A Phase II, Open-Label, Multicenter Trial to Investigate the Clinical Activity and Safety of Avelumab (MSB0010718C) in Subjects With Merkel Cell Carcinoma
Phase: PHASE2
Conditions: Carcinoma, Merkel Cell
Sponsor: EMD Serono Research & Development Institute, Inc.

MSB0010718C
MSB0010718C in Merkel Cell Carcinoma
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Clinical Trial Protocol
Clinical Trial Protocol Number
EMR100070-003
Title
A Phase II, open-label, multicenter trial to 
investigate the clinical activity and safety of 
avelumab (MSB0010718C) in subjects with 
Merkel cell carcinoma
Short Trial Name
JAVELIN Merkel 200
Trial Phase
Phase II
IND Number
EudraCT Number
2014-000445-79
Coordinating Investigator
Sponsor
For all countries except the USA:
Merck KGaA, Frankfurter Str. 250, 
Darmstadt, Germany
For sites in the USA:
EMD Serono, Inc
One Technology Place, 
Rockland, MA 02370, USA
Medical Responsible: 
45A Middlesex Turnpike
Billerica, MA 01821, USA
Tel:  
Fax: 
Clinical Trial Protocol Version
25 May 2018 / Version 12.0
Replaces Clinical Trial Protocol Version
23 May 2017 / Version 11.0
Current Clinical Trial Protocol 
Amendment
Amendment No. 11 / 25 May 2018
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 
affiliate. Copyright © 2018 by Merck KGaA, Darmstadt, Germany, or its affiliate. All rights 
reserved.
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Table of Contents
Table of Contents
..............................................................................................................2
Table of Tables
..............................................................................................................6
Table of Figures
..............................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................13
2
Sponsor, Investigators, and Trial Administrative Structure ...............33
2.1
Investigational Sites............................................................................33
2.2
Trial Coordination / Monitoring.........................................................33
2.3
Review Committees............................................................................34
2.3.1
Safety Monitoring Committee............................................................34
2.3.2
Independent Endpoint Review Committee.........................................34
3
Background Information.....................................................................34
3.1
Merkel Cell Carcinoma.......................................................................34
3.2
Treatment Options for Merkel Cell Carcinoma..................................35
3.3
Programmed Death Receptor and Ligands.........................................36
3.4
Avelumab............................................................................................36
3.4.3
Infusion-Related Reactions / Hypersensitivity...................................43
3.4.4
Clinical Laboratory Evaluations.........................................................44
3.4.5
Vital Signs, Physical Findings, and Other Observations Related to 
Safety..................................................................................................45
3.4.6
Pharmacokinetic Results.....................................................................45
3.4.7
Clinical Pharmacodynamics ...............................................................47
3.5
Rationale for the Current Clinical Trial..............................................48
3.6
Summary of the Overall Benefit and Risk..........................................48
4
Trial Objectives ..................................................................................50
5
Investigational Plan ............................................................................51
5.1
Overall Trial Design and Plan ............................................................51
5.1.1
Overall Design....................................................................................51
5.1.2
Trial Endpoints ...................................................................................53
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5.1.3
Trial Medication Administration and Schedule..................................55
5.1.4
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation .................................................................55
5.2
Discussion of Trial Design .................................................................56
5.2.1
Inclusion of Special Populations ........................................................57
5.3
Selection of Trial Population..............................................................57
5.3.1
Inclusion Criteria ................................................................................57
5.3.2
Exclusion Criteria...............................................................................59
5.4
Criteria for Randomization/Initiation of Treatment with the 
Investigational Medicinal Product......................................................60
5.5
Criteria for Subject Withdrawal..........................................................61
5.5.1
Criteria for Withdrawal from Study Drug due to Therapeutic 
Failure.................................................................................................61
5.5.2
Withdrawal from the Trial..................................................................62
5.5.3
Withdrawal from the Investigational Medicinal Product ...................62
5.6
Premature Discontinuation of the Trial ..............................................63
5.7
Definition of End of Trial...................................................................63
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................63
6.1
Description of Investigational Medicinal Product..............................64
6.2
Dosage and Administration ................................................................64
6.3
Assignment to Treatment Groups.......................................................64
6.4
Other Drugs to be Used in the Trial....................................................64
6.5
Concomitant Medications and Therapies ...........................................65
6.5.1
Permitted Medicines...........................................................................65
6.5.2
Nonpermitted Medicines ....................................................................65
6.5.3
Other Trial Considerations .................................................................66
6.5.4
Special Precautions.............................................................................67
6.6
Packaging and Labeling......................................................................77
6.7
Storage, Handling, and Preparation....................................................78
6.8
Investigational Medicinal Product Accountability.............................78
6.9
Assessment of Investigational Medicinal Product Compliance .........79
6.10
Method of Blinding.............................................................................80
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6.11
Emergency Unblinding.......................................................................80
6.12
Treatment of Overdose .......................................................................80
6.13
Medical Care of Subjects After End of Trial......................................80
7
Trial Procedures and Assessments......................................................80
7.1
Schedule of Assessments....................................................................80
7.1.1
Screening and Baseline Procedures and Assessments........................80
7.1.2
Treatment Period ................................................................................82
7.1.3
End of Treatment ................................................................................85
7.1.4
Safety Follow-up ................................................................................86
7.1.5
Post Treatment Follow-up ..................................................................87
7.1.6
Blood Draws for Clinical Assessments ..............................................87
7.2
Demographic and Other Baseline Characteristics ..............................87
7.2.1
Demographic Data..............................................................................87
7.2.2
Diagnosis of Merkel Cell Carcinoma .................................................88
7.2.3
Medical History ..................................................................................88
7.2.4
Vital Signs and Physical Examination................................................88
7.2.5
CT or MRI Scans and Photography for Tumor Assessment at 
Baseline...............................................................................................89
7.2.6
Cardiac Assessments ..........................................................................89
7.2.7
Clinical Laboratory Tests ...................................................................89
7.3
Assessment of Efficacy.......................................................................89
7.4
Assessment of Safety..........................................................................92
7.4.1
Adverse Events ...................................................................................93
7.4.2
Pregnancy and In Utero Drug Exposure.............................................98
7.4.3
Laboratory Assessments .....................................................................98
7.4.4
Vital Signs, Physical Examinations, and Other Assessments...........100
7.5
Pharmacokinetics..............................................................................100
7.5.1
Body Fluid(s)....................................................................................101
7.5.2
Pharmacokinetic Calculations ..........................................................101
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7.6.3
ADA Analysis...................................................................................103
7.7
Other Assessments............................................................................104
7.7.1
Health-related Quality of Life ..........................................................104
8
Statistics............................................................................................105
8.1
Sample Size ......................................................................................105
8.2
Randomization..................................................................................107
8.3
Endpoints..........................................................................................107
8.3.1
Primary Endpoint..............................................................................107
8.3.2
Secondary Endpoints ........................................................................107
8.3.3
Safety Endpoints...............................................................................110
8.4
Analysis Sets.....................................................................................111
8.5
Description of Statistical Analyses...................................................111
8.5.1
General Considerations.....................................................................111
8.5.2
Analysis of Primary Endpoint ..........................................................111
8.5.3
Analysis of Secondary 
 Endpoints..........................112
8.5.4
Safety Analyses ................................................................................114
8.5.5
Subgroup Analyses ...........................................................................115
8.6
Interim Analysis................................................................................115
9
Ethical and Regulatory Aspects........................................................116
9.1
Responsibilities of the Investigator ..................................................116
9.2
Subject Information and Informed Consent .....................................116
9.3
Subject Identification and Privacy....................................................117
9.4
Emergency Medical Support and Subject Card................................118
9.5
Clinical Trial Insurance and Compensation to Subjects...................118
9.6
Independent Ethics Committee or Institutional Review Board........118
9.7
Health Authorities.............................................................................119
10
Trial Management.............................................................................119
10.1
Case Report Form Handling.............................................................119
10.2
Source Data and Subject Files..........................................................119
10.3
Investigator Site File and Archiving.................................................120
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10.4
Monitoring, Quality Assurance, and Inspection by Health 
Authorities ........................................................................................121
10.5
Changes to the Clinical Trial Protocol..............................................121
10.6
Clinical Trial Report and Publication Policy....................................121
10.6.1
Clinical Trial Report.........................................................................121
10.6.2
Publication........................................................................................121
11
References.........................................................................................123
Appendices
..........................................................................................................127
Appendix I
Schedule of Assessments..................................................................128
Appendix II
Eastern Cooperative Oncology Group Performance Status..............136
Appendix III
Guidance on Contraception ..............................................................137
Appendix IV
Skin Lesion Selection and Photographic Image Acquisition 
Procedures.........................................................................................138
Appendix V
Protocol Amendments and List of Changes .....................................140
Appendix VI
Signature Pages and Responsible Persons for the Trial....................153
Signature Page – Protocol Lead.......................................................................................154
Signature Page – Coordinating Investigator ....................................................................155
Signature Page – Principal Investigator...........................................................................156
Table of Tables
Table 1
Most Frequently Reported Treatment-Emergent Adverse Events 
During Dose Expansion (≥10% of Subjects).....................................39
Table 2
Most Frequently Reported Treatment-Emergent Adverse Events 
Grade ≥ 3 During Dose Expansion (> 1.5% of Subjects)...................40
Table 3
Most Frequently Reported Treatment-related Treatment-Emergent 
Adverse Events During Dose Expansion (≥ 5% of Subjects).............41
Table 4
Treatment Modification for Symptoms of Infusion-Related 
Reactions Caused by Avelumab.........................................................68
Table 5
Management of Immune-Related Adverse Events.............................71
Table 6
Overall Responses Derived from Changes in Index, Nonindex, 
and New Lesions.................................................................................92
Table 7
Required Full Laboratory Safety Tests...............................................99
Table 8
Confidence Intervals for Different Durable Response Rates ...........107
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Table 9
Pat A: General Censoring Rules for Progression-free Survival and 
Duration of Response .......................................................................108
Table 10
Part A: Special Case Censoring Rules for Progression-free 
Survival.............................................................................................109
Table 11
Part B: Outcome and Event Dates for Progression-free Survival 
and Duration of Response Analyses.................................................109
Table of Figures
Figure 1
Assessment and Initial Management of Tumor Lysis Syndrome.......70
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List of Abbreviations
ACTH
Adrenocorticotropic hormone
ADA
Antidrug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADR
Adverse drug reaction
AE(s)
Adverse event(s)
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANA
Antinuclear antibody
ANC
Absolute neutrophil count
ANCA
Antineutrophil cytoplasmic antibody
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUCtau
Area under the concentration-time curve 
β-HCG
β-human chorionic gonadotropin
BOR
Best overall response
BUN
Blood urea nitrogen
CI
Confidence interval(s)
CK20
Cytokeratin 20
Cmax
Maximum plasma concentration observed postdose
Cmin
Minimum postdose (trough) concentration
CNS
Central nervous system
CR
Complete response
CRO
Contract Research Organization
CRP
C-reactive protein
CT 
Computed tomography 
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CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte antigen-4
DLT
Dose-limiting toxicity
DRR
Durable response rate
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
EMA
European Medicines Agency
EQ-5D
EuroQol-EQ-5D
EU
European Union
FACT-M
Functional Assessment of Cancer Therapy – Melanoma
FDA
Food and Drug Administration
FFPE
Formalin fixed, paraffin embedded
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GMP
Good Manufacturing Practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ICU
Intensive care unit
IEC
Independent Ethics Committee
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IERC
Independent Endpoint Review Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
INR
International normalized ratio
irAE
Immune-related adverse event
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive voice response system
LBCI
Lower boundary of the confidence interval
LDH
Lactate dehydrogenase
MCC
Merkel cell carcinoma
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Merkel cell polyoma virus
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Operations
MRI
Magnetic resonance imaging
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NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute 
NK
Natural killer
NSAID
Nonsteroidal anti-inflammatory drug
ORR
Objective response rate
OS
Overall survival 
PD
Progressive disease
PD-1
Programmed death 1
PD-L1
Programmed death ligand 1
PD-L2
Programmed death ligand 2
PFS
Progression-free survival
PGx
Pharmacogenetics 
PK
Pharmacokinetic(s)
PR
Partial response
RBC
Red blood cell
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RF
Rheumatoid factor
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Stable disease
SEER
Surveillance, Epidemiology, and End Results
SMC
Safety Monitoring Committee
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Half-life
T4
Free thyroxine
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TEAE
Treatment-emergent adverse event
TGF-β
Transforming growth factor beta
TLS
Tumor lysis syndrome
tmax
Time to reach maximum concentration
TO
Target occupancy
TSH
Thyroid-stimulating hormone
TTP
Time to progression
UBCI
Upper boundary of the confidence interval
ULN
Upper limit of normal
US
United States
WBC
White blood cell
WHO
World Health Organization
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1
Synopsis
Trial title
A Phase II, open-label, multicenter trial to investigate the 
clinical activity and safety of avelumab (MSB0010718C)
in subjects with Merkel cell carcinoma
Trial number
EMR100070-003
EudraCT number
2014-000445-79
Sponsor
For all countries except the United States:
Merck KGaA, Frankfurter Str. 250, Darmstadt,
Germany
For sites in the United States:
EMD Serono, Inc
One Technology Place, Rockland, MA 02730, USA
Phase
II
Trial under IND
yes
no
FDA "covered trial"
yes
no
Trial centers/countries
The trial will be conducted globally in approximately 
60 sites, including in North America (approximately 
15 sites in the United States [US]), European Union (EU), 
Australia, Japan, and Switzerland.
Planned trial period
(first enrollment-last subject 
out)
First subject in: Q3, 2014
Last subject out: Q2, 2023
Trial objectives
Primary objective
Part A:  The primary objective is to assess the clinical 
activity of avelumab as determined by the objective 
response rate (ORR) according to Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST 1.1) by an 
Independent Endpoint Review Committee (IERC) in 
subjects with metastatic Merkel cells carcinoma (MCC)
after failing first-line chemotherapy.
Part B:  The primary objective is to evaluate the clinical 
activity of avelumab as first-line treatment for metastatic 
or distally recurrent MCC as determined by the durable 
response rate (DRR) according to RECIST 1.1 by an 
IERC.
Secondary objectives
Part A:  Secondary objectives are as follows:
!
To assess the duration of response according to 
RECIST 1.1
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!
To assess the progression-free survival time 
(PFS) according to RECIST 1.1
!
To assess the safety profile of avelumab in 
subjects with MCC
!
To assess the overall survival (OS) time
!
To assess response status according to RECIST 
1.1 at 6 and 12 months after start of study 
treatment
!
To characterize the population pharmacokinetics 
(PK) of avelumab in subjects with MCC by sparse
sampling
!
To evaluate the immunogenicity of avelumab and 
to correlate it to exposure 
Part B:  Secondary objectives are as follows:
!
To assess the OS time
!
To assess ORR according to RECIST 1.1
!
To assess the duration of response according to 
RECIST 1.1
!
To assess the PFS according to RECIST 1.1
!
To assess the safety profile of avelumab in 
subjects with MCC
!
To assess response status according to RECIST 
1.1 at 6 and 12 months after start of study 
treatment
!
To characterize the population PK of avelumab in 
subjects with MCC by sparse sampling
!
To evaluate the immunogenicity of avelumab and 
to correlate it to exposure 
 
 
 
 
 
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Trial design and plan
This is a multicenter, international, single-arm, 
open-label, Phase II trial in two parts that will evaluate 
the efficacy and safety of avelumab in subjects with 
metastatic MCC.  In Part A, subjects must have received 
at least 1 line of chemotherapy for the treatment of 
metastatic MCC.  In Part B, subjects must be treatment 
naïve to systemic therapy in the metastatic setting.
In Part A, up to 84 eligible subjects will receive avelumab
at a dose of 10 mg/kg as a 1-hour intravenous (IV) 
infusion (-10 minutes / +20 minutes, that is, over 50 to 
80 minutes) once every 2 weeks.  In Part B, up to 
112 eligible subjects are planned to be enrolled and will 
receive avelumab at a dose of 10 mg/kg as a 1-hour 
intravenous (IV) infusion (-10 minutes / +20 minutes, 
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that is, over 50 to 80 minutes) once every 2 weeks.  
Tumor measurements (including the assessment of skin 
lesions by physical examination) to determine response 
will be performed every 6 weeks until 12 months after the 
first study drug administration, then every 12 weeks and 
response to the treatment will be evaluated by RECIST 
1.1.  Treatment will continue until
! therapeutic failure (subjects may stay on treatment 
beyond observation of progressive disease [PD]
provided there is no significant clinical deterioration);
! unacceptable toxicity; or
! any criterion for withdrawal from the trial or the study 
drug is fulfilled.
Significant clinical deterioration is defined as
! new symptoms or worsening of symptoms that cannot 
be managed by optimal supportive care or disease 
localization that require immediate medical or surgical 
intervention (for example, lesion close to the spine), 
and/or
! change in Eastern Cooperative Oncology Group 
Performance Status (ECOG PS) to ≥ 3 that lasts more 
than 14 days.
Decisions regarding medical management of subjects 
will be made by the Investigator; however, the primary 
and secondary endpoint determinations will be according 
to tumor assessments performed by the IERC.
The date of the first observation of PD by RECIST 1.1 by 
the IERC will be used to determine the date of the PD as 
well as the duration of response in all subjects, including 
the subjects for which treatment was maintained beyond 
first determination of disease progression.
Adverse events will be assessed throughout the trial 
period and evaluated using the National Cancer Institute 
(NCI) Common Technology Criteria version 4.0
(CTCAE v 4.0).  
Health-related quality of life will be assessed using a 
generic instrument (EuroQol EQ-5D [EQ-5D]), a 
cancer-specific instrument including a melanoma-
specific module (Functional Assessment of Cancer 
Therapy 
–
Melanoma 
[FACT-M]), 
and 
subject 
interviews (optional).
In Part A there will be 1 interim analysis for futility after 
20 subjects have been enrolled and observed for at least 
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3 months and 1 interim analysis for efficacy 6 months 
after 56 subjects have been enrolled. 
The primary 
analysis will be conducted 6 months after the accrual of 
the last subject and a further exploratory analysis will be 
conducted 12 months after the accrual of the last subject. 
In Part B there will be 1 interim analysis at 3 months after 
the accrual of the 25th subject, with additional interim 
analyses possible. 
The primary analysis will be 
conducted 15 months after the accrual of the last subject.
For both Parts A and B, subject follow-up for progression 
and survival will continue until 5 years after the last 
subject receives the last dose of avelumab or the last 
subject dies, whichever occurs first. 
Under some 
circumstances, subjects may not be followed for 5 years 
for survival in this study, for example, subjects may be 
offered to enroll into a rollover study, or the Sponsor may 
terminate the study early.
Planned number of subjects
Eighty-four subjects are planned to be enrolled in Part A 
and 112 subjects in Part B of this study.
Schedule of visits and 
assessments
Screening/Baseline Assessments (Day -18 to first 
treatment)
Screening will include the informed consent, recording 
of the demographic information, the complete medical 
history, and baseline medical condition; a complete 
physical examination including vital signs, body weight, 
and 
height, 
mapping 
of 
skin 
lesions, 
12-lead 
electrocardiogram (ECG) and a determination of the 
ECOG PS; AE and concomitant medication assessments; 
safety laboratory assessments; the tumor evaluation 
(including brain) by computed tomography (CT) scan or 
magnetic resonance imaging (MRI; for trial sites in 
Germany, only MRI is to be used) as well as tumor 
markers; collection of tumor tissue prior to the first study 
drug administration is required for all subjects (fresh 
biopsy or recent biopsy [within 4 weeks prior to 
enrollment provided as block or slides, blocks 
preferable], for subjects unable to provide a fresh or 
recent biopsy, archival material is acceptable [blocks 
preferable]); bone scan (as clinically indicated); serum 
β-human chorionic gonadotropin (β-HCG) pregnancy 
test for females of childbearing potential; blood hepatitis 
B virus (HBV), hepatitis C virus (HCV), human 
immunodeficiency 
virus 
(HIV) 
testing, 
adrenocorticotropic hormone, antinuclear antibody, 
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antineutrophil cytoplasmic antibody, rheumatoid factor, 
free thyroxine, and thyroid-stimulating hormone.  Blood 
samples for baseline PK and immunogenicity (antidrug 
antibody [ADA] tests, previously referred to as human 
antihuman antibody [HAHA]) sampling as well as for 
(Part A) and exploratory 
 
 
(Part B) will be collected before or on Day 1 
before trial treatment starts. The EQ-5D and FACT-M 
questionnaires will be administered at baseline to collect 
subjects’ baseline health-related quality of life data. In 
addition, optional subject interviews will be conducted to
collect subjects’
experience with MCC
and their 
experience with prior treatment for MCC.
 
 
Treatment phase
Visits will take place every 2 weeks (1 treatment cycle).  
Note: subjects with liver metastases at Baseline will have 
visits every week up to Week 7.
Safety (including AEs and concomitant medications, 
laboratory 
values, 
ECOG 
PS, 
weight, 
physical 
examinations, vital signs, ECG, β-HCG for females of 
childbearing potential), PK, immunogenicity, and tumor 
response assessments will be conducted at designated 
times throughout the trial.
The main assessments are as follows:
! The EQ-5D and FACT-M will be completed by 
subjects prior to any study related procedures at 
Week 7, and then once every 6 weeks thereafter while 
on treatment.
! Subject interviews (optional in both Part A and Part B)
will be conducted at Week 13 and at 6 months of 
treatment to collect subjects’ current experience with 
their disease, the study drug, and their experience 
within the trial.  
! Tumor responses (including the assessment of skin 
lesions by physical examination) will be assessed 
every 6 weeks, per RECIST 1.1 until 12 months after 
the first study drug administration, then every 
12 weeks.
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! For Part A, PK samples will be collected from all 
subjects prior to each study drug infusion through 
Week 15, then Week 25, and then at 12-week intervals 
while on treatment.  Post infusion samples will be 
collected at Weeks 1, 7, 13, and 25, and then at 
12-week intervals while on treatment.  For Part B the 
PK schedule is prior to each study drug infusion 
through Week 7, every 6 weeks through Week 25, and 
then at 12-week intervals thereafter while on 
treatment. Post study drug administration samples 
will be collected at the end of infusion at Weeks 1, 7, 
and 25.
! Samples for immunogenicity (ADA analysis) will be 
collected at Day 1 (Screening / Baseline sample) and
within 2 hours before infusion on Days 15, 29, 
43 (every 2 weeks) and then every 6 weeks thereafter 
while on treatment.  For Part B the ADA schedule is
Day 1 (Screening / Baseline sample) and within 
2 hours before infusion through Week 7, every 
6 weeks through Week 25, and then at 12-week 
intervals thereafter while on treatment.
Discontinuation visit, End-of-Treatment visit, Safety 
Follow-up visit, and Post-treatment follow-up
For Part A, all subjects who discontinue trial treatment 
prematurely for an AE should have a full safety 
evaluation and immune monitoring and assessment of 
at the time of 
discontinuation (Discontinuation visit).
For Part B, all subjects who discontinue treatment
regardless of the reason will have a Discontinuation visit
within 7 days of the decision to discontinue treatment.  
The Discontinuation visit will include a full safety 
evaluation, PK sampling, and sampling for exploratory 
.
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For all subjects who have completed treatment, an 
End-of-Treatment visit should be scheduled 4 weeks
(Part A) / 30 days (Part B) after the last administration of 
avelumab.
The End-of-Treatment visit is scheduled 4 weeks (Part A) 
/ 30 days (Part B) after the last administration of 
avelumab, but before any new therapy is started, if 
possible.  The visit will comprise a full assessment of 
safety parameters, the EQ-5D and FACT-M assessments, 
immunogenicity (Part B only), PK sampling (Part B 
only), and immune monitoring and 
 
 
 and tumor response assessment as appropriate.
Safety and Post-treatment Follow-up
For Part A, all subjects will have a subsequent visit 
scheduled 10 weeks after the last administration of 
avelumab.  The visit will include a full assessment of 
safety 
parameters, 
immune 
monitoring 
and
.
For Part B, all subjects will have a subsequent visit 
scheduled 90
days (± 1 Week) after the last 
administration of the study drug. The visit will include a 
full assessment of safety parameters, immune monitoring 
and
.
Subjects with an adverse drug reaction (ADR) ongoing at 
the End-of-Treatment visit must be followed up until the 
ADR resolves, becomes stable, or is considered not 
clinically significant by the Investigator.
For subjects who discontinue treatment prior to Week 13, 
off-treatment interviews (optional, both Part A and 
Part B) will be scheduled for 13 weeks and 6 months from 
the start of treatment to collect subjects’ current 
experience with their disease, the study drug, and their 
experience within the trial. In case of discontinuation 
later than Week 13 but prior to 6 months of treatment, an 
off-treatment interview (optional, both Part A and Part B) 
will be scheduled for 6 months from the start of 
treatment.  
For both Parts A and B, subjects without PD at the 
End-of-Treatment 
visit 
will 
be 
followed 
until
disease progression (CT / MRI scans every 6 weeks until 
12 months after the first study drug administration, then 
every 12 weeks).  
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For both parts, subjects will be followed for any AE 
suspected to be related to trial treatment, especially for 
the occurrence of new autoimmune events up to 3 months 
after the last dose of avelumab.
For both Parts A and B, after the End-of-Treatment visit, 
subjects will be followed quarterly for survival (including 
assessment of any further tumor therapy).  The survival 
follow-up will continue for up to 5 years after the last 
subject receives the last dose of avelumab or last subject 
dies, whichever occurs earlier.  
Diagnosis and main inclusion 
and exclusion criteria
Inclusion criteria 
1. Signed written informed consent
2. Male or female subjects aged ≥ 18 years
3. Histologically proven MCC 
a) Confirmation 
of 
the 
diagnosis 
by 
immuno-histochemistry detection of CK20 (or 
other appropriate cytokeratin expression such as 
pancytokeratin, AE1/AE3, or Cam5.2; local 
laboratory testing) in the tumor cell is mandatory
b) Subjects must have metastatic disease; subjects 
with non-metastatic MCC that is only recurrent or 
unresectable are NOT eligible; for Part B, M1 
status must be confirmed at entry
c) For Part A:  Subjects must have received at least 
1 line of chemotherapy for the treatment of 
metastatic MCC and must have progressed after 
the most recent line of chemotherapy that was 
administered.  Subjects must have received at 
least one of the following chemotherapy regimens 
for 
treatment 
of 
metastatic 
MCC:  
Cyclophosphamide, 
topotecan, 
doxorubicine, 
epirubicin, vincristine, carboplatin, cisplatin, 
etoposide in combination with carboplatin or 
cisplatin
d) For Part B:  Subjects must not have received any 
prior systemic treatment for metastatic MCC.  
Prior chemotherapy treatment in the adjuvant 
setting (no clinically detectable disease; no 
metastatic disease) is allowable if the end of 
treatment occurred at least 6 months prior to study 
start.
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4. For Part A:  Collection of biopsy material is required 
(fresh biopsy or recent biopsy [within 4 weeks prior 
to enrollment], for subjects unable to provide a fresh 
or recent biopsy, archival material is acceptable).  For 
Part B:
1) Priority:  A recently obtained formalin-fixed, 
paraffin-embedded (FFPE) block containing 
tumor tissue (preferably within 6 months). If no 
tumor tissue is available, a fresh biopsy will be 
required.
2) Priority:  If the tumor containing FFPE tissue 
block cannot be provided in total, sections from 
this block should be provided that are freshly cut
(within 1 week).  Preferably, 25 slides should be 
provided; if not possible, a minimum of 10 slides 
in consultation with the Medical Monitor is 
required
5. ECOG PS of 0 to 1 at trial entry 
6. Estimated life expectancy of more than 12 weeks
7. Disease 
must 
be 
measurable 
with 
at 
least 
1 unidimensional measurable lesion by RECIST 1.1
(including skin lesions)
8. Adequate hematological function defined by white 
blood cell (WBC) count ≥3 × 109/L with absolute 
neutrophil count (ANC) ≥1.5 × 109/L, lymphocyte 
count ≥0.5 × 109/L, platelet count ≥100 × 109/L, and 
hemoglobin ≥9 g/dL (may have been transfused)
9. Adequate hepatic function defined by a total bilirubin 
level ≤1.5 × the upper limit of normal (ULN) range
and aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) levels ≤2.5 × ULN for all 
subjects
10. Adequate renal function defined by an estimated 
creatinine clearance > 30 mL/min according to the 
Cockcroft-Gault formula or by 24 hour urine 
collection for creatinine clearance or according to 
local institutional standard method
11. Highly effective contraception (that is, methods with 
a failure rate of less than 1% per year) for both male 
and female subjects if the risk of conception exists 
(Note:  The effects of the study treatment on the 
developing human fetus are unknown; thus, women 
of childbearing potential and men must agree to use 
highly effective contraception, defined in Appendix 
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III or as stipulated in national or local guidelines.  
Highly effective contraception must be used 28 days 
prior to first study treatment administration, for the 
duration of study treatment, and at least for 60 days 
after stopping study treatment.  Should a woman 
become pregnant or suspect she is pregnant while she 
or her partner is participating in this study, the 
treating physician should be informed immediately.)
Exclusion criteria
1. Participation in another interventional clinical trial 
within the past 30 days (participation in observational 
studies is permitted)
2. Concurrent treatment with a nonpermitted drug
3. Prior therapy with any antibody/drug targeting T-cell 
coregulatory proteins (immune checkpoints) such as 
antiprogrammed death 1 (PD-1), anti-PD-L1, or 
anticytotoxic T-lymphocyte antigen-4 (CTLA-4) 
antibody; for Part B, the Investigator must consult 
with the Medical Monitor and consider other 
co-regulatory targets such as 4-1BB
4. Concurrent anticancer treatment (for example, 
cytoreductive therapy, radiotherapy [with the 
exception of palliative bone-directed radiotherapy, or 
radiotherapy administered on non-target superficial 
lesions], immune therapy, or cytokine therapy except 
for erythropoietin).  Radiotherapy administered to 
superficial lesions is not allowed if such lesions are 
considered target lesions in the efficacy evaluation or 
may influence the efficacy evaluation of the 
investigational agent
5. Major surgery for any reason, except diagnostic 
biopsy, within 4 weeks and/or if the subject has not 
fully recovered from the surgery within 4 weeks
6. Concurrent systemic therapy with steroids or other 
immunosuppressive 
agents, 
or 
use 
of 
any 
investigational drug within 28 days before the start of 
trial treatment.  Short-term administration of systemic 
steroids (that is,
for allergic reactions or the 
management of immune-related
adverse events 
[irAE]) while on study is allowed.  Also, subjects 
requiring hormone replacement with corticosteroids 
for adrenal insufficiency are eligible if the steroids are 
administered only for the purpose of hormonal 
replacement and at doses ≤10 mg or equivalent 
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prednisone per day.
Note: Subjects receiving 
bisphosphonate or denosumab are eligible 
7. Subjects with active central nervous system (CNS) 
metastases are excluded.  Subjects with a history of 
treated CNS metastases (by surgery or radiation 
therapy) are not eligible unless  they have fully 
recovered 
from 
treatment, 
demonstrated 
no 
progression for at least 2 months, and do not require 
continued steroid therapy 
8. For Part A:  Previous malignant disease (other than 
MCC) within the last 5 years with the exception of 
basal or squamous cell carcinoma of the skin or 
cervical carcinoma in situ.
For Part B: Previous malignant disease (other than 
MCC) within the last 5 years with the exception of 
basal or squamous cell carcinoma of the skin or
carcinoma in situ (skin, bladder, cervical, colorectal, 
breast, or low grade prostatic intraepithelial neoplasia 
or Grade 1 prostate cancer) 
9. Prior organ transplantation, including allogeneic 
stem-cell transplantation 
10. For Part A, known history of testing positive for HIV 
or known acquired immunodeficiency syndrome 
(AIDS), or any positive test for hepatitis B virus 
(HBV) or hepatitis C virus (HCV) indicating acute or 
chronic infection.  For Part B, known history of 
testing positive for HIV or known AIDS or HBV or 
HCV infection at screening (positive HBV surface 
antigen or HCV RNA if anti-HCV antibody screening 
test positive)
11. Active or history of any autoimmune disease (except 
for subjects with vitiligo) or immunodeficiencies that 
required treatment with systemic immunosuppressive 
drugs 
12. Known 
severe 
hypersensitivity 
reactions 
to 
monoclonal antibodies (Grade ≥ 3 NCI-CTCAE 
v 4.0), any history of anaphylaxis, or uncontrolled 
asthma (that is, 3 or more features of partially
controlled asthma)
13. Persisting toxicity related to prior therapy Grade > 1 
NCI-CTCAE v 4.0; however, sensory neuropathy 
Grade ≤ 2 is acceptable
14. Pregnancy or lactation
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15. Known alcohol or drug abuse
16. Clinically significant (that is, active) cardiovascular 
disease: 
cerebral 
vascular 
accident
/
stroke 
(< 6
months prior to enrollment), myocardial 
infarction (< 6 months prior to enrollment), unstable 
angina, congestive heart failure (New York Heart 
Association Classification Class ≥II), or serious 
cardiac arrhythmia requiring medication
17. All 
other 
significant 
diseases 
(for 
example,
inflammatory bowel disease), which, in the opinion 
of the Investigator, might impair the subject’s 
tolerance of trial treatment
18. Any psychiatric condition that would prohibit the 
understanding or rendering of informed consent
19. Legal incapacity or limited legal capacity
20. Nononcology vaccine therapies for prevention of 
infectious disease (for example, seasonal flu vaccine, 
human papilloma virus vaccine) within 4 weeks of 
study drug administration. Vaccination while on trial
is also prohibited except for administration of 
inactivated vaccines (for example, inactivated 
seasonal influenza vaccine)
Investigational Medicinal 
Product: dose / mode of 
administration / dosing schedule
Avelumab will be administered as a 1-hour IV infusion
(-10 minutes / +20 minutes, that is, over 50 to 80 minutes)
at 10 mg/kg once every 2-week treatment cycle. In order 
to mitigate infusion-related reactions, subjects will 
receive pretreatment with antihistamine and 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. 
Steroids as premedication are not acceptable.  This 
regimen may be modified based on local treatment 
standards and guidelines as appropriate.
The dose of avelumab will be calculated based on the 
weight of the subject determined on the day of (for Part 
A), or within 3 days of each drug administration (Part B).
Immediate access to an intensive care unit or equivalent 
environment and appropriate medical therapy (including 
IV
epinephrine, 
corticosteroids, 
antihistamines, 
bronchodilators, and oxygen) must be in place for use in 
the treatment of potential infusion-related reactions.
Infusion of avelumab will be stopped in case of Grade ≥2 
infusion-related, allergic, or hypersensitivity reactions 
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(according to NCI-CTCAE v 4.0). Following avelumab
infusions, subjects should be observed based upon 
clinical judgment and presence / severity of prior infusion 
reactions.  In the case of Grade 1 or 2 infusion reactions, 
the infusion rate should be decreased by 50%. 
Reference therapy: dose / mode 
of administration/dosing 
schedule
Not applicable.
Planned treatment duration per 
subject
Subjects will receive avelumab treatment until significant 
clinical deterioration, unacceptable toxicity, or any 
criterion for withdrawal from the trial or study drug is 
fulfilled.
For Part A:  Subjects who have experienced a confirmed 
complete response (CR) should be treated for a maximum 
of 12 months and a minimum of 6 months after 
confirmation, at the discretion of the Investigator. If the 
Investigator believes that a subject may benefit from
treatment beyond 12 months, it may be permissible after 
discussion with the sponsor.  Part B:  Subjects who have 
experienced a confirmed CR should be treated for a 
minimum of 12 months after confirmation, at the 
discretion of the Investigator.  If the Investigator believes 
that a subject may benefit from treatment beyond 
12 months, it may be permissible after discussion with 
the sponsor.  For both Part A and Part B, in case a subject 
with a confirmed CR relapses after stopping treatment,
but prior to the end of the trial, 1 re-initiation of treatment 
is allowed at the discretion of the Investigator and 
agreement of the trial Medical Monitor.  In order to be 
eligible for retreatment, the subject must not have 
experienced any toxicity that led
to treatment 
discontinuation of the initial avelumab therapy.  Subjects 
who re-initiate treatment will stay on study and will be 
treated and monitored according to the protocol and the 
“until progression” schedule in the Schedule of 
Assessments.
Primary endpoint
Part A:  The primary endpoint for the trial is the 
confirmed BOR, per RECIST 1.1, as determined by an 
IERC.  
Both CR and partial response (PR) must be confirmed by 
a second tumor assessment that will be performed 
preferably at the regularly scheduled 6-week assessment 
interval, but no sooner than 5 weeks after the initial 
documentation of CR or PR.
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Part B: 
The primary endpoint is durable response, 
defined as objective response (CR or PR) according to 
RECIST 1.1, determined by an IERC, with a duration of 
at least 6 months.
Secondary
 
endpoints
Part A:  Secondary endpoints include
! duration of response according to RECIST 1.1 as 
determined by an IERC,
! PFS time according to RECIST 1.1 as determined by 
an IERC, 
! occurrence and severity of treatment-related AEs 
according to NCI-CTCAE v 4.0, 
! OS time,
! response status according to RECIST 1.1 at 6 and 
12 months after start of study treatment,
! serum titers of anti-avelumab antibodies, and
! population PK profile of avelumab (sparse sampling).
 
 
 
 
 
 
  
 
 
 
Part B:  Secondary endpoints include
! OS time,
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! confirmed BOR per RECIST 1.1 as determined by an 
IERC,
! duration of response according to RECIST 1.1 as 
determined by an IERC,
! PFS time according to RECIST 1.1 as determined by 
an IERC, 
! occurrence and severity of treatment-related AEs 
according to NCI-CTCAE v 4.0, 
! response status according to RECIST 1.1 at 6 and 
12 months after start of study treatment,
! serum titers of anti-avelumab antibodies, and
! population PK profile of avelumab (sparse sampling).
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics
For Part A, blood samples for determination of avelumab
will be collected prior to each study drug infusion
through Week 15, then Week 25, and then at 12-week 
intervals while on treatment.  Post infusion samples will 
be collected at Weeks 1, 7, 13, and 25, and then at 
12-week intervals while on treatment.  For Part B, blood 
samples for determination of avelumab will be collected 
prior to each study drug infusion through Week 7, every 
6 weeks through Week 25, and then at 12-week intervals 
thereafter while on treatment. 
Post study drug 
administration samples will be collected at the end of 
infusion at Weeks 1, 7, and 25.  Samples will also be 
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collected at the Discontinuation and End-of-Treatment 
visits.
Biomarkers/
Pharmacogenetics (PGx)
 
 
 
  
 
 
 
 
 
 
Statistical methods (includes 
sample size calculation)
Part A
The primary endpoint of the trial is the confirmed BOR 
according to RECIST 1.1, based on independent review 
of tumor assessments.  The trial aims at demonstrating an 
ORR greater than 20% by the exact binomial test.  
The primary analysis population for all analyses of 
efficacy and safety is the Safety population, consisting of 
all subjects that received at least 1 dose of trial treatment.  
Analyses of efficacy variables may also be performed on 
subgroups of interest as needed.
The planned total sample size is 84 subjects.  The primary 
analysis will be performed 6 months after the accrual of 
the last subject and a further exploratory analysis will be 
conducted at 12 months after the accrual of the last 
subject. There will also be an interim analysis for futility 
after 20 subjects have been enrolled and observed for at 
least 3 months and an interim analysis for efficacy 
6 months after 56 subjects have been enrolled.
The following assumptions are made for the sample size 
calculation:
! ORR of 35%
! overall alpha = 0.025 (1-sided) for the test of the null 
hypothesis of an ORR ≤ 20%
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The following analyses are planned for the study: 
! Futility:  Enrollment will be stopped for futility if no 
response (confirmed or unconfirmed) is observed in 
the first 20 subjects after 3 months of follow-up.
! Efficacy:  A group sequential testing approach will be 
applied.  The null hypothesis can be rejected if 
20 subjects in the interim analysis after 56 subjects, or 
25 subjects in the primary analysis after 84 subjects, 
show a confirmed PR or CR according to RECIST 1.1. 
The corresponding nominal p-values of the exact 
binomial test are 0.0045 and 0.0214, respectively. The 
resulting overall probability of reaching a positive 
result in the interim or primary analysis under the null 
hypothesis assumption of an ORR ≤20% is ≤0.0225.
Under the given assumptions, the power to reject the null 
hypothesis at the interim or the primary analysis is 
approximately 87%. 
Part B
The primary endpoint is durable response, defined as 
objective response (CR or PR) according to RECIST 1.1, 
determined by an IERC, with a duration of at least 
6 months. 
The primary analysis population for all analyses of 
efficacy and safety is the Safety population, consisting of 
all subjects that received at least 1 dose of trial treatment.
The planned total sample size is 112 subjects for 
addressing the primary objective, relevant subgroup 
analyses, consistency, and further safety assessments.  
Assuming a true DRR of 45%, the probability to observe 
lower bound of the exact 95% confidence interval (CI) 
above 20% would be > 99% and above 30% would be 
90%.  The primary analysis will be performed 15 months 
after the accrual of the last subject. 
Part B of the study aims to estimate the DRR with a 
sufficient level of precision.  For example, an observed 
DRR of 28.6% would lead to an exact (Clopper-Pearson) 
95% CI of (20.4%; 37.9%), an observed DRR of 40.2% 
would lead to a 95% CI of (31.0%; 49.9%), and an 
observed DRR of 44.6% would lead to an exact 95% CI 
of (35.2%; 54.3%). 
An interim exploratory analysis will be conducted at 
3 months after the accrual of the 25th subject, with 
additional interim analyses possible.  
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Endpoint analysis
The confirmed BOR according to RECIST 1.1 is defined 
as the best response obtained among all tumor assessment 
visits after start of trial treatment until documented 
disease progression, excluding assessments after start of 
subsequent anticancer therapy, taking into account the 
following requirement for confirmation:  PR or CR needs 
to be confirmed, preferably at the regularly scheduled 
6-week assessment interval, but no sooner than 5 weeks 
after the initial documentation of CR or PR.
The ORR will be determined as the proportion of subjects 
with a confirmed BOR of PR or CR.
The duration of response will be calculated for each 
subject with a confirmed response (CR or PR) as the time 
from first observation of response until first observation 
of documented disease progression or death within 
12 weeks of the last tumor assessment, whichever occurs 
first. The duration of response will be analyzed using the 
Kaplan-Meier method.
The PFS time, according to RECIST 1.1, will be defined 
from first administration of trial treatment until first 
observation of PD or death within 12 weeks of the last 
tumor assessment or first administration of trial treatment 
(whichever is later). The PFS time will be analyzed using 
the Kaplan-Meier method. In particular, the progression-
free rate at 6
months will be estimated with 
corresponding 2-sided 95% CI. 
The OS time will be defined as the time from first 
administration of trial treatment until death. The OS time 
will be analyzed using the Kaplan-Meier method.  In 
particular, the survival rate at 6 and 12 months will be 
estimated with corresponding 2-sided 95% CI.
Safety endpoints, including AEs, clinical laboratory 
assessments, vital signs, and ECG parameters, will be 
analyzed descriptively. 
The EQ-5D and FACT-M scores will be analyzed 
descriptively at all scheduled administrations, including 
a description of missing assessments.
Subject interviews will be analyzed by a qualitative 
thematic analysis on the de-identified transcripts of the 
interviews using ATLAS.ti software and based on the 
grounded theory to enable the focus of the analysis on the 
perspective of the subjects. 
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Additional endpoint analysis in Part B: The DRR will be 
determined as the proportion of subjects with a durable 
response, that is, with a minimum duration of 6 months.
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2
Sponsor, Investigators, and Trial Administrative Structure
The Sponsor of this clinical trial with avelumab is EMD Serono Inc, Rockland, MA, in the USA 
and Merck KGaA, Darmstadt, Germany, in rest of world.
This trial requires a significant logistic and administrative structure for its efficient execution. 
Details of such structures and associated procedures will be defined in a separate Manual of 
Operations (MOP).  This will be prepared under the supervision of the clinical trial leader in close 
collaboration with the responsible units at the Sponsor.
2.1
Investigational Sites
The trial will be conducted globally in approximately 60 sites, including in North America 
(approximately 15 sites in the United States [US]), European Union (EU), Australia, Japan, and 
Switzerland.
2.2
Trial Coordination / Monitoring
The Sponsor will coordinate the trial and will provide the support of Contract Research 
Organizations (CRO) for some activities of the trial. Sponsor Global Clinical Operations will 
perform oversight of the activities performed by the CROs.
The Clinical Trial Supplies department of the Sponsor will supply the trial medication of 
avelumab, which will be distributed to the sites by the CRO. 
Subject enrollment will be managed by an interactive voice response system (IVRS).
Safety laboratory assessments will be performed locally by investigational sites and also by a 
central laboratory. Pharmacokinetic (PK), exploratory 
 
assessments will be performed under the responsibility and / or supervision of the Sponsor. 
The Global Drug Safety Department, Merck KGaA, Darmstadt, Germany, or their designated 
representatives will supervise drug safety and the timely reporting of adverse events (AEs) and 
serious adverse events (SAEs).
Quality assurance of the trial conduct will be performed by the Development Quality Assurance 
Department, Merck KGaA, Darmstadt, Germany.
The department of Global Biostatistics will supervise the statistical analyses (with the exception 
of the PK data analyses), which will be outsourced to a CRO.
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2.3
Review Committees
2.3.1
Safety Monitoring Committee
To ensure subjects’ safety during the trial, a safety monitoring committee (SMC) will periodically 
review safety data.  The SMC will be composed of a minimum of 3 members, including a trial 
Investigator, a statistician, and an independent physician.  The SMC consists of permanent 
members from the Sponsor and/or CRO (Global Drug Safety Representative, Program Lead, 
Medical Lead, Biostatistician, Medical Monitor), and the Coordinating Investigator.  The full 
membership, mandate, and processes of the SMC is detailed in the SMC charter. As of Protocol 
Amendment 10, the planned periodic review of safety data by the SMC was no longer scheduled
given the safety data have been analysed as per the statistical plan and submitted to health 
authorities for review.
2.3.2
Independent Endpoint Review Committee
The Independent Endpoint Review Committee (IERC) will be composed of a minimum of 
3 members for Part A, and a minimum of 4 members for Part B.  The role of the IERC will be to 
review radiographic image findings and physical findings (skin lesion mapping / physical 
assessments) for the determination of the BOR and date of disease progression for each subject.  
The full membership, mandate, and processes of the IERC will be detailed in the IERC charter for 
Part A, which is a single radiology review and two-oncologist review committee, and for Part B, 
which is a double radiology review with adjudication and single oncologist review.
3
Background Information
3.1
Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin, which can 
be distinguished from other malignancies by its expression of cytokeratin 20 (CK20, Becker 2010).  
Although relatively rare, with an estimated 1500 new cases in 2008 in the United States (last date 
with available data), the incidence of MCC is increasing.  The incidence of MCC increases with 
age, predominantly affects the white population, and is roughly twice as prevalent in white males 
as white females (Agelli 2003, Albores-Saavedra 2010).  More recent data from the Surveillance, 
Epidemiology, and End Results (SEER) Program database confirm the higher incidence in males 
compared with females in the US (2).  Similar trends are seen in northern European countries 
(Mills 2006, Kaae 2010, Kukko 2012, Reichgelt 2011). The 5-year survival rate for patients with 
MCC is 75%, 59%, and 25% for primary tumors, lymph node metastases (and/or local 
recurrences), and distant metastases, respectively (Becker 2010).
The risk of developing MCC is increased from 5- to 50-fold in immune-suppressed individuals 
(transplant recipients, individuals with lymphoproliferative malignancies such as chronic 
lymphocytic leukemia, or individuals with human immunodeficiency virus [HIV] infections 
[Becker 2010, Bhatia 2011]).  Furthermore, MCC tumor regression has been reported following 
improvement in immune system function in immune compromised individuals (Burak 2003, 
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Muirhead 2007, Bhatia 2011).  These findings suggest a strong link between the immune 
suppression and development and progression of MCC.
Recently, a polyoma virus, Merkel cell polyoma virus (MCV) has been identified (Feng 2008) and 
has been detected in 40% to 100% of patient samples (Rollison 2010). While the role of MCV in 
the pathogenesis of MCC is still unclear, there is evidence that the virus is causal of disease
(Spurgeon 2013).  Additionally, as with other immunogenic tumors, patients with MCV-positive 
tumors have a better overall survival compared with patients with MCV-negative tumors (Sihto 
2009).
3.2
Treatment Options for Merkel Cell Carcinoma
For local and regional disease, surgery (local excision with wide margins) followed by radiation 
therapy are the primary treatment options; however, despite local excision, MCC locoregional 
recurrences are frequent, and usually occur within the first 2 years of primary diagnoses.  
Approximately one-third of patients will experience recurrence, a significant proportion with 
metastatic disease (Medina-Franco 2001, Soult 2012).
At the initiation of this study, there was no Food and Drug Administration (FDA) approved 
treatment for nonresectable, recurrent,
advanced,
or metastatic MCC.  The National 
Comprehensive Cancer Network (NCCN) guidelines recommend multidisciplinary tumor board 
consultation for patients with metastatic disease to consider any or a combination of radiation, 
surgery, and chemotherapy (NCCN 2016).  The specific treatment regimen for patients with distant 
metastasis must be individually tailored.
Most NCCN institutions only use chemotherapy with or without surgery and / or radiation therapy 
for Stage IV, distant metastatic disease (M1).
The most common regimen used for regional disease is cisplatin or carboplatin with or without 
etoposide. The NCCN panel recommends cisplatin or carboplatin with or without etoposide as the 
choice of treatment (Pectasides 2006). Topotecan has also been used in some instances (for 
example, older patients). Cyclophosphamide in combination with doxorubicin and vincristine 
used to be a commonly administered regimen, but it is associated with significant toxicity. Despite 
these recommendations, data are insufficient to assess whether chemotherapeutic regimens 
improve either relapse-free survival or overall survival in MCC patients with distant metastatic 
disease (Voog 1999, Tai 2000, Poulsen 2003).  In fact, though MCC is often initially 
chemosensitive, tumor responses are rarely durable, with the 2-year survival rate for patients with
stage IV disease at approximately 26% (Lemos 2010).
There are no prospective clinical trial data available for patients who received chemotherapy for 
second-line treatment of mMCC (Nghiem 2016). 
The only published report summarizing 
observations of clinical outcomes in a purely distant mMCC population of subjects who had 
received first-line chemotherapy and second-line chemotherapy in the metastatic setting is a report 
by Iyer et al.  The DRR observed with 1L chemotherapy was 17.7% (95% CI 9.2, 29.5) and median 
DOR was 2.8 months for 1L chemotherapy (Iyer 2016 and personal communication). 
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At the initiation of this study, there was one prospective single-arm trial of subjects with locally 
advanced and distant metastatic MCC treated with a PD-1 blockade that demonstrates response to 
this treatment modality (Nghiem 2016).
3.3
Programmed Death Receptor and Ligands
The programmed death 1 (PD-1) receptor and PD-1 ligands 1 and 2 (PD-L1, PD-L2) play integral 
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 1999, Freeman 2000, Dong 2002, Topalian 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 2002, Iwai 2002).
In the clinical setting, treatment with antibodies that block the PD-1 – anti-PD-L1 interaction have 
been reported to produce objective response rates of 7% to 38% in patients with advanced or 
metastatic solid tumors, with tolerable safety profiles (Brahmer 2012, Topalian 2012b, 
Hamid 2013).  Notably, responses appeared prolonged, with durations of 1 year or more for the 
majority of patients.
Of importance to the current trial, previous studies have demonstrated PD-L1 tumor cell 
expression in 49% of MCC patient samples (49 patients sampled) and expression in tumor 
infiltrating lymphocytes in 55% of patient samples.  Of note, of the PD-L1 positive samples, 28 of 
29 samples showed colocalization with immune infiltrates (Lipson 2013).  These findings, coupled 
with the sited response rates and long response durations in other solid tumors make PD-L1 an 
attractive target in patients with MCC.
3.4
Avelumab
The Investigational Medicinal Product (IMP) for the present trial is avelumab, a human 
monoclonal antibody of the immunoglobulin (Ig) G1 isotype. This anti-PD-L1 therapeutic 
antibody concept is being developed in oncological settings by Merck KGaA, Darmstadt, 
Germany, and by its subsidiary, EMD Serono Inc., Rockland, MA, USA. Avelumab has received 
regulatory approval for treatment of metastatic MCC by health authorities in all countries 
conducting this protocol.
Avelumab selectively binds to PD-L1 and competitively blocks its interaction with PD-1.  
Compared with anti-PD-1 antibodies that target T-cells, avelumab targets tumor cells, and 
therefore is expected to have fewer side effects, including a lower risk of autoimmune-related 
safety issues, as blockade of PD-L1 leaves the PD-L2 / PD-1 pathway intact to promote peripheral 
self-tolerance (Latchman 2001).  For complete details of the in vitro and nonclinical studies, please 
refer to the Investigator’s Brochure (IB).
At the time of the initiation of this study, avelumab was in early clinical development with 
2 ongoing Phase I studies in subjects with solid tumors (refer to the latest IB for latest information on 
clinical development and approvals):
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3.4.1.1
Safety Results
Expansion: All adverse events
 
 
 
 
 
 
 
 
 
 
 
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Blood chemistry
A considerable proportion of subjects (up to over 60% for some measure
expansion cohort experienced blood chemistry laboratory abnormalities; how
abnormalities were relatively mild (Grade 1 or 2).  Grade 3 or 4 blood chem
occurred less frequently. The following Grade 3 or 4 abnormalities were ob
subjects: GGT increased, which was reported in 87 subjects (18.1%) treated in the dose expansion 
phase, hyponatremia (32 subjects, 6.7%), and AST increased (30 subjects, 6.3%).
3.4.5
Vital Signs, Physical Findings, and Other Observations 
Related to Safety
 
Vital sign and body weight abnormalities were summarized. For this analysis, the abnormalities 
were defined as:
! Systolic blood pressure ≤ 95 mmHg as well as a decrease from baseline ≥ 20 mmHg or ≥ 160 
mmHg as well as an increase from baseline ≥20 mmHg 
! Diastolic blood pressure ≤ 45 mmHg as well as a decrease from baseline ≥10 mmHg or DBP 
≥ 110 mmHg as well as an increase from baseline ≥ 10 mmHg 
! Pulse rate ≤50 beats per minute (bpm) as well as a decrease from baseline ≥ 20 bpm or pulse 
rate ≥ 120 bpm as well as an increase from baseline ≥ 20 bpm
! Increase or decrease in body weight from baseline ≥ 10%
A small fraction of all subjects experienced vital sign abnormalities as defined above during study 
treatment, with pulse rate ≥ 120 bpm and increase from Baseline ≥ 20 bpm (41 subjects, 8.5%) 
representing the most notable change.
3.4.6
Pharmacokinetic Results
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3.4.7
Clinical Pharmacodynamics
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3.5
Rationale for the Current Clinical Trial
The evaluation of an anti-PD-L1 antibody for the treatment of metastatic MCC is supported by
! the particular biology of this viral-induced tumor and its link to immunosuppression,
! the expression of PD-L1 by MCC tumor cells and by adjacent immune infiltrates, and
! the clinical activity reported by other anti-PD-L1 investigational drugs in the context of the 
expression of PD-L1 at the surface of the tumor or in the tumor micro-environment.
3.6
Summary of the Overall Benefit and Risk
The risk-benefit relationship has been carefully considered in the planning of the trial.  Based on 
the nonclinical and Phase I data available to date, the conduct of the trial is considered justifiable 
using the dose and dose regimen of the avelumab as specified in this clinical trial protocol.  A 
Safety Monitoring Committee (SMC, see Section 2.3.1) will assess the risk-benefit ratio on an 
ongoing basis.  The trial shall be discontinued in the event of any new findings that indicate a 
relevant deterioration of the risk-benefit relationship that would render continuation of the trial 
unjustifiable.
The primary risks of exposure to avelumab include: 
! infusion-related reactions and
! irAEs (other than infusion-related reactions).
At the time of preparation of this Amendment, safety data from 50 subjects treated with avelumab
at doses ranging from 1 to 20 mg/kg during dose escalation and 480 subjects at a dose of 10 mg/kg 
in dose expansion were available. Key safety findings, including irAEs and infusion-related 
reactions, are described in Section 3.4.1. 
Overall, the safety data of avelumab suggest an acceptable safety profile of the compound.
Most of the observed events were either in line with those expected in patients with advanced solid 
tumors or with similar class effects of monoclonal antibodies blocking the PD-1/PD-L1 axis. 
Respective risk mitigation measures have been implemented in all ongoing clinical studies with 
avelumab.
Already implemented risk mitigation measures for infusion-related reactions/hypersensitivity have 
been extended by a mandatory premedication with antihistamine
and paracetamol 
(acetaminophen) for all subjects 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.  A premedication regimen of diphenhydramine and 
paracetamol (acetaminophen, IV or oral equivalent) is recommended. This regimen may be 
modified based on local treatment standards and guidelines as appropriate. 
In addition, since avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), 
there is a potential risk of tumor lysis syndrome (see Section 6.5.4.3). 
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As noted above (Section 3.3), trials with antibodies that block the PD-1 – anti-PD-L1 interaction 
have been reported to produce objective response rates of 7% to 38% in patients with advanced or 
metastatic solid tumors (Brahmer 2012, Topalian 2012b, Hamid 2013), with response durations of 
1 year or more for the majority of patients.
Given the poor prognosis of subjects with metastatic MCC, the lack of treatment options for 
second-line patients, and the safety profile of avelumab as currently demonstrated by ongoing 
Phase I trials, the risk-benefit ratio of treatment with avelumab in the targeted trial population is 
considered positive for Part A of this study.
With regard to Part B, in first-line treatment, patients face poor prognosis and lack of treatment 
options.  The NCCN MCC guidelines highlight clinical trials where possible due to lack of survival 
evidence for chemotherapy in first line treatment (NCCN 2016).  European guidelines similarly 
note the lack of survival benefit of chemotherapy and mention palliative care due to the poor 
prognosis, especially in elderly patients (Becker 2010, Boccara 2012).  When chemotherapy is 
used, regimens similar to small cell lung cancer such as carboplatin with etoposide are common, 
although NCCN notes “the literature does provide evidence that Merkel cell carcinoma is 
chemosensitive, although the responses are not durable”.  Overall, there is poor prognosis, with 
2-year survival rate of 26% in Stage IV disease (Lemos 2010).  The benefit of avelumab in 
metastatic MCC as initial therapy is unknown; however, preliminary results from an ongoing 
Phase II study in second-line or greater metastatic disease has documented an ORR greater than a
predefined futility rate (data not shown).  Also, a similar mechanism of action (pembrolizumab, 
an anti-PD-1 antibody) has demonstrated a substantial ORR (71% in evaluable patients) in 
treatment naïve metastatic or unresectable MCC (Nghiem 2016).  Given the known clinical activity 
of avelumab in a variety of tumor types (refer to avelumab IB) and given the expression of PD-L1 
with CD8 T cell presence in Merkel cell tumors (Afanasiev 2013) it is plausible that avelumab 
offers benefit.  Overall, given the poor prognosis, lack of treatment options based on evidence and 
its known safety profile, avelumab is considered to have a positive risk-benefit ratio for Part B of 
this study.  
In Part B, subjects with prior adjuvant chemotherapy experience (but not in the metastatic setting) 
are allowed.  This inclusion is justified given the lack of evidence of survival benefit for 
chemotherapy in the adjuvant setting (NCCN 2016) and, therefore, poor prognosis for first line 
patients regardless of prior adjuvant treatment history.  Such subjects must meet entry criteria that 
include adequate absolute lymphocyte and neutrophil counts and resolution of prior events must 
have completed adjuvant chemotherapy more than 6 months prior to the current trial, therefore, 
they are expected to have largely recovered from immune suppressive effects of chemotherapy.  
This clinical trial will be conducted in compliance with the clinical trial protocol, Good Clinical 
Practice (International Council for Harmonisation [ICH] Topic E6, Good Clinical Practice [GCP]),
and the applicable national regulatory requirements.
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4
Trial Objectives
Primary
Part A:  The primary objective of the trial is to assess the clinical activity of avelumab as 
determined by the objective response rate (ORR) according to Response Evaluation Criteria in 
Solid Tumors version 1.1 (RECIST 1.1; Eisenhauer 2009) in subjects with metastatic MCC after 
failing first-line chemotherapy.
Part B:  The primary objective is to evaluate the clinical activity of avelumab as first-line treatment 
for metastatic or distally recurrent MCC as determined by the durable response rate (DRR) 
according to RECIST 1.1 by an IERC.
Secondary
Part A:  Secondary objectives are as follows:
! To assess the duration of response according to RECIST 1.1
! To assess the progression-free survival time (PFS) according to RECIST 1.1
! To assess the safety profile of avelumab in subjects with MCC
! To assess overall survival (OS) time 
! To assess response status according to RECIST 1.1 at 6 and 12 months after start of study 
treatment
! To characterize the population PK of avelumab in subjects with MCC by sparse sampling
! To evaluate the immunogenicity of avelumab and to correlate it to exposure 
Part B:  Secondary objectives are as follows:
! To assess the OS time
! To assess ORR according to RECIST 1.1
! To assess the duration of response according to RECIST 1.1
! To assess the PFS according to RECIST 1.1
! To assess the safety profile of avelumab in subjects with MCC
! To assess response status according to RECIST 1.1 at 6 and 12 months after start of study 
treatment
! To characterize the population PK of avelumab in subjects with MCC by sparse sampling
! To evaluate the immunogenicity of avelumab and to correlate it to exposure 
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Exploratory objectives
Part A:  Exploratory objectives are as follows:
Part B:  Exploratory objectives are as follows:
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a multicenter, international, single-arm, open-label, Phase II, trial in 2 parts that will 
evaluate the efficacy and safety of avelumab in subjects with metastatic MCC. In Part A, subjects
must have received at least one line of chemotherapy for the treatment of metastatic MCC. In 
Part B, subjects must be treatment naïve to systemic therapy in the metastatic setting. Part B will 
serve as the confirmatory study required to meet conditions for some health authority approvals of 
avelumab for treatment of metastatic MCC.
5.1.1
Overall Design
In Part A, up to 84 subjects are planned to be enrolled and in Part B, up to 112 eligible subjects 
are planned to be enrolled.  In both Part A and Part B, subjects will receive avelumab at a dose of 
10 mg/kg once every 2 weeks.  Tumor measurements (including the assessment of skin lesions by 
physical examination) to determine response will be performed every 6 weeks until 12 months 
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after the first study drug administration, then every 12 weeks thereafter and response to the 
treatment will be evaluated by RECIST 1.1.  Treatment will continue until:
!
therapeutic failure (subjects may stay on treatment beyond radiological disease progression 
provided there is no significant clinical deterioration, see Section 5.5.1), 
!
unacceptable toxicity, or
!
any criterion for withdrawal from the trial or study drug is fulfilled (see Section 5.5).
For Part A:  Subjects who have experienced a confirmed complete response (CR) should be treated 
for a minimum of 6 months and a maximum of 12 months after confirmation, at the discretion of 
the Investigator. If the Investigator believes that a subject may benefit from treatment beyond 
12 months, it may be permissible after discussion with the sponsor. Part B:  Subjects who have 
experienced a confirmed CR should be treated for a minimum of 12 months after confirmation, at 
the discretion of the Investigator.  If the Investigator believes that a subject may benefit from 
treatment beyond 12 months, it may be permissible after discussion with the sponsor.  For both 
Part A and Part B, in case a subject with a confirmed CR relapses after stopping treatment, but 
prior to the end of the trial, 1 re-initiation of treatment is allowed at the discretion of the 
Investigator and agreement of the trial Medical Monitor.  In order to be eligible for retreatment, 
the subject must not have experienced any toxicity that led to treatment discontinuation of the 
initial avelumab therapy.  Subjects who re-initiate treatment will stay on study and will be treated 
and monitored according to the protocol and the “until progression” schedule in the Schedule of 
Assessments (see Appendix I).
Assessments will be made by the Investigators for the purpose of subject management, but the
primary and secondary endpoint determinations will be supported by tumor assessments performed 
by an IERC (see Sections 2.3.2 and 7.3).
Subjects will attend clinic visits at regular intervals to receive study drug and for efficacy and 
safety assessments (see Section 7.1.2).
For Part A, the primary endpoint for the trial will be the confirmed BOR, as per RECIST 1.1, as 
determined by the IERC.  Both CR and partial response (PR) must be confirmed by a second tumor 
assessment, preferably performed at the regularly scheduled 6-week assessment interval, but no 
sooner than 5 weeks after the initial documentation of CR or PR. Confirmation of PR can be 
confirmed at an assessment later than the next assessment after the initial documentation of PR.
For Part B, the primary endpoint is durable response, defined as objective response (CR or PR) 
according to RECIST 1.1, determined by an IERC, with a duration of at least 6 months.
Safety endpoints include AEs, assessed throughout the trial and evaluated using the NCI Common 
Technology Criteria version 4.0 (CTCAE v 4.0), clinical laboratory assessments, vital signs, and 
ECG parameters.
Health-related quality of life questionnaires, EuroQol-EQ-5D (EQ-5D) and Functional 
Assessment of Cancer Therapy – Melanoma (FACT-M), will be administered to subjects at 
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baseline, every 6 weeks while on study treatment, and at the End-of Treatment visit.  In addition, 
subject interviews will be conducted in order to collect subjects’ previous experience with the 
disease and its treatment and their current experience within the trial.  For Part A and Part B of the 
study, subject interviews will be optional (box on the Informed Consent Form [ICF] indicating 
consent for interviews must be checked and a Contact Order Form including subject contact details 
should be completed and sent to the independent unit in charge of managing the interviews).
For Part A, there will be 1 interim analysis for futility after 20 subjects have been enrolled and 
observed for at least 3 months and 1 interim analysis for efficacy 6 months after 56 subjects have 
been enrolled.  If no unconfirmed response according to RECIST 1.1 is seen in the first interim 
analysis, then enrollment will be stopped until the SMC makes a recommendation as to whether 
the trial should continue.  If efficacy goals are met at the second interim analysis, enrollment will 
continue to the planned full number of subjects in order to collect further data on the primary and 
secondary endpoints.  The primary analysis will be conducted 6 months after the accrual of the last 
subject and a further exploratory analysis will be conducted 12 months after the accrual of the last 
subject. The trial will continue as specified in Section 5.7.  
In Part B, there will be 1 interim analysis at 3 months after the accrual of the 25th subject, with 
additional interim analyses possible. The primary analysis will be conducted 15 months after the 
accrual of the last subject. The trial will continue as specified in Section 5.7.
5.1.2
Trial Endpoints
5.1.2.1
Primary Endpoints
For Part A, the primary endpoint is the confirmed BOR for each subject, per RECIST 1.1, as 
determined by the IERC (see Section 7.3).
For Part B, the primary endpoint is durable response, defined as objective response (CR or PR) 
according to RECIST 1.1, determined by an IERC, with a duration of at least 6 months.
5.1.2.2
Secondary Endpoints and Exploratory Endpoints
Part A: Secondary endpoints include:
! duration of response according to RECIST 1.1 as determined by an IERC,
! PFS time according to RECIST 1.1 as determined by an IERC, 
! occurrence, number, and severity of treatment-related AEs according to NCI-CTCAE v 4.0,
clinical laboratory assessments, vital signs, and ECG parameters,
! OS time, 
! response status according to RECIST 1.1 at 6 and 12 months after start of study treatment,
! serum titers of anti-avelumab antibodies, and
! population PK profile of avelumab (sparse sampling).
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Part A:  Exploratory endpoints include:
Part B:  Secondary endpoints include:
! OS time,
! confirmed BOR per RECIST 1.1 as determined by an IERC,
! duration of response according to RECIST 1.1 as determined by an IERC,
! PFS time according to RECIST 1.1 as determined by an IERC, 
! occurrence and severity of treatment-related AEs according to NCI-CTCAE v 4.0, 
! response status according to RECIST 1.1 at 6 and 12 months after start of study treatment,
! serum titers of anti-avelumab antibodies, and
! population PK profile of avelumab (sparse sampling).
Part B:  Exploratory endpoints include:
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5.1.3
Trial Medication Administration and Schedule
Subjects will receive IV infusion of avelumab (10 mg/kg over 1 hour [-10 minutes / +20 minutes, 
that is, over 50 to 80 minutes]) once every 2 weeks (one treatment cycle).  The trial treatment 
schedule is illustrated in Appendix I.
In order to mitigate infusion-related reactions, a 
premedication regimen of antihistamine (diphenhydramine or equivalent) and paracetamol
(acetaminophen, IV or oral equivalent) is required 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. This regimen may be modified based 
on local treatment standards and guidelines as appropriate. Steroids as premedication are not 
acceptable.
The formulation and packaging information of avelumab is provided in Sections 6.1 and 6.6, 
respectively.
5.1.4
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation
5.1.4.1
Dose Modification
The dose of avelumab will be calculated based on the weight of the subject determined on the day 
of (for Part A), or within 3 days of each drug administration (Part B).
Each subject will stay on the avelumab assigned dose of 10 mg/kg unless treatment needs to be 
stopped.  Dosing modifications (changes in infusion rate) and dose delays are described in Section 
5.1.4.2.  There are to be no dose reductions.
5.1.4.2
Adverse 
Drug 
Reactions 
Requiring 
Treatment 
Discontinuation or Modifications
The following ADRs require permanent treatment discontinuation of avelumab:
Any Grade 4 ADRs require treatment discontinuation with avelumab except for single 
laboratory values out of normal range that are unlikely related to trial treatment as assessed by the 
Investigator, do not have any clinical correlate, and resolve within 7 days with adequate medical 
management.
Any Grade 3 ADRs require treatment discontinuation with avelumab except for any of the 
following:
! Transient (≤ 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management
! Transient (≤ 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to Grade ≤1
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! Single laboratory values out of normal range (excluding Grade ≥3 liver function test increase) 
that are unlikely related to trial treatment according to the Investigator, do not have any clinical 
correlate, and resolve to Grade ≤ 1 within 7 days with adequate medical management
! Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumor
! Change in Eastern Cooperative Oncology Group Performance Status (ECOG PS) to ≥ 3 that
does not resolve to ∀2 within 14 days (infusions should not be given on the following cycle, if 
the ECOG PS is ≥ 3 on the day of study drug administration)
! Asymptomatic Grade ≥ 3 lipase or amylase elevation not associated with clinical manifestations 
of pancreatitis. Medical Monitor must be consulted for such lipase and amylase abnormalities.
Any Grade 2 ADR should be managed as follows:
! Infusion should not be given in case of ongoing Grade 2 ADR on the day of study treatment 
administration.
! Treatment can be resumed according to the original schedule once the ADR has resolved to
Grade ≤ 1. Up to 2 subsequent study drug may be omitted.  If more than 2 doses are skipped, 
treatment may be resumed after consultation with the Medical Monitor. 
Infusion-related reactions, hypersensitivity reactions (Grades 1 to 4), tumor lysis syndrome, and 
irAEs should be handled according to guidelines in Sections 6.5.4.1, 6.5.4.2, 6.5.4.3, and 6.5.4.4, 
respectively.
5.2
Discussion of Trial Design
This is a Phase II single-arm trial to determine the efficacy and safety of avelumab in subjects with 
metastatic MCC.  There is currently no approved treatment for advanced or metastatic MCC; thus 
a single-arm trial is appropriate.  Furthermore, as there is no solid evidence of therapeutic efficacy 
in any second-line chemotherapy regimen, no concomitant therapy is justified.  Planned interim 
analyses during the trial ensure a minimum number of subjects are exposed to the study drug in 
the case of insufficient clinical activity.  The dosing regimen is based upon the current ongoing 
Phase I trials.  The primary endpoint will be the confirmed BOR according to RECIST 1.1.  
Responses provide a direct measure of antitumor activity in subjects treated with the study drug.  
The confirmed BOR will be used to determine the ORR, which is suitable for a single-arm Phase 
II trial.  The response status at 6 and 12 months after start of treatment, duration of response, and 
PFS and OS times will also be determined and will serve to assess whether the ORR is associated 
with lasting clinical benefit.  A within-subject comparison of PFS time on study versus TTP on 
prior treatment will also serve as a comparative evaluation of subjects’ outcome under treatment 
with avelumab.
With regard to Part B, the benefit of avelumab in metastatic MCC as initial therapy is unknown;
however, preliminary results from an ongoing Phase II study (Part A of this study) in second-line 
or greater metastatic disease has documented an ORR greater than a predefined futility rate (data 
not shown).  Also, a similar mechanism of action (pembrolizumab, an anti-PD-1 antibody) has 
demonstrated a substantial ORR (71% in evaluable patients) in treatment naïve metastatic or 
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unresectable MCC (Nghiem 2016).  Given the known clinical activity of avelumab in a variety of 
tumor types (refer to avelumab IB) and given the expression of PD-L1 with CD8 T cell presence 
in Merkel cell tumors (Afanasiev 2013) it is plausible that avelumab offers benefit. Further risk / 
benefit considerations are discussed in Section 3.6.
With regard to Part B, DRR is reasonable as a primary endpoint based on several factors.  In a 
disease setting that is highly chemoresponsive but with short duration (NCCN 2016), DRR may 
describe response in a more clinically meaningful way compared with ORR.  Adopting DRR of 
6 months as a time-sensitive endpoint for the analysis of the Part B appears logical, especially 
since 6 months is viewed as a clinically relevant timepoint when considering response duration in 
metastatic MCC patients, given the fact that median survival in metastatic MCC is 9 months 
(Voog 1999) and that chemo-responses are noted as “not durable” by NCCN with median duration 
of response in Stage IV cited as 3 to 9 months (Iyer 2016, Satpute 2014, Tai 2000, Voog 1999, 
Sharma 1991).  Also, the recent precedent of Imlygic regular approval by FDA based on a DRR 
endpoint suggests that DRR of 6 months is clinically meaningful (Imlygic SBA).  In order to 
provide an estimation of the DRR, a total of 112 subjects will be enrolled (see Section 8.1). 
5.2.1
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. Signed written informed consent
2. Male or female subjects aged ≥18 years
3. Histologically proven MCC 
a.
Confirmation of the diagnosis by immunohistochemistry detection of CK20 (or other 
appropriate cytokeratin expression such as pancytokeratin, AE1/AE3, or Cam5.2; local 
laboratory testing) in the tumor cell is mandatory
b. Subjects must have metastatic disease; subjects with non-metastatic MCC that is only 
recurrent or unresectable are NOT eligible; for Part B, M1 status must be confirmed at 
entry
c.
For Part A:  Subjects must have received at least 1 line of chemotherapy for the treatment 
of metastatic MCC and must have progressed after the most recent line of chemotherapy 
that was administered.  Subjects must have received at least one of the following 
chemotherapy regimens for treatment of metastatic MCC:  Cyclophosphamide, 
topotecan, doxorubicine, epirubicin, vincristine, carboplatin, cisplatin, etoposide in 
combination with carboplatin or cisplatin
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d. For Part B:  Subjects must not have received any prior systemic treatment for metastatic 
MCC.  Prior chemotherapy treatment in the adjuvant setting (no clinically detectable 
disease; no metastatic disease) is allowable if the end of treatment occurred at least 
6 months prior to study start
4. For Part A:  Collection of biopsy material is required (fresh biopsy or recent biopsy [within 
4 weeks prior to enrollment], for subjects unable to provide a fresh or recent biopsy, archival 
material is acceptable).
For Part B: 
1) Priority:  A recently obtained formalin-fixed, paraffin-embedded (FFPE) block containing 
tumor tissue (preferably within 6 months). If no tumor tissue is available, fresh biopsy will 
be required
2) Priority:  If the tumor containing FFPE tissue block cannot be provided in total, sections 
from this block should be provided that are freshly cut (within 1 week).  Preferably, 
25 slides should be provided; if not possible, a minimum of 10 slides in consultation with 
the Medical Monitor is required
5. ECOG PS of 0 to 1 at trial entry 
6. Estimated life expectancy of more than 12 weeks
7. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1
(including skin lesions)
8. Adequate hematological function defined by WBC count ≥3 × 109/L with absolute neutrophil 
count (ANC) ≥1.5 × 109/L, lymphocyte count ≥ 0.5 × 109/L, platelet count ≥100 × 109/L, and 
hemoglobin ≥9 g/dL (may have been transfused)
9. Adequate hepatic function defined by a total bilirubin level ≤1.5 × the upper limit of normal
(ULN) range and AST and ALT levels ≤2.5 × ULN for all subjects
10. Adequate renal function defined by an estimated creatinine clearance > 30 mL/min according 
to the Cockcroft-Gault formula or by 24 hour urine collection for creatinine clearance or 
according to local institutional standard method
11. Highly effective contraception (that is, methods with a failure rate of less than 1% per year) 
for both male and female subjects if the risk of conception exists (Note:  The effects of the 
study treatment on the developing human fetus are unknown; thus, women of childbearing 
potential and men must agree to use highly effective contraception, defined in Appendix III or 
as stipulated in national or local guidelines.  Highly effective contraception must be used 
28 days prior to first study treatment administration, for the duration of study treatment, and at 
least for 60 days after stopping study treatment.  Should a woman become pregnant or suspect 
she is pregnant while she or her partner is participating in this study, the treating physician 
should be informed immediately.)
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5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. Participation in another interventional clinical trial within the past 30 days (participation in 
observational studies are permitted)
2. Concurrent treatment with a nonpermitted drug
3. Prior therapy with any antibody/drug targeting T-cell coregulatory proteins (immune 
checkpoints) such as anti-PD-1, anti-PD-L1, or anticytotoxic T-lymphocyte antigen-4 
(CTLA-4) antibody; for Part B, the Investigator must consult with the Medical Monitor and 
consider other co-regulatory targets such as 4-1BB
4. Concurrent anticancer treatment (for example, cytoreductive therapy, radiotherapy [with the 
exception of palliative bone-directed radiotherapy, or radiotherapy administered on non-target
superficial lesions], immune therapy, or cytokine therapy except for erythropoietin).  
Radiotherapy administered to superficial lesions is not allowed if such lesions are considered 
target lesions in the efficacy evaluation or may influence the efficacy evaluation of the 
investigational agent
5. Major surgery for any reason, except diagnostic biopsy, within 4 weeks and/or if the subject 
has not fully recovered from the surgery within 4 weeks
6. Concurrent systemic therapy with steroids or other immunosuppressive agents, or use of any 
investigational drug within 28 days before the start of trial treatment.  Short-term 
administration of systemic steroids (that is, for allergic reactions or the management of irAEs) 
is allowed while on study.  Also, subjects requiring hormone replacement with corticosteroids 
for adrenal insufficiency are eligible if the steroids are administered only for the purpose of 
hormonal replacement and at doses ≤ 10 mg or equivalent prednisone per day.  Note: Subjects 
receiving bisphosphonate or denosumab are eligible 
7. Subjects with active central nervous system (CNS) metastases are excluded.  Subjects with a 
history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless  they 
have fully recovered from treatment, demonstrated no progression for at least 2 months, and 
do not require continued steroid therapy
8. For Part A:  Previous malignant disease (other than MCC) within the last 5 years with the 
exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ
For Part B:  Previous malignant disease (other than MCC) within the last 5 years with the 
exception of basal or squamous cell carcinoma of the skin or carcinoma in situ (skin, bladder, 
cervical, colorectal, breast, or low grade prostatic intraepithelial neoplasia or Grade 1 prostate 
cancer) 
9. Prior organ transplantation, including allogeneic stem-cell transplantation 
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10. For Part A, known history of testing positive for HIV or known acquired immunodeficiency 
syndrome (AIDS) or any positive test for hepatitis B virus (HBV) or hepatitis C virus (HCV)
indicating acute or chronic infection.  For Part B, known history of testing positive for HIV or 
known AIDS or HBV or HCV infection at screening (positive HBV surface antigen or HCV 
RNA if anti-HCV antibody screening test positive)
11. Active or history of any autoimmune disease (except for subjects with vitiligo) or 
immunodeficiencies that required treatment with systemic immunosuppressive drugs
12. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE 
v 4.0), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partly 
controlled asthma)
13. Persisting toxicity related to prior therapy Grade > 1 NCI-CTCAE v 4.0; however, sensory 
neuropathy Grade ≤ 2 is acceptable
14. Pregnancy or lactation
15. Known alcohol or drug abuse
16. Clinically significant (that is, active) cardiovascular disease: cerebral vascular accident / stroke 
(< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), 
unstable 
angina, 
congestive 
heart 
failure 
(New 
York 
Heart
Association 
Classification Class ≥II), or serious cardiac arrhythmia requiring medication 
17. All other significant diseases (for example, inflammatory bowel disease), which, in the opinion 
of the Investigator, might impair the subject’s tolerance of trial treatment
18. Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent
19. Legal incapacity or limited legal capacity
20. Nononcology vaccine therapies for prevention of infectious disease (for example, seasonal flu 
vaccine, human papilloma virus vaccine) within 4 weeks of study drug administration.  
Vaccination while on trial is also prohibited except for administration of inactivated vaccines
(for example, inactivated seasonal influenza vaccine)
5.4
Criteria for Randomization/Initiation of Treatment with the 
Investigational Medicinal Product 
The inclusion and exclusion criteria will be checked at the Screening visit. Eligible subjects will 
be enrolled before treatment start after verification of fulfilling all inclusion criteria without 
matching any exclusion criterion.
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5.5
Criteria for Subject Withdrawal
5.5.1
Criteria for Withdrawal from Study Drug due to Therapeutic 
Failure
Subjects may continue avelumab treatment beyond radiological disease progression in the absence 
of significant clinical deterioration and, if in the opinion of the Investigator, the subject will benefit 
from continued treatment.
Before stopping the treatment with avelumab, progressive disease (PD) should be confirmed 
by imaging, preferably 6 weeks (but no later) after progression has been diagnosed according 
to RECIST 1.1.
If progression is based on the occurrence of a new lesion in an area not scanned at baseline, a 
further on-trial scan 6 weeks later should be performed. Treatment during the confirmation period 
should continue as scheduled, despite a first observation of progression (according to RECIST 
1.1), until confirmation has been made, and further if there is no significant clinical deterioration 
defined as:
!
there are no new symptoms or worsening of existing symptoms,
!
there is no change in ECOG PS to ≥ 3 that lasts more than 14 days, or
!
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 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) that 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
! 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
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The decision to continue treatment should be discussed with the Medical Monitor and documented 
in the trial records.
Subjects who experience significant clinical deterioration, as defined above, in the absence of 
confirmed PD should be discontinued from further treatment with avelumab.
The treatment with avelumab should be stopped immediately, if the subject does not tolerate 
avelumab anymore or if therapeutic failures occur, which requires urgent additional drug or results 
in clinical progression/deterioration.
5.5.2
Withdrawal from the Trial
Subjects are free to discontinue the trial at any time without giving their reasons.
A subject must be withdrawn in the event of any of the following:
!
Withdrawal of the subject’s consent
!
Participation in any other therapeutic trial during the treatment duration of this trial
If a subject fails to attend scheduled trial assessments, the Investigator must determine the reasons 
and the circumstances as completely and accurately as possible.
In case of premature withdrawal from the trial (prior to the End-of-Treatment visit), the 
investigations scheduled for the last visit should be performed (see Section 7.1.3 for the 
End-of-Treatment visit), if possible, with focus on the most relevant assessments. In any case, the 
appropriate electronic case report form (eCRF) section must be completed.
If a subject is withdrawn prior to progression for any reason, they will not be replaced.
5.5.3
Withdrawal from the Investigational Medicinal Product
The subject must be withdrawn in the event of any of the following:
! Therapeutic failure as outlined in Section 5.5.1
! Occurrence of an exclusion criterion, which is clinically relevant and affects the subject’s 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor
! Therapeutic failure requiring urgent additional drug (if applicable)
! Occurrence of any Grade ≥ 3 ADRs as defined in Section 5.1.4.2
! Occurrence of AEs, resulting in the discontinuation of the study drug being desired or 
considered necessary by the Investigator and/or the subject 
! Occurrence of pregnancy 
! Use of a nonpermitted concomitant drug, as defined in Section 6.5.2, where the predefined 
consequence is withdrawal from the study drug
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! Noncompliance (see Section 6.9)
5.6
Premature Discontinuation of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
! New information leading to unfavorable risk-benefit judgment of the study drug, for example,
due to
 evidence of inefficacy of the study drug,
 occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions, or
 other unfavorable safety findings.
(Note: evidence of inefficacy may arise from this trial or from other trials; unfavorable safety 
findings may arise from clinical or non-clinical examinations, for example, toxicology.)
! Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons
! Poor enrollment of subjects making completion of the trial within an acceptable time frame 
unlikely
! Discontinuation of development of the Sponsor’s study drug
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
will be informed about the discontinuation of the trial in accordance with applicable regulations.
The whole trial may be terminated or suspended upon request of Health Authorities.
5.7
Definition of End of Trial
If the trial is not terminated for a reason given in Section 5.6, the survival will continue until 5 years
after the last subject receives the last dose of avelumab or the last subject dies, whichever occurs 
first. Under some circumstances, subjects may not be followed for 5 years for survival in this 
study, for example, subjects may be offered to enroll into a rollover study, or the Sponsor may 
terminate the study early.  
The Sponsor may terminate the study at any time, but will not do so unless appropriate access to 
avelumab is in place for subjects receiving it such as an expanded access program, roll-over study, 
market authorization, or other mechanism.  
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term IMP refers to the investigational drug undergoing a clinical trial, as well as to any 
comparator drug or placebo (as applicable). In this trial, the IMP is avelumab and no comparator 
drug or placebo is involved.
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6.1
Description of Investigational Medicinal Product
Avelumab is a sterile, clear, and colorless solution intended for IV administration. It is presented 
at a concentration of 10 mg/mL (Part A only) and 20 mg/mL (Part A and Part B) in single-use 
glass vials closed with a rubber stopper and sealed with an aluminum yellow polypropylene flip 
off seal and supplied as 1 vial per box (it is allowable subjects in Part A receiving 10 mg/mL study 
drug to be transitioned to 20 mg/mL drug as needed).
6.2
Dosage and Administration
Subjects will receive an IV infusion of avelumab at a dose of 10 mg/kg (over the duration of 1 hour
[-10 minutes / +20 minutes, that is, over 50 to 80 minutes]) once every 2 weeks (refer to Appendix
I). A premedication regimen with an antihistamine and paracetamol (acetaminophen) is required
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. 
This regimen may be modified based on local treatment standards and guidelines as appropriate.  
Modifications of the infusion rate due to infusion-related reactions are described in Section 6.5.4.1.  
The dose of avelumab will be calculated based on the weight of the subject determined on the day 
of (for Part A), or within 3 days of each drug administration (Part B). Subjects will receive 
avelumab once every 2 weeks until the criteria in sections 5.5 through 5.7 are met.
6.3
Assignment to Treatment Groups
The Investigator or delegate will assign a unique subject identifier number to eligible subjects in 
chronological order at the time of informed consent signature. Subject identifiers will comprise 
17 digits, the first 10 digits representing the trial number, the following 3 digits representing the 
site number, and the last 4 digits representing the subject number, which is allocated sequentially 
starting with 0001.  Subject enrollment will be managed by an IVRS.
The Sponsor’s / CRO’s Responsible Medical must confirm enrollment after receipt of the 
appropriate information relating to subject entry criteria.
This trial is not randomized; therefore, no central treatment allocation is planned.
6.4
Other Drugs to be Used in the Trial
Subjects must be pretreated with an antihistamine and 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. This 
regimen may be modified based on local treatment standards and guidelines as appropriate.
Immediate access to an ICU or equivalent environment and appropriate medical therapy (including 
epinephrine, corticosteroids, IV antihistamines, bronchodilators, and oxygen) must be available 
for use in the treatment of infusion-related reactions. Infusion of avelumab will be stopped in case 
of Grade ≥2 infusion-related, allergic, or anaphylactoid reactions. Following avelumab infusions, 
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subjects should be observed based upon clinical judgment and presence / severity of prior infusion 
reactions. 
As with all monoclonal antibody therapies, there is a risk of allergic reaction. Avelumab
should be administered in a setting that allows for immediate access and administration of 
therapy for severe allergic / hypersensitivity reactions, such as the ability to implement 
immediate resuscitation measures. Steroids (dexamethasone 10 mg), epinephrine (1:1000 
dilution), allergy medications (antihistamines), or equivalents should be available for 
immediate access.
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. 
Guidelines for management of infusion-related reactions and severe 
hypersensitivity and flu-like symptoms according to the NCI are found in Sections 6.5.4.1 and 
6.5.4.2, respectively. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf. Subjects should be instructed to report any delayed 
reactions to the Investigator immediately.
6.5
Concomitant Medications and Therapies
6.5.1
Permitted Medicines
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary for the subjects’ welfare and will not interfere with the study drug may be given at the 
Investigator’s discretion.
Other drugs to be used for prophylaxis, treatment of hypersensitivity reactions, and treatment of 
fever or flu-like symptoms are described in Section 6.5.4.2.
The Investigator will record all concomitant medications taken by the subject during the trial, from 
the date of signature of informed consent, in the appropriate section of the eCRF.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
Palliative bone-directed radiotherapy may be administered during the trial.  Once a skin target 
lesion is irradiated, all subsequent tumor assessments will be censored from the efficacy analysis.  
The assessment of PD will be made according to RECIST 1.1 (Eisenhauer 2009) and not based on 
the necessity for palliative bone directed-radiotherapy.
6.5.2
Nonpermitted Medicines
As stated for the exclusion criteria in 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 
anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody or concurrent anticancer treatment (for example,
cytoreductive therapy, radiotherapy [with the exception of palliative bone-directed radiotherapy, 
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or radiotherapy administered on non-target 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 trial treatment. Steroids as premedication are not acceptable.
In addition, the following treatments must not be administered during the trial:
! Immunotherapy, immunosuppressive drugs (that is, chemotherapy or systemic corticosteroids 
except for short-term treatment of allergic reactions or for the treatment of irAEs), or other 
experimental pharmaceutical products. Short-term administration of systemic steroid (that is,
for allergic reactions, management of patients with allergy to radiographic contrast media, or 
the management of irAEs) is allowed.  Steroids with no or minimal systemic effect (topical, 
inhalation) are allowed.
Also, hormone replacement with corticosteroids for adrenal 
insufficiency is allowed if the steroids are administered only for the purpose of hormonal 
replacement and at doses ≤ 10 mg or equivalent prednisone per day.
! Any vaccine therapies for the prevention of infectious disease (for example, seasonal flu 
vaccine, human papilloma virus vaccine) except administration of the inactive influenza 
vaccine
! Growth factors (granulocyte colony stimulating factor or granulocyte macrophage colony 
stimulating factor). Exception: Erythropoietin and darbepoietin alpha may be prescribed at the 
Investigator’s discretion
If the administration of a nonpermitted concomitant drug becomes necessary during the trial, the 
subject will be withdrawn from trial treatment (the Sponsor may be contacted to discuss whether 
the trial treatment must be discontinued).
Medications other than those specifically excluded in this trial (see above) may be administered 
for the management of symptoms associated with the administration of avelumab as required. 
These might include analgesics, antinausea medications, antihistamines, diuretics, anti-anxiety 
medications, and medication for pain management, including narcotic agents.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
6.5.3
Other Trial Considerations
The following nondrug therapies must not be administered during the trial (and within 28 days 
before the start of trial treatment):
! Surgery to any tumor lesion for symptom management or tumor control is not permitted during 
the study treatment. For any other surgical interventions planned during the study, study 
treatment should be delayed to allow subject’s recovery, for up to a maximum of 4 weeks (also
see Section 5.5.1 for details of treatment management beyond initial assessment of PD)
! Herbal remedies with immunostimulating properties (for example, mistletoe extract) or known 
to potentially interfere with major organ function (for example, hypericin)
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! Subjects should not abuse alcohol or other drugs during the trial
Any diagnostic biopsies collected for clinical reasons during the trial should be documented as a 
concomitant procedure including the outcome of available pathological reports.
6.5.4
Special Precautions
As a routine precaution, subjects enrolled in this trial should be observed based upon clinical 
judgment and presence / severity of prior infusion reactions, in an area with resuscitation 
equipment and emergency agents. At all times during avelumab treatment, immediate emergency 
treatment of an infusion-related reaction or a severe hypersensitivity reaction according to 
institutional standards must be assured. In order to treat possible hypersensitivity 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. 
Infusion of avelumab will be stopped in case of Grade ≥ 2 hypersensitivity, inflammatory response, 
or infusion-related reaction. The treatment recommendations for infusion-related reactions, severe 
hypersensitivity reactions, and tumor lysis syndrome according to the NCI are as outlined in 
Sections 6.5.4.1, 6.5.4.2, and 6.5.4.3, respectively.
Investigators should also monitor subjects closely for potential irAEs, which may become manifest 
earliest after weeks of treatment. Such events may consist of persistent rash, diarrhea and colitis, 
autoimmune hepatitis, arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other 
inflammatory eye conditions. The spectrum of hypothetical irAEs also includes formation of auto-
antibodies like anti-nuclear antibodies (ANAs) or antineutrophil cytoplasmic antibodies (ANCAs).
6.5.4.1
Infusion-Related Reactions
A. Symptoms
!
Fever
!
Chills
!
Rigors
!
Diaphoresis
!
Headache
B. Management (and according to Table 4)
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Table 4
Treatment Modification for Symptoms of Infusion-Related Reactions 
Caused by Avelumab
NCI-CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not indicated; 
intervention not indicated.
Decrease the avelumab infusion rate by 50% and monitor 
closely for any worsening.
Grade 2 – moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ∀24 h.
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 (for example, 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.
IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Once the avelumab infusion rate has been decreased by 50% or interrupted due to an 
infusion-related reaction, it must remain decreased for all subsequent infusions.  If a subject 
experiences a Grade 3 or 4 infusion-related reaction at any time, the subject must discontinue 
avelumab.
6.5.4.2
Severe Hypersensitivity Reactions and Flu-Like Symptoms
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf). Subjects should be instructed to report any delayed 
reactions to the Investigator immediately.
A. Symptoms
!
Impaired airway
!
Decreased oxygen saturation (< 92%)
!
Confusion
!
Lethargy
!
Hypotension
!
Pale / clammy skin
!
Cyanosis
B. Management
1. Epinephrine injection and dexamethasone infusion
2. Patient should be placed on monitor immediately 
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3. Alert ICU for possible transfer if required
For prophylaxis of flu-like symptoms, 25 mg of indomethacin or comparable nonsteroidal 
anti-inflammatory drug (NSAID) dose (for example, ibuprofen 600 mg, naproxen sodium 500 mg) 
may be administered 2 hours before and 8 hours after the start of each dose of avelumab IV 
infusion.  Alternative treatments for fever (for example, paracetamol) may be given to subjects at 
the discretion of the Investigator.
6.5.4.3
Tumor Lysis Syndrome
In addition, since avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), 
there is a potential risk of tumor lysis syndrome. Should this occur, subjects should be treated per 
the local guidelines and the management algorithm (Figure 1) published by Howard et al (Howard 
2011).
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Figure 1
Assessment and Initial Management of Tumor Lysis Syndrome
TLS=tumor lysis syndrome.
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia
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6.5.4.4
Immune-Related Adverse Events
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of irAEs 
is mainly dependent upon severity (NCI-CTCAE grade):
! Grade 1 to 2:  treat symptomatically or with moderate dose steroids, more frequent monitoring
! Grade 1 to 2 (persistent):  manage similar to high grade AE (Grade 3 to 4)
! Grade 3 to 4:  treat with high dose corticosteroids
Treatment of irAEs should follow guidelines set forth in Table 5.
Table 5
Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea / Colitis
(NCI-CTCAE v4.0)
Management
Follow-up
Grade 1
Diarrhea: < 4 stools/day over Baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment (eg, 
loperamide)
Close monitoring for worsening symptoms
Educate subject to report worsening immediately
If worsens:
Treat as Grade 2 or 3/4 
Grade 2
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated < 24 hours; 
not interfering with ADL
Colitis: abdominal pain; blood in stool 
Delay avelumab therapy
Symptomatic treatment
If improves to Grade ≤ 1: 
Resume avelumab therapy
If persists > 5 to 7 days or 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 ADL
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Withhold avelumab for Grade 3.
Permanently discontinue 
avelumab therapy for Grade 4 or 
recurrent Grade 3
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade ≤ 1, then taper over 
at least 1 month; resume avelumab therapy 
following steroids taper (for initial Grade 3)
If worsens, persists > 3 to 5 days, or recurs after 
improvement:
Add infliximab 5 mg/kg (if no contraindication), 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
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Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Management
Follow-up
Grade 1 to 2 
Covering ≤ 30% body surface area 
Symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
Continue avelumab therapy
If Grade 2 persists > 1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay avelumab therapy
Consider 0.5 to 1.0 mg/kg/day prednisone or 
equivalent. Once improving, taper steroids over at 
least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume avelumab
therapy following steroids taper
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4
Grade 3: Covering > 30% body surface 
area; 
Grade 4: life threatening consequences 
Withhold avelumab for Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day prednisone  
or equivalent
Add prophylactic antibiotics for 
opportunistic infections
If improves to Grade 1: 
Taper steroids over at least 1 month; resume 
avelumab therapy following steroids taper (for 
initial Grade 3)
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Radiographic changes only 
Consider delay of avelumab
therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2
Mild to moderate new symptoms 
Delay avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily, 
consider hospitalization 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
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 
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opportunistic infections
Consider bronchoscopy, lung 
biopsy 
Grade of Pneumonitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 3 to 4
Grade 3: Severe new symptoms; New /
worsening hypoxia; 
Grade 4: life-threatening 
Discontinue avelumab therapy
Hospitalize 
Pulmonary and Infectious 
Disease consults
1.0 to 2.0 mg/kg/day  prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
If not improving after 48 hours or worsening: 
Add additional immunosuppression (for example,
infliximab, cyclophosphamide, IV
immunoglobulin, or mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Grade 1 AST or ALT > ULN to 3.0 ×
ULN and / or total bilirubin > ULN to
1.5 × ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4 
Grade 2
AST or ALT > 3.0 to ≤ 5 × ULN and /
or total bilirubin > 1.5 to ≤ 3 × ULN 
Delay avelumab therapy
Increase frequency of 
monitoring to every 3 days 
If returns to Grade ≤ 1: 
Resume routine monitoring, resume avelumab
therapy
If elevations persist > 5 to 7 days or worsen: 
Treat as Grade 3 to 4
Grade 3 to 4
AST or ALT > 5 × ULN and / or total 
bilirubin > 3 × ULN 
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 (for trial 
sites in Germany, only MRI is to 
be used)
If returns to Grade ≤1: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, worsens or 
rebounds: 
Add mycophenolate mofetil 1 gram (g) twice daily 
If no response within an additional 3 to 5 days, 
consider other immunosuppressants per local 
guidelines 
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Renal irAEs
Grade of Creatinine Increased
(NCI-CTCAE v4)
Management
Follow-up
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.
Endocrine irAEs
Endocrine Disorder
Management
Follow-up
Grade 1 or Grade 2 endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I diabetes 
mellitus)
Continue avelumab therapy
Endocrinology consult if needed
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.  
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Continue hormone replacement/suppression and 
monitoring of endocrine function as appropriate.
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Grade 3 or Grade 4 endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I diabetes 
mellitus)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate.  
Rule-out secondary 
endocrinopathies (i.e. 
hypopituitarism / hypophysitis)
Resume avelumab once symptoms and/or laboratory 
tests improve to Grade ≤ 1 (with or without hormone 
replacement/suppression).
Continue hormone replacement/suppression and 
monitoring of endocrine function as appropriate. 
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (i.e. subnormal serum 
FT4 with inappropriately low 
TSH and/or low serum cortisol 
with inappropriately low ACTH):
! Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, GH / 
IGF-1, PRL, testosterone in 
men, estrogens in women) 
! Hormone replacement /
suppressive therapy as 
appropriate 
! Perform pituitary MRI and 
visual field examination as 
indicated
If hypophysitis confirmed:
! Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month
! Withhold avelumab if 
moderate, severe or life-
threatening symptoms of 
hypophysitis and/or abnormal 
MRI. Consider hospitalization. 
Initiate corticosteroids (1 to 
2 mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during at 
least 1 month.
! Add prophylactic antibiotics 
for opportunistic infections.
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.
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Cardiac irAEs
Myocarditis
Management
Follow-up
New onset of cardiac signs or symptoms 
and / or new laboratory cardiac 
biomarker elevations (e.g. troponin, 
CK-MB, BNP) or cardiac imaging 
abnormalities suggestive of myocarditis
Withhold avelumab therapy.
Hospitalize.
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management
Cardiology consult to establish 
etiology and rule out immune-
related myocarditis.
Guideline based supportive 
treatment as per cardiology 
consult.a
Consider myocardial biopsy if 
recommended per cardiology 
consult.
If symptoms improve and immune-related etiology 
is ruled out, re-start avelumab therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-related 
etiology is suspected or confirmed following 
cardiology consult, manage as immune-related
Immune-related myocarditis 
Permanently discontinue 
avelumab.
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.a
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 (e.g. azathioprine, 
cyclosporine A)
a Local guidelines, or eg, European Society of Cardiology or American Heart Association guidelines.
European Society of Cardiology guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
American Heart Association guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs or 
symptoms suggestive of a potential 
irAE
Withhold avelumab therapy 
pending clinical investigation
If irAE is ruled out, manage as appropriate 
according to the diagnosis and consider re-starting 
avelumab therapy
If irAE is confirmed, treat as Grade 2 or 3 irAE.
Grade 2 irAE  or first occurrence of 
Grade 3 irAE
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day prednisone  
or equivalent  
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month and resume 
avelumab therapy following steroids taper.
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Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
Recurrence of same Grade 3 irAEs
Permanently discontinue 
avelumab therapy
1.0 to 2.0 mg/kg/day prednisone  
or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month.
Grade 4 
Permanently discontinue 
avelumab therapy
1.0 to 2.0 mg/kg/day prednisone  
or equivalent and/or other 
immunosuppressant as needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult.
If improves to Grade ≤ 1: 
Taper steroids over at least 1 month
Requirement for 10 mg per day or 
greater prednisone or equivalent for 
more than 12 weeks for reasons other 
than hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 irAE lasting 12 
weeks or longer
Permanently discontinue 
avelumab therapy
Specialty consult
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB;  CT= computed tomography; 
FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1; irAE=immune related adverse 
event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging; NCI CTCAE=National Cancer Institute 
Common Terminology Criteria for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid stimulating hormone; 
ULN=upper limit of normal.
6.6
Packaging and Labeling
Avelumab is formulated as a 10.0 mg/mL (Part A only) and 20 mg/mL (Part A and Part B) solution 
and is supplied by the Sponsor in single-use glass vials, stopper with a rubber septum.
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable Good Manufacturing Practice (GMP) guidelines. Avelumab will be packed in boxes 
(1 vial per box). The information on the study drug will be in accordance with approved 
submission documents. 
Avelumab will be shipped in transport cool containers (2°C to 8°C) that are monitored with 
temperature control devices.
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6.7
Storage, Handling, and Preparation
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain bacteriostatic 
preservatives. Any spills that occur should be cleaned up using the facility’s standard cleanup 
procedures for biologic products.
Avelumab drug product must be stored at 2°C to 8°C until use, with a temperature log maintained 
daily.
All medication boxes supplied to each trial site must be stored carefully, safely, and 
separately from other drugs.
Avelumab drug product stored at room temperature (23°C to 27°C) or at elevated temperatures 
(38°C to 42°C) for extended periods is subject to degradation. Avelumab must not be frozen. 
Rough shaking of avelumab must be avoided.
For application in this trial, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection) supplied in an infusion bag. Detailed information on infusion bags 
and medical devices to be used for the preparation of the dilutions and subsequent administration 
will be provided in the MOP.
Avelumab must not be used for any purpose other than the trial. The administration of study drug
to subjects who have not been enrolled into the trial is not covered by the trial insurance.
Any unused portion of the solution should be discarded in biohazard waste disposal with final 
disposal by accepted local and national standards of incineration.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring accountability for study drug, including reconciliation 
of drugs and maintenance of drug records.
! Upon receipt of study drug, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the 
Sponsor and returning it to the Sponsor. A copy will be retained for the Investigator File.
! The dispensing of the study drug will be carefully recorded on the appropriate drug 
accountability forms provided by the Sponsor and an accurate accounting will be available for 
verification by the Sponsor’s Monitor at each monitoring visit.
! study drug accountability records will include:
 confirmation of study drug delivery to the trial site;
 the inventory at the site of study drug provided by the Sponsor and prepared at the site;
 the use of each dose by each subject;
 the return to the Sponsor or alternative disposition of unused study drug; and
 dates, quantities, batch numbers, expiry dates and (for study drug prepared at the site) 
formulation, as well as the subjects’ trial numbers.
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! The Investigator should maintain records that adequately document:
 that the subjects were provided the doses specified by the clinical trial 
protocol/amendment(s); and
 that all study drug provided by the Sponsor was fully reconciled.
Unused study drug must not be discarded or used for any purpose other than the present trial. Any 
study drug that has been dispensed to a subject must not be redispensed to a different subject.
The Sponsor’s Monitor will periodically collect the study drug accountability forms and will check 
all returns (both unused and used containers) before arranging for their return to the Sponsor or 
authorizing their destruction by the trial site.
At the conclusion or termination of this trial, trial site personnel and the Clinical Trial Monitor will 
conduct a final product supply inventory on the Investigational Drug Accountability Forms and all 
unused containers will be destroyed. Instructions for destruction of product will be provided to 
the site. The clinical trial monitor will be supplied with a copy for filing of the Investigational 
Drug Accountability Forms. This documentation must contain a record of clinical supplies used, 
unused, and destroyed and shall include information on:
! all administered units,
! all unused units,
! all destroyed units (during the trial),
! all destroyed units at the end of the trial,
! date of destruction(s),
! name and signature of the Investigator/pharmacist.
It must be ensured at each trial site that the study drug is not used:
! after the expiry date, and
! after the retest date unless the study drug is reanalyzed and its retest date extended.
This is to be closely monitored by the trial monitor.
6.9
Assessment of Investigational Medicinal Product Compliance
In this trial, subjects will receive trial treatment (avelumab IV infusions) at the investigational site. 
Well-trained medical staff will monitor and perform the study drug administration. 
The 
information of each study drug administration including the date, time, and dose of study drug will 
be recorded on the eCRF. The Investigator will make sure that the information entered into the 
eCRF regarding drug administration is accurate for each subject. Any reason for noncompliance 
should be documented.
Noncompliance is defined as a subject missing > 1 cycle of trial treatment for nonmedical reasons
(see Section 5.5.2). If 1 cycle was missed and the interval between the subsequent treatment cycle 
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and the last administered treatment cycle is longer than 4 weeks for nonmedical reasons, the criteria 
of insufficient compliance are met as well.
6.10
Method of Blinding
Not applicable.
6.11
Emergency Unblinding
Not applicable.
6.12
Treatment of Overdose
An overdose is defined as any dose ≥ 10% than the calculated dose for that particular 
administration. Any overdose must be recorded in the study drug 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 Drug Safety department in an expedited 
manner using the appropriate reporting form (see Section 7.4.1.4).
There are no known symptoms of avelumab overdose to date. The Investigator should use his or 
her clinical judgment when treating an overdose of the study drug.
6.13
Medical Care of Subjects After End of Trial
After a subject has completed the trial or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the trial site’s standard of care and generally accepted 
medical practice and depending on the subject’s individual medical needs.
Upon withdrawal from the trial, subjects may receive whatever care they and their physicians agree 
upon. Subjects will be followed for survival and AEs as specified in Section 7.1.4.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
A complete Schedule of Assessments is provided in Appendix I.
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent according to the procedure described in Section 9.2.
7.1.1
Screening and Baseline Procedures and Assessments
The Screening procedures and baseline assessments will be completed within 18 days before trial 
treatment starts.
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During the Screening period and before any trial related investigations and assessments are started, 
the subjects will be asked to sign the ICF. The subjects’ information that will be documented 
during Screening includes the demographic information (birth date, sex, and race) and the 
complete medical history, including the history of MCC, previous and concomitant medications, 
and baseline medical condition (the information of concomitant medications and AEs will be 
monitored throughout the trial treatment period). Moreover, an Emergency Medical Support card 
will be handed out at the baseline assessments visit.
During Screening, subjects will undergo a complete physical examination, including recording 
body height and weight, vital signs, 12-lead ECG, and a determination of the ECOG PS (Appendix 
II). The EQ-5D and FACT-M questionnaires will be administered to subjects and completed by 
the subjects at baseline to collect baseline data about their health-related quality of life.
Additionally, subjects will be interviewed (optional for both Part A and Part B, see Section 7.7.1) 
by a trained experienced interviewer in order to collect subjects’ experience with MCC and their 
experience with prior treatment for MCC.
The Screening laboratory examination includes hematology, hemostaseology, full serum 
chemistry, and full urinalysis (dipstick plus microscopic evaluation).
Adrenocorticotropic 
hormone (ACTH), antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA),
rheumatoid factor (RF), free thyroxine (T4), and thyroid-stimulating hormone (TSH) will also be 
assessed at Screening. 
 
During Screening, a serum β-human chorionic gonadotropin (β-HCG) pregnancy test will be 
performed for females of childbearing potential and blood hepatitis B virus (HBV), hepatitis C 
virus (HCV), and HIV testing will be performed for all screening subjects as these conditions are 
trial entry exclusion criteria (see Section 5.3.2). Females who are postmenopausal (age-related 
amenorrhea ≥ 12 consecutive months and increased follicle-stimulating hormone [FSH] 
> 40 mIU/mL), or who have undergone hysterectomy or bilateral oophorectomy are exempt from 
pregnancy testing. If necessary to confirm postmenopausal status, an FSH will be drawn at 
Screening.
The tumor evaluation (type and staging, etc.), including mapping of skin lesions, will be performed 
using computed tomography (CT) scan or magnetic resonance imaging (MRI; if MRI is used, CT 
of chest is mandatory; for trial sites in Germany, only MRI is to be used) as well as tumor markers 
or any other established methods (see Section 7.2.5 for details).  A brain CT / MRI scan is required 
at Screening if not performed within the previous 6 weeks.
A bone scan should be done at 
Screening as clinically indicated. If any skin lesions are assessed by physical examination and 
selected as target or nontarget lesions, standardized photographic image collection is required.
Collection of tumor biopsies will also be done during this period, unless tissue (blocks or slides, 
blocks preferable) from a recent biopsy (within 4 weeks of enrollment) is available.  For subjects 
unable to provide a fresh or recent biopsy, archival material is acceptable [blocks preferable], for 
Part B, preferably less than 6 months old). Subjects are required to provide tumor tissue samples, 
see Section 7.6 for details. Criteria for determining the adequacy of tumor tissue are described in 
the Study Manual.  Subjects who undergo a biopsy specifically as part of the Screening
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assessments for this protocol will be permitted to participate in the protocol provided they meet all 
other inclusion criteria and no exclusion criteria.
The blood samples for baseline PK and immunogenicity (antidrug antibody [ADA] tests, 
previously referred to as human antihuman antibody [HAHA]) as well as for 
 
 
.
For Part A and Part B, subject eligibility will need to be confirmed by the CRO before the first 
administration of the study drug.
7.1.2
Treatment Period
In this trial, the treatment will be given until therapeutic failure (see Section 5.5.1), unacceptable 
toxicity, or any criterion for withdrawal from the trial or study drug is fulfilled (see Section 5.5.3).
For Part A:  Subjects who have experienced a confirmed CR should be treated for a minimum of 
6 months and a maximum of 12 months and after confirmation, at the discretion of the Investigator.  
In Part B, subjects should complete a minimum of 12 months after confirmed CR.  If the 
Investigator believes that a subject may benefit from treatment beyond 12 months, it may be 
permissible after discussion with the sponsor.  Part B:  Subjects who have experienced a confirmed 
CR should be treated for a minimum of 12 months after confirmation, at the discretion of the 
Investigator.  If the Investigator believes that a subject may benefit from treatment beyond 
12 months, it may be permissible after discussion with the sponsor.  For both Part A and Part B, 
in case a subject with a confirmed CR relapses after stopping treatment, but prior to the end of the 
trial, 1 re-initiation of treatment is allowed at the discretion of the Investigator and agreement of 
the trial Medical Monitor.  In order to be eligible for retreatment, the subject must not have 
experienced any toxicity that led to treatment discontinuation of the initial avelumab therapy.  
Subjects who re-initiate treatment will stay on study and will be treated and monitored according 
to the protocol and the “until progression” schedule in the Schedule of Assessments (see Appendix 
I).
Subjects will be asked to visit the investigational site every 2 weeks while on treatment. A time 
window of up to 3 days before or 1 day after the scheduled visit day (-3/+1 days) will be permitted 
for all trial procedures. In addition, the tumor evaluation (see Section 7.3) has a tumor assessment 
visiting time window of 5 days prior to dosing (-5 days).
Subjects will receive avelumab by IV infusion following pretreatment with antihistamine and 
paracetamol (acetaminophen) once every 2 weeks (see Section 6.2). A premedication regimen of 
diphenhydramine and paracetamol (acetaminophen, IV or oral equivalent) is recommended 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.  
This regimen may be modified based on local treatment standards and guidelines as appropriate.
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7.1.2.1
Part A 
During the treatment period, the following assessments will be performed (see Appendix I for the 
detailed schedule):
! The EQ-5D and FACT-M will be completed by subjects prior to any study related procedures 
at Week 7, and then once every 6 weeks thereafter while on treatment.
! Subject interviews (optional) by a trained experienced interviewer to collect subjects’ current
experience with their disease and its treatment (at Week 13 and at 6 months of treatment, see 
Section 7.7.1).
! AEs and concomitant medications will be documented at each trial visit.
! ECOG PS will be assessed at Day 1 (unless the Screening ECOG PS was performed within 
3 days prior to Day 1) and at each study visit thereafter.
! Physical examinations will be performed at each treatment visit until Week 13 and every 
6 weeks thereafter.  Such examinations will include a comprehensive skin examination for 
tumor.
! Vital signs and body weight will be assessed in each treatment visit.
! A 12-lead ECG (assessed prior to infusion and 2 hours ± 20 minutes after the end of infusion) 
will be assessed at each treatment visit up to and including Week 13, and every 6 weeks 
thereafter until 18 months, after which subjects no longer require on treatment ECGs.
! The laboratory hematology, hemostaseology will be assessed at each visit. Core serum 
chemistry tests will be assessed at Weeks 1, 7, 9, and 11 and after Week 13, every 2 weeks 
thereafter and full serum chemistry (including core chemistry) will be assessed at Weeks 3, 5, 
and 13 and then every 6 weeks thereafter. In addition, for subjects with liver metastases at 
Baseline, samples for ALT, AST, total bilirubin, and alkaline phosphatase determination will 
be collected at Weeks 2, 4, and 6. A basic urinalysis (dipstick) will be performed at each 
on treatment visit.  If the basic urinalysis is abnormal, a full urinalysis should be performed.
! A urine β-HCG pregnancy test will be performed at each treatment visit (before each 
administration of the study drug) for females of childbearing potential.
! Tumor evaluation (see Section 7.3) will be performed at Week 7, and then once every 6 weeks
thereafter, with a tumor assessment visiting time window of 5 days prior to dosing. After 
Week 55 (12 months) from the first treatment, tumor assessments will be every 12 weeks.
! PK samples will be collected from all subjects receiving avelumab within 2 hours prior to each 
study drug administration through Week 15, then Week 25, and then at 12-week intervals
thereafter while on treatment.  Post study drug administration samples will be collected at the 
end of infusion and 2 to 8 hours after the end of infusion (later is better, depending on how long 
the subject will stay in the clinic) at Weeks 1, 7, 13, and 25, and then at 12-week intervals 
thereafter while on treatment (see Section 7.5 for details). 
! ACTH, ANA, ANCA, RF, free T4, and TSH will be measured at Week 13, Week 25, and if 
clinically indicated. 
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! ADA samples will be drawn at Week 1 prior to the first administration of study drug (Screening
/ Baseline sample) and within 2 hours prior to study drug administration at Weeks 3, 5, 7, and 
13 and then every 6 weeks thereafter while on treatment (see Section 7.6.3).
!
 
 
!
 
7.1.2.2
Part B
During the treatment period, the following assessments will be performed (see Appendix I for the 
detailed schedule):
! The EQ-5D and FACT-M will be completed by subjects prior to any study related procedures 
at Week 7, and then once every 6 weeks thereafter while on treatment.
! Subject interviews (optional) by a trained experienced interviewer to collect subjects’ current
experience with their disease and its treatment (at Week 13 and at 6 months of treatment, see 
Section 7.7.1).
! AEs and concomitant medications will be documented at each treatment visit.
! ECOG PS will be assessed at Day 1 (unless the Screening ECOG PS was performed within 
3 days prior to Day 1) and at each treatment visit thereafter.
! Physical examinations (directed to signs and symptoms) will be performed at each visit through 
Week 13 and then every 6 weeks thereafter.  Such examinations may include a comprehensive 
skin examination for tumor.
! Vital signs and body weight will be assessed in each treatment visit (body weight may be 
collected within 3 days prior to infusion).
! The laboratory hematology, hemostaseology will be assessed at each treatment visit. Core 
serum chemistry tests will be assessed at each visit. A basic urinalysis (dipstick) will be 
performed on the Day 1 visit prior to administration of study drug.  If the basic urinalysis is 
abnormal, then a full urinalysis should be performed. Urinalysis after Day 1 should be 
performed as clinically indicated.
! A urine or serum β-HCG pregnancy test according to local practice will be performed at 
Weeks 1, 5, 9, and 13 and then every 4 weeks thereafter for females of childbearing potential.
Results of the most recent pregnancy test should be available prior to the next treatment.
! Tumor evaluation (see Section 7.3) will be performed at Week 7, and then once every 6 weeks
thereafter, with a tumor assessment visiting time window of 5 days prior to dosing. After 
Week 55 (12 months) from the first treatment, tumor assessments will be every 12 weeks.
! PK samples will be collected from all subjects receiving avelumab within 2 hours prior to each 
study drug infusion through Week 7, every 6 weeks through Week 25, and then at 12-week 
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intervals thereafter while on treatment. Post study drug administration samples will be collected 
at the end of infusion at Weeks 1, 7, and 25.
! Free T4, and TSH will be measured at Week 1, Week 7, Week 13, and every 6 weeks during 
the treatment period. 
! ACTH, ANA, ANCA, and RF will be measured at Week 13, Week 25, and if clinically 
indicated.
! ADA samples will be drawn at Week 1 prior to the first administration of study drug (Screening 
/ Baseline sample) and within 2 hours prior infusion through Week 7, every 6 weeks through 
Week 25, and then at 12-week intervals thereafter while on treatment (see Section 7.6.3).
!
 
 
!
 
!
 
7.1.3
End of Treatment
Discontinuation visit 
For Part A, a discontinuation visit for safety evaluation should take place as soon as possible after 
the last administration of avelumab (at least within 7 days) in case treatment was discontinued 
because of the occurrence of an AE. For Part B, all subjects will have a Discontinuation visit 
regardless of the reason for discontinuation.  The discontinuation visit consists of:
! documentation of AEs and concomitant medication;
! physical examination, including vital signs, and body weight;
! the 12-lead ECGs;
! the laboratory hematology, hemostaseology, and full serum chemistry, and basic urinalysis;
!
 
;
! ECOG PS; and
! PK sampling (subjects in Part B only).
End-of-Treatment visit
The End-of-Treatment visit is scheduled either 28 days (Part A) or 30 Days (±5 days, Part B) after 
the last administration of avelumab, but before any new therapy is started, if possible, whichever 
occurs earlier.  The End-of-Treatment visit will comprise a full assessment for safety, 
immunogenicity, and tumor response as appropriate, and will include the following (refer to 
Appendix I):
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! The EQ-5D and FACT-M questionnaires
! AEs, and concomitant medications, ECOG PS
! Physical examination including vital signs, body weight, and skin tumor extent
! The 12-lead ECGs
! The laboratory hematology, hemostaseology, full serum chemistry, and full urinalysis (dipstick 
plus microscopic evaluation)
! The urine β-HCG pregnancy test (in females of childbearing potential)
! The tumor evaluation per 6 or 12 weekly schedule (only to be performed if no disease 
progression was documented previously)
! ACTH, ANA, ANCA, RF, T4, and TSH levels
! ADA sampling
! PK sampling (Part B only)
!
!
!
7.1.4
Safety Follow-up
For Part A, all subjects will have a subsequent visit scheduled 10 weeks after the last administration 
of avelumab. For Part B, the visit will be 90 days (± 1 week).  The visit will include the following 
full assessment of safety parameters (refer to Appendix I):
! AEs and concomitant medications will be documented, including further anticancer therapy.
! Vital signs and body weight will be measured.
! Physical examination will be performed.
! ECOG PS will be assessed. 
! 12-lead ECG will be assessed.
! Laboratory testing consisting of the following will be assessed:
! Hematology, hemostaseology, core serum chemistry, and basic urinalysis (dipstick only)
! ACTH, ANA, ANCA, RF, T4, and TSH levels
! PK sample
! ADA sample (part B only)
!
 
.
! A urine β-HCG pregnancy test (in females of childbearing potential) will be conducted.
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7.1.5
Post Treatment Follow-up
Subjects with an ADR ongoing at the End-of Treatment visit must be followed up until the ADR 
resolves, becomes stable, or is considered not clinically significant by the Investigator. In addition, 
subjects will be followed for any AE suspected to be related to trial treatment, especially for the 
occurrence of new autoimmune events up to 3 months after the last dose of avelumab.
For subjects who discontinue treatment prior to Week 13, off-treatment interviews (optional for 
both Part A and Part B) will be scheduled for 13 weeks and 6 months from the start of treatment 
to collect subjects’ current experience with their disease, the study drug, and their experience 
within the trial. In case of discontinuation later than Week 13 but prior to 6 months of treatment, 
an off-treatment interview (optional for both Part A and Part B) will be scheduled for 6 months 
from the start of treatment.
For Part A, subjects without PD at the End-of-Treatment visit will be followed up for disease 
progression until PD (CT / MRI scans every 6 weeks until Week 55 [12 months] after the first 
study drug administration, then every 12 weeks using the same procedures and review as while on 
treatment; for trial sites in Germany, only MRI is to be used). 
 
 
For Part B, subjects without PD at the End-of-Treatment visit will be followed for disease 
progression until PD (CT / MRI scans every 6 weeks until Week 55 [12 months] after the first 
study drug administration, then every 12 weeks).
After the End-of-Treatment visit, subjects will be followed quarterly for survival (including 
assessment of any further tumor therapy). The survival follow-up will continue for up to 5 years
after the last subject receives the last dose of avelumab or last subject dies, whichever occurs earlier
(see Section 5.7 for details of the end of study).
7.1.6
Blood Draws for Clinical Assessments
The overall amount of blood to be drawn from a single subject must not exceed 120 mL/day and 
550 mL in an 8-week period for safety laboratory testing, pregnancy testing, PK analyses, 
exploratory 
 investigation, and antibody evaluation.
7.2
Demographic and Other Baseline Characteristics
The assessments and procedures described in this section must be performed during the Screening
period.
7.2.1
Demographic Data
The following demographic data will be recoded:
! Subject identifier
! Date of birth
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! Sex
! Race
7.2.2
Diagnosis of Merkel Cell Carcinoma
The tumor disease information that will be documented and verified at the Screening visit for each 
subject includes:
! detailed history of the tumor, including histopathological diagnosis (including documentation 
of CK20 or other appropriate cytokeratin expression such as pancytokeratin, AE1/AE3, or 
Cam5.2), 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 and 
chemotherapy, immunotherapy);
! any other conditions that were treated with chemotherapy, radiation therapy, or immunotherapy;
! current cancer signs and symptoms and side effects from current and previous anticancer 
treatments; 
! current cancer disease status; and
! for Part B M1 status must be confirmed at entry
7.2.3
Medical History
In order to determine the subject’s eligibility to the trial, a complete medical history of each subject 
will be collected and documented during Screening, which will include, but may not be limited to, 
the following:
! Past and concomitant nonmalignant diseases and treatments
! All medications taken and procedures carried out within 30 days prior to Screening
For the trial entry, all the subjects must fulfill all inclusion criteria described in Section 5.3.1, and 
none of the subjects should have any exclusion criterion from the list described in Section 5.3.2.
7.2.4
Vital Signs and Physical Examination
Vital signs including body temperature, respiratory rate, heart rate (after 5-minute rest), and arterial 
blood pressure (after 5-minute rest) will be recorded at trial entry. 
A complete physical examination (including, in general, appearance, dermatological, head / neck, 
pulmonary, cardiovascular, gastrointestinal, genitourinary, lymphatic, musculoskeletal system, 
extremities, eyes [inspection and vision control], nose, throat, and neurologic status) will be 
performed and the results documented.
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The ECOG PS will be documented during the Screening phase and at each scheduled visit (if the 
Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated 
at Day 1).
Body weight and height will be recorded.
7.2.5
CT or MRI Scans and Photography for Tumor Assessment at 
Baseline
A CT scan or MRI (if MRI is used, CT of chest is mandatory; for trial sites in Germany, only MRI 
is to be used) of the chest, abdomen, and pelvis (at a minimum and other established assessments 
of tumor burden if CT / MRI imaging is not sufficient for the individual subject, including mapping 
of skin lesions) will be performed within 18 days prior to trial treatment start in order to document 
the baseline status of the tumor disease using RECIST 1.1 target and nontarget lesions (the 
Screening CT / MRI does not need to be repeated if having been done within 4 weeks prior to first 
treatment). Baseline tumor burden should be determined as outlined in Section 7.3.  A brain CT / 
MRI scan is required at Screening if not performed within the previous 6 weeks.
A bone scan should be done at Screening as clinically indicated.
Any skin lesions assessed by physical examination and selected as a target or nontarget lesion at 
Baseline will have photographic image collection performed within 18 days prior to trial treatment 
start in order to document the Baseline status of the tumor disease (see Appendix IV).
7.2.6
Cardiac Assessments
A 12-lead ECG will be recorded after the subject has been in a supine position breathing quietly 
for 5 minutes. The ECG results will be used to evaluate the heart rate, atrial ventricular conduction, 
QR and QT intervals, and possible arrhythmias.
7.2.7
Clinical Laboratory Tests
Blood samples will be collected at Screening for clinical laboratory parameter evaluations. These 
clinical laboratory test results will serve not only as the baseline values for subsequent safety 
clinical laboratory evaluations during the trial, but also help to make sure that each enrolled subject 
fulfills all the trial entry criteria and does not meet any of the trial exclusion criteria for laboratory 
parameters as listed in Section 5.3. Detailed description of laboratory assessments is provided in 
Section 7.4.3.
7.3
Assessment of Efficacy
All radiographic images and physical findings including photographs (skin lesion mapping) and 
physical assessments used for the determination of disease progression must be submitted to the 
IERC vendor and will be reviewed by an IERC (see Section 5.1.2.2). The IERC will make the 
determination as to whether the criteria for tumor response or progression according to RECIST 
1.1 have been met.  
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For each subject, tumor response assessment will be performed by CT scan or MRI (if MRI is 
used, CT of chest is mandatory; for trial sites in Germany, only MRI is to be used) imaging of the 
chest/abdomen/pelvis at a minimum plus other anatomical sites as specifically required) and other 
established assessments of tumor burden if CT / MRI imaging is insufficient for the individual 
subject. All the scans performed at baseline and other imaging performed as clinically required 
(other supportive imaging) need to be repeated at subsequent visits. In general, lesions detected 
at baseline need to be followed using the same imaging methodology and preferably the same 
imaging equipment at subsequent tumor evaluation visits. If lesions are no longer detectable, the 
same anatomical sites evaluated at baseline must be followed at every tumor assessment visit using 
the same imaging and photography methods as used at baseline.
An examination for clinical lesions, including mapping of skin lesions, should also be conducted 
at each tumor assessment.  For skin lesions to be identified as target lesions, a minimum longest 
diameter of 10 mm is required. In the case of skin lesions, documentation by color photography
using standardized procedures, including an accurate measurement scale within the image, is 
required.  Refer to Appendix IV for standardized photography procedures with detailed 
requirements for lesion selection and photographic image acquisition.  Clinical lesions will 
be considered measurable only when they are superficial and visible (for example, skin nodules, 
palpable lymph nodes). Skin lesions can be used as target lesions using measurements by caliper 
if they fulfill RECIST 1.1 for target lesions.
The presence of new cutaneous lesions will be 
considered diagnostic of progression for RECIST 1.1, and any lesions detected by physical 
examination only should be documented by photography.  
A brain CT / MRI scan is required at Screening if not performed within the previous 6 weeks.  
Brain CT / MRI scans should be performed, if clinically indicated by development of new specific 
symptoms (for trial sites in Germany, only MRI is to be used).
A bone scan should be done at Screening and beyond as clinically indicated. 
For each subject, the Investigator will designate 1 or more of the following measures of tumor 
status to follow for determining response: CT or MRI images of primary and/or metastatic tumor 
masses, physical examination findings, and the results of other assessments. All available images 
collected during the trial period will be considered. The most appropriate measures to evaluate 
the tumor status of a subject should be used. The measure(s) to be chosen for sequential evaluation 
during the trial have to correspond to the measures used to document the progressive tumor status 
that qualifies the subject for enrollment. The tumor response assessment will be assessed and 
listed according to the schedule of assessments (refer to Appendix I).
Tumor responses to treatment will be assigned by the IERC based on the evaluation of the response 
of target, nontarget, and new lesions according to RECIST 1.1 (all measurements should be 
recorded in metric notation, see Eisenhauer 2009).
! To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized in 
target and nontarget lesions as described in Eisenhauer 2009.
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Results for these evaluations will be recorded with as much specificity as possible so that pre- and 
post-treatment results will provide the best opportunity for evaluating tumor response. 
Any CR or PR should be confirmed, preferably at the scheduled 6-week interval, but no sooner
than 5 weeks after the initial documentation of CR or PR. Confirmation of PR can be confirmed 
at an assessment later than the next assessment after the initial documentation of PR.
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. 
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7.4
Assessment of Safety
The safety profile of the study drug will be assessed through the recording, reporting, and 
analyzing of baseline medical conditions, AEs, physical examination findings including vital signs 
and laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
throughout the course of the trial, from the time of the subject’s signature of informed consent. 
Trial site personnel will report any AE, whether observed by the Investigator or reported by the 
subject (see Section 7.4.1.2, “Methods of Recording and Assessing Adverse Events”). Given the 
intended mechanism of action of the study drug, particular attention will be given to AEs that may 
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follow the enhanced T-cell activation, such as dermatitis, colitis, hepatitis, uveitis, or other 
immune-related reactions. Ophthalmologic examinations should be performed, when clinically 
indicated, for signs or symptoms of uveitis.
The reporting period for AEs is described in Section 7.4.1.3.
The safety assessments will be performed according to the Schedule of Assessments (refer to 
Appendix I).
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity/intensity of each AE.
Investigators will reference the NCI-CTCAE v 4.0 (publication date: 28 May 2009). This is a 
descriptive terminology that can be used for AE reporting.
A general grading (severity / intensity) scale is provided at the beginning of the referenced 
document, and specific event grades are also provided.
If a particular AE’s severity / intensity is not specifically graded by the guidance document, the 
Investigator is to revert to the general NCI-CTCAE 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
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According to the Sponsor’s convention, if a severity/intensity of Grade 4 or 5 is applied to an AE, 
then the Investigator must also report the event as a serious adverse event (SAE; see definition
below) as per Section 7.4.1.4; however, a laboratory abnormality with a severity/intensity of Grade 
4, such as anemia or neutropenia, is considered serious only if the condition meets one of the 
serious criteria described below.
In the case of death, the primary cause of death (or the event leading to death) should be recorded 
and reported as an SAE. “Fatal” will be recorded as the outcome of this respective event; death 
will not be recorded as separate event. Only if no cause of death can be reported (for example,
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 drug using 
the following definitions. Decisive factors for the assessment of causal relationship of an AE to 
avelumab include, but may not be limited to, temporal relationship between the AE and avelumab, 
known side effects of avelumab, medical history, concomitant medication, course of the 
underlying disease, trial procedures.
Not related: Not reasonably suspected to be related to the study drug. The AE could not 
medically (pharmacologically/clinically) be attributed to the study drug under trial
in this clinical trial protocol. A reasonable alternative explanation must be available.
Related:
Suspected 
related 
to 
the 
study 
drug.
The 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the study drug under trial in this 
clinical trial protocol. 
Abnormal laboratory findings and other abnormal investigational findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) of Grade < 3 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 of Grade < 3 fulfills these criteria, the identified 
medical condition (for example, anemia, increased ALT) must be reported as the AE rather than 
the abnormal value itself.  
Adverse Drug Reaction (ADR)
ADRs are defined in this trial as any AEs suspected to be related to avelumab by the Investigator 
and / or Sponsor.
Serious adverse event (SAE)
A SAE is any untoward medical occurrence that at any dose:
! Results in death,
! Is life-threatening,
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NOTE: The term “life-threatening” in this definition refers to an event in which the subject is at 
risk of death at the time of the event; it does not refer to an event that hypothetically might cause 
death if it were more severe.
! requires inpatient hospitalization or prolongation of existing hospitalization,
! results in persistent or significant disability / incapacity,
! is a congenital anomaly / birth defect, or
! 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 one 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 a study drug
is also considered a SAE and all such cases should be reported in an expedited manner as described 
in Section 7.4.1.4.
Events that do not meet the definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, 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 (for example, undesirable effects of any 
administered treatment) must be documented and reported as SAEs.
Events not to be considered as AEs / SAEs 
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are NOT to be considered AEs.
AE / SAEs observed in association with disease progression
Disease progression recorded in the course of efficacy assessments only, but without any adverse 
signs or symptoms should not be reported as adverse events.
However, if adverse signs and symptoms occur in association with disease progression then these 
should be recorded as AEs or reported as SAEs, if they meet criteria for seriousness.
Predefined AEs of special interest for safety monitoring 
Any AE that is suspicious to be a potential irAE will be considered AEs of special interest (AESI).
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7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit and during subjects interviews (optional for both Part A and Part B), the subject 
will be queried on changes in his or her condition. During the reporting period of the trial any 
unfavorable changes in the subject’s condition will be recorded as AEs, whether reported by the 
subject or observed by the Investigator.
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
Among these AEs, all SAEs must be additionally documented and reported using the appropriate 
Report Form as described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and times to be completed when it is important to assess the time of AE onset 
relative to the recorded treatment administration time), its severity, its relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken (including 
dose modification or discontinuation of the study drug), 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 Guidelines.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is included into the trial 
(date of first signature of informed consent) and continues through the trial’s post-treatment safety 
follow-up period, defined as 10 weeks (Part A) / 90 days (Part B) after the last study drug
administration.
Any SAE assessed as related to avelumab must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration.
7.4.1.4
Procedure for Reporting Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (that is, within a maximum 24 hours after becoming aware of the event) inform the 
Sponsor or designee using the SAE Report Form 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 provided immediately thereafter.
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report). 
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
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reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee 
and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations.
Requests for follow-up will usually be made by the responsible Monitor, although in exceptional 
circumstances, the Global Drug Safety department of the Sponsor may contact the Investigator 
directly to obtain clarification or to discuss a particularly critical event.
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 or her subjects to the IEC / IRB that 
approved the trial.
In accordance with ICH GCP guidelines, the Sponsor will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s /
IRB’s approval / favorable opinion to continue the trial.” In particular and in line with respective 
regulations, the Sponsor or designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (that is, suspected 
unexpected serious adverse reactions [SUSARs]). The Investigator should place copies of Safety 
reports in the Investigator Site File. National regulations with regard to Safety report notifications 
to Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor or designee will provide 
appropriate Safety reports directly to the concerned lead IEC / IRB and will maintain records of 
these notifications. When direct reporting by the Sponsor is not clearly defined by national or 
site-specific regulations, the Investigator will be responsible for promptly notifying the concerned 
IEC / IRB of any Safety reports provided by the Sponsor or designee and of filing copies of all 
related correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs / SUSARs / Safety Issues will be carried out in accordance with that 
Directive and with the related detailed guidance.
7.4.1.6
Monitoring of Subjects with Adverse Events
Any AE that occurs during the course of a clinical trial must be monitored and followed up and 
are assessed for final outcome at the Safety Follow-up visit. All SAEs ongoing at the Safety
Follow-up visit must be monitored and followed up by the Investigator until stabilization or until 
the outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable 
attempts to obtain this information must be made and documented. It is also the responsibility of 
the Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed.
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7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator as related to trial treatment (for example, 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 Pregnancy 
Report Form, which must be transmitted according to the same process 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 subject is withdrawn from the trial.
The Investigator must notify the Sponsor or designee of these outcomes using the Pregnancy 
Report Form, and in case of an abnormal outcome, the SAE Report Form when the subject sustains 
an event and the Parent-Child / Fetus Adverse Event Report Form when the child / fetus sustains 
an event).
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days from delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from study drug immediately. The Sponsor or designee must be notified without 
delay and the subject must be followed as mentioned above.
7.4.3
Laboratory Assessments
It is essential that the Sponsor be provided with a list of laboratory normal ranges before shipment 
of study drug. Any change in laboratory normal ranges during the trial will additionally be 
forwarded to the CRO and the Sponsor.
Blood samples will be taken from nonfasted subjects. All routine laboratory analyses will be 
performed at a laboratory facility local to the investigational site and relevant results must be 
available and checked before administration of avelumab. 
The report of the results must be retained as a part of the subject’s medical record or source 
documents. Blood samples for the full safety tests listed in Table 7 will be taken from non-fasted 
subjects during the Screening phase (18 days prior to the first treatment administration), during the 
treatment phase as specified in the table and in Appendix I, at the End-of-Treatment visit, and at 
the Safety Follow-up visit. The ACTH, ANA, ANCA, RF, T4, TSH, and urinalysis will only be 
assessed at the time points defined in Table 7 and Appendix I. If confirmation of a subject’s 
postmenopausal status is necessary, a FSH level will also be performed at Screening, see Section 
7.1.1.
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Table 7
Required Full Laboratory Safety Tests
Full Chemistry
Hematology
Albumin
Absolute lymphocyte count
Alkaline phosphatase*
ANC
ALT*
Hematocrit
Amylase**
Hemoglobin
AST*
Platelet count
GGT
RBC count
BUN/total urea*
WBC count and differential count
Calcium*
RBC morphology
Chloride*
Reticulocytes
Cholesterol
MCH
Creatine kinase
Mean corpuscular volume
Creatinine*
MCHC
CRP
Glucose*
Hemostaseology
LDH
aPTT
Lipase**
Prothrombin time/INR
Phosphorus/Phosphates*
Magnesium*
Basic Urinalysis (dipstick, including macroscopic appearance, 
bilirubin, blood, color, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity, urobilinogen)
Full urinalysis (dipstick plus microscopic evaluation) to be 
performed only at the Screening and End-of-Treatment visits
and a basic urinalysis prior to each administration of the study 
drug.
Potassium*
Sodium*
Total bilirubin*
Total protein
Uric acid
Totality of binding ADAs
Triglycerides
ACTH, ANA, ANCA, RF, TSH, and T4
For Part A, to be assessed at the Screening visit, Week 13, 
Week 25, and at the End-of Treatment visit.
For Part B, only ACTH, ANA, ANCA, RF, T4, and TSH will 
be collected at Screening visit, Week 13, Week 25, 
End-of-Treatment, and Safety Follow-up visits. T4 and TSH to 
be assessed in Week 1, Week 7, Week 13, and then every 
6 weeks while on treatment and at the 30-day
End-of-Treatment visit.
Hormone
FSH (if applicable)
ADA = antidrug antibody, ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, 
ANA=antinuclear antibody, ANC=absolute neutrophil count, ANCA=antineutrophil cytoplasmic antibody, 
aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, 
CRP=C-reactive protein, FSH=follicle-stimulating hormone, GGT=gamma-glutamyultransferase, 
INR=international normalized ratio, LDH=lactate dehydrogenase, MCH=mean corpuscular hemoglobin, 
MCHC=mean corpuscular hemoglobin concentration, RBC=red blood cell, RF=rheumatoid factor; 
TSH=thyroid-stimulating hormone, T4=free thyroxine, WBC=white blood cell.
* Core serum chemistries in Part A and Part B
** Included in core serum chemistries only for Part B
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If a subject has a clinically significant abnormal laboratory test value that is not present at baseline, 
the test will be repeated weekly and the subject will be followed until the test value has returned 
to the normal range or the Investigator has determined that the abnormality is chronic or stable.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
The ECOG PS will be assessed at Screening and at subsequent visits as indicated in the Schedule 
of Assessments and documented in the eCRF.
Body weight will be measured at Screening and at subsequent visits as indicated in the Schedule 
of Assessments and documented in the eCRF. Body height will be measured at Screening only.
A physical examination will be conducted at Screening and at subsequent visits as indicated in the 
Schedule of Assessments (Appendix I) and documented in the eCRF (detailed description in 
Section 7.1).  Results of the physical examination, including any abnormalities, will be 
documented in the eCRF. Abnormal findings are to be reassessed at subsequent visits.
A 12-lead ECG will be recorded as indicated in the Schedule of Assessments (Appendix I).
All newly diagnosed or worsening conditions, signs, and symptoms observed from Screening, 
whether related to trial treatment or not, are to be reported as AEs.
For female subjects of childbearing potential, serum β-HCG pregnancy test will be carried out 
during the Screening phase. A urine β-HCG test will be performed as indicated in the Schedule 
of Assessments (Appendix I). 
Subjects that are postmenopausal (age-related amenorrhea 
≥12 consecutive months and FSH > 40 mIU/mL), or who have undergone hysterectomy or 
bilateral oophorectomy are exempt from pregnancy testing.
7.5
Pharmacokinetics
For Part A:  Blood samples for population PK determinations will be collected from all subjects
within 2 hours prior to each study drug administration through Week 15, then at Week 25, and 
then at 12-week intervals thereafter while on treatment.  Post study drug administration samples 
will be collected at the end of infusion and 2 to 8 hours after the end of infusion (later is better, 
depending on how long the subject will stay in the clinic) at Weeks 1, 7, 13, and 25, and then at 
12-week intervals thereafter while on treatment.  Exact sampling times will be recorded.  Samples 
will also be collected at the 10-week Safety Follow-up visit.
For Part B: Blood samples for population PK determinations will be collected from all subjects 
within 2 hours prior to each study drug administration through Week 7, every 6 weeks through 
Week 25, and then at 12-week intervals thereafter while on treatment.  Post study drug 
administration samples will be collected at the end of infusion at Weeks 1, 7, and 25.  Samples 
will also be collected at the 7-day Discontinuation visit, the 30-day End-of-Treatment visit, and 
the 90-day Safety Follow-up visit.
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7.5.1
Body Fluid(s)
Whole blood sufficient to provide 2 mL of plasma / serum will be collected for PK assessments.  
Further details will be summarized in the Laboratory Manual.
7.5.2
Pharmacokinetic Calculations
The methodology and software to be used and PK calculations and parameters will be specified in 
the Statistical Analysis Plan (SAP).
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7.6.3
ADA Analysis
For Part A:  The blood sample for baseline ADA analysis will be collected before trial treatment 
start. Further serum samples for ADA analysis will be collected within 2 hours before infusion on 
Days 15, 29, 43 (every 2 weeks) and then every 6 weeks thereafter while on treatment and at the 
End-of-Treatment visit. Samples positive for ADAs will be re-analyzed to determine the titer.
For Part B:  The blood sample for baseline ADA analysis will be collected before trial treatment 
start. Further serum samples for ADA analysis will be collected within 2 hours before infusion 
through Week 7, every 6 weeks through Week 25, then at 12-week intervals thereafter while on 
treatment, and at the End-of-Treatment visit. Samples positive for ADAs will be re-analyzed to 
determine the titer.
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7.7
Other Assessments
7.7.1
Health-related Quality of Life
Health-related quality of life will be assessed using a generic instrument (EQ-5D), a 
cancer-specific instrument including a melanoma-specific module (FACT-M), and subject 
interviews (optional for both Part A and Part B).
EQ-5D. The EuroQol EQ-5D was developed in 1990 to assess health outcome from a wide variety 
of interventions on a common scale, for purposes of evaluation, allocation and monitoring
(EuroQol 1990, Herdman 2011).  It includes 5 items assessing mobility, self-care, usual activities, 
pain / discomfort, anxiety / depression on a 5-level response scale (EQ-5D-5L). It also includes a 
visual analogue scale ranging from 0 to 100 for self-rated health status. A higher score indicates 
better health status. Utilities can be derived from the EQ-5D, ranging from 0.0 (worst health state) 
to 1.0 (best health state).  
FACT-M. The FACT-M includes in addition to the generic core (FACT-G) a 24-item module 
that addresses specific aspects of melanoma (Cormier 2005). The objective of the FACT-G is to 
measure health-related quality of life of people with chronic illnesses through 27 items across 
4 domains: physical well-being, social / family well-being, emotional well-being, and functional 
well-being. The global score ranges from 0 to 108, with a higher score indicating better quality of 
life.  The FACT-M adds 20 items related to physical well-being, 3 to emotional well-being, and 
1 to social well-being. 
Merkel cell carcinoma and melanoma are both aggressive skin 
malignancies; despite some differences between MCC and melanoma, including worse prognosis 
for MCC, the content of the FACT-M seems appropriate to assess quality of life in subjects with 
MCC.
Subject interviews (optional for both Part A and Part B). Subjects will be invited to participate 
in semi-structured interviews at the Screening / Baseline visit prior to initiation of trial treatment 
and at Week 13 and 6 months (for both subjects on treatment and off treatment) in order to collect 
information about their previous experience with MCC and its treatment and their current 
experience within the trial, including their experience with the trial treatment.  Consent to 
participate in the interviews will be indicated by a check in the appropriate box on the ICF.
A Contact Order Form including subject contact details will be completed and sent to a dedicated 
independent unit in charge of scheduling and setting up the interviews.
The interviews will be conducted by a trained experienced interviewer, preferably by telephone,
(face to face interviews will be conducted where telephone interviews are not feasible), in the local 
language and will last approximately 30 minutes.  For baseline and on-treatment interviews, the
interviews should be scheduled on the day of the visit or within 5 days prior to the visit and will 
be conducted prior to study drug administration or any other study-related assessments.  Wherever 
possible, if the subject can have access to a quiet room and a phone is available, the interview can 
be scheduled while the subject is attending the visit at the hospital.  In any other case, the subject 
will be contacted at home.  For subjects who discontinue treatment prior to Week 13 or 6 months, 
subjects will be contacted at home for the scheduled interview.
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The main themes to be explored at baseline include subjects’ experience of the disease, in order to 
document the symptoms and manifestations, and the subsequent impact on subjects’ lives.  
The main theme to be explored during post-baseline interviews (Week 13 and 6 months for both 
subjects on treatment and off treatment) will be the experience of the treatment received since 
inclusion into the study.  
The interviews will be audio recorded in a de-identified way.  The audio files will serve as source 
documents and will be archived in Trial Master File. Any additional copy of audio recordings 
temporarily retained by interviewers and / or transcription unit will be destroyed after transcription 
process completion. The audio recordings will be transcribed word by word for the analysis (see 
Section 8.5.3.2).
8
Statistics
8.1
Sample Size
Sample Size in Part A:
The primary endpoint of the trial is the confirmed BOR according to RECIST 1.1, based on 
independent review of tumor assessments. The ORR will be determined as the proportion of 
subjects with a confirmed BOR of PR or CR. The trial aims at demonstrating an ORR greater than 
20% by means of an exact binomial test.
The planned total sample size is 84 subjects. There will be 1 interim analysis for futility after 
20 subjects have been enrolled and observed for at least 3 months and 1 interim analysis for 
efficacy 6 months after 56 subjects have been enrolled. The primary analysis will be conducted 
6 months after the accrual of the last subject. An exploratory analysis of secondary and exploratory 
endpoints will be conducted 12 months after the accrual of the last subject.
The following assumptions are made for the sample size calculation:
! ORR of 35%
! overall alpha = 0.025 (1-sided) for the test of the null hypothesis of an ORR ≤20%
The following analyses are planned:
! Futility:  Enrollment will be stopped for futility if no response (confirmed or unconfirmed) is 
observed in the first 20 subjects after 3 months of follow-up.
! Efficacy:  A two-stage group sequential testing approach will be applied for efficacy.  The null 
hypothesis can be rejected if 20 subjects in the interim analysis after 56 subjects, or 25 subjects 
in the primary analysis after 84 subjects, show a confirmed PR or CR according to RECIST 1.1. 
The corresponding nominal p-values of the exact binomial test are 0.0045 and 0.0214, 
respectively. The resulting overall probability of reaching a positive result in the interim or 
primary analysis under the null hypothesis assumption of an ORR ≤20% is ≤0.0225, as derived 
from the binomial distribution according to Jennison and Turnbull (Jennison 2000); therefore 
the overall type I error rate is controlled at a level of 2.5% (one-sided).
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Under the given assumptions, the power to reject the null hypothesis at the interim or the primary 
analysis is approximately 87%. 
Justification of the assumption of a response rate of 35% to define the trial sample size  
Data presented at the International Association for Study of Lung Cancer annual meeting in 2013 
suggest the blocking of PD-L1 through the administration of anti-PD-L1 monoclonal antibody has 
antitumor activity in tumors whose micro-environment express PD-L1. Indeed, a response rate of 
83% was reported (5/6) in patients where more than 10% of the immune-infiltrating cells were 
PD-L1 positive. In addition, the expression of PD-L1 at the surface of the tumor has also been 
correlated with clinical activity of anti-PD-L1.  Robust expression of PD-L1 in the immune-
infiltrating cells of MCC has been reported in the literature (Lipson 2013) and confirmed by the 
Sponsor.  
On these grounds, the expression of PD-L1 by the immune infiltrating cells as well as the 
expression of PD-L1 at the surface of MCC constitute a very strong rationale for the evaluation of 
avelumab in that disease. Extrapolation of the response rate observed with the Genentech PD-L1 
(up to 80% in PD-L1+ tumor cells and up to 80% in patients with more than 10% of the tumor 
infiltrating cells expressing PD-L1) suggest that a clinically significant overall response rate can 
be expected from anti PD-L1. Since a response rate of approximately 20% has been reported in 
several  tumor types where only a fraction of the tumors express PD-L1 at the surface of the tumors 
or at the surface of immune infiltrating cells, it is considered that an expected response rate of 35% 
is a reasonable hypothesis.
Sample Size in Part B:
The planned total sample size for Part B is 112 subjects for addressing the primary objective, 
relevant subgroup analyses, consistency, and further safety assessments.  Assuming a true DRR of 
45%, the probability to observe lower bound of the exact 95% confidence interval (CI) above 20% 
would be > 99% and above 30% would be 90%.
A historical reference for the DRR under first-line chemotherapy is based on P. Nghiem (personal 
communication), and Iyer 2016, which showed 11 of 62 patients meeting the definition of 6 months
durable response, i.e. a DRR of 17.7% (95% CI: 9.2, 29.5).  Part B of the study aims to estimate 
the DRR with a sufficient level of precision.  For example, with 112 subjects, an observed DRR 
of 28.6% would lead to an exact (Clopper-Pearson) 95% CI of (20.4%; 37.9%), which would 
exclude the observed DRR in Iyer et al, an observed DRR of 40.2% would lead to a 95% CI of 
(31.0%; 49.9%), which would exclude the upper bound of the 95% CI of Iyer et al, and an observed 
DRR of 44.6% would lead to an exact 95% CI of (35.2%; 54.3%).  
The two-sided 95% Clopper-Pearson confidence intervals for different observed values for the 
DRR are provided in Table 8.
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Table 8
Confidence Intervals for Different Durable Response Rates
N
DRR (%)
n
LBCI (%)
UBCI (%)
112
28.6
32
20.4
37.9
112
40.2
45
31.0
49.9
112
44.6
50
35.2
54.3
CI = confidence interval; LBCI = lower boundary of the confidence interval; N, n = number of subjects;
ORR = objective response rate; UBCI = upper boundary of the confidence interval.
The primary analysis will be conducted 15 months after the accrual of the last subject.
8.2
Randomization
Not applicable.
8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint for Part A of the trial is the confirmed BOR, per RECIST 1.1, as determined 
by an IERC and defined as the best response obtained among all tumor assessment visits after start 
of trial treatment until documented disease progression, excluding assessments after start of 
subsequent anticancer therapy, taking into account the following requirement for confirmation: 
PR or CR needs to be confirmed at a subsequent tumor assessment, preferably 6 weeks after the 
initial observation of response and according to the normal 6-week assessment schedule (or a 
subsequent assessment for PR), but no sooner than 5 weeks after the initial documentation of CR 
or PR.
For Part B, the primary endpoint is durable response, defined as objective response (CR or PR) 
according to RECIST 1.1, determined by an IERC, with a duration of at least 6 months. Duration 
of response will be calculated as specified in Section 8.3.2. Subjects for whom the duration of 
response is censored will be treated as failures (successes) in the analysis of durable response if 
the censored duration of response is below (at least) 6 months, respectively.
The date of a tumor assessment is defined as the earliest lesion measurement date corresponding 
to the respective visit that is documented in the eCRF. Details of determination of tumor response
date at each time point will be provided in IERC charter document.
8.3.2
Secondary Endpoints
The duration of response will be calculated for each subject with a confirmed response as the time 
from first observation of response until first observation of documented disease progression or 
death within 12 weeks of the last tumor assessment, whichever occurs first.
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For subjects with a confirmed response but neither documented disease progression nor death 
within 12 weeks after the last tumor assessment, as of the cut-off date for the analysis, the duration 
of response will be censored at the date of the last tumor assessment. Detailed censoring rules for 
duration of response can be found in Table 9 for Part A and in Table 11 for Part B.
The response status at 6 and 12 months after start of trial treatment according to RECIST 1.1 (as 
determined by the IERC) will be determined.  A subject will be considered to be in response at the 
given timepoint (6 or 12 months after the start of the subject’s treatment) if the subject had a 
documented response (PR or CR) prior to that timepoint, and neither died nor experienced disease 
progression according to the RECIST 1.1 nor was lost to follow-up up to the given timepoint. 
The PFS time, according to the RECIST 1.1, will be defined from first administration of trial 
treatment until first observation of PD or death within 12 weeks of the last tumor assessment or 
first administration of trial treatment (whichever is later). Details on determination of the first 
disease progression date will be specified in the IERC charter.
If a subject has neither a progression date nor a death date within 12 weeks after the last tumor 
assessment as of the data inclusion cut-off date for the analysis, the PFS time will be regarded as 
censored on the date of last known tumor assessment, or date of the first administration of trial 
treatment if the subject does not have any postbaseline tumor assessment. In Part B, PFS time will 
be regarded as censored on the date of last adequate tumor assessment (ie, having a result that is 
not non-evaluable or not available) if the subject begins a new anticancer therapy.
For Part A, subjects with both of the following conditions fulfilled, the general censoring rules
apply as presented in Table 9.
! Baseline tumor assessment 
! At least one tumor assessment after start of treatment
Table 9
Part A: General Censoring Rules for Progression-free Survival and 
Duration of Response
Date of event / censoring
Censoring
PD according to RECIST as assessed by the IERC
Date of PD
No
No PD 
If death within 12 weeks after last 
tumor assessment or first 
administration of trial treatment
Date of death
No
If death not within 12 weeks after last 
tumor assessment or first 
administration of trial treatment
Date of last known tumor 
assessment
Yes
IERC=Independent Endpoint Review Committee, PD=progressive disease.
For Part A, subjects with no tumor assessment at baseline or no tumor response assessment 
postbaseline, the special censoring rules as presented in Table 10, which overrule the general 
censoring rules, apply. 
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Table 10
Part A: Special Case Censoring Rules for Progression-free Survival
Date of event / censoring
Censoring
No tumor assessment 
at baseline
If death within 12 weeks after first 
administration of trial treatment
Date of death
No
If death not within 12 weeks after first 
administration of trial treatment
Date of first administration of 
trial treatment
Yes
No tumor response 
assessment post 
baseline
If death within 12 weeks after first 
administration of trial treatment
Date of death
No
If death not within 12 weeks after first 
administration of trial treatment
Date of first administration of 
trial treatment
Yes
For Part B subjects, the censoring rules for PFS and duration of response are presented in Table 
11.
Table 11
Part B: Outcome and Event Dates for Progression-free Survival and 
Duration of Response Analyses
Scenario
Date of event / censoring
Outcome
No baseline assessment
Date of first study treatment
Censoreda
Progression or death ≤ xx weeks after last 
tumor assessment or ≤ xx weeks after 
treatment start date, where xx is 12 weeks 
through 12 months from start of treatment, 
and 24 weeks thereafter.
Date of progression or death
Event
Progression or death > xx weeks after the 
last tumor assessment, where xx is 12 
weeks through 12 months from start of 
treatment, and 24 weeks thereafter.
Date of last adequate tumor 
assessment
Censored
No progression
Date of last adequate tumor 
assessment
Censored
Treatment discontinuation due to 
“Disease progression” without  
documented progression
Not applicable
Information collected on treatment 
discontinuation page is ignored since 
outcome should be derived based on 
documented progression only. General 
censoring rule is applied.
New anticancer therapy given
Date of last adequate tumor 
assessment before anticancer 
therapy is given
Censored
a However if the subject dies ≤ 12 weeks after treatment start date the death is an event with date on death date.
The OS time will be defined as the time from first administration of trial treatment until the date 
of death. The OS time is considered a key secondary endpoint.
For subjects who are still alive at the time of data analysis or who are lost to follow up, OS time 
will be censored at the last recorded date that the subject is known to be alive (date of last contact, 
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last visit date, date of last trial treatment administration or date of last scan, whichever is the latest)
as of the data cut-off date for the analysis.
In Part B, BOR as determined by IERC will be defined in the same was as in Part A (see 
Section 8.3.1).
Other secondary endpoints include serum titers of anti-avelumab antibodies (ADA) and PK profile
(sparse sampling).
8.3.3
Safety Endpoints
Safety endpoints include AEs, clinical laboratory assessments, vital signs, and ECG parameters.
8.3.4
Exploratory Endpoints 
Exploratory endpoints for Part A include
Exploratory endpoints for Part B include
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8.4
Analysis Sets
The primary analysis population for all analyses of efficacy, safety, and health-related quality of 
life is the Safety population.
The Safety population will include all subjects who received at least 1 dose of trial treatment.
The Per-Protocol (PP) population will be the subset of the Safety population that is compliant with 
the protocol and excludes subjects with protocol violations. The protocol violation criteria will be 
outlined in the SAP. The per-protocol population will be used for additional sensitivity analyses 
for the primary and secondary efficacy endpoints.
Analysis of efficacy variables may also be performed on subgroups of interest and will be outlined 
in the Statistical Analysis Plan.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
Full details of the planned analyses will be described in the trial SAP.
All data recorded during the trial will be presented in individual data listings performed on the 
Safety population. All data will be evaluated as observed, and no imputation method for missing 
values will be used unless otherwise specified in the SAP. 
Descriptive statistics will be used to summarize the trial results, that is, statistics for continuous 
variables may include means, medians, ranges, and appropriate measures of variability. Qualitative 
variables will be summarized by counts and percentages. The uncertainty of estimates will be 
assessed by CIs. Unless otherwise specified, the calculation of proportions will be based on the 
sample size of the population of interest. Counts of missing observations will be included in the 
denominator and presented as a separate category if not otherwise specified in the SAP.
The estimation of PK parameters will be performed using WinNonlin® version 5.0 or higher. All 
other statistical analyses will be performed using SAS® version 9.2 or higher, or R 
(www.r-project.org), version 2.15.2 or higher.
8.5.2
Analysis of Primary Endpoint
Part A
The primary endpoint for Part A is the BOR according to RECIST 1.1, as determined by an IERC.
For a BOR of PR or CR, confirmation of the response according to RECIST 1.1 (Eisenhauer 2009)
will be required, preferably at the regularly scheduled 6-week assessment interval, but no sooner
than 5 weeks after the initial documentation of CR or PR. Confirmation of PR can be confirmed 
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at an assessment later than the next assessment after the initial documentation of PR.  A BOR of 
SD requires that a timepoint overall response of SD has been determined at a timepoint at least 
6 weeks after start of study treatment. The response at each scheduled tumor assessment and the 
BOR will be listed for each subject. The number and proportion of BOR (defined as CR + PR) 
will be tabulated. The ORR will be determined as the proportion of subjects with a confirmed 
BOR of PR or CR.  
The test statistic of the exact binomial test will be calculated and compared with the thresholds 
given in Section 8.1 to determine whether the null hypothesis of an ORR ≤20% can be rejected at 
the interim analysis, or, if not rejected at the interim, at the primary analysis.  The 2-sided 99.1% 
CI and the 95.9% CI will be constructed using the Clopper-Pearson method for ORR to form 
repeated CIs according to Jennison and Turnbull (Jennison 2000) at the interim analysis and 
primary analysis, respectively. The nominal p-value from the exact binomial test will also be 
reported.
Part B:
For Part B, the primary endpoint is durable response, defined as objective response (CR or PR) 
according to RECIST 1.1, determined by an IERC, with a duration of at least 6 months. Duration 
of response will be calculated as specified in Section 8.3.2. Subjects for whom the duration of 
response is censored will be treated as failures (successes) in the analysis of durable response if 
the censored duration of response is below (at least) 6 months, respectively. The number and 
proportion of subjects with a durable response will be tabulated. The DRR will be determined as 
the proportion of subjects with a durable response. The 95% CI for the DRR will be calculated 
using the Clopper-Pearson method. There will be 1 interim analysis at 3 months after the accrual 
of the 25th subject, with additional interim analyses possible. All interim analyses in Part B will 
be exploratory.
8.5.3
Analysis of Secondary and Exploratory Endpoints
8.5.3.1
Analysis of Secondary Endpoints 
Duration of response will be calculated for each subject with a confirmed response according to 
RECIST 1.1.  The Kaplan-Meier method will be used to estimate parameters for duration of 
response, PFS time, and OS time (including the median with corresponding 2-sided 95% CIs).  In 
particular, the PFS rate at 6 months will be estimated with corresponding two-sided 95% CIs, and 
the survival rate at 6 and 12 months will be estimated with corresponding two-sided 95% CIs. The 
CIs for the median will be calculated according to Brookmeyer and Crowley (1982) and the CIs 
for the survival function estimates at the time points defined above will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (1980). The estimate of the standard error 
will be computed using Greenwood’s formula. The PFS time and OS time will also be presented 
in subject listings.
The proportion of subjects with response at 6 and 12 months after start of study treatment will be 
determined as the proportion of subjects in response among all subjects that have started study 
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treatment at least 6 (12) months prior to the time of the analysis, respectively. Clopper-Pearson 
95% CIs will be reported as well.
In Part B, the BOR as determined by IERC will be analyzed descriptively, using the same methods 
outlined in Section 8.5.2 for Part A.
Safety endpoints, including AEs, clinical laboratory assessments, vital signs, and ECG parameters,
will be analyzed descriptively.
8.5.3.2
Analysis of Exploratory Endpoints
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8.5.3.3
Pharmacokinetic Profile
Trough serum / plasma concentrations of avelumab will be determined by a validated method at 
the times listed in the Schedule of Assessments (Appendix I). The primary PK analysis will be a 
population PK analysis based on sparse sampling.  If appropriate, the data may be added to data 
from other studies.
8.5.3.4
Serum Titers of Anti-Avelumab Antibodies (ADA)
Immunogenicity testing strategy will be implemented and conducted in line with:
! Immunogenicity 
Assessment 
of 
Biotechnology-Derived 
Therapeutic 
Proteins 
(EMEA/CHMP/BMWP/14327/2006) 
! Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use 
(EMA/CHMP/BMWP/86289/2010) 
! FDA Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic 
Proteins (FDA; December 2009, draft)
A qualified method that uses an acid dissociation step to detect antidrug antibodies in the presence 
of excess drug in human serum will be applied. The ADA titers of positive samples will be 
determined. Positive samples will be analyzed for neutralizing capability.
8.5.4
Safety Analyses
The on-treatment period is defined as the time from the first study drug administration to the last 
drug administration date + 30 days or the earliest date of subsequent anticancer drug therapy minus 
1 day, whichever occurs first, unless otherwise stated.
Adverse events
All AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Severity of AEs will be graded using the NCI-CTCAE v 4.0 toxicity grading scale. 
The incidence of TEAEs, regardless of attribution and TEAEs defined as possibly related to 
avelumab will be summarized by Preferred Term and System Organ Class, and described in terms 
of intensity and relationship to avelumab. Treatment-emergent AEs (TEAEs) are those events 
with onset dates occurring during the on-treatment period or if the worsening of an event is during 
the on-treatment period.  Any AEs with an onset or worsening date after the on-treatment period 
will be reported separately.
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Descriptive statistics will be examined for indications of dose-related ADRs.
Laboratory variables 
Laboratory results will be classified by grade according to NCI-CTCAE. The worst on-trial grades 
after the first trial treatment will be summarized. Shifts in toxicity grading from first treatment to 
highest grade will be displayed. Results for variables that are not part of NCI-CTCAE will be 
presented as below, within, or above normal limits. Only subjects with postbaseline laboratory 
values will be included in these analyses. 
Physical examination (including vital signs and 12-lead ECGs)
Physical examination including vital signs (body temperature, respiratory rate, heart rate, and 
blood pressure) and 12-lead ECG as indicated in the Schedule of Assessments (Appendix I) will 
be presented. 
Further details will be provided in the SAP based on current safety experience applying the latest 
MedDRA version.
8.5.5
Subgroup Analyses
Analysis of efficacy variables may be performed on subgroups of interest as needed. The detailed 
subgroups will be outlined in the SAP.  
8.6
Interim Analysis
Part A:
There will be 1 interim analysis for futility after 20 subjects have been enrolled and observed for 
at least 3 months, and 1 interim analysis for efficacy 6 months after 56 subjects have been enrolled. 
If no unconfirmed response according to RECIST 1.1 is seen in the first interim analysis, then 
enrollment will be stopped unless the SMC makes a recommendation that the trial should continue.  
The second interim analysis will be conducted 6 months after enrollment of the 56th subject.  It 
will comprise a full evaluation of all efficacy and safety endpoints.  The analysis of efficacy in this 
interim analysis will be restricted to the first 56 subjects that were enrolled, as determined by the 
date and time of first administration of study treatment.  If efficacy goals are met at the second 
interim analysis, enrollment will continue to the planned full number of subjects in order to collect 
further data on the primary and secondary endpoints.  The primary analysis will be conducted 
6 months after the accrual of the last subject and a further exploratory analysis of secondary and 
exploratory endpoints will be conducted 12 months after the accrual of the last subject. The 
survival follow-up will continue for up to 5 years after the last subject receives the last dose of 
avelumab or last subject dies, whichever occurs earlier. Before the partial database lock for the 
primary analysis, there will be no dissemination of the interim analyses results to Investigators
beyond the SMC. Other than the two planned interim analyses and the ongoing safety monitoring 
during the trial, no further interim analyses will be conducted.
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Part B:
In Part B there will be 1 interim analysis at 3 months after the accrual of the 25th subject, with 
additional interim analyses possible. The primary analysis will be conducted 15 months after the 
accrual of the last subject. The date of accrual is determined as the date of the first dose of study 
treatment.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at his/her site. He / she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on 
GCP (ICH Topic E6, 1996) and applicable regulatory requirements. In particular, the Investigator 
must ensure that only subjects who have given their informed consent are included in the trial.
In 1998, the US FDA introduced a regulation (21 CFR, Part 54) entitled “Financial Disclosure by 
Clinical Investigators.”
For trials conducted in any country that could result in a product 
submission to the FDA for marketing approval and could contribute significantly to the 
demonstration of efficacy and safety of the study drug (named “covered trials” by the FDA), the 
Investigator and all sub-Investigators are obliged to disclose any financial interest that they, their 
spouses, or their dependent children may have in the Sponsor or the Sponsor’s product under study. 
This information is required during the trial and for 12 months following completion of the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the trial is his/her written informed 
consent. The subject’s written informed consent to participate in the trial must be given before 
any trial-related activities are carried out. A separate specific PGx ICF will be provided to subjects 
who are willing to participate in this optional procedure, which refers to the extraction and analysis 
of DNA from blood and / or tumor biopsy in order to better understand how gene(s) may affect 
the efficacy of avelumab.
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if permitted 
by local regulations). A subject information sheet in the local language and prepared in accordance 
with the Note for Guidance on GCP (ICH Topic E6, 1996) will be provided by the Sponsor for the 
purpose of obtaining informed consent. In addition to providing this written information to a 
potential subject, the Investigator or his/her designate will inform the subject verbally of all 
pertinent aspects of the trial. The language used in doing so must be chosen so that the information 
can be fully and readily understood by lay persons. 
Depending on national regulations, a person other than the Investigator may inform the subject 
and sign the ICF, as above.
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Where the information is provided by the Investigator, the ICF must be signed and personally 
dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing, and inspection purposes. A copy of the signed and dated information and 
ICF should be provided to the subject prior to participation.
Subjects will be invited to participate in an optional health-related quality of life interview process.  
For both Part A and Part B, subjects will be free to accept or refuse to participate. Acceptance to 
participate in the interviews will be documented by a check mark in the appropriate box on the 
ICF.  Upon acceptance, the subject will be asked to complete a contact order form to enable the 
scheduling of interviews.
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 and be submitted again to the IEC / IRB for review and 
favorable opinion. The agreed, revised information will be provided to each subject in the trial for 
signing and dating. The Investigator will explain the changes to the previous version.
9.3
Subject Identification and Privacy
A unique subject number will be assigned to each subject at inclusion, immediately after informed 
consent has been obtained. This number will serve as the subject’s identifier in the trial as well as 
in the clinical trial database.
The subject’s data collected in the trial will be stored under this number. Only the Investigator 
will be able to link the subject’s trial data to the subject via an identification list kept at the site. 
The subject’s original medical data that are reviewed at the site during source data verification by 
the Monitor, audits, and Health Authority inspections will be kept strictly confidential.
For subjects participating in the optional health-related quality of life interviews, interviewers will 
follow a semi-structured interview guide specifically developed for the current trial.  Interviewers 
will start by mentioning the date of the interview and subject ID.  Audio files of the interviews will 
be transcribed and de-identified (any identifying information such as dates, names, locations will 
be removed).  The de-identified transcripts will be delivered for analysis and a single audiofile will 
be kept as a source document in the Trial Master File.  Any copies of the audiofile will be destroyed 
immediately upon confirmation of receipt of the transcript.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject contact details and data. Subjects will be informed accordingly and will be 
requested to give their consent on contact details data handling procedures in accordance with 
national regulations.  In order to secure data privacy protection, patient contact details will be sent 
to a dedicated unit in charge of scheduling and setting up the interviews independently from study 
sponsor, monitor, data management and data analysis structures and other study stakeholders. The 
specific information about patient contact details management will be provided on a Contact Order 
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Form to be completed by Investigator and patient, signed by the patient and sent to the unit in 
charge of scheduling and setting up the interviews. This form will not include health data.
9.4
Emergency Medical Support and Subject Card
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor or designee. The 
Emergency Medical Support card is based on the need to provide clinical trial subjects with a way 
of identifying themselves as participating in a clinical trial, and subsequently to give health care 
providers access to the information about this participation that may be needed to determine the 
course of the subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical trial; and this may include the possibility of emergency unblinding if needed, in case of 
blinded trials.
Clinical trial Investigators, who are already aware of the clinical trial protocol and treatment, have 
other means of accessing the necessary medical information for the management of emergencies 
occurring in their subjects.
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, she or he will 
answer any questions. Any subsequent action will follow the standard processes established for 
the Investigators.
In cases where the Investigator is not available, Merck Serono / EMD Serono R&D provides the 
appropriate means to contact a Sponsor physician. This includes the provision of a 24-hour contact 
number at a call center, whereby the health care providers will be given access to the appropriate 
Sponsor physician to assist with the medical emergency and to provide support for the subject 
concerned.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage shall be provided for each country participating in the trial. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents (such as the ICF) to the responsible IEC / IRB for its 
favorable opinion/approval. The written favorable opinion/approval of the IEC / IRB will be filed 
in the Investigator Site File, and a copy will be filed with the CRO.
The trial must not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC / IRB. The IEC / IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
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of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained.
Amendments to the clinical trial will also be submitted to the concerned IEC/IRB before 
implementation in case of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC / IRB during the course of the trial in accordance with national regulations 
and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information and ICF) will be submitted or notified to the 
Health Authorities in accordance with the regulations of the countries involved in the trial.
10
Trial Management
10.1
Case Report Form Handling
The Investigator or designee will be responsible for entering trial data in the eCRF provided by 
the CRO and follow the data entry guidelines.  It is the Investigator’s responsibility to ensure the 
accuracy of the data entered in the eCRFs and to sign the case report forms.
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 CRO will be responsible for data review 
and processing, in accordance with the CRO’s data management procedures. Database lock will 
occur once quality control procedures and quality assurance procedures (if applicable) have been 
completed. Copies of the eCRFs will be provided to the Investigators at the completion of the 
trial.
10.2
Source Data and Subject Files
The Investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible. In 
particular, the following data should be available in this file: 
! Subject’s full name
! Date of birth
! Sex
! Race
! Height
! Weight
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! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the trial)
! Tumor disease information
! Trial identification (EMR100070-003)
! Date of subject’s inclusion into the trial (that is, date of giving informed consent)
! Subject number in the trial
! Dates of the subject’s visits to the site
! Any medical examinations and clinical findings predefined in the clinical trial protocol
! All AEs observed in the subject
! Date of subject’s end of trial
! Date of and reason for early withdrawal of the subject from the trial or from study drug, if 
applicable
It must be possible to identify each subject by using this subject file.
Additionally, any other documents containing source data must be filed. This includes original 
printouts of data recorded or generated by automated instruments, photographic negatives, X-rays, 
CT or MRI scan images, ECG recordings, laboratory value listings, etc. Such documents must 
include at least the subject number and the date when the procedure was performed. Information 
should be printed by the instrument used to perform the assessment or measurement, if possible. 
Information that cannot be printed by an automated instrument will be entered manually. Medical 
evaluation of such records should be documented as necessary and the documentation signed and 
dated by the Investigator.
10.3
Investigator Site File and Archiving
The Investigator will be provided with an Investigator Site File upon initiation of the trial. This 
file will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial. It must be available for review by the Monitor, and must be ready 
for Sponsor audit as well as for inspection by Health Authorities during and after the trial, and 
must be safely archived for at least 15 years (or per local requirements or as otherwise notified by 
the Sponsor) after the end of the trial. The documents to be thus archived include the Subject 
Identification List and the signed subject ICFs. If archiving of the Investigator Site File is no 
longer possible at the site, the Investigator must notify the Sponsor.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer.
In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
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10.4
Monitoring, Quality Assurance, and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH Note for Guidance on GCP (ICH Topic 
E6, 1996). The site Monitor will perform visits to the trial site at regular intervals.
Representatives of the Sponsor’s Quality Assurance unit or a designated organization, as well as 
Health Authorities, must be permitted to inspect all trial-related documents and other materials at 
the site, including the Investigator Site File, the completed eCRFs, the study drug, and the subjects’ 
original medical records/files.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent quality assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the Health Authorities and 
to the relevant IEC/IRB for approval or favorable opinion. In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations.
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the subject’s informed consent prior to implementation (see Section 9.2).
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report according to ICH Topic E3 will be written by 
the Sponsor 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 trial sites, for Part A (Kaufman 2016; Kaufman 2018)  and separately 
for Part B.
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require presubmission review by the Sponsor.
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The Sponsor will not suppress or veto publications, but maintains the right to delay publication in 
order to protect intellectual property rights.
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11
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Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
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Appendices
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Appendix I
Schedule of Assessments
Part A
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
Discontinuation (x)/ 
End-of-Treatment 
Visit (X)
Safety Follow-
up Visit
Post-
Treatment 
Follow-upb
Day -18 to 
First 
Treatment
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
Until 
Progression
Up to 7 / 28 Days 
after Last 
Treatmentc,d
10 Weeks 
after Last 
Treatment
Every 3 
monthsb
W1
W2
W3
W4
W5
W6
W7
W9
W11 W13
D1
D8
D15
D22
D29
D36
D43
D57
D71
D85
Written informed consent
X
Inclusion / exclusion criteria
X
Medical history
X
Demographic data
X
EQ-5D and FACT-Me
X
X
X
6 weekly
- /X
Optional subject interviewsf
X
Xf
6 monthsf
HBV, HCV, and HIV testing
X
Physical examination, including 
height at Screening
X
X
X
X
X
X
X
X
6 weekly
x/X
X
Vital signs
X
X
X
X
X
X
X
X
2 weekly
x/X
X
Weight
X
X
X
X
X
X
X
X
2 weekly
x/X
X
ECOG PS
Xg
X
X
X
X
X
X
X
2 weekly
x/X
X
Enrollment (if eligible)h
X
ECGi
X
X
X
X
X
X
X
X
6 weeklyi
x/X
X
Hematology and hemostaseology
X
X
X
X
X
X
X
X
2 weekly
x/X
X
Core serum chemistryj
X
Xj
Xj
Xj
X
X
X
2 weekly
X
Full serum chemistryk
X
X
X
X
6 weekly
x/X
Urinalysisl
X
X
X
X
X
X
X
X
2 weekly
x/X
X
β-HCG pregnancy testm
X
X
X
X
X
X
X
X
2 weekly
- /X
X
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Part A
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
Discontinuation (x)/ 
End-of-Treatment 
Visit (X)
Safety Follow-
up Visit
Post-
Treatment 
Follow-upb
Day -18 to 
First 
Treatment
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
Until 
Progression
Up to 7 / 28 Days 
after Last 
Treatmentc,d
10 Weeks 
after Last 
Treatment
Every 3 
monthsb
W1
W2
W3
W4
W5
W6
W7
W9
W11 W13
D1
D8
D15
D22
D29
D36
D43
D57
D71
D85
Tumor evaluation / staging (CT 
Scan / MRI / mapping skin 
lesions / tumor markers / other 
established methods)n,o
X
X
X
6 weekly up 
to 
12 months 
then 
12 weekly
- /X
X
Documentation of AEs and 
concomitant medication
X
X
X
X
X
X
X
X
X
X
X
2 weekly
x/X
X
X
ACTH, ANA, ANCA, RF, free 
T4, and TSH
X
X
Week 25 
and as 
indicated
- /X
X
PK samplingp
Xp
Xp
Xp
Xp
Xp
Xp
Xp
Weeks 15 
and 25p
then every 
12 weeks
Xp
ADA samplingq
X
X
X
X
X
6 weekly
- /X
Pretreatment and study drug
administrationr
X
X
X
X
X
X
X
2 weekly
Tumor tissue (biopsy)t
X
ACTH=adrenocorticotropic hormone, ADA=antidrug antibody, AE=adverse events, ALT=alanine aminotransferase, ANA=antinuclear antibody, ANCA=antineutrophil cytoplasmic 
antibody, AST=aspartate aminotransferase, β-HCG=β-human chorionic gonadotropin, BUN=blood urea nitrogen, CR=complete response, CT=computer tomography, 
ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, EQ-5D=EuroQol-EQ-5D, FACT-M=functional assessment of cancer 
therapy-melanoma, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, MCV=Merkel cell polyoma virus, MRI=magnetic resonance imaging, 
PK=pharmacokinetics, PR=partial response, RECIST=Response Evaluation Criteria in Solid Tumors version 1.1, RF=rheumatoid factor, SAE=serious adverse event, T4=free 
thyroxine, TSH=thyroid-stimulating hormone.
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a
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 trial procedures. 
b
Subjects with an adverse drug reaction ongoing at the End-of-Treatment visit and for any SAE suspected to be related to trial treatment occurring up to 3 months after the last 
dose of avelumab and thereafter will continue to be followed.  Subjects without progressive disease at End-of-Treatment visit will be followed up for disease progression until 
PD (CT / MRI scans every 6 weeks; for trial sites in Germany, only MRI is to be used). In addition, subjects will be followed quarterly for survival (including assessment of 
any further tumor therapy). The survival follow-up will continue for up to 5 years after the last subject receives the last dose of avelumab, or last subject dies, whichever occurs 
earlier (see Section 7.1.5 for details).
c
Tumor evaluation at the End-of-Treatment visit should only be performed if no disease progression has been documented previously.
d
If another antineoplastic therapy is administered before the end of this 28-day period, the End-of-Treatment visit should be conducted, if possible, prior to the start of this new 
therapy.
e
The EQ-5D and FACT-M questionnaires should be completed by subjects at Screening, and prior to any study related procedures at Week 7, then once every 6 weeks thereafter 
while on treatment and at the End-of Treatment visit.  
f
Subject interviews (optional; box on the Informed Consent Form indicating consent for interviews must be checked) will be conducted at Screening, Week 13, and 6 months 
(for both subjects on treatment and off treatment; see Section 7.7.1 for details). For subjects consenting to the interviews, a Contact Order Form including subject contact details 
will be completed and sent to the independent unit in charge of managing the interviews).
g
If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.
h
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion (Section 5.3.2). 
i
12-lead ECG should be assessed during screening, prior to infusion and 2 hours ± 20 minutes after the end of infusion at each visit on Days 1, 15, 29, 43, 57, 71, and 85 and 
every 6 weeks thereafter (until 18 months, after which on-treatment ECGs will not be required), at the Discontinuation / End-of-Treatment visit and Safety-Follow-up visit.
j
Core serum chemistry includes liver function panel (alkaline phosphatase, ALT, AST, bilirubin), acute chemistry panel (sodium, potassium, chloride, BUN / total urea, 
creatinine, glucose), and mineral panel (magnesium, phosphorus, calcium). For subjects with liver metastases at Baseline, additional blood samples for ALT, AST, total 
bilirubin, and alkaline phosphatase determination will be drawn at Weeks 2, 4, and 6.
k
Full chemistry panel (including core chemistry) and other laboratory studies are detailed in Table 7.  Follicle-stimulating hormone at Screening, if applicable (Section 7.1.1).
l
Full urinalysis (dipstick plus microscopic evaluation) at the Screening and End-of-Treatment visits and a basic urinalysis (dipstick only) at each visit indicated prior to 
administration of study drug.  If the basic urinalysis is abnormal, then a full urinalysis should be performed.
m
β-HCG should be determined from serum at Screening and from urine sample thereafter. Results of the most recent pregnancy test should be available prior to next dosing of 
study drug.
n
In general, the tumor visit time window is 5 days prior to dosing. In case a tumor response according to RECIST 1.1 is documented during the course of the trial, confirmation 
of the response should be performed according to RECIST 1.1, preferably at the regularly scheduled 6-week assessment interval, but no sooner than 5 weeks after the initial 
documentation of CR or PR. Confirmation of PR can be confirmed at an assessment later than the next assessment after the initial documentation of PR.  A CT scan or MRI (if 
MRI is used, CT of chest is mandatory; for trial sites in Germany, only MRI is to be used) should always be used in addition to mapping of skin lesions. The tumor evaluation 
(see Section 7.3) has a tumor assessment visiting time window of 5 days prior to dosing (-5 days).
o
A brain CT / MRI scan is required at Screening if not performed within the previous 6 weeks, and beyond as clinically indicated.  A bone scan should be done at Screening and 
beyond as clinically indicated. Bone metastases detected at Screening need to be followed at the tumor evaluation visits.
p
Blood samples for PK determinations will be collected from all subjects within 2 hours prior to each study drug administration through Week 15, then at Week 25, and then at 
12-week intervals while on treatment.  Post study drug administration samples will be collected at the end of infusion and 2 to 8 hours after the end of infusion (later is better, 
depending on how long the subject will stay in the clinic) at Weeks 1, 7, 13, and 25, and then at 12-week intervals while on treatment.  Exact sampling times will be recorded.  
Samples will be collected at the 10-week Safety Follow-up visit. Remaining sample from the 10-week safety follow-up visit may be used to test ADA. PK and ADA samples 
collected at the same predose time point may be used interchangeably if the dedicated sample has insufficient quantity, as the subject and his / her parent / legal representative 
will have consented to all collections and tests.
q
The blood sample for Screening / Baseline ADA analysis will be collected prior to study drug administration and on Day 1.  On trial samples will be collected within 2 hours
prior to study drug infusion on Days 15, 29, 43 (every 2 weeks), then every 6 weeks thereafter while on treatment, and at the End-of-Treatment visit.
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r
Subjects must receive pretreatment with antihistamine (diphenhydramine, or equivalent) and paracetamol (acetaminophen, oral or IV) prior to the first 4 infusions of avelumab
(10 mg/kg IV over 1 hour [-10 minutes / +20 minutes, that is, over 50 to 80 minutes]). 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.
t
A biopsy should be collected at Screening, unless tissue (blocks or slides) from a recent biopsy (within 4 weeks) is available.  Samples can be provided as block or slides (blocks 
are preferable; see Section 7.6 for details). For subjects unable to provide a fresh or recent biopsy, archival material is acceptable [blocks preferable).
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Part B
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
Follow-upb
Day -18 to 
First 
Treatment
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Discontinuation
Visit Within 
7 days of 
decision to 
discontinueb
End-of-Treatment 
Visit 30 (±5) Days 
after Last 
Treatmentc,d
Safety 
Follow-up 
Visit 
90 Days 
(±1 week) after 
Last Treatment
Long-term 
Follow-up
Every 3 
monthsb
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Written informed consent
X
Inclusion / exclusion criteria
X
Medical history
X
Demographic data
X
EQ-5D and FACT-Me
X
X
X
6 weekly
X
Subject interviewsf
X
Xf
6 monthsf
HBV, HCV, and HIV testing
X
Physical examination, including
height at Screeningg
X
X
X
X
X
X
X
X
6 weekly
X
X
X
Vital signs
X
X
X
X
X
X
X
X
2 weekly
X
X
X
Weight
X
X
X
X
X
X
X
X
2 weekly
X
X
X
ECOG PSh
Xh
X
X
X
X
X
X
X
2 weekly
X
X
X
Enrollment (if eligible)i
X
ECGj
X
X
X
X
Hematology and 
hemostaseology
X
X
X
X
X
X
X
X
2 weekly
X
X
X
Core serum chemistryk
X
X
X
X
X
X
X
2 weekly
X
Full serum chemistryl
X
X
X
Urinalysism
X
X
X
X
X
β-HCG pregnancy testn
X
X
X
X
X
4 weekly
X
X
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Part B
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
Follow-upb
Day -18 to 
First 
Treatment
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Discontinuation
Visit Within 
7 days of 
decision to 
discontinueb
End-of-Treatment 
Visit 30 (±5) Days 
after Last 
Treatmentc,d
Safety 
Follow-up 
Visit 
90 Days 
(±1 week) after 
Last Treatment
Long-term 
Follow-up
Every 3 
monthsb
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Tumor evaluation / staging (CT 
Scan / MRI / mapping skin 
lesions / tumor markers / other 
established methods)b,o,p
X
X
X
6 weekly up 
to 
12 months 
then 
12 weekly
X
Xb
Documentation of AEs and 
concomitant medication
X
X
X
X
X
X
X
X
2 weekly
X
X
X
ACTH, ANA, ANCA, and RF
X
X
Week 25 
and as 
indicated 
X
X
Free T4 and TSH
X
X
X
X
6 weekly
X
X
PK samplingq
Xq
Xq
Xq
Xq
Xq
6 weekly to 
Week 25q
then every 
12 weeks
X
X
X
ADA samplingr
X
X
X
X
X
6 weekly to 
Week 25
then every 
12 weeks
X
X
Pretreatment and study drug
administrations
X
X
X
X
X
X
X
2 weekly
Tumor tissue (biopsy)u
X
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Part B
Measure
Screening/
Baseline 
Assessments
Treatment Phasea
Follow-upb
Day -18 to 
First 
Treatment
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Discontinuation
Visit Within 
7 days of 
decision to 
discontinueb
End-of-Treatment 
Visit 30 (±5) Days 
after Last 
Treatmentc,d
Safety 
Follow-up 
Visit 
90 Days 
(±1 week) after 
Last Treatment
Long-term 
Follow-up
Every 3 
monthsb
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
ACTH=adrenocorticotropic hormone, ADA=antidrug antibody, AE=adverse events, ANA=antinuclear antibody, ANCA=antineutrophil cytoplasmic antibody, β-HCG=β-human 
chorionic gonadotropin, CR=complete response, CT=computer tomography, ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, 
EQ-5D=EuroQol-EQ-5D, FACT-M=functional assessment of cancer therapy-melanoma, HBV=hepatitis B virus, HCV=hepatitis C virus, HIV=human immunodeficiency virus, 
MCV= Merkel cell polyoma virus, MRI=magnetic resonance imaging, PD=progressive disease, PK=pharmacokinetics, PR=partial response, RECIST=Response Evaluation Criteria in 
Solid Tumors version 1.1, RF=rheumatoid factor, SAE=serious adverse event, T4=free thyroxine, TSH=thyroid-stimulating hormone.
a
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 trial procedures.  
b
All subjects in Part B will have a Discontinuation visit within 7 days of the decision to discontinue treatment.  Subjects with an adverse drug reaction ongoing at the End-of-Treatment visit and 
for any SAE suspected to be related to trial treatment occurring up to 3 months after the last dose of avelumab and thereafter will continue to be followed.  Subjects without progressive disease 
at End-of-Treatment visit will be followed up for disease progression until PD (CT / MRI scans every 6 weeks through 1 year from start of treatment then every 12 weeks thereafter; for trial sites 
in Germany, only MRI is to be used).  In addition, subjects will be followed quarterly for survival (including assessment of any further tumor therapy).  The survival follow-up will continue for 
up to 5 years after the last subject receives the last dose of avelumab, or last subject dies, whichever occurs earlier (see Section 7.1.5 for details).
c
Tumor evaluation at the End-of-Treatment visit should only be performed if no disease progression has been documented previously.
d
If another antineoplastic therapy is administered before the end of this 28-day period, the End-of-Treatment visit should be conducted, if possible, prior to the start of this new therapy.
e
The EQ-5D and FACT-M questionnaires should be completed by subjects at Screening, and prior to any study related procedures (including CT or MRI scans) at Week 7, then once every 
6 weeks thereafter while on treatment and at the End-of Treatment visit.  
f
Subject interviews (optional; box on the Informed Consent Form indicating consent for interviews must be checked) will be conducted at Screening, Week 13, and 6 months (for both subjects 
on treatment and off treatment; see Section 7.7.1 for details).  For subjects consenting to the interviews, a Contact Order Form including subject contact details will be completed and sent to the 
independent unit in charge of managing the interviews).
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g
A full physical examination should be performed at Screening and the Discontinuation visit (as required).  Physical examinations at all other visits should be directed to signs and symptoms.  
Only subjects with liver metastases at Baseline are required to have a physical examination at Weeks 4 and 6.
h
If the Screening ECOG PS was performed within 3 days prior to Day 1, it does not have to be repeated at Visit 1.
i
Enrollment will be done after the confirmation of fulfilling all screening inclusion criteria (Section 5.3.1) without matching any exclusion criterion (Section 5.3.2). 
j
12-lead ECG should be assessed during screening and at the Discontinuation and End-of-Treatment visits.
k
Core serum chemistry is detailed in Table 7. 
l
Full chemistry panel (including core chemistry) and other laboratory studies are detailed in Table 7.  Follicle-stimulating hormone at Screening, if applicable (Section 7.1.1).
m
Full urinalysis (dipstick plus microscopic evaluation) at the Screening and End-of-Treatment visits and a basic urinalysis (dipstick only) at Day 1 visit prior to administration of study drug and 
at the Discontinuation and Safety Follow-up visits.  If the basic urinalysis is abnormal, then a full urinalysis should be performed.  Urinalysis after Day 1 should be performed as clinically 
indicated.
n
β-HCG should be determined from serum at Screening and from urine sample thereafter.  Results of the most recent pregnancy test should be available prior to next dosing of study drug.
o
In general, the tumor visit time window is 5 days prior to dosing.  In case a tumor response according to RECIST 1.1 is documented during the course of the trial, confirmation of the response 
should be performed according to RECIST 1.1, preferably at the regularly scheduled 6-week assessment interval, but no sooner than 5 weeks after the initial documentation of CR or PR.  
Confirmation of PR can be confirmed at an assessment later than the next assessment after the initial documentation of PR.  A CT scan or MRI (if MRI is used, CT of chest is mandatory; for 
trial sites in Germany, only MRI is to be used) should always be used in addition to mapping of skin lesions. The tumor evaluation (see Section 7.3) has a tumor assessment visiting time window 
of 5 days prior to dosing (-5 days).
p
A brain CT / MRI scan is required at Screening if not performed within the previous 6 weeks, and beyond as clinically indicated.  A bone scan should be done at Screening and beyond as 
clinically indicated.  Bone metastases detected at Screening need to be followed at the tumor evaluation visits.
q
Blood samples for PK determinations will be collected from all subjects within 2 hours prior to each study drug administration through Week 7, every 6 weeks through Week 25, and then at 
12-week intervals thereafter while on treatment.  Post study drug administration samples will be collected at the end of infusion at Weeks 1, 7, and 25.  Exact sampling times will be recorded.  
Samples will also be collected at the 7-day Discontinuation, 30-day End-of-Treatment, and 90-day Safety Follow-up Visits. PK and ADA samples collected at the same predose time point may 
be used interchangeably if the dedicated sample has insufficient quantity, as the subject and his/her parent/legal representative will have consented to all collections and test.
r
The blood sample for Screening / Baseline ADA analysis will be collected prior to study drug administration on Day 1.  On trial samples will be collected within 2 hours prior to study drug 
infusion through Week 7, every 6 weeks through Week 25, and then at 12 week intervals thereafter while on treatment. Samples will also be collected at the 30-day End-of-Treatment visit and 
the 90-day Safety Follow-up visit. PK and ADA samples collected at the same predose time point may be used interchangeably if the dedicated sample has insufficient quantity, as the subject 
and his/her parent/legal representative will have consented to all collections and test.
s
Subjects must receive pretreatment with antihistamine (diphenhydramine or equivalent) and paracetamol (acetaminophen, oral or IV), prior to the first 4 infusions of avelumab (10 mg/kg IV 
over 1 hour [-10 minutes / +20 minutes, that is, over 50 to 80 minutes]).  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.  
u
A biopsy should be collected at Screening (see Section 5.3.1, inclusion criterion #4 for details).
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Appendix II
Eastern Cooperative Oncology Group Performance Status
ECOG PSa
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, for example, light house work, office work
2
Ambulatory and capable of all self-care, but unable to carry out any work activities; up and about 
> 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair > 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
ECOG PS=Eastern Cooperative Oncology Group Performance Status.
a.
Oken 1982.
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Appendix III Guidance on Contraception
Birth control methods considered as highly effective
According to the CTFG “Recommendations related to contraception and pregnancy testing in 
clinical trials” methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods, such as:
! combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation1 (oral, intravaginal, transdermal)
! progesterone-only hormonal contraception associated with inhibition of ovulation1 (oral, 
injectable, implantable2)
! intrauterine device (IUD)2
! intrauterine hormone-releasing system (IUS)2
! bilateral tubal occlusion2
! vasectomized partner2,3
! sexual abstinence4
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method
2 Contraception methods in the context of this guidance are considered to have low user dependency
3 Vasectomised partner is a highly effective birth control method provided that the partner is the sole sexual partner 
of the woman of childbearing potential trial participant and that the vasectomized partner has received medical 
assessment of the surgical success
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability 
of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the subject.
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Appendix IV Skin Lesion Selection and Photographic Image Acquisition 
Procedures
Biomedical Systems Confidential & Proprietary 
CONFIDENTIAL: This document belongs to Biomedical Systems and may contain 
confidential information belonging to the sender or its clients. The information is intended 
only for these individuals. 
Introduction 
EMR100070-003 is a Phase II, open-label, multicenter trial to investigate the clinical activity and 
safety of avelumab (MSB0010718C) in subjects with Merkel cell carcinoma. 
Tumor measurements (including the assessment of skin lesions by physical examination) to 
determine response will be performed every 6 weeks until 12 months after the first study drug 
administration, then every 12 weeks and response to the treatment will be evaluated by 
RECIST 1.1. 
An examination for clinical lesions, including mapping of skin lesions, should also be conducted 
at each tumor assessment. All radiographic images and physical findings including photographs 
(skin lesion mapping) and physical assessments will be used for the determination of disease 
progression. 
Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1 
(including skin lesions). Any lesions detected by physical examination only should be documented 
by photography. 
Reference to RECIST 1.1 for Target Lesions 
Clinical lesions will only be considered measurable when they are superficial and ≥10mm diameter 
as assessed using calipers (eg, skin nodules). For the case of skin lesions, documentation by color 
photography including a ruler to estimate the size of the lesion is suggested (Eiesenhauer 2009). 
When lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be 
undertaken since it is more objective and may also be reviewed at the end of the study. 
Radiographic target lesions must be measured in at least 1 dimension (longest diameter in the plane 
of measurement will be recorded) with a minimum longest axis of ≥ 10 mm imaged with scale in 
color photography of a superficial clinical lesion (eg, skin nodule) (Eiesenhauer 2009).
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Sites will follow the procedures outlined by Biomedical Systems to set-up the provided camera 
and equipment, subject preparation, measuring lesions with the measurement scale and acquiring 
photographs. 
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Appendix V
Protocol Amendments and List of Changes
Previous Protocol Amendments
Amendment 
Number
Substantial (yes/no)
Date
Region or Country
Included in the 
current document    
(Y/N)
Amendment 1
Yes
10 April 2014
Global
Yes
Amendment 2
Yes
06 June 2014
Global
Yes
No
17 July 2014
Japan
No
Yes
17 November 2014
France
Yes
Amendment 3
Yes
05 September 2014
Global
Yes
Yes
05 September 2014
United States
Yes
No
05 September 2014
European Union
Notification only
05 September 2014
Australia 
No
05 September 2014
Japan
Notification only
05 September 2014
Switzerland
Amendment 4
Yes
17 November
Global
Yes
Amendment 5
Yes
22 December 2014
Global
Yes
Amendment 6
Yes
26 February 2015
Global
Yes
Amendment 7
Yes
08 January 2016
Global
Yes
Amendment 8
Yes
31 March 2016
Global
Yes
Amendment 9
Yes
20 October 2016
Global
Yes
Amendment 10
Yes
23 May 2017
Global
Yes
Amendment Number: Amendment 11.0, 25 May 2018
Rationale: Updated the survival follow-up language for Part A to align with Part B and to ensure 
complete data collection for both parts of the study.
Major Scientific Changes:
! Clarified that survival follow-up for 5 years is for both Parts A and B
! Added new language regarding continued treatment past initial determination of PD
! Modified mandatory 2-hour post infusion observation to be based on based upon clinical 
judgment and presence / severity of prior infusion reactions
Administrative Changes
! Change of Coordinating Investigator
! Updated Medical Responsible address and contact information
! Change of Sponsor Biostatistician 
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List of Changes
Main changes to the clinical study protocol text are presented in the table below. Minor 
typographical, grammatical, formatting, or other changes not affecting the study conduct are not 
included.
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.
Based on the CT-1 guideline, this amendment is considered substantial due to the change in the 
Co-ordinating Investigator and a change in post infusion medical monitoring procedures.
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Comparison with Clinical Trial Protocol Version 11.0 / Amendment 10, 23 May 2017
Change
Section
Pages
Previous Wording Plus New 
Wording
New Wording
Rationale
Updated name of the 
Coordinating 
Investigator
Cover page 
1
 
 
 
 
 
Change in 
Coordinating 
Investigator
Updated address for 
Medical Responsible 
Cover page 
1
Merck Serono SIA
23A Duntes str. Riga, LV1005, Latvia
Tel:  
Fax:
45A Middlesex Turnpike
Billerica, MA 01821, USA
Tel:  
Fax: 
45A Middlesex Turnpike
Billerica, MA 01821, USA
Tel:  
Fax: 
To update most recent 
contact information
Changed last subject 
out
Synopsis –
Planned trial 
period
(first enrollment-
last subject out)
13
Last subject out:  Q1, 2029 Q2, 2023
Last subject out:  Q2, 2023
To allow for 5-year 
survival follow-up
Clarified that survival 
follow-up for 5 years 
is for both Parts A and 
B
Synopsis – Trial 
design and plan
17
In Part A there will be 1 interim 
analysis for futility after 20 subjects 
have been enrolled and observed for at 
least 3 months and 1 interim analysis 
for efficacy 6 months after 56 subjects 
In Part A there will be 1 interim 
analysis for futility after 20 subjects 
have been enrolled and observed for at 
least 3 months and 1 interim analysis 
for efficacy 6 months after 56 subjects 
For consistency 
between Part A and 
Part B and to ensure 
complete data 
collection to evaluate 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Pages
Previous Wording Plus New 
Wording
New Wording
Rationale
have been enrolled.  The primary 
analysis will be conducted 6 months 
after the accrual of the last subject and 
a further exploratory analysis will be 
conducted 12 months after the accrual 
of the last subject.  Subject follow-up 
for progression and survival will 
continue until 1 year after the last 
subject receives the last dose of 
avelumab.
In Part B there will be 1 interim 
analysis at 3 months after the accrual 
of the 25th subject, with additional 
interim analyses possible.  The 
primary analysis will be conducted 
15 months after the accrual of the last 
subject.
Subject For both Parts A and B, 
subject follow-up for progression and 
survival will continue until 5 years 
after the last subject receives the last 
dose of avelumab or the last subject 
dies, whichever occurs first.  Under 
some circumstances, subjects may not 
be followed for 5 years for survival in 
this study, for example, subjects may 
be offered to enroll into a rollover 
study, or the Sponsor may terminate 
the study early.
have been enrolled.  The primary 
analysis will be conducted 6 months 
after the accrual of the last subject and 
a further exploratory analysis will be 
conducted 12 months after the accrual 
of the last subject.  
In Part B there will be 1 interim 
analysis at 3 months after the accrual 
of the 25th subject, with additional 
interim analyses possible.  The 
primary analysis will be conducted 
15 months after the accrual of the last 
subject.
For both Parts A and B, subject
follow-up for progression and survival 
will continue until 5 years after the last 
subject receives the last dose of 
avelumab or the last subject dies, 
whichever occurs first.  Under some 
circumstances, subjects may not be 
followed for 5 years for survival in this 
study, for example, subjects may be 
offered to enroll into a rollover study, 
or the Sponsor may terminate the study 
early.
the duration of 
response in subjects 
with response 
regardless of whether 
they discontinued 
study drug or not. 
Clarified that survival 
follow-up for 5 years 
is for both Parts A and 
B
Synopsis –  
Schedule of visits 
and assessments
21
After For both Parts A and B, after
the End-of-Treatment visit, subjects 
will be followed quarterly for survival 
(including assessment of any further 
tumor therapy).  The survival follow 
up will continue for up to 5 years after 
the last subject receives the last dose of 
For both Parts A and B, after the 
End-of-Treatment visit, subjects will 
be followed quarterly for survival 
(including assessment of any further 
tumor therapy).  The survival follow 
up will continue for up to 5 years after 
the last subject receives the last dose of 
For clarity to ensure 
complete data 
collection for both 
parts of the study
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Wording
New Wording
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avelumab 
or 
last 
subject 
dies, 
whichever occurs earlier.
avelumab 
or 
last 
subject 
dies, 
whichever occurs earlier.
Deleted the 
mandatory 2-hour 
post-infusion 
observation
Synopsis -
Investigational 
Medicinal 
Product: dose / 
mode of 
administration / 
dosing schedule
6.4  Other Drugs 
to be Used in the 
Trial
26 
64
Following 
avelumab 
infusions, 
subjects must should be observed for 
2 hours post infusion for potential 
infusion-related reactions for the first 4 
infusions.  Starting with the fifth 
infusion, observation should be based 
upon clinical judgment and presence / 
severity of prior infusion reactions.    
Following 
avelumab 
infusions, 
subjects should be observed based 
upon clinical judgment and presence / 
severity of prior infusion reactions.    
Deleted the mandatory 
observation based on 
the latest avelumab 
safety information
Updated language 
regarding the review 
of safety data by the 
SMC
2.3.1  Safety 
Monitoring 
Committee
34
To ensure subjects’ safety during the 
trial, a safety monitoring committee 
(SMC) will periodically review safety 
data.  The SMC will be composed of a 
minimum of 3 members, including a 
trial Investigator, a statistician, and an 
independent physician.  The SMC 
consists of permanent members from 
the Sponsor and/or CRO (Global Drug 
Safety Representative, Program Lead, 
Medical Lead, Biostatistician, Medical 
Monitor), 
and 
the 
Coordinating 
Investigator.  The full membership, 
mandate, and processes of the SMC is 
detailed in the SMC charter.  As of the 
writing 
of 
this 
amendment 
(Amendment 10), the avelumab safety 
profile has been well-characterized in 
more than 1500 subjects and is 
considered generally manageable and 
tolerable.  As such, as of this 
amendment (Amendment 10), the 
planned periodic review of safety data 
by the SMC is no longer intended and 
To ensure subjects’ safety during the 
trial, a safety monitoring committee 
(SMC) will periodically review safety 
data.  The SMC will be composed of a 
minimum of 3 members, including a 
trial Investigator, a statistician, and an 
independent physician.  The SMC 
consists of permanent members from 
the Sponsor and/or CRO (Global Drug 
Safety Representative, Program Lead, 
Medical Lead, Biostatistician, Medical 
Monitor), 
and 
the 
Coordinating 
Investigator.  The full membership, 
mandate, and processes of the SMC is 
detailed in the SMC charter.  As of 
Protocol Amendment 10, the planned 
periodic review of safety data by the 
SMC was no longer scheduled given 
the safety data have been analysed as
per the statistical plan and submitted to 
health authorities for review.
Regular review of 
safety data by the 
SMC no longer 
deemed necessary due 
to the now well 
characterized 
avelumab safety 
profile
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Wording
New Wording
Rationale
no regular meetings of the SMC will 
be 
scheduled.
As 
of 
Protocol 
Amendment 
10, 
the 
planned 
periodic review of safety data by the 
SMC was no longer scheduled given 
the safety data have been analysed 
as per the statistical plan and 
submitted to health authorities for 
review.
Added language 
regarding regulatory 
approval and modified 
text to refer to the 
latest IB for 
information on 
avelumab clinical 
development 
3.4  Avelumab
35
The Investigational Medicinal Product 
(IMP) for the present trial is avelumab, 
a fully human monoclonal antibody of 
the immunoglobulin (Ig) G1 isotype.  
This anti-PD-L1 therapeutic antibody 
concept 
is 
being 
developed 
in 
oncological settings by Merck KGaA, 
Darmstadt, Germany, and by its 
subsidiary, 
EMD 
Serono 
Inc., 
Rockland, MA, USA. Avelumab has 
received regulatory approval for 
treatment of metastatic MCC by 
health authorities in all countries 
conducting this protocol.
…
Avelumab is currently At the time of 
the initiation of this study, avelumab 
was in early clinical development with 
2 ongoing Phase I studies in subjects 
with solid tumors (refer to the latest 
IB for latest information on clinical 
development and approvals):
The Investigational Medicinal Product 
(IMP) for the present trial is avelumab, 
a human monoclonal antibody of the 
immunoglobulin (Ig) G1 isotype.  This 
anti-PD-L1 
therapeutic 
antibody 
concept 
is 
being 
developed 
in 
oncological settings by Merck KGaA, 
Darmstadt, Germany, and by its 
subsidiary, 
EMD 
Serono 
Inc., 
Rockland, MA, USA. Avelumab has 
received 
regulatory 
approval 
for 
treatment of metastatic MCC by health 
authorities in all countries conducting 
this protocol.
…
At the time of the initiation of this 
study, avelumab was in early clinical 
development with 2 ongoing Phase I 
studies in subjects with solid tumors 
(refer to the latest IB for latest 
information on clinical development 
and approvals):
Updated to indicate to 
IRB/IECs the current 
status of that 
avelumab is approved 
for treatment of 
metastatic MCC by 
the health authorities 
in all countries 
conducting this trial 
and to reflect ongoing 
development
Added language 
specifying importance 
of Part B
5.1 Overall Trial 
Design and Plan
51
This is a multicenter, international, 
single-arm, open-label, Phase II, trial 
in 2 parts that will evaluate the efficacy 
and safety of avelumab in subjects 
with metastatic MCC.  In Part A, 
This is a multicenter, international, 
single-arm, open-label, Phase II, trial 
in 2 parts that will evaluate the efficacy 
and safety of avelumab in subjects 
with metastatic MCC.  In Part A, 
To ensure clarity for 
Investigators, country 
reviewers and 
IRB/IEC reviewers of 
importance of 
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subjects must have received at least 
one line of chemotherapy for the 
treatment of metastatic MCC.  In Part 
B, subjects must be treatment naïve to 
systemic therapy in the metastatic 
setting. Part B will serve as the 
confirmatory study required to meet 
conditions for some health authority 
approvals 
of 
avelumab 
for 
treatment of metastatic MCC.
subjects must have received at least 
one line of chemotherapy for the 
treatment of metastatic MCC.  In Part 
B, subjects must be treatment naïve to 
systemic therapy in the metastatic 
setting. Part B will serve as the 
confirmatory study required to meet 
conditions for some health authority 
approvals of avelumab for treatment of 
metastatic MCC.
completion of the trial, 
even with health 
authority approvals.
Modified end of trial 
language to correct 
possible discrepancy
5.1.1 Overall 
Design
52
… The primary analysis will be 
conducted 6 months after the accrual 
of the last subject and a further 
exploratory analysis will be conducted 
12 months after the accrual of the last 
subject.  The trial will be continued 
until 1 year after the last subject 
receives the last dose of avelumab
continue as specified in Section 5.7.
In Part B, there will be 1 interim 
analysis at 3 months after the accrual 
of the 25th subject, with additional 
interim analyses possible.  The 
primary analysis will be conducted 15 
months after the accrual of the last 
subject. The trial will continue as 
specified in Section 5.7.
… The primary analysis will be 
conducted 6 months after the accrual 
of the last subject and a further 
exploratory analysis will be conducted 
12 months after the accrual of the last 
subject.  The trial will continue as 
specified in Section 5.7.
In Part B, there will be 1 interim 
analysis at 3 months after the accrual 
of the 25th subject, with additional 
interim analyses possible.  The 
primary analysis will be conducted 15 
months after the accrual of the last 
subject. The trial will continue as 
specified in Section 5.7.
To correct possible 
discrepancy and for 
consistency between 
Part A and Part B and 
to ensure complete 
data collection to 
evaluate the duration 
of response in subjects 
with response 
regardless of whether 
they discontinued 
study drug or not.
Added new language 
regarding continued 
treatment past initial 
determination of PD
5.5.1  Criteria for 
Withdrawal from 
Study Drug due 
to Therapeutic 
Failure
60
…
If progression is based on the 
occurrence of a new lesion in an area 
not scanned at baseline, a further 
on-trial scan 6 weeks later should be 
performed.  Treatment during the 
confirmation period should continue as 
scheduled, despite a first observation 
of progression (according to RECIST 
…
If progression is based on the 
occurrence of a new lesion in an area 
not scanned at baseline, a further on-
trial scan 6 weeks later should be 
performed.  Treatment during the 
confirmation period should continue as 
scheduled, despite a first observation 
of progression (according to RECIST 
Added for consistency 
with other protocols in 
the avelumab program
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1.1), until confirmation has been made, 
and further if there is no significant 
clinical deterioration defined as:
•  there are no new symptoms or 
worsening of existing symptoms,
•  there is no change in ECOG PS to 
≥3 that lasts more than 14 days, or
•  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 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) that in the 
1.1), until confirmation has been made, 
and further if there is no significant 
clinical deterioration defined as:
•  there are no new symptoms or 
worsening of existing symptoms,
•  there is no change in ECOG PS to 
≥3 that lasts more than 14 days, or
•  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 
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) that in the opinion 
of the Investigator may be surgically 
removed or treated with palliative 
radiation 
therapy, 
subjects 
may 
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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.
•  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 trial records.
Subjects who experience significant 
clinical 
deterioration, 
as 
defined 
above, in the absence of confirmed PD 
should be discontinued from further 
treatment with avelumab.
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.
•  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 trial 
records.
Subjects who experience significant 
clinical 
deterioration, 
as 
defined 
above, in the absence of confirmed PD 
should be discontinued from further 
treatment with avelumab.
Modified text to 
include allowing 
steroid use for 
management of 
patients with allergy 
to radiographic 
contrast media
6.5.2 
Nonpermitted 
Medicines
65
• Immunotherapy, immunosuppressive 
drugs (that is, chemotherapy or 
systemic corticosteroids except for 
short-term 
treatment 
of 
allergic 
reactions or for the treatment of 
irAEs), 
or 
other 
experimental 
pharmaceutical products.  Short-term 
administration of systemic steroid (that 
is, for allergic reactions, management 
of 
patients 
with 
allergy 
to 
radiographic contrast media, or the 
management of irAEs) is allowed.  
• Immunotherapy, immunosuppressive 
drugs (that is, chemotherapy or 
systemic corticosteroids except for 
short-term 
treatment 
of 
allergic 
reactions or for the treatment of 
irAEs), 
or 
other 
experimental 
pharmaceutical products.  Short-term 
administration of systemic steroid (that
is, for allergic reactions, management 
of patients with allergy to radiographic 
contrast media, or the management of 
irAEs) is allowed.  Steroids with no or 
For additional 
guidance to 
Investigators and to 
align with ongoing 
avelumab 
development program
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Steroids with no or minimal systemic 
effect (topical, inhalation) are allowed.  
Also, hormone replacement with 
corticosteroids 
for 
adrenal 
insufficiency is allowed if the steroids 
are administered only for the purpose 
of hormonal replacement and at doses 
≤ 10 mg or equivalent prednisone per 
day.
minimal systemic effect (topical, 
inhalation) 
are 
allowed. 
 
Also, 
hormone 
replacement 
with 
corticosteroids 
for 
adrenal 
insufficiency is allowed if the steroids 
are administered only for the purpose 
of hormonal replacement and at doses 
≤ 10 mg or equivalent prednisone per 
day.
Updated language 
regarding surgery 
during study treatment
6.5.3  Other Trial 
Considerations
65
The following nondrug therapies must 
not be administered during the trial 
(and within 28 days before the start of 
trial treatment):
•  Major surgery (excluding prior 
diagnostic biopsy) Surgery to any 
tumor 
lesion 
for 
symptom 
management or tumor control is not 
permitted 
during 
the 
study 
treatment. For any other surgical 
interventions planned during the 
study, study treatment should be 
delayed to allow subject’s recovery, 
for up to a maximum of 4 weeks 
(also see Section 5.5.1 for details of 
treatment 
management 
beyond 
initial assessment of PD)
The following nondrug therapies must 
not be administered during the trial 
(and within 28 days before the start of 
trial treatment):
•  Surgery to any tumor lesion for 
symptom 
management 
or 
tumor 
control is not permitted during the 
study treatment. For any other surgical 
interventions planned during the study, 
study treatment should be delayed to 
allow subject’s recovery, for up to a 
maximum of 4 weeks (also see Section 
5.5.1 
for 
details 
of 
treatment 
management beyond initial assessment 
of PD)
For additional 
guidance to 
Investigators and to 
align with ongoing 
avelumab 
development program
Deleted the 
mandatory 2-hour 
post-infusion 
observation
6.5.4  Special 
Precautions
66
As a routine precaution, subjects 
enrolled in this trial must be observed 
for 2 hours post infusion for the first 
4 infusions should be observed based 
upon clinical judgment and presence 
/ severity of prior infusion reactions, 
in an area with resuscitation equipment 
and emergency agents.  
As a routine precaution, subjects 
enrolled in this trial should be 
observed based upon clinical judgment 
and presence / severity of prior 
infusion reactions, in an area with 
resuscitation 
equipment 
and 
emergency agents.  
Changed the 
mandatory observation 
based on the latest 
avelumab safety 
information
Clarified that 
persistent Grade 2 
6.5.4.4 Immune-
Related Adverse 
71
If Grade 2 persists > 1 to 2 weeks or 
If Grade 2 persists > 1 to 2 weeks or 
For alignment with 
latest IB resulting 
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dermatologic irAEs 
should result in 
treatment delay
Events
recurs: 
Consider skin biopsy 
Delay avelumab therapy
recurs: 
Consider skin biopsy 
Delay avelumab therapy
from latest safety 
information
For Part A – deleted 
“1 year” for limit of 
follow-up time for 
disease progression 
For Part B, modified 
language to clarify to 
allow for survival 
follow-up after PD
7.1.5 Post 
Treatment 
Follow-up
86
For Part A, subjects without PD at the 
End-of-Treatment 
visit 
will 
be 
followed up for disease progression
until PD (CT / MRI scans every 6 
weeks until Week 55 [12 months] after 
the first study drug administration, 
then every 12 weeks using the same 
procedures and review as while on 
treatment; for trial sites in Germany, 
only MRI is to be used) for up to 1 
year.  
 
 
 
 
 
 
For Part B, subjects without PD at the 
End of Treatment visit will be 
followed until for disease progression 
until PD (CT / MRI scans every 
6 weeks until Week 55 [12 months] 
after 
the 
first 
study 
drug 
administration, then every 12 weeks).
After the End-of-Treatment visit, 
subjects will be followed quarterly for 
survival (including assessment of any 
further tumor therapy).  The survival 
follow up will continue for up to 
5 years after the last subject receives 
the last dose of avelumab or last 
subject dies, whichever occurs earlier 
(see Section 5.7 for details of the end 
of study).
For Part A, subjects without PD at the 
End-of-Treatment 
visit 
will 
be 
followed up for disease progression 
until PD (CT / MRI scans every 6 
weeks until Week 55 [12 months] after 
the first study drug administration, 
then every 12 weeks using the same 
procedures and review as while on 
treatment; for trial sites in Germany, 
only MRI is to be used). 
 
 
 
For Part B, subjects without PD at the 
End of Treatment visit will be 
followed for disease progression until 
PD (CT / MRI scans every 6 weeks 
until Week 55 [12 months] after the 
first study drug administration, then 
every 12 weeks).
After the End-of-Treatment visit, 
subjects will be followed quarterly for 
survival (including assessment of any 
further tumor therapy).  The survival 
follow up will continue for up to 
5 years after the last subject receives 
the last dose of avelumab or last 
subject dies, whichever occurs earlier 
(see Section 5.7 for details of the end 
of study).
For consistency 
between Part A and 
Part B and to ensure 
complete data 
collection to evaluate 
the duration of 
response in subjects 
with response 
regardless of whether 
they discontinued 
study drug or not. 
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Updated address for 
Medical Responsible 
Signature page
172
Riga, LV1005, Latvia
45A Middlesex Turnpike
Billerica, MA 01821, USA
45A Middlesex Turnpike
Billerica, MA 01821, USA
To update most recent 
contact information
Updated name of the 
Coordinating 
Investigator
Signature page
173
 
 
 
 
 
 
 
 
Change in 
Coordinating 
Investigator
deleted “1 year” for 
limit of follow-up 
time for disease 
progression
Appendix I 
Schedule of 
Assessments –
Part A – footnote 
129
b  Subjects with an adverse drug
reaction 
ongoing 
at 
the 
End-of-Treatment visit and for any 
SAE suspected to be related to trial 
b  Subjects with an adverse drug
reaction 
ongoing 
at 
the 
End-of-Treatment visit and for any 
SAE suspected to be related to trial 
For consistency 
between Part A and 
Part B and to ensure 
complete data 
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“b”
treatment occurring up to 3 months 
after the last dose of avelumab and 
thereafter will continue to be followed.  
Subjects without progressive disease at 
End-of-Treatment 
visit 
will 
be 
followed up for disease progression 
until PD (CT / MRI scans every 
6 weeks; for trial sites in Germany, 
only MRI is to be used) for up to 1 
year.  In addition, subjects will be 
followed 
quarterly 
for 
survival 
(including assessment of any further 
tumor 
therapy). 
 
The 
survival 
follow-up will continue for up to 
5 years after the last subject receives 
the last dose of avelumab, or last 
subject dies, whichever occurs earlier 
(see Section 7.1.5 for details).
treatment occurring up to 3 months 
after the last dose of avelumab and 
thereafter will continue to be followed.  
Subjects without progressive disease at 
End-of-Treatment 
visit 
will 
be 
followed up for disease progression 
until PD (CT / MRI scans every 
6 weeks; for trial sites in Germany, 
only MRI is to be used).  In addition, 
subjects will be followed quarterly for 
survival (including assessment of any 
further tumor therapy).  The survival 
follow-up will continue for up to 
5 years after the last subject receives 
the last dose of avelumab, or last 
subject dies, whichever occurs earlier 
(see Section 7.1.5 for details).
collection to evaluate 
the duration of 
response in subjects 
with response 
regardless of whether 
they discontinued 
study drug or not. 
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Appendix VI Signature Pages and Responsible Persons for the Trial
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Signature Page – Protocol Lead  
Title
A Phase II, open-label, multicenter trial to 
investigate the clinical activity and safety of 
avelumab (MSB0010718C) in subjects with Merkel 
cell carcinoma
IND Number
EudraCT Number
2014-000445-79
Clinical Trial Protocol Date / Version
25 May 2018 / Version 12.0
Protocol Lead responsible for designing the clinical trial:
I approve the design of the clinical trial.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function
Institution
Merck Serono SIA
Address
45A Middlesex Turnpike
Billerica, MA 01821, USA
Telephone number
Fax number
E-mail address
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Signature Page – Coordinating Investigator  
Title
A Phase II, open-label, multicenter trial to 
investigate the clinical activity and safety of 
avelumab (MSB0010718C) in subjects with Merkel 
cell carcinoma
IND Number
EudraCT Number
2014-000445-79
Clinical Trial Protocol Date / Version
25 May 2018 / Version 12.0
Coordinating Investigator
I agree to conduct the clinical trial in accordance with this clinical trial protocol and in compliance 
with Good Clinical Practice and all applicable regulatory requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function
Institution
Address
Telephone number
   
Fax number
E-mail address
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Signature Page – Principal Investigator
Title
A Phase II, open-label, multicenter trial to 
investigate the clinical activity and safety of 
avelumab (MSB0010718C) in subjects with Merkel 
cell carcinoma
IND Number
EudraCT Number
2014-000445-79
Clinical Trial Protocol Date / Version
25 May 2018 / Version 12.0
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 Harmonisation (ICH) Good Clinical Practice 
(ICH Topic E6 GCP) and all applicable Health Authority requirements and national laws.
! I will not deviate from the clinical trial protocol without prior written permission from the 
Sponsor and prior review and written approval from the Institutional Review Board or 
Independent Ethics Committee, except where necessary to prevent immediate danger to the 
subject.
I understand that some Health Authorities require the Sponsors of clinical trials to obtain and 
supply, when required, details about the Investigators’ ownership interests in the Sponsor or 
Investigational Medicinal Product and information regarding any financial ties with the Sponsor. 
The Sponsor will use any such information that is collected solely for the purpose of complying 
with the regulatory requirements. I, therefore agree, to supply the Sponsor with any necessary 
information regarding ownership interest and financial ties (including those of my spouse and 
dependent children), and to provide updates as necessary.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic qualifications
Position (job title)
Address of Institution
Phone, fax, e-mail
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Further Sponsor Responsible Persons
Name, academic degree
Function
Institution
Merck KgaA
Address
Frankfurter Strasse 250, 
Postcode: F135/301, 64293 Darmstadt, Germany
Telephone number
 
E-mail address
Name
Function
Institution
EMD Serono Global Clinical Operations
Address
45A Middlesex Turnpike, Billerica, MA 01821, USA
Telephone number
Fax number
E-mail address
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PPD
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