after start of treatment of the 75th subject. 
There may be minor deviation from this requirement due to combined data transfer used for 
multiple interim analyses, i.e. a few subjects may not reach the time point for the second 
post-baseline tumor assessment scheduled in Week 13, which is considered as acceptable.  
o Final data cut-off will be 1 year after the last subject in the expansion phase receives his or 
her last dose of avelumab. 
• Analysis results will be summarized by cohort(s) and/or pooled across cohorts, depending upon 
the purpose of the reporting. Primary analysis for a cohort will include data summarized by 
that cohort. Final analysis will include data from all the expansion cohorts. 
• Analysis of primary gastric and GEJ cancer cohort will be primarily stratified by the status of 
disease progression after first line chemotherapy. 


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• Data collected after re-initiation of treatment will not be included for safety and efficacy 
analyses except for PK, overall survival, and disposition.  
• All data will be evaluated as observed, and no imputation method for missing values will be 
used, unless otherwise specified.  
• Duration will be calculated as stop date – start date + 1, unless otherwise specified. 
• The time since an event (e.g. time since first diagnosis, time since last dose) will be calculated 
as reference date minus date of event.   
• The first day (Day 1) of study treatment is defined as the day of the first administration of 
avelumab, unless otherwise stated. The last dose date of study treatment is defined as the day 
of the last administration of avelumab, prior to the re-initiation of study treatment if applicable. 
• Baseline is defined as the last non-missing observation prior to the administration of first dose 
of study treatment. Additionally, baseline for HR and QT/corrected QT (QTc) assessments will 
be derived from the visit where both HR and QT are not missing. If duplicate or triplicate 
ECGs are collected, baseline for each ECG measurement is the average of the pre-dose 
replicate measurements on the baseline day. QT interval correction based Fridericia’s or 
Bazett's formula (QTcF/QTcB) will be derived based on HR and QT. The average of the 
replicate measurements should be determined after the derivation of the individual parameter 
at each time point. 
• If the laboratory assessments are not done for scheduled visit but they are available for 
unscheduled visit on Day 1 from a different laboratory, the unscheduled visit will be included 
for the derivation of baseline; if there are multiple non-missing assessments on Day 1, the 
assessment from scheduled visit will be used for the derivation of baseline. 
• On-treatment period will be defined as the time from the first dose of study treatment to 
min(last dose date + 30 days, earliest date of subsequent anti-cancer drug therapy – 1 day). If 
the earliest date of subsequent anti-cancer drug therapy is a partial date and only day is missing, 
it will be imputed as the last day of the month. If both day and month are missing, no imputation 
should be performed. The imputed date will be used for defining on-treatment period as well 
as confirming immune-related progressive disease (irPD). 
• All statistical analyses will be performed using SAS® Version 9.1.3 or higher. 
• There will be no difference between scheduled and un-scheduled visits except for by-visit 
analysis of safety analyses and baseline derivation. 
• The assignments of visit windows are described in Table 5 for the purpose of by-visit analyses 
of safety data: 
o Baseline will be derived as described above. 
o No visit windowing will be performed at discontinuation, end of treatment, or safety follow-
up visits for laboratory, vital sign, and ECG data, and 2hr post dose assessment on Week 1 
Day 1 for ECG data. Instead, the earliest non-missing observation among the unscheduled 
or scheduled assessments for each visit (discontinuation, end of treatment, or safety follow-
up) will be used for the analysis. For 2hr post dose assessment on Week 1 Day 1 ECG data, 
the earliest non-missing observation on Week 1 Day 1 will be used for the analysis. 


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o Scheduled and unscheduled assessments are included for visit windowing. Assessments on 
or after re-initiation of treatment are not be included for visit windowing. 
o If there are multiple assessments for any specified visit and some of them are from scheduled 
visits, the assessment from scheduled visit with the closest distance to the planned study day 
will be used for analysis.  
o If there are multiple assessments for any specified visit and none of them are from scheduled 
visits, the assessment with the closest distance to the planned study day will be used for 
analysis.  
o  If there are two or more unscheduled assessments with same distance to the planned study 
day such as (-1/+1 day), the assessment prior to the planned study day such as -1 day will be 
used for windowing.  
o There is no difference for visit windowing between tests from core serum chemistry panel 
and tests from full serum chemistry panel. Some subjects had non-core serum chemistry tests 
assessed at the scheduled visits only intended for core serum chemistry. Multiple protocol 
amendments are also taken into the consideration, as the full serum chemistry and 
hematology panels were assessed weekly until week 7 and bi-weekly thereafter prior to the 
approval of Protocol Amendment 7. 
o For ECG assessment associated with study treatment dose, only assessments where time 
point (prior to infusion or 2 hr after infusion) are not missing will be considered for the 
analysis. 
Table 5  
Visit Window Definition for Safety Assessment 
Assigned 
Study 
Day 
(Inclusive) 
Planned Study 
Day 
(AWTARGE
T) 
Analysis 
Visit 
(N) 
(AVISITN) 
Analysis 
Visit 
(AVISIT) 
Assessment 
From 
(AWLO) 
To 
(AWHI) 
 
 
 
 
~ 
1 
 
1 
Baseline 
Lab, Vital Sign, ECG 
1 
1 
1 
2 
Week 1 Day 1*  
ECG 
5 
11 
8 
3 
Week 2 Day 5-11 
Lab, Vital Sign 
12 
18 
15 
4 
Week 3 Day 12-18 
Lab, Vital Sign 
5 
18 
15 
4 
Week 3 Day 5-18 
ECG 
19 
25 
22 
5 
Week 4 Day 19-25 
Lab, Vital Sign 
19 
25 
22 
5 
Week 4 Day 19-25 
ECG 
26 
32 
29 
6 
Week 5 Day 26-32 
Lab, Vital Sign 
26 
36 
29 
6 
Week 5 Day 26-36 
ECG 
33 
39 
36 
7 
Week 6 Day 33-39 
Lab, Vital Sign 


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40 
50 
43 
8 
Week 7 Day 40-50 
Lab, Vital Sign 
37 
50 
43 
8 
Week 7 Day 37-50 
ECG 
51 
64 
57 
10 
Week 9 Day 51-64 
Lab, Vital Sign, ECG 
65 
78 
71 
12 
Week 11 Day 65-78 
Lab, Vital Sign, ECG 
79 
92 
85 
14 
Week 13 Day 79-92 
Lab, Vital Sign 
79 
106 
85 
14 
Week 13 Day 79-106 
ECG 
93 
106 
99 
16 
Week 15 Day 93-106 
Lab, Vital Sign 
107 
120 
113 
18 
Week 17 Day 107-120 
Lab, Vital Sign 
121 
134 
127 
20 
Week 19 Day 121-134 
Lab, Vital Sign 
107 
148 
127 
20 
Week 19 Day 107-148 
ECG 
135 
148 
141 
22 
Week 21 Day 135-148 
Lab, Vital Sign 
149 
162 
155 
24 
Week 23 Day 149-162 
Lab, Vital Sign 
163 
176 
169 
26 
Week 25 Day 163-176 
Lab, Vital Sign 
149 
190 
169 
26 
Week 25 Day 149-190 
ECG 
177 
190 
183 
28 
Week 27 Day 177-190 
Lab, Vital Sign 
191 
204 
197 
30 
Week 29 Day 191-204 
Lab, Vital Sign 
205 
218 
211 
32 
Week 31 Day 205-218 
Lab, Vital Sign 
191 
232 
211 
32 
Week 31 Day 191-232 
ECG 
* only applies to 2 hr post dose, AWLO = Analysis Window Beginning Timepoint, AWHI = Analysis Window Ending 
Timepoint, AWTARGET = Analysis Window Target, AVISIT = Analysis Visit, AVISITN = Analysis Visit (N). 
• Presentation of continuous and qualitative variables: 
o Continuous variables will be summarized using descriptive statistics i.e., number of non-
missing values and number of missing values, [i.e. n (missing)], mean, median, standard 
deviation, minimum, maximum and first and third quartile (Q1 and Q3). CI may be estimated 
for some of the endpoints, if appropriate. 
o Qualitative variables will be summarized by counts and percentages. Unless otherwise 
stated, 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. 
12 
Trial Subjects 
The subsections in this section include specifications for reporting subject disposition and 
treatment/trial discontinuations. Additionally procedures for reporting protocol deviations are 
provided. 


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12.1 
Disposition of Subjects and Discontinuations 
Summary of analysis sets will be tabulated using frequency and percentage by cohort(s) and/or 
pooled across cohorts, depending upon the purpose of the reporting, on all the subjects who signed 
ICF, the number of subjects in SAF will be used as the denominator: 
• All subjects who signed ICF 
• Number of subjects in the safety analysis set 
• Number of subjects in the full analysis set 
• Number of subjects in the PD-L1 positive full analysis set, if applicable 
• Number of subjects in the efficacy analysis set, if applicable 
• Number of subjects in the PD-L1 positive efficacy analysis set, if applicable 
• Number of subjects in the full analysis set/PD-L1 positive full analysis set with 6/13 weeks (or 
4 or 6 months) follow-up period, if applicable 
One table will provide the reasons for permanent discontinuation of study treatment and for end 
of study as collected on the Treatment Termination, and End of Study (if data is available) eCRF 
pages, respectively. The number and percentage of subjects in each disposition category will be 
presented in the table based on the SAF analysis set: 
• Number of subjects in the SAF analysis set 
• Number of subjects still on treatment 
• Number of subjects off-treatment 
• Reasons off-treatment 
o Adverse event 
o Lost to follow-up 
o Protocol non-compliance 
o Death 
o Disease progression 
o Withdrew consent 
o Other 
• Number of subjects in follow-up 
• Number of subjects who discontinued from the study 
• Reasons off-study 
o Study reached predefined end 
o Lost to follow-up 
o Death 


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o Withdrew consent 
o Other 
• Number of subjects with treatment reinitiated 
The number and percentage of screened and/or dosed subjects may be summarized by geographic 
region, country and clinical site or by expansion cohort depending on the purpose of reporting.  
The follow-up time (weeks) in the study will be calculated as (the analysis cut-off date – the first 
dose date + 1)/7. Summary statistics (mean, standard deviation, median etc.) will be presented in 
a table. 
The listing of subject disposition will include all subjects who signed ICF (i.e. including screening 
failures). The listing will include the following information (if applicable): subject identifier, date 
of informed consent, included in the trial, reason for inclusion/exclusion, first/last dosing date, 
reason off-treatment, date and reason off-study, flags for SAF, FAS, and EFF (or PD-L1 positive 
FAS, and PD-L1 positive EFF for Urothelial carcinoma efficacy cohort), and flags to identify if 
subjects are included for each interim analysis (if applicable). The reason off-treatment will be 
retrieved from the End of Treatment eCRF page. 
A secondary listing for reason for end of treatment due to AEs will also be provided. The listing 
will be restricted to the SAF subjects who discontinued study treatment for the primary reason of 
an AE, and will include the following information: subject identifier, first/last dosing date, date 
off-treatment, and the relevant AE system organ classes (SOCs), preferred terms (PTs) and AE 
relationship to the study treatment. 
12.2 
Protocol Deviations 
12.2.1 
Minor Protocol Deviation 
A minor protocol deviation can be defined as any deviation from the study protocol that does not 
materially affect the safety of the subjects and/or the conduct of the study and/or its evaluation. 
An example of a minor protocol deviation would include a missed PK blood sample. 
12.2.2 
Important Protocol Deviation 
Important (previously used terminology major) protocol deviations is one that materially affects 
the safety of the subjects and/or the evaluation of primary or key secondary efficacy endpoints of 
the study.  
Current ICH and EU GCP guidelines list the important protocol deviations that must be listed in 
the clinical report. These include: 
• subjects that are dosed on the study despite not satisfying the inclusion criteria; 
• subjects that develop withdrawal criteria whilst on the study but are not withdrawn; 
• subjects that receive the wrong treatment or an incorrect dose; 


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• subjects that receive an excluded concomitant medication. 
• deviation from GCP. 
Important protocol deviations will be based upon the eCRF database and determined for all 
subjects by either medical review processes or programming based on the inclusion/exclusion 
criteria or other criteria presented in the protocol. The results will be included into SDTM, if 
identified by means of medical review. The ADaM datasets will include both, those identified by 
medical review and those identified by programming. 
Important protocol deviations are specified in Appendix 20.1, and will be summarized in a table 
and presented in a data listing. All protocol deviations included into SDTM will be presented in a 
data listing. 
13 
Demographics and Other Baseline Characteristics 
The demographics and other baseline characteristics will be summarized on the SAF. 
13.1 
Demographics 
The demographics and baseline characteristics table will include descriptive statistics for the 
following variables: 
• Age (in years) 
• Age category (<65/≥65 years) 
o 65-<75  
o 75-<85  
o ≥ 85 
• Sex 
• Race 
• Pooled Geographical region 
o North America  
o Europe  
o Asia 
o Rest of the World (Australia and/or Latin America will be included as additional pooled 
geographical regions if including > 10% of the overall randomized population) 
North America contains subjects from United States, Europe contains subjects from Belgium, 
Czech Republic, Germany, France, United Kingdom, Hungary, and Poland, and Asia contains 
subjects from South Korea and Taiwan.  
• Height (cm) 


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• Weight (kg) 
• Body Mass Index (BMI) (kg/m2) 
• ECOG performance status 
• Nicotine use status (Never used/ Regular user/ Occasional user/ Former user) 
Baseline weight and height will be the last non-missing values prior to the first dose of study 
treatment from the Vital Signs eCRF page while baseline ECOG will be derived from the data 
collected on the ECOG eCRF page. Nicotine use status will be extracted from Nicotine 
Consumption eCRF page. 
Age and BMI will be derived as: 
• Age (year) = (date of informed consent – date of birth + 1)/365.25. 
o In case of missing day only: Age (years) = (year/month of given informed consent – 
year/month of birth)/12 
o In case only year of birth is given: Age (years) = (year of given informed consent - year of 
birth) 
• BMI (kg/m2) = weight(kg)/[height(m)]2.  
The integer part of the calculated age will be used for reporting purpose.  
The listing of demographics and baseline characteristics will include the following information: 
subject identifier, age, sex, race, country/geographic region, height (cm), weight (kg), BMI 
(kg/m2), and ECOG. 
The listing of nicotine consumption will be produced with the following data: nicotine use status, 
frequency of nicotine use, start/end date of nicotine consumption, nicotine consumption habit, and 
duration of consumption (years). 
Lesion assessments at screening will be grouped into the following categories and summarized 
using descriptive statistics (count and percentage) in a table: 
• Tumor size at baseline: The sum of target lesion diameters ≥ vs < median in each cohort. 
• Presence of metastases at baseline (present, absent). Target or non-target lesions that are 
categorized as ‘metastasis’ are classified as metastases. This only applies to urothelial 
carcinoma cohorts. 
Baseline albumin and hemoglobin will be classified as follows and summarized in a table using 
descriptive statistics (frequency and percentage). 
• Albumin (< 35 g/L vs. ≥ 35 g/L) 
• Hemoglobin (< 100 g/L vs. ≥ 100 g/L) 
Baseline Bellmunt Score will be classified as 0, 1, 2, or 3 as a sum of the sub-scores of baseline 
ECOG, baseline Hgb, and baseline liver mets, defined as follows and summarized in a table using 


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descriptive statistics (frequency and percentage; for urothelial carcinoma secondary and efficacy 
cohorts). 
 
 
Baseline value 
Bellmunt sub-score 
Baseline ECOG 
0 
0 
>0 
1 
Baseline Hemoglobin 
>=100 g/L 
0 
< 100 g/L 
1 
Baseline Liver 
Metastasis 
N 
0 
Y 
1 
• Baseline eCcr (≤30, 30 - ≤50, 50 - <60, ≥60; for urothelial carcinoma secondary and efficacy 
cohorts) 
• Time since last prior anti-cancer chemotherapy (<3, ≥3 - <6, ≥6; for urothelial carcinoma 
secondary and efficacy cohorts) 
13.2 
Medical History 
Medical history will be coded using the latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA). Medical history will be summarized as the numbers and 
percentages of subjects by MedDRA PT as event category and MedDRA SOC as summary 
category, and sorted by SOC and PT in alphabetical order. Each subject will be counted only once 
within each PT or SOC. 
Listing of medical history data by subject will include coded terms and all the relevant data fields 
as collected on the Medical History eCRF page.  
13.3 
Disease History 
Disease histories are collected on NSCL Cancer Diagnosis, Colorectal Cancer Diagnosis, Gastric 
and GEJ Cancer, Castrate-Resistant Prostate Cancer, Melanoma Diagnosis, Ovarian Cancer, 
Metastatic Breast Cancer, Adrenocortical Carcinoma Diagnosis, Mesothelioma Cancer Diagnosis, 
Renal Cell Carcinoma Diagnosis, Head and Neck Cancer Diagnosis, and Urothelial Carcinoma 
Diagnosis eCRF pages. Partial date will be imputed as described in the Section 18.1.  
The disease history table will include descriptive statistics for the following variables: 
• Sub-site of tumor 
Summary of tumor sub-sites applies to NSCLC, MBC, Gastric and GEJ cancer, CRC, ovarian 
cancer, melanoma cancer, ACC, mesothelioma, urothelial carcinoma, HNSCC where pre-defined 
sub-sites or standard terms will be captured on the eCRF pages. 
• Time since first diagnosis (years), defined as (the first dosing date – the date of first 
diagnosis)/365.25 


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• Time since metastatic or locally advanced disease (months), defined as (the first dosing date – 
the date of first occurrence of metastatic or locally advanced disease)/30.4375 
• Time since last disease progression (months), defined as (the first dosing date - the date of last 
progression of disease)/30.4375 
• Tumor Node Metastasis Classification of Malignant Tumors (TNM) at initial diagnosis  
• TNM at study entry  
Listing of disease history will be provided with all relevant data (tumor sub-site, initial diagnosis 
date, first occurrence of metastatic or locally advanced disease, date of last disease progression, 
TNM classification) and derived variables used in the above table. 
Eligibility for platinum-based therapy is collected on Platinum Ineligibility eCRF page for 
urothelial carcinoma and HNSCC cohorts. It will be summarized for the following categories: 
• Eligibility for platinum-based therapy 
o Yes 
o No 
 Impaired renal function 
 Hearing loss (25 decibels at 2 contiguous frequencies) 
 Peripheral neuropathy 
 Other 
Listing of eligibility for platinum-based therapy will be provided with all relevant data (eligibility, 
reason for ineligibility, and date ineligibility defined). 
13.4 
PD-L1 Expression Status and Biomarker  
PD-L1 expression status will be collected using Pathology Report Form. The percentages of viable 
tumor cells that exhibit PD-L1 membrane staining at any intensity are evaluated. No staining 
should be scored as “0”, weak staining as “1+”, moderate staining as “2+”, and strong staining as 
“3+”.  
PD-L1 expression status will be classified as positive or negative based on the following cut-offs: 
• For tumor cells: 
o Subjects will be considered PD-L1 expression positive (negative) if at least (less than) 5% 
of the tumor cells show PD-L1 membrane staining ≥1+, respectively. This will be used as 
the primary cut-off. 
o Subjects will be considered PD-L1 expression positive (negative) if at least (less than) 25% 
of the tumor cells show PD-L1 membrane staining ≥2+, respectively. This will be considered 
as secondary cut-off. 


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o Subject will be considered PD-L1 expression positive (negative) if at least (less than) 1% of 
the tumor cells show PD-L1 membrane staining ≥1+, respectively. This will be used as the 
tertiary cut-off. 
o Subject will be considered PD-L1 expression positive (negative) if at least (less than) 50% 
of the tumor cells show PD-L1 membrane staining ≥1+, respectively. This will be used as 
the ‘50% cut-off’. 
o Subject will be considered PD-L1 expression positive (negative) if at least (less than) 80% 
of the tumor cells show PD-L1 membrane staining ≥1+, respectively. This will be used as 
the ‘80% cut-off’. 
• For Immune cells: 
Subjects will be considered PD-L1 expression positive with regard to immune cell expression if 
tumor has ‘PD-L1 hotspots’ with at least 10% PD-L1 expressing immune cells. Subjects with an 
evaluable specimen not meeting this criterion are considered PD-L1 expression negative with 
regard to immune cell expression. The PD-L1 expression negative subjects will contain subjects 
from the following categories: 
o Negative 1: if there are no tumor associated immune cells (TAICs) present in the specimen. 
o Negative 2: if there are TAICs present but no ‘PD-L1 hotspots’. 
o Negative 3: if tumor has ‘PD-L1 hotspots’ with <1% PD-L1 expressing immune cells. 
o Negative 4: if tumor has ‘PD-L1 hotspots’ with 1-9% PD-L1 expressing immune cells.  
PD-L1 expression status will be summarized using the following variables: 
• PD-L1 expression status based on tertiary cut-off for tumor cells (positive/ negative/ not 
evaluable) 
• PD-L1 expression status based on primary cut-off for tumor cells (positive/ negative/ not 
evaluable) 
• PD-L1 expression status based on secondary cut-off for tumor cells (positive/ negative 1, 
negative 2 / not evaluable) 
o Negative 1: subjects with  <5% tumor cells with staining ≥1+ 
o Negative 2: subjects with ≥5% tumor cells with staining ≥1+, but <25% tumor cells with 
staining ≥2+ 
o Negative: combined subjects from Negative 1 and Negative 2 as mentioned above 
• PD-L1 expression status based on ‘50% cut-off’ for tumor cells (positive/ negative/ not 
evaluable) 
• PD-L1 expression status based on ‘80% cut-off’ for tumor cells (positive/ negative/ not 
evaluable) 
• PD-L1 expression status based on immune cells (positive/ negative1, negative 2, negative 3, 
negative 4 / not evaluable if data is collected, or positive/ negative/ not present) 


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• % of tumor cells with any staining (grade ≥1+) as continuous variable 
• % of tumor cells with at least 2+ staining as continuous variable 
The percentage of tumor cells with any staining (grade ≥1+) stratified by PD-L1 expression status 
based on immune cells will be displayed graphically using a boxplot. The association between PD-
L1 expression and NSCLC histology (adenocarcinoma, squamous cell carcinoma, others) will be 
summarized using frequency and percentage in a table. 
For the gastric and GEJ cancer cohorts, PD-L1 expression is in addition scored with alternative 
scoring methodologies, where three scoring methods to evaluate PD-L1 expression status will be 
used as follows: 
• Conventional tumor cell (TC) (cell number-based percentage) scoring method 
• Immune cell (IC) rescoring method 
• Aggregated (TC + IC) scoring method 
Aggregate PD-L1 expression score combines TC and IC scores, and the results will be 
categorized as follows: 
• <1% for both TC and IC vs ≥1% for either TC or IC 
• <5% for both TC and IC vs ≥5% for either TC or IC 
• <25% for both TC and IC vs ≥25% for either TC or IC 
Additional details of these scoring algorithms are specified in the Pathology Report Form (PRF). 
PD-L1 expression status (positive vs. negative) at baseline with different cutoff values will be 
summarized in total for each scoring method. PD-L1 assay status of percentage of PD-L1 positive 
tumor cells will be summarized as below: 
• <1% 
• ≥1% to <5% (cut-off is 1%) 
• ≥5% to <25%, (cut-off is 5%) 
• ≥25% (cut-off is 25%) 
The dates of sample collection for PD-L1 expression analysis will be summarized using the 
following variables. All subjects with valid PD-L1 expression results will be included for the 
analysis. 
• Time from sampling date to first dose date (months), defined as (the first dosing date – the date 
of tissue sampling)/30.4375 
• Timing related to the first date of prior anti-cancer therapy for metastatic or locally advanced 
disease (before/ after). If the sampling date is prior to the first date of prior anti-cancer therapy 
for metastatic or locally advanced disease, it is considered as ‘before’; otherwise, it is 
considered as ‘after’. 


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• Number of any prior anti-cancer therapy lines: missing/ 1/ 2/ 3/ 4/ ≥5 
• Number of prior anti-cancer therapy lines for metastatic or locally advanced disease: missing/ 
0/ 1/ 2/ 3/ 4/ ≥5. 
For the primary gastric and GEJ cancer cohort, the following will be summarized for Not 
Progressed First Line Cancer (FLC) per drug category: 
• Duration of latest prior anti-cancer regimen (Days) 
• Duration of latest prior anti-cancer regimen start date to first study treatment (Days) 
The prior anti-cancer drugs will also be extensively detailed with the number and percentage of 
subjects by the Anatomical Therapeutic Chemical (ATC) class level 2 and PT in a table. A subject 
will be counted only once within a given drug class and within a given drug name, even if he/she 
received the same medication at different times. If any prior anti-cancer medication is classified 
into multiple ATC classes, the medication will be summarized separately under each of these ATC 
classes. In case any specific medication does not have ATC classification level 2 coded term, it 
will be summarized under “Unavailable ATC classification” category. The summary will be sorted 
on decreasing frequency of drug class and decreasing frequency of drug name in a given drug 
class, based on the incidence in the “Overall” column. In case of equal frequency regarding drug 
class (respectively drug name), alphabetical order will be used. 
The listings of prior anti-cancer treatments and procedures will also be provided: a) listing of prior 
anti-cancer drug therapies, b) listing of prior anti-cancer radiotherapies, and c) listing of prior anti-
cancer surgeries. These will include subject identifier and all the relevant collected data-fields on 
the corresponding eCRF pages. 
14.2 
Prior and Concomitant Medications/Procedures 
Prior and concomitant procedures are collected on the Concomitant Procedures Details eCRF page. 
Prior and concomitant medications are collected on the Concomitant Medications Details eCRF 
page. 
Medications started prior to first dose date of study treatment and continued into the on-treatment 
period as well as those started during on-treatment period are referred to as concomitant 
medications. Prior medications are defined as the medications started and stopped prior to the first 
dose date of study treatment. Post medications are defined as any medications started after on-
treatment period. 
Summary of concomitant medications will include the number and percentage of subjects by ATC 
classification level 2 and PT. A subject 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 summarize 
separately under each of these ATC classes. In case any specific medication does not have ATC 
classification level 2 coded term, it will be summarized under “Unavailable ATC classification” 
category. The summary of concomitant medications will be sorted on decreasing frequency of drug 
class and decreasing frequency of drug name in a given drug class, based on the incidence in the 


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“Overall” column. In case of equal frequency regarding drug class (respectively drug name), 
alphabetical order will be used. 
Prior and concomitant medication data will be listed from the Concomitant Medications eCRF 
page. Following variables will be included in the prior and concomitant medication listing: subject 
identifier, prior/ concomitant/ post medication, and all corresponding data field on the 
corresponding eCRF page. 
Prior and concomitant procedures data will be listed from the Concomitant Procedures Details 
eCRF page. Subject identifier and all collected data-field on the corresponding eCRF page will be 
included in the listing. 
14.3 
Subsequent Anti-Cancer Therapies/Procedures 
Anti-cancer treatment after discontinuation will be provided in a data listing with data retrieved 
from Anti-Cancer Treatment After Discontinuation, Radiotherapy After Discontinuation, and 
Surgery After Discontinuation eCRF pages. A table for anti-cancer treatment after discontinuation 
will be added for primary analysis. 
15 
Treatment Compliance and Exposure 
Analysis of exposure will be based on the calculated actual dose levels (total dose 
administered/weight, mg/kg). The last non-missing weight of the subject on or prior to the day of 
dosing will be used for the calculation.  
The summary of treatment exposure and compliance based on the SAF analysis set will include 
the following variables per subject (a cycle refers to the planned dosing interval of two weeks): 
• Treatment duration (in weeks), defined as (the last dose date – the first dose date + 14)/7  
• Number of administrations as continuous variable 
• Cumulative dose (mg/kg), defined as sum of actual dose levels  
• Dose intensity (mg/kg/cycle), defined as cumulative dose (mg/kg) / (0.5 * treatment duration 
(week))  
• Relative dose intensity (%), defined as actual dose intensity (mg/kg/cycle) * 100/ planned dose 
level (mg/kg/cycle). 
• Relative dose intensity by the following categories: 
o >0.9 
o >0.8-0.9 
o <=0.8 
Individual relative dose intensity (%) is calculated as actual dose level (mg/kg)/ planned dose level 
(mg/kg) × 100 for each administration of study medication. A dose reduction is defined as actual 
non-zero dose < 90% of planned dose, or individual relative dose intensity < 90%. A table based 


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on SAF will be prepared to summarize the number and percentage of subjects with at least one 
dose reduction, and a breakdown by the number of dose reductions (1/2/3/≥4).  
Per protocol, avelumab will be administered as 1-hour i.v. infusion. Subjects will receive the study 
treatment once every 2 weeks. Dose delays will be grouped into the following categories based on 
the deviation of the actual to the planned treatment administration day (relative to the previous 
non-zero dose date): no delay (including 1-2 days delays), 3-6 days delay, 7 or more days delay. 
For example, if one subject receives the study treatment on day 1, then the next study treatment 
administration date will be on day 15; however, if the subject receives the study treatment at day 
16 or 17, this is considered as ‘no delay’. Any zero dose prior to the last treatment administration 
is considered as a dose interruption. 
The summary of dose delays will be based on the SAF and include the following categories: 
• No delay 
• 3-6 days delay 
• 7 or more days delay 
The categorization is based on the maximum length of delay, i.e. the worst case of delay if subjects 
have multiple dose delays.  
A listing of study treatment administration will include subject identifier, study day, # of days 
relative to prior treatment, infusion rate, most recent body weight prior to infusion, actual/planned 
dose, batch ID, dose reduction/dose delay or interruption, and other relevant information collected 
on the Cohort Treatment MSB0010718C Administration Details eCRF page. A subset of this 
listing will be created for subjects with at least one dose reduction. 
A listing of treatment exposure and compliance will include subject identifier, assigned dose level, 
and above derived variables summarized in the tables. 
In order to mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg 
diphenhydramine and 650 mg acetaminophen (i.v. or oral equivalent) is mandatory 30 to 
60 minutes prior to each dose of study treatment starting on January 29, 2014. The compliance to 
this requirement will be summarized as numbers of subjects with 0, 1, 2, 3, 4 doses among the first 
4 treatment administrations that were administered without pre-medication. For example: if a 
subject discontinued after 3 doses, and 2 of them were administered with premedication, the 
number for that subject would be 1. 
A listing of premedication will include subject identifier, reported medication term, the relative 
time to the start of infusion, date/time of premedication, and dose (unit). A listing containing 
subject identifier, visit, and unique study treatment batch ID will also be created.  


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16.1 
Primary Endpoint Analyses 
The primary endpoint in the efficacy expansion cohorts is the confirmed BOR according to 
RECIST 1.1 and as adjudicated by an IERC, defined as the best response obtained among all tumor 
assessment visits after start of study treatment until documented disease progression (taking into 
account the requirement for confirmation). Only tumor assessments performed before the start of 
any further anti-cancer treatment will be considered in the assessment of BOR. 
For the gastric / GEJ cancer, HNSCC, and ovarian cancer efficacy expansion cohorts, the primary 
analysis of the BOR by IERC will be conducted in the FAS, defined as all treated subjects. The 
number and proportion of BOR (defined as CR + PR) will be tabulated. The ORR will be 
determined as the proportion of subjects with a confirmed BOR of PR or CR. An exact binomial 
test will be performed at a 1-sided alpha level of 0.025. The primary analysis is planned 6 months 
after start of treatment of the last subject in the given cohort. Interim analyses will be conducted 
after 60% of the subjects in the given cohort have been followed up for 13 weeks. Analyses are 
considered positive if the lower limit of the 95% confidence interval exceed 10%. Confidence 
intervals will be constructed using the Clopper-Pearson method.  
For the urothelial carcinoma efficacy expansion cohort, the analysis of the BOR by IERC will be 
conducted in the PD-L1 positive FAS followed by the FAS. The number and proportion of BOR 
(defined as CR + PR) will be tabulated. The ORR will be determined as the proportion of subjects 
with a confirmed BOR of PR or CR. An exact binomial test will be performed in the PD-L1 
positive FAS and in the FAS to determine whether the null hypothesis of an ORR ≤ 10% can be 
rejected at the 1-sided alpha level of 0.025.  Interim analyses will be conducted at 4 and 6 months 
after the first dose date of last subject of the 109 subjects enrolled in the urothelial carcinoma 
efficacy expansion cohort prior to Protocol Amendment 13. Respective cut-off dates are 
18Jan2016 and 19Mar2016. Analyses are considered positive if the lower limit of the 95% CI of 
the confirmed BOR exceeds 10%. Confidence intervals will be constructed using the Clopper-
Pearson method.  
The tumor response will be based on the IERC assessment of overall response at each time point. 
Details of determination of tumor response are provided in Imaging Review charter document. A 
separate Imaging Data Management Plan and Data Transfer Plan will be created to summarize the 
details of the data structure and data delivery schedule of IERC assessment results. 
The following are the requirements for confirmation of CR or PR or of minimum SD duration:   
• CR or PR needs to be confirmed at a subsequent tumor assessment, preferably at the 
regularly scheduled 6-week assessment interval, but no sooner than 4 weeks after the initial 
documentation of CR or PR.  
• The minimum duration for a BOR of SD is defined as at least 37 days after start of study 
treatment accounting for permitted deviations from the tumor assessment visit schedule.  
Table 6 summarizes the derivation rules for the BOR when confirmation from subsequent 
assessment is needed (1). It is reasonable to consider a subject with time point response of PR-SD-


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PR, PR-NE-PR or CR-NE-CR as a confirmed response as long as the second CR or PR is >= 28 
days away from the first time point. 
Table 6 
Best overall response when confirmation of CR/PR required 
Initial overall response 
Subsequent overall response 
Confirmed time point overall response 
CR 
CR 
CR provided subsequent CR is >=28 days away from the first 
time point 
CR 
PR 
SD provided minimum criteria for SD duration met; otherwise, 
PD 
CR 
SD 
SD provided minimum criteria for SD duration met; otherwise, 
PD 
CR 
PD 
SD provided minimum criteria for SD duration met; otherwise, 
PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise, 
NE 
PR 
CR 
PR provided subsequent CR is >=28 days away from the first 
time point 
PR 
PR 
PR provided subsequent PR is >=28 days away from the first 
time point 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise, 
NE 
SD 
Any 
SD provided minimum criteria for SD duration met, otherwise, 
NE 
PD 
Any 
PD 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = Not evaluable. 
If a subject only has a response value of NE or the only response value is SD and is within 36 days of the first dose date the 
best response will be NE.   
In addition, the unadjusted 95% CIs of the ORR will also be calculated with the Clopper-Pearson 
method at the interim and primary analyses in order to provide comparable results based on the 
FAS and subgroup analysis. The number and percentage of subjects with BOR of CR, PR, SD, 
Non-CR/Non-PD, PD, and NE will be tabulated. 
16.2 
Secondary Endpoint Analyses 
Clinical efficacy parameters will be analyzed descriptively in the FAS, and, in addition, for the 
urothelial carcinoma efficacy expansion cohort, in the PD-L1 positive FAS. Pooling of data from 
subjects with at least 6 months follow-up period in the urothelial carcinoma efficacy and secondary 
cohorts may be considered to enhance precision of estimates if data is sufficiently homogeneous. 
The following efficacy endpoints will be considered: The confirmed and unconfirmed BOR, per 
RECIST 1.1, as adjudicated by an IERC and per investigator assessment; irBOR according to 
modified irRC per investigator assessment, DR, TTR, and PFS time according to RECIST 1.1 
criteria per IERC and investigator assessment; DR, TTR, and irPFS time according to irRC criteria 


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per investigator assessment; OS time. Subgroup analyses specified in Section 16.2.6 and summary 
of demographics will also be presented for pooled population.  
The percent change in target lesions from baseline 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 as: 
• Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum of 
target lesions at baseline) * 100% 
The tumor shrinkage will be calculated based on investigator assessment for all the expansion 
cohorts and, in addition, based on IERC data for efficacy expansion cohorts and the urothelial 
carcinoma secondary cohort. The percent change from baseline in target lesions per time point as 
well as other relevant information will be presented in a data listing. The percent change from 
baseline in target lesions as well as the first occurrence of new lesion and subject off treatment 
overall and by PD-L1 expression status will be displayed against time point (weeks) in spider plots. 
The maximum reduction from baseline in the sum of target lesion diameters overall and by PD-L1 
expression status will be presented per subject in waterfall plots. The PD-L1 expression status will 
be displayed using different colors or line styles in the plots. The time point of a tumor assessment 
per investigator is defined as the earliest scan date of the respective visit. 
BOR per investigator assessment will be determined according to RECIST 1.1 for all the expansion 
cohorts. CR/PR will be confirmed per Table 5 in Section 16.1. irBOR is defined as the best result 
obtained among all tumor assessment visits from baseline until immune related disease progression 
(i.e., confirmed irPD), and will be determined according to modified irRC per investigator 
assessment, taking confirmation requirements into account as detailed below. Only tumor 
assessments performed before the start of any further anti-cancer treatment will be considered in 
the assessment of BOR/irBOR. In addition to the confirmed BOR/ irBOR, the unconfirmed BOR 
will be derived for the interim and/or primary analyses. The date of unconfirmed BOR / confirmed 
BOR / irBOR will be the date of the best result that is first observed, or first confirmed if the 
confirmation is required. In case of different dates of scans within the same tumor assessment visit, 
the earliest scan date should be used as the date of tumor assessment. 
Subjects with a BOR of NE will be summarized by reason for having NE status and displayed in 
a listing with relevant data. The following reasons will be used: 
• No post-baseline assessments 
• All post-baseline assessments have overall response NE 
• New anticancer therapy started before first post-baseline assessment 
• SD of insufficient duration (<6 weeks after start date without further evaluable tumor 
assessment) 
• PD too late (>12 weeks after start date) 


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A contingency table will be created to compare the following tumor assessment results between 
IERC and investigators: 
• BOR (NE / PD /(Non-CR/Non-PD) / SD / CR / PR / CR+PR) 
• Disease Progression (No event / PD / Death) 
For irBOR, the response of immune-related complete response (irCR), immune-related partial 
response (irPR), and irPD need to be confirmed by a second, consecutive assessment at least 4 
weeks apart as described in Table 7 (1, 2). It is reasonable to consider a subject with time point 
response of irPR-irSD-irPR, irPR-NE-irPR or irCR-NE-irCR as a confirmed response as long as 
the second irCR or irPR is more than 28 days away from the first time point. irPD is also considered 
to be confirmed if the following event occurs: 
• If subject is assessed with time point response of irPD-NE-irPD as long as the second irPD is 
more than 28 days away from the first time point; or 
• If subject dies within 84 days after the initial observation of irPD; or 
• If subject receives subsequent anti-cancer drug therapy within 84 days after the initial 
observation of irPD; or 
• If subject experiences clinical deterioration as assessed by investigator and recorded as reason 
for treatment discontinuation prior to or within 84 days after the assessment of irPD.  
In case a subject with a confirmed CR relapses within 1 year after stopping treatment, one re-
initiation of treatment is allowed according to Protocol. If the subject has irPD assessed at the same 
visit as the PD prior to the initiation of treatment, the irPD will be considered as confirmed. 
Immune-related stable disease (irSD) duration is required to be no less than 37 days from Day 1.  
Table 7 
Immune-related BOR when confirmation of irCR, irPR, irPD required 
Initial overall 
response 
Subsequent overall 
response 
Confirmed time point overall response 
irCR 
irCR 
irCR provided subsequent irCR is >=28 days away from the first time point 
irCR 
irPR 
irSD provided minimum criteria for irSD duration met; otherwise, irPD 
irCR 
irSD 
irSD provided minimum criteria for irSD duration met; otherwise, irPD 
irCR 
irPD 
irSD provided minimum criteria for irSD duration met; otherwise, irPD 
irCR 
NE 
irSD provided minimum criteria for irSD duration met, otherwise, NE 
irPR 
irCR 
irPR provided subsequent irCR is >=28 days away from the first time point 
irPR 
irPR 
irPR provided subsequent irPR is >=28 days away from the first time point 
irPR 
irSD 
irSD 
irPR 
irPD 
irSD provided minimum criteria for irSD duration met, otherwise, irPD 
irPR 
NE 
irSD provided minimum criteria for irSD duration met, otherwise, NE 
irSD 
Any 
irSD provided minimum criteria for irSD duration met, otherwise, NE 
irPD 
irPD 
irPD provided subsequent irPD is >=28 days away from the first time point,  death  
or take subsequent anti-cancer drug therapy within 84 days  after the first time 
point, or clinical deterioration. 


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Initial overall 
response 
Subsequent overall 
response 
Confirmed time point overall response 
irPD 
Missing 
irPD if subject dies or takes subsequent anti-cancer drug therapy within 84 days 
after the initial observation of irPD, or clinical deterioration, otherwise, NE 
NE 
NE 
NE 
irCR = immune-related complete response, irPR = immune related partial response, irSD = immune related stable disease, irPD 
= immune related progressive disease, and NE = Not evaluable. 
If a subject only has a response value of NE or the only response value is irSD and is within 36 days of the first dose date the 
best response will be NE   
 
In general, efficacy analyses on secondary endpoints will be performed as follows: 
• Unconfirmed response at week 13 only applies to the interim analyses performed on the first 
75 subjects for all the primary cohorts. 
• Unconfirmed BOR and PFS per investigator assessment applies to all the interim analyses for 
all the expansion cohorts. 
• Unconfirmed/confirmed BOR and PFS per IERC apply to the interim analyses for the efficacy 
expansion cohorts and the urothelial carcinoma secondary cohort if data is available. 
• All the endpoints (unconfirmed/confirmed BOR, irBOR, PFS/irPFS, DR/immune-related DR, 
TTR, OS) per investigator assessment except for unconfirmed response at week 13 apply to 
primary analysis for all the expansion cohort. PFS, TTR and DR per IERC will also be analyzed 
for efficacy expansion cohort and the urothelial carcinoma secondary cohort if data is 
available.  
The details will be provided in the Table, Listing, and Figure Shells document.  
16.2.1 
Objective Tumor Response According to RECIST 1.1 or 
Modified irRC (per investigator assessment) 
Objective tumor response is defined as having a BOR assessment of unconfirmed/confirmed 
CR/PR, or having an irBOR assessment of irCR/irPR. Objective tumor response will be evaluated 
by ORR or immune-related objective response rate (irORR) for each cohort, defined as the number 
of subjects reached a best overall response of CR/PR (irCR/irPR) divided by the number of 
subjects in the FAS (PD-L1 positive FAS)/ EFF (PD-L1 positive EFF). Time to objective response 
will be calculated as: 
(Date of the first documented objective response (PR or CR) – date of the first dose +1)/7 (weeks) 
Two-sided 80% and 95% exact CIs for ORR or irORR will be estimated using Clopper-Pearson 
method for each cohort. Additionally, the number and percentage of subjects with BOR of CR, 
PR, SD, PD, and NE or irBOR of irCR, irPR, irSD, irPD, and NE will be tabulated. 
These evaluations will be presented in data listings with detailed information collected per eCRF 
pages as well as BOR and irBOR for all the subjects from the FAS subjects. Time to response, 
time of progression, and duration of study treatment will be displayed in a bar chart for subjects 
with objective response.  


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16.2.2 
Duration of Response According to RECIST 1.1 or Modified 
irRC 
DR is measured from the time measurement criteria are first met for CR/PR or irCR/irPR 
(whichever is first recorded) until the first date that progressive disease or death within 84 days of 
last tumor assessment is objectively documented. The analysis of DR will be performed among 
the subjects who had unconfirmed/confirmed CR/PR or irCR/irPR. 
DR will be censored in the following scenarios: 
• Subjects who have not experienced an event (PD or death) will be right-censored on the date 
of their last evaluable tumor assessment. 
• If death without previously documented PD is observed after more than 84 days (12 weeks) of 
last tumor assessment, subject will be right-censored at the date of the last evaluable tumor 
assessment. 
DR = (date of PD or death/censoring – date of first documented objective response + 1)/30.4375 
(months). 
The Kaplan-Meier method will be used to estimate parameters for duration of response. Kaplan-
Meier estimates (product-limit estimates) will be presented together with a summary of associated 
statistics including corresponding two-sided 95% CIs. In particular, the proportion of duration of 
responses at 6 and 12 months will be estimated with corresponding two-sided 95% CIs. The CIs 
for the median will be calculated according to Brookmeyer and Crowley (4) and CIs for the 
survival function estimates at the above defined time points will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (5) (CONFTYPE = loglog default option in 
SAS PROC LIFETEST). The estimate of the standard error will be computed using Greenwood's 
formula.  A listing with pertinent information will be provided.  
16.2.3 
Progression-Free Survival According to RECIST 1.1 or 
Modified irRC 
PFS time is defined as the time from first administration of study treatment until date of the first 
documentation of PD or death by any cause (whichever occurs first), when death occurs within 84 
days of last tumor assessment or first administration of study treatment (whichever is later).  
PFS will be censored in the following scenarios: 
• Subjects who do not have any post-baseline tumor assessment, or do not have a baseline tumor 
assessment, and die (when applicable) more than 84 days after initial avelumab dose will be 
right-censored on the date of first dose of study treatment. 
• Subjects who have not experienced an event (PD or death) will be right-censored on the date 
of their last evaluable tumor assessment.  
• If death without previously documented PD is observed after more than 84 days of last 
evaluable tumor assessment, subject will be right-censored at the date of the last evaluable 
tumor assessment.  


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PFS = (date of PD or death/censoring - date of the first dose + 1)/30.4375 (months). 
The analysis of PFS will be performed with a Kaplan-Meier method with the same approach as for 
duration of response described in Section 16.2.2. Kaplan-Meier estimates (product-limit estimates) 
will be presented together with a summary of associated statistics including corresponding two-
sided 95% CIs. In particular, the proportion of PFS at 3, 6, and 12 months will be estimated with 
corresponding two-sided 95% CIs. Kaplan-Meier plots of PFS time and listing of PFS will be 
provided as well. 
Frequency (number and percentage) of patients with each event type (PD or death) and censoring 
reasons will be presented. Censoring reasons are as follows: 
• Ongoing in the study without an event (PD or death) 
• No baseline assessment 
• No adequate post-baseline assessments 
• No documented PD and death more than 84 days after last evaluable tumor assessment. 
The PFS time or censoring time and the reasons for censoring will also be presented in a patient 
listing. 
16.2.4 
Overall Survival 
OS is defined as the time from first dose to death due to any cause. For subjects who are still alive 
at the time of data analysis or who are lost to follow up, OS time will be censored at the date of 
last contact as specified in Section 18.1.  
OS = (date of death/censoring – date of the first dose + 1)/30.4375 (months). 
The analysis of OS time will be performed with a Kaplan-Meier method with the same approach 
as for duration of response described in Section 16.2.2. Kaplan-Meier estimates (product-limit 
estimates) will be presented together with a summary of associated statistics including 
corresponding two-sided 95% CIs. In particular, the proportion of overall survival at 6, 12, and 24 
months will be estimated with corresponding two-sided 95% CIs.   
The Kaplan-Meier plots of OS time and listing of OS will provided as well. 
Frequency (number and percentage) of patients with an event type (death) and censoring reasons 
will be presented. Censoring reasons are as follows: 
• Alive 
• Withdrawal of consent 
• Lost to follow-up 
Lost to follow-up will include the following subjects:  
• Lost to follow-up status is collected on the eCRF page prior to the analysis cut-off; 


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• Subjects with the last contact date > 14 weeks prior to the analysis cut-off date (duration of 14 
weeks is based on the assessment schedule of every 12 week for survival follow-up interval + 
2 week window). 
The OS time or censoring time and the reasons for censoring will also be presented in a patient 
listing. 
16.2.5 
Time to Response per RECIST v1.1 or Modified irRC 
TTR will be analyzed for subjects with confirmed CR/PR based on investigator and/or IERC 
assessments and subjects with irCR/irPR based on investigator assessment. 
 
TTR (in weeks) = (first date of objective response – first dose date +1)/7 
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. Q1, 
Q3). 
16.2.6 
Subgroup Analyses 
Subgroup analyses will be performed according to the following parameters: 
• PD-L1 expression status based on: 
o Tumor cell (positive, negative) 
 Positive: ≥1% of the tumor cells show PD-L1 membrane staining intensity 
≥1+. Negative: <1% of the tumor cells show PD-L1 membrane staining 
intensity ≥1+. Evaluable: positive + negative. 
 Positive: ≥5% of the tumor cells show PD-L1 membrane staining intensity 
≥1+. Negative: <5% of the tumor cells show PD-L1 membrane staining 
intensity ≥1+. Evaluable: positive + negative. 
 Positive: ≥25% of the tumor cells show PD-L1 membrane staining intensity 
≥2+. Negative 1: <5% of the tumor cells show PD-L1 membrane staining 
intensity ≥1+. Negative 2: ≥5% of the tumor cells show PD-L1 membrane 
staining intensity ≥1+ but <25% of the tumor cells show PD-L1 membrane 
staining intensity ≥2+. Negative: negative 1 + negative 2. Evaluable: 
positive + negative. 
 Positive: ≥50% of the tumor cells show PD-L1 membrane staining intensity 
≥1+. Negative: <50% of the tumor cells show PD-L1 membrane staining 
intensity ≥1+. Evaluable: positive + negative. 
 Positive: ≥80% of the tumor cells show PD-L1 membrane staining intensity 
≥1+. Negative: <80% of the tumor cells show PD-L1 membrane staining 
intensity ≥1+. Evaluable: positive + negative. 
 


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Immune cell (positive, negative, evaluable (positive + negative)). Subjects will be considered 
PD-L1 positive if tumor has hotspots with at least 10% PD-L1 expressing immune cells (see 
also Section 13.4).  
• Demographics 
o Age (<65, ≥65 years) 
o Sex (male, female) 
o Race (white, others) 
o ECOG (0, ≥1) 
• Pooled Geographical region 
o North America  
o Europe  
o Asia 
• Region (Asia, Non-Asia) for gastric and GEJ cohorts 
• Smoking status: never smoked, ever smoked (containing regular user, occasional user, and 
former user). 
• Histology (adenocarcinoma, squamous cell carcinoma, others). This only applies to NSCLC 
cohorts. 
• Tumor sub-site (oral cavity, oropharynx and hypopharynx, larynx). This only applies to 
HNSCC cohorts. 
• Tumor size at baseline: sum of target lesion diameters ≥ vs < median 
• Presence of metastases at baseline (present, absent). Target or non-target lesions that are 
categorized as ‘metastasis’ are classified as metastases.  
• Prior anti-cancer drug therapy 
o # of any prior anti-cancer therapy lines (≤1, 2, ≥3). 
o # of prior anti-cancer therapy lines for metastatic or locally advanced disease (≤1, 2, ≥3).  
o # of any prior anti-cancer therapy lines (≤1, >1: for NSCLC post platinum doublet). 
o # of prior anti-cancer therapy lines for metastatic or locally advanced disease (≤1, >1: for 
NSCLC post platinum doublet).  
• NSCLC biomarker 
o EGFR (normal, abnormal, unknown) 
o KRAS (normal, abnormal, unknown) 
o ALK (normal, abnormal, unknown) 
o EGFR/ALK (normal, abnormal, unknown) 
• MBC biomarker: HER2- (ER- and PR-), HER2- (ER+ or PR+), HER2+, or unknown 


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• Gastric and GEJ cancer biomarker: HER2+, HER2-, or unknown 
• HNSCC biomarker: HPV+, HPV-, or unknown 
• Gastric and GEJ cancer and ovarian cancer biomarker: MSI (low vs. stable vs. high) 
• Gastric and GEJ cancer biomarker: EBV (positive vs. negative) 
• MBC and ovarian cancer biomarker: BRCA1/2, mutant (if at least one mutation in both genes) 
vs. wildtype (no mutation in BRCA1 and BRCA2) 
• Gastric and GEJ cancer biomarker: PD-L1 expression status according to each of the three 
alternative scoring methods (conventional tumor cell (TC) scoring, immune cell (IC) scoring, 
aggregated (TC + IC) scoring): PD-L1 assay status at cut-off value as follows: 
o < 1% vs. >=1% 
o < 5% vs. >=5% 
o < 25% vs. >=25% 
• Eligibility for platinum-based therapy (yes, no) for urothelial carcinoma cohort 
• Baseline laboratory assessment (only presented for urothelial carcinoma efficacy and 
secondary cohorts) 
o Albumin (< 35 g/L vs. ≥ 35 g/L) 
o Hemoglobin (< 100 g/L vs. ≥ 100 g/L) 
• Baseline Bellmunt Scores (only presented for urothelial carcinoma efficacy and secondary 
cohorts) 
• Time since last prior anti-cancer chemotherapy (only presented for urothelial carcinoma 
efficacy and secondary cohorts) 
• Sub-site of tumor (only presented for urothelial carcinoma efficacy and secondary cohorts) 
o Upper tract defined as ureter or renal pelvis 
o Lower tract defined as bladder or urethral  
Frequency of objective response, percentage, and 95% CI of ORR will be estimated for all the 
subgroup analyses on BOR or irBOR. CI will be based on exact Clopper-Pearson method. For 
subgroup analyses of BOR or irBOR based on PD-L1 expression status, the p-value and 80% CI 
will be provided as well. The p-value will be based on Fisher’s exact test for association between 
PD-L1 status (positive vs. negative) and ORR. 
Same statistics will be provided for the subgroup analyses on PFS, irPFS, and OS as those provided 
for non-subgroup analyses on PFS, irPFS, and OS, respectively. For subgroup analysis by PD-L1 
status, the hazard ratios and their associated 95% CIs will be estimated by Cox Proportional 
Hazards model using PD-L1 status (negative as reference) as covariate.  
The subgroup analyses are exploratory for all the cohorts and will be primarily performed on IERC 
data for efficacy expansion cohorts and the urothelial carcinoma secondary cohort. Subgroup 


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analysis will not be performed if the largest subgroup covers ≥ 90% of the subjects. Subgroup 
analysis to be performed depends on the cohorts and type of analysis, but in general: 
• Subgroup analysis by PD-L1 status applies to interim and primary analyses for all the 
expansion cohorts if PD-L1 data is available. 
• Subgroup analyses by demographic and prior anti-cancer therapy line apply to all the 
expansion cohorts. Subgroup analysis by sex is excluded for MBC, CRPC, and ovarian cancer 
cohorts. 
• Subgroup analysis by geographic region applies to all the cohorts with subjects enrolled from 
different regions. 
• Subgroup analysis of tumor response (confirmed/unconfirmed BOR, irBOR) by baseline 
tumor size applies to all expansion cohorts. 
• Subgroup analysis of tumor response (confirmed/unconfirmed BOR, irBOR) and PFS by the 
status of metastases at baseline applies to urothelial carcinoma cohorts only. 
• Subgroup analysis by biomarker applies to interim and primary analyses for NSCLC, MBC, 
gastric and GEJ cancer, HNSCC cohorts based on the above definitions. 
• Subgroup analysis by histology or tumor sub-site applies to NSCLC or HNSCC cohorts, 
respectively. 
• Subgroup analysis by smoking status applies to NSCLC and HNSCC cohorts. 
• Subgroup analyses by eligibility of platinum-based therapy and baseline albumin and 
hemoglobin apply to urothelial carcinoma cohorts only. 
Subgroup analyses may be also performed on selected sub-population such as PD-L1+ subjects 
based on tertiary cut-off defined in Section 13.4. The details will be provided in the Table, Listing, 
and Figure Shells document. 
The association between unconfirmed/confirmed objective response and PD-L1 status (based on 
tertiary cut-off) will be stratified by PD-L1 sampling time related to the first date of prior anti-
cancer therapy for metastatic or locally advanced disease (before, after) and summarized in a table. 
This will apply to post-platinum doublet NSCLC cohort. 
The maximum target lesion percentage reduction vs. percentage of tumor cells with any staining 
(≥1+) or with ≥2+ staining will be displayed graphically using scatterplot. 
Subgroup information and BOR, PFS, or OS will be presented in three separate data listings. 
16.2.7 
Sensitivity Analyses 
If there is a more than 5% difference in the number of subjects between FAS and EFF analysis 
set or between PD-L1 positive FAS and PD-L1 positive EFF analysis set, tumor response based 
on BOR and irBOR per IERC or investigator assessment will be repeated using EFF analysis set 
or PD-L1 positive EFF analysis set. 


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prior to the performance of a descriptive analysis. PK concentrations which are erroneous due to 
a protocol violation (as defined in the CTP), documented handling error or analytical error (as 
documented in the bioanalytical report) may be excluded from the PK analysis if agreed upon prior 
to performing a statistical analyses. In this case the rational for exclusion must be provided in the 
Clinical Trial Report (CTR). Any other PK concentrations that appear implausible to the 
Pharmacokineticist/PK/PD Data Analyst must not be excluded from the analysis. Any implausible 
data will be documented in the Clinical Trial Report (CTR). Any exclusions will be listed and 
flagged. 
16.4.2 
Descriptive PK Analysis 
Avelumab serum concentrations will be provided in listings and descriptively summarized by day 
and nominal time using the number of non-missing observations (N), arithmetic mean (Mean), 
standard deviation (SD), coefficient of variation (CV%), minimum (Min), median (Median) and 
maximum (Max). The pre-dose samples will be considered as if they had been taken 
simultaneously with the administration.  
PK concentrations at the end of each infusion (CEOI) and trough concentrations (Ctrough - 
concentration at the end of a dosing interval) will be summarized descriptively by nominal day on 
scheduled visits for all tumor types. Descriptive statistics for Ctrough and CEOI will additionally show 
the geometric mean (GeoMean), the geometric coefficient of variation (GeoCV) and the 95% 
confidence interval for the GeoMean (Lower CI 95% GeoMean, Upper CI 95% GeoMean). 
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK/PD concentration data: 
 
Mean, Min, Median, Max: 
3 significant digits 
SD: 
4 significant digits 
CV%: 
1 decimal place 
The following conventions will be applied when reporting descriptive statistics of CEOI and Ctrough 
data: 
 
Mean, Min, Median, Max, GeoMean, 95% CI: 3 significant digits 
SD: 
4 significant digits 
CV%, GeoCV%: 
1 decimal place 
 


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Individual Ctrough and CEOI values will be plotted against actual time points on a linear scale, for all 
subjects by group (cohort and dose level). Arithmetic mean Ctrough  ±SD and arithmetic mean CEOI 
±SD will also be plotted by group (cohort and dose level), on a linear scale.   
16.4.3 
Population Pharmacokinetic Analysis 
Sampled PK profiles from study EMR100070-001 will be analyzed jointly with data from other 
studies by non-linear mixed effect approach, in order to describe the PK concentration time profile 
followed by multiple dose infusion of avelumab, to identify covariates explaining (part of) the 
between patient PK variability and to estimate the residual PK inter-individual variability. The PK 
analysis set will be used. More details will be given in a separate Data Analysis Plan for Population 
Pharmacokinetic Analysis. The results will be reported separately.  
16.4.4 
Relation of Pharmacokinetics to Efficacy in Urothelial 
Carcinoma Cohorts  
The exposure-response analysis will include subjects with urothelial carcinoma from the Full 
Analysis Set (secondary cohort of urothelial carcinoma and efficacy expansion cohort of urothelial 
carcinoma). The analyses will be based on a data cut-off for the urothelial carcinoma efficacy 
expansion cohort, i.e. 6 months after start of treatment of the 109th subject.  
The objectives of this exploratory population exposure response analysis are: To assess the 
relationships between objective response (OR), overall survival (OS), and progression-free 
survival (PFS) with avelumab exposure (e.g., single dose trough concentration (Ctrough_sd), steady-
state Ctrough_SS,), and steady-state AUC_ss, and single dose AUC_sd) in the presence of other 
relevant covariates.  
For OR, the patients will be classified as responder or non-responder based on best overall response 
(BOR) according to RECIST 1.1 following IERC assessment (responder: CR and PR; non-
responder: stable disease [SD], progressive disease [PD], non-evaluable [NE]). OS and PFS will 
be reported in months.   
Population PK parameters, as determined by the final population modeling analysis will be used 
to derive individual exposure metrics including, but are not limited to Ctrough_sd, Ctrough_SS, AUC_ss 
and AUC_sd. In addition, observed concentration values (i.e. observed single dose Ctrough, observed 
stead-state Ctrough) may be used to represent exposures. 
Multivariable regression models will be employed with a stepwise variable selection process. The 
covariates will be inserted subsequently to the regression model starting with the covariate linked 
to the smallest p value (corresponding to the Wald chi-square statistic, given the covariates 
degrees-of-freedom) not yet included to the model if the corresponding p value is below or equal 
the inclusion threshold of 15%. After each forward step (i.e. inclusion of a new covariate) the new 
larger regression model passes a backward step, in which subsequently all covariates are excluded 
(starting with the covariate linked to the highest p value) if their Wald chi-square p-values lie 
above the exclusion threshold of 40%. The stepwise procedure stops when no further effect can be 
added or the previously added effect in the forward step was removed in the next backward step.  


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The interpretation and final inclusion of the covariate(s) in the final model will depend on 
biological plausibility, dataset attributes and clinical significance of the covariate in question.   
Covariates to be tested consider potential prognostic factors including the following in Table 8: 
Table 8 
 Table of potential covariates for regression models 
Category  
Covariates 
Demographics 
race, sex, age, baseline body weight 
Prior Treatments 
Prior radiotherapy (Y/N), Number of prior anti-cancer drug therapies, Prior adjuvant 
therapy 
Safety laboratory 
information at 
baseline 
Albumin, alkaline phosphatase, bilirubin, alanine aminotransferase, aspartate 
aminotransferase, platelet count, lactate dehydrogenase at baseline, eGFR*, hemoglobin 
Disease-related 
laboratory values 
PD-L1 status 
Disease 
Status/Treatment 
Baseline ECOG Status (0/1/2) 
Concomitant medication of Corticosteroids for systemic use (Y/N) 
Metastatic disease** at enrolment (study entry) – liver metastasis, other metastasis, no 
metastasis 
Number of non-target lesions at baseline 
Tumor burden at baseline (mm) 
Tumor sub-site (Lower tract / Upper tract) 
Eligibility of platinum-based therapy *** (Y/N) 
 
 
 
*eGFR is calculated as follows: 
eGFR=32788*CREAT**(-1.154)*AGE**(-0.203) + SEX*0.742+MRACE*1.210 
where CREAT is serum creatinine (μmol/L), AGE is age (years), Sex is a flag for sex (0 for 
males, 1 for females) and MRACE is a flag for race (1 for Black or African American, 0 
otherwise). CREAT(mg/dL)*88.4=CREAT(µmol/L) 
** as evaluated by local or central tumor assessments 
*** Subjects are considered eligible for platinum-based therapy in case they receive cisplatin 
as a prior anti-cancer treatment. 
 
Missing time-invariant categorical covariates will be set to be a separate category distinct from 
other categories. If the percentage of missing values is below 10%, the missing values should be 
imputed based on modeler’s decision to balance the distribution of the categorical covariate. 
Missing time-invariant continuous covariates will be to the population median or excluded from 
the analysis if the percentage of missing values is equal or larger than 25%. 
The exposure-response relationship for BOR will be performed using R or NONMEM 7.3. 
Exposure-response calculations regarding PFS and OS will be performed using the software SAS 
9.3 or R. 


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16.4.4.1 
Objective Response: Logistic Regression Model 
Multivariate logistic regression of the following form will be used to evaluate potential 
relationships between OR and exposure: 
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑃𝑃) = 𝑙𝑙𝑙𝑙𝑙𝑙ቀ
𝑃𝑃
1−𝑃𝑃ቁ= 𝛽𝛽0 + 𝛽𝛽1 ∙𝐶𝐶+ 𝛽𝛽2 ∙𝑋𝑋2 + 𝛽𝛽3 ∙𝑋𝑋3 + ⋯+ 𝛽𝛽𝑛𝑛∙𝑋𝑋𝑛𝑛  
 
 
(1) 
Where P represents probability of being responder, β0 hypothetically represents the odds of the 
event occurring without any exposure. β1 represents a linear effect of the exposure. C represents 
exposure metric. βj represents the estimate of the effect of an additional covariate where j = 2, . . ., 
n and for a total of n− 1 covariates (Xn).  
16.4.4.2 
Objective Response: Nonlinear logistic regression  
The classical logistic model assumes linear relationship of the logit with exposure, meaning that 
probability of response can asymptotically reach 100% for an infinite exposure, which is 
unrealistic. Therefore, an exploratory nonlinear logistic regression will be performed using an 
Emax function (Equation 2) instead of the linear function as shown in Equation 1.   
𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙(𝑃𝑃) = 𝑙𝑙𝑙𝑙𝑙𝑙ቀ
𝑃𝑃
1−𝑃𝑃ቁ= 𝛽𝛽0 +
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸 ×𝐶𝐶
𝐶𝐶+𝐸𝐸𝐸𝐸50  
                    
 
 
(2) 
Here, P is the probability of response, β0 hypothetically represents the odds of the event occurring 
without any exposure, Emax is the maximum drug effect, EC50 is the exposure level where 50% 
of maximum drug effect is reached. C represents exposure metric 
16.4.4.3 
Overall survival and progression free survival: Cox 
Proportional Hazards Model 
Progression free survival (PFS) and overall survival (OS) were captured as events and non-events 
and therefore the drug exposure response model will be developed using time-to-event analysis. A 
Cox proportional hazards model will be used to assess the relationship for OS and PFS versus 
avelumab exposure as well as to explore prognostic factors (covariates) for each endpoint. The 
exposure metrics will include, but are not limited to, Ctrough_sd, Ctrough_SS and AUC_ss, AUC_sd 
Validity of the assumption of proportionality of hazards for the covariates could be verified by 
residual analysis (plots). Maximum likelihood estimates of the parameters will include hazard 
ratios and 95% confidence intervals. 
The Cox proportional hazards model is the most commonly used multivariate approach for 
analyzing survival time data in medical research. It is a survival analysis regression model, which 
describes the relation between the event incidence, as expressed by the hazard function and a set 
of covariates. Mathematically, the Cox model is written as: 
ℎ(𝑡𝑡) = ℎ0(𝑡𝑡) ∗exp(𝛽𝛽1 ∙𝐶𝐶+ 𝛽𝛽2 ∙𝑋𝑋2 + 𝛽𝛽3 ∙𝑋𝑋3 + ⋯+ 𝛽𝛽𝑛𝑛∙𝑋𝑋𝑛𝑛) 
 
(3) 
Where the hazard function ℎ(𝑡𝑡) is dependent on (or determined by) a set of 𝑛𝑛 covariates (C, 
𝑥𝑥2, … , 𝑥𝑥𝑛𝑛) including exposure metric (C), whose impact is measured by the size of the respective 


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regression coefficients (𝛽𝛽1, … . , 𝛽𝛽𝑛𝑛). An appealing feature of the Cox model is that the baseline 
hazard function ℎ0(𝑡𝑡) is estimated non-parametrically, and so unlike most other statistical models, 
the survival times are not assumed to follow a particular statistical distribution. 
The Cox model is essentially a multiple linear regression of the logarithm of the hazard on the 
covariables, with the baseline hazard being an ‘intercept’ term that varies with time. The covariates 
then act multiplicatively on the hazard at any point in time, and this provides us with the key 
assumption of the proportional hazards model: the hazard of the event in any group is a constant 
multiple of the hazard in any other. In case of ties, the discrete logistic likelihood  
𝐿𝐿(𝛽𝛽1, … , 𝛽𝛽𝑛𝑛) = ∏
exp (β1 ∑
𝐶𝐶𝑗𝑗+⋯+ 𝛽𝛽𝑛𝑛∑
𝑋𝑋𝑛𝑛𝑛𝑛)
𝑗𝑗∈𝐷𝐷𝑖𝑖
𝑗𝑗∈𝐷𝐷𝑖𝑖
∑
exp (β1 ∑
𝐶𝐶𝑞𝑞𝑙𝑙+⋯+ 𝛽𝛽𝑛𝑛∑
𝑋𝑋𝑛𝑛𝑞𝑞𝑙𝑙)
𝑗𝑗∈𝐷𝐷𝑖𝑖
𝑑𝑑𝑖𝑖
𝑙𝑙=1
𝑞𝑞 ∈ 𝑄𝑄𝑖𝑖
𝑘𝑘
𝑖𝑖=1
   
 
(4) 
is maximized for the estimation of regression coefficients. The term 𝐷𝐷𝑖𝑖 in equation (4) denotes the 
set of subjects failing at time point 𝑖𝑖 for distinct event time points 𝑖𝑖= 1, … , 𝑘𝑘 (with 𝑑𝑑𝑖𝑖 as number 
of subjects failing at time point 𝑖𝑖). The set 𝑄𝑄𝑖𝑖 includes all 𝑑𝑑𝑖𝑖-tuples (𝑞𝑞1, … , 𝑞𝑞𝑑𝑑𝑖𝑖) of subjects, which 
are under risk at time point 𝑖𝑖. 
Correlation plots will be produced to explore co-linearity of relevant covariates to exposure and 
correlation coefficients will be reported.  
16.5 
Immunogenicity 
ADA (referred to as HAHA in CRF and SDTM) was assessed before the study treatment start, and 
on Days 15, 29, 43, 57, 71, 85, 127, and 169 prior to the start of infusion, and at the end of treatment 
visit. If the sample is positive for ADA, it will be re-analyzed to determine the titer and nAb. The 
ADA results will be derived based on the algorithm in Table 9. Subjects will be characterized into 
different ADA categories based on the criteria in Table 10. 
Table 9 Algorithm for the Derivation of ADA Results 
Sample Screen Result 
Confirmatory 
Titer 
ADA Result 
Negative 
NA 
NA 
Negative 
NR 
NA 
NA 
NR 
Positive 
Negative 
NA 
Negative 
Positive 
NR 
NA 
NR 
Positive 
Positive 
Number 
Number 
Positive 
Positive 
NR 
Positive-TNR 
NR = no result, NA = not applicable, TNR = titer no result. 


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Table 10 Subjects Characterized based on ADA Results 
Category 
Definition 
Subject at Risk (Denominator for Incidence) 
Never 
positive 
No positive results at any time point 
Number of subjects with at least one valid result at 
any time point 
Ever positive 
At least one positive result at any time point 
Number of subjects with at least one valid result at 
any timepoint 
Pre-existing 
A positive ADA result prior to treatment with avelumab 
Number of subjects with valid baseline result 
Treatment 
boosted 
A positive ADA result prior to treatment with avelumab 
and the titer ≥ 8*baseline titer while on avelumab 
treatment 
Number of subjects with valid baseline and at least 
one valid post-baseline result 
Treatment 
emergent 
Not positive prior to treatment with avelumab and with at 
least one positive post-baseline result 
Number of subjects with at least one valid post-
baseline result and without positive baseline results 
(including missing, NR) 
Transient 
positive 
If treatment emergent subjects have (a single positive 
evaluation, or duration between first and last positive 
result <16 weeks) and last assessment not positive. 
Number of subjects with at least one valid post-
baseline result and without positive baseline results 
(including missing, NR) 
Persistent 
positive 
If treatment emergent subjects have duration between 
first and last positive result ≥16 weeks or a positive 
evaluation at the last assessment 
Number of subjects with at least one valid post-
baseline result and without positive baseline results 
(including missing, NR) 
Samples with a reportable ADA titer will also be tested in the neutralizing antibody (nAb) assay. 
NAb results are positive or negative in a single assay and only derived when not performed because 
ADA was negative (see Table 11). Subjects will be characterized into different nAb categories 
based on the criteria in Table 12. For nAb, treatment-boosted is not applicable since no titer result 
is available. 
Table 1  
Algorithm for the Derivation of nAb Results 
ADA Confirmatory Result 
nAb Result 
Derived nAb Result 
Negative 
NA 
Negative 
NR 
NA 
NR 
NA 
NA 
Negative 
Positive 
NR 
NR 
Positive 
Positive 
Positive 
Positive 
Negative 
Negative 
ADA = antidrug antibody, NA = not applicable, nAb = neutralizing antibody, NR = no result. 


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Table 2 
Subjects Characterized based on nAb Results 
Category 
Definition 
Subject at Risk (Denominator for Incidence) 
Never 
positive 
No nAb positive results at any time point 
Number of subjects with at least one valid 
ADA result at any time point 
Ever 
positive 
At least one nAb positive result at any time point 
Number of subjects with at least one valid 
ADA result at any time point 
Pre-
existing 
A positive nAb result prior to treatment with 
avelumab 
Number of subjects with valid ADA baseline 
result 
Treatment 
emergent 
Not nAb positive prior to treatment with avelumab 
and with at least one nAb positive post-baseline 
result 
Number of subjects with at least one ADA 
valid post-baseline result and without nAb 
positive baseline results (including missing, 
NR) 
Transient 
positive 
If treatment emergent subjects have (a single nAb 
positive evaluation, or duration between first and 
last nAb positive result <16 weeks) and last ADA 
assessment not nAb positive. 
Number of subjects with at least one ADA 
valid post-baseline result and without nAb 
positive baseline results (including missing, 
NR) 
Persistent 
positive 
If treatment emergent subjects have duration 
between first and last nAb positive result ≥16 weeks 
or a nAb positive evaluation at the last ADA 
assessment 
Number of subjects with at least one ADA 
valid post-baseline result and without nAb 
positive baseline results (including missing, 
NR) 
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result. 
The frequency and percentage of each ADA and nAb category will be presented in tables by 
cohort. Listings of ADA and nAb results from ADA ever-positive subjects will be prepared. 
For the ADA ever-positive subjects, a listing will be prepared by cohort with subject ID, start and 
stop of treatment, date of onset, time to onset (weeks since treatment start) and last date of ADA 
positive results, as well as date of onset, time to onset and last date of nAb positive results, 
confirmed BOR and confirmed BOR date, DOR, PFS time or censoring time and reason for 
censoring, and OS time or censoring time and reason for censoring.  Confirmed BOR will be based 
upon IERC results for the efficacy expansion cohorts and secondary UC cohort and investigator 
results otherwise.  
For the ADA ever-positive subjects by cohort, the percent change from baseline in target lesions 
as well as the first occurrence of a new lesion and subject off treatment will be displayed against 
time point (weeks) in a line plot. Additional symbols will indicate the first and last ADA positive 
result and, if applicable, the first and last nAb positive result. 
16.5.1 
Subset Analysis by IgE 
Anti-avelumab IgE will be assessed in a subset of samples covering ADA results and IgE positive 
and negative subjects from SAF analysis set. This analysis will only be performed for CSRs with 
integration across all dose expansion cohorts. 
A listing of IgE result, ADA result, pre-dose avelumab concentration (mg/L), and IRR status will 
be prepared for each sample tested. Avelumab concentrations, IgE assessments, ADA results, and 


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IRR status will be matched by visit/ dosing date for each subject. IRR status is derived as positive 
or negative if subjects have at least one or no treatment emergent IRR started on the dosing date 
or the following day, respectively. IgE status is derived as negative if the non-missing value is < 
0.1, or positive if the value is ≥ 0.1. A descriptive (count and percentage) summary table will be 
presented for IgE status by IRR status and ADA result, the denominator will be the number of 
samples with valid ADA and IgE results from subjects dosed at the corresponding visit.  
Two scatterplots will be created to graphically display the data, one for IgE results vs. ADA titer, 
and one for IgE results vs. avelumab concentration (µg/mL). ADA results of negative or positive-
TNR, IgE value or avelumab concentration below LLOQ will be set to 0 in the plot. 
17 
Safety Evaluation 
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as AEs, laboratory tests and vital signs. 
All safety analyses will be performed using the SAF, unless otherwise specified. 
All safety parameters will be summarized by cohort(s) and/or pooled across cohorts, depending 
upon the purpose of the reporting. Primary and final analyses for a cohort will include safety data 
summarized by that cohort unless integrated safety analysis is performed on the same data cut. 
17.1 
Adverse Events 
The severity of AEs will be graded using the NCI-CTCAE, version 4.0 except where CTCAE 
grades are missing. No imputation of missing grades will be performed. AEs will be coded 
according to latest available version of MedDRA. AEs of special interest include IRRs and 
immune related adverse events (irAEs), which are detailed in Section 17.1.4 and 17.1.5, 
respectively. 
• Treatment Emergent Adverse Events: TEAEs are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period as defined in Section 11. 
• Related Adverse Events: adverse events with relationship to study treatment (relationship 
with study treatment = related) reported by the investigator and those of unknown relationship 
(i.e. no answer to the question “Relationship with study treatment”). 
• Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF page, 
serious adverse event = yes). 
• Adverse Events Leading to 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 or toxicity grade = 5). 


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• Original Definition Immune Related Adverse Events (irAE): irAEs are identified according 
to a pre-specified search list of MedDRA PTs, documented in a version-controlled repository 
maintained by the Sponsor and finalized for analysis prior to database lock. The original 
definition irAEs are utilized when the process for irAE medical review is either not followed or 
has not yet been completed for the delivery. 
• Updated Definition Immune Related Adverse Events: irAEs according to case definition 
classified by medical review. Details are included in Table 15 in Appendix II. 
• Updated Definition Infusion Related Reaction: IRRs are identified based on a list of 
MedDRA PTs.  The detailed criteria of the timing relationship to infusion are specified in Table 
16 in Appendix II. 
AEs will be summarized using the MedDRA PT as event category and MedDRA primary SOC as 
summary category. All AE tables will be restricted to TEAEs unless otherwise specified. 
Each subject will be counted only once within each PT or SOC and recording period. If a subject 
experiences more than one AE within a PT or SOC for the same recording period, only the AE 
with the strongest relationship or the worst severity, as appropriate, will be included in the 
summaries of relationship and severity. AEs with missing classifications regarding relationship to 
study treatment and start date greater or equal to start of study treatment will be considered as 
related to study treatment. AEs with missing toxicity grade will be counted into ‘any grade’ in the 
summarization by toxicity grade. 
The AE tables will include the number and percentage of subjects with at least one TEAE, by 
MedDRA primary SOC (sorted by decreasing SOC frequencies within the overall column) and by 
PT (sorted by decreasing PT frequencies in overall column within SOC), unless otherwise stated. 
17.1.1 
All Adverse Events 
All AEs will be tabulated in the following tables. 
• The overall summary of AEs table will include the following summaries: 
o TEAEs 
o TEAEs, grade ≥ 3 
o Related TEAEs 
o Related TEAEs, grade ≥ 3 
o TEAEs leading to permanent treatment discontinuation 
o Related TEAEs leading to permanent treatment discontinuation 
o Serious TEAEs  
o Related serious TEAEs 


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o TEAEs leading to death 
o Related TEAEs leading to death 
o Treatment emergent irAEs 
o Related treatment emergent irAEs 
o Treatment emergent IRRs 
o Related treatment emergent IRRs  
• Incidence of TEAEs by SOC, PT, and worst grade 
• Incidence of related TEAEs by SOC, PT, and worst grade 
• Incidence of TEAEs by SOC and PT: displaying in separate columns the All TEAEs / Related 
TEAEs / Grade ≥3 TEAEs / Related Grade ≥3 TEAEs 
• Incidence of TEAEs leading to death by SOC and PT 
• Incidence of related TEAEs leading to death by SOC and PT 
• Incidence of non-serious TEAEs by SOC and PT 
Listing of AEs including all relevant information such as AE SOC/PT, start/stop date, duration of 
AE, toxicity grade, relationship to the study treatment, action taken with study treatment, and 
outcome etc., will be provided. A separate listing of AEs started or worsened after on-treatment 
period will also be provided. 
17.1.2 
Adverse Events Leading to Treatment Discontinuation 
Following summary tables will be produced: 
• Incidence of TEAEs leading to permanent treatment discontinuation by SOC and PT 
• Incidence of related TEAEs leading to permanent treatment discontinuation by SOC and PT  
The listing of AEs leading to permanent treatment discontinuation will also be provided with the 
relevant information such as AE SOC/PT, start/stop date, toxicity grade, and outcome etc.  
17.1.3 
Serious Adverse Events 
Following summary tables will be produced: 
• Incidence of serious TEAEs by SOC and PT 
• Incidence of related serious TEAEs by SOC and PT 
The listings of SAEs will also be provided with the relevant information such as AE SOC/PT, 
start/stop date, toxicity grade, relationship to the study treatment, action taken with study 
treatment, and outcome etc. 


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17.1.4 
Infusion Related Reaction 
IRRs will be summarized by the follow variables: 
• Number of subjects with at least one event by the worst toxicity grade (grade 1/ grade 2/ grade 
3/ grade 4/ grade 5/ missing grade) 
• Number of subjects with IRR leading to permanent treatment discontinuation 
• Time related to first onset (infusion 1/ infusion 2/ infusion 3/ infusion 4 or later).  The events 
should be assigned to the actual drug infusions that the subject received, not to the planned 
dates. An IRR is assigned to a drug infusion if its onset is at the same date (but not before 
dosing) or the following day of drug infusion.   
• Number of subjects with at least one event by the worst toxicity grade that occurred in the 
presence of premedication (grade 1/ grade 2/ grade 3/ grade 4/ grade 5/ missing grade). The 
denominator will be the number of subjects with at least one dose administered in the presence 
of pre-medication. The maximum toxicity will be derived among those IRRs that occurred in 
the presence of premedication. 
• Number of subjects with at least one event by the worst toxicity grade that occurred in the 
absence of premedication (grade 1/ grade 2/ grade 3/ grade 4/ grade 5/ missing grade). The 
denominator will be the number of subjects with at least one dose administered in the absence 
of pre-medication. The maximum toxicity will be derived among those IRRs that occurred in 
the absence of premedication.         
The listing of IRRs will be provided with the relevant information such as AE SOC/PT, start/stop 
date, toxicity grade, relationship to the study treatment, action taken with study treatment, 
outcome, premedication, and study medication batch ID etc. 
17.1.5 
Immune Related Adverse Event 
Treatment emergent irAEs will be summarized using the following variables: 
• The overall summary of treatment emergent irAEs will include the following categories: 
o irAEs 
o Related irAEs 
o irAEs, grade ≥3   
o Related irAEs, grade ≥3 
o irAEs leading to permanent treatment discontinuation 
o Related irAEs leading to permanent treatment discontinuation 
o Serious irAEs  
o Related serious irAEs 


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o irAEs leading to death 
o Related irAEs leading to death 
• Incidence of irAEs by SOC and PT: displaying in separate columns the All irAEs / Related 
irAEs / Grade ≥3 irAEs / Related Grade ≥3 irAEs 
• Incidence of irAEs by SOC and PT and worst grade 
• Incidence of related irAEs by SOC and PT and worst grade  
• Incidence of irAEs leading to permanent treatment discontinuation by SOC and PT  
• Incidence of related irAEs leading to permanent treatment discontinuation by SOC and PT  
• Incidence of irAEs leading to death  
• 
Incidence of related irAEs leading to death  
A listing containing all the PTs used to identify irAEs and a listing containing all the irAEs in the 
study will be generated as well. A separate listing of irAEs started or worsened after on-treatment 
period will also be provided 
17.1.6 
Subgroup Analysis of Adverse Events 
A listing of immunogenicity data and TEAEs will be provided containing subject ID, cohort (if 
more than one included in CSR), age, gender, study treatment start and stop date, all dates with 
positive ADA result, all dates with positive nAb results, preferred term of TEAE, TEAE start date, 
stop date, CTCAE toxicity grade and flags for immune-related adverse event or infusion related 
reaction or reason for permanent treatment discontinuation, as well as ADA status group.  
Only subjects which are pre-existing positive, transient treatment-emergent positive, or persistent 
treatment-emergent positive will be listed. 
17.2 
Deaths 
All deaths will be tabulated and listed for the SAF subjects. The death table will include the 
following information: 
• Number of subjects who died 
o Primary reason for death  
 Disease progression 
 Adverse event related to study treatment  
 Adverse event not related to study treatment  
 Other 
 Unknown 
• Number of subjects who died within 30 days of the last study treatment administration 


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o Primary reason for death  
 Disease progression 
 Adverse event related to study treatment  
 Adverse event not related to study treatment  
 Other 
 Unknown 
• Number of subjects who died within 60 days of the first study treatment administration 
o Primary reason for death  
 Disease progression 
 Adverse event related to study treatment  
 Adverse event not related to study treatment  
 Other 
 Unknown 
The listing of deaths will be provided with all the relevant information such as death date and 
reason for death. The death data will be ascertained from the dedicated Report of Death eCRF 
form. 
17.3 
Clinical Laboratory Evaluation 
Laboratory abnormalities are classified according to NCI-CTCAE toxicity grading version 4.03 or 
based on normal ranges collected from laboratories. The toxicity grading is only related to the lab 
values itself and does not respect the non-numeric information as described in the CTC grading 
definition. CTCAE gradable parameters and associated toxicities are listed in Table 13.  
Table 13  CTCAE Gradable Parameters and Associated Toxicities 
Panel 
Parameter (test) 
Low direction toxicity 
High direction toxicity 
Hematology 
Hemoglobin (HB) 
Anemia 
hemoglobin increased 
 
Leukocytes 
white blood cell decreased 
 
 
Lymphocytes 
lymphocyte count decreased 
lymphocyte count increased 
 
Neutrophils/ 
absolute 
neutrophils 
count (ANC) 
neutrophil count decreased 
 
 
Platelet count (PLT) 
platelet count decreased 
 
Chemistry 
Albumin 
Hypoalbuminemia 
 
 
Alkaline phosphatase (ALP) 
 
alkaline phosphatase increased 
 
Alanine aminotransferase (ALT) 
 
ALT increased 
 
Amylase 
 
serum amylase increased 
 
Aspartate aminotransferase (AST) 
 
AST increased 


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Bilirubin (total) 
 
blood bilirubin increased 
 
Cholesterol 
 
cholesterol high 
 
Creatinine 
 
creatinine increased 
 
Creatinine clearance 
chronic kidney disease 
 
 
Creatine kinase (CPK) 
 
CPK increased 
 
Potassium 
Hypokalemia 
hyperkalemia 
 
Sodium 
Hyponatremia 
hypernatremia 
 
Magnesium  
Hypomagnesemia 
hypermagnesemia 
 
Calcium 
Hypocalcemia 
hypercalcemia 
 
Glucose 
Hypoglycemia 
hyperglycemia 
 
Gamma glutamyl transferase (GGT)  
 
GGT increased 
 
Lipase 
 
lipase increased 
 
Phosphates 
Hypophosphatemia 
 
 
Triglycerides 
 
hypertriglyceridemia 
Coagulation 
Prothrombin time INR 
 
INR increased 
 
Activated Partial thromboplastin time 
(aPTT) 
 
aPTT prolonged 
Grade 1 and 2 hyperglycemia are based on fasting glucose, they will not be graded for this study 
because blood samples are taken from non-fasted subjects. 
For calcium, CTCAE grading is based on corrected calcium and ionized calcium (CALCIO), if 
available. Corrected calcium is calculated from albumin and calcium as follows 
 Corrected calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL) - 4], or  
Corrected calcium (mmol/L) = Calcium (mmol/L) + 0.02 (40 - Serum albumin [g/L]). 
Chronic kidney disease will be graded based on estimated creatinine clearance rate (eCcr, ml/min), 
which is derived using Cockcroft-Gault formula: 
𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= (140 −𝐴𝐴𝐴𝐴𝐴𝐴) × 𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊ℎ𝑡𝑡(𝑘𝑘𝑘𝑘) × 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 (µ𝑚𝑚𝑚𝑚𝑚𝑚/𝐿𝐿)
 
where the constant is 1.23 for men and 1.04 for women. 
The corrected eCcr is derived as: 
 
 
 
Corrected eCcr (ml/min/1.73m2) = eCcr × 1.73 / BSA 
where BSA (body surface area, m2) = ([baseline height (cm) × weight (kg)] / 3600)0.5. 
The following are non-CTCAE gradable parameters collected in this study, their abnormalities are 
assessed as low, high, normal based on the comparison of observed values with normal ranges. 


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• Hematology: hematocrit, red blood cell (RBC), reticulocytes, mean corpuscular hemoglobin 
(MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration 
(MCHC). 
• Serum Chemistry: chlorine, C-reactive protein, lactate dehydrogenase (LDH), total protein, 
total urea, uric acid.  
• Hormone: adrenocorticotropic hormone (ACTH), anti-nuclear antibody (ANA), anti-
neutrophil cytoplasmic antibody (ANCA), rheumatoid factor (RF), free thyroxine (Free T4), 
thyroid-stimulating hormone (TSH). 
Laboratory abnormalities will be summarized using the worst grade during the on-treatment 
period. For these parameters which are graded with two toxicities such as potassium (hypokalemia/ 
hyperkalemia), the toxicities will be summarized separately. Low direction toxicity (eg. 
hypokalemia) grades at baseline and post-baseline will be set to 0 when the variables are derived 
for summarizing high direction toxicity (e.g. hyperkalemia), and vice versa.  
The change and percent change from baseline will be derived for parameters with numeric results. 
17.3.1 
Hematology and Clinical Chemistry Parameters  
CTCAE gradable parameters 
The laboratory toxicities will be tabulated by the worst on-treatment CTCAE grade or the shift of 
CTCAE grade from baseline to worst grade during on-treatment period using descriptive statistics 
(count and percentage). The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary. 
• The worst grade during the on-treatment period will be summarized considering only patients 
with post baseline laboratory samples: Laboratory tests by NCI-CTCAE grade (0, 1, 2, 3, 4, 
and missing).  
• The shift table will summarize baseline CTCAE grade vs. the worst on-treatment CTCAE 
grade (grade = 0, 1, 2, 3, 4, missing).  
Non-CTCAE gradable parameters 
Hematology, chemistry, and hormone evaluations which can’t be graded per CTCAE will be 
summarized as:  
• Shift from baseline value (low, normal, high) to above normal during on-treatment period 
• Shift from baseline value (low, normal, high) to below normal during on-treatment period 
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean, 
SD, median, Q1, Q3, minimum, and maximum) of actual values, absolute changes and percent 
changes from baseline to each visit over time. This summarization will apply to hematology and 
chemistry parameters with numeric results assessed at baseline, post-baseline, discontinuation, end 
of treatment, and/or safety follow-up visits based on visit windows specified in Section 11. 


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The listings (hematology, chemistry, and hormone) will include all the laboratory parameters as 
available in the database with the relevant information such as visit, assessment date, parameter, 
value, normal ranges etc. Listings will be sorted by subject identifier, group variable, parameter, 
assessment date or visit. 
Liver function parameters 
ALT, AST, ALP, and total bilirubin are used individually or together to assess possible drug 
induced liver toxicity. The ratios of test result over upper limit of normal (ULN) for individual test 
or combined tests will be calculated and classified for these parameters during the on-treatment 
period.  
Summary of liver function tests will include the following categories.  The number and percentage 
of subjects with each of the following during the on-treatment period will be summarized by 
cohort, if applicable: 
• AST ≥3*ULN / ≥5*ULN / ≥10*ULN / ≥20*ULN. 
• ALT ≥3*ULN / ≥5*ULN / ≥10*ULN / ≥20*ULN. 
• (ALT or AST)  ≥ 3*ULN/  ≥ 5*ULN/ ≥ 10*ULN/ ≥ 20*ULN 
• Total bilirubin ≥2*ULN 
• Concurrent ALT ≥ 3*ULN and TBILI ≥ 2*ULN 
• Concurrent AST ≥ 3*ULN and TBILI ≥ 2*ULN 
• (ALT or AST) ≥3*ULN concurrently with total bilirubin ≥2*ULN. 
• (ALT or AST) ≥3*ULN concurrently with total bilirubin ≥2*ULN and ALP >2*ULN. 
• (ALT or AST) ≥3*ULN concurrently with total bilirubin ≥2*ULN and (ALP ≤2*ULN or 
missing). 
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, i.e a subject 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 and percentage by cohort.  
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created to 
graphically display 
• 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). 
Listing of subjects with ALT or AST ≥3*ULN or total bilirubin ≥2*ULN will include variables 
subject identifier, visit, date of collection, study day, parameter (ALT, AST, ALP, total bilirubin), 
result, unit, result/ULN, CTCAE grade. 


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17.3.2 
Other Laboratory Parameters  
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected data-fields on the eCRF.  
• Coagulation: aPTT, prothrombin time INR 
• Urinalysis: all urinalysis parameters 
• Other parameters: such as immunology, soluble factor 
• Pregnancy test 
• Serology 
17.4 
Vital Signs 
Summary of vital signs will be based on the SAF. The potentially clinically significant changes 
from baseline as below in vital signs will be derived and summarized with subject incidence and 
percentage during the on-treatment period: 
• ≥ 10% weight increase 
• ≥ 10% weight decreases 
• ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg in systolic blood pressure 
• ≥ 160 mmHg and increased from baseline ≥ 20 mmHg in systolic blood pressure 
• ≤ 45 mmHg and decrease from baseline ≥ 10 mmHg in diastolic blood pressure 
• ≥ 110 mmHg and increased from baseline ≥ 10 mmHg in diastolic blood pressure 
• ≤ 50 bpm and decrease from baseline ≥ 20 bpm in pulse rate 
• ≥ 120 bpm and increase from baseline ≥ 20 bpm in pulse rate 
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean, 
SD, median, Q1, Q3, minimum, and maximum) of actual values, absolute changes and percent 
changes from baseline to each visit based on visit windows specified in Section 11. This 
summarization will apply to weight, blood pressure, respiratory rate, pulse, and temperature 
assessed at baseline, post-baseline, discontinuation, end of treatment, and safety follow-up visits. 
Data listing of all vital signs will be provided with all relevant information such as visit, assessment 
date, parameter, and results. 
17.5 
Other Safety or Tolerability Evaluations 
The incidence and percentage of subjects with potentially clinically significant abnormalities 
(PCSA) for 12-lead ECG parameters will be summarized for scheduled visits during the on-
treatment period based on the SAF. The PCSA criteria are provided in the Table 14. 


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Table 14 
Potentially Clinically Significant Abnormalities Criteria for ECG 
Test 
Potentially Clinically Significant Abnormalities (PCSA) Criteria 
Heart Rate (HR) 
≤ 50 bpm and decrease from baseline ≥ 20 bpm 
≥ 120 bpm and increased from baseline ≥ 20 bpm 
PR Interval 
≥ 220 ms and increase from baseline ≥ 20 ms 
QRS 
 ≥ 120 ms 
QTcF, QTcB absolute 
interval >450 - ≤ 480 ms 
interval >480 - ≤ 500 ms 
interval >500 ms 
QTcF, QTcB change 
from baseline 
Increase from baseline > 30 - ≤ 60 ms 
Increase from baseline > 60 ms 
QT interval will be corrected based on Fridericia’s formula (QTcF= QT/ √𝑅𝑅𝑅𝑅
3
) and RR=60/HR, 
Bazett's formula (QTcB= QT/ √RR) and RR=60/HR, and lineal regression, if possible. The 
correction be linear regression (QTcP) will be performed as: 
• Fit a linear regression model QT = a + b * RR to baseline QT and RR data of the SAF subjects. 
• Use the estimated slope,  
^b , to correct QT 
• Corrected QT will be computed as QTcP = QT + 
^b * (1- RR ) 
Baseline QTcF/QTcB/QTcP will be derived from the visit that QT and HR are flagged as baseline. 
If there are multiple assessments at the same visit and time point, the average will be calculated 
for each parameter and used for the analysis.  
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean, 
SD, median, Q1, Q3, minimum, and maximum) of actual values (with 95% CI of the mean), 
absolute changes from baseline (with 90% CI of the mean) to each visit based on visit windows 
specified in Section 11. This summarization will apply to heart rate, QRS interval, QT interval, 
PR interval, QTcB, and QTcF assessed at baseline, post-baseline, discontinuation, end of 
treatment, and/or safety follow-up visits. 
Listings of 12-lead ECGs will be provided with all relevant information such as visit, date/time of 
assessment, parameter, and results. 
The ECOG shift from baseline to highest on-treatment score will be summarized by cohort based 
on SAF analysis set. Missing category will be included and the number of subjects in each cohort 
will be used as the denominator. 
ECOG performance status will also be presented in a data listing. 
Data of subject status and survival follow-up will be provided in a listing. 


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18 
Reporting Conventions 
• Reporting will require placement of decimals, and this will depend on the raw data collected. 
Generally, mean and median should be displayed one more decimal place than the raw data 
and standard deviation should be displayed two more decimal place than the raw data. 
Percentages will be reported as one decimal place.  
• The rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. E.g. 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. 
• The following conversion factors will be used to convert days to months or years, where 
applicable: 1 month = 30.4375 days and 1 year = 365.25 days. 
• Data listings will be sorted by dose level, subject identifier, visit or date (if applicable), or 
parameters, as appropriate. 
18.1 
Date of Last Contact 
The date of last contact will be derived for patients not known to have died at the analysis cut-off 
using the latest complete date among the following: 
• All patient assessment dates (blood draws (laboratory, PK), vital signs, performance status, 
ECG, tumor assessments) 
• Start and end dates of anti-cancer therapies administered after study treatment discontinuation. 
• AE start and end dates 
• Last date of contact collected on the ‘Subject Status/Survival Follow-up’ eCRF (do not use 
date of survival follow-up assessment unless status is ‘alive’) 
• Study treatment start and end dates 
• Date of discontinuation on disposition eCRF pages (do not use if reason for discontinuation 
is lost to follow-up). 
Only dates associated with actual examinations of the patient will be used in the derivation.  Dates 
associated with a technical operation unrelated to patient status such as the date a blood sample 
was processed will not be used. Assessment dates after the cut-off date will not be applied to derive 
the last contact date. 
18.2 
Incomplete Dates 
Missing or partial start dates for adverse events will be imputed as following: 
• When the start Date of the AE is missing (but Month & Year is available), then the AE date 
will be imputed to the "1st Date of the reported Month" (e.g. if reported date is --/JAN/09, 
imputed date will be 01/JAN/09).  If the reported AE Month = the Month of the First Dosing 
date, then the AE date will be imputed to the "1st Dosing date" (e.g. if AE reported date is --
/JAN/09, and the First doing date is 13/JAN/09, then the AE imputed date will be 13/JAN/09).  


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• When the Date & the Month of the AE is missing (but Year is available), then the AE date 
will be imputed to the "1st Date of the 1st Month of the reported Year" (e.g. if reported date 
is --/--/09, imputed date will be 01/JAN/09). If the reported AE Year = the Year of the First 
Dosing date, then the AE date & month will be imputed to the "1st Dosing date" (e.g. if AE 
reported date is --/--/09, and the First dosing date is 13/APR/09, then the AE imputed date will 
be 13/APR/09).  
• When the date is completely missing, no imputation will be performed and the AE will be 
considered as treatment emergent, unless there is rational to clarify otherwise, eg. AE stop 
date is prior to the first dose date. 
Missing or partial dates for concomitant medications will be imputed as following: 
• If the start day of medication is missing, it will be imputed to the first day of the month; if the 
stop day is missing, it will be imputed to the last day of the month. If both day and month are 
missing, the start date will be imputed as the first day of the year and stop date will be imputed 
as the last day of the year. If the start or stop date is completely missing, no imputation will 
be performed and the determination of pre-medication or post-medication will be based on 
non-missing stop or start date, respectively; otherwise, the medication will be considered as 
concomitant.  
Missing or partial dates for disease history (initial diagnosis date, first occurrence of metastatic or 
locally advanced disease, date of last progression of disease) will be imputed as following: 
• 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. 
Partial dates for prior anti-cancer drug therapies will be imputed as following: 
• If the day is missing, it will be imputed to the first day of the month; if both day and month 
are missing, no imputation will be performed. 
Missing or partial death dates will be imputed based on the last contact date: 
• If the date is missing it will be imputed as day after date of last contact from the CRF survival 
page 
• If the day or 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 
If the day is missing from the date of last contact it will be imputed to 1st day of the month and 
year of last contact only if derived from the survival page. 
No other dates will be imputed. 


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19 
References 
1. Eisenhauer EA. New response evaluation criteria in solid tumours: Revised RECIST 
guideline (version 1.1). Eur J Cancer 2009;45:228-47. 
2. Wolchok et al. Guidelines for the evaluation of immune therapy activity in solid tumors: 
immune-related response criteria. Clin Cancer Res 2009;15(23):7412-20. 
3. Jennison C, Turnbull BW. In: Group Sequential Methods with Applications to Clinical 
Trials. Chapman & Hall/CRC, Boca Raton, 2000. 
4. Brookmeyer R, Crowley J. A Confidence Interval for the Median Survival Time. 
Biometrics 1982;38:29–41. 
5. Kalbﬂeisch JD, Prentice RL. The Statistical Analysis of Failure Time Data, New York: 
John Wiley & Sons 1980. 
 
 
 


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20 
Appendices 
Appendix I 
Important Protocol Deviations 
 
 
Category of 
Protocol 
Deviation 
Description of 
Protocol 
Deviation 
Deviation 
Code 
Protocol 
Section  
Variable [dataset]  
Proposed check / comment  
Inclusion criteria:  
For the subject to 
be eligible for 
inclusion, each 
criterion must be 
checked ‘YES’: 
 
 
 
 
 
 
Criterion1: Signed 
written informed 
consent. 
Eligibility and 
Entry Criteria 
 
Subject did not 
meet inclusion 
criterion 1 (signed 
inform consent 
form). 
PDEV01 
Section 
5.3.1 
DM. RFICDTC 
list if DM. RFICDTC is missing or if 
DM.RFICDTC<Earliest date of SV.SVSTDTC. 
 
Medical Review Required. 
Criterion2: Male or 
female subjects 
aged >=18 years. 
Eligibility and 
Entry Criteria 
 
Subject did not 
meet inclusion 
criterion 2 (age >= 
18 years). 
PDEV02 
Section 
5.3.1 
DM.AGE 
List if DM.AGE<18. 


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Category of 
Protocol 
Deviation 
Description of 
Protocol 
Deviation 
Deviation 
Code 
Protocol 
Section  
Variable [dataset]  
Proposed check / comment  
Criterion3: 
Histologically or 
cytologically 
proven metastatic 
or locally advanced 
solid tumor or 
related prior anti-
cancer therapy.  
Eligibility and 
Entry Criteria 
 
Subject did not 
meet inclusion 
criterion 3 
(histologically or 
cytologically 
proven metastatic 
or locally 
advanced solid 
tumor or prior anti-
cancer therapy for 
metastatic or 
locally advanced 
disease). 
PDEV03 
Section 
5.3.1 
XX.XXDTC where 
XXTESTCD='TBP
ALL'; 
SUPPXX.QNAM(F
RESHDTC, 
FRESHTB), QVAL;   
CM.CMTRT, 
CMINDC 
 
Medical review required or programming. 
 
List if subject did not meet all of the following 
requirements (depending on cohort):                         
A. Tumor tissue is available - 1) there is at least 
one record in XX (XX.XXDTC ne missing where 
XXTESTCD='TBPALL' and XXCAT='TUMOR 
BIOPSY OR BLOCK') for all cohorts or at least 
one  record (missing < XX.XXDTC < TRTSDT 
where XXTESTCD='TBPALL' and XXCAT= 
'UNSCHEDULED TUMOR BIOPSY OR BLOCK') 
for expansion subjects ; or 2) there is at least one 
records in SUPPXX (SUPPXX.QVAL='Y' where 
QNAM= 'FRESHTB') for all cohorts;                          
B. At least one prior anti-cancer therapy for 
NSCLC and ACC subjects - 1) there is at least 
one record in CM where CMCAT='PRIOR ANTI-
CANCER TREATMENT' and CMSCAT='DRUG 
THERAPY' and CMTRT ne missing and 
CMINDC=('METASTATIC', 'LOCALLY 
ADVANCED', 'PALLIATIVE') for subjects where 
ACTARMCD=(MSB_EXP_NSCLC, 
MSB_EXP_ACC);                                                  
C. No prior anti-cancer therapy for first line 
NSCLC subjects: - 1) there is NO record in CM 
where CMCAT='PRIOR ANTI-CANCER 
TREATMENT' and CMSCAT='DRUG THERAPY' 
and CMTRT ne missing and CMINDC= 
('METASTATIC', 'LOCALLY ADVANCED', 
'PALLIATIVE') for subjects where 
ACTARMCD=(MSB_EXP_FLNSCLC).                      


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Category of 
Protocol 
Deviation 
Description of 
Protocol 
Deviation 
Deviation 
Code 
Protocol 
Section  
Variable [dataset]  
Proposed check / comment  
Criterion5: Disease 
must be 
measurable at 
least 1 dimension 
except for CRPC 
or MBC (dose 
escalation).  
Eligibility and 
Entry Criteria  
Subject did not 
meet inclusion 
criterion 5 
(measurable 
disease at least 
one dimension 
except for CRPC 
and escalation 
MBC subjects). 
PDEV04 
Section 
5.3.1 
TR.TRORRES, 
TRTESTCD; 
SUPPTR.QNAM, 
QVAL. 
list if TR.TRORRES is missing or not assessable 
where TRTESTCD=’ SUMDIAM' and TRCAT= 
'RECIST' and SUPPTR.QVAL=’SCREENING’ 
where QNAM=’ASMNTVIS’. Do not check this for 
subjects where SUPPDM.QVAL = ’ CASTRATE- 
RESISTANT PROSTATE CANCER’ where 
QNAM=’COHORT’ or SUPPDM.QVAL=’ DOSE 
ESCALATION AND DLT/MTD COHORTS’ where 
QNAM=’COHORT’ and MHLOC in (‘NIPPLE’ 
‘CENTRAL PORTION OF BREAST’ ‘UPPER-
INNER QUADRANT OF BREAST (UIQ)’ ‘LOWER-
INNER QUADRANT OF BREAST (LIQ)’ ‘UPPER-
OUTER QUADRANT OF BREAST (UOQ)’ 
‘LOWER-OUTER QUADRANT OF BREAST (LOQ)’ 
‘AXILLARY TAIL OF BREAST’ ‘OVERLAPPING 
LESION OF BREAST ‘BREAST, NOS’) 
Criterion9: 
Effective 
contraception for 
both male and 
female subjects if 
the risk of 
conception exists. 
Eligibility and 
Entry Criteria  
Subject did not 
meet inclusion 
criterion 9 
(effective 
contraception). 
PDEV05 
Section 
5.3.1 
 
 Medical review required 
Exclusion criteria:  
For the subject to 
be eligible for 
inclusion, each 
criterion must be 
checked ‘NO’: 
 
 
 
 
 
 
1. Concurrent 
treatment with a 
non-permitted 
drug. 
Eligibility and 
Entry Criteria  
Subject met 
exclusion criterion 
1 (non-permitted 
drug). 
PDEV06 
Section 
5.3.2 
 
Medical review required 


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Category of 
Protocol 
Deviation 
Description of 
Protocol 
Deviation 
Deviation 
Code 
Protocol 
Section  
Variable [dataset]  
Proposed check / comment  
2. Prior therapy 
with any 
antibody/drug 
targeting T cell co-
regulatory proteins.  
Eligibility and 
Entry Criteria  
Subject met 
exclusion criterion 
2 (prior therapy 
with any 
antibody/drug 
targeting T cell co-
regulatory 
proteins). 
PDEV07 
Section 
5.3.2 
 
Medical review required 
3. Concurrent 
anticancer 
treatment, major 
surgery, concurrent 
systemic therapy 
with steroids or 
other 
immunosuppressiv
e agents, or use of 
any investigational 
drug within 28 days 
before the start of 
trial treatment. 
Eligibility and 
Entry Criteria  
Subject met 
exclusion criterion 
3 (concurrent anti-
cancer therapy or 
surgery, 
concurrent 
systemic therapy 
with steroids or 
other),  
PDEV08 
Section 
5.3.2 
 
Medical review required 
4. Previous 
malignant disease 
other than the 
target malignancy 
to be investigated 
in this trial within 
the last 5 years 
with the exception 
of basal or 
squamous cell 
carcinoma of the 
skin or cervical 
carcinoma in situ 
Eligibility and 
Entry Criteria  
Subject met 
exclusion criterion 
4 (previous 
malignant disease 
other than the 
target malignancy 
to be investigated 
in this trial within 
the last 5 years). 
PDEV09 
Section 
5.3.2 
 
Medical review required 
12. Pregnancy or 
lactation period. 
Eligibility and 
Entry Criteria  
Subject met 
exclusion criterion 
12 (pregnancy or 
lactation period). 
PDEV10 
Section 
5.3.2 
PREG.PRRLTCD 
Medical review required. 


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Category of 
Protocol 
Deviation 
Description of 
Protocol 
Deviation 
Deviation 
Code 
Protocol 
Section  
Variable [dataset]  
Proposed check / comment  
Non-permitted 
concomitant 
medication during 
the study 
Concomitant 
Medication 
Criteria  
Subject took 
prohibited 
medication during 
the study. 
PDEV11 
Section 
6.5.2 
CMED.CMTERM 
Medical review required 
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn; 
 
Other Criteria  
Subject became 
pregnant, but 
continued on the 
study. 
PDEV12 
Section 
5.5.2 
LB.LBORRES, 
BTESTCD; 
DS.DSSTDTC,  
DSSCATE; 
 
 
Medical review required. 
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn; 
 
Other Criteria  
Subjects had 
ECOG>=3, did not 
resolved to <=2 by 
day 14 of next 
cycle, and 
continued on the 
study. 
PDEV13 
Section 
5.1.7.2 
and 5.5.2 
XP.XPORRES, 
XPDY; 
DS.DSSTDTC,  
DSSCATE; 
 
 
Medical review required. 
 
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn; 
 
Other Criteria  
Subject developed 
grade 4 AE, but 
continued on the 
study. 
PDEV14 
Section 
5.1.7.2 
and 5.5.2 
ADAE.ATOXGRN, 
TRTEMFL, AREL; 
SDTM.AE.AEACNOT
H; SUPPAE.QVAL, 
QNAM 
 
List if TOXGRN=4 and AREL=’Related’ and 
TRTEMFL=’Y’ and (SUPPAE.QVAL^=’Drug 
Withdrawn’ where QNAM in (ACNMSB, 
ACNMSB3) and  SDTM.AEACNOTH^=’LED TO 
STUDY TERMINATION’) 
 
Subjects that 
developed 
withdrawal criteria 
whilst on the study 
but were not 
withdrawn; 
 
Other Criteria  
Subject developed 
grade 3 AE, but 
continued on the 
study. 
PDEV15 
Section 
5.1.7.2 
and 5.5.2 
ADAE.ASEVN, 
TRTEMFL, 
AEDECOD, 
AEDUR. 
DS.DSSTDTC,  
DSSCATE; 
 
 
Medical review required. 


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Category of 
Protocol 
Deviation 
Description of 
Protocol 
Deviation 
Deviation 
Code 
Protocol 
Section  
Variable [dataset]  
Proposed check / comment  
Subjects 
overdosed 
(>=110%  of  
assigned dose)  
IP Compliance  
Subject was 
overdosed. 
PDEV16 
Medical 
defined. 
ADEXSUM.AVAL 
where 
PARAMACD=’ 
RDOSINT’  or 
‘TRTCMP’ 
list if  
individual or cumulative relative dose intensity 
>=110 
Deviation from 
GCP 
Other Criteria 
GCP deviation 
 
Section 
3.7 
 
Medical review required. 
NA 
Other Criteria 
Other protocol 
deviation 
PDEV99 
Medical 
defined 
 
Medical review required. 


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Appendix II 
Description of the Case Review for Assessment of Immune-Related AEs 
and Definition of Infusion Related Reactions 
In order to thoroughly and consistently analyze potential immune-mediated adverse events (AEs), 
a two-level approach is proposed including: 
1. A MedDRA Preferred Term (PT) query is proposed for each event category (i.e., immune-
mediated rash, colitis, pneumonitis, hepatitis, nephritis and renal dysfunction, 
endocrinopathies and other immune-mediated adverse reactions). 
2. AEs identified by the MedDRA PT queries will then be medically reviewed using 
predefined case definitions for immune-mediated adverse reactions. 
Level 1: 
To identify potentially immune-mediated AEs, the MedDRA PT queries will be used to search for 
AEs of interest in the clinical database. The proposed event categories such as: 
Immune-mediated rash, Immune-mediated colitis, Immune-mediated pneumonitis, Immune-
mediated hepatitis, Immune-mediated nephritis and renal dysfunction, Immune-mediated 
endocrinopathies (Thyroid disorders: Hypothyroidism, Hyperthyroidism, and Thyroiditis), 
Immune-mediated endocrinopathies (Adrenal insufficiency, Immune-mediated endocrinopathies 
(Type 1 Diabetes Mellitus), Immune-mediated endocrinopathies (Pituitary dysfunction), Immune-
mediated endocrinopathies (Hypogonadism), Other immune-mediated adverse events. Further 
details e.g. MedDRA PT queries are regularly updated based on the current MedDRA version. 
In order to standardize the MedDRA PT queries as much as possible, High Level Terms (HLT) 
and Standardized MedDRA Queries (SMQ) were used whenever a choice, that was considered 
reflective of the events of interest, was available. 
Level 2: 
In a second level (medical review), the potential immune-mediated AEs identified from the search 
performed at Level 1, will be reviewed by qualified medical personnel to determine whether the 
AE meets the criteria (case definition) for an immune-mediated adverse reaction based on the 
following algorithm: 
Table 15           Algorithm for immune-related adverse reactions 
 
Criteria 
Description 
Onset 
AE onset after 1st avelumab administration until up to 90 days after last dose 
Duration 
AE does not spontaneously resolve (i.e., without corticosteroids/ immunosuppressant 
treatment) within 7 days after onset 
Immunosuppressive 
therapy 
AE treated with corticosteroid or other immunosuppressant therapy. 
For endocrinopathies only:  AE required hormone replacement* and /or (corticosteroid 
or other immunosuppressive therapy) 


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Etiology 
No other clear etiology or 
Histopathology/biopsy consistent with immune-mediated event 
All criteria listed in the left column need to be fulfilled for an event to meet the case definition of immune-mediated 
reaction. 
*Hormone replacement will be evaluated for specific endocrinopathy disorders only as follows: 
• 
Thyroid disorders (HLT): Thyroid therapy (ATC codes (H03A, H03B)) 
• 
Diabetes mellitus (including hyperglycemia): Insulin (ATC code A10A) 
Infusion related reactions are identified based on a list of MedDRA PTs and criteria on the timely 
relationship according to Table 16. 
Table 16         Criteria for infusion related reactions 
 
Infusion related reactions 
 
Reactions - Considered when onset is on the day of avelumab 
infusion (during or after the infusion) or the day after the 
avelumab infusion (irrespective of resolution date): 
• 
Infusion related reaction 
• 
Drug hypersensitivity 
• 
Anaphylactic reaction 
• 
Hypersensitivity 
• 
Type 1 hypersensitivity 
 
Signs and Symptoms - occurring on the day of avelumab 
infusion (during or after the infusion) and resolved with end 
date within 2 days after onset 
• 
Pyrexia 
• 
Chills 
• 
Flushing 
• 
Hypotension 
• 
Dyspnea 
• 
Wheezing 
• 
Back pain 
• 
Abdominal pain 
• 
Urticaria