Clinical trial NCT03523390
Conditions: Metastatic Solid Tumors
Keywords: Metastatic Solid Tumors Avelumab MSB0010718C
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-04-24; Completion date: 2021-02-08
Enrollment: 24 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study was to evaluate the maximum tolerated dose (MTD) and pharmacokinetics (PK) of Avelumab monotherapy in Chinese subjects.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Avelumab 3 mg/kg Q2W intervention 2: Avelumab 10 mg/kg Q2W intervention 3: Avelumab 20 mg/kg Q2W intervention 4: Avelumab 10 mg/kg QW
Intervention descriptions: intervention 1: Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 3 milligrams per kilogram (mg/kg) once every 2 weeks (Q2W) until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs. intervention 2: Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs. intervention 3: Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 20 mg/kg Q2W until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs. intervention 4: Participants received intravenous infusion of Avelumab over 1 hour duration at a dose of 10 mg/kg every week (QW) for the first 12 weeks followed by once every 2 weeks, started at Week 13 until disease progression, significant clinical deterioration, unacceptable toxicity, or any criterion for withdrawal from the study or from Avelumab occurs.

Protocol documents:
Prot_000.pdf: 
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Phase I/Ib Multiple Ascending Dose Study in China
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Clinical Study Protocol
Clinical Study Protocol Number
MS100070-0035
Title
A Phase I/Ib Study to Evaluate the Safety, Tolerability,
and Pharmacokinetics of Avelumab in Chinese Subjects 
with Locally Advanced Unresectable or Metastatic Solid 
Tumors with Expansion to Selected Indication(s)
Phase
I/Ib
IND Number
Not applicable
EudraCT Number
Not applicable
Coordinating Investigator
 
Tel: 
Fax:
Sponsor
Merck KGaA, Darmstadt, Germany
Medical Responsible:
Merck Serono (Beijing), Pharmaceutical R&D Co. Ltd.
25F NUO Center Office No.2A, Jiangtai Road，
Chaoyang District, Beijing China 100016
People’s Republic of China
Tel.: 
Fax: 
Clinical Study Protocol Version
17 May 2019 / Version 4.0 including amendment 3.0
Replaces Version
23 February 2018 / Version 3.0
- Confidential -
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 © 2019 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures ......................................................................................................8
List of Abbreviations ...........................................................................................................9
1
Synopsis..............................................................................................12
2
Sponsor, Investigators and Study Administrative Structure...............34
2.1
Safety Monitoring Committee............................................................35
3
Background Information.....................................................................35
3.1
Programmed Death Receptor and Ligands.........................................35
3.2
Avelumab............................................................................................36
3.2.1
Safety..................................................................................................36
3.2.2
Pharmacokinetics................................................................................37
3.2.3
Clinical Pharmacodynamics ...............................................................39
3.3
Rationale for the Study.......................................................................39
3.3.1
Rationale for 10 mg/kg Once Weekly Dose-Escalation Cohort.........39
3.4
Summary of Overall Benefit and Risk................................................40
4
Study Objectives.................................................................................41
4.1
Primary Objectives .............................................................................41
4.2
Secondary Objectives .........................................................................41
5
Investigational Plan ............................................................................42
5.1
Overall Study Design and Plan...........................................................42
5.1.1
Overall Study Design..........................................................................42
5.1.2
Investigational Medicinal Product Administration and Schedule ......44
5.1.3
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation .................................................................46
5.2
Discussion of Study Design................................................................47
5.2.1
Study Population.................................................................................48
5.2.2
Avelumab Dose Selection...................................................................48
5.2.3
Rationale for the Primary Endpoints ..................................................48
5.2.4
Rationale for the Secondary Endpoints ..............................................49
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5.2.6
Inclusion of Special Populations ........................................................49
5.3
Selection of Study Population ............................................................49
5.3.1
Inclusion Criteria ................................................................................49
5.3.2
Exclusion Criteria...............................................................................50
5.4
Criteria for Initiation of Study Treatment...........................................53
5.5
Criteria for Subject Withdrawal..........................................................53
5.5.1
Withdrawal from the Study ................................................................53
5.5.2
Withdrawal from the Investigational Medicinal Product ...................53
5.6
Premature Termination of the Study...................................................54
5.7
Definition of End of Study .................................................................55
6
Investigational Medicinal Product and Other Drugs Used in the 
Study...................................................................................................55
6.1
Description of the Investigational Medicinal Product........................55
6.2
Dosage and Administration ................................................................55
6.3
Assignment to Treatment Groups.......................................................57
6.4
Noninvestigational Medicinal Products to be Used............................58
6.5
Concomitant Medications and Therapies ...........................................58
6.5.1
Permitted Medicines and Therapies....................................................58
6.5.2
Prohibited Medicines..........................................................................59
6.5.3
Other Nonpermitted Interventions......................................................60
6.5.4
Special Precautions.............................................................................60
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................61
6.6
Packaging and Labeling of the Investigational Medicinal Product....68
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................68
6.8
Investigational Medicinal Product Accountability.............................69
6.9
Assessment of Investigational Medicinal Product Compliance .........71
6.10
Blinding ..............................................................................................71
6.11
Emergency Unblinding.......................................................................71
6.12
Treatment of Overdose .......................................................................71
6.13
Medical Care of Subjects After End of Study ....................................71
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7
Study Procedures and Assessments....................................................72
7.1
Schedule of Assessments....................................................................72
7.1.1
Clinical Screening...............................................................................72
7.1.2
Treatment Phase..................................................................................73
7.1.3
End-of-Treatment Visit.......................................................................74
7.1.4
Safety Follow-up ................................................................................75
7.1.5
Long-term Follow-up..........................................................................76
7.2
Demographic and Other Baseline Characteristics ..............................76
7.2.1
Demographic Data..............................................................................76
7.2.2
Diagnosis of Tumor............................................................................77
7.2.3
Medical History ..................................................................................77
7.2.4
Other Baseline Assessments...............................................................77
7.4
Safety Assessments.............................................................................80
7.4.1
Adverse Events ...................................................................................81
7.4.2
Pregnancy and In Utero Drug Exposure.............................................86
7.4.3
Clinical Laboratory Assessments .......................................................87
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............88
7.5
Pharmacokinetics................................................................................89
7.5.1
Pharmacokinetic Parameters...............................................................91
7.7
Antidrug Antibody Response .............................................................92
8
Statistics..............................................................................................94
8.2
Randomization....................................................................................94
8.3
Endpoints............................................................................................94
8.3.1
Primary Endpoints ..............................................................................94
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8.3.2
Secondary Endpoints ..........................................................................94
8.3.3
Safety Endpoints.................................................................................94
8.4
Analysis Sets.......................................................................................95
8.5
Description of Statistical Analyses.....................................................95
8.5.1
General Considerations.......................................................................95
8.5.2
Analysis of Primary Endpoints...........................................................95
8.5.3
Analysis of Secondary and Safety Endpoints.....................................96
8.6
Reporting of Planned Analyses ..........................................................99
9
Ethical and Regulatory Aspects..........................................................99
9.1
Responsibilities of the Investigator ....................................................99
9.2
Subject Information and Informed Consent .......................................99
9.3
Subject Identification and Privacy....................................................100
9.4
Emergency Medical Support and Subject Card................................101
9.5
Clinical Study Insurance and Compensation to Subjects .................101
9.6
Independent Ethics Committee/Institutional Review Board ............101
9.7
Health Authorities.............................................................................102
10
Study Management ...........................................................................102
10.1
Case Report Form Handling.............................................................102
10.2
Source Data and Subject Files..........................................................102
10.3
Investigator Site File and Archiving.................................................103
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................104
10.5
Changes to the Clinical Study Protocol............................................104
10.6
Clinical Study Report and Publication Policy ..................................104
10.6.1
Clinical Study Report .......................................................................104
10.6.2
Publication........................................................................................104
11
References Cited in the Text.............................................................106
12
Appendices .......................................................................................108
Appendix I
Signature Pages and Responsible Persons for the Study..................108
Signature Page – Protocol Lead.......................................................................................109
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Signature Page – Coordinating Investigator ....................................................................110
Signature Page – Principal Investigator...........................................................................111
Sponsor Responsible Persons Not Named on the Cover Page ........................................112
Appendix III
Guidance on Contraception ..............................................................118
Appendix IV
Eastern Cooperative Oncology Group Performance Status..............119
Appendix V
Protocol Amendment and List of Changes.......................................120
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Table of In-Text Tables
Table 1-1
Schedule of Assessments for Subjects Receiving Avelumab Once 
Every 2 Weeks....................................................................................19
Table 1-2
Schedule of Assessments for Subjects Receiving Avelumab Once 
a Week for the First 12 Weeks Followed by Once Every 2 Weeks 
(10 mg/kg Once Weekly Cohort) .......................................................25
Table 1-3
Schedule of Assessments – Pharmacokinetic and Antidrug 
Antibody Sampling for Subjects Receiving Avelumab Once Every 
2 Weeks ..............................................................................................30
Table 1-4
Schedule of Assessments - Pharmacokinetic and Antidrug 
Antibody Sampling for Subjects Receiving Avelumab Once a 
Week for the First 12 Weeks Followed by Once Every 2 Weeks 
(10 mg/kg Once Weekly Cohort) .......................................................32
Table 1-5
Schedule of Assessments-Pharmacokinetic and Antidrug 
Antibody Sampling for Retreated Subjects ........................................33
Table 3-1
Main Pharmacokinetic Parameters after First Dose of Avelumab .....38
Table 6-1
Management of Hypersensitivity and Infusion-related Reactions 
Caused by Avelumab..........................................................................62
Table 6-2
Management of Immune-related Adverse Events ..............................63
Table 7-1
Required Laboratory Panel Tests........................................................88
Table 1-2
Schedule of Assessments for Subjects Receiving Avelumab Once 
a Week for the First 12 Weeks Followed by Once Every 2 Weeks 
(10 mg/kg Once Weekly Cohort) .....................................................130
Table 1-3
Schedule of Assessments – Pharmacokinetic and Antidrug 
Antibody Sampling for Subjects Receiving Avelumab Once Every 
2 Weeks ............................................................................................136
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Table of In-Text Figures
Figure 5-1
Schematic of the Study Design for Dose Escalation ..........................42
Figure 5-2
Study Phases per Subject....................................................................44
Figure 5-3
Dose Escalation Algorithm for Doses up to 20 mg/kg of 
Avelumab............................................................................................46
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List of Abbreviations
λz
Terminal elimination rate constant
ADA
Antidrug antibody
ADR
Adverse drug reaction
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC0-∞
Area under the concentration-time curve from zero to infinity
AUC0-t
Area under the concentration-time curve from zero to time t
CI
Confidence interval
Clast
Last quantifiable concentration
Cmax
Maximum concentration
Cmin
Minimum concentration
CR
Complete response
CRA
Clinical Research Associate
CRF
Case report form
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T lymphocyte antigen 4
Ctrough
The concentration observed immediately before next dosing
DCR
Disease control rate
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EOT
End-of-Treatment
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ESCC
Esophageal squamous cell carcinoma
FDA
Food and Drug Administration
FFPE
Formalin-fixed, paraffin-embedded
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
HAHA
Human antihuman antibody
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
irAE
Immune-related adverse event
IRB
Institutional Review Board
IV
Intravenous(ly)
IVRS
Interactive voice response system
LFT
Liver function test
Mb
per megabase
MCC
Merkel cell carcinoma
MMR
Mismatch repair
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
PD
Progressive disease/disease progression
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PK
Pharmacokinetic(s)
PR
Partial response
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable disease
SMC
Safety Monitoring Committee
t1/2
Elimination half-life
T4
Thyroxine
TEAE
Treatment-emergent adverse event
TIL
Tumor infiltrating lymphocyte
TLS
Tumor lysis syndrome
tmax
Time to maximum concentration
TTR
Time to response 
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
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1
Synopsis
Clinical Study Protocol Number
MS100070-0035
Title
A Phase I/Ib Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of Avelumab in Chinese Subjects 
with Locally Advanced Unresectable or Metastatic 
Solid Tumors with Expansion to Selected Indication(s)
Study Phase
I/Ib
IND Number
Not applicable
FDA covered study
No
EudraCT Number
Not applicable
Coordinating Investigator
Sponsor
Merck KGaA, Darmstadt, Germany
Sponsor Legal Representative in 
the European Union
Merck KGaA, Darmstadt, Germany
Study centers/countries
The study will be conducted at approximately 3 sites in 
mainland China.
Planned study period
(first subject in-last subject out)
First subject in: Q1 2018
Last subject out: Q4 2019
Trial Registry
Clinicaltrials.gov
Chinadrugtrials.org.cn
Objectives:
Primary Objectives:
! To evaluate the maximum tolerated dose (MTD) of avelumab (MSB0010718C)
monotherapy in Chinese subjects.
! To characterize the pharmacokinetics (PK) of avelumab in Chinese subjects.
Secondary Objectives:
! To determine the safety and tolerability of avelumab by assessing treatment-emergent 
adverse events (TEAEs) and treatment-related adverse events (AEs) for all dose groups 
according to the National Cancer Institute (NCI)-Common Terminology Criteria for 
Adverse Events (CTCAE) Version (v) 4.03 in Chinese subjects.
! To characterize immunogenicity of avelumab in Chinese subjects.
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Methodology: 
This is a Phase I/Ib, open-label, dose-escalation study.
Dose escalation will be performed at the following 3 dose levels, subjects will receive 
avelumab by intravenous (IV) infusion over 1 hour once every 2 weeks:
! 3 mg/kg
! 10 mg/kg
! 20 mg/kg
The dose escalation uses a modified “3 + 3” design. Thus, 3 or 6 subjects will be enrolled at 
each dose level. 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 (dose-limiting toxicity [DLT] 
observation period). In order to assess the safety of avelumab, a Safety Monitoring Committee
(SMC), responsible for dose escalation decisions, will be established. Safety and tolerability of 
avelumab at a given dose level in Chinese subjects will be confirmed if no DLT observed in 
the first 3 subjects or less than 2 out of 6 subjects in the corresponding dose cohort.
Once the safety of avelumab at 20 mg/kg once every 2 weeks have been established and can 
be regarded as safe (ie, no DLT observed in the first 3 subjects or less than 2 out of 6 subjects 
experience a DLT), a new cohort of 10 mg/kg administered once weekly can be immediately
initiated in 6 evaluable subjects to assess safety of a more frequent dosing. Subjects in this
cohort of 6 evaluable 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 starting at Week 13, once every 
2 weeks thereafter (this cohort will not be subjected to DLT evaluation as a primary endpoint). 
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Planned number of subjects: 
Approximately 21 subjects (up to approximately 24 subjects).
Primary endpoints: 
! Occurrence of DLTs during the DLT observation period (first 21 days of treatment; 
excluding 10 mg/kg once weekly cohort).
! PK profiles in Chinese subjects.
Secondary endpoints:
! Occurrence of TEAEs for all dose groups according to NCI-CTCAE v4.03.
! Occurrence of treatment-related AEs for all dose groups according to NCI-CTCAE v4.03.
! Serum titers of antidrug antibodies (ADA) against avelumab.
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Pharmacokinetics:
! AUC0-t: area under the concentration-time curve from time zero to time t (calculated by 
linear trapezoidal summation).
! AUC0-tau: area under the concentration-time curve from time zero to tau, the respective 
dosing interval, ie, one- or two-week (calculated by linear trapezoidal summation).
! AUC0-∞: area under the concentration-time curve from time zero to infinity (calculated by 
linear trapezoidal summation and extrapolated to infinity using the last quantifiable 
concentration/terminal elimination rate constant [Clast/λz]).
! λz: terminal elimination rate constant. The value of λz is determined from the slope of the 
regression line of log (concentration) versus time.
! Cmax: maximum serum concentration.
! Ctrough: serum concentration observed immediately before next dosing.
! Clast: last quantifiable concentration.
! tmax: time to maximum concentration.
! t1/2: elimination half-life determined as 0.693/λz.
Diagnosis and key inclusion and exclusion criteria:
Key inclusion criteria 
! Signed written informed consent prior to any study-related procedures are undertaken that 
are not part of standard patient management.
! Chinese men or women aged ≥18 years.
! Histologically or cytologically proven locally advanced unresectable or metastatic solid 
tumors, for which no standard therapy exists, or standard therapy has failed.
! Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at study entry.
! Availability of a recently obtained formalin-fixed, paraffin-embedded block containing 
tumor tissue (biopsy from a non-irradiated area within 6 months) or 12 or more unstained 
tumor slides suitable for biomarker detection.
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Key exclusion criteria
! Prior therapy with any antibody/drug targeting T cell coregulatory proteins (immune 
checkpoints) such as programmed death 1 (PD-1), PD-L1, cytotoxic T-lymphocyte 
antigen-4 (CTLA-4), 4-1BB, LAG-3, TIM-3 or anti-CD127.
! Persisting toxicity related to prior therapy (Grade ≥2 NCI-CTCAE v4.03, except Grade < 3 
neuropathy and alopecia of any grade).
! Concurrent anticancer treatment (eg, cytoreductive therapy, radiotherapy [with the 
exception of limited palliative bone-directed radiotherapy], immune therapy, or cytokine 
therapy except for erythropoietin).
! Concurrent immunosuppressive agents (except for corticosteroids at physiologic 
replacement dose, equivalent to ≤10 mg prednisone daily).
! Severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3 NCI-CTCAE v4.03).
! Active brain metastases (except those treated locally and have not been progressing for at 
least 2 weeks after the completion of therapy, with no steroid maintenance therapy required, 
and no ongoing neurological symptoms related to brain localization of the disease).
! Any history of anaphylaxis*, or uncontrolled asthma (ie, 3 or more features of partially 
controlled asthma).
*Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. 
It is characterized by rapidly developing, life-threatening problems (CTCAE Grading 3-5).
Investigational Medicinal Product: dose/ mode of administration/ dosing schedule:
Avelumab will be administered from a starting dose of 3 mg/kg up to a maximum dose of 
20 mg/kg by IV infusion over 1 hour with the regimen of once every week or every 2 weeks
until disease progression, significant clinical deterioration, unacceptable toxicity, or any 
criterion for withdrawal from the study or from avelumab occurs. For the every week regimen 
(6 subjects in the 10 mg/kg once weekly cohort), subjects will receive avelumab every week
for 12 consecutive weeks and then starting at Week 13, once every 2 weeks thereafter.
To mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg 
diphenhydramine and 500 to 650 mg acetaminophen (IV or oral equivalent) is mandatory 
approximately 30 to 60 minutes prior to the first 4 doses of avelumab. Premedication should 
be administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity of prior infusion reactions. This regimen may be modified based on local 
treatment standards and guidelines as appropriate. However, the prophylactic use of systemic 
corticosteroids is not permitted.
Reference therapy: dose/mode of administration/dosing schedule:
Not applicable.
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Planned study and treatment duration per subject:
Subjects will complete the following study phases/visits:
! Clinical Screening, to be completed within 14 days prior to the first administration of 
avelumab.
! Treatment Phase.
! End-of-Treatment (EOT) Visit to be completed within 7 days after the decision to 
discontinue avelumab.
! Safety Follow-up, comprising a Safety Follow-up Visit to be performed 30 days after the 
last dose of avelumab and a phone call 90 days after the last dose of avelumab.
! Long-term Follow-up, with visits to be performed every 12 weeks until 2 years after the last 
subject receives the last dose of avelumab or the last subject dies, whichever comes first. 
Each subject will continue to receive avelumab according to the protocol until:
! disease progression according to RECIST 1.1 assessed by Investigator,
! significant clinical deterioration (clinical progression),
! unacceptable toxicity, or
! any criterion for withdrawal from the study or avelumab, is met.
Subjects may continue avelumab beyond RECIST 1.1-defined disease progression if their 
ECOG performance status has remained stable, there are no new symptoms or worsening of 
existing symptoms, and if, in the opinion of the Investigator, the subject will benefit from 
continued treatment with avelumab.
Subjects receiving avelumab who have experienced a complete response (CR) should be 
treated for a minimum of 12 months and/or until disease progression or unacceptable toxicity, 
after confirmation of response.
If a subject with confirmed CR relapses after stopping treatment, but prior to the end of the 
study, 1 re-initiation of treatment is allowed at the discretion of the Investigator and with the 
agreement of the Sponsor Medical Monitor. Subjects who re-initiate treatment (retreated 
subjects) will stay on the study and be treated and monitored according to the protocol.
Statistical methods:
The sample size estimated for the study is not based on any statistical assumptions. Rather, it 
follows the “3 + 3” rule, a well-established methodology for the design of dose-finding studies
in oncology.
For the primary endpoints, the number and proportion of subjects experiencing DLTs will be 
reported by dose level (excluding 10 mg/kg once weekly cohort). Pharmacokinetic parameters 
will be summarized using descriptive statistics. The point estimate of ORR/median DOR and 
95% CIs will be calculated.
The primary analysis, including all endpoints analyses, for study data will be conducted at the 
time when all subjects complete PK sample collection (including all samples collected if the 
Document No. 
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treatment discontinued earlier than Week 13). The data cutoff time point for primary analysis 
is set at Week 13 (Day 85) of the last subject.
The data from primary analysis will be summarized in the Clinical Study Report (CSR). 
The final analysis of study data will be conducted after End of Study, which is defined as the 
last patient complete 90-day Safety Follow-up Phone Call or last patient died, whichever comes 
first. Additional data from primary analysis up to this cutoff date will be analyzed and presented 
as an addendum of CSR.
Document No. 
Object No. 
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Table 1-1
Schedule of Assessments for Subjects Receiving Avelumab Once Every 2 Weeks
Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Until progression
Within 7 days after decision 
to discontinue IMP3,4
30 days ( ± 5 days) after last 
IMP
Phone Call 90 days 
( ± 5 days) after last IMP
Every 12 weeks ( ± 7 days)5
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Written informed 
consent 
X
Inclusion/exclusion 
criteria
X
Medical history7
X
Demographic data
X
Hepatitis B, hepatitis 
C, and HIV tests
X
Full physical 
examination8
X
X
X
Document No.
Object No.
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Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Until progression
Within 7 days after decision 
to discontinue IMP3,4
30 days ( ± 5 days) after last 
IMP
Phone Call 90 days 
( ± 5 days) after last IMP
Every 12 weeks ( ± 7 days)5
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Symptom-directed 
physical exam8
As indicated throughout the Treatment Phase
Height
X
Vital signs
X
X
X
X
X
X
X
X
2-weekly
X
X
Weight
X
X
X
X
X
X
X
X
2-weekly
X
X
ECOG PS9
X
X9
X
X
X
X
X
X
2-weekly
X
X
Enrolment (if 
eligible)10
X
DLT assessment11
X
X11
12-lead ECG
X
X
X
X
As indicated and decided by Investigator
X
Hematology and 
hemostaseology
X
X
X
X
X
X
X
2-weekly
X
X
Core serum 
chemistry12
X
X
X
X
2-weekly
X
Full serum 
chemistry13
X
X
X
6-weekly
X
Document No.
Object No.
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Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Until progression
Within 7 days after decision 
to discontinue IMP3,4
30 days ( ± 5 days) after last 
IMP
Phone Call 90 days 
( ± 5 days) after last IMP
Every 12 weeks ( ± 7 days)5
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Full urinalysis14
X
X
Basic urinalysis14
X
X
6-weekly
Serum beta-hCG 
pregnancy test (if 
applicable)15
X
Urine pregnancy test 
(if applicable)15
X
X
X
X
4-weekly
X
Premedication21
X
X
X
X
Avelumab
administration
X
X
X
X
X
X
X
2-weekly
Concomitant 
medication and 
procedures22
Collected at each study visit through the 30-day Safety Follow-up Visit
Document No.
Object No.
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CCI
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Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Until progression
Within 7 days after decision 
to discontinue IMP3,4
30 days ( ± 5 days) after last 
IMP
Phone Call 90 days 
( ± 5 days) after last IMP
Every 12 weeks ( ± 7 days)5
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
AE collection23
AEs are collected through the 30-day Safety Follow-up Visit
Treatment-related nonserious AEs are collected until the 90-day Safety Follow-up Phone Call
SAE collection24
All SAEs are documented until the 90-day Safety Follow-up Phone Call
Ongoing SAEs at the 30-day Safety Follow-up Visit will be followed up
Free T4 and TSH
X
X
X
6-weekly
X
X
PK sampling25
See Table 1-3
ADA sampling25
See Table 1-3
Survival26
X
X
X
X
X
X
X
Every visit
X
X
X
X
Further anticancer
therapy26
X
X
X
ADA: antidrug antibody; AE: adverse event; CR: complete response; CT: computed tomography; D: Day; DLT: dose-limiting toxicity; ECG: electrocardiogram; 
ECOG PS: Eastern Cooperative Oncology Group performance status; EOT: End-of-Treatment; hCG: human chorionic gonadotropin; HIV: Human 
immunodeficiency virus; ICF: Informed consent form; IMP: investigational medicinal product; MRI: magnetic resonance imaging; PD: progressive disease; 
PK: pharmacokinetics; PR: partial response; RECIST: response evaluation criteria in solid tumors; SAE: serious adverse event; 
T4: thyroxine; TSH: thyroid-stimulating hormone; V: Visit; W: Week.
Document No.
Object No.
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CCI
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MS100070-0035
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1.
A time window of up to 3 days before or 1 day after the scheduled visit day (- 3/+ 1 days) is permitted for all study procedures (except for PK sampling visits 
on Day 2 and 3, see Table 1-3). The calculation of the dose of avelumab will be based on the weight of the subject determined within 72 hours prior to the day 
of drug administration.
2.
All subjects will have an EOT Visit within 7 days after the decision to discontinue avelumab. In addition, subjects will be followed every 12 weeks ( ± 7 days) 
for survival (including assessment of any further anticancer therapy).
4.
If another anticancer therapy is administered before the end of this 7-day period, the EOT Visit should be conducted prior to the start of this new therapy, if 
possible. The EOT Visit may be performed on the day of the decision to discontinue avelumab.
7.
Medical history should include history of cancer, previous and ongoing medications, previous surgeries, radiotherapies, baseline medical conditions, smoking 
and alcohol history, and family cancer history.
8.
A full physical examination will be conducted at Clinical Screening, at the EOT Visit and at the 30-day Safety Follow-up Visit. During the Treatment Phase, the 
physical examination will be symptom-directed.
9.
If the Clinical Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1/Cycle 1 Day 1.
10. Enrolment will be done after confirmation that the subject meets all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion
(Section 5.3.2). 
11. The observation period for DLTs is the 21-day period after the first administration of avelumab for subjects with data used for implementing the dose-
escalation algorithm for dose determination (the DLT assessment is not applicable for the 6 subjects in 10 mg/kg once weekly cohort).
12. Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin), acute chemistry 
panel (sodium, potassium, chloride, blood urea nitrogen/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.
13. Full chemistry panel and other laboratory studies are detailed in Section 7.4.3. Follicle-stimulating hormone at Clinical Screening, if applicable.
14. Full urinalysis (protein content required, and optional parameters albumin and immunoglobulin G to be tested depending on study site capability) at Clinical 
Screening/baseline, and EOT; basic urinalysis (protein content only) on Days 43 and 85, and then every 6 weeks thereafter prior to administration of 
avelumab. If urinalysis (full or basic) is positive for protein, sediment will be evaluated.
15. In serum at Clinical Screening; in urine thereafter. Results of the most recent pregnancy test should be available prior to next administration of avelumab.
Document No.
Object No.
CCI
CCI
CCI
CCI
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MS100070-0035
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21. Premedication is mandatory approximately 30 to 60 minutes prior to the first 4 doses of avelumab. Premedication should be administered for subsequent 
avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions. This regimen may be modified based on local treatment 
standards and guidelines as appropriate. However, the prophylactic use of systemic corticosteroids is not permitted.
22. Concomitant medications and procedures will be documented at each study visit until the 30-day Safety Follow-up Visit. 
23. All AEs will be documented at each study visit until the 30-day Safety Follow-up Visit. After this visit, only treatment-related nonserious AEs have to be 
documented until the 90-day Safety Follow-up Phone Call. 
24. All SAEs will be documented at each study visit until the 90-day Safety Follow-up Phone Call. After this, all ongoing SAEs must be monitored and followed 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 study 
drug must be reported whenever it occurs, irrespective of the time elapsed since the last administration of avelumab. At 90 days ( ± 5 days) after the last dose 
of avelumab, subjects will be contacted by telephone to collect information on new or ongoing SAEs and treatment-related nonserious AEs.
25. Blood samples for PK and ADA will be collected as detailed in Table 1-3.
26. Subjects will be followed every 12 weeks ( ± 7 days) for survival (including assessment of any further anticancer therapy).
Document No.
Object No.
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CCI
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MS100070-0035
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Table 1-2
Schedule of Assessments for Subjects Receiving Avelumab Once a Week for the First 12 Weeks Followed by 
Once Every 2 Weeks (10 mg/kg Once Weekly Cohort)
Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Written informed 
consent
X
Inclusion/exclusion 
criteria
X
Medical history4
X
Demographic data
X
Hepatitis B, 
hepatitis C and HIV
tests
X
Full physical 
examination5
X
Symptom-directed 
physical exam5
As indicated throughout the Treatment Phase
Height
X
Document No.
Object No.
CCI
CCI
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Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
ECOG PS6
X
X6
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Enrolment (if 
eligible)7
X
12-lead ECG
X
X
X
X
As indicated and decided by Investigator
Hematology and 
hemostaseology
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Core serum 
chemistry8
X
X
X
X
X
X
X
X
X
X
2-weekly
Full serum 
chemistry9
X
X
X
6-weekly
Full urinalysis10
X
Basic urinalysis10
X
X
6-weekly
Serum beta-hCG 
pregnancy test (if 
applicable)11
X
Urine pregnancy 
test (if applicable)11
X
X
X
X
4-weekly
Document No.
Object No.
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Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Premedication17
X
X
X
X
Avelumab
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Concomitant 
medication and 
procedures
Collected at each study visit until the 30-day Safety Follow-up Visit
AE collection18
AEs are collected through the 30-day Safety Follow-up Visit
Treatment-related nonserious AEs are collected until the 90-day Safety Follow-up Phone Call
SAE collection19
All SAEs are documented until the 90-day Safety Follow-up Phone Call
Ongoing SAEs at the 30-day Safety Follow-up Visit will be followed up
Free T4 and TSH
X
X
X
6-weekly
PK sampling20
See Table 1-4
ADA sampling20
See Table 1-4
Survival21
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 
visit
Document No.
Object No.
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CCI
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Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Further anticancer 
therapy21
Collected through Safety Follow-up and Long-term Follow-up
ADA: antidrug antibody; AE: adverse event; CR: complete response; CT: computed tomography; D: Day; DLT: dose-limiting toxicity; ECG: electrocardiogram; 
ECOG PS: Eastern Cooperative Oncology Group performance status; EOT: End-of-Treatment; hCG: human chorionic gonadotropin; HIV: Human 
immunodeficiency virus; ICF: Informed consent form; IMP: investigational medicinal product; MRI: magnetic resonance imaging; PD; progressive disease; 
; PK: pharmacokinetics; PR: partial response; RECIST: response evaluation criteria in solid tumors; SAE: serious adverse 
event; T4: thyroxine; TSH: thyroid-stimulating hormone; V: Visit; W: Week.
1.
A time window of 1 day before or 1 day after the scheduled visit day (- 1/+ 1 days) is permitted for all study procedures while subjects receiving avelumab 
once weekly (12 consecutive weeks). A time window of up to 3 days before or 1 day after the scheduled visit day (- 3/+ 1 days) is permitted for all study 
procedures while subjects receiving avelumab once every 2 weeks (Week 13 and thereafter). The calculation of the dose of avelumab will be based on the 
weight of subject determined within 72 hours prior to the day of drug administration.
2.
Columns of EOT Visit, Safety Follow-up, and the Long-term Follow-up Visits are omitted due to layout readability. The procedures at EOT Visit, Safety 
Follow-up, and the Long-term Follow-up are identical to the procedures planned for subjects receiving avelumab once every 2 weeks (as shown in Table 1-1).
4.
Medical history should include history of cancer, previous and ongoing medications, previous surgeries, radiotherapies, baseline medical conditions, smoking 
and alcohol history, and family cancer history.
5.
A full physical examination will be conducted at Clinical Screening, at the EOT Visit and at the 30-day Safety Follow-up Visit. During the Treatment Phase, the 
physical examination will be symptom-directed.
6.
If the Clinical Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1/Cycle 1 Day 1.
7.
Enrolment will be done after confirmation that the subject meets all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion
(Section 5.3.2). 
Document No.
Object No.
CCI
CCI
CCI
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MS100070-0035
C O N F I D E N T I A L
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8.
Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin), acute chemistry 
panel (sodium, potassium, chloride, blood urea nitrogen/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.
9.
Full chemistry panel and other laboratory studies are detailed in Section 7.4.3. Follicle-stimulating hormone at Clinical Screening, if applicable.
10. Full urinalysis (protein content required, and optional parameters albumin and immunoglobulin G to be tested depending on study site capability) at Clinical 
Screening/baseline, and EOT; basic urinalysis (protein content only) on Days 43 and 85, and then every 6 weeks thereafter prior to administration of 
avelumab. If urinalysis (full or basic) is positive for protein, sediment will be evaluated.
11. In serum at Clinical Screening; in urine thereafter. Results of the most recent pregnancy test should be available prior to next administration of avelumab.
17. Premedication is mandatory approximately 30 to 60 minutes prior to the first 4 doses of avelumab. Premedication should be administered for subsequent 
avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions. This regimen may be modified based on local treatment 
standards and guidelines as appropriate. However, the prophylactic use of systemic corticosteroids is not permitted.
18. All AEs will be documented at each study visit until the 30-day Safety Follow-up Visit. After this visit, only treatment-related nonserious AEs have to be 
documented until the 90-day Safety Follow-up Phone Call. 
19. All SAEs will be documented at each study visit until the 90-day Safety Follow-up Phone Call. After this, all ongoing SAEs must be monitored and followed 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 study 
drug must be reported whenever it occurs, irrespective of the time elapsed since the last administration of avelumab. At 90 days ( ± 5 days) after the last dose 
of avelumab, subjects will be contacted by telephone to collect information on new or ongoing SAEs and treatment-related nonserious AEs.
20. Blood samples for PK and ADA will be collected as detailed in Table 1-4.
21. Subjects will be followed every 12 weeks ( ± 7 days) for survival (including assessment of any further anticancer therapy).
Document No.
Object No.
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CCI
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MS100070-0035
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Table 1-3
Schedule of Assessments – Pharmacokinetic and Antidrug Antibody Sampling for Subjects Receiving 
Avelumab Once Every 2 Weeks
Assessment
Treatment Phase
EOT Visit
Safety 
Follow-up
V1
V2
V3
V4
V7
Until 
Progressi
on
Within 7 days 
after decision to 
discontinue IMP
30 days ( ± 5 
days) after last 
IMP
W1
W1
W1
W2
W3
W5
W7
W13
D1
D2
D3
D8
D15
D29
D43
D85
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
End of 
infusio
n
Prior to 
infusio
n
End of 
infusi
on
PK sampling1
X
X
X
X
X
X
X
X
X
X
X
X
X
6-weekly 
up to W25 
(D169), 
then 12-
weekly
X
X
ADA sampling2
X
X
X
X
X
6-weekly 
up to W25 
(D169), 
then 12 
weekly to 
EOT
X
ADA: antidrug antibody; D: Day; EOT: End-of-Treatment; IMP: investigational medicinal product; PK: pharmacokinetics; V: Visit; W: Week.
1.
For subjects receiving avelumab once every 2 weeks, PK serum samples will be collected at the following time points:
-
Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion.
-
Day 2: 2 samples will be collected 24 and 36 hours after the end of the infusion.
-
Day 3: a single sample will be collected 48 hours after the end of the infusion.
-
Day 8: a single sample will be collected 168 hours after the end of the infusion. 
-
Days 15, 29, 43, 85, 127, and 169 (Week 25): samples will be collected within 2 hours prior to infusion (trough value) and immediately after the 
infusion is completed (peak value).
-
Every 12 weeks beyond Week 25: a single sample will be collected within 2 hours prior to infusion (trough value).
-
EOT Visit.
-
30-day Safety Follow-up Visit.
Document No.
Object No.
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*The time window for PK sampling time points are: + 10 minutes for the end of infusion sample collection on Day 1; ± 10 minutes for 0.5 and 1 hour after 
the end of infusion; ± 20 minutes for 2, 4, and 6 hours after the end of infusion; ± 2 hours for 12, 24, 36, 48, and 168 hours after the end of infusion. The 
time window for PK sampling time points is applicable for all scheduled PK sample collection for all subjects.
2.
For subjects receiving avelumab once every 2 weeks, ADA serum samples will be collected at the following time points:
-
Day 1 (baseline): the baseline sample should be collected within 2 hours prior to the first administration of avelumab, ie, either during Clinical 
Screening or predose on Day 1.
-
Days 15, 29, 43, 85, 127 and 169: samples will be collected within 2 hours prior to infusion.
-
After Day 169, 1 sample (within 2 hours prior to infusion) every 12 weeks until the EOT Visit.
-
30-day Safety Follow-up Visit.
Document No.
Object No.
CCI
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Table 1-4
Schedule of Assessments - Pharmacokinetic and Antidrug Antibody Sampling for Subjects Receiving 
Avelumab Once a Week for the First 12 Weeks Followed by Once Every 2 Weeks (10 mg/kg Once Weekly 
Cohort)
Assessment
Treatment Phase
EOT Visit
Safety 
Follow-up
V1
V2
V3
V5
V7
V13
V14
V16
V19
Until 
Progressi
on
Within 7 days 
after decision to 
discontinue IMP
30 days ( ± 5 
days) after last 
IMP
W1
W2
W3
W5
W7
W13
W15
W19
W25
D1
D8
D15
D29
D43
D85
Day99
Day127
D169
Prior to 
infusio
n
End of 
infusi
on
Prior 
to 
infusi
on
Prior 
to 
infusi
on
Prior 
to 
infusi
on
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
Prior to 
infusio
n
Prior to 
infusio
n
End of 
infusi
on
PK sampling1
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 12 
weeks, 
same as 
Week 5
X
X
ADA sampling2
X
X
X
X
X
X
X
Every 12 
weeks, 
same as 
Week 5
X
ADA: antidrug antibody; D: Day; EOT: End-of-Treatment; IMP: investigational medicinal product; PK: pharmacokinetics; V: Visit; W: Week.
1.
For 6 subjects receiving avelumab once a week, PK serum samples will be collected within 2 hours prior to each infusion at Weeks 1, 2, 3, 5, and 7, 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 30-day Safety Follow-up Visit. 
2.
For 6 subjects receiving avelumab once a week, blood samples for ADA (immunogenicity) analysis will be collected within 2 hours prior to each infusion at 
Weeks 1, 3, 5, 7 (every 2 weeks), at Weeks 13, 19, and 25 (every 6 weeks), and then every 12 weeks while on treatment, and at the 30-day Safety Follow-up 
Visit.
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Table 1-5
Schedule of Assessments-Pharmacokinetic and Antidrug Antibody Sampling for Retreated Subjects 
Assessment for retreated subjects1
Treatment Phase
EOT Visit
V1
V1
V1 or V2
Within 7 days after 
decision 
to 
discontinue IMP
W1
W1
W2
D1
D3
D8
PK sampling2
X
X
ADA sampling3
X
X
ADA: antidrug antibody; CR: complete response; D: Day; ECG: electrocardiogram; EOT: End-of-Treatment; hCG: human chorionic gonadotropin; IMP: investigational 
medicinal product; PD: progressive disease; PK: pharmacokinetics; T4: thyroxine; TSH: thyroid-stimulating hormone; V: Visit; W: Week.
1.
For subjects who achieve a CR on avelumab therapy and subsequently develop PD after stopping therapy prior to the end of the study, one re-initiation of 
treatment at the same dose and schedule is allowed at the discretion of the Investigator and with the agreement of the Sponsor Medical Monitor. To be eligible 
for retreatment, the subject must not have experienced any toxicity that led to discontinuation of the initial avelumab therapy. Prior to retreatment, malignant 
disease must 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 retreatment. The following procedures will be repeated prior to the re-initiation of 
treatment: full physical examination, 12-lead ECG, hematology and hemostaseology, full serum chemistry, full urinalysis, serum beta-hCG pregnancy test (if 
applicable), free T4 and TSH. For other assessments for retreated subjects, please see Table 1-1 or Table 1-2.
2.
PK samples will be collected within 2 hours prior to the first retreatment infusion (predose) on Day 1 and at the EOT Visit.
3.
ADA samples will be collected within 2 hours prior to the first retreatment infusion (predose) on Day 1 and at the EOT Visit.
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2
Sponsor, Investigators and Study Administrative Structure
The Sponsor of this clinical study with avelumab (MSB0010718C) is Merck KGaA, Darmstadt, 
Germany.
This study 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. This will be prepared under the supervision of the Clinical Trial Leader in close 
collaboration with the responsible units at the Sponsor. 
The study will be conducted at approximately 3 enrolling study sites in mainland China. 
The Coordinating Investigator represents all Investigators with respect to decisions and discussions 
regarding this study, consistent with the International Council for Harmonization (ICH) Topic E6 
Good Clinical Practice (GCP; hereafter referred to as ICH GCP). The Coordinating Investigator 
will provide expert medical input and advice relating to the study design and execution and is 
responsible for the review and signoff of the Clinical Study Report.
Signature pages for the Protocol Lead and the Coordinating Investigator, as well as a list of 
Sponsor responsible persons, are provided in Section 12, Appendix I.
The study will appear in the following clinical study registries: clinicaltrials.gov and 
chinadrugtrials.org.cn.
The Sponsor will coordinate the study and will enlist the support of Contract Research 
Organizations (CROs) for some of the study activities. The Sponsor’s Global Clinical Operations 
will perform oversight of the activities performed by the CRO(s).
The Sponsor’s Clinical Trial Supplies department will supply the investigational medicinal product 
(IMP), avelumab, which will be distributed to the study sites by the CRO(s). 
The assignment of subject number and allocation of IMP will be managed by an interactive voice 
response system (IVRS).
Safety laboratory assessments (see Section 7.4.3; except antidrug antibody [ADA] in Table 7-1) 
will be performed locally by the study sites. Pharmacokinetic (PK), pharmacodynamic, ADA 
against avelumab, and biomarker assessments will be performed by central laboratories under the 
responsibility of the Sponsor. 
The Global Patient Safety department of 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 study conduct will be performed by the Development Quality Assurance 
department of Merck KGaA, Darmstadt, Germany. 
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The statistical analyses will be performed by a CRO and supervised by the Sponsor’s Global 
Biostatistics department.
2.1
Safety Monitoring Committee 
To ensure subjects’ safety during the study, a Safety Monitoring Committee (SMC) will review 
the safety data on a regular basis. The SMC consists of permanent members from the Sponsor (eg, 
but not limited to, early development lead, medical lead, and Global Patient Safety representative), 
the Coordinating Investigator as well as of ad hoc members (eg, but not limited to, all participating 
Principal Investigators [as applicable]). During the study, 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 enrolment, 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 
has been completed for all subjects enrolled in this cohort. The SMC may modify the frequency 
of meetings as deemed appropriate by the SMC during the course of the study. 
The membership and specific working procedures of the SMC will be described in an SMC 
Charter, which will be established prior to the start of subject recruitment.
3
Background Information
3.1
Programmed Death Receptor and Ligands
The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1, PD-L2) play major
roles in immune regulation. Expressed on activated T cells, PD-1 is activated by PD-L1 and PD-L2 
expressed by stromal cells, tumor cells, or both, initiating T cell death and localized immune 
suppression (Dong et al 1999; Dong et al 2002; Freeman et al 2000; Topalian et al 2012a),
potentially providing an immune-tolerant environment for tumor development and growth. 
Conversely, inhibition of this interaction can enhance local T cell responses and mediate antitumor 
activity in nonclinical animal models (Dong et al 2002; Iwai et al 2002).
In the clinical setting, treatment with antibodies that block the PD-1–PD-L1 interaction have been 
reported to produce ORRs of 7% to 38% in patients with advanced or metastatic solid tumors, with 
tolerable safety profiles (Hamid et al 2013; Brahmer et al 2012; Topalian et al 2012b). Notably, 
responses appeared prolonged, with durations of 1 year or more for the majority of patients
(Topalian et al 2012b).
The use of immune checkpoint blockade, a class of immune therapy, to inhibit the PD-1/PD-L1 
axis has demonstrated clinical benefit in subjects with advanced non-small cell lung cancer 
(NSCLC), melanoma, renal cell carcinoma, and several other tumor types, but clinical data from 
these studies also indicate that the efficacy of PD-1/PD-L1 blockade may not be limited to these 
specific tumor types.
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3.2
Avelumab
The IMP for the present study is avelumab (MSB0010718C). Avelumab is a fully human 
monoclonal antibody of the immunoglobulin G1 isotype. This anti-PD-L1 therapeutic antibody 
concept is being developed in oncological settings by Merck KGaA, Darmstadt, Germany, and its 
subsidiary, EMD Serono R&D, Billerica, MA, United States.
Avelumab selectively binds to PD-L1 and competitively blocks the interaction between PD-L1 
and its receptors PD-1 and B7.1. This removes the suppressive effects of PD-L1 on antitumor 
CD8+ T cells, resulting in the restoration of cytotoxic T cell response. Compared with anti-PD-1 
antibodies that target T cells, avelumab targets tumor cells and may potentially offer the chance of 
fewer AEs, 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 (Latchman et al 2001).
 
In light of recent data demonstrating the clinical efficacy of an anti-PD-L1 antibody in advanced 
gastric cancer, and given the clinical importance of PD-L1 expression in gastric cancer tumor cells
(Oki et al 2014) and the mode of action of avelumab, avelumab has potential as a therapy for 
patients with various advanced solid tumors. 
Avelumab is currently being evaluated in multiple settings, including the following oncology 
indications: solid tumors, Merkel cell carcinoma (MCC), NSCLC, gastric and gastroesophageal 
junction cancer, metastatic breast cancer, colorectal cancer, castrate-resistant prostate cancer, 
melanoma, ovarian cancer, adrenocortical carcinoma, mesothelioma, urothelial carcinoma, 
bladder and renal cell carcinoma. The ongoing clinical study program for avelumab is described 
in more detail in the most current IB. Please refer to the IB for the most up-to-date information.
3.2.1
Safety
As of 05 November 2015, the safety profile of avelumab has been evaluated based on data from 
more than 1400 subjects in 4 ongoing studies in subjects with various solid tumors: Study
EMR100070-001, Study EMR100070-002 (local Japanese study), Study EMR100070-003 in 
MCC, and Study EMR100070-004 in NSCLC.
Available safety and efficacy data for the avelumab program are discussed in the IB and establish 
a positive benefit-risk ratio for conducting Phase III studies with 10 mg/kg of avelumab. Highlights 
of the safety data relevant to the development of this Clinical Study Protocol are provided below.
Study EMR100070-001 is a global Phase I study mainly conducted in a Western population. As 
of 05 November 2015, 53 subjects had been treated in the dose escalation phase of the study and 
a total of 1300 subjects had been treated in the treatment expansion phase, comprising the 
16 pooled tumor expansion cohorts. All 1353 subjects received at least 1 dose and were
followed-up for at least 4 weeks from the first dose.
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According to the study protocol, the DLT assessment was performed on 19 out of the 53 subjects 
who participated in the 3 + 3 dose escalation algorithm (1 mg/kg [n = 4], 3 mg/kg [n = 3], 
10 mg/kg [n = 6], and 20 mg/kg [n = 6]). None of the subjects treated with doses up to 10 mg/kg 
experienced a DLT, and the 10 mg/kg dose of avelumab was thus considered a safe and 
well-tolerated dose for further investigation in the expansion cohorts. One DLT was observed in 
the 6 subjects who received 20 mg/kg of avelumab. The event, which occurred 18 days after the 
subject received the first 20 mg/kg dose of avelumab, was a Grade 3 immune-related disorder with 
creatine kinase increase, myositis, and myocarditis, considered related to avelumab by the 
Investigator. Avelumab was permanently discontinued and the subject was placed on steroid 
therapy. Within 2 weeks, the elevated creatine kinase level had returned to within the normal range, 
and 23 days after its onset, the event of autoimmune disorder was considered resolved with 
sequelae (right bundle branch block). 
The majority of subjects in the dose expansion cohorts received the proposed treatment dose of 
10 mg/kg of avelumab. The safety data from subjects with different tumor types treated with 
avelumab suggests an acceptable safety profile of the compound. Most of the observed events were 
either in line with those expected in subjects with advanced solid tumors or were similar to class 
effects of monoclonal antibodies blocking the PD-1/PD-L1 axis. Infusion-related reactions 
including 
hypersensitivity 
reactions, 
and 
immune-mediated 
adverse 
reactions 
(eg, hypothyroidism, pneumonitis, hyperthyroidism, arthritis, adrenal insufficiency, autoimmune 
hepatitis, colitis, thyroiditis or myositis) have been identified as important risks for avelumab. 
Study EMR100070-002 is being conducted in Japan only. As of the cutoff date of 
17 December 2015, 17 subjects had been treated in the dose escalation phase with up to 20 mg/kg 
of avelumab once every 2 weeks, and 35 subjects with gastric cancer had been treated in the 
treatment expansion phase at 10 mg/kg once every 2 weeks. At 20 mg/kg every 2 weeks, the 
maximum tolerated dose (MTD) for Japanese subjects has not been exceeded and, to date, no new 
safety concerns have been observed in the gastric expansion cohort. 
Please refer to the most current IB for more details. Based on the available safety data, appropriate 
risk mitigation measures have been implemented in all ongoing clinical studies with avelumab, 
and are included in the current study (see Sections 6.4, 6.5.4, and 6.5.5).
3.2.2
Pharmacokinetics 
Pharmacokinetic assessments have been performed in the ongoing Studies EMR100070-001 and 
EMR100070-002. The results presented in Sections 3.2.2.1 and 3.2.2.2 are based on the data 
available as of 19 May 2015 (EMR100070-001) and 13 October 2014 (EMR100070-002), 
respectively.
3.2.2.1
Study EMR100070-001
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab have 
been characterized in 77 mainly Caucasian subjects treated in the dose escalation and expansion 
cohort of the Phase I Study EMR100070-001 by standard noncompartmental analysis based on 
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rich serum concentration-time data obtained over a complete dosing interval of 2 weeks (= tau). 
The exposure parameters maximum concentration (Cmax) and area under the concentration-time 
curve (AUC) after first dose generally increased in an approximately dose-proportional manner in 
the range from 3 to 20 mg/kg. The concentration at the end of dose interval (Cmin) increased 
proportionally with dose between 10 to 20 mg/kg, but more than proportionally for doses between 
1 to 10 mg/kg. The total systemic clearance was low, 0.37 mL/h/kg ± 0.11 mL/h/kg at the 
10 mg/kg dose (n = 40). 
The terminal half-life (t1/2) increased with dose. However, the average values were 102 hours and 
120 hours for 10 mg/kg and 20 mg/kg doses, respectively, with no significant difference between 
these 2 dose groups. Trough concentrations were obtained for the majority of subjects enrolled in 
the study. The mean ± standard deviation trough concentration at the end of the first cycle for all 
cohorts receiving 80%-120% of the planned 10 mg/kg dose was 21 ± 12 μg/mL (n = 283). This 
median trough concentration increased during subsequent cycles to 25 ± 16 μg/mL (2nd cycle) 
(n = 269), 27 ± 17 μg/mL (3rd) (n = 202), 27 ± 17 μg/mL (4th) (n = 171), 28 ± 19 μg/mL (5th) 
(n = 145), 29 ± 18 μg/mL (6th) (n = 122), 34 ± 18 μg/mL (9th) (n = 81), and 36 ± 18 μg/mL 
(12th cycle) (n = 55). 
3.2.2.2
Study EMR100070-002
A preliminary analysis of the PK data from this Japanese Phase I study was performed based on 
the serum concentration of avelumab obtained from 5 subjects treated with 3 mg/kg, 6 subjects 
treated with 10 mg/kg, and 6 subjects treated with 20 mg/kg following a 1-hour intravenous (IV)
infusion once every 2 weeks.
Although a formal analysis has not been conducted, it is apparent that the preliminary 
concentrations obtained over time and the clearance during the first dosing interval were similar 
in Japanese and Caucasian subjects (Table 3-1). 
Table 3-1
Main Pharmacokinetic Parameters after First Dose of Avelumab
Pharmacokinetic 
Parameter
mean (StD)
Study EMR100070-001 
(Caucasian Subjects)
Study EMR100070-002 
(Japanese Subjects)
3 mg/kg
(n=13)
10 mg/kg
(n=40)
20 mg/kg
(n=21)
3 mg/kg
(n=5)
10 mg/kg
(n=6)
20 mg/kg
(n=6)
Cmax (μg/mL)
82 (22)
301 (102)
489 (140)
65 (14)
182 (35)
462 (61)
Cmin (μg/mL)
3.5 (2.6)
22 (12)
50 (35)
3.4 (2.1)
24 (15)
44 (15)
AUC0-t (μg/mL*h)
6207
(1865)
25785
(7262)
46054
(16153)
5586 
(1422)
21447
(8525)
48263
(11237)
t½ (h)
85 (21)
102 (28)
120 (42)
92 (26)
127 (34)
115 (14)
AUC0-t: area under the concentration-time curve from 0 to last quantifiable concentration; Cmax: maximum 
concentration; Cmin: minimum (trough) concentration; StD: standard deviation; t1/2: terminal half-life.
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3.2.3
Clinical Pharmacodynamics
In vitro target occupancy was measured using flow cytometry on peripheral blood CD3+ T cells 
from 8 healthy volunteers after spiking 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 an unspiked sample. A 50% target occupancy was observed at a 
mean drug concentration ( ± standard deviation) of 0.122 μg/mL ± 0.042 μg/mL, 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 
EMR100070-001 Phase I study (n = 9). For doses of 10 mg/kg, target occupancy was greater than 
90% for these 4 subjects, at Cmin levels ranging between 12.69 and 26.87 μg/mL. Also, at the 
3 mg/kg dose, available target occupancy data for 2 subjects with trough levels ranging from 
4.56 to 6.99 μg/mL, showed greater than 90% target occupancy at trough exposure levels. At the
dose level of 1 mg/kg, 2 out of 3 subjects displayed less than 90% target occupancy at trough 
serum concentrations and 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 
study 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 was insufficient in 3 of the 13 subjects to assure full 
target occupancy; therefore, in order to achieve target saturation during the whole Treatment Phase
in all subjects, the dose of 10 mg/kg once every 2 weeks was selected as the dose for further 
investigation in the Phase Ib expansion cohorts and for subsequent clinical studies. 
3.3
Rationale for the Study
This study is conducted to investigate primarily the tolerability, safety, and PK of avelumab as a 
single agent in Chinese subjects and will be included in the submission for marketing authorization 
in China. In addition, the study will also explore the efficacy of avelumab in Chinese patients with 
locally advanced unresectable or metastatic solid tumor and the correlation between specific 
biomarker and efficacy of avelumab.
3.3.1
Rationale for 10 mg/kg Once Weekly Dose-Escalation Cohort
Avelumab dosing regimen of 10 mg/kg once weekly for the first 12 weeks followed by once every 
2 weeks starting at Week 13 would be evaluated with the following considerations:
! An exposure-efficacy response relationship was observed in second-line NSCLC subjects 
treated with 10 mg/kg once every 2 weeks. In 184 avelumab-treated subjects, unselected for 
PD-L1 expression, ORRs were 8.7%, 10.9%, 19.6%, and 17.4% for increasing quartiles of 
trough concentrations after first dose (Ctroughfirst-dose Q1-4). Using ≥1%, ≥5%, ≥50%, and 
≥80% PD-L1 staining cutoffs, subjects in the upper half of exposure (Ctroughfirst-dose Q3-4 
[n = 92]), had ORRs of 25% (n = 59), 26% (n = 39), 33% (n = 21), and 43% (n = 14), 
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respectively (data on file). The trends of longer progression-free survival (PFS) and OS for 
subjects in the higher exposure quartiles based on steady state trough concentration was also 
seen in the cohorts of urothelial cancer, gastric cancer, and others.
! Population PK analysis and simulation showed that a 10 mg/kg once every week regimen will
increase the exposure, 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 exposure-efficacy analyses described above.
! In the above second-line NSCLC cohort, higher avelumab exposure was associated with a 
modest increase in immune-related AEs (irAEs). For all other AEs analyzed, AE incidence 
appeared to not increase with increasing exposure. And 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). 
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.
3.4
Summary of Overall Benefit and Risk 
 
 
 For further details regarding the dose selection rationale, please refer to the IB. An SMC 
is planned for the ongoing assessment of the risk-benefit ratio (see Section 2.1). The study will be 
discontinued in the event of any new findings that indicate a relevant deterioration of the 
risk-benefit relationship for avelumab and would render continuation of the study unjustifiable.
The primary known identified risks of exposure to avelumab include: 
! Infusion-related reactions.
! Immune-related adverse events (irAEs).
As of 05 November 2015, 3 (0.2%) of the 1300 subjects treated with avelumab in the pooled 
expansion cohort in Study EMR1000070-001 had experienced a Grade 4 infusion reaction; 
therefore, 
already 
implemented 
risk 
mitigation 
measures 
for 
infusion-related 
reactions/hypersensitivity have been extended by a mandatory premedication with histamine-1 
receptor blockers and acetaminophen for all subjects prior to the first 4 infusions of avelumab. 
Premedication with an antihistamine and with paracetamol (acetaminophen) approximately 30 to 
60 minutes prior to the first 4 doses of avelumab is mandatory (eg, 25 to 50 mg diphenhydramine 
and 500 to 650 mg paracetamol [acetaminophen] IV or oral equivalent). Premedication should be 
administered for subsequent avelumab doses based upon clinical judgment and presence/severity 
of prior infusion reactions. This regimen may be modified based on local treatment standards and 
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guidelines, as appropriate. However, the prophylactic use of systemic corticosteroids is not 
permitted.
As noted in Section 3.1, studies with antibodies that block the PD-1–PD-L1 interaction have been 
reported to produce ORRs of 7% to 38% in subjects with advanced or metastatic solid tumors 
(Hamid et al 2013; Brahmer et al 2012; Topalian et al 2012b), with response durations of 1 year 
or more for the majority of subjects (Topalian et al 2012b).
This clinical study will be conducted in compliance with the Clinical Study Protocol, ICH GCP, 
and the applicable national regulatory requirements.
4
Study Objectives
4.1
Primary Objectives
! To evaluate the MTD of avelumab monotherapy in Chinese subjects.
! To characterize the PK of avelumab in Chinese subjects.
4.2
Secondary Objectives
! To determine the safety and tolerability of avelumab by assessing treatment-emergent adverse 
events (TEAEs) and treatment-related AEs for all dose groups according to the NCI-Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 in Chinese subjects.
! To characterize immunogenicity of avelumab in Chinese subjects.
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5
Investigational Plan
5.1
Overall Study Design and Plan
5.1.1
Overall Study Design
This is a Phase I/Ib, open-label, dose-escalation study for MTD evaluation. Additional safety and 
efficacy data may be obtained from the participating patients (Figure 5-1). Results from the current 
study may facilitate the design of expansion study on tumor types of interest to be conducted in 
the future.
Figure 5-1
Schematic of the Study Design for Dose Escalation
DLT: dose-limiting toxicity; PK: pharmacokinetics; Q2W: every 2 weeks; QW: every week; SMC: Safety Monitoring 
Committee.
5.1.1.1
Dose Escalation Design
The dose escalation of this study is based on a modified “3 + 3” cohort design. An initial cohort 
of 3 Chinese subjects with metastatic or locally advanced solid tumors will receive 3 mg/kg of 
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avelumab (IMP) once every 2 weeks. Each of these first 3 subjects will be observed for 21 days
(DLT observation period). The SMC will review the safety data, including DLTs, and advise on 
further escalation to the next cohort (10 mg/kg of avelumab once every 2 weeks). As this study 
represents the introduction of avelumab into a new region, the 3 mg/kg dose has been selected as 
the starting dose, a minus 1 dose level to avelumab 10 mg/kg, as an extra precaution to further 
mitigate risks in Chinese subjects (Figure 5-3).
The 10 mg/kg once every 2 weeks cohort will enroll 6 Chinese subjects with metastatic or locally 
advanced solid tumors. Since more than 1400 subjects have been exposed to avelumab at a dose
of 10 mg/kg once every 2 weeks and it has been well tolerated, it is unlikely that there are ethnic 
differences with respect to avelumab safety and PK; therefore staggered enrolment (3 + 3) will not 
be used for the 10 mg/kg once every 2 weeks cohort and all 6 slots will be opened at the same time 
for competitive recruitment.
After completion of 10 mg/kg once every 2 weeks cohort, the avelumab dose will be further 
escalated up to 20 mg/kg once every 2 weeks to characterize the safety and PK of avelumab at a 
higher dose level. A staggered “3 + 3” enrolment will be used for the 20 mg/kg avelumab cohort. 
Once the safety of avelumab at 20 mg/kg once every 2 weeks have been established and can be 
regarded as safe (ie, no DLT observed in the first 3 subjects or less than 2 out of the 6 subjects 
experience a DLT), a new cohort of 10 mg/kg administered once weekly can be immediately 
initiated to assess safety of already established dose strength with a more frequent dose 
administration. Six (6) evaluable subjects are planned to be included in this cohort. The DLT 
assessment is not applicable for the 6 subjects in the 10 mg/kg once weekly cohort. Subjects in 
this cohort will receive avelumab at 10 mg/kg once weekly for the first 12 weeks. Starting from 
Week 13, dose frequency will be changed to once every 2 weeks. All 6 slots will be opened at the 
same time for competitive recruitment.
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 
has been completed for all subjects enrolled in this cohort (see Section 2.1).
See Section 5.1.2.1.2 and Figure 5-3 for further details of the dose escalation algorithm, and 
Section 5.2.2 for a discussion of the rationale for dose selection.
Subjects will not be replaced unless the subject does not fulfill the requirement for dose 
determination. Dose determination is achieved when the subject receives 2 doses of avelumab at 
the scheduled regimen and completes the minimal 21-day safety observation period (DLT 
observation period) unless they discontinue due to a DLT. For the definition of a DLT, see
Section 7.4.1.1.
The design of the dose escalation is based on Studies EMR100070-001 and EMR100070-002 and 
therefore allows for the ethnic sensitivity of avelumab to be evaluated across studies.
The overall study design is shown in Figure 5-1.
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5.1.1.2
Study Phases for Each Subject
Each subject enrolled in this study will undergo the following study phases/visits: Clinical 
Screening, Treatment Phase, End-of-Treatment (EOT) Visit, Safety Follow-up (30-day Safety 
Follow-up Visit and 90-day Phone Call), and Long-term Follow-up. Further details are provided 
in Figure 5-2 and Section 7.1.
Figure 5-2
Study Phases per Subject
5.1.2
Investigational Medicinal Product
Administration and 
Schedule
The Schedule of Assessment for the study, including the treatment schedule, is provided in Table
1-1 (for all subjects receiving avelumab once every 2 weeks); Table 1-2 (for 6 subjects receiving 
avelumab once a week for the first 12 weeks followed by once every 2 weeks).
5.1.2.1
Avelumab 
Subjects will receive an IV infusion of avelumab (over 1 hour [- 10 minutes/+ 20 minutes, ie, 50 to 
80 minutes]) once every 2 weeks or every week (10 mg/kg once weekly cohort) for the first 12 
weeks, then starting with 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 the day of drug 
administration. The dose of avelumab used for the previous administration can be repeated if the 
change in subject’s weight is < 10% than the weight used for the last dose calculation. If the weight 
change is ≥10%, the intended dose should be recalculated.
In order to mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg 
diphenhydramine and 500 to 650 mg acetaminophen (IV or oral equivalent) is mandatory
approximately 30 to 60 minutes prior to the first 4 doses of avelumab. Premedication should be 
administered for subsequent avelumab doses based upon clinical judgment and presence/severity 
of prior infusion reactions. This regimen may be modified based on local treatment standards and 
guidelines, as appropriate. However, the prophylactic use of systemic corticosteroids is not 
permitted. (See Section 6.4).
Formulation and packaging information for avelumab are provided in Sections 6.1 and 6.6, 
respectively.
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5.1.2.1.1
Avelumab Starting Dose
The starting dose of avelumab in Chinese subjects, ie, subjects in the first dose escalation cohort, 
will be 3 mg/kg.
5.1.2.1.2
Dose Escalation Scheme
Subjects will receive avelumab by IV infusion over 1 hour once every 2 weeks. Dose escalation 
of avelumab will be performed according to the following dose levels, representing a 3.3 or 2 times
increase at each escalation. Each subject will receive a fixed dose of avelumab according to their 
allocated dose level:
! 3 mg/kg
! 10 mg/kg
! 20 mg/kg
The dose escalation criteria are as follows:
For each dose level, DLTs (as defined in Section 7.4.1.1) will be assessed during the 21 days after 
administration of avelumab. The criteria for moving from 3 mg/kg to 10 mg/kg of avelumab is if 
no subject experiences a DLT in the first 3 subjects. No additional 3 subjects will be enrolled. If 1 
out of the first 3 subjects in the 3 mg/kg cohort experiences a DLT, this cohort will be expanded 
to 6 subjects. If ≥2 out of 3 or 6 subjects in the 3 mg/kg cohort experience a DLT, the study will 
be placed on hold. See also Section 2.1.
In the 10 mg/kg once every 2 weeks cohort, 6 slots will be opened at the same time for competitive 
enrolment of 6 subjects. If less than 2 out of the 6 subjects in this cohort experience a DLT, the 
dose of 10 mg/kg will be considered safe in Chinese subjects. If 2 or more subjects experience a 
DLT, the study will be placed on hold.
After completion of the 10 mg/kg once every 2 weeks cohort, the dose of avelumab will be 
escalated to 20 mg/kg once every 2 weeks in order to characterize the safety and PK of avelumab 
at a higher dose level. The criteria for moving from 10 mg/kg to 20 mg/kg of avelumab is if less 
than 2 out of 6 subjects experience a DLT at the 10 mg/kg dose level (once every 2 weeks cohort).
Staggered “3 + 3” enrolment will be used for the 20 mg/kg cohort. If no subject experiences a DLT 
in the first 3 subjects, the avelumab dose level at 20 mg/kg once every 2 weeks will be regarded 
as safe in Chinese subjects; the additional 3 subjects will be enrolled to fill up the cohort for PK 
evaluation, but they will not be subjected to further DLT evaluation.
If 1 subject in the first 3 subjects experiences a DLT (confirmed by SMC only), an additional 
3 subjects will be enrolled. If less than 2 out of the 6 subjects experience a DLT, the dose of 
20 mg/kg will be considered safe in Chinese subjects. If ≥2 out of 3 or 6 subjects experience a 
DLT, the 20 mg/kg cohort will be put on hold (the decision will be made by SMC).
A schematic of the dose escalation algorithm is presented in Figure 5-3.
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Figure 5-3
Dose Escalation Algorithm for Doses up to 20 mg/kg of Avelumab
DLT: dose-limiting toxicity; Q2W: every 2 weeks; QW: every week.
At the conclusion of the 21-day DLT observation period for each cohort (excluding 10 mg/kg once 
weekly cohort), a data review will be conducted. The SMC (including Principal Investigators), is 
responsible for making dose escalation decisions. The SMC will decide whether or not to escalate 
the dose of avelumab to the next level, or whether an interim dose level will be added by reviewing 
the safety data after all subjects of a cohort have completed the DLT observation period (see 
Section 2.1 and SMC Charter).
5.1.3
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation
Dose Modification for Avelumab
Each subject will stay on the avelumab dose level assigned in the study unless the treatment needs 
to be stopped. Dosing modifications (changes in infusion rate) and dose delays are described in 
Sections 6.5.4 and 6.5.5. There will be no dose reductions.
Treatment with avelumab can be skipped for a delay of up to 4 weeks from the previous dose for 
any non-related AEs, laboratory abnormalities, or intercurrent illness, which in the judgment of 
the Investigator warrants delaying the dose of study medication. If dosing is delayed more than 
4 weeks, treatment may be resumed only after consultation with the study Medical Monitor. Any 
delay in dosing in excess of 12 weeks is not permitted.
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5.1.3.1
Adverse 
Drug 
Reactions
Requiring 
Treatment 
Discontinuation or Modifications
The following adverse drug reactions (ADRs) require permanent discontinuation or treatment 
modification of avelumab treatment:
! Any Grade 4 ADRs: permanently discontinue avelumab except for laboratory values out of
normal range that do not have any clinical correlation.
! Any Grade 3 ADRs:
o
Withhold avelumab except for laboratory values out of normal range that do not have 
any clinical correlate.
o
Permanently discontinue avelumab if toxicity does not resolve to Grade ≤ 1 or baseline 
within 12 weeks of last administration or if the same Grade 3 toxicity recurs (consider 
consult with the medical monitor before permanently discontinuing the treatment).
! Infusion should not be given if ECOG performance status is ≥ 3 on the day of study treatment 
administration. Treatment should be discontinued if ECOG performance status has not 
improved to ≤ 2 by the next scheduled treatment administration.
! Any Grade 2 ADRs should be managed as follows:
o
Infusion should not be given in case of ongoing Grade 2 ADR on the day of study 
treatment administration.
o
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 2 doses are 
skipped, treatment may be resumed after consultation with the Medical Monitor.
*Original schedule is defined as “the dosing schedule calculated according to first dose”.
If dosing is delayed more than 4 weeks, treatment may be resumed after consultation with the 
study Medical Monitor. Any delay in dosing in excess of 12 weeks is not permitted.
Infusion-related reactions and irAEs should be handled according to the guidelines provided in
Sections 6.5.5.1 and 6.5.5.2, respectively.
5.2
Discussion of Study Design
Although the MTD of avelumab as a single agent has been evaluated in 2 other Phase I studies 
(the global EMR100070-001 study and the Japanese EMR100070-002 study), the Health 
Authority in China requires that a dedicated study be performed to assess the safety, tolerability,
and PK of avelumab in Chinese subjects. Thus, this Phase I/Ib, open-label, dose-escalation study 
is designed to assess the PK, safety, tolerability, and also exploring efficacy of avelumab in 
Chinese adults with locally advanced unresectable or metastatic solid tumors who have failed 
standard of care or for whom no standard of care exists.
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5.2.1
Study Population
The target population comprises subjects with metastatic or locally advanced unresectable solid 
tumors who fail standard therapy or subjects for whom no standard therapy exists. Candidate tumor 
types in the study may include tumors with known reports of PD-L1 overexpression, such as MCC, 
NSCLC, gastric/gastroesophageal junction cancer, esophageal cancer, urothelial cancer, 
melanoma, castration-resistance prostate cancer, ovarian cancer, head and neck squamous cell 
carcinoma, renal cell carcinoma, adenoid cystic carcinoma, mesothelioma, liver cancer 
(hepatocellular carcinoma and biliary), nasopharyngeal cancer, or other tumor types that are 
considered appropriate by Investigators. 
5.2.2
Avelumab Dose Selection
Two Phase I studies (the global EMR100070-001 study and the Japanese EMR100070-002 study) 
have already evaluated the MTD of avelumab and established the recommended Phase II dose 
(RP2D) of avelumab as a single agent as 10 mg/kg every 2 weeks. The 3 dose levels selected for 
this study (3, 10, and 20 mg/kg of avelumab) are the same as those studied in the 
EMR1000070-001, and -002 studies. At the dose level of 10 mg/kg, avelumab will be evaluated 
in 2 dose regimens: 10 mg/kg once every 2 weeks, and 10 mg/kg every week for 12 weeks, 
followed by transition to once every 2 weeks at Week 13 for the remainder of the treatment period. 
The rationale for the regimen of 10 mg/kg once weekly is described in Section 3.3.1. This will 
allow the safety, tolerability and PK of all 3 dose levels (2 regimens at the level of 10 mg/kg) of 
avelumab to be compared across studies, including with respect to ethnic sensitivity.
Furthermore, within the dose range of 1 mg/kg to 20 mg/kg, avelumab was shown to be well 
tolerated and is deemed to have an acceptable safety profile. In this first study in Chinese subjects 
with solid tumor there is added value in evaluating 20 mg/kg of avelumab with respect to safety 
and tolerability, and hence to provide a margin for the likely RP2D at 10 mg/kg in future 
development. In addition, with 3 dose levels ranging from 3 mg/kg to 20 mg/kg, a more 
informative assessment of the dose-exposure-response relationship may be obtained.
5.2.3
Rationale for the Primary Endpoints
The occurrence of DLTs is considered to be an appropriate endpoint to assess safety and 
tolerability in this dose escalation Phase I study. 
Pharmacokinetic data from approximately 30 Chinese subjects is deemed necessary to meet 
regulatory requirements and will be used for ethnic sensitivity assessment. The PK of avelumab, 
a monoclonal antibody binding to a tumor surface target, may present important features, eg, target 
mediated disposition and nonlinearity. A number of factors, including the dose levels and tumor 
target expression, may also play a role in the PK and 
behavior. 
Pharmacokinetic data will be collected to explore these PK and 
characteristics.
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5.2.4
Rationale for the Secondary Endpoints
Secondary safety and immunogenicity endpoints will be assessed and used to support evaluation 
of the primary endpoints.
5.2.6
Inclusion of Special Populations
Not applicable.
5.3
Selection of Study Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled in this study.
Prior to performing any study assessments that are 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.
5.3.1
Inclusion Criteria
1.
Signed written informed consent.
2.
Chinese men or women ≥18 years of age.
3.
Availability of a recently obtained FFPE block containing tumor tissue (biopsy from a 
non-irradiated area within 6 months) or 12 or more unstained tumor slides suitable for 
biomarker detection (see Section 7.6).
4.
Histologically or cytologically proven locally advanced unresectable or metastatic solid 
tumor, for which no standard therapy exists or standard therapy has failed.
5.
ECOG performance status of 0 or 1 at study entry.
6.
Estimated life expectancy of at least 3 months.
7.
Adequate hematological function as defined below:
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o White blood cell count ≥3 × 109/L
o Absolute neutrophil count ≥1.5 × 109/L
o Lymphocyte count ≥0.5 × 109/L
o Platelet count ≥100 × 109/L
o Hemoglobin ≥90 g/L (may have been transfused).
8.
Adequate liver function as defined below: 
o Total bilirubin ≤1.5 × upper limit of normal (ULN)
o Aspartate aminotransferase (AST) ≤2.5 × ULN 
o Alanine aminotransferase (ALT) ≤2.5 × ULN.
9. Adequate renal function as defined below: 
o Estimated creatinine clearance ≥50 mL/min according to Cockcroft-Gault formula.
10.
Negative blood pregnancy test at Clinical Screening for women of childbearing potential. 
For the purposes of this study, women of childbearing potential are defined as: All female 
subjects after puberty unless they have age-related natural (spontaneous) amenorrhea 
≥12 consecutive months and increased follicle-stimulating hormone (FSH) > 40 mIU/mL,
are surgically sterile, or are sexually inactive.
11.
Highly effective contraception (ie, methods with a failure rate of less than 1% per year) for 
both men and women if the risk of conception exists. See Section 12, Appendix III for further 
guidance on methods of contraception that are considered highly effective.
Note: The effects of avelumab on the developing human fetus are unknown; thus, women of 
childbearing potential and men must agree to use effective contraception, as defined in Section 12, 
Appendix III, or as stipulated in national or local guidelines. Highly effective contraception must 
be used from Clinical Screening, for the duration of the study treatment, and until at least 60 days 
after stopping avelumab. 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
1.
Prior therapy with any antibody/drug targeting T cell coregulatory proteins (immune 
checkpoints) such as PD-1, PD-L1, cytotoxic T-lymphocyte antigen-4 (CTLA-4), 4-1BB, 
LAG-3, TIM-3 or anti-CD127. Prior therapy with a cancer vaccine is acceptable.
2.
Concurrent anticancer treatment(s) (eg, cytoreductive therapy, radiotherapy [with the 
exception of *palliative bone-directed radiotherapy and radiotherapy administered to 
superficial lesions], immune therapy, or cytokine therapy except for erythropoietin). 
Radiation to more than 30% of the bone marrow or with a wide field of radiation should not 
be used within 28 days prior to the first administration of avelumab and is prohibited 
throughout the study.
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*Palliative bone-directed radiotherapy should be within a limited field of radiation and for 
palliation only. It should be a short course, according to local institutional recommendation, and 
should be completed at least 7 days prior to the first administration of avelumab.
3.
Major surgery for any reason, except diagnostic biopsy, within 28 days of the first 
administration of avelumab and/or if the subject has not fully recovered from the surgery 
within 28 days of the first administration of avelumab.
4.
Concurrent use of nonpermitted drug(s) (see Section 6.5.2). 
5.
Rapidly progressive disease (eg, tumor lysis syndrome).
6.
All subjects with active brain metastases, except those meeting the following criteria:
o Brain metastases that have been treated locally, and have not been progressing for at 
least 2 weeks after the completion of therapy, and no steroid maintenance therapy is 
required, AND
o No ongoing neurological symptoms that are related to brain localization of the disease 
(sequelae that are a consequence of the treatment of brain metastases are acceptable).
Note: Subjects with mild residual neurologic deficit that is permanent as a result of prior brain 
metastases after local treatment are eligible provided the residual lesion is stable for at least 
4 weeks and without evidence of enlarging, and the subject is not on steroid therapy.
7.
Previous malignant disease other than the target malignancies to be investigated in this study,
with the exception of in situ carcinoma of the cervix, or adequately treated 
non-melanomatous cancers of the skin, or other malignancy treated at least 5 years 
previously with surgery and/or radiotherapy, and there is no evidence of recurrence since 
that time.
8.
Subjects who have received any investigational product within a period of time that is less 
than the cycle length used for that treatment or equal to 28 days (whichever is shorter) prior 
to the first administration of avelumab.
9.
Prior solid organ or bone marrow transplant.
10.
Significant acute or chronic infections including, for example:
o Uncontrolled acute infection.
o Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome. Subjects who do not know their HIV status are 
required to undergo HIV testing, subject to the provision of informed consent. Subjects 
who do not know their HIV status who are unwilling to undergo HIV testing are not 
eligible for the study (see Section 7.1.1).
o Positive test for hepatitis B virus surface antigen and/or confirmatory hepatitis C virus 
ribonucleic acid (if antihepatitis C virus antibody tested positive); tests to be performed 
at Clinical Screening.
11.
Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent:
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o Subjects with Type I diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible.
o Subjects receiving immunosuppressive agents (such as steroids) for any reason should 
be tapered off these drugs before initiation of avelumab (with the exception of subjects 
with adrenal insufficiency, who may continue corticosteroids at physiologic 
replacement doses, equivalent to ≤10 mg prednisone daily). Subjects who are not 
allowed to taper off immunosuppressive agents should be excluded. Administration of 
steroids for other conditions through a route known to result in a minimal systemic 
exposure (topical, intranasal, intra-ocular, or inhalation) are acceptable.
12.
Previous or ongoing administration of systemic steroids for the management of an acute 
allergic phenomenon is acceptable as long as it is anticipated that the administration of 
steroids will be completed in 14 days, or that the daily dose after 14 days will be ≤10 mg/day 
of prednisone or equivalent.
13.
Known 
severe 
hypersensitivity 
reactions 
to 
monoclonal 
antibodies 
(Grade ≥3 
NCI-CTCAE v4.03), any history of anaphylaxis*, or uncontrolled asthma (that is, 3 or more 
features of partially controlled asthma).
*Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. It is 
characterized by rapidly developing, life-threatening problems (CTCAE Grading 3-5).
14.
Persisting toxicity related to prior therapy (including any prior investigational therapy) of 
Grade ≥2 NCI-CTCAE v4.03 (except < Grade 3 neuropathy and alopecia of any grade).
15.
Pregnancy or lactation.
16.
Known alcohol or drug abuse.
17.
History of uncontrolled intercurrent illness including but not limited to: 
o Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or 
lower), or
o Uncontrolled active infection, or 
o Uncontrolled diabetes (eg, hemoglobin A1c ≥8%).
18.
Clinically significant (that is, active) cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to 
enrolment), unstable angina pectoris, congestive heart failure (New York Heart Association 
Classification Class ≥II), or serious cardiac arrhythmia requiring medication (including 
corrected QT interval prolongation of > 470 msec calculated according to Fridericia and/or 
pacemaker or prior diagnosis of congenital long QT syndrome).
19.
All other significant diseases (eg, inflammatory bowel disease, colitis, pneumonitis, and 
fibrosis), which, in the opinion of the Investigator, might impair the subject’s tolerance of 
avelumab.
20.
Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent or that would limit compliance with study requirements.
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21.
Vaccination within 28 days of the first administration of avelumab and throughout the study
is prohibited, except for administration of inactivated vaccines (eg, inactivated influenza 
vaccines).
22.
Legal incapacity or limited legal capacity.
5.4
Criteria for Initiation of Study Treatment
The inclusion and exclusion criteria will be checked during Clinical Screening. Eligible subjects 
will be enrolled prior to the initiation of avelumab and after verification that the subject fulfils all 
inclusion criteria without meeting any of the exclusion criteria.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from the Study
Subjects are free to discontinue the study at any time without giving their reason(s). Withdrawal 
of consent will be considered withdrawal from the study. In case of withdrawal from the study, the 
assessments scheduled for the last visit (EOT Visit) should be performed, if possible, with focus 
on the most relevant assessments (see Section 7.1.3). In any case, the appropriate EOT electronic 
case report form (eCRF) page must be completed. In case of withdrawal from the treatment, 
subjects will be asked to continue safety and Long-term Follow-up, which includes the collection 
of data on survival and subsequent anticancer therapy. 
A subject must be withdrawn in the event of any of the following:
! Withdrawal of the subject’s consent. If the subject withdraws consent, it must be clearly stated 
if the subject is also withdrawing their consent from the posttreatment follow-up assessments.
! Participation in any other study during the Treatment Phase of this study; however, subjects 
will continue to be followed for survival.
! Lost to follow-up. 
If a subject will have no further study data collected because he/she withdraws from the study 
completely or fails to return for visits, the Investigator must determine the primary reason for the
subject’s withdrawal as completely and accurately as possible and record this information in the 
eCRF page. For a subject who is “lost to follow-up”, the Investigator should show “due diligence” 
by documenting in the source documents the steps taken to contact the subject, eg, dates of 
telephone calls, registered letters, etc. Public records may be assessed to determine vital status 
information (alive/dead) for a subject who is lost to follow-up, as permitted by local laws.
5.5.2
Withdrawal from the Investigational Medicinal Product
The subject must be withdrawn from avelumab administration in the event of any of the following:
! Progressive disease (PD) per RECIST 1.1 assessed by Investigator (Note: Subjects receiving 
avelumab may continue past the initial determination of PD if the subject’s ECOG performance 
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status has remained stable, and if, in the opinion of the Investigator, the subject will benefit 
from continued treatment [see Section 6.2]).
! Significant clinical deterioration (clinical progression) is defined as new symptoms that are 
deemed by the Investigator to be clinically significant or significant worsening of existing 
symptoms.
! 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).
! Unacceptable toxicity:
o Occurrence of any Grade ≥4 ADRs (see Section 5.1.3.1).
o Occurrence of AEs, resulting in the discontinuation of avelumab being desired or 
considered necessary by the Investigator and/or the subject (if applicable).
! Occurrence of pregnancy.
! Use of a nonpermitted concomitant drug, as defined in Section 6.5.2, where the predefined 
consequence is withdrawal from avelumab.
! Withdrawal of the subject’s consent to continue avelumab (if a subject withdraws consent, the 
subject will be asked to continue tumor assessments if RECIST 1.1-defined PD by Investigator 
does not occur).
! Noncompliance (as defined in Section 6.9).
5.6
Premature Termination of the Study
The whole study may be discontinued prematurely in the event of any of the following:
! New information leading to unfavorable risk-benefit judgment of the study drug, eg, due to:
o Evidence of inefficacy* of the study drug.
o Occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions.
o Other unfavorable safety findings*.
*Evidence of inefficacy may arise from this study or from other studies; unfavorable safety 
findings may arise from clinical or nonclinical examinations, eg, toxicology.
! Sponsor’s decision that continuation of the study is unjustifiable for medical or ethical reasons.
! Poor enrolment of subjects making completion of the study within an acceptable time frame 
unlikely.
! Discontinuation of development of the Sponsor’s study drug.
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Should premature termination of the study occur, the subject should be seen as soon as possible 
and the same assessments as required for a prematurely withdrawn subject should be performed, 
as described in Section 7.1.3. The Investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the subject’s 
interest.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
will be informed about the discontinuation of the study in accordance with applicable regulations.
The whole study may be terminated or suspended upon request of the Health Authorities.
5.7
Definition of End of Study
If the study is not terminated for a reason given in Section 5.6, the End of Study is defined as the 
last subject complete 90-day Safety Follow-up Phone Call or the last subject died, whichever 
comes first.
6
Investigational Medicinal Product and Other Drugs Used in 
the Study
The term IMP refers to the investigational drug undergoing a clinical study, as well as to any 
comparator drug or placebo (as applicable). In this study, the IMP is avelumab and no comparator 
drug or placebo is involved.
6.1
Description of the Investigational Medicinal Product
Avelumab is a sterile, clear, and colorless solution intended for IV administration. It is presented 
at a concentration of 20 mg/mL in 
 and sealed 
with an 
.
6.2
Dosage and Administration
Subjects will receive an IV infusion of avelumab over 1 hour (- 10 minutes/+ 20 minutes, ie, over 
50 to 80 minutes) once every 2 weeks or every week for the first 12 weeks, then starting with 
Week 13, once every 2 weeks thereafter.
In order to mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg 
diphenhydramine and 500 to 650 mg acetaminophen (IV or oral equivalent) is mandatory 
approximately 30 to 60 minutes prior to the first 4 doses of avelumab (see Section 6.4).
Premedication should be administered for subsequent avelumab doses based upon clinical 
judgment and presence/severity of prior infusion reactions. This regimen may be modified based 
on local treatment standards and guidelines, as appropriate. However, the prophylactic use of 
systemic corticosteroids is not permitted. Modifications of the infusion rate to be made in the event 
of infusion-related reactions are described in Section 6.5.5.1.
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The starting dose of avelumab is 3 mg/kg (dose escalation according to modified 3 + 3 design up 
to 20 mg/kg is intended). 
The dose of avelumab will be calculated based on the weight of the subject determined within 
72 hours prior to the day of drug administration. The dose of avelumab used for the previous 
administration can be repeated if the change in the subject’s weight is < 10% than the weight used 
for the last dose calculation. Every subject will receive avelumab at the protocol-scheduled dose 
until confirmed progression
by Investigator, significant clinical deterioration (clinical 
progression), unacceptable toxicity, or until they meet any of the protocol-defined criteria for 
withdrawal from the study or from avelumab (see Sections 5.5.1and 5.5.2), or any of the criteria 
in Section 5.6 are met. Dose modification of avelumab (change in infusion rate) is discussed in 
Section 5.1.3.
Treatment with avelumab may be continued despite RECIST 1.1-defined progression at any time, 
if the Investigator considers the subject will continue to receive clinical benefit by continuing 
treatment with avelumab and if the “Criteria for Continuation of Treatment Beyond Progression”
are met.
Criteria for Continuation of Treatment Beyond Progression
! No new symptoms or worsening of existing symptoms.
! Tolerance to avelumab.
! No decrease in ECOG performance status.
! The Investigator does not consider it necessary to administer a salvage therapy.
If disease progression is due to brain metastasis, subjects may continue avelumab treatment after 
the local treatment of the brain lesions provided that the above criteria are met in addition to the 
following and in consultation with the Medical Monitor:
! Brain metastases have been treated locally and are clinically stable for at least 2 weeks prior to 
re-initiation of treatment with avelumab 
! There are no ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
! Subjects must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent).
In addition, if disease progression is mainly due to a metastatic lesion (nodal or visceral) which in 
the opinion of the Investigator may be surgically removed or treated with palliative radiation
therapy, subjects may continue avelumab treatment after the local treatment of such a lesion 
provided that:
! It has been at least 2 weeks (post minor surgery) or 4 weeks (post major surgery) and the subject 
has fully recovered from the surgery.
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! It has been at least 2 weeks since the subject’s last dose of radiation therapy and any toxicity 
related to the radiation therapy is recovered to < Grade 2.
The decision to continue treatment should be discussed with the Medical Monitor and documented 
in the study records. For subjects who continue avelumab beyond RECIST 1.1-defined 
progression. If discontinuation occurs due to progression and a definitive diagnosis/radiographic 
confirmation is not made at the time of discontinuation, a second imaging scan may be allowed 
for confirmation of PD (Confirmed Discontinuation) (see Sections 7.3.3). If PD is not confirmed
and the subject wishes to continue study treatment, this will be allowed provided they meet the 
Criteria for Continuation of Treatment Beyond Progression. Monitoring should continue according 
to the Schedule of Assessment (Table 1-1 and Table 1-2). Treatment with avelumab should be 
stopped immediately if the subject does not tolerate avelumab anymore, or if therapeutic failure 
occurs.
Subjects receiving avelumab who have experienced a CR should be treated for a minimum of 
12 months and/or until disease progression or unacceptable toxicity, after confirmation of 
response. 
For subjects who achieve a confirmed CR on avelumab and subsequently develop PD after 
stopping therapy, but prior to the End of Study (defined in Section 5.7), 1 re-initiation of treatment 
at the same dose and schedule is allowed at the discretion of the Investigator and with the 
agreement of the Sponsor Medical Monitor (retreated subjects). To be eligible for retreatment, the 
subject must not have experienced any toxicity that led to discontinuation of the initial avelumab 
therapy (see Section 5.5.2). Prior to retreatment, malignant disease must 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 also be available and verified prior to 
retreatment. Retreated subjects will stay on the study and be treated and monitored according to 
the Clinical Study Protocol.
6.3
Assignment to Treatment Groups
Once the subject has provided the signed ICF(s) and has been determined to meet inclusion and 
exclusion criteria, the Investigator or their delegate will assign a unique Subject Identifier Number 
and request the study treatment assignment by using the IVRS. Subject Identifiers will comprise 
17 digits, the first 10 digits representing the Study Number, the next 3 digits representing the Site 
Number, and the last 4 digits representing the Subject Number, which will be allocated 
sequentially starting with 0001. Once the Subject Number is assigned, it must not be reused for 
any other subject and the Subject Number for that individual must not be changed, even if the 
subject undergoes re-testing of laboratory parameters that do not meet the inclusion criteria during 
the 14-day Clinical Screening window (see Section 7.1.1).
If the subject fails to be started on treatment for any reason, the reason and the subject’s 
demographic information should be collected. Other information, such as the reason for not 
starting treatment, the corresponding eCRF sections should be completed (see Section 7.1.1.1).
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The following IMP allocation will be managed manually by Investigator, who assesses how many 
vials needed for a subject and pick up themselves. The vial number is linked via the GMP qualified 
system to the corresponding treatment as well as to the subject.
6.4
Noninvestigational Medicinal Products to be Used
In order to mitigate infusion-related reactions, a premedication regimen of 25 to 50 mg 
diphenhydramine and 500 to 650 mg acetaminophen (IV or oral equivalent) is mandatory 
approximately 30 to 60 minutes prior to the first 4 doses of avelumab. This regimen may be 
modified based on local treatment standards and guidelines, as appropriate. However, the 
prophylactic use of systemic corticosteroids is not permitted.
Infusion of avelumab will be stopped in case of Grade ≥2 infusion-related, allergic, or 
anaphylactic reactions. Following avelumab infusion, subjects must be observed for 2 hours after 
the infusion for potential infusion-related reactions.
If an allergic reaction occurs, the subject must be treated according to the best available medical 
practice. Guidelines for the management of infusion-related reactions are provided in
Section 6.5.5.1. Subjects should be instructed to report any delayed reactions to the Investigator
immediately.
6.5
Concomitant Medications and Therapies
6.5.1
Permitted Medicines and Therapies
Any medications (other than those excluded by the Clinical Study Protocol) considered necessary 
for the subjects’ welfare and which will not interfere with avelumab may be given at the 
Investigator’s discretion.
The Investigator will record all concomitant medications taken by the subject during the study, 
from the date of signature of informed consent, in the appropriate section of the eCRF.
Medications other than those specifically excluded in this study (see Section 6.5.2) may be 
administered for the management of symptoms associated with the administration of avelumab as 
required. These might include analgesics, antinausea medications, antihistamines, diuretics, 
antianxiety medications, and medications for pain management, including narcotic agents.
Any additional concomitant therapy that becomes necessary during the study and any change to 
existing concomitant drugs must be recorded in the corresponding section of the eCRF, noting the 
name, dose, duration, and indication of each drug.
Palliative bone-directed radiotherapy (eg, local radiotherapy for analgesic purposes or for lytic 
lesions at risk of fracture) may be administered during the study. The assessment of PD will be 
made according to RECIST 1.1 (Section 12, Appendix II) and not based on the necessity for 
palliative bone-directed radiotherapy. Bone-directed radiotherapy should be within a limited field 
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of radiation and for palliation only; the course should be short, according to local institutional 
recommendation.
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions, or anticipated emergency situations.
6.5.2
Prohibited Medicines
As stated in the exclusion criteria (Section 5.3.2), subjects must not have had prior therapy with 
any antibody or drug targeting T cell coregulatory proteins (immune checkpoints) such as PD-1, 
PD-L1, CTLA-4, 4-1BB, LAG 3, TIM 3 or anti-CD127, or concurrent anticancer treatment (eg, 
cytoreductive therapy, radiotherapy [with the exception of palliative bone-directed radiotherapy, 
and radiotherapy administered to superficial lesions], immune therapy, or cytokine therapy except 
for erythropoietin), major surgery (excluding prior diagnostic biopsy), concurrent systemic therapy 
with steroids or other immunosuppressive agents, or use of any investigational drug within 28 days 
before the start of study treatment.
In addition, the following treatments must not be administered during the study:
! Immunotherapy, immunosuppressive drugs, ie, chemotherapy or systemic corticosteroids 
except:
o
When required for the treatment of irAEs or infusion-related reactions / 
hypersensitivity.
o
Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or 
equivalent.
o
Systemic corticosteroids for management of patients with allergy to CT Intravenous
Radiographic Contrast Media.
! Any vaccine therapies for the prevention of infectious disease (eg, seasonal influenza vaccine, 
human papilloma virus vaccine) except administration of the inactive vaccine.
! Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony 
stimulating factor). Exception: erythropoietin and darbepoetin alpha may be prescribed at the 
Investigator’s discretion.
If the administration of a nonpermitted concomitant drug becomes necessary during the study, the 
subject will be withdrawn from treatment with avelumab (see Section 5.5.2). The Sponsor may be 
contacted to discuss whether avelumab must be discontinued.
6.5.2.1
Clarification of Corticosteroid Use
Data indicate that corticosteroids may inhibit and interfere with T cell function (Schleimer et al 
1984; Khan 2008). Furthermore, as with all immunotherapies intended to augment cell-mediated 
immunity, there is a risk that concomitant immunosuppressive agents such as corticosteroids will 
counteract the intended benefit. However, studies with anticytotoxic T-lymphocyte antigen-4 
compounds indicate that short-term use of steroids can be employed without compromising 
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clinical outcomes (Weber et al 2012). Therefore, the use of corticosteroids during this study is 
restricted as follows:
! Therapeutic use: limited to the treatment of infusion-related reactions and short-term treatment 
of irAEs. The course of corticosteroid treatment should be completed as soon as clinically 
feasible and before resuming the next cycle of avelumab provided the event has resolved to a 
Grade 1 or less.
! Physiologic use: replacement for adrenal insufficiency at doses equivalent to ≤10 mg 
prednisone daily are acceptable.
! Prophylactic use: prophylactic use, eg, for the prevention of acute infusion-related reactions,
constitutes concomitant use and is prohibited.
6.5.3
Other Nonpermitted Interventions
The following nondrug therapies must not be administered during the study:
! Radiotherapy (except for palliative bone-directed radiotherapy [see Sections 5.3.2 and 6.5.1] or 
radiotherapy administered to superficial lesions).
! Herbal remedies with immunostimulating properties (eg, mistletoe extract) or known to 
potentially interfere with major organ function (eg, hypericin).
! Traditional Chinese medicine that has an approved indication in treating cancer from the China 
Food and Drug Administration.
6.5.4
Special Precautions
As a routine precaution, subjects enrolled in this study must be observed for 2 hours after the
infusion of avelumab in an area with resuscitation equipment and emergency agents. At all times 
during study 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 1:1000 
dilution or equivalents should always be available along with equipment for assisted ventilation.
Please also refer to Section 6.4.
Infusion of avelumab will be stopped in case of ≥Grade 2 hypersensitivity, inflammatory
response, or anaphylactic reaction. The treatment recommendations for infusion-related reactions, 
according to the NCI are outlined in Section 6.5.5.1. All infusion-related reactions occurring 
during the infusion of avelumab or within 2 hours after completion of the administration of 
avelumab should be reported as irAEs.
Investigators should also monitor subjects closely for potential irAEs, which may 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.
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6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
6.5.5.1
Infusion-related Reactions
In order to mitigate infusion-related reactions, patients have to be premedicated with an 
antihistamine and with paracetamol (acetaminophen) prior to the first 4 infusions of avelumab. 
Premedication should be administered for subsequent avelumab doses based upon clinical 
judgment and presence/severity of prior infusion reactions.
Management of infusion-related reactions should follow guidelines set forth in Table 6-1.
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Table 6-1
Management of Hypersensitivity and 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 avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2: Moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
nonsteroidal antiinflammatory drug, narcotics, 
intravenous fluids); prophylactic medications indicated 
for ≤24 hours
!
Temporarily discontinue avelumab infusion
!
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity and monitor closely 
for any worsening.
Grade 3 or Grade 4: Severe or Life-threatening 
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae
Grade 4: Life-threatening consequences; urgent 
intervention indicated
!
Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject
!
Subjects have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment.
NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Events.
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for the next scheduled infusion. If no infusion-
related reaction is observed in the next scheduled infusion the infusion rate may be returned to 
baseline at the all subsequent infusions. If an infusion reaction occurs, all details about drug 
preparation and infusion must be recorded.
Subjects should be instructed to report any delayed reactions to the Investigator immediately.
Additional Modification for Subjects with Grade 2 Infusion-related Reactions
If, in the event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 6-1 (including reducing the infusion rate 
by 50%), the Investigator may consider treatment with corticosteroids and the infusion should be 
stopped for that day. At the next cycle, the Investigator may consider the addition of H2-blocker 
antihistamines (eg, famotidine or ranitidine), meperidine or ibuprofen in addition to the mandatory 
premedication, for selected subjects. However, prophylactic steroids are NOT permitted (please 
refer to Section 6.5.2.1). 
6.5.5.2
Immune-related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment of irAEs is 
mainly dependent upon severity (ie, 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).
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! Grade 3 to 4: treat with high-dose corticosteroids.
Treatment of irAEs should follow the guidelines provided in Table 6-2.
Table 6-2
Management of Immune-related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis 
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1
Diarrhea: < 4 stools/day over 
baseline
Colitis: asymptomatic
Continue avelumab therapy
Symptomatic treatment (eg, 
loperamide)
Close monitoring for worsening 
symptoms
Educate subject to report worsening 
immediately
If worsens: treat as Grade 2, 3, or 4
Grade 2
Diarrhea: 4 to 6 stools per day over 
baseline; iv fluids indicated 
< 24 hours; not interfering with 
activities of daily living
Colitis: abdominal pain; blood in 
stool
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade ≤1: resume 
avelumab therapy
If persists > 5 to 7 days or recurs:
treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): ≥7 stools per 
day over baseline; incontinence; iv
fluids ≥24 hours; interfering with 
activities of daily living
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, 
perforation
Withhold avelumab for Grade 3
Permanently discontinue avelumab 
for Grade 4 or recurrent Grade 3
1.0 to 2.0 mg/kg/day prednisone iv
or equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consider lower endoscopy
If improves:
Continue steroids until Grade ≤1, 
then taper over at least 1 month, 
resume avelumab therapy following 
steroids taper (for initial Grade 3)
If worsens, persists > 3 to 5 days or 
recurs after improvement:
add infliximab 5 mg/kg (if no 
contraindication)
Note: infliximab should not be used 
in cases of perforation or sepsis
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering ≤30% body surface area
Continue avelumab therapy
Symptomatic therapy (eg,
antihistamines, topical steroids)
If persists > 1 to 2 weeks or recurs:
Withhold avelumab therapy
Consider skin biopsy
Consider 0.5 to 1.0 mg/kg/day 
prednisone or equivalent Once 
improving, taper steroids over at 
least 1 month, consider prophylactic 
antibiotics for opportunistic 
infections, and resume avelumab 
therapy following steroids taper
If worsens: treat as Grade 3 to 4
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Grade 3 to 4
Grade 3: Covering > 30% body 
surface area; 
Grade 4: Life-threatening 
consequences
Withhold avelumab for Grade 3.
Permanently discontinue for Grade 
4 or recurrent Grade 3
Consider skin biopsy
Dermatology consult
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade 1:
Taper steroids over at least 
1 month; resume avelumab therapy
following steroids taper (for initial 
Grade 3)
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only
Consider withholding avelumab 
therapy
Monitor for symptoms every 2 to 
3 days
Consider Pulmonary and Infectious 
Disease consults
Re-assess at least every 3 weeks
If worsens: 
treat as Grade 2 or Grade 3 to 4
Grade 2
Mild to moderate new symptoms
Withhold avelumab therapy
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consider bronchoscopy, lung biopsy
Re-assess every 1 to 3 days
If improves: 
When symptoms return to 
Grade ≤1, taper steroids over at 
least 1 month, and then resume 
avelumab therapy following steroids 
taper
If not improving after 2 weeks or 
worsening: treat as Grade 3 to 4
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4: life-threatening
Permanently discontinue avelumab 
therapy
Hospitalize
Pulmonary and Infectious Disease 
consults
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consider bronchoscopy, lung biopsy
If improves to Grade ≤1: 
taper steroids over at least 1 month
If not improving after 48 hours or 
worsening: 
add additional immunosuppression 
(eg, infliximab, cyclophosphamide, 
iv immunoglobulin, or 
mycophenolate mofetil)
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and/or total bilirubin > ULN to 
1.5 x ULN
Continue avelumab therapy
Continue liver function monitoring 
If worsens: treat as Grade 2 or 3 to 
4
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Grade 2
AST or ALT > 3.0 to ≤5 × ULN 
and/or total bilirubin > 1.5 to ≤3 × 
ULN
Withhold avelumab therapy 
Increase frequency of monitoring to 
every 3 days
If returns to Grade ≤1:
Resume routine monitoring; resume 
avelumab therapy 
If elevation persists > 5 to 7 days or
worsens: Treat as Grade 3 to 4
Grade 3 to 4
AST or ALT > 5 × ULN and /or total 
bilirubin > 3 × ULN
Permanently discontinue avelumab 
therapy
Increase frequency of monitoring to 
every 1 to 2 days
1.0 to 2.0 mg/kg/day prednisone or
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Consult gastroenterologist/
hepatologist
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
warranted
If returns to Grade ≤1:
taper steroids over at least 1 month
If does not improve in > 3 to 5 days, 
worsens or rebounds:
add mycophenolate mofetil 1 g 
twice daily
If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines
Renal irAEs
Grade of Creatinine Increased
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 × 
ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4
Grade 2 to 3
Creatinine increased > 1.5 and ≤6
× ULN
Withhold avelumab therapy
Increase frequency of monitoring to
every 3 days
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade ≤1:
Taper steroids over at least 
1 month, and resume avelumab
therapy following steroids taper.
If worsens: 
Treat as Grade 4.
Grade 4
Creatinine increased > 6 × ULN
Permanently discontinue avelumab 
therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade ≤1:
Taper steroids over at least 1 month
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and/or new laboratory 
cardiac biomarker elevations (eg,
troponin, CK-MB, BNP) or cardiac 
imaging abnormalities suggestive of 
myocarditis.
Withhold avelumab therapy
Hospitalize
In the presence of life-threatening 
cardiac decompensation, consider 
transfer to a facility experienced in 
advanced heart failure and 
arrhythmia management
If symptoms improve and 
immune-mediated etiology is ruled 
out, re-start avelumab therapy
If symptoms do not improve/worsen, 
viral myocarditis is excluded, and 
immune-mediated etiology is 
suspected or confirmed following 
cardiology consult, manage as 
immune-mediated myocarditis
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Cardiology consult to establish 
etiology and rule out 
immune-mediated myocarditis
Guideline based supportive 
treatment as per cardiology consulta
Consider myocardial biopsy if 
recommended per cardiology
consult
Immune-mediated myocarditis
Permanently discontinue avelumab.
Guideline based supportive 
treatment as appropriate as per 
cardiology consulta
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections
Once improving, taper steroids over 
at least 1 month 
If no improvement or worsening, 
consider additional 
immunosuppressants (eg,
azathioprine, cyclosporine A)
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
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue avelumab therapy
Endocrinology consult if needed
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
antithyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate
Rule out secondary
endocrinopathies (ie,
hypopituitarism / hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine function as 
appropriate
Grade 3 or Grade 4 
endocrinopathies (hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
antithyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency), or insulin (for 
type I diabetes mellitus) as 
appropriate
Rule out secondary 
endocrinopathies (ie, 
hypopituitarism / hypophysitis)
Resume avelumab once symptoms 
and/or laboratory tests improve to 
Grade ≤1 (with or without hormone 
replacement/suppression)
Continue hormone replacement/ 
suppression and monitoring of 
endocrine function as appropriate 
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Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed (ie,
subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH):
!
Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, GH/IGF-1, 
PRL, testosterone in men, 
estrogens in women) 
!
Hormone replacement/ 
suppressive therapy as 
appropriate 
!
Perform pituitary MRI and 
visual field examination as 
indicated
If hypophysitis confirmed:
!
Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month
!
Withhold avelumab if moderate,
severe symptoms or life-
threatening symptoms of 
hypophysitis and/or abnormal 
MRI. Consider hospitalization. 
Initiate corticosteroids (1 to 
2 mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month
!
Add prophylactic antibiotics for 
opportunistic infections
Resume avelumab once symptoms 
and hormone tests improve to
Grade ≤1 (with or without hormone 
replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.
Continue hormone replacement/
suppression therapy as appropriate.
Other irAEs (not described above)
Grade of other irAEs
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold avelumab therapy pending 
clinical investigation
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy
If irAE is confirmed, treat as Grade 
2 or 3 irAE
Grade 2 irAE or first occurrence 
of Grade 3 irAE 
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤1: 
Taper steroids over at least 1 month 
and resume avelumab therapy
following steroids taper 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent
If improves to Grade ≤1: 
Taper steroids over at least 1 month 
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Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
Grade 4 
Permanently discontinue avelumab 
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent and/or 
other immunosuppressant as 
needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult
If improves to Grade ≤1: 
Taper steroids over at least 1 month 
Requirement for 10 mg per day or 
greater prednisone or equivalent 
for more than 12 weeks for 
reasons other than hormonal 
replacement for adrenal 
insufficiency
Persistent Grade 2 or 3 irAE
lasting 12 weeks or longer
Permanently discontinue avelumab 
therapy
Specialty consult
ACTH: adrenocorticotropic hormone; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BNP: 
B-type natriuretic peptide; CK-MB: creatine kinase MB; CT: computerized tomography; FSH: follicle-stimulating 
hormone; FT4: free thyroxine; GH: growth hormone; IGF-1: insulin-like growth factor 1; irAE: immune-related 
adverse event; iv: intravenous; LH: luteinizing hormone; MRI: magnetic resonance imaging; NCI-CTCAE v4.03: 
National Cancer Institute-Common Terminology Criteria for Adverse Events, Version 4.03; PRL: prolactin; TSH: 
thyroid-stimulating hormone; ULN: upper limit of normal.
6.6
Packaging and Labeling of the Investigational Medicinal
Product
Avelumab is formulated as a 20 mg/mL solution in
 
. The Sponsor’s Clinical Trial
Supplies department will supply the IMP, avelumab, which will be distributed to the study sites 
by the CRO(s).
Packaging and labeling of the IMP will be in accordance with applicable local regulatory 
requirements and applicable Good Manufacturing Practice guidelines. Avelumab will be packed 
in boxes containing a suitable number of vials. The information on the IMP will be in accordance 
with approved submission documents.
Avelumab will be shipped in transport cool containers 
, according to the storage and 
shipping conditions. Shipments will be monitored with temperature control devices.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
For use in this study, avelumab drug product must be diluted with 
 
 can be used if needed. It is recommended 
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that the diluted avelumab solution is used immediately. If not used immediately, the diluted drug 
product can be stored up to 
 or up to 
. 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 Manual of Preparation.
Avelumab must be stored at 
 until use, with a temperature log maintained daily. All 
medication boxes supplied to each study site must be stored carefully, safely, and separately from 
other drugs.
Avelumab stored at room temperature 
 or at elevated temperatures 
 
for extended periods is subject to degradation. Avelumab must not be frozen. Rough shaking of 
avelumab must be avoided. Further information will be provided in the Manual of Preparation.
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.
Storage, handling, preparation, and disposal of avelumab should be according to local institutional 
guidelines. 
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 Site File.
! Dispensing of avelumab 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 
Clinical Research Associate (CRA) (or equivalent) at each monitoring visit.
! IMP accountability records will include:
1.
Confirmation of IMP delivery to the study site.
2.
The inventory at the site of IMP provided by the Sponsor and prepared at the site.
3.
The use of each dose by each subject.
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4.
Destruction of unused treatment product (unused product will not be returned to the 
Sponsor).
5.
Dates, quantities, batch numbers, expiry dates and (for IMP prepared at the site) 
formulation, as well as the subjects’ Study Identifier Numbers.
! The Investigator should maintain records that adequately document:
1.
That the subjects were provided the doses specified by the Clinical Study 
Protocol/amendment(s).
2.
That all IMP provided by the Sponsor was fully reconciled.
Unused avelumab must not be discarded or used for any purpose other than this study. Any 
avelumab that has been dispensed to a subject must not be re-dispensed to a different subject.
The CRA will periodically collect the IMP accountability forms and will check all returns (both 
unused and used containers) before authorizing their destruction by the Sponsor or Sponsor 
delagate whenever applicable. However, it is also acceptable that IMP destruction is managed per 
site individual SOP regarding clinical study IMP destruction if applicable, and further document 
by CRA.
At the conclusion or termination of this study, site personnel and the CRA will conduct a final 
product supply inventory on the Investigational Drug Accountability Forms and all unused 
containers will be destroyed. Instructions for destruction of avelumab will be provided to the site. 
The CRA will be supplied with a copy of the Investigational Drug Accountability Forms for filing. 
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(s) of destruction(s).
! Name and signature of the Investigator/pharmacist.
In addition, it must be ensured at each study site that the IMP is not used:
! After the expiry date.
! After the retest date, unless the IMP is re-analyzed and its retest date extended.
This is to be closely monitored by the CRA.
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6.9
Assessment of Investigational Medicinal Product Compliance
In this study, subjects will receive the IMP (avelumab by IV infusion) at the study site. Well trained 
medical staff will monitor and perform administration of avelumab. Details of each administration 
of avelumab including the date, time, and dose will be recorded on the eCRF. The Investigator will 
make sure that the information entered onto the eCRF regarding administration is accurate for each 
subject. Any reason for noncompliance should be documented.
Noncompliance is defined as a subject missing > 1 cycle of avelumab for nonmedical reasons. If 
1 cycle is missed and the interval between the subsequent treatment cycle and the last administered 
treatment cycle is longer than 4 weeks for nonmedical reasons, the criteria for insufficient 
compliance are met. Should these situations occur, the subject should be withdrawn from avelumab 
treatment (see Section 5.5.2).
6.10
Blinding
Not applicable.
6.11
Emergency Unblinding
Not applicable. 
6.12
Treatment of Overdose
An overdose is defined as any dose 20% greater than the highest daily dose (20 mg/kg) included 
in the Clinical Study Protocol. Any overdose must be recorded in the IMP section of the eCRF.
For monitoring purposes, any case of overdose, whether or not associated with an AE (serious or 
nonserious), must be reported to the Sponsor’s Global Patient 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.
6.13
Medical Care of Subjects After End of Study
After a subject has completed the study or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the site’s standard of care and generally accepted 
medical practice and depending on the subject’s individual medical needs.
Upon withdrawal from avelumab administration, subjects may receive whatever care they and their 
physicians agree upon. Subjects will be followed for survival and AEs (as described in 
Section 7.1.5).
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7
Study Procedures and Assessments
7.1
Schedule of Assessments
The Schedule of Assessment is provided in Table 1-1 for subjects receiving avelumab once every 
2 weeks; in Table 1-2 for subjects receiving avelumab once a week for the first 12 weeks followed 
by once every 2 weeks (10 mg/kg once weekly cohort).
Prior to performing any study assessments that are 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(s) (see Section 9.2).
7.1.1
Clinical Screening
There is a 28-day washout/recovery period for prior anticancer treatment (eg, cytoreductive 
therapy, radiotherapy [with the exception of a short course of palliative bone-directed radiotherapy 
to a limited field of radiation, and radiotherapy administered to superficial lesions], which must be 
completed at least 7 days prior to the first administration of avelumab [see Section 5.3.2], immune 
therapy, or cytokine therapy except for erythropoietin) and major surgery before the start of study 
treatment. Radiation to more than 30% of the bone marrow or with a wide field of radiation should 
be completed at least 28 days prior to the first administration of avelumab.
The Clinical Screening procedures and baseline assessments will be completed within 14 days 
prior to the first administration of avelumab. 
The subject information to be documented during Clinical Screening includes demographic 
information (birth date, sex, and race) and a complete medical history including the history of the 
tumor disease, previous and concomitant medications, previous surgeries and radiotherapies, and 
baseline medical conditions; information on concomitant medications and AEs will be monitored 
throughout the Treatment Phase. In addition, the subject will be given an Emergency Medical 
Support card at the baseline assessments visit. 
During Clinical Screening, subjects will undergo a full physical examination including recording
body height, vital signs including body weight, 12-lead electrocardiogram (ECG), and a 
determination of the ECOG performance status (Table 1-1). 
The screening laboratory examination includes hematology, hemostaseology, full serum
chemistry, and full urinalysis (protein content required, and optional parameters albumin and 
immunoglobulin G to be tested depending on study site capability). Free thyroxine (T4) and 
thyroid-stimulating hormone (TSH) will also be assessed at Clinical Screening (baseline) (Table 
7-1).
Blood testing for hepatitis B virus and hepatitis C virus will be performed during Clinical 
Screening for all subjects, In addition, the subject’s HIV status must be known as a condition of 
study entry (see Section 5.3.2, Exclusion Criterion 10). If necessary to determine HIV status, a 
blood sample for HIV testing should be collected at Clinical Screening, subject to the provision of 
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informed consent for HIV testing as per local and national-specific regulations. Where consent is 
required, subjects who do not know their HIV status and who do not consent to HIV testing will 
not be allowed to enroll in the study.
During Clinical Screening, a serum β-human chorionic gonadotropin pregnancy test will be 
performed for all women of childbearing potential. Women are to be considered to be of 
childbearing potential unless they have age-related natural (spontaneous) amenorrhea 
≥12 consecutive months and increased FSH > 40 mIU/mL, are surgically sterile, or are sexually 
inactive. Women who are not of childbearing potential are exempt from pregnancy testing. If 
necessary to confirm childbearing potential, a blood sample for FSH analysis will be collected at 
Clinical Screening.
Following completion of the above Clinical Screening assessments, baseline samples for ADA 
against avelumab should be collected prior to the first administration of avelumab, ie, either during 
Clinical Screening or predose on Day 1.
Failure to establish subject eligibility within a 14-day period constitutes Clinical Screening failure 
and the subject should be excluded from the study. Section 7.1.1.1 details the information to be 
collected for any subject who fails Clinical Screening. Rescreening of subjects is not allowed, 
however, laboratory parameters that do not meet the inclusion criteria may be re-tested within the 
14-day Clinical Screening window following consultation with the Medical Monitor.
7.1.1.1
Information to be Collected on Clinical Screening Failures
Subjects who sign the ICF but do not start study treatment for any reason will be considered 
Clinical Screening failures. The following eCRF pages must be completed for all Clinical 
Screening failures:
! Clinical Screening Disposition page (including reason for the subject not starting study
treatment).
! Informed consent.
! Demography.
! Adverse events (only if an SAE occurs).
! Inclusion/exclusion criteria.
7.1.2
Treatment Phase
The Treatment Phase begins on Cycle 1 Day 1 with the first administration of avelumab and will 
continue until progression (see Sections 6.2 and 7.3.3), significant clinical deterioration (clinical 
progression), unacceptable toxicity, or any criterion for withdrawal from the study or IMP occurs
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(see Sections 5.5.1 and 5.5.2). However, a subject may remain on avelumab beyond RECIST 
1.1-defined disease progression if their ECOG performance status has remained stable, there are 
no new symptoms or worsening of existing symptoms, and, if in the opinion of the Investigator, 
the subject will benefit from continued treatment with avelumab (see Section 6.2). For subjects 
who continue avelumab beyond progression, treatment should be stopped immediately if the 
subject no longer tolerates avelumab or if therapeutic failure occurs. See Section 6.2.
Re-initiation of avelumab may be allowed in a subject who discontinues administration of 
avelumab but subsequently fails to confirm and verify original PD and meets the Criteria for 
Continuation of Treatment Beyond Progression (See Section 6.2 and 7.3.3).
Subjects receiving avelumab who have experienced a CR should be treated for a minimum of 
12 months, and/or until disease progression or unacceptable toxicity, after confirmation of 
response. 
For subjects receiving avelumab once every 2 weeks, subjects will be asked to visit the study site 
every 2 weeks during the Treatment Phase. 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 PK 
sampling visits on Days 2 and 3).
For subjects receiving avelumab once weekly, subjects will be asked to visit the study site once 
weekly for the first 12 weeks, and then once every 2 weeks starting at Week 13 during the 
Treatment Phase. A time window of 1 day before or 1 day after the scheduled visit day 
(- 1/+ 1 days) is permitted for all study procedures while subjects receiving avelumab once weekly 
(12 consecutive 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 while subjects receiving avelumab 
once every 2 weeks (Week 13 and thereafter).
The assessments to be performed during the Treatment Phase are detailed in Table 1-1 for subjects 
receiving avelumab once every 2 weeks; in Table 1-2 for subjects receiving avelumab once a week 
for the first 12 weeks followed by once every 2 weeks (10 mg/kg once weekly cohort).
7.1.3
End-of-Treatment Visit
Subjects must undergo an EOT Visit after discontinuation of avelumab for any reason. The EOT 
Visit should be performed within 7 days after the decision to discontinue treatment, but before any 
new anticancer therapy is started (if possible), whichever occurs earlier. The EOT Visit may be 
performed on the day of the decision to discontinue avelumab.
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Any subject who experiences an AE that mandates discontinuation of avelumab should have an 
EOT Visit as soon as possible after the decision to discontinue avelumab (within 7 days).
The EOT Visit eCRF page should be completed with a visit date reflecting the date the 
discontinuation decision was made, with the last known date the subject received avelumab, and 
1 of the following reasons: 
! Adverse event(s).
! Abnormal laboratory value(s).
! Abnormal test procedure result(s).
! Protocol violation.
! Subject withdrew consent.
! Lost to follow-up.
! Death (must state if death is due to “Study Indication” or “Other” reason).
! Treatment duration completed as per protocol (for subjects who experience a confirmed CR; 
see Section 6.2).
! Other reasons, including clinical deteriorations, administrative problems.
Please refer to Table 1-1, Table 1-3, Table 1-4, and Table 1-5 for the specific assessments to be 
performed at the EOT Visit.
7.1.4
Safety Follow-up
The safety parameters to be assessed during the Safety Follow-up (30-day Safety Follow-up Visit 
and 90-day Phone Call) are detailed in Table 1-1, Table 1-3, and Table 1-4.
7.1.4.1
30-day Safety Follow-up Visit
All subjects will have a Safety Follow-up Visit scheduled 30 days ( ± 5 days) after the last 
administration of avelumab.
After the EOT Visit, all AEs have to be documented until the 30-day Safety Follow-up Visit. After 
this visit, all SAEs and all treatment-related nonserious AEs must be documented until the 90-day 
Safety Follow-up Phone Call. Subjects with an ongoing SAE at the 30-day Safety Follow-up Visit 
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must be monitored and followed up by the Investigator until stabilization or until the outcome is 
known.
7.1.4.2
90-Day Phone Call
At 90 days ( ± 5 days) after the last dose of avelumab, subjects will be contacted by telephone to 
collect information on new or ongoing SAEs and treatment-related nonserious AEs. Any SAE 
assessed as related to study treatment must be reported whenever it occurs, irrespective of the time 
elapsed since the last administration of avelumab. Subjects will also be asked about any anticancer
therapy.
7.1.5
Long-term Follow-up
Subjects with an SAE ongoing after the Safety Follow-up Phone Call 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”.
After the EOT Visit, subjects will be followed every 12 weeks ( ± 7 days) for survival (including 
the assessment of any further anticancer therapy). Survival follow-up will continue until 2 years 
after the last subject receives the last dose of avelumab, or the last subject dies, whichever occurs 
first. Additional survival follow-up data may be collected at the time of primary and final analyses 
if the last follow-up data were collected more than 30 days earlier. Under some circumstances, 
subjects may not be followed for survival for 2 years in this study, eg, subjects may be given the 
opportunity to participate in a rollover study, or the Sponsor may terminate the study early.
Each subject will be followed for survival until death, lost to follow-up, or the cutoff date of the
End of Study (Section 5.7). 
The assessments to be performed at the Long-term Follow-up Visits are detailed in Table 1-1.
7.2
Demographic and Other Baseline Characteristics
The assessments and procedures described in this section must be performed during Clinical 
Screening.
7.2.1
Demographic Data
At screening, the following data will be collected:
! Date of birth
! Sex
! Race
! Ethnicity.
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7.2.2
Diagnosis of Tumor 
The tumor disease information to be documented and verified at the Clinical 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
of malignant tumors at diagnosis.
! All therapy used for prior treatment of the tumor (including surgery, radiotherapy, 
chemotherapy, and immunotherapy).
! Any other conditions that were treated with chemotherapy, radiation therapy, or
immunotherapy.
! Current cancer signs and symptoms, and AEs effects from current and/or previous anticancer
treatments.
! Current cancer disease status.
7.2.3
Medical History 
In order to determine the subject’s eligibility to participate in the study, a complete medical history 
will be collected and documented during Clinical Screening. This will include, but may not be 
limited to, the following:
! Past and concomitant nonmalignant diseases and treatments.
! Past and concomitant malignant diseases and treatments.
! All medications (including herbal medications) taken and procedures carried out within 30 days 
prior to screening.
! Smoking and alcohol history.
! Family cancer history.
7.2.4
Other Baseline Assessments
All other baseline measurements, such as tumor evaluation, vital signs, complete physical 
examination, ECOG performance status (see Section 12, Appendix IV), clinical laboratory 
parameters, 12-lead ECG, and biomarker will be assessed as detailed in Table 1-1 and Table 1-2. 
Please refer to Sections 7.3.1 and 7.3.2 for details of baseline tumor evaluations, Section 7.4 for 
baseline safety evaluations,
. 
For study entry, all subjects must fulfill all the inclusion criteria described in Section 5.3.1 and not 
meet any of the exclusion criterion described in Section 5.3.2.
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7.4
Safety Assessments
The safety profile of avelumab will be assessed through the recording, reporting, and analyzing of 
baseline medical conditions, AEs, physical examination findings, vital signs, and laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the study, from the time of the subject’s signature of informed consent. 
Study site personnel will report any AE, whether observed by the Investigator or reported by the 
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subject (see Section 7.4.1.2). Given the intended mechanism of action of avelumab, 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 Table 1-1 and Table 1-2.
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 v4.03 (publication date: 14 June 2010). 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 the severity/intensity of a particular AE 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.
The 5 general grades are:
! Grade 1: Mild
! Grade 2: Moderate
! Grade 3: Severe
! Grade 4: Life-threatening or disabling
! Grade 5: Death.
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According to the Sponsor’s convention, if a severity/intensity of Grade 4 or Grade 5 is applied to 
an AE, then the Investigator must also report the event as an SAE. However, a laboratory 
abnormality with a severity/intensity of Grade 4, such as anemia or neutropenia, is considered 
serious only if the condition meets one of the serious criteria described below.
In the case of death, the primary cause of death (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 (eg, 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 study treatment
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, study procedures. 
Not related: Not suspected to be reasonably related to the study treatment. The AE could not 
medically (pharmacologically/clinically) be attributed to the treatment under study 
in this protocol. A reasonable alternative explanation must be available.
Related:
Suspected to be reasonably related to the study treatment. The AE could medically
(pharmacologically/clinically) be attributed to the IMP under study in this protocol.
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (eg, 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 fulfils these criteria, the identified medical condition (eg, anemia, increased ALT) 
must be reported as the AE rather than the abnormal value itself.
Adverse Drug Reaction
An ADR is defined in this study as any AE suspected to be related to avelumab by the Investigator 
and/or Sponsor. 
Serious Adverse Event
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.
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! 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 a Serious Adverse Event
Elective hospitalizations to administer, or to simplify study treatment or study procedures (eg, 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 (eg, undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
Events Not to Be Considered as Adverse Events or Serious Adverse Events
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as baseline medical conditions and are NOT to be considered AEs.
Adverse Events/Serious Adverse Events Observed in Association with Disease Progression
Progression of the disease/disorder being studied assessed by measurement of lesions on
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the patient’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome 
is fatal within the adverse event reporting period (as defined in Section 7.4.1.3). 
Predefined AEs of Special Interest for Safety Monitoring
Any AE that is suspected to be a potential irAE and infusion-related reactions will be considered 
an adverse event of special interest. 
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Dose-limiting Toxicity
A DLT is defined as a ≥Grade 3 ADR according to the NCI-CTCAE v4.03, occurring during the 
DLT observation period of the dose escalation cohorts. An ADR is defined in this study as any AE
suspected to be related to avelumab by the Investigator and/or Sponsor. A DLT must be confirmed 
by the SMC as being related to avelumab.
A DLT is specifically defined as any Grade ≥3 toxicity that is possibly, probably, or definitely 
related to avelumab, occurring during the DLT observation period, 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 skin toxicity, or Grade 3 LFT (ALT, AST, or gamma-glutamyl transferase) increase 
that resolves to ≤Grade 1 in less than 7 days after medical management (eg, 
immunosuppressant treatment) has been initiated.
! Grade 3 diarrhea unless to be discontinued according to Treatment Guidelines. In this case it 
would be an DLT again.
! Single laboratory values out of normal range that are unlikely to be related to avelumab
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.
The ADRs (including DLTs) that require permanent discontinuation of avelumab are described in
Section 5.1.3.1.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each study visit, the subject will be queried on changes in his/her condition. During the reporting 
period of the study, 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 (as defined in Section 7.4.1.3) will be reported on an ongoing basis in the appropriate 
section of the eCRF. Among these AEs and all SAEs must also be documented and reported using 
the appropriate SAE eCRF page (SAESIDT) as described in Section 7.4.1.4.
It is important that each AE report includes a description of the event, its duration (onset and 
resolution dates [/times “/times” to be completed when it is important to assess the time of AE 
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onset relative to the recorded treatment administration time]), its severity, its relationship with the 
study drug, 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 eCRF 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 in the study
(date of first signature of informed consent) and continues through the 30-days ( ± 5 days) Safety 
Follow-up Visit. After the Safety Follow-up Visit all SAEs and treatment-related nonserious AEs 
need to be documented up until the Safety Follow-up Phone Call, which is defined as 90 days 
( ± 5 days) after the last administration of avelumab.
Any SAE suspected to be related to avelumab must be reported whenever it occurs, irrespective of 
the time elapsed since the last administration of avelumab.
7.4.1.4
Procedure for Reporting Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (ie, within a maximum 24 hours after becoming aware of the event) inform the 
Sponsor or designee using the SAE Report Form in eCRF following specific completion 
instructions.
In exceptional circumstances an SAE (or follow-up information) may be reported by telephone; in 
these cases, an SAE Report Form must be completed immediately thereafter in eCRF.
Relevant pages from the eCRF may be provided in parallel (eg, medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (eg, laboratory 
results, hospital report, or autopsy report).
The Investigator must respond to any requests for follow-up information (eg, 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 Patient Safety department may contact the Investigator directly to obtain 
clarification or to discuss a particularly critical event.
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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.
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 study.
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 study, or alter 
the IEC/IRB’s approval/favorable opinion to continue the study.” 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). 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.
7.4.1.6
Monitoring of Subjects with Adverse Events
Adverse events are recorded and assessed continuously throughout the study and are assessed for 
final outcome at the 30-day Safety Follow-up (Section 7.1.4.1). After the 30-day Safety Follow-up
Visit, all new and ongoing SAEs and all treatment-related nonserious AEs ongoing at the 90-day 
Safety Follow-up Phone Call (Section 7.1.4.2) 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 the study drug (eg, 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 eCRF. 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 paper Pregnancy Report Form, which 
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must be transmitted according to the same timeline as described for SAE reporting in
Section 7.4.1.4.
Investigators must actively follow-up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the study.
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 study, the subject must 
be discontinued from avelumab administration immediately. The Sponsor or designee must be 
notified without delay and the subject must be followed as described above.
7.4.3
Clinical Laboratory Assessments
It is essential that the Sponsor be provided with a list of local laboratory normal ranges before 
shipment of the IMP. Any change in laboratory normal ranges during the study should also be 
forwarded to the CRO and the Sponsor.
Blood samples will be taken from subjects and prior to administration of avelumab. All routine 
laboratory analyses will be performed at a laboratory facility local to the study site and relevant 
results essential for subject management decisions (hematology, biochemistry, LFTs) must be 
available and reviewed prior to administration of avelumab. The report of the results must be 
retained as a part of the subject’s medical record or source documents and documented on the 
eCRF. Blood samples for the tests listed in Table 7-1 will be taken from subjects during Clinical 
Screening (within 14 days prior to the first administration of avelumab), at the EOT Visit, 30-day 
Safety Follow-up Visit, and during the Treatment Phase at the time points specified in Table 1-1
and Table 1-2. In case of LFT elevation (AST, ALT, and/or total bilirubin) requiring additional 
laboratory draws (see Section 6.5.5.2 and Table 6-2), unscheduled laboratory tests will be 
performed. 
Free thyroxine, TSH, and urinalysis will be assessed at the time points specified in the Schedule 
of Assessments (Table 1-1 and Table 1-2).
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.
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Table 7-1
Required Laboratory Panel Tests
Full Chemistry
Hematology
Albumin
Absolute lymphocyte count
Alkaline phosphatase1
Absolute neutrophil count
Alanine aminotransferase1
Hematocrit
Amylase 
Hemoglobin 
Aspartate aminotransferase1
Platelet count 
Gamma-glutamyl transferase
Red blood cells 
Blood urea nitrogen/total urea1
White blood cells and differential count 
Calcium1
Red blood cell morphology (optional4)
Chloride1
Reticulocytes 
Cholesterol
Mean corpuscular hemoglobin 
Creatine kinase
Mean corpuscular volume (optional4)
Creatinine1
Mean corpuscular hemoglobin concentration
C-reactive protein
Hemostaseology 
Glucose1
Activated partial thromboplastin time (aPTT)
Lactate dehydrogenase
Prothrombin time/International Normalized Ratio (INR)
Lipase
Hormone
Phosphorus/phosphates1
Follicle-stimulating hormone (if applicable) 
Magnesium1
Thyroid-stimulating hormone (TSH)
Potassium1
Free thyroxine (T4)
Sodium1
Antibodies
Total bilirubin1
Totality of binding antidrug antibody (ADA) (Section 7.7)
Total protein
Urinalysis3
Uric acid
Full: protein content2, albumin (optional4) and 
immunoglobulin G (optional4)
Triglycerides
Basic (dipstick): protein content only2
Hemoglobin A1c
1Core serum chemistries.
2If urinalysis is positive for protein, sediment will also be evaluated. 
3Urinalysis is not required for subjects with urothelial cancers.
4To be assessed depending on study site capability. For urinalysis parameters, study sites not able to assess urine 
albumin and immunoglobulin will only test for urine protein content.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
The ECOG performance status (see Section 12, Appendix IV) will be assessed at Clinical 
Screening and at subsequent visits as indicated in the Schedule of Assessments (Table 1-1 and
Table 1-2) and documented in the eCRF, even if the IMP is on hold for the subject. More frequent 
examination may be performed at the Investigator’s discretion, if medically indicated.
Body weight (to the nearest 0.1 kilogram [kg]) will be measured at Clinical Screening and at 
subsequent visits as indicated in the Schedule of Assessments (Table 1-1 and Table 1-2) and 
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documented in the eCRF. Body height in centimeters (cm) will be measured at Clinical Screening 
only.
Physical examination will include an examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, and a 
basic nervous system evaluation. A full physical examination will be conducted at Clinical 
Screening, at the EOT Visit, and at the 30-day Safety Follow-up Visit. At visits during the 
Treatment Phase (see Schedule of Assessments [Table 1-1 and Table 1-2]), the physical 
examination will be symptom-directed. Results from the physical examination, including any 
abnormalities, will be documented in the eCRF. Abnormal findings are to be reassessed at 
subsequent visits. Details of the physical examination must be present in the source documentation 
at the study site. 
A 12-lead ECG will be performed and recorded at Clinical Screening and as indicated in the 
Schedule of Assessments (Table 1-1 and Table 1-2). All subjects will have ECG assessment at 
baseline, and at the first 3 times of study drug treatment after avelumab infusion. In following 
visits, ECG will be arranged if considered necessary by the Investigator. Electrocardiograms will 
be performed in the supine position after the subject has been breathing quietly for 5 minutes. The 
ECG results will be used to evaluate heart rate, atrial-ventricular conduction, QR* and QT 
intervals, and possible arrhythmias. Interpretation of the ECG trace must be made by a qualified 
physician and documented on the ECG eCRF. Each ECG trace should be labeled with the Study 
Number, Subject Identifier Number, and date, and kept in the source documents at the site. 
Significant findings that were present prior to the signing of informed consent must be included in 
the Medical History eCRF page. All newly diagnosed or worsening conditions, signs and 
symptoms observed since screening, whether related to the study drug or not, are to be reported as 
AEs on the Adverse Event eCRF page.
For women of childbearing potential, a serum β-human chorionic gonatropin pregnancy test will 
be carried out during Clinical Screening. Thereafter, a urine pregnancy test will be performed every 
4 weeks during the Treatment Phase prior to administration of avelumab and at the visits indicated 
in the Schedule of Assessments (Table 1-1 and Table 1-2). Results of the most recent pregnancy 
test should be available prior to the next administration of avelumab. Female subjects who are not 
considered to be of childbearing potential (age-related natural [spontaneous] amenorrhea 
≥12 consecutive months and increased FSH > 40 mIU/mL), or who are surgically sterile or are 
sexually inactive, are exempt from pregnancy testing.
*ECG QR value may not be applicable in some study sites according to site routine practice (which 
does not report QR value).
7.5
Pharmacokinetics
Full PK blood samples will be collected from all subjects according to the following schedules as 
indicated in Table 1-3 and Table 1-4.
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For subjects receiving avelumab once every 2 weeks:
! Day 1: within 2 hours prior to and at the end of the 1-hour infusion and at 0.5, 1, 2, 4, 6, and 
12 hours after the end of the infusion.
! Day 2: 2 samples will be collected 24 and 36 hours after the end of the infusion.
! Day 3: a single sample will be collected 48 hours after the end of the infusion.
! Day 8: a single sample will be collected 168 hours after the end of the infusion. 
! Days 15, 29, 43, 85, 127, and 169 (Week 25): samples will be collected within 2 hours prior to 
infusion (trough value) and immediately after the infusion is completed (peak value).
! Every 12 weeks beyond Week 25: a single sample will be collected within 2 hours prior to 
infusion (trough value).
! EOT Visit.
! 30-day Safety Follow-up Visit.
*The time window for PK sampling time points are: +10 minutes for the end of infusion sample 
collection on Day 1; ± 10 minutes for 0.5 and 1 hour after the end of infusion; ± 20 minutes for 2, 
4, and 6 hours after the end of infusion; ± 2 hours for 12, 24, 36, 48, and 168 hours after the end 
of infusion. The time window for PK sampling time points is applicable for all scheduled PK 
sample collection for all subjects.
For the 6 subjects receiving avelumab once a week:
! Within 2 hours prior to each infusion at Weeks 1, 2, 3, 5, and 7, at Weeks 13, 15, 19, and 25, 
and then at 12-week intervals while on treatment. 
! At the end of infusion (within 15 minutes) at Weeks 1, 7, 13, and 25. 
! EOT Visit.
! 30-day Safety Follow-up Visit.
The collection of blood samples with exact date and clock time of avelumab administrations 
(relative to the previous and next doses of avelumab) and sample collection will be recorded on 
the corresponding eCRF page. Whole blood sufficient to provide 1.5 mL of serum will be collected 
for all PK assessments. Postinfusion samples should be collected from a site other than the 
avelumab infusion site (ie, contralateral arm) on the days of infusion. If the infusion is interrupted, 
the reason for interruption will be documented on the eCRF.
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Further instructions for PK sample collection and handling will be provided in a separate 
Laboratory Manual. 
7.5.1
Pharmacokinetic Parameters
The following PK parameters will be calculated using noncompartmental analysis:
! AUC0-t: area under the concentration-time curve from time zero to time t (calculated by linear 
trapezoidal summation).
! AUC0-tau: area under the concentration-time curve from time zero to tau, the respective dosing 
interval, ie, 1-week or 2-week (calculated by linear trapezoidal summation).
! AUC0-∞: area under the concentration-time curve from time zero 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) versus time.
! Cmax: maximum serum concentration.
! Ctrough: serum concentration observed immediately before next dosing.
! Clast: last quantifiable concentration.
! tmax: time to maximum concentration.
! t1/2: elimination half-life determined as 0.693/λz.
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7.7
Antidrug Antibody Response
Full ADA serum samples will be collected from all subjects according to the following schedule
as indicated in Table 1-3 and Table 1-4.
For subjects receiving avelumab once every 2 weeks:
! Day 1 (baseline): the baseline sample should be collected within 2 hours prior to the first 
administration of avelumab, ie, either during Clinical Screening or predose on Day 1.
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! Days 15, 29, 43, 85, 127, and 169: samples will be collected within 2 hours prior to infusion.
! After Day 169, 1 sample (within 2 hours prior to infusion) every 12 weeks until the EOT Visit.
! 30-day Safety Follow-up Visit. 
For subjects receiving avelumab once a week:
! Within 2 hours prior to each infusion at Weeks 1, 3, 5, 7 (every 2 weeks), at Weeks 13, 19, and 
25 (every 6 weeks), and then every 12 weeks while on treatment.
! 30-day Safety Follow-up Visit.
Blood samples for ADA analysis must be collected prior to avelumab administration (Table 1-3
and Table 1-4).
For retreated subjects (ie, those who achieve a CR on avelumab, subsequently develop PD after 
stopping therapy, and then re-initiate treatment), ADA samples will be collected according to the 
following schedule as indicated in Table 1-5:
! Day 1 of retreatment infusion: within 2 hours prior to the infusion.
! EOT Visit.
The immunogenicity testing strategy will be implemented and conducted in line with the following 
guidance documents:
! European 
Medicines 
Agency 
Guidance: 
Immunogenicity 
Assessment 
of 
Biotechnology-derived Therapeutic Proteins, 2007.
! European Medicines Agency Guidance:
Immunogenicity Assessment of Monoclonal 
Antibodies Intended for In Vivo Clinical Use, 2010.
! Food and Drug Administration (FDA) Guidance for Industry: Assay Development for 
Immunogenicity Testing of Therapeutic Proteins, 2009.
A qualified method that uses an acid dissociation step to detect ADAs in the presence of excess 
drug in human serum may be applied. Removal of drug after acid treatment is not required. The 
ADA titers of positive samples will be determined.
In the event of anaphylactic reactions, the ADA samples from affected subjects will be investigated 
for the presence of drug-specific immunoglobulin E using a novel Phadia® ImmunoCAP® method 
developed for this purpose. 
Further details of the analysis will be provided separately. 
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8
Statistics
8.2
Randomization
Not applicable.
8.3
Endpoints
8.3.1
Primary Endpoints
The primary endpoints are: 
! Occurrence of DLTs during the DLT observation period (first 21 days of treatment; excluding 
10 mg/kg once weekly cohort).
! Pharmacokinetic profiles in Chinese subjects.
8.3.2
Secondary Endpoints 
The secondary endpoints of the study include: 
! Occurrence of TEAEs for all dose groups according to NCI-CTCAE v4.03.
! Occurrence of treatment-related AEs for all dose groups according to NCI-CTCAE v4.03.
! Serum titers of ADA against avelumab.
8.3.3
Safety Endpoints
In addition to the endpoints specified as primary and secondary endpoints, laboratory parameters 
will be evaluated. 
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8.4
Analysis Sets
! Screening Analysis Set: all subjects who signed the ICF(s).
! DLT Analysis Set: all subjects with data used for implementing the dose-escalation schedule
(excluding 6 subjects in 10 mg/kg once weekly cohort). These subjects should have received 
all avelumab administrations in the DLT observation period (first 21 days of treatment) or 
should have stopped treatment because of DLTs in the DLT observation period.
! Safety Analysis Set: all subjects who have received at least 1 dose of avelumab. The Safety 
Analysis Set will be used for all analyses of safety and efficacy.
! Efficacy Population: all subjects who have received at least 1 dose of avelumab and have 
measurable disease at baseline according to Investigator assessment.
! PK Analysis Set: all subjects who have completed at least 1 infusion of avelumab, and who 
have provided valid PK samples.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
All data recorded during the study will be presented in individual data listings for the Safety 
Analysis Set. Unless otherwise specified, all data will be evaluated as observed, and no imputation 
method for missing values will be used. All data will be presented in a descriptive manner. 
Descriptive statistics will be used to summarize the study results, ie, 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.
Full details of the planned analyses will be provided in the SAP.
8.5.2
Analysis of Primary Endpoints
8.5.2.1
DLTs in Dose Escalation Cohorts
DLT is defined in Section 7.4.1.1.  The number and proportion of subjects experiencing DLTs will 
be reported by dose level based on the DLT Analysis Set (excluding 10 mg/kg once weekly cohort). 
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8.5.2.2
Pharmacokinetics Profile
Serum concentrations of avelumab will be determined by a validated method at the time points 
described in the Schedule of Assessments (Table 1-3, Table 1-4, and Table 1-5).
The PK parameters to be estimated and reported for the PK Analysis Set are defined in 
Section 7.5.1.
The PK parameters will be summarized using descriptive statistics. Additional PK analysis/display 
may be generated at the discretion of the pharmacokineticist.
8.5.3
Analysis of Secondary and Safety Endpoints
8.5.3.1
Analysis of Safety Endpoints
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 Analysis Set. 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, 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 administration of avelumab to the last 
administration of avelumab date plus 30 days or the earliest date of subsequent anticancer drug 
therapy minus 1 day, whichever occurs first.
Adverse Events
All AEs will be coded according to the Medical Dictionary for Regulatory Activities. Severity of 
AEs will be graded using the NCI-CTCAE v4.03 toxicity grading scale.
Treatment-emergent AEs are those events with an onset date occurring 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 study 
treatment will be summarized by Preferred Term and System Organ Class, and described in terms 
of intensity and relationship to study treatment. Adverse events (serious and nonserious) will be 
considered TEAEs, except for AEs which started prior to the first administration of avelumab 
(unless a worsening of the event is recorded after the first administration of avelumab, in which 
case the event will be considered a TEAE). All premature terminations will be summarized by the 
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 v4.03. The worst on study 
grades after the first administration of avelumab 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
postbaseline laboratory values will be included in these analyses.
Physical Examination (Including Vital Signs and 12-lead Electrocardiograms)
Physical examination data, including vital signs (body temperature, respiratory rate, heart rate, and 
blood pressure) and 12-lead ECG recorded at the time points indicated in Table 1-1 and Table 1-2
will be presented.
Further details will be provided in the SAP based on the current safety experience.
8.5.3.2
Serum Titers of Antidrug Antibodies
The immunogenicity analysis will include a listing of ADA results as positive or negative, and if 
applicable, a numeric titer value. 
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8.6
Reporting of Planned Analyses
The primary analysis, including all endpoints analyses, for study data will be conducted at the time 
when all subjects complete PK sample collection at Week 13 (including all samples collected if 
the treatment discontinued earlier than Week 13). The data cutoff time point for primary analysis 
is set at Week 13 (Day 85) of the last subject. 
The data from primary analysis will be summarized in the Clinical Study Report (CSR).
The final analysis of study data will be conducted after End of Study, which is defined as the last 
patient complete 90-day Safety Follow-up Phone Call or last patient died, whichever comes first.
Additional data from primary analysis up to this cutoff date will be analyzed and presented as an 
addendum of CSR.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the study at the site and will ensure that the study 
is performed in accordance with this Clinical Study Protocol, the ethical principles outlined in the 
Declaration of Helsinki, ICH GCP, China GCP, and any other applicable regulations. The 
Investigator must ensure that only subjects who have given informed consent are included in the 
study.
According to USA Code of Federal Regulations Part 54.2 (e), for studies conducted in any country 
that could result in a product submission to the USA FDA for marketing approval and could 
contribute significantly to the demonstration of efficacy and safety of an IMP (which are 
considered “covered clinical studies” by the FDA), the Investigator and all Subinvestigators 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 
study and for 12 months following completion of the study.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the study is his/her written informed 
consent. The subject’s written informed consent to participate in the study must be given before 
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any study-related activities are performed. The information of HIV testing and biomarker will be 
included in the ICF.
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 GCP 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 
study. The language used in doing so must be chosen so that the information can be fully and 
readily understood by lay persons. The subject will be given sufficient time to read the information 
and the opportunity to ask questions and to request additional information and clarification.
Depending on national regulations, a person other than the Investigator may inform the subject 
and sign the ICF, as above.
After the information is provided by the Investigator, the ICF must be signed and personally dated 
by the subject who is willing to participate into the trial 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 study for signing and dating. The Investigator will explain the changes to the previous version.
The subject will be given sufficient time to read the information and the opportunity to ask 
questions and to request additional information and clarification about the changes.
9.3
Subject Identification and Privacy
A unique Subject Identifier Number will be assigned to each subject, immediately after informed 
consent has been obtained. This number will serve as the subject’s identifier in the study as well 
as in the clinical study database. All subject data collected in the study will be stored under the 
appropriate subject number. Only the Investigator will be able to link study data to an individual 
subject via an identification list kept at the site. For each subject, original medical data will be 
accessible for the purposes of source data verification by the monitor, audits and regulatory 
inspections, but subject confidentiality will be strictly maintained.
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.
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Blood and 
 samples will be stored for up to 10 years after study completion. During 
this time, samples may be re-analyzed for newly identified 
 or with new or improved 
technology. After 10 years, the samples will be destroyed or fully anonymized or a new IEC/IRB 
approval and informed consent will be requested to keep the samples for an additional period. If 
tumor tissue remains, the site will be notified and the 
 will be returned to the site upon 
request. If the site does not request the return of the 
, it will be destroyed.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the Sponsor or 
designee for use during study participation in order to provide subjects with a way of identifying 
themselves as participating in a clinical study and to give healthcare providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the subject.
The first point of contact for all emergencies will be the 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, they will answer any questions. Any 
subsequent action will follow the standard process established for Investigators.
In cases where the Investigator is not available, the Sponsor or designee provides the appropriate 
means to contact a Sponsor or delegate physician. This includes the provision of a 24-hour contact 
number at a call center, whereby healthcare providers will be given access to the appropriate 
Sponsor physician to assist with the medical emergency.
9.5
Clinical Study Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating to the study. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent Ethics Committee/Institutional Review Board
Prior to commencement of the study at a given site, the Clinical Study 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 study 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 
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 study, the Clinical Study Protocol version and the 
Subject Information and ICF version reviewed should be provided. Where possible, copies of the 
meeting minutes should be obtained.
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Amendments to the study 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 study in accordance with national regulations and 
requirements.
9.7
Health Authorities
The Clinical Study Protocol and any applicable documentation (eg, IMP Dossier, Subject 
Information, and the ICF) will be submitted or notified to the Health Authorities in accordance 
with the regulations of all local and national regulations for each site.
10
Study Management
10.1
Case Report Form Handling
The main purpose of the eCRF is to document data required by the Clinical Study Protocol in a 
complete, accurate, legible, and timely manner. The data in the eCRF should be consistent with 
the relevant source documents.
The Investigator or designee is responsible for ensuring that data collected in the course of this 
study are accurate and documented appropriately on all applicable forms (eg, eCRFs), in 
accordance with the data entry guidelines. The data will then be processed, evaluated, and stored 
in anonymous form in accordance with applicable data protection regulations. The Investigator 
must ensure that the eCRFs and any other associated documents forwarded to Sponsor or its 
designated organization contain no mention of any subject names.
The data will be entered into a validated database. The CRO will follow the standards of the 
Sponsor in the database design and data structure. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s or designee’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 study.
Please refer to the Manual of Operations for eCRF handling guidelines.
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 study. It must be possible to identify each subject 
by using this subject file. 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.
! Medical history and concomitant diseases.
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! Prior and concomitant therapies (including changes during the study).
! Tumor disease information.
! Study
identification, that is, the Sponsor Study
Number for this clinical study
(MS100070-0035), and Subject Number.
! Date of subject’s inclusion into the study (ie, date the subject gave informed consent).
! Dates of the subject’s visits to the site.
! Any medical examinations and clinical findings predefined in the Clinical Study Protocol.
! All AEs observed in the subject.
! Date that the subject left the study, including any reason for early withdrawal from the study or 
IMP (if applicable).
All 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 Identifier 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.
Electronic subject files will be printed, with printouts signed and dated by the Investigator, and 
kept in a safe place at the site. When the CRA performs source data verification, electronic subject 
file will be spot checked by CRA as predefined in the monitoring visit plan.
10.3
Investigator Site File and Archiving
Upon initiation of the study, the Investigator will be provided with an Investigator Site File upon 
initiation of the study. This file will contain all documents necessary for the conduct of the study
and will be updated and completed throughout the study. 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 study, 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 study. 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 study will be monitored in accordance with the ICH GCP, and any other applicable 
regulations. The site CRA will perform visits to the study 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 study-related documents and other materials 
at the site, including the Investigator Site File, the completed CRFs, the IMP, and the subjects’ 
original medical records/files.
The Clinical Study Protocol, each step of the data capture procedures, and the handling of the data, 
including the final Clinical Study Report, will be subject to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the study to ensure the validity and 
integrity of the study data.
10.5
Changes to the Clinical Study Protocol
Changes to the Clinical Study 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 study
requires the subject’s informed consent prior to implementation (see Section 9.2).
10.6
Clinical Study Report and Publication Policy
10.6.1
Clinical Study Report
After completion of the study, or completion of a particular cohort or cohorts if applicable, a 
Clinical Study Report according to ICH Topic E3 will be written by the Sponsor or the designated 
CRO in consultation with the Coordinating 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 study sites that participated the study. 
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study. 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 presubmission 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.
Posting of data on Clinicaltrials.gov is planned and will occur 12 months after the last clinic visit 
of the final study subject or another appropriate date to meet applicable requirements.
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11
References Cited in the Text
Bohnsack O, Ludajic K, Hoos A. Adaption of the immune-related response criteria: irRECIST. 
ESMO. 2014; abstract 4958.
Boland CR, Thibodeau SN, Hamilton SR et al. A national cancer institute workshop on 
microsatellite instability for cancer detection and familial predisposition: development of 
international criteria for the determination of microsatellite instability in colorectal cancer. Cancer 
Res. 1998; 58(22):5248-57.
Brahmer JR, Tykodi SS, Chow LQ et al. Safety and activity of anti-PD-L1 antibody in patients 
with advanced cancer. N Engl J Med. 2012; 366(26):2455-65.
 
Doi T, Piha-Paul SA, Jalal SI et al. Pembrolizumab (MK-3475) for patients (pts) with advanced 
esophageal carcinoma: Preliminary results from KEYNOTE-028. J Clin Oncol. 2015; 33(suppl 
15):4010.
Dong H, Strome SE, Salomao DR et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a 
potential mechanism of immune evasion. Nat Med. 2002; 8(8):793-800.
Dong H, Zhu G, Tamada K et al. B7-H1, a third member of the B7 family, co-stimulates T-cell 
proliferation and interleukin-10 secretion. Nat Med. 1999; 5(12):1365-9.
Dulak AM, Stojanov P, Peng S et al. Exome and whole-genome sequencing of esophageal 
adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet. 2013; 
45(5):478-86.
Freeman GJ, Long AJ, Iwai Y et al. Engagement of the PD-1 immunoinhibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000; 
192(7):1027-34.
Hamid O, Robert C, Daud A et al. Safety and Tumor Responses with lambrolizumab (anti-PD-1) 
in Melanoma. N Engl J Med. 2013; 369(2):134-44.
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011; 364(19):1844-54. 
Iwai Y, Ishida M, Tanaka Y et al. Involvement of PD-L1 on tumor cells in the escape from host 
immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002; 
99(19):12293-7.
Khan MM. Immunosuppressive Agents. In: Immunopharmacology. New York: Springer; 2008. 
Latchman Y, Wood CR, Chernova T et al. PD-L2 is a second ligand for PD-1 and inhibits T cell 
activation. Nat Immunol. 2001; 2(3):261-8.
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Le DT, Uram JN, Wang H et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N 
Engl J Med. 2015; 372(26): 2509-20.
Lin DC, Hao JJ, Nagata Y et al. Genomic and molecular characterization of esophageal squamous 
cell carcinoma. Nature Genetics. 2014; 46 (5): 467-73.
Matsumoto Y, Nagasaka T, Kambara T et al. Microsatellite instability and clinicopathological 
features in esophageal squamous cell cancer. Oncol Rep. 2007; 18(5):1123-27.
Oki E, Okano S, Ando K et al. HER2 and programmed death-1 ligand-1 (PD-L1) expression in 
gastric carcinoma. J Clin Oncol. 2014; 32(suppl):abstr e15041.
Pandilla R, Kotapalli V, Gowrishankar S et al. Distinct genetic aberrations in oesophageal adeno 
and squamous carcinoma. Eur J Clin Invest. 2013; 43(12):1233-39.
Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T cell-mediated cytotoxicity by 
anti-inflammatory steroids. J Immunol 1984; 132(1):266-71. 
Topalian SL, Drake CG, Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway to activate 
antitumor immunity. Curr Opin Immunol. 2012a; 24(2):207-12.
Topalian SL, Hodi F, Brahmer JR et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. N Engl J Med. 2012b; 366(26):2443-54.
Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics 
of response with ipilimumab. J Clin Oncol 2012; 30(21):2691-7. 
Rizvi NA, Hellmanne MD, Snyder A et al. Mutational landscape determines sensitivity to PD-1 
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Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015; 
348 (6230): 69-74. 
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Appendices
Appendix I
Signature Pages and Responsible Persons for the Study
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Signature Page – Protocol Lead
Study Title:
A Phase I/Ib Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Avelumab in 
Chinese 
Subjects 
with 
Locally 
Advanced 
Unresectable or Metastatic Solid Tumors with 
Expansion to Selected Indication(s)
Clinical Study Protocol Date / 
Version:
17 May 2019/ Version 4.0
Protocol Lead
I approve the design of the clinical study:
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Medical Responsible
Institution:
Merck Serono (Beijing), Pharmaceutical R&D Co. Ltd.
Address:
25F NUO Center Office
No.2A, Jiangtai Road，Chaoyang District, 
Beijing China 100016
Telephone number:
Fax number:
E-mail address:
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Signature Page – Coordinating Investigator
Study Title
A Phase I/Ib Study to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of Avelumab in Chinese 
Subjects with Locally Advanced Unresectable or 
Metastatic Solid Tumors with Expansion to Selected 
Indication(s)
Clinical Study Protocol Date / 
Version
17 May 2019/ Version 4.0
I approve the design of the clinical study and I understand and will conduct the study according to 
the Clinical Study Protocol, any approved protocol amendments, International Council for
Harmonization Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
 
Address:
Telephone number:
Fax number:
E-mail address:
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Signature Page – Principal Investigator
Study Title
A Phase I/Ib Study to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Avelumab in 
Chinese 
Subjects 
with 
Locally 
Advanced 
Unresectable or Metastatic Solid Tumors with 
Expansion to Selected Indication(s)
Clinical Study Protocol Date / 
Version
17 May 2019/ Version 4.0
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, any approved protocol
amendments, International Council for Harmonization Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials to 
obtain and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such information 
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 to meet 
Health Authority requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons Not Named on the Cover Page
Name, academic degree:
Function / Title:
Clinical Trial Lead
Institution:
Merck Serono R&D Beijing
Address:
21F, Nuo Center
No. 2 Jiang Tai Road
Beijing 100016
People’s Republic of China
Telephone number:
Fax number:
E-mail address:
Name, academic degree:
Function / Title:
Institution:
Merck Serono R&D Beijing
Address:
21F, Nuo Center
No. 2 Jiang Tai Road
Beijing 100016
People’s Republic of China
Telephone number:
Fax number:
E-mail address:
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Name, academic degree:
Function / Title:
Institution:
Merck KGaA
Address:
21F, NUO Center
No.2A, Jiangtai Road
10016 Beijing
People’s Republic of China
Telephone number:
Fax number:
E-mail address:
Name, academic degree:
Function/Title:
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45A Middlesex Turnpike 
Billerica, MA 01821
USA
Telephone number:
E-mail address:
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C
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Appendix III
Guidance on Contraception
Birth control methods considered as highly effective.
According to the Clinical Trials Facilitation Group (CTFG) Recommendations Related to 
Contraception and Pregnancy Testing in Clinical Trials, 2014, 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 device2
!
intrauterine hormone-releasing system2
! bilateral tubal occlusion2
! vasectomized partner2,3
! sexual abstinence4.
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method.
2Contraception methods in the context of this guidance are considered to have low user dependency.
3Vasectomized partner is a highly effective birth control method provided that the partner is the sole sexual partner of 
the woman of childbearing potential study participant and that the vasectomized partner has received medical 
assessment of the surgical success.
4In 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 study and the preferred and usual 
lifestyle of the subject.
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Appendix IV
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group Performance Status1
Grade
Eastern Cooperative Oncology Group
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, eg, light house work, 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
Death
1Oken MM, Creech RH, Tormey DC et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982; 5:649-55.
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Appendix V
Protocol Amendment and List of Changes
Amendment 3.0:
Previous Protocol Amendments
Yes.
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or 
Country
Included in the 
Current 
Document
(Y/N)
1.0
Y
10 May 2017
China
N
2.0
Y
23 February 2018
China
N
3.0
N
17 May 2019
China
Y
Rationale for Changes
This non-substantial amendment is executed due to Sponsor’s decision to clarify the secondary 
endpoint and corresponding procedures as well as the correction period of concomitant 
medications.
Since only the titers of ADA are to be detected and analyzed in the study. Definition of ADA 
isotype as well as the neutralizing capacity against avelumab will not be evaluated. The secondary 
endpoint stated in the protocol “Serum titers, isotypes and neutralizing capacity of ADA against 
avelumab” therefore will be justified as “Serum titers of ADA against avelumab” only. 
Furthermore, there will not be procedures regarding analysis of isotypes or neutralizing capacity 
of ADA executed in this study.
The collection period of concomitant medications is revised to be in line with adverse event 
recording. Additional descriptions regarding explantion/clarification of specific term or 
procedures previously addressed by note to files are also included. The amendment also includes 
the correction of administrative, minor editorial changes and inconsistencies throughout the 
document that have been identified since the finalization of the clinical trial protocol.
Changes Made
The changes of this protocol amendment (Amendment No.3) are:
1. To change medical responsible personnel after replacement.
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2. To clarify the secondary endpoint “Serum titers, isotypes and neutralizing capacity of ADA
against avelumab”. The secondary endpoint stated in the protocol will be justified as 
“Serum titers of ADA against avelumab” only. 
3. To clarify the collection period of concomitant medication to be in line with adverse event 
recording.
4. Correct the footnotes of Table 1-1 and Table 1-2, unify the wording of 
 
 
.
5. To add a footnote in Table 1-2 to address that the procedure of EOT, Safety Follow-up, as 
well as the Long-term Follow-up schedules for subjects in the 10 mg/kg weekly group are 
identical to Table 1-1.
6. To add the description “The time window for PK sampling time points is applicable for all 
scheduled PK sample collection for all subjects” to footnote 1 of Table 1-3, following the 
description of PK sampling time points.
7. To add a note to define anaphylaxis in No.13 exclusion criteria.
8. To add a note to clarify that “ECG QR value may not be applicable for some sites” to 
Section 7.4.4 Vital Signs, Physical Examinations, and Other Assessments.
9. To add a note to specify the original schedule means “the dosing schedule which is 
calculated according to first dose” to Section 5.1.3.1 Adverse Drug Reactions Requiring 
Treatment Discontinuation or Modifications.
The changes to be made to the clinical trial protocol are described below.
List of Changes
All changes with the exception of minor editorial changes to the Clinical Study Protocol text are 
presented in the table below. Additions and amended text are shown in bold. If the original Clinical 
Study 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 Study Protocol Version 3.0, 23 February 2018 (Amendment No. 3)
Change
Section
Pages
(V3.0)
Previous Wording
New Wording
Revised Sponsor 
medical responsible
affiliations
Cover page
1
Jack Chen
Jack Chen Silvia Sun
Revised and corrected 
the secondary enpoint
Synopsis
Section 
8.3.2
14
94
!
Occurrence of TEAEs for all dose groups according to 
NCI-CTCAE v4.03.
!
Occurrence of treatment-related AEs for all dose groups 
according to NCI-CTCAE v4.03.
!
Serum titers, isotypes and neutralizing capacity of 
antidrug antibodies (ADA) against avelumab.
!
Occurrence of TEAEs for all dose groups according to 
NCI-CTCAE v4.03.
!
Occurrence of treatment-related AEs for all dose groups 
according to NCI-CTCAE v4.03.
!
Serum titers, isotypes and neutralizing capacity of 
antidrug antibodies (ADA) against avelumab.
Revised key
exclusion criteria, add 
footnote to define 
anaphylaxis
Synopsis
Section 
5.3.2
16
52
!
Any history of anaphylaxis, or uncontrolled asthma (ie, 3 
or more features of partially controlled asthma).
!
Any history of anaphylaxis*, or uncontrolled asthma (ie, 
3 or more features of partially controlled asthma).
*Anaphylaxis is a severe, life-threatening, generalized
or systemic hypersensitivity reaction. It is 
characterized by rapidly developing, life-threatening 
problems (CTCAE Grading 3-5).
Revised exclusion 
criteria 13, add 
footnote to define 
anaphylaxis
Section 
5.3.2
52
13. Known severe hypersensitivity reactions to monoclonal 
antibodies (Grade ≥3 NCI-CTCAE v4.03), any history of 
anaphylaxis, or uncontrolled asthma (that is, 3 or more 
features of partially controlled asthma).
13. Known severe hypersensitivity reactions to monoclonal 
antibodies (Grade ≥3 NCI-CTCAE v4.03), any history 
of anaphylaxis*, or uncontrolled asthma (that is, 3 or 
more features of partially controlled asthma).
!
*Anaphylaxis is a severe, life-threatening, generalized
or systemic hypersensitivity reaction. It is 
characterized by rapidly developing, life-threatening 
problems (CTCAE Grading 3-5).
Added definition of 
“original schedule” to 
address the actions 
for managing adverse 
drug reactions
Section 
5.1.3.1
47
!
Any Grade 2 ADRs should be managed as follows:
o
Infusion should not be given in case of ongoing 
Grade 2 ADR on the day of study treatment 
administration.
o
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 2 doses are skipped, treatment may be 
resumed after consultation with the Medical 
Monitor.
!
Any Grade 2 ADRs should be managed as follows:
o
Infusion should not be given in case of ongoing 
Grade 2 ADR on the day of study treatment 
administration.
o
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 2 doses are skipped, treatment may be 
resumed after consultation with the Medical 
Monitor.
*Original schedule is defined as “the dosing schedule 
calculated according to first dose”.
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Change
Section
Pages
(V3.0)
Previous Wording
New Wording
Clarified the
reporting of ECG 
results regarding QR 
value may be 
different from study 
site according to 
routine practices at 
each site
Section 
7.4.4
89
A 12 lead ECG will be performed and recorded at Clinical 
Screening and as indicated in the Schedule of Assessments 
(Table 1-1 and Table 1-2). Electrocardiograms will be 
performed in the supine position after the subject has been 
breathing quietly for 5 minutes. The ECG results will be 
used to evaluate heart rate, atrial-ventricular conduction, QR 
and QT intervals, and possible arrhythmias. Interpretation of 
the ECG trace must be made by a qualified physician and 
documented on the ECG eCRF. Each ECG trace should be 
labeled with the Study Number, Subject Identifier Number, 
and date, and kept in the source documents at the site.
Significant findings that were present prior to the signing of 
informed consent (for main study) must be included in the 
Medical History eCRF page. All newly diagnosed or 
worsening conditions, signs and symptoms observed since 
screening, whether related to the study drug or not, are to be 
reported as AEs on the Adverse Event eCRF page.
For women of childbearing potential, a serum β-human 
chorionic gonatropin pregnancy test will be carried out 
during Clinical Screening. Thereafter, a urine pregnancy test 
will be performed every 4 weeks during the Treatment Phase 
prior to administration of avelumab and at the visits 
indicated in the Schedule of Assessments (Table 1-1 and 
Table 1-2). Results of the most recent pregnancy test should 
be available prior to the next administration of avelumab. 
Female subjects who are not considered to be of childbearing 
potential (age-related natural [spontaneous] amenorrhea 
≥12 consecutive months and increased FSH > 40 mIU/mL), 
or who are surgically sterile or are sexually inactive, are 
exempt from pregnancy testing.
A 12 lead ECG will be performed and recorded at Clinical 
Screening and as indicated in the Schedule of Assessments 
(Table 1-1 and Table 1-2). Electrocardiograms will be 
performed in the supine position after the subject has been 
breathing quietly for 5 minutes. The ECG results will be used 
to evaluate heart rate, atrial-ventricular conduction, QR* and 
QT intervals, and possible arrhythmias. Interpretation of the 
ECG trace must be made by a qualified physician and
documented on the ECG eCRF. Each ECG trace should be 
labeled with the Study Number, Subject Identifier Number, 
and date, and kept in the source documents at the site.
Significant findings that were present prior to the signing of 
informed consent (for main study) must be included in the 
Medical History eCRF page. All newly diagnosed or 
worsening conditions, signs and symptoms observed since 
screening, whether related to the study drug or not, are to be 
reported as AEs on the Adverse Event eCRF page.
For women of childbearing potential, a serum β-human 
chorionic gonatropin pregnancy test will be carried out 
during Clinical Screening. Thereafter, a urine pregnancy test 
will be performed every 4 weeks during the Treatment Phase 
prior to administration of avelumab and at the visits 
indicated in the Schedule of Assessments (Table 1-1 and 
Table 1-2). Results of the most recent pregnancy test should 
be available prior to the next administration of avelumab. 
Female subjects who are not considered to be of childbearing 
potential (age-related natural [spontaneous] amenorrhea 
≥12 consecutive months and increased FSH > 40 mIU/mL), 
or who are surgically sterile or are sexually inactive, are 
exempt from pregnancy testing.
*ECG QR value may not be applicable in some study 
sites according to site routine practice (which does not 
report QR value).
Added clarification 
regarding PK 
sampling time 
window is applicable 
for all sugjects
Section 7.5
90
*The time window for PK sampling time points are: +10 
minutes for the end of infusion sample collection on Day 1; 
± 10 minutes for 0.5 and 1 hour after the end of infusion; 
± 20 minutes for 2, 4, and 6 hours after the end of infusion; 
± 2 hours for 12, 24, 36, 48, and 168 hours after the end of 
infusion. 
*The time window for PK sampling time points are: +10 
minutes for the end of infusion sample collection on Day 1; 
± 10 minutes for 0.5 and 1 hour after the end of infusion; 
± 20 minutes for 2, 4, and 6 hours after the end of infusion; 
± 2 hours for 12, 24, 36, 48, and 168 hours after the end of 
infusion. The time window for PK sampling time points is 
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Change
Section
Pages
(V3.0)
Previous Wording
New Wording
applicable for all subjects scheduled PK sample 
collection for all subjects.
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Changes in tables (Amendment Version 3.0)
Table 1-1
Schedule of Assessments for Subjects Receiving Avelumab Once Every 2 Weeks
Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Unt
il 
pro
gre
i
Wit
hin 
30 
day
Pho
ne 
Eve
ry 
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Written informed consent 
X
Inclusion/exclusion criteria
X
Medical history7
X
Demographic data
X
Hepatitis B, hepatitis C, and 
HIV tests
X
Full physical examination8
X
X
X
Symptom-directed physical 
exam8
As indicated throughout the Treatment Phase
Height
X
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Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Unt
il 
pro
gre
i
Wit
hin 
30 
day
Pho
ne 
Eve
ry 
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Vital signs
X
X
X
X
X
X
X
X
2-weekly
X
X
Weight
X
X
X
X
X
X
X
X
2-weekly
X
X
ECOG PS9
X
X9
X
X
X
X
X
X
2-weekly
X
X
Enrolment (if eligible)10
X
DLT assessment11
X
X11
12-lead ECG
X
X
X
X
As indicated and decided by Investigator
X
Hematology and 
hemostaseology
X
X
X
X
X
X
X
2-weekly
X
X
Core serum chemistry12
X
X
X
X
2-weekly
X
Full serum chemistry13
X
X
X
6-weekly
X
Full urinalysis14
X
X
Basic urinalysis14
X
X
6-weekly
Serum beta-hCG pregnancy 
test (if applicable)15
X
Urine pregnancy test (if 
applicable)15
X
X
X
X
4-weekly
X
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Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Unt
il 
pro
gre
i
Wit
hin 
30 
day
Pho
ne 
Eve
ry 
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Premedication21
X
X
X
X
Avelumab administration
X
X
X
X
X
X
X
2-weekly
Concomitant medication and 
procedures22
Collected at each study visit until through the 30-day Safety Follow-up Visit
AE collection23
AEs are collected through the 30-day Safety Follow-up Visit
Treatment-related nonserious AEs are collected until the 90-day Safety Follow-up Phone Call
SAE collection24
All SAEs are documented until the 90-day Safety Follow-up Phone Call
Ongoing SAEs at the 30-day Safety Follow-up Visit will be followed up
Free T4 and TSH
X
X
X
6-weekly
X
X
PK sampling25
See Table 1-3
ADA sampling25
See Table 1-3
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Assessment
Clinical Screening
/Baseline 
Assessments
Treatment Phase1
EOT Visit2
Safety Follow-up2
Long-term Follow-
up2
≤Day -14 to 
Day -1
V1
V2
V3
V4
V5
V6
V7
Unt
il 
pro
gre
i
Wit
hin 
30 
day
Pho
ne 
Eve
ry 
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Survival26
X
X
X
X
X
X
X
Every visit
X
X
X
X
Further anticancer therapy26
X
X
X
ADA: antidrug antibody; AE: adverse event; CR: complete response; CT: computed tomography; D: Day; DLT: dose-limiting toxicity; ECG: electrocardiogram; 
ECOG PS: Eastern Cooperative Oncology Group performance status; EOT: End-of-Treatment; hCG: human chorionic gonadotropin; HIV: Human 
immunodeficiency virus; ICF: Informed consent form; IMP: investigational medicinal product; MRI: magnetic resonance imaging; PD: progressive disease; 
PK: pharmacokinetics; PR: partial response; RECIST: response evaluation criteria in solid tumors; SAE: serious adverse event; 
T4: thyroxine; TSH: thyroid-stimulating hormone; V: Visit; W: Week.
1.
A time window of up to 3 days before or 1 day after the scheduled visit day (- 3/+ 1 days) is permitted for all study procedures (except for PK sampling visits 
on Day 2 and 3, see Table 1-3). The calculation of the dose of avelumab will be based on the weight of the subject determined within 72 hours prior to the day 
of drug administration.
2.
All subjects will have an EOT Visit within 7 days after the decision to discontinue avelumab. In addition, subjects will be followed every 12 weeks ( ± 7 days) 
for survival (including assessment of any further anticancer therapy).
4.
If another anticancer therapy is administered before the end of this 7-day period, the EOT Visit should be conducted prior to the start of this new therapy, if 
possible. The EOT Visit may be performed on the day of the decision to discontinue avelumab.
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7.
Medical history should include history of cancer, previous and ongoing medications, previous surgeries, radiotherapies, baseline medical conditions, smoking 
and alcohol history, and family cancer history.
8.
A full physical examination will be conducted at Clinical Screening, at the EOT Visit and at the 30-day Safety Follow-up Visit. During the Treatment Phase, the 
physical examination will be symptom-directed.
9.
If the Clinical Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1/Cycle 1 Day 1.
10. Enrolment will be done after confirmation that the subject meets all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion
(Section 5.3.2). 
11. The observation period for DLTs is the 21-day period after the first administration of avelumab for subjects with data used for implementing the dose-
escalation algorithm for dose determination (the DLT assessment is not applicable for the 6 subjects in 10 mg/kg once weekly cohort).
12. Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin), acute chemistry 
panel (sodium, potassium, chloride, blood urea nitrogen/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.
13. Full chemistry panel and other laboratory studies are detailed in Section 7.4.3. Follicle-stimulating hormone at Clinical Screening, if applicable.
14. Full urinalysis (protein content required, and optional parameters albumin and immunoglobulin G to be tested depending on study site capability) at Clinical 
Screening/baseline, and EOT; basic urinalysis (protein content only) on Days 43 and 85, and then every 6 weeks thereafter prior to administration of 
avelumab. If urinalysis (full or basic) is positive for protein, sediment will be evaluated.
15. In serum at Clinical Screening; in urine thereafter. Results of the most recent pregnancy test should be available prior to next administration of avelumab.
16. A CT scan or MRI of the chest, abdomen, and pelvis (if MRI is used, CT of chest is mandatory) will be performed within 14 days prior to the first administration 
of avelumab in order to document baseline status of the tumor disease using RECIST 1.1 target and nontarget lesions. If a CT/MRI scan was performed within 
2 weeks prior to the first administration of avelumab and is available and of adequate quality, the screening CT/MRI does not need to be performed. Tumor 
evaluation at each visit after screening may not exactly be on the same day for study drug treatment, instead it may differ from the scheduled visit date. The 
tumor evaluation has a tumor assessment window of 5 days prior to the planned tumor assessment date (- 5 days) according to first dosing date throughout 
the Treatment Phase (Section 7.1.2)
17. Brain CT/MRI scan (either, with contrast preferred) is required at Clinical Screening if not performed within the previous 14 days. Thereafter, brain CT/MRI 
scan should be done if clinically indicated by development of new specific symptoms. A bone scan should be done at Clinical Screening and beyond as 
clinically indicated. Bone metastases detected at Clinical Screening need to be followed at tumor evaluation visits.
18. The tumor assessment visit time window is 5 days prior to dosing (- 5 days) for tumor evaluation 5 days prior to the planned tumor assessment date 
(- 5 days) according to first dosing day during the Treatment Phase, and ± 5 days after the EOT Visit. CT or MRI scan (if MRI is used, CT of chest is 
mandatory) should always be used. CT/MRI scan will be performed at baseline, every 6 weeks (- 5 days) during the first 12 months of the study, and then 
every 12 weeks (- 5 days) until progression.
20. Disease response determinations, including progressive disease assessments associated with study endpoints, will be supported by tumor assessments 
performed by Investigator. 
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21. Premedication is mandatory approximately 30 to 60 minutes prior to the first 4 doses of avelumab. Premedication should be administered for subsequent 
avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions. This regimen may be modified based on local treatment 
standards and guidelines as appropriate. However, the prophylactic use of systemic corticosteroids is not permitted.
22. Concomitant medications and procedures will be documented at each study visit until the EOT Visituntil the 30-day Safety Follow-up Visit. 
23. All AEs will be documented at each study visit until the 30-day Safety Follow-up Visit. After this visit, only treatment-related nonserious AEs have to be 
documented until the 90-day Safety Follow-up Phone Call. 
24. All SAEs will be documented at each study visit until the 90-day Safety Follow-up Phone Call. After this, all ongoing SAEs must be monitored and followed 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 study 
drug must be reported whenever it occurs, irrespective of the time elapsed since the last administration of avelumab. At 90 days ( ± 5 days) after the last dose 
of avelumab, subjects will be contacted by telephone to collect information on new or ongoing SAEs and treatment-related nonserious AEs.
25. Blood samples for PK and ADA will be collected as detailed in Table 1-3.
26. Subjects will be followed every 12 weeks ( ± 7 days) for survival (including assessment of any further anticancer therapy).
Table 12-3
Schedule of Assessments for Subjects Receiving Avelumab Once a Week for the First 12 Weeks Followed by 
Once Every 2 Weeks (10 mg/kg Once Weekly Cohort)
Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Document No.
Object No
CCI
CCI
CCI


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Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035
C O N F I D E N T I A L
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Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Written informed 
consent
X
Inclusion/exclusion 
criteria
X
Medical history43
X
Demographic data
X
Hepatitis B, 
hepatitis C and HIV
tests
X
Full physical 
examination54
X
Symptom-directed 
physical exam54
As indicated throughout the Treatment Phase
Height
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
ECOG PS65
X
X65
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Enrolment (if 
eligible)76
X
12-lead ECG
X
X
X
X
As indicated and decided by Investigator
Document No.
Object No
CCI
CCI


Avelumab
Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035
C O N F I D E N T I A L
I N F O R M A T I O N
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Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Hematology and 
hemostaseology
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Core serum 
chemistry87
X
X
X
X
X
X
X
X
X
X
2-weekly
Full serum 
chemistry98
X
X
X
6-weekly
Full urinalysis109
X
Basic urinalysis109
X
X
6-weekly
Serum beta-hCG
pregnancy test (if 
applicable)1110
X
Urine pregnancy 
test (if 
applicable)1110
X
X
X
X
4-weekly
Premedication1716
X
X
X
X
Document No.
Object No
CCI
CCI
CCI


Avelumab
Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035
C O N F I D E N T I A L
I N F O R M A T I O N
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Assessment2
Clinical Screening 
/Baseline 
Assessments
Treatment Phase1
≤Day -14 to Day -1
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
Until progression
W1
W2
W3
W4
W5
W6
W7
W8
W9
W10
W11
W12
W13
(Roll-over into 
Once every-2-
weeks dosing)
D1
D8
D15
D22
D29
D36
D43
D50
D57
D64
D71
D78
D85
Avelumab
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
2-weekly
Concomitant 
medication and 
procedures
Collected at each study visit until the EOT Visit until the 30-day Safety Follow-up Visit
AE collection1817
AEs are collected through the 30-day Safety Follow-up Visit
Treatment-related nonserious AEs are collected until the 90-day Safety Follow-up Phone Call
SAE collection1918
All SAEs are documented until the 90-day Safety Follow-up Phone Call
Ongoing SAEs at the 30-day Safety Follow-up Visit will be followed up
Free T4 and TSH
X
X
X
6-weekly
PK sampling2019
See Table 1-4
ADA sampling2019
See Table 1-4
Survival2120
X
X
X
X
X
X
X
X
X
X
X
X
X
Every 
visit
Further anticancer 
therapy2120
Collected through Safety Follow-up and Long-term Follow-up
ADA: antidrug antibody; AE: adverse event; CR: complete response; CT: computed tomography; D: Day; DLT: dose-limiting toxicity; ECG: electrocardiogram; 
ECOG PS: Eastern Cooperative Oncology Group performance status; EOT: End-of-Treatment; hCG: human chorionic gonadotropin; HIV: Human 
immunodeficiency virus; ICF: Informed consent form; IMP: investigational medicinal product; MRI: magnetic resonance imaging; PD; progressive disease; 
; PK: pharmacokinetics; PR: partial response; RECIST: response evaluation criteria in solid tumors; SAE: serious adverse 
event; T4: thyroxine; TSH: thyroid-stimulating hormone; V: Visit; W: Week.
Document No.
Object No
CCI
CCI
CCI


Avelumab
Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035
C O N F I D E N T I A L
I N F O R M A T I O N
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1.
A time window of 1 day before or 1 day after the scheduled visit day (- 1/+ 1 days) is permitted for all study procedures while subjects receiving avelumab 
once weekly (12 consecutive weeks). A time window of up to 3 days before or 1 day after the scheduled visit day (- 3/+ 1 days) is permitted for all study 
procedures while subjects receiving avelumab once every 2 weeks (Week 13 and thereafter). The calculation of the dose of avelumab will be based on the 
weight of subject determined within 72 hours prior to the day of drug administration.
2.
Columns of EOT Visit, Safety Follow-up, and the Long-term Follow-up Visits are omitted due to layout readability. The procedures at EOT Visit, 
Safety Follow-up, and the Long-term Follow-up are identical to the procedures planned for subjects receiving avelumab once every 2 weeks (as 
shown in Table 1-1).
3.
2. Mandatory for study entry. A recently obtained formalin-fixed, paraffin-embedded block containing tumor tissue (biopsy from a non-irradiated area within 
6 months) or 12 or more slides (preferably, approximately 25 slides) is required for all subjects. Endoscopic biopsies, core needle biopsies, excisional 
biopsies, punch biopsies, and surgical specimens are suitable. Fine needle aspiration biopsies are not suitable. Samples can be provided as block or slides.
4.
3. Medical history should include history of cancer, previous and ongoing medications, previous surgeries, radiotherapies, baseline medical conditions, 
smoking and alcohol history, and family cancer history.
5.
4. A full physical examination will be conducted at Clinical Screening, at the EOT Visit and at the 30-day Safety Follow-up Visit. During the Treatment Phase, 
the physical examination will be symptom-directed.
6.
5. If the Clinical Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1/Cycle 1 Day 1.
7.
6. Enrolment will be done after confirmation that the subject meets all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion 
(Section 5.3.2). 
8.
7. Core serum chemistry includes liver function panel (alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin), acute chemistry 
panel (sodium, potassium, chloride, blood urea nitrogen/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.
9.
8. Full chemistry panel and other laboratory studies are detailed in Section 7.4.3. Follicle-stimulating hormone at Clinical Screening, if applicable.
10. 9. Full urinalysis (protein content required, and optional parameters albumin and immunoglobulin G to be tested depending on study site capability) at Clinical 
Screening/baseline, and EOT; basic urinalysis (protein content only) on Days 43 and 85, and then every 6 weeks thereafter prior to administration of 
avelumab. If urinalysis (full or basic) is positive for protein, sediment will be evaluated.
11. 10. In serum at Clinical Screening; in urine thereafter. Results of the most recent pregnancy test should be available prior to next administration of avelumab.
Document No.
Object No
CCI
CCI
CCI


Avelumab
Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035
C O N F I D E N T I A L
I N F O R M A T I O N
135/137
17. 16. Premedication is mandatory approximately 30 to 60 minutes prior to the first 4 doses of avelumab. Premedication should be administered for subsequent 
avelumab doses based upon clinical judgment and presence/severity of prior infusion reactions. This regimen may be modified based on local treatment 
standards and guidelines as appropriate. However, the prophylactic use of systemic corticosteroids is not permitted.
18. 17. All AEs will be documented at each study visit until the 30-day Safety Follow-up Visit. After this visit, only treatment-related nonserious AEs have to be 
documented until the 90-day Safety Follow-up Phone Call. 
19. 18. All SAEs will be documented at each study visit until the 90-day Safety Follow-up Phone Call. After this, all ongoing SAEs must be monitored and followed 
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 
study drug must be reported whenever it occurs, irrespective of the time elapsed since the last administration of avelumab. At 90 days ( ± 5 days) after the last 
dose of avelumab, subjects will be contacted by telephone to collect information on new or ongoing SAEs and treatment-related nonserious AEs.
20. 19. Blood samples for PK and ADA will be collected as detailed in Table 1-4.
21. 20. Subjects will be followed every 12 weeks ( ± 7 days) for survival (including assessment of any further anticancer therapy).
Document No.
Object No
CCI
CCI
CCI


Avelumab
Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035
C O N F I D E N T I A L
I N F O R M A T I O N
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Table 12-4
Schedule of Assessments – Pharmacokinetic and Antidrug Antibody Sampling for Subjects Receiving 
Avelumab Once Every 2 Weeks
Assessment
Treatment Phase
EOT Visit
Safety 
Follow-up
V1
V2
V3
V4
V7
Until 
Progressi
on
Within 7 days 
after decision to 
discontinue IMP
30 days ( ± 5 
days) after last 
IMP
W1
W1
W1
W2
W3
W5
W7
W13
D1
D2
D3
D8
D15
D29
D43
D85
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
End of 
infusi
on
Prior to 
infusio
n
End of 
infusio
n
Prior to 
infusio
n
End of 
infusi
on
PK sampling1
X
X
X
X
X
X
X
X
X
X
X
X
X
6-weekly 
up to W25 
(D169), 
then 12-
weekly
X
X
ADA sampling2
X
X
X
X
X
6-weekly 
up to W25 
(D169), 
then 12 
weekly to 
EOT
X
ADA: antidrug antibody; D: Day; EOT: End-of-Treatment; IMP: investigational medicinal product; PK: pharmacokinetics; V: Visit; W: Week.
1.
For subjects receiving avelumab once every 2 weeks, PK serum samples will be collected at the following time points:
-
Day 1: within 2 hours prior to and at the end of the 1-hour infusion, and at 0.5, 1, 2, 4, 6, and 12 hours after the end of the infusion.
-
Day 2: 2 samples will be collected 24 and 36 hours after the end of the infusion.
-
Day 3: a single sample will be collected 48 hours after the end of the infusion.
-
Day 8: a single sample will be collected 168 hours after the end of the infusion. 
-
Days 15, 29, 43, 85, 127, and 169 (Week 25): samples will be collected within 2 hours prior to infusion (trough value) and immediately after the 
infusion is completed (peak value).
-
Every 12 weeks beyond Week 25: a single sample will be collected within 2 hours prior to infusion (trough value).
-
EOT Visit.
-
30-day Safety Follow-up Visit.
Document No.
Object No
CCI
CCI


Avelumab
Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035
C O N F I D E N T I A L
I N F O R M A T I O N
137/137
*The time window for PK sampling timepoints are: + 10 minutes for the end of infusion sample collection on Day 1; ± 10 minutes for 0.5 and 1 hour after the 
end of infusion; ± 20 minutes for 2, 4, and 6 hours after the end of infusion; ± 2 hours for 12, 24, 36, 48, and 168 hours after the end of infusion. The time 
window for PK sampling time points is applicable for all scheduled PK sample collection for all subjects.
2.
For subjects receiving avelumab once every 2 weeks, ADA serum samples will be collected at the following time points:
-
Day 1 (baseline): the baseline sample should be collected within 2 hours prior to the first administration of avelumab, ie, either during Clinical 
Screening or predose on Day 1.
-
Days 15, 29, 43, 85, 127 and 169: samples will be collected within 2 hours prior to infusion.
-
After Day 169, 1 sample (within 2 hours prior to infusion) every 12 weeks until the EOT Visit.
-
30-day Safety Follow-up Visit.
Document No.
Object No
CCI
CCI

SAP_001.pdf: 




Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
3/55
1
Table of Contents
Integrated Analysis Plan ......................................................................................................1
Signature Page
..............................................................................................................2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................6
3
Modification History ............................................................................9
4
Purpose of the Integrated Analysis Plan...............................................9
5
Objectives and Endpoints .....................................................................9
6
Overview of Planned Analyses...........................................................10
6.1
Interim Analysis..................................................................................10
6.2
Primary Analysis ................................................................................10
6.3
Final Analysis .....................................................................................10
7
Changes to the Planned Analyses in the Clinical Trial Protocol........11
8
Protocol Deviations and Analysis Sets...............................................11
8.1
Definition of Protocol Deviations.......................................................11
8.2
Definition of Analysis Sets.................................................................11
9
General Specifications for Data Analyses ..........................................12
9.1
Data Handling After Cut-off Date ......................................................12
9.2
Pooling of Centers ..............................................................................12
9.3
Presentation and Definition of General Considerations .....................12
9.3.1
Presentation of Continuous and Qualitative Variables.......................12
9.3.2
Definition of Baseline.........................................................................13
9.3.3
Definition of Duration ........................................................................13
9.3.4
Conversion Factors.............................................................................13
9.3.5
Handling of Missing Data...................................................................13
9.3.6
Presentation of PK Concentration Data..............................................14
9.3.7
Presentation of PK Parameter Data ....................................................14
9.3.8
Software..............................................................................................15
10
Trial Subjects......................................................................................15
10.1
Disposition of Subjects and Discontinuations....................................15


Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
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10.2
Protocol Deviations ............................................................................16
10.2.1
Important Protocol Deviations............................................................16
11
Demographics and Other Baseline Characteristics.............................16
11.1
Demographics.....................................................................................16
11.2
Medical History ..................................................................................17
11.3
Other Baseline Characteristics............................................................17
12
Previous or Concomitant Medications/Procedures.............................19
12.1
Prior Anti-Cancer Treatment and Procedures.....................................19
12.2
Prior or Concomitant Medication and Procedures..............................20
12.3
Anti-cancer Post-treatment .................................................................21
13
Treatment Compliance and Exposure.................................................21
13.1
Pre-medication....................................................................................21
13.2
Exposure to Study Drug......................................................................21
13.3
Treatment Re-Initiation ......................................................................24
15
Safety Analyses ..................................................................................28
15.1
Dose Limiting Toxicity (DLT)...........................................................29
15.2
Adverse Events (AE) ..........................................................................29
15.2.1
All Adverse Events.............................................................................31
15.2.2
Adverse Events Leading to Treatment Discontinuation.....................32
15.2.3
The listing of all AEs leading to avelumab discontinuation will 
also be provided Deaths......................................................................32
CCI


Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
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15.2.4
Serious Adverse Events ......................................................................33
15.2.5
Adverse Events of Special Interest.....................................................33
15.3
Clinical Laboratory Evaluation...........................................................34
15.4
Vital Signs ..........................................................................................37
15.5
Other Safety or Tolerability Evaluations............................................38
15.5.1
ECG ....................................................................................................38
15.5.2
Eastern Cooperative Oncology Group/ ECOG Performance Status...39
16
Analyses of Other Endpoints..............................................................39
16.1
Pharmacokinetics................................................................................39
16.2
Pharmacodynamics.............................................................................41
16.3
Immunogenicity..................................................................................42
16.4
Quality of Life ....................................................................................43
17
Reference ............................................................................................44
18
Appendix.............................................................................................45
18.1
Important Protocol Deviations............................................................45
18.2
Description of the Case Definition for Assessment of Immune-
Related AEs and IRRs ........................................................................48
18.3
CTCAE Toxicities of Laboratory Evaluations ...................................50
Integrated Analysis Plan ......................................................................................................1
Signature Page
2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................9
3
Modification History ..........................................................................12
4
Purpose of the Integrated Analysis Plan.............................................12
5
Objectives and Endpoints ...................................................................12
6
Overview of Planned Analyses...........................................................13
6.1
Interim Analysis..................................................................................13
6.2
Primary Analysis ................................................................................13
6.3
Final Analysis .....................................................................................13
7
Changes to the Planned Analyses in the Clinical Trial Protocol........14
CCI


Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
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8
Protocol Deviations and Analysis Sets...............................................14
8.1
Definition of Protocol Deviations.......................................................14
8.2
Definition of Analysis Sets.................................................................14
9
General Specifications for Data Analyses ..........................................15
9.1
Data Handling After Cut-off Date ......................................................15
9.2
Pooling of Centers ..............................................................................15
9.3
Presentation and Definition of General Considerations .....................15
9.3.1
Presentation of Continuous and Qualitative Variables.......................15
9.3.2
Definition of Baseline.........................................................................16
9.3.3
Definition of Duration ........................................................................16
9.3.4
Conversion Factors.............................................................................16
9.3.5
Handling of Missing Data...................................................................16
9.3.6
Presentation of PK Concentration Data..............................................17
9.3.7
Presentation of PK Parameter Data ....................................................17
9.3.8
Software..............................................................................................18
10
Trial Subjects......................................................................................18
10.1
Disposition of Subjects and Discontinuations....................................18
10.2
Protocol Deviations ............................................................................19
10.2.1
Important Protocol Deviations............................................................19
11
Demographics and Other Baseline Characteristics.............................19
11.1
Demographics.....................................................................................19
11.2
Medical History ..................................................................................20
11.3
Other Baseline Characteristics............................................................20
12
Previous or Concomitant Medications/Procedures.............................22
12.1
Prior Anti-Cancer Treatment and Procedures.....................................22
12.2
Prior or Concomitant Medication and Procedures..............................23
12.3
Anti-cancer Post-treatment .................................................................24
13
Treatment Compliance and Exposure.................................................24
13.1
Pre-medication....................................................................................24
13.2
Exposure to Study Drug......................................................................24
13.3
Treatment Re-Initiation ......................................................................27
CCI


Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
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15
Safety Analyses ..................................................................................31
15.1
Dose Limiting Toxicity (DLT)...........................................................32
15.2
Adverse Events (AE) ..........................................................................32
15.2.1
All Adverse Events.............................................................................34
15.2.2
Adverse Events Leading to Treatment Discontinuation.....................35
15.2.3
The listing of all AEs leading to avelumab discontinuation will 
also be provided Deaths......................................................................35
15.2.4
Serious Adverse Events......................................................................36
15.2.5
Adverse Events of Special Interest.....................................................36
15.3
Clinical Laboratory Evaluation...........................................................37
15.4
Vital Signs ..........................................................................................40
15.5
Other Safety or Tolerability Evaluations............................................41
15.5.1
ECG ....................................................................................................41
15.5.2
Eastern Cooperative Oncology Group/ ECOG Performance Status...42
16
Analyses of Other Endpoints..............................................................42
16.1
Pharmacokinetics................................................................................42
16.2
Pharmacodynamics.............................................................................44
16.3
Immunogenicity..................................................................................45
16.4
Quality of Life ....................................................................................46
17
Reference ............................................................................................47
18
Appendix.............................................................................................48
CCI
CCI


Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
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18.1
Important Protocol Deviations............................................................48
18.2
Description of the Case Definition for Assessment of Immune-
Related AEs and IRRs ........................................................................51
18.3
CTCAE Toxicities of Laboratory Evaluations ...................................53


Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
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2
List of Abbreviations and Definition of Terms
ADA
Antidrug antibody
AE 
Adverse event
ALT 
Alanine aminotransferase
AST 
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical classification
AUC
Area under the concentration-time curve
AUC0-∞
Area under the concentration-time curve from time zero to infinity
AUC0-t
Area under the concentration-time curve from time zero to time t
AUC0-tau
Area under the concentration-time curve from time zero to tau, the 
respective dosing interval, i.e., one- or two-week
AUC0-tau/dose
Dose-normalized AUC0-tau
AUCextra%
Percentage of area under the serum concentration-time curve from 
time zero to infinity (AUC0-∞) obtained by extrapolation
BLQ
Below the limit of quantification
BMI
Body mass index
Clast
Last quantifiable concentration
Cmax
Maximum serum concentration
Cmax/dose
Dose-normalized Cmax
Cmin
Minimum serum concentration
Ctrough
Serum concentration observed immediately before next dosing
CR 
Complete response
CRF
Case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DCR
Disease control rate
DLT 
Dose-limiting toxicity
CCI


Avelumab   
                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
C O N F I D E N T I A L
I N F O R M A T I O N
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ECG
Electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
eCRF 
Electronic case report form
EOT 
End-of-Treatment
GeoCV%
Geometric coefficient of variation
GeoMean 
Geometric mean
HIV 
Human immunodeficiency virus
ICF 
Informed Consent Form
ICH 
International Council for Harmonization
IMP 
Investigational medicinal product
irAE 
Immune-related adverse event
IV 
Intravenous(ly)
!z
Terminal elimination rate constant
Max
Maximum
Mean
Arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MSI 
Microsatellite instability
MTD 
Maximum tolerated dose
NCI 
National Cancer Institute
NE
Not Evaluable
PD 
Progressive disease/disease progression
PK 
Pharmacokinetic(s)
CCI
CCI
CCI
CCI
CCI
CCI


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MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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PT
Preferred Term
RECIST 
Response Evaluation Criteria in Solid Tumors
SAE 
Serious adverse event
SCR
Screening Analysis Set
SDTM
Study Data Tabulation Model
SEM
Standard error of the mean
SOC
System Organ Class
IAP 
Integrated Analysis Plan
IRR
Infusion Related Reactions
SD
Stable disease or standard deviation
SOD
Sum of longest diameter for non-nodal lesion and short axis for 
nodal lesion
t1/2
Elimination half-life
T4 
Thyroxine
TEAE 
Treatment-emergent adverse event
TIL 
Tumor infiltrating lymphocyte
tmax
Time to reach maximum serum concentration
TTR 
Time to response
TSH 
Thyroid-stimulating hormone
ULN 
Upper limit of normal


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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3
Modification History
Unique
Identifier for
Version
Date of
IAP Version
Author
Changes from the Previous Version
Draft 0.1
03NOV2017
Not Applicable
Draft 0.2
02MAR2018
Modified per sponsor’s comments received on 
22DEC2017 and 02FEB2018
Draft 0.3
11MAY2018
Modified per sponsor’s comments received on 
26MAR2018 and 10MAY2018.
Draft 0.4
29MAY2018
Modified per sponsor’s comments received on 
21MAY2018 and 24MAY2018.
Final 1.0
01JUN2018
Modified per sponsor’s comments received on
25MAY2018 and 31MAY2018.
Final 2.0
13AUG2019
1.
Add appendix of irAE and IRR
2.
Add appendix of Toxicities for Laboratory 
Evaluations
3.
Modify Section 12.2 Medications
4.
Clarify ADA in secondary endpoint. 
5.
Add rule for incomplete date of 
prior/concomitant medication.
6.
Modify definition of re-initiation
4
Purpose of the Integrated Analysis Plan
The purpose of this IAP is to document technical and detailed specifications for the final analysis 
of data collected for protocol MS100070-0035.
Results of the analyses described in this IAP will be included in the Clinical Study Report (CSR). 
Additionally, the planned analyses identified in this IAP will be included in regulatory submissions 
or future manuscripts. Any post-hoc, or unplanned analyses performed to provide results for 
inclusion in the CSR but not identified in this prospective IAP will be clearly identified in the CSR. 
The IAP is based upon section 8 (Statistics) of the trial protocol and protocol amendments and is 
prepared in compliance with ICH E9.
5
Objectives and Endpoints
Objective
Endpoint
IAP 
section
Primary
Objective
∀
To evaluate the maximum tolerated dose (MTD) of 
avelumab (MSB0010718C) monotherapy in Chinese 
subjects.
∀
To characterize the pharmacokinetics (PK) of 
avelumab in Chinese subjects.
Primary Endpoint
∀
Occurrence of DLTs during the 
DLT observation period (first 
21 days of treatment; excluding 
10 mg/kg once weekly cohort).
∀
PK profiles in Chinese subjects.
15
16.1
16.2
PPD
PPD
PPD
PPD
PPD
PPD


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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Secondary 
Objective
∀
To determine the safety and tolerability of avelumab by 
assessing treatment-emergent adverse events (TEAEs) 
and treatment-related AEs for all dose groups 
according to the NCI-Common Terminology Criteria 
for Adverse Events (CTCAE) v4.03.
∀
To characterize immunogenicity of avelumab in 
Chinese subjects.
Secondary Endpoint
∀
Occurrence of TEAEs for all dose 
groups according to NCI-CTCAE 
v4.03.
∀
Occurrence of treatment-related 
AEs for all dose groups according 
to NCI-CTCAE v4.03.
∀
Serum titers of ADA against 
avelumab.
14
15
6
Overview of Planned Analyses
6.1
Interim Analysis
NA.
6.2
Primary Analysis
The primary analysis, including all endpoints analyses, for study data will be conducted at the time 
when all subjects complete PK sample collection (including all samples collected if the treatment 
discontinued earlier than Week 13). The data cut-off time point for primary analysis is set at 
Week 13 (Day 85) of the last subject. 
The data from primary analysis will be summarized in the Clinical Study Report (CSR). 
6.3
Final Analysis
The final analysis of study data will be conducted after End of Study, which is defined as the last 
patient complete 90-day safety follow-up phone call or last patient died, whichever comes first. 
CCI


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MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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Additional data from primary analysis up to this cut-off date will be analyzed and presented as an 
addendum of CSR.
7
Changes to the Planned Analyses in the Clinical Trial Protocol
Biomarker related analysis are not planned in this IAP because biomarker testing will be done at 
a later time.
8
Protocol Deviations and Analysis Sets
8.1
Definition of Protocol Deviations 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being. 
Important protocol deviations include:
Subjects that receive study medication despite not satisfying the inclusion criteria or 
violating exclusion 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.
The following important deviations will be identified and confirmed prior to or at the Data 
Review Meeting:
Deviations from the inclusion and exclusion criteria; 
Deviations post inclusion.
Important protocol deviations are specified in Appendix 18.1, and will be summarized in a table 
and presented in a data listing. All-important protocol deviations should be documented in SDTM
datasets in which identified through sites monitoring, medical review or programming.
8.2
Definition of Analysis Sets
Screening Analysis Set (SCR): all subjects who signed the ICF(s).
DLT Analysis Set (DLT): all subjects with data used for implementing the dose-escalation 
schedule (excluding 6 subjects in 10 mg/kg once weekly cohort). These subjects should have 
received all avelumab administrations in the DLT observation period (first 21 days of treatment) 
or should have stopped treatment because of DLTs in the DLT observation period.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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Safety Analysis Set (SAF): all subjects who have received at least 1 dose of avelumab. The Safety 
Analysis Set will be used for all analyses of safety and efficacy.
Efficacy Population: all subjects who have received at least 1 dose of avelumab and have 
measurable disease at baseline according to Investigator assessment.
PK Analysis Set: all subjects who receive at least one dose of avelumab, and provide at least one 
measurable post-dose concentration.
Immunogenicity Analysis Set: The immunogenicity analysis set will include all subjects who 
receive any dose of avelumab and who have at least one valid ADA result (including negative, 
positive-TNR).
9
General Specifications for Data Analyses
9.1
Data Handling After Cut-off Date
Data after cut-off date do not undergo the cleaning process. The only exception is the date of death
on “DEATH” eCRF page and the date last known to be alive from the “FUPSTAT” eCRF page.
Generally, data others than the date of death and the date last known to be alive obtained after the 
cut-off will not be displayed in any listings or used for summary statistics, e.g., laboratory values 
of samples taken after cut-off date, AE with onset date after cutoff date etc. will not be included 
in any analysis or listing. However, AEs or medications with onset date before the cut-off will be 
displayed even if their end date is after the cut-off; either as ongoing or the end date will be reported 
(even though it is after the cut-off). 
The data handling for cut-off date will be implemented at SDTM level.
9.2
Pooling of Centers
In order to provide overall estimates of the treatment effect, data will be pooled across centers. 
The factor center will not be considered in statistical models.
9.3
Presentation and Definition of General Considerations 
9.3.1
Presentation of Continuous and Qualitative Variables
Continuous variables will be summarized using descriptive statistics, i.e. 

number of subjects (N), number of subjects with non-missing values 

mean, standard deviation (SD)

median, 25th Percentile - 75th Percentile (Q1-Q3)


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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
minimum (Min) and maximum (Max)
Qualitative variables will be summarized by counts and percentages.               
Unless otherwise stated the calculation of proportions will be based on the number of subjects of 
the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category.
9.3.2
Definition of Baseline
The last non-missing measurement (scheduled or unscheduled) prior to the first trial drug 
administration will be used as the baseline measurement. Definition of baseline value will be used 
as baseline for all safety and efficacy analysis. If an assessment is planned to be performed on 
Week 1 Day 1 and the assessment is performed on the same day as the first dose of study treatment, 
it will be assumed that it was performed prior to study treatment administration if assessment time 
point is not collected or is missing. If assessment time points are collected, the observed time point 
will be used to determine pre-dose on study day 1 for baseline calculation. Unscheduled 
assessments will be used in the determination of baseline. However, if time is missing, an 
unscheduled assessment on study day 1 will be considered to have been obtained after study 
treatment administration.
9.3.3
Definition of Duration
Duration will be calculated by the difference of start and stop date + 1, unless otherwise specified.
9.3.4
Conversion Factors
The following conversion factors will be used to convert days into weeks or months or years, or 
vice versa:

1 week = 7 days

1 month = 30.4375 days

1 year = 365.25 days
9.3.5
Handling of Missing Data
Unless otherwise specified (Section 11, 13, 14 and 15), missing data will not be imputed. 
In all subject data listing imputed values will be presented. In all listings imputed information will 
be flagged. Partial dates, which are not to be imputed according to this IAP, will be presented in 
the format like “_____YYYY”. In case imputation is defined, imputed date with flag (i.e., D for 
day, M for month) will be reported.


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MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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Missing statistics, e.g. when they cannot be calculated, should be presented as “NA”.  For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “NA”.
9.3.6
Presentation of PK Concentration Data
Individual PK concentrations will be reported with the same precision as the source data provided 
by the bioanalytical laboratory or clinical laboratory regardless of how many significant figures or 
decimal places the data carry. Actual elapsed sample collection times will be rounded to 2 decimal 
places for reporting purposes only, in by-subject listings.
Pharmacokinetic concentration data will be descriptively summarized using: number of non-
missing observations (n), arithmetic mean (Mean), standard deviation (SD), coefficient of 
variation (CV%), minimum (Min), median (Median), and maximum (Max). 
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 concentration data:

Mean, Min, Median, Max: 
3 significant digits

SD:
4 significant digits

CV%:
1 decimal place
Values below the lower limit of quantification (LLOQ) will be taken as zero in the calculation of 
descriptive statistics for avelumab serum concentrations.
9.3.7
Presentation of PK Parameter Data
Pharmacokinetic parameter data will be descriptively summarized using: number of non-missing 
observations (n), number of missing observations (n), Mean, SD, CV%, standard error of the mean 
(SEM), Min, Median, Max, geometric mean (GeoMean), the geometric coefficient of variation 
(GeoCV%), and the 95% confidence interval (CI) for the GeoMean (LCI 95% GM, UCI 95% 
GM). 
Pharmacokinetic parameter Cmax will be reported with the same precision as the source data and 
tmax will be reported to two decimal places. All other PK parameters will be reported to 3 significant 
figures. In export datasets, as well as in the Study Data Tabulation Model (SDTM) PP/XD domain, 
PK parameters will be provided with full precision, and will not be rounded. Descriptive statistics 
of PK parameter data will be calculated using full precision values, and rounded for reporting 
purposes only. 
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data:

Mean, Min, Median, Max, GeoMean, 95% CI: 
3 significant digits


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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
SD, SEM:
4 significant digits

CV%, GeoCV%:
1 decimal place 
9.3.8
Software
All statistical analyses will be performed using SAS® software version 9.4. 
Pharmacokinetic parameters will be derived using noncompartmental methods with the validated 
computer program Phoenix® WinNonlin® 6.4 or higher (Certara, L.P., Princeton, New Jersey, 
USA). Pharmacokinetic figures will be developed using SigmaPlot® 12.5 or higher (Systat 
Software, Inc, San Jose, California, USA), Phoenix®WinNonlin® 6.4 or higher, or SAS® Windows 
Version 9.4 or higher (Statistical Analysis System, SAS-Institute, Cary, North Carolina, USA).
10
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.
10.1
Disposition of Subjects and Discontinuations
Descriptive statistics will be used to summarize subject disposition and reason for discontinuation
by dose level/cohort and in overall, based on the electronic case report form (eCRF) data.

Number of subjects screened

Number of subjects who discontinued before treatment overall and by the main reason

Number of subjects who discontinued from the trial after randomization, grouped by the 
primary reason

Number of subjects who discontinued from the trial treatment by the primary reason (e.g. 
subject did not meet all eligibility criteria, adverse event, lost to follow-up, protocol non-
compliance, death, progressive disease, withdrew consent from avelumab, other)

Number of subjects who received at least 1 dose of trial treatment 

Number of subjects still on treatment

Number of subjects re-initiated the trial treatment 


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MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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10.2
Protocol Deviations
10.2.1
Important Protocol Deviations
The following summary tables and listings of important protocol deviations will be provided in 
Screening analysis set (separately for the inclusion/exclusion criteria or post inclusion deviations):

Frequency table per reason of important protocol deviations

Listing of important protocol deviations
11
Demographics and Other Baseline Characteristics
Analysis sets: Safety analysis set
11.1
Demographics
Demographic characteristics will be summarized by dose level/cohort and overall as follows:

Sex: Male, Female.

Race: Asian, Other.

Ethnicity: Chinese, Other.

Age (years): descriptive statistics.

Age categories: < 65 years, ≥65 years (further break-down: 65 - < 75 years, 75 - < 85 
years, ≥85 years).
Specifications for computation:

Age (years): (date of given informed consent – date of birth + 1) / 365.25. The integer part 
of the calculated age will be used for reporting purpose.

In case of missing day for at least one date, but month and year available for both 
dates:
For the derivation of age, the day of informed consent and the day of birth will be set to 1 
       and the formula above will be used.

In case of missing month for at least one date, but year available for both dates: 
For the derivation of age, the day and the month of informed consent and the day and month 
       of birth will be set to 1 and the formula above will be used.

BMI (kg/m2) = weight(kg)/[height(m)]2
A supportive demographic listing will be provided.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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11.2
Medical History
The summary tables by dose level/cohort and overall for Medical History will also be provided 
detailing the number and percentage of subjects by Medical Dictionary for Regulatory Activities 
(MedDRA) in terms of primary System Organ Class (SOC) (ordered alphabetically) and Preferred 
Term (PT) (ordered alphabetically); each subject will be counted only once within each PT or SOC
(eCRF” MEDICAL HISTORY”).
Medical history will be displayed in terms of primary SOC and PT in alphabetical order and also 
listed.
11.3
Other Baseline Characteristics
Information of other baseline characteristics collected at the baseline evaluation visit will be 
summarized in total and by dose level/cohort. Summary statistics will be presented for:

Serology: Hepatitis B, hepatitis C, and HIV tests

Nicotine use status: Never, Regular, Occasional, Former

Nicotine Consumption: summary statistics

Alcohol use status: Never, Regular, Occasional, Former

ECOG performance status
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 more than 50% of waking hours.
3: Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4: Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5: Dead.
Baseline 
characteristics 
with 
respect 
to 
vital 
signs, 
physical 
examinations, 
and 
hematology/biochemistry will be part of Section 15.
Disease history
Disease history is collected in “DISEASE HISTORY” pages.
Summary statistics for the following parameters will be presented by treatment dose 

Site of primary tumor


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MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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
Metastatic sites

Time since initial diagnosis (months) 

Time since documented, locally advanced, inoperable or metastatic disease (months)

TNM classification at initial diagnosis: each T, N, M category will be described (TX, T0, 
N1, etc.)

TNM classification at study entry
Specifications for computation:

Time since initial cancer diagnosis (months) = (date of first avelumab administration – date 
of initial cancer diagnosis)/30.4375

Time since documented, locally advanced, inoperable or metastatic disease (months) = 
(date of first avelumab administration – date of documented, locally advanced, inoperable 
or metastatic disease)/30.4375

Time since progression disease (months) = (date of first administration – date of
progression disease) / 30.4375
Incomplete dates for disease history (initial diagnosis date, date of documented, locally advanced, 
inoperable or metastatic disease diagnosis, date of response or progression in prior treatment) will 
be imputed as follows:

If the day is missing, it will be imputed to the 15th day of the month.

If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st.

If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st.

If the date is completely missing, no imputation will be performed.
Listing of disease history will be provided with all relevant data (primary site of tumor, sub-site,
initial diagnosis date, first occurrence of locally advanced, inoperable or metastatic disease, 
histopathological classification, metastasis site, TNM classification, etc.) and derived variables 
used in the above table.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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12
Previous or Concomitant Medications/Procedures
12.1
Prior Anti-Cancer Treatment and Procedures
The prior anti-cancer treatments and procedures are collected under the “PRIOR ANTI-CANCER 
SURGERIES”, “PRIOR ANTI-CANCER DRUG THERAPIES”, “PRIOR ANTI-CANCER 
RADIOTHERAPY”, eCRF pages.
The overall summary of presence of prior anti-cancer treatments/procedures tables will include:

Number of subjects with at least one prior anti-cancer drug therapy

Type of therapies: Cytotoxic therapy / Endocrine therapy / Monoclonal antibodies therapy 
/ Molecular Target Therapy / Immunotherapy / Other

Intent of therapy: Neoadjuvant / Adjuvant / Metastatic or Locally advanced

Best response: Complete Response (CR) / Partial Response (PR) / Stable Disease (SD) / 
Progressive Disease (PD) / Non-Complete Response/Non-Progressive Disease (Non CR/
Non PD) / Not Evaluable / Unknown

Time since documented progression disease (months)

Number of subjects with at least one prior radiotherapy 

Total dose (Gy), (mCi)

Number of fractions

Best response: Complete Response (CR) / Partial Response (PR) / Stable Disease (SD) / 
Progressive Disease (PD) / Non-Complete Response/Non-Progressive Disease (Non 
CR/Non PD) / Not Evaluable / Unknown

Number of subjects with at least one prior anti-cancer surgery 

Curative intent for surgery: yes/no

Outcome of surgery: No residual tumor after resection (R0) / Tumor/metastases not 
resected completely with microscopic residual lesions (R1) / Tumor/metastases not 
resected completely with macroscopic residual lesions (R2) / Metastases not resected (NR) 
/ Other 
The following listings of prior anti-cancer treatments and procedures will also be provided: 

Listing of prior anti-cancer drug therapies

Listing of prior surgeries

Listing of prior radiotherapy


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MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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12.2
Prior or Concomitant Medication and Procedures
Medications
Concomitant medications are medications, other than trial medications, which are taken by 
subjects any time on-trial (on or after day 1 of treatment); Or any medication which are taken 
within 30 days after last dose of trial drug. Prior medications are medications, other than trial 
medications and premedications, which started and stopped before administration of trial drug.
Prior and Concomitant medications will be summarized from the “CONCOMITANT 
MEDICATIONS DETAILS” eCRF page. ATC-2nd level and PT will be tabulated as given from 
the WHO-DD dictionary current version. In case multiple ATC’s are assigned to a drug, all ATC-
2nd level will be used for reporting. Prior and Concomitant medications will be listed. The listing 
will include: subject identification number, dose level/cohort and all corresponding collected data-
field on the corresponding eCRF pages, as well as a flag to identify each medication as Prior or 
Concomitant.
Incomplete prior/concomitant medication dates will be imputed as follows:

If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment.

If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015. 

If both the day and month of medication start date are missing but the start year is equal to 
the start of study treatment, then the medication date will be replaced by the start of study 
treatment. For example, if the medication start date is --/---/2014, and study treatment start 
date is 19/NOV/2014, then the imputed medication start date will be 19/NOV/2014.

In all other cases the missing medication day or missing medication month will be replaced 
by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing only), 
if not resulting in a date later than the date of patient's death. In the latter case the date of 
death will be used to impute the incomplete stop date. 

In all other cases the incomplete medication stop date will not be imputed.
Procedures
Prior and concomitant status for Procedures is defined using the same rule as for medications.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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Prior and Concomitant procedures will also be listed including: subject identification number, 
cohort and all corresponding collected data-field on the corresponding eCRF page. A flag will be 
added to identify each procedure as Prior or Concomitant.
12.3
Anti-cancer Post-treatment
The data collected from the “ANTI-CANCER TREATMENT AFTER DISCONTINUATION, 
RADIOTHERAPY AFTER DISCONTINUATION DETAILS and SURGERY AFTER 
DISCONTINUATION DETAILS” eCRF page will be listed.
The anti-cancer treatments after discontinuation will also be summarized in terms of:
Number of subjects with at least one anti-cancer drug therapy after discontinuation

Type of therapies: Cytotoxic therapy / Endocrine therapy / Monoclonal antibodies therapy 
/ Small molecules / Immunotherapy / Other

Intent of therapy: Neoadjuvant / Adjuvant / Metastatic or Locally advanced

Best response: Complete Response (CR) / Partial Response (PR) / Stable Disease (SD) / 
Progressive Disease (PD) / Non-Complete Response/Non-Progressive Disease (Non CR /
Non PD) / Not Evaluable/ Unknown
13
Treatment Compliance and Exposure
Analysis Sets: Safety analysis set
13.1
Pre-medication
The number of subjects receiving pre-medication will be summarized for each treatment visit 
based on “PREMEDICATION DETAILS” eCRF page (subjects for whom the question “Has the
subject received premedication before avelumab infusion?” (eCRF PREMEDICATION) is 
answered “Yes” at the corresponding visit). Percentages will be calculated on the number of 
subjects who actually received an infusion at the associated visit. In addition, a listing of 
premedication displaying dose cohort, subject identifier, date and time of administration, name of 
treatment, dose, unit and route of administration will be provided.
13.2
Exposure to Study Drug
The extent of exposure for avelumab will be characterized by duration (weeks), number of 
administrations, cumulative dose (mg/kg), dose intensity (mg/kg/cycle), relative dose intensity, 
number of dose delays.
Descriptive statistics will be used to summarize treatment exposure, based on the data being 
collected in “AVELUMAB ADMINISTRATION DETAILS” page of eCRF. Summaries will be 
performed on the safety analysis set. Subjects will receive an IV infusion of avelumab (over 1 hour 


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[- 10 minutes/+ 20 minutes, i.e., 50 to 80 minutes]) once every 2 weeks or, if 20 mg/kg once every 
2 weeks have been established, 10 mg/kg every week for the first 12 weeks and once every 2 weeks 
thereafter starting at Week 13.
Safety analyses will be performed on the Safety Analysis Set. The safety endpoints will be 
tabulated by dose level and cohort, using descriptive statistics.
(1) Avelumab (3, 10, 20 mg/kg) once every 2 weeks (Q2W):

The duration of avelumab (weeks) during the study is defined as:
date of last dose of avelumab - date of first dose of avelumab + 14
7


The cumulative actual treatment dose (mg/kg) of avelumab per subject is the sum of the 
calculated actual dose levels of avelumab that the subject received (i.e. total dose 
administered (mg/kg)).

The dose intensity of avelumab (mg/kg/cycle) per subject is defined as:

Cumulative dose of avelumab  
0.5*[(date of last dose of avelumab – date of first dose of avelumab + 14) / 7]

Total number of infusions received (n)

Relative dose intensity of therapy (%): The relative dose intensity per cycle is defined 
as 100 × actual dose intensity per cycle (mg/kg/cycle)/ (planed dose level per cycle
(mg/kg/cycle)]
(2) Avelumab (10 mg/kg) once weekly (Q1W) for 12 consecutive weeks and then starting at 
Week 13, once every 2 weeks (Q2W):

The duration of avelumab (weeks) for first 12 weeks receiving Q1W dose per 
subject is defined as:
Date of last dose of avelumab(Q1W) – date of first dose of avelumab(Q1W) + 7  
7


The duration of avelumab (weeks) for subsequent weeks receiving Q2W dose per 
subject is defined as:


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Date of last dose of avelumab(Q2W) – date of first dose of avelumab(Q2W) + 14  
7


The cumulative actual treatment dose (mg/kg) of avelumab receiving Q1W dose per 
subject is the sum of the calculated actual dose levels of avelumab that the subject received
of Q1W dose (i.e. total Q1W dose administered (mg/kg)).

The cumulative actual treatment dose (mg/kg) of avelumab receiving Q2W dose per 
subject is the sum of the calculated actual dose levels of avelumab that the subject received
of Q2W dose (i.e. total Q2W dose administered (mg/kg)).

The dose intensity of avelumab (mg/kg/cycle) for first 12 weeks receiving Q1W dose 
per subject is defined as:

Cumulative dose of avelumab (Q1W)  
(date of last dose of avelumab(Q1W)  – date of first dose of avelumab(Q1W)  + 7) / 7

The dose intensity of avelumab (mg/kg/cycle) for subsequent weeks receiving Q2W 
dose per subject is defined as:

Cumulative dose of avelumab (Q2W)
0.5*[(date of last dose of avelumab(Q2W) – date of first dose of avelumab(Q2W) + 14) / 7]

Total number of infusions received (n) for Q1W dose and Q2W dose, respectively

Relative dose intensity of therapy (%) for Q1W dose: The relative dose intensity per 
cycle is defined as 100 × actual dose intensity per cycle (mg/kg/cycle) for Q1W dose/ 
(planed dose level per cycle(mg/kg/cycle) for Q1W dose

Relative dose intensity of therapy (%) for Q2W dose: The relative dose intensity per 
cycle is defined as 100 × actual dose intensity per cycle (mg/kg/cycle) for Q2W/ (planed 
dose level per cycle (mg/kg/cycle) for Q2W dose. 
Dose reduction is not allowed per protocol and will not be summarized. 
Per protocol, Avelumab will be administered as 1-hour intravenous infusion. Subjects will receive
the trial treatment once every 2 weeks (excluding 10 mg/kg once weekly cohort). 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 


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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 safety analysis set 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 drug administration will include subject identifier, assigned dose level/cohort, 
number of days relative to previous administration date, dose delay (yes/no), duration of
administration and other relevant information collected on the Avelumab Administration Details 
eCRF page.
13.3
Treatment Re-Initiation
For subjects (Who achieve a confirmed CR on Avelumab and subsequently develop PD after 
stopping therapy; Who under disease progression due to brain metastasis; Who under disease 
progression mainly due to a metastatic lesion (nodal or visceral)) will be treated as EOT, but can 
reinitiate Avelumab therapy if the relevant criteria are met, per investigator and medical monitor 
decision. Treatment re-initiation and discontinuation after re-initiation will be tabulated and 
presented in the subject disposition.
For subjects who ever achieved CR, also defined as retreated subjects according to protocol, sparse 
PK and ADA blood samples will be collected according to the schedule as indicated in protocol 
Table 1-5. However, for subjects who under disease progression due to brain metastasis or a 
metastatic lesion (nodal or visceral), PK and ADA blood samples will be collected according to 
the schedule as indicated in protocol Table 1-3(Table 1-4), or Table 1-5. 
CCI


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CCI
CCI


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CCI


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CCCI


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15
Safety Analyses
Safety analyses will be done on the safety analysis set and according to the as-treated principle.
CCI


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15.1
Dose Limiting Toxicity (DLT)
The primary endpoint of the study is:

Occurrence of DLTs during the DLT observation period. The number and proportion of 
subjects experiencing DLTs will be reported by dose level based on the DLT Analysis 
Set (excluding 10 mg/kg once weekly cohort).
Dose limiting toxicity (DLT) refers to relevant toxicity induced by the drug during the first 21 days 
of treatment; excluding10 mg/kg once weekly cohort, severity of which is clinically unacceptable, 
limiting further dose escalation. According to toxicity evaluation criteria in NCI CTCAE V4.03, 
the observation period for a DLT is the 21-day period after the first administration of avelumab 
for subjects with data used for implementing the dose-escalation algorithm for dose determination.
DLT data will be captured from the eCRF “ADVERSE EVENTS DETAILS” form.
The Incidence rates of DLT per each dose level during DLT observation will be presented as well 
as by SOC and PT. DLT summary will be based on DLT set.
15.2
Adverse Events (AE)
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.
If the severity/intensity of a particular AE is not specifically graded by the guidance document, the 
Investigator is instructed to revert to the general definitions of Grade 1 through Grade 5 and use 
his or her best medical judgment.
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
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). The severity of AEs will be graded by the investigator using the NCI-CTCAE version 
4.03.
Treatment emergent adverse events (TEAEs) are those events that emerge during treatment having 
been absent pre-treatment, or worsen relative to the pre-treatment state and with onset dates 


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occurring within the first dosing day of study dose levels until 30 days after the last dose of study 
treatment.
All analyses described Error! Reference source not found.will be based on TEAEs (started 
during the on-treatment period) if not otherwise specified. The AE listings will include all AEs 
(whether treatment-emergent or not). AEs outside the on-treatment period will be flagged in the 
listings. A separate listing including AEs started after the on-treatment period will also be 
provided. 

Related Adverse Events: adverse events with relationship to study treatment (as 

Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported 
by the investigator and those of unknown relationship (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).

Related SAEs

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).

Related AE Leading to Treatment Discontinuation

Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5).

Related AE Leading to Death

Immune Related Adverse Events (irAE): immune related adverse events are 
identified via customized MedDRA PT queries and additionally classified by 
investigator according to case definition (two level approach). Details are included in 
Appendix 18.2.

Infusion Related Reactions (IRR): IRRs are identified based on a list of MedDRA 
PTs. The detailed criteria of the timing relationship to infusion are specified in Appendix 
18.2.
Incomplete AE-related dates will be handled as follows:

Incomplete or missing start date:
o
In case the onset date is completely missing or the onset is in the same year (if the 
onset year is available only) or the onset is in the same month and year (if the day 
is missing) as start of study treatment, then the onset date will be replaced by the 
minimum of start of study treatment date and AE resolution date (imputed, if 
incomplete).
o
In all other cases the missing onset day or onset month will be replaced by 01.

Incomplete or missing stop date:


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o
Incomplete stop dates will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of subject's death. In the latter 
case the date of death will be used to impute the incomplete stop date.
o
In all other cases, the incomplete stop date will not be imputed.
AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA). The severity of AEs will be graded by the investigator using the NCI-CTCAE version 
4.03.
The AE reporting period for safety surveillance begins when the subject is included in the study 
(date of first signature of informed consent) and continues for all SAEs and treatment-related non-
serious AEs through to the study’s Safety Follow-up Phone Call, defined as 90 days (± 7 days) 
after the last administration of avelumab. Any SAE suspected to be related to avelumab must be 
reported whenever it occurs, irrespective of the time elapsed since the last administration of 
avelumab.
15.2.1
All Adverse Events
Treatment-emergent Adverse events will be summarized by worst severity (according to NCI-
CTCAE version 4.03) per subject, using MedDRA (latest version) PT as event category and 
MedDRA (latest version) SOC body term as Body System category. 
Unless otherwise stated adverse events will be displayed in terms of frequency tables: PT and 
primary SOC in alphabetical order. 
If an adverse event is reported for a given subject more than once during treatment, the worst 
severity and the strongest relationship to trial treatment will be tabulated.
Adverse events related to trial treatment are those events with relationship unrelated or related. In 
case a subject had events with missing and non-missing grades, the maximum of the non-missing 
grades will be displayed.
An overview table of TEAEs will be provided detailing the number and percentage of subjects 
with:

Any TEAE

Any trial drug related TEAE

Any serious TEAE

Any trial drug related serious TEAE

Any TEAE by NCI-CTCAE severity grade (3, 4)

Any trial drug related TEAE by NCI-CTCAE severity grade (3, 4) 

Any TEAE leading to treatment discontinuation

Any trial drug related TEAE leading to treatment discontinuation


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
Any TEAE leading to death

Any related TEAE leading to death

Treatment-emergent irAEs

Related treatment-emergent irAEs

Treatment-emergent IRRs

Related treatment-emergent IRRs 
The following summary tables will also be provided for TEAEs detailing the number and 
percentage of subjects by MedDRA primary SOC (ordered alphabetically) and PT (ordered 
alphabetically):

TEAEs

Trial drug related TEAEs 

TEAEs by worst grade (for each subject, maximal grade within the same preferred term)

Trial drug related TEAEs by worst grade

Grade 3/4 TEAEs

Grade 3/4 related TEAEs

TEAEs leading to death

Trial drug related TEAEs leading to death
All TEAEs will be listed to support these tables.
15.2.2
Adverse Events Leading to Treatment Discontinuation
The frequency (number and percentage) of patients with each of the following will be presented 
for TEAEs leading to permanent discontinuation of avelumab, by treatment dose group:

AEs leading to discontinuation of avelumab by SOC and PT

Related AEs leading to discontinuation of avelumab by SOC and PT 
15.2.3
The listing of all AEs leading to avelumab discontinuation will 
also be provided Deaths
The frequency (number and percentage) of patients who died during the trial period and who died 
within 30 days after last dose or 60 days after first dose of avelumab as well as the primary reason 
for death, will be tabulated based on information from the “DEATH” and “SUBJECT STATUS / 
SURVIVAL FOLLOW-UP” eCRF page. 
The following summaries will be provided:


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
All deaths 

Number of deaths within 30 days after last dose of study treatment

Number of deaths within 60 days after first dose of study treatment

Primary Reason of death

Progressive disease and/or disease related condition

Event unrelated to avelumab

Event related to avelumab

Event related to Physician's Choice

Unknown 
In addition, date and cause of death will be provided in an individual subject data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
number of infusions received for treatment, day relative to first infusion and day relative to most 
recent infusion) and will include the following information:

AEs with fatal outcome (list preferred terms of AEs with outcome = Fatal, as well as AEs 
of Grade 5)

Flag for death within 30 days of last trial drug treatment

Flag for death within 60 days of first trial drug treatment
15.2.4
Serious Adverse Events
The following summary tables will be provided for serious TEAEs detailing the number and 
percentage of subjects by MedDRA primary SOC (ordered alphabetically) and PT (ordered 
alphabetically); each subject will be counted only once within each PT or SOC:

SAEs by SOC and PT

Related SAEs by SOC and PT
The listings of all SAEs will also be provided including a flag for SAEs with onset outside of the 
on-treatment period.
15.2.5
Adverse Events of Special Interest
Any AE that is suspected to be a potential irAE and infusion related reactions will be considered 
an adverse event of special interest (AESI). The frequency (number and percentage) of patients 
with each of the following will be presented for treatment emergent irAEs, by dose level/cohort: 

Any irAEs


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
Any related irAEs

Any serious irAEs

Any related serious irAEs

Any irAEs by NCI-CTCAE severity grade (3, 4)

Trial treatment related irAEs by NCI-CTCAE severity grade (3, 4) 

Any irAEs leading to treatment discontinuation

Any related irAEs leading to treatment discontinuation

Any irAEs leading to death

Any related irAEs leading to death
The frequency (number and percentage) of patients with each of the following will be presented 
for treatment emergent IRRs, by treatment cohort: 

Any IRRs

Any related IRRs

Any serious IRRs 

Any related serious IRRs 

Any IRRs by NCI-CTCAE severity grade (3, 4)

Trial treatment related IRRs by NCI-CTCAE severity grade (3, 4) 

Any IRRs leading to treatment discontinuation

Any related IRRs leading to treatment discontinuation

Any IRRs leading to death

Any related IRRs leading to death
15.3
Clinical Laboratory Evaluation
All laboratory assessments are performed at local laboratories and comply with local requirements.
Laboratory values (including corresponding normal ranges) from local laboratories will be 
converted into the standard units by data management. The results in standard units will be used 
for the analyses.


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Laboratory results will be classified according to the NCI-CTCAE toxicity grading version 4.03. 
If toxicities for high and low values of a specific parameter are defined, these toxicities will be 
analyzed separately for the parameter as “Parameter low” and “Parameter high” (appendix 18.3).
Laboratory results that are not part of the NCI-CTCAE will be presented according to the 
categories: below normal limits, within normal limits and above normal limits (according to the 
local laboratories normal ranges).

Hematology: Hematocrit, Hemoglobin, Platelet count, Red blood cells (RBC) count, 
White Blood Cell Count, Absolute lymphocytes count, Lymphocytes, Absolute 
Neutrophils count, Neutrophils, Absolute monocyte count, Monocytes, Absolute 
eosinophil count, Eosinophils, Absolute basophil count, Basophils, RBC morphology, 
Absolute reticulocytes count, Reticulocytes, Mean corpuscular hemoglobin (MCH), Mean 
corpuscular volume (MCV), Mean corpuscular hemoglobin concentration (MCHC).

Hemostaseology: Activated partial thromboplastin time (aPTT), Prothrombin time (PT), 
International Normalized Ratio (INR).

Biochemistry: Albumin, Alkaline phosphatase, Alanine Aminotransferase (ALT), 
Amylase, Aspartate Aminotransferase (AST), Gamma Glutamyl Transpeptidase (GGT), 
Blood Urea Nitrogen (BUN), Urea, Calcium, Chloride, Cholesterol, Creatine kinase, 
Creatinine, C-Reactive Protein (CRP), Glucose, Lactate dehydrogenase (LDH), Lipase, 
Phosphorus, Magnesium, Potassium, Sodium, Total bilirubin, Protein total, Uric acid, 
Triglycerides, Hemoglobin A1c.

Hormonal tests: Free Thyroxine (T4), Thyroid-Stimulating Hormone (TSH), Follicle-
stimulating hormone.

Urinalysis: pH, Specific gravity, Protein content, Sediment analysis, Albumin, 
Immunoglobulin G.
NCI-CTCAE grades available:
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). The above analyses apply to the following hematology and 
biochemistry parameters which can be graded per NCI-CTCAE:

Hematology: Hemoglobin, Lymphocytes, Neutrophils, Platelets, White Blood Cell.


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
Biochemistry:
Creatinine, Alanine Aminotransferase, Aspartate Aminotransferase, 
Gamma Glutamyl Transferase, Total Bilirubin, Lipase, Amylase, Albumin, Alkaline 
Phosphatase, Glucose, Uric Acid, Sodium, Potassium, Calcium, Magnesium, Cholesterol,
Creatine kinase, Triglyceride, Phosphorus.
Tables will summarize, separately for hematology and biochemistry parameters, the shift from 
baseline grade to worst on-treatment grade by parameters and dose level. 
NCI-CTCAE grades not available:
The worst on-treatment value for hematology and biochemistry parameters which cannot be 
graded per NCI-CTCAE will be summarized by parameter according to the local laboratories 
normal ranges as follows:

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. 
The above analyses apply to the following hematology and biochemistry parameters which cannot 
be graded per NCI-CTCAE:

Hematology: Hematocrit, Red Blood Cells, RBC morphology, Monocytes, Eosinophils, 
Basophils, Reticulocytes, MCH, MCV,MCHC.

Biochemistry: Total Protein, Blood Urea Nitrogen, Blood Urea, Chloride, C-Reactive 
Protein (CRP), Glucose, Lactate dehydrogenase, Hemoglobin A1c.
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 safety follow-up visits.
Listing of clinically significant hematology values and listing of clinically significant biochemistry 
values will also be provided. Clinically significant values are defined as values with associated 
NCI-CTCAE grade greater or equal to 3. The following information will be included in those 
listings:

Selected dosing information: date of first/last administration

Laboratory parameter with unit

Visit of laboratory parameter measurement

Collection date of laboratory parameter

Value of laboratory parameter

Local laboratories normal ranges for laboratory parameter (lower limit of normal and upper 
limit of normal)


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
Normal range indicator for value of the laboratory parameter (Low, Normal, High)

Associated grade for value of the laboratory parameter according to NCI-CTCAE if 
applicable.
Other laboratory parameters
The following laboratory parameters collected in the CRF will be presented in specific listing 
presenting all collected data-fields in the CRF.

Hemostaseology: Activated partial thromboplastin time (aPTT), Prothrombin time (PT), 
International Normalized Ratio (INR)

Hormone: Free T4 and TSH

Urinalysis: all urinalysis parameters

Pregnancy test

Serology
15.4
Vital Signs
The following Vital Signs measurements will be reported for this study:

Heart rate (beats/min)

Body temperature (⁰C)

Respiration rate (breaths/min)

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Weight (kg)
The maximum changes of vital sign measurements screening/baseline to maximum changes after 
start of 1st treatment will be grouped as follows: 
Body temperature increase
< 1C, 1-<2C, 2-<3C, 3 C
Heart rate increase from baseline <100 beats/min ; ≥100 
beats/min
20 beats/min, >20 – 40 beats/min, >40 
beats/min
Heart rate decrease from baseline <100 beats/min; ≥100 
beats/min
20 beats/min, >20 – 40 beats/min, >40 
beats/min
SBP increase from baseline <140 mmHg; ≥140 mmHg 
20 mmHg, >20 – 40 mmHg, >40 mmHg
SBP decrease from baseline <140 mmHg; ≥140 mmHg,
20 mmHg, >20 – 40 mmHg, >40 mmHg
DBP increase from baseline <90 mmHg; ≥90 mmHg 
20 mmHg, >20 – 40 mmHg, >40 mmHg


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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DBP decrease from baseline <90 mmHg; ≥90 mmHg,
20 mmHg, >20 – 40 mmHg, >40 mmHg
Respiration rate increase from baseline <20 breaths/min; ≥20 
breaths/min
5 breaths/min, >5 – 10 breaths/min, >10 
breaths/min
Respiration rate decrease from baseline <20 breaths/min; ≥20 
breaths/min
5 breaths/min, >5 – 10 breaths/min, >10 
breaths/min
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean,
SD, median, Q1, Q3, minimum, and maximum) of actual values, and absolute changes from 
baseline to each visit.
A listing of vital signs will be prepared in addition. The listing will also include dose level/cohort, 
subject identifier, vital sign parameter (unit), visit, date/time, value, baseline value, and change 
from baseline, and flags for potentially clinically meaningful changes. The listing will be sorted 
by dose level/cohort, subject identifier, vital sign parameter and vital sign measurement date/time.
15.5
Other Safety or Tolerability Evaluations
15.5.1
ECG
A shift table from baseline to the worst on-treatment conclusion will be tabulated with the 
subsequent categories:

Normal ECG

Abnormal ECG

ECG abnormalities non-clinically significant

ECG abnormalities clinically significant

Missing 

Overall
Conclusions are sorted as Normal/Abnormal non-clinically significant/Abnormal clinically 
significant, the latest one being considered as the worst. If no post-baseline data are available the 
worst on-treatment result will be accounted as missing. If significance is not provided, the 
conclusion will be classified as “Abnormal ECG”. This “Abnormal ECG” category will count 
abnormal conclusion with missing significance only.
Quantitative data will also be examined for trends using descriptive statistics (n, missing, mean, 
SD, median, Q1, Q3, minimum, and maximum) of actual values and absolute changes from 
baseline to each visit.
A listing of ECG values will be provided with all information included from the ECG where the 
abnormality was observed. 


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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15.5.2
Eastern Cooperative Oncology Group/ ECOG Performance 
Status
Shifts in ECOG performance status from baseline to worst on-treatment performance status will 
be summarized by dose level/cohort. Missing category will also be included.
A listing will also be provided for ECOG performance status.
16
Analyses of Other Endpoints 
16.1
Pharmacokinetics
Serum concentrations and PK parameters will be listed by dose level, study day, and/or scheduled 
time point, as appropriate, and summarized using descriptive statistics as described in 
Section Error! Reference source not found.. 
Graphical displays of individual and mean (± SD for linear profiles only) serum concentration-
Graphical displays of individual and mean (± SD for linear profiles only) serum concentration-
time profiles will be presented on linear and semi-logarithmic scales by dose level up to 336 hours 
post-dose for the bi-weekly cohorts.  Mean (± SD, linear profiles only) trough serum 
concentration-time profiles will be prepared for the once-weekly and bi-weekly cohorts. Individual 
serum concentration-time profiles will be presented on linear scale by study day for the once-
weekly cohort.
For the PK analysis, pre-dose sample concentrations that are below the limit of quantification 
(BLQ) will be assigned a numerical value of zero for the calculation of AUC. On Day 1, any 
missing pre-dose value will also be assigned a numerical value of zero for the calculation of AUC. 
Any anomalous concentration values observed at pre-dose will be used as such in the PK analysis 
and identified in the CSR. All post-dose BLQ concentrations will be set to ‘zero’ in all cases.
Noncompartmental computation of PK parameters will be performed for the 3 mg/kg, 10 mg/kg, 
and 20 mg/kg once every 2 weeks dose escalation cohorts. Pharmacokinetic parameters will be 
evaluated and listed for all patients who provide sufficient concentration-time data. At least 3 valid, 
post-dose concentrations will be required in the PK profile to obtain any PK parameter estimate.
Individual PK parameters will be calculated using actual elapsed time from dose with a maximum 
of 14 significant digits in the time data (or using scheduled time if actual time is not available). 
The pre-dose sample will be considered as if it had been taken simultaneously with the 
administration of IMP. For any interim analyses, nominal time from dose will be used to calculate 
PK parameters.
Partial area AUC0-tau should be calculated using the scheduled dosing interval, as defined in the 
CTP. The actual dosing interval calculated from CRF time data should not be used. The following 
rules apply when calculating the partial area AUC0-tau within the observed time interval fromT1 to 
T2:


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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If the start time of the interval (T1) occurs before the first observation, the observation at 
T1 will be estimated using the linear interpolant between the first data point and C0. For 
single dose data C0 = 0 when the drug was administered via an extravascular route or via 
infusion, and C0 is the estimated dosing time intercept when the drug was administered as 
an IV bolus.
If either T1 or T2 falls within the time range in which samples were taken, but does not 
coincide with an observed data point, then a linear interpolation is performed to estimate 
the corresponding concentration value.
If the end time of the interval (T2) occurs after the last measurable concentration and the 
terminal regression (λz) is estimable, then λz is used to estimate the concentration at T2. The 
linear trapezoidal rule will be used to calculate the area from the last observation time to 
the end time of the partial area (T2). If λz cannot be estimated the partial area will not be 
calculated.
For each subject in the PK analysis set the following PK parameters will be calculated for 
avelumab on Day 1 in the bi-weekly cohorts, if possible:
AUC0-t
The area under the concentration-time curve from time zero (dosing time) to the 
last sampling time (tlast) at which the concentration is at or above the lower limit of 
quantification. Calculated using the mixed log linear trapezoidal rule (linear up, log 
down). Units: h*µg/mL.
AUC0-tau
The area under the serum concentration-time curve from time zero (dosing time) to 
tau (336 hours), calculated using the mixed log linear trapezoidal rule (linear up, 
log down). Units: h*µg/mL.
AUC0-∞
The area under the serum concentration-time curve from time zero (dosing time) 
extrapolated to infinity, based on the predicted value for the concentration at tlast ,
as 
estimated 
using 
the 
linear 
regression 
from 
λz
determination.
AUC0-∞=AUC0-t+Clast pred/ λz. Units: h*µg/mL.
AUCextra%
The AUC from time tlast extrapolated to infinity given as a percentage of AUC0-. 
AUCextra% = (extrapolated area/AUC0-∞)*100. The predicted AUC0-∞should be 
used. Units: %.
z
Terminal elimination rate constant, determined from the slope of the regression line 
of log(concentration) versus time. Units: h-1.
Cmax
Maximum serum concentration observed, obtained directly from the concentration 
versus time curve. Units: µg/mL.
Clast
Last quantifiable serum concentration observed, obtained directly from the 
concentration versus time curve. Units: µg/mL.
Ctrough
The concentration observed immediately before next dosing.  Units: µg/mL.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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tmax
Time to reach maximum serum concentration, obtained directly from the 
concentration versus time curve. Units: h.
t1/2
Terminal elimination half-life, determined as ln(2)/z.  Units: h.
AUC0-t/dose
Dose-normalized AUC0-t. Actual mg/kg dose administered will be used in the 
calculation of this parameter. Units: (h*µg/mL)/(mg/kg).
AUC0-tau/dose Dose-normalized AUC0-tau. Actual mg/kg dose administered will be used in the 
calculation of this parameter. Units: (h*µg/mL)/(mg/kg).
Cmax/dose
Dose-normalized Cmax. Actual mg/kg dose administered will be used in the 
calculation of this parameter. Units: (µg/mL)/(mg/kg)
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 (λz low, λz upp) to determine λz (t1/2, Interval). 

Number of data points (Nλ) included in the log-linear regression analysis to determine λz.

Goodness of fit statistic (Rsq) for calculation of λz.  
The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on the log-transformed scale. Phoenix 
WinNonlin best-fit methodology will be used as standard. The last quantifiable concentration 
should always be included in the regression analysis, while the concentration at tmax and any 
concentrations <LLOQ which occur after the last quantifiable data point should not be used. 
The coefficient of correlation (Rsq) should be ≥0.800 and the observation period over which the 
regression line is estimated should be at least twofold the resulting t1/2 itself.  If%AUCextra is greater 
than 20%, the rate constants and all derived parameters (e.g., t1/2, AUC0-∞) will be included in the 
parameter outputs and descriptive statistics but will be flagged and discussed appropriately. Any 
flags should be included in the study specific SDTM.
Scatter-plots of individual patient data and GeoMean values of Cmax/dose, AUC0-tau/dose, and 
AUC0-t/dose versus dose will be prepared.
Dose proportionality of PK parameters will be assessed graphically based on exposure data (AUC0-
tau and Cmax).
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing.
16.2
Pharmacodynamics
NA.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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16.3
Immunogenicity
Antidrug antibody (ADA) are assessed before the trial treatment infusion on Days 1, 15, 29, 43, 
85, 127, 169. After Day 169, 1 sample (within 2 hours prior to infusion) every 12 weeks until the 
EOT visit and at the safety follow-up visit (30 days ± 5 days after last treatment) for subjects 
receiving Avelumab once every 2 weeks. For 10 mg/kg once weekly cohort, ADA are assessed 
before the trial treatment infusion on Days 1, 15, 29, 43, 85, 127, 169, and then every 12 weeks 
while on treatment, and at the safety follow-up visit.  If the sample is positive for ADA, it will be 
re-analyzed to determine the titer. The ADA results will be derived based on the algorithm as the 
following table.
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
NA
Positive-TNR
NR = no result, NA = not applicable, TNR = titer no result.
Negative, number, or positive-TNR are valid results while number and positive-TNR are 
considered as positive. Subjects will be characterized into different categories based on the below 
criteria. 
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 
postbaseline result and without positive 
baseline results (including missing, NR)


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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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 
postbaseline 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 
postbaseline result and without positive 
baseline results (including missing, NR)
The frequency and percentage of each category will be presented by dose level/cohort and overall 
in tables based on Safety Analysis Set. 
Listings of ADA results from ever positive ADA subjects will be prepared.

Overview on ADA status: Subject ID, dose level, age, gender, ADA Status, Study Day of 
Start of ADA response, Duration of ADA immunogenicity response (weeks)

Listing of ADA and Ctrough concentrations: Subject ID, dose level, age, Visit and Visit 
Date, ADA result, Date of last prior avelumab infusion, Days since last avelumab 
infusion, Date of last available predose drug concentration at or before ADA assessment 
and corresponding drug concentration

Listing of all PK concentrations, Subject ID, dose level, age, Visit and Visit Date, 
Nominal time, observed avelumab serum concentration, Actual date/time; Hours since
last avelumab infusion.

Listing of immunogenicity data and adverse events (AEs): Subject ID, dose level, age, 
sex, study treatment start and stop date, all dates with positive ADA result, AE start date, 
stop date, preferred term, CTCAE toxicity grade, seriousness, and applicable flags for 
immune-related adverse event (irAE), infusion related reaction (IRR), serious adverse 
event (SAE), or reason for permanent treatment discontinuation.

Listing of immunogenicity data and efficacy endpoints: Subject ID, dose level, age, 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, 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.
16.4
Quality of Life
NA.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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17
Reference
U.S. Department of Health and Human Services, National Institutes of Health National Cancer 
Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. 14 June 
2010.
CCI




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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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Criterion 2: 
Concurrent anticancer treatment(s) (e.g., 
cytoreductive therapy, radiotherapy [with the 
exception of *palliative bone-directed 
radiotherapy and radiotherapy administered 
to superficial lesions], immune therapy, or 
cytokine therapy except for erythropoietin). 
Radiation to more than 30% of the bone 
marrow or with a wide field of radiation 
should not be used within 28 days prior to 
the first administration of avelumab and is 
prohibited throughout the study 
Eligibility and
Entry Criteria
Subject met
exclusion criterion
2
PDEV04
Important
Section
5.3.2
Medical Review required.
Criterion 18:
Clinically significant (that is, active) 
cardiovascular disease: cerebral vascular 
accident/stroke (< 6 months prior to 
enrolment), myocardial infarction (< 6 
months prior to enrolment), unstable angina 
pectoris, congestive heart failure (New York 
Heart Association Classification Class ≥ II), 
or serious cardiac arrhythmia requiring 
medication (including corrected QT interval 
prolongation of > 470 msec calculated 
according to Fridericia and/or pacemaker or 
prior diagnosis of congenital long QT 
syndrome)
Eligibility and
Entry Criteria
Subject met
exclusion criterion
18
PDEV05
Important
Section
5.3.2
Medical Review required.
Subjects that develop withdrawal criteria 
whilst on the study but are not withdrawn
Other criteria
Subject developed 
Significant clinical 
deterioration, but 
continued on the study
PDEV06
Important
Section 5.5.2
Medical review required/ 
Programmatically checked.
Subjects that develop withdrawal criteria 
whilst on the study but are not withdrawn
Other criteria
Subject developed 
Grade ≥4 ADRs, but 
continued on the study
PDEV07
Important
Section 5.5.2
Medical review required/ 
Programmatically checked.
Subjects that develop withdrawal criteria 
whilst on the study but are not withdrawn
Other criteria
Subject developed AE 
resulting in the 
discontinuation of 
avelumab being desired 
or considered necessary 
by the Investigator 
and/or the subject, but 
PDEV08
Important
Section 5.5.2
Medical review required.




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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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18.2
Description of the Case Definition for Assessment of Immune-
Related AEs and IRRs
Immune-Related Adverse Events
Immune-related adverse events (irAEs) will be identified programmatically. AEs which satisfy all
of the following criteria will be flagged as immune-related:
1) The AE preferred term matches a preferred term on the list of pre-selected MedDRA terms.
2) The AE onset occurs after the first study drug administration and no more than 90 days after
last dose.
3) On the AE details eCRF page [aedt], the question “Were Corticosteroids, Immunosuppressants, 
or hormonal therapy (e.g. Thyroid, insulin) applied?” has the answer “Yes” selected.
4) On the irAE specific eCRF page  [irae], either:
a. The question “Does any of the following provide a clear etiology for the event?” has the answer 
“No” selected, indicating that the AE is not attributable to underlying cancer disease/PD, prior or 
concomitant medications/procedures, nor another medical condition such as an infection, pre-
existing disease or investigator´s choice of alternative etiology other than irAE.
OR
b. The irAE specific eCRF indicates that a biopsy was performed and the question “Is the
histopathology/biopsy consistent with an immune-related event?” has the answer “Yes” selected.
In the case that criteria (1) through (3) are met, and entries for condition (4) are missing, the
following rules will be applied:
• If the answer to “Does any of the following provide a clear etiology for the event?” (4a) is 
missing, the event will be considered as irAE (irrespective of biopsy results).
• If the answer to “Is the histopathology/biopsy consistent with an immune-mediated event?” (4b) 
is missing, or if no biopsy was performed, and condition (4a) is not satisfied (i.e. “Yes” is selected 
as the answer to the question “Does any of the following provide a clear etiology for the event?”), 
the event will be considered as a non-irAE.


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                                       Phase I/Ib Multiple Ascending Dose Study in China
MS100070-0035                                                                                   13AUG2019 / Version Final 2.0
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Infusion Related Reactions
Infusion related reactions are identified based on a list of MedDRA PTs and criteria on the timely
relationship according to table below:
Criteria for infusion related reactions
Infusion related reactions
Reactions - Considered when onset is on the day of study drug
infusion (during or after the infusion) or the day after the study
drug infusion (irrespective of resolution date):
Infusion related reaction
Drug hypersensitivity
Anaphylactic reaction
Hypersensitivity
Type 1 hypersensitivity
Signs and Symptoms - occurring on the day of study drug
infusion (during or after the infusion) and resolved with end date
within 2 days after onset
Pyrexia
Chills
Flushing
Hypotension
Dyspnoea
Wheezing
Back pain
Abdominal pain
Urticaria








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