A Phase III Open-Label, Multicenter Trial of Avelumab (MSB0010718C) Versus Docetaxel in Subjects With Non-Small Cell Lung Cancer That Has Progressed After a Platinum-Containing Doublet
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: EMD Serono Research & Development Institute, Inc.

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Clinical Trial Protocol
Clinical Trial Protocol Number
EMR100070-004
Title
A Phase III open-label, multicenter trial of avelumab 
(MSB0010718C) versus docetaxel in subjects with 
non-small cell lung cancer that has progressed after a 
platinum-containing doublet
Short Trial Name
JAVELIN Lung 200
Phase
III
IND Number
IND 
EudraCT Number
2014-005060-15
Coordinating Investigator
 
 
Sponsor
For all countries except the USA:
Merck KGaA, Frankfurter Str. 250, 
64293 Darmstadt, Germany
For sites in the USA:
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike, 
Billerica, MA 01821, USA
Medical Responsible: 
Tel:  
Fax:
Clinical Trial Protocol Version
10 January 2017 / Version 6.0
Replaces Version
29 November 2016 / Version 5.0
Current 
Clinical 
Trial 
Protocol 
Amendment
Amendment No. 5 / 10 January 2017
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This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck  KGaA, Darmstadt, Germany, or its 
subsidiaries. Copyright © 2017 by Merck KGaA, Darmstadt, Germany, or its affiliate. All rights 
reserved.
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Table of Contents
Table of Contents
..............................................................................................................3
Table of Tables
..............................................................................................................7
Table of Figures
..............................................................................................................8
List of Abbreviations ...........................................................................................................9
1
Synopsis..............................................................................................14
2
Sponsor, Investigators, and Trial Administrative Structure ...............31
2.1
Investigational Sites............................................................................31
2.2
Trial Coordination / Monitoring.........................................................31
2.3
Review Committees............................................................................32
2.3.1
Independent Data Monitoring Committee..........................................32
2.3.2
Central Reader and Independent Endpoint Review Committee.........32
3
Background Information.....................................................................32
3.1
Non-Small Cell Lung Cancer .............................................................32
3.2
Programmed Death Receptor and Ligands.........................................33
3.3
Avelumab............................................................................................33
3.3.1
Trial EMR100070-001........................................................................34
3.3.2
Pharmacokinetic .................................................................................42
3.3.3
Clinical Pharmacodynamics ...............................................................43
3.4
Rationale for the Current Clinical Trial..............................................44
3.5
Summary of the Overall Benefit and Risk..........................................44
4
Trial Objectives ..................................................................................45
5
Investigational Plan ............................................................................46
5.1
Overall Trial Design and Plan ............................................................46
5.1.1
Overall Design....................................................................................46
5.1.2
Trial Endpoints ...................................................................................48
5.1.3
Trial Medication Administration and Schedule..................................49
5.1.4
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation .................................................................49
5.2
Discussion of Trial Design .................................................................51
5.2.1
Inclusion of Special Populations ........................................................52
5.2.2
Rationale for Exclusion of Subjects with Epidermal Growth 
Factor Receptor Mutation...................................................................52
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5.3
Selection of Trial Population..............................................................52
5.3.1
Inclusion Criteria ................................................................................53
5.3.2
Exclusion Criteria...............................................................................54
5.4
Criteria for Randomization / Initiation of Treatment with the 
Investigational Medicinal Product......................................................56
5.5
Criteria for Subject Withdrawal..........................................................56
5.5.1
Criteria for Withdrawal from Trial Treatment....................................56
5.5.2
Withdrawal from the Trial..................................................................57
5.6
Premature Discontinuation of the Trial ..............................................58
5.7
Definition of End of Trial...................................................................58
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................58
6.1
Description of Investigational Medicinal Product..............................59
6.1.1
Avelumab............................................................................................59
6.1.2
Docetaxel ............................................................................................59
6.2
Dosage and Administration ................................................................59
6.2.1
Avelumab Dosage and Administration...............................................59
6.2.2
Docetaxel Dosage and Administration...............................................61
6.3
Assignment to Treatment Groups.......................................................61
6.4
Other Drugs to be Used in the Trial....................................................61
6.5
Concomitant Medications and Therapies ...........................................62
6.5.1
Permitted Medicines...........................................................................62
6.5.2
Nonpermitted Medicines ....................................................................63
6.5.3
Other Trial Considerations .................................................................64
6.5.4
Special Precautions.............................................................................64
6.6
Packaging and Labeling......................................................................72
6.7
Storage, Handling, and Preparation....................................................72
6.8
Investigational Medicinal Product Accountability.............................73
6.9
Assessment of Investigational Medicinal Product Compliance .........74
6.10
Method of Blinding.............................................................................75
6.11
Emergency Unblinding.......................................................................75
6.12
Treatment of Overdose .......................................................................75
6.13
Medical Care of Subjects After End of Treatment.............................75
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7
Trial Procedures and Assessments......................................................75
7.1
Schedule of Assessments....................................................................75
7.1.1
Screening and Baseline Procedures and Assessments........................76
7.1.2
Treatment Period ................................................................................77
7.1.3
End-of-Treatment ...............................................................................79
7.1.4
Safety Follow-up ................................................................................80
7.1.5
Long-term Follow-up..........................................................................81
7.1.6
Blood Draws for Clinical Assessments ..............................................81
7.2
Demographic and Other Baseline Characteristics ..............................81
7.2.1
Demographic Data..............................................................................81
7.2.2
Diagnosis of Non-Small Cell Lung Cancer........................................82
7.2.3
Medical History ..................................................................................82
7.2.4
Vital Signs and Physical Examination................................................82
7.2.5
CT or MRI Scans for Tumor Assessment at Baseline........................83
7.2.6
Cardiac Assessments ..........................................................................83
7.2.7
Clinical Laboratory Tests ...................................................................83
7.3
Assessment of Efficacy.......................................................................83
7.4
Assessment of Safety..........................................................................85
7.4.1
Adverse Events ...................................................................................85
7.4.2
Pregnancy and In Utero Drug Exposure.............................................90
7.4.3
Clinical Laboratory Assessments .......................................................90
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............93
7.7
Other Assessments..............................................................................96
7.7.1
Subject-Reported Outcomes / Quality of Life....................................96
8
Statistics..............................................................................................97
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8.1
Sample Size ........................................................................................97
8.2
Randomization....................................................................................97
8.3
Endpoints............................................................................................98
8.3.1
Primary Endpoint................................................................................98
8.3.2
Secondary Endpoints ..........................................................................98
8.3.3
Safety Endpoints...............................................................................100
8.3.4
Exploratory Endpoints......................................................................100
8.4
Analysis Sets.....................................................................................101
8.5
Description of Statistical Analyses...................................................101
8.5.1
General Considerations.....................................................................101
8.5.2
Analysis of Primary Endpoint ..........................................................103
8.5.3
Analysis of Secondary Endpoints.....................................................104
8.5.4
Analysis of Exploratory Endpoints...................................................105
8.5.5
Safety Analyses ................................................................................106
8.5.6
Subgroup Analyses ...........................................................................107
8.6
Interim Analysis................................................................................107
9
Ethical and Regulatory Aspects........................................................108
9.1
Responsibilities of the Investigator ..................................................108
9.2
Subject Information and Informed Consent .....................................109
9.3
Subject Identification and Privacy....................................................109
9.4
Emergency Medical Support and Subject Card................................110
9.5
Clinical Trial Insurance and Compensation to Subjects...................110
9.6
Independent Ethics Committee or Institutional Review Board........110
9.7
Health Authorities.............................................................................111
10
Trial Management.............................................................................111
10.1
Case Report Form Handling.............................................................111
10.2
Source Data and Subject Files..........................................................111
10.3
Investigator Site File and Archiving.................................................112
10.4
Monitoring, Quality Assurance, and Inspection by Health 
Authorities ........................................................................................113
10.5
Changes to the Clinical Trial Protocol..............................................113
10.6
Clinical Trial Report and Publication Policy....................................113
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10.6.1
Clinical Trial Report.........................................................................113
10.6.2
Publication........................................................................................113
11
References.........................................................................................115
12
Appendices .......................................................................................118
Appendix I
Schedules of Assessments ................................................................119
Appendix II
Eastern Cooperative Oncology Group Performance Status..............127
Appendix III 
Guidance on Contraception ..............................................................128
Appendix IV
Protocol Amendments and List of Changes .....................................129
Appendix V
Signature Pages and Responsible Persons for the Trial....................135
Signature Page – Protocol Lead.......................................................................................136
Signature Page – Coordinating Investigator ....................................................................137
Signature Page – Principal Investigator...........................................................................138
Table of Tables
Table 3.1
Most Frequently Reported TEAEs During Dose Expansion 
(M 10% of Subjects) ............................................................................36
Table 3.2
Most Frequently Reported TEAEs M Grade 3 During Dose 
Expansion (> 1.5% of Subjects) .........................................................37
Table 3.3
Most Frequently Reported Treatment-related TEAEs During Dose 
Expansion (M 5% of Subjects) ............................................................38
Table 6.1
Treatment Modification for Symptoms of Infusion-Related 
Reactions Caused by Avelumab.........................................................65
Table 6.2
Management of Immune-Related Adverse Events.............................68
Table 7.1
Required Full Laboratory Safety Tests...............................................92
Table 8.1
General Censoring Rules for Progression-free Survival ....................99
Table 8.2
Censoring Rules for Duration of Overall Survival Follow-up .........104
Table 12.1
Avelumab Arm .................................................................................119
Table 12.3
Docetaxel Arm..................................................................................124
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Table of Figures
Figure 6.1
Assessment and Initial Management of Tumor Lysis Syndrome.......67
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List of Abbreviations
ACTH
Adrenocorticotropic hormone
ADA
Anti-drug antibody
ADCC
Antibody-dependent cell-mediated cytotoxicity
ADL
Activities of daily living
ADR
Adverse drug reaction
AE(s)
Adverse event(s)
AESI
Adverse event of special interest
ALK
Anaplastic lymphoma kinase
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 
P-HCG
P-human chorionic gonadotropin
BOR
Best overall response
BUN
Blood urea nitrogen
CI
Confidence interval(s)
Cmax
Maximum plasma concentration observed postdose
Cmin
Minimum postdose (trough) concentration
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
CYP3A4
Cytochrome P450 3A4
DBP
Diastolic blood pressure
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D
EuroQOL 5-dimensions questionnaire 
FDA
Food and Drug Administration
FFPE
Formalin fixed, paraffin embedded
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GMP
Good Manufacturing Practice
H1
Histamine H1 receptor
HAHA
Human antihuman antibody
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
ICF
Informed Consent Form
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ICH
International Council for Harmonisation
ICU
Intensive Care Unit
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
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
ITT
Intention-to-treat 
IV
Intravenous
IVRS
Interactive voice response system
LDH
Lactate dehydrogenase
LFT
Liver function test
LLN
Lower limit of normal
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MedDRA
Medical Dictionary for Regulatory Activities
MOP
Manual of Operations
MRI
Magnetic resonance imaging
NCI
National Cancer Institute 
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
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ORR
Objective response rate
OS
Overall survival 
PD
Progressive disease
PD-1
Programmed death 1
PD-L1
Programmed death ligand 1
PD-L1+
PD-L1 positive
PD-L2
Programmed death ligand 2
PFS
Progression-free survival
 
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(s)
Serious adverse event(s)
SAP
Statistical Analysis Plan
SBP
Systolic blood pressure
SD
Stable disease
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Half-life
T4
Free thyroxine
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
TLS
Tumor lysis syndrome
tmax
Time to reach maximum concentration
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TO
Target occupancy
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
USA
United States
WBC
White blood cell
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1
Synopsis
Trial title
A Phase III open-label, multicenter trial of avelumab 
(MSB0010718C) versus docetaxel in subjects with 
non-small cell lung cancer that has progressed after a 
platinum-containing doublet
Trial number
EMR 100070-004
EudraCT number
2014-005060-15
Sponsor
For all countries except the United States:
Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt,
Germany
For sites in the United States:
EMD Serono Research & Development Institute, Inc.
45A Middlesex Turnpike, Billerica, MA 01821, USA
Phase
III
Trial under IND
yes
no
FDA "covered trial"
yes
no
Trial centers/countries
The trial will be conducted at approximately 290 sites 
globally in North America, South America, Asia, Africa, 
and Europe.
Planned trial period
(first enrollment-last subject 
out)
First subject in: Q1, 2015
Last subject out: Q1, 2018
Trial objectives
Primary objective
To demonstrate superiority with regard to overall 
survival (OS) of avelumab versus docetaxel in subjects 
with programmed death ligand 1 (PD-L1) positive (+; as 
determined by a companion diagnostic test under 
development), non-small cell lung cancer (NSCLC) after 
failure of a platinum-based doublet
Secondary objectives
Secondary objectives are as follows:
! To demonstrate superiority with regard to OS of 
avelumab versus docetaxel in the Full Analysis Set 
(FAS)
! To demonstrate superiority with regard to
the 
objective response rate (ORR) of avelumab versus 
docetaxel in PD-L1+ subjects
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! To demonstrate superiority with regard to progression 
free survival (PFS) of avelumab versus docetaxel in 
PD-L1+ subjects
! To demonstrate superiority with regard to the ORR of 
avelumab versus docetaxel in the FAS
! To demonstrate superiority with regard to PFS of 
avelumab versus docetaxel in the FAS
! To compare the subject-reported outcomes / quality of 
life when treated with avelumab versus docetaxel 
using the EuroQOL
5-dimensions questionnaire 
(EQ-5D) and the European Organization for Research 
and Treatment of Cancer (EORTC) QLQ-C30 and 
module QLQ-LC13 in the FAS
! To determine the safety and tolerability of avelumab
Exploratory objectives
Exploratory objectives are as follows:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial design and plan
This is a multicenter, international, randomized, 
open-label, Phase III trial in subjects with locally 
advanced unresectable, metastatic, or recurrent NSCLC 
that has progressed after a platinum doublet.
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Approximately 750 subjects, among them approximately 
522 PD-L1 assay positive subjects, will be randomized in 
a 1:1 ratio to receive either
! avelumab at a dose of 10 mg/kg as a 1-hour 
intravenous (IV) infusion once every 2 weeks, or
! docetaxel at a starting dose of 75 mg/m2 (per label) by 
IV infusion once every 3 weeks.
Subjects will be stratified according to PD-L1 assay 
status (positive versus negative expression in tumor cells) 
and
NSCLC 
histology
(squamous
cell
versus 
non-squamous cell).
Tumor measurements by computed tomography (CT) 
scan or magnetic resonance imaging (MRI) will be 
performed every 6 weeks from randomization until 
Week 55 (12 months) and then every 12 weeks thereafter 
to determine response to treatment.  A central imaging 
laboratory will be used to read and interpret all CT / MRI 
data; however, treatment decisions will be made by the 
treating Investigator.  Response will be evaluated using 
the Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1).
Treatment will continue until disease progression,
significant clinical deterioration, unacceptable toxicity, 
any criterion for withdrawal from the trial or trial drug is 
fulfilled.  For subjects receiving avelumab, treatment 
may continue past the initial determination of disease 
progression per RECIST 1.1 if the subject’s performance 
status has remained stable, and if in the opinion of the 
Investigator, the subject will benefit from continued 
treatment and if other criteria are fulfilled as outlined in 
the protocol. Subjects receiving avelumab who have 
experienced a confirmed complete response (CR) should 
be treated for a maximum of
24
months after 
confirmation, at the discretion of the Investigator.  If the 
Investigator believes that a subject may benefit from 
treatment beyond 24 months, it may be permissible after 
discussion with the Sponsor.  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 Medical Monitor.  In order to be eligible 
for re-treatment, 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 trial and will be treated and 
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monitored according to the protocol and the “until 
progression” schedule in the Schedule of Assessments.
Patients assigned to docetaxel will not be allowed to 
crossover to avelumab as long as superiority of avelumab
versus docetaxel in terms of the primary objective has not 
been demonstrated in the planned interim or final 
analysis.
Decisions regarding medical management of subjects 
will be made by the Investigator; however, the secondary 
endpoint
determinations
(response 
and 
disease 
progression) will be according to the central imaging 
assessment and review by a blinded Independent 
Endpoint Review Committee (IERC).
Adverse events (AEs) will be assessed throughout and 
evaluated using the National Cancer Institute (NCI) 
Common Technology Criteria version for Adverse 
Events version 4.03 (CTCAE v 4.03).  
Periodic evaluations of the trial data will be conducted by
an Independent Data Monitoring Committee (IDMC) to
ensure subject safety, the validity and scientific merit of
the trial, and to evaluate efficacy at the 75% interim 
analysis.
Planned number of subjects
Approximately 750
subjects
will be randomized.  
Accrual will proceed up to a target number of 
approximately 522 PD-L1+ subjects.
Schedule of visits and 
assessments
Screening/Baseline Assessments (Day -28 to 
Randomization)
Subject enrollment will be randomized and managed by 
an interactive voice response system (IVRS).
Screening procedures will include the following:
! Signing of the informed consent and confirmation by 
the IVRS that the subject has not had disqualifying 
prior treatment
! Collection of tumor tissue. Tumor tissue must be 
available within 10 calendar days after the subject has 
signed the Informed Consent Form (ICF) in order to 
establish the PD-L1 status of the tumor.  Tumor tissue 
can be archival or resulting from a screening biopsy of 
the subject if no archival tissue is available (biopsies 
are only to be obtained from safely accessible tumor 
tissue / sites).  Randomization cannot occur until 
PD-L1 expression has been determined by a 
companion diagnostic test under development and
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performed centrally (Investigators / trial site 
personnel will be blinded to the results of the 
PD-L1 expression determination)
! Recording of the demographic information, complete 
medical history, and Baseline medical condition
! A physical examination including vital signs, body 
weight, and height, 12-lead electrocardiogram (ECG),
and a determination of the Eastern Cooperative 
Oncology Group Performance Status (ECOG PS)
! With the use of a validated electronic tablet or 
validated 
site 
pad, 
subjects
will 
complete 
subject-reported 
outcomes
/ 
quality 
of 
life
questionnaires
! AE and concomitant medication assessments
! Safety laboratory assessments
! Tumor evaluation by CT scan or MRI (a bone scan 
should be done at Screening as clinically indicated)
! Serum P-human chorionic gonadotropin (P-HCG) 
pregnancy test for females of childbearing potential
! Blood samples for hepatitis B virus (HBV) and
hepatitis C virus (HCV) testing  (local laboratory)
Treatment period
Treatment period begins the day of randomization and 
ends when a decision is made to stop the trial drug by the 
Investigator or when consent is withdrawn by the subject.
Once eligibility is established, (including when the 
Central Laboratory has confirmed that the PD-L1 status 
for the patient has been determined), subjects will be 
randomized in a 1:1 ratio using the IVRS to receive either 
avelumab or docetaxel.
The treatment should start
within 4
days
after 
randomization.
Visits will take place every 2 weeks (-3 / +1 days) for 
subjects assigned to avelumab and every 3 weeks (-3 / +1 
days) for subjects assigned to receive docetaxel.
All the laboratory samples and vital signs will be 
collected prior to each trial drug
administration.  
Administration of trial drug will take place only after 
relevant results have been checked by a medically 
qualified person.
Safety (including AEs and concomitant medications
[weekly contact], laboratory values, ECOG PS, physical 
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examinations, and vital signs), PK, immunogenicity, and
tumor response assessments will be conducted at 
designated times throughout the trial.
The main assessments are as follows:
! Tumor responses will be assessed every 6 weeks from 
randomization (within 5 days prior to the scheduled 
tumor assessment), per RECIST 1.1 until Week 55 
(12 months) and then every 12 weeks thereafter while 
on trial.
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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! With the use of a validated electronic tablet or 
validated site pad, subject-reported outcomes / quality 
of life questionnaires will be completed by the subject 
after randomization (before the first administration of 
the trial treatment) then prior to administration of trial 
treatment and before any trial-related procedures
(including collection of biological samples) at Week 
1, Week 3 (treatment administration 2), Week 7
(treatment administration 4), and Week 13 (treatment 
administration 7) for subjects receiving avelumab and 
at Week 1, Week 4 (treatment administration 2), Week 
7
(treatment administration 3), and Week 13 
(treatment administration 5) for subjects receiving 
docetaxel and every 6 weeks thereafter while on 
treatment for all subjects
! AEs and concomitant medications will be documented 
at each visit
Trial treatment will be administered by IV infusion once 
every 2 weeks for avelumab and once every 3 weeks for 
docetaxel until disease progression, significant clinical 
deterioration (clinical progression), discontinuation for 
unacceptable toxicity, or withdrawal of consent. Note: 
For subjects receiving avelumab, treatment may continue 
past the initial determination of disease progression per 
RECIST 1.1 if the subject’s ECOG PS has remained 
stable, and if in the opinion of the Investigator, the 
subject will benefit from continued treatment and if other 
criteria are fulfilled as outlined in the protocol, that is, no 
new symptoms or worsening of existing symptoms and 
no decrease in performance score.
Discontinuation visit
Any subject who experiences an AE that mandates 
discontinuation of trial treatment should have a 
Discontinuation visit within 7 days of the decision to 
discontinue trial treatment.  
Follow-up phase
The Follow-up Phase starts when the decision has been 
made to stop trial drug treatment.
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Subjects will have 
! an End-of-Treatment visit at 28 days (± 5 days)  after
the last administration of trial treatment or before the 
start of any other antineoplastic therapy, and
! a Safety Follow-up visit 12 weeks (± 2 weeks) after 
the last administration of trial treatment.
During these two visits there will be a full assessment of 
safety parameters
(including ECG at the Early 
Discontinuation / End-of-Treatment
visit
using a 
validated electronic tablet or validated site pad), 
subject-reported 
outcomes 
/ 
quality 
of 
life
(Discontinuation / End-of-Treatment visit),
 
 (End-of-Treatment visit only), and for subjects 
who were assigned to avelumab, 
 
 
 
After the End-of-Treatment visit only treatment related 
AEs have to be documented until the Safety Follow-up 
visit, defined as 12 weeks (± 2 weeks) after the last trial 
treatment administration.
Subjects with a serious AE (SAE) ongoing at the Safety
follow-up visit must be followed up by the Investigator 
until stabilization or until outcome is known, unless the 
subject is documented as “lost to follow-up.”
Subjects who discontinue the trial treatment for reasons 
other than disease progression according to RECIST 1.1 
will be followed up every 6 weeks (± 5 days) until 
Week 55 (12 months) and then every 12 weeks thereafter
for radiographic assessment until disease progression, 
lost to follow-up, or withdrawal of informed consent.
After the End-of-Treatment visit, subjects will be 
followed quarterly (that is, every 3 months ± 1 week) for 
survival (including assessment of any further tumor 
therapy).  The survival follow-up will continue a 
maximum of 5 years after the last subject receives the last 
dose of avelumab. Subject-reported outcomes / quality 
of life questionnaires will be assessed at the Early 
Discontinuation / End-of-Treatment visit.
Diagnosis and main inclusion 
and exclusion criteria
Inclusion criteria 
1.
Signed written informed consent before any 
trial-related procedure is undertaken that is not part 
of the standard patient management
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2.
Male or female subjects aged M 18 years
3.
Availability of a formalin-fixed, paraffin-embedded 
block containing tumor tissue or 7 unstained tumor 
slides suitable for PD-L1 expression assessment
4.
Tumor determined to be evaluable for PD-L1
expression per the evaluation of a central laboratory
5.
Subjects with histologically confirmed Stage 
IIIb/IV or recurrent NSCLC who have experienced 
disease progression
6.
Subjects must have progressed after an acceptable 
therapy defined as follows:
a.
Subjects must have progressed during or after a 
minimum of 2
cycles of 1 course of a 
platinum-based 
combination 
therapy
administered for the treatment of a metastatic
disease. A history of continuation (use of a 
non-platinum agent from initial combination) or 
switch (use of a different agent) maintenance 
therapy is permitted provided there was no 
progression after the initial combination.  A 
switch of agents during treatment for the 
management of toxicities is also permitted 
provided there was no progression after the 
initial combination
OR
b. Subjects must have progressed within 6 months 
of completion of a platinum-based adjuvant, 
neoadjuvant, or definitive chemotherapy, or 
concomitant chemoradiation regimen for locally 
advanced disease
7.
Subjects with non-squamous cell NSCLC of 
unknown epidermal growth factor receptor (EGFR)
mutation status will require testing (local laboratory, 
or central laboratory if local testing is not available).  
Subjects with a tumor that harbors an activating 
EGFR mutation will not be eligible (see Exclusion 
Criterion 3)
8.
ECOG PS of 0 to 1 at trial entry 
9.
Estimated life expectancy of more than 12 weeks
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10. Adequate hematological function defined by WBC
count M 2.5 × 109/L with absolute neutrophil count 
(ANC) M 1.5 × 109/L, lymphocyte count M 0.5 × 
109/L, platelet count M 100 × 109/L, and hemoglobin 
M 9 g/dL (may have been transfused)
11. Adequate hepatic function defined by a total bilirubin 
level Z 1.5 × the upper limit of normal (ULN) range
and aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) levels Z 2.5 × ULN for all 
subjects
12. Adequate renal function defined by an estimated 
creatinine clearance > 30 mL/min according to the 
Cockcroft-Gault formula
(or local institutional 
standard method)
13. 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).
All subjects who are randomized to the docetaxel arm 
are required to use effective contraception for up to 
3 months after docetaxel treatment for women of 
childbearing potential and male subjects will be 
advised not to father a child during the 3 months after 
treatment with docetaxel.  Male subjects will be 
requested to seek advice on conservation of sperm 
prior to treatment.  
Exclusion criteria
1.
In the United States only, subjects with a squamous 
cell histology will be excluded 
2.
Systemic anticancer therapy administered after 
disease 
progression 
during 
or 
following 
a 
platinum-based combination
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3.
Subjects with non-squamous cell NSCLC whose 
disease harbors EGFR mutation(s) and / or anaplastic 
lymphoma kinase (ALK) rearrangement will not be 
eligible for this trial. Subjects of unknown ALK and
/ or EGFR mutation status will require testing at 
screening (local laboratory, or central laboratory if 
local testing is not available)
4.
Prior therapy with any antibody / drug targeting 
T-cell coregulatory proteins (immune checkpoints) 
such as PD-1, PD-L1, or cytotoxic T-lymphocyte 
antigen-4 (CTLA-4).  
5.
Concurrent anticancer treatment (for example, 
cytoreductive therapy, radiotherapy [with the 
exception of palliative bone-directed radiotherapy], 
immune therapy, or cytokine therapy except for 
erythropoietin)
6.
Major surgery for any reason, except diagnostic 
biopsy, within 4 weeks of randomization and/or if the 
subject has not fully recovered from the surgery 
within 4 weeks of randomization
7.
Subjects receiving immunosuppressive agents (such 
as steroids) for any reason should be tapered off these 
drugs before initiation of the trial treatment (with the 
exception of patients with adrenal insufficiency, who 
may 
continue 
corticosteroids 
at
physiologic 
replacement dose, equivalent to Z 10 mg prednisone 
daily).
8.
All subjects with brain metastases, except those 
meeting the following criteria:
a.
Brain metastases have been treated locally, and
b. 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)
9.
Previous malignant disease (other than NSCLC) 
within the last 5 years with the exception of basal or 
squamous cell carcinoma of the skin or carcinoma in 
situ (bladder, cervical, colorectal, breast)
10. Prior organ transplantation, including allogeneic 
stem-cell transplantation 
11. Significant acute or chronic infections including, 
among others:
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!
Known history of testing positive test for 
human immunodeficiency virus (HIV)
or 
known acquired immunodeficiency syndrome 
!
HBV or HCV infection at screening (positive 
HBV surface antigen
or HCV
RNA if 
anti-HCV antibody screening test positive)
12. Active autoimmune disease that might deteriorate 
when receiving an immunostimulatory agent:
a.
Subjects with diabetes type I, vitiligo, psoriasis, 
hypo- or hyperthyroid disease not requiring 
immunosuppressive treatment are eligible
b. Subjects requiring hormone replacement with 
corticosteroids are eligible if the steroids are 
administered only for the purpose of hormonal 
replacement and at doses Z 10 mg or equivalent 
prednisone per day
c.
Administration of steroids through a route 
known to result in a minimal systemic exposure 
(topical, intranasal, intro-ocular, or inhalation)
are acceptable
13. Previous or ongoing administration of systemic 
steroids for the management of an acute allergic 
phenomenon is acceptable as long as it is anticipated 
that the administration of steroids will be completed 
in 14 days, or that the daily dose after 14 days will be 
Z 10 mg per day of equivalent prednisone
14. Known 
severe 
hypersensitivity 
reactions 
to 
monoclonal antibodies (Grade M 3 NCI-CTCAE 
v 4.03), any history of anaphylaxis, or uncontrolled 
asthma (that is, 3 or more features of partially
controlled asthma)
15. History of hypersensitivity reaction to taxanes
16. History of hypersensitivity to Polysorbate 80 that led
to 
unacceptable 
toxicity 
requiring
treatment 
cessation
17. Persisting toxicity related to prior therapy of Grade 
> 1 NCI-CTCAE v 4.03 (except neuropathy, see 
exclusion criterion #18)
18. Neuropathy M Grade 3
19. Pregnancy or lactation
20. Known alcohol or drug abuse
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21. 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 M II), or serious 
uncontrolled 
cardiac 
arrhythmia
requiring 
medication
22. 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
23. Any psychiatric condition that would prohibit the 
understanding or rendering of informed consent
24. Vaccination within 4 weeks of the first dose of 
avelumab and while on trial is prohibited except for 
administration 
of 
inactivated 
vaccines 
(for 
example, inactivated influenza vaccines)
25. Legal incapacity or limited legal capacity
Investigational Medicinal 
Product: dose/mode of 
administration/dosing schedule
Avelumab will be administered as a 1-hour IV infusion
at 10 mg/kg once every 2-week treatment cycle. In order 
to mitigate infusion-related reactions, subjects will 
receive pretreatment with histamine H1 receptor (H1)
blockers and acetaminophen 30 to 60 minutes prior to 
every avelumab infusion.  Premedication with an 
antihistamine and with paracetamol (acetaminophen) 
approximately 30 to 60 minutes prior to each dose of 
avelumab is mandatory (for example, 25-50 mg 
diphenhydramine 
and 
500-650 
mg 
paracetamol 
[acetaminophen] IV or oral equivalent).  
The dose of avelumab will be calculated based on the 
weight of the subject determined within 72 hours prior to 
the day of drug administration.  The dose of avelumab 
used for the previous administration can be repeated if 
the change in the subject’s weight is 10% or less of 
weight used for the last dose calculation.
Since this trial consists of the administration of 
recombinant antibodies to some subjects, there is the 
potential that a subset of subjects might experience 
infusion reactions that may require immediate medical 
attention; therefore, immediate access to an intensive 
care unit or equivalent environment and appropriate 
medical 
therapy 
(including 
IV
epinephrine, 
corticosteroids, antihistamines, bronchodilators, and 
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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 M 2
infusion-related, allergic, or hypersensitivity reactions 
(according to NCI-CTCAE v 4.03). Following avelumab
infusions, subjects must be observed for 2 hours 
post-infusion for potential infusion-related reactions. 
If the subject experiences an infusion-related reaction of 
Grade 2, the infusion rate of the subsequent 
administration of avelumab will be reduced by 50%.  If a 
subject experiences a Grade 3 or 4 infusion-related 
reaction at any time, the subject must discontinue 
avelumab.
Reference therapy: dose/mode of 
administration/dosing schedule
Subjects randomized to docetaxel will be administered 
docetaxel according to the country-approved label at a 
starting dose of 75 mg/m2 by IV infusion over 1 hour.  
Dose adjustments can be made according to label
instructions and local institutional practices.
Additionally, in order to reduce the incidence and 
severity of fluid retention as well as the severity of 
hypersensitivity reactions, subjects will be administered 
dexamethasone 8 mg orally at 12, 3, and 1 hour(s) prior 
to
each docetaxel infusion per docetaxel label 
instructions, or equivalent, per local institutional 
practice.
Planned treatment duration per 
subject
Subjects will receive trial treatment until progressive 
disease (PD) per RECIST 1.1, significant clinical 
deterioration
(clinical 
progression), 
unacceptable 
toxicity, withdrawal of consent, or if any criterion for 
withdrawal from the trial or trial treatment is fulfilled.
For subjects receiving avelumab, treatment may continue 
past the initial determination of disease progression per 
RECIST 1.1 if the subject’s ECOG PS has remained 
stable, and if in the opinion of the Investigator, the 
subject will benefit from continued treatment and if other 
criteria are fulfilled as outlined in the protocol, that is, no 
new symptoms or worsening of existing symptoms and 
no decrease in performance score.
Subjects receiving avelumab who have experienced a CR
should be treated for a maximum of 24 months after 
confirmation, at the discretion of the Investigator.  If the 
Investigator believes that a subject may benefit from 
treatment beyond 24 months, it may be permissible after 
discussion with the Sponsor.  In case a subject with a 
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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 Medical Monitor.  In order to be eligible 
for re-treatment, 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 trial and will be treated and 
monitored according to the protocol.
Patients assigned to docetaxel will not be allowed to 
crossover to avelumab as long as superiority of avelumab
versus docetaxel in terms of the primary objective has not 
been demonstrated in the planned interim or final 
analysis.
Primary endpoint
The primary endpoint for the trial is OS time, defined as 
the time (in months) from randomization to the date of 
death.
Secondary/exploratory 
endpoints
Secondary endpoints include
! PFS time according to RECIST 1.1 and as adjudicated 
by the IERC, 
! Best overall response (BOR) according to RECIST
1.1 and as adjudicated by the IERC, 
! changes in subject-reported outcomes / quality of life 
as assessed by the EQ-5D and the EORTC QLQ-C30
and module QLQ-LC13 questionnaire, and 
! the safety profile of the trial drugs as measured by the 
incidence 
of 
AEs, 
SAEs, 
clinical 
laboratory 
assessments, vital signs, physical examination, ECG 
parameters, and ECOG PS.
Exploratory endpoints include
 
 
 
 
 
 
 
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Statistical methods (includes 
sample size calculation)
The primary endpoint for the trial, OS time, will be
analyzed using a stratified log-rank test taking the 
randomization strata into account. The primary analysis 
population will be the subjects with PD-L1+ tumors in 
the FAS. 
The final analysis will be performed after 337 events in 
PD-L1+ subjects have been observed.  There will also be 
an interim analysis for efficacy after 75% of the events
(253 deaths) in PD-L1+ subjects have been observed, 
using an O’Brien-Fleming stopping boundary.
The 
nominal one-sided alpha levels are 0.0100 and 0.0219 for 
the interim and final analysis, respectively.
The following assumptions are made for the sample size 
calculation:
! Hazard ratio (HR) of 0.70 corresponding to an 
increase in median OS time from 8 months in the 
control arm to 11.43 months in the investigational arm
! 1:1 randomization
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! Alpha = 0.025 (1-sided)
! Power = 90%
! Uniform accrual over a period of 10 months 
! A follow-up time of 11 months after randomization of 
the last subject
! An expected drop-out rate of 5% 
! An interim analysis for efficacy after 75% of events
(deaths) in PD-L1+ subjects have been observed, 
stopping for efficacy if the criteria are met
A sample size of approximately 522 PD-L1+ subjects is 
planned in order to observe 337 events (deaths) at the 
final analysis. The total number of randomized subjects 
is expected to be approximately 750 subjects, based on 
an estimated prevalence of approximately 70% PD-L1+
subjects. The 75% interim analysis will be performed
when 253 events have been observed. An IDMC will be 
convened to perform the evaluation at the interim 
analysis.
In case the analysis of OS in the primary analysis 
population of PD-L1+ subjects demonstrates superiority 
of avelumab versus docetaxel at the interim or the final 
analysis, the following confirmatory analyses are 
planned, using a hierarchical test procedure with the 
following order to control the overall significance level 
at 0.025 one-sided:
! OS in the PD-L1+ subset of the FAS; 
! OS in the FAS;
! BOR in the PD-L1+ subset of the FAS;
! PFS in the PD-L1+ subset of the FAS;
! BOR in the FAS;
! PFS in the FAS.
Safety data will be summarized. Adverse events will be 
summarized by incidence, severity, seriousness and 
relationship to trial drug.
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2
Sponsor, Investigators, and Trial Administrative Structure
The Sponsor of this clinical trial with avelumab is EMD Serono Research & Development 
Institute, Inc. (EMD Serono R&D), Billerica, MA, in the United States (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 at approximately 290 sites globally in North America (with 
approximately 30 sites in the USA), South America, Asia, Africa, and Europe.
2.2
Trial Coordination / Monitoring
The Sponsor will coordinate the trial and will provide the support of Contract Research 
Organizations (CRO) for some activities of the trial. Sponsor Global Clinical Operations will 
perform oversight of the activities performed by the CROs.
The Sponsor will supply the trial medication of avelumab.  A CRO will distribute trial drug
(avelumab and docetaxel) to the sites.
The Coordinating Investigator (to be named), represents all Investigators for decisions and 
discussions regarding this trial, consistent with the International Council for Harmonisation (ICH) 
Topic E6 Good Clinical Practice (GCP; hereafter referred to as ICH GCP). The Coordinating 
Investigator will provide expert medical input and advice relating to trial design and execution and 
is responsible for the review and signoff of the clinical trial report. Signature pages for the Protocol 
Lead and the Coordinating Investigator as well as a list of Sponsor responsible persons are in
Appendix IV. 
Subject enrollment will be randomized and managed by an interactive voice response system
(IVRS).
Safety laboratory assessments will be performed locally by investigational sites. 
 
 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.
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The department of 
, Merck KGaA, Darmstadt, Germany, will supervise the 
statistical analyses, which will be outsourced to a CRO.
2.3
Review Committees
2.3.1
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will perform the evaluation at the interim 
analysis and will be composed of a minimum of 3 members who do not have any conflict of 
interests with the trial Sponsor, including 2 clinicians and a biostatistician.  The IDMC will also
periodically review safety data. The full membership, mandate, and processes of the IDMC will 
be detailed in the IDMC charter.
2.3.2
Central 
Reader
and 
Independent 
Endpoint 
Review 
Committee
A central facility will read and interpret all radiographic scans for this trial.  The data for all images 
will be transferred from each trial site to the central reading center for evaluation. All scans will 
be evaluated at the central facility in accordance with Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1, see reference 1). The imaging data will be transferred to the 
Sponsor or designee at regular intervals throughout the trial.  A manual from the vendor will be 
provided to each trial site. 
The Independent Endpoint Review Committee (IERC) will perform a blinded determination as to 
whether the criteria for tumor response or progression according to RECIST 1.1 have been met.  
The role of the IERC will be to review radiographic image findings for the determination of the
time point overall response and date of disease progression according to RECIST 1.1 for each 
subject.  The full membership, mandate, and processes of the IERC will be detailed in the IERC 
charter.
3
Background Information
3.1
Non-Small Cell Lung Cancer
Lung cancer is the leading cause of cancer death in men and women in the USA and results in 
more cancer deaths than breast cancer, prostate cancer, and colorectal cancer combined.  The 
American Cancer Society estimated that in 2014 there would be 224,210 new cases of lung cancer 
in the USA alone, and 159,260 people would die from their lung cancers (2).  In 2014 in the EU, 
187,300 and 84,500 deaths are predicted from lung cancer for men and women, respectively (3).  
Worldwide, an estimated 1.8 million new cases of lung cancer were diagnosed in 2012, 
approximately 13% of the total of all new cancers diagnosed (4).  Non-small cell lung cancer 
(NSCLC) accounts for approximately 80% of all cases of lung cancer. 
In NSCLC, results of standard therapy are poor except for the most localized cancers where surgery 
and / or combined modality therapy can provide cure in a small percentage of patients.  In 
advanced-stage disease, chemotherapy offers modest benefit, though overall survival is poor (5,
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6).  There are 5 agents indicated for the treatment of advanced NSCLC in the second-line setting:  
docetaxel, pemetrexed, and the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, and crizotinib.  
These agents have an overall response rate of < 10% in an unselected patient population (7-10) 
and there is a growing body of evidence suggesting chemotherapy is preferable to erlotinib and 
gefitinib, especially in patients whose tumors do not harbor epidermal growth factor receptor 
(EGFR) activating mutations (11).    
3.2
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 (12-15), 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 (14, 16).
In the clinical setting, treatment with antibodies that block the PD-1 – 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 (17-20).  Notably, responses appeared prolonged, with 
durations of 1 year or more for the majority of patients.
There are relatively few studies looking at PD-L1 expression in NSCLC and estimates of the 
proportion of patients with PD-L1 positive (PD-L1+) tumors vary widely from 25% to close to 
60% (21, 22); however, treatment of unselected patient populations with NSCLC with antibodies
directed against PD-1 or PD-L1 showed some clinical activity, with 30 responses recorded in 
188 patients (18-20). 
3.3
Avelumab
The Investigational Medicinal Product (IMP) for the present trial is avelumab (*avelumab is the 
proposed International Nonproprietary Name for the anti-PD-L1 monoclonal antibody 
MSB0010718C), 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 R&D, Billerica, MA, USA.
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 (23).  For complete details of the in vitro and nonclinical studies, please refer to the 
Investigator’s Brochure.
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Avelumab is currently in clinical development with 2 ongoing Phase I studies in subjects with solid 
tumors and a Phase II trial in subjects with Merkel cell carcinoma:
! Trial EMR100070-001 is “a Phase I, open-label, multiple-ascending dose trial to investigate the
safety, tolerability, pharmacokinetics, biological, and clinical activity of avelumab in subjects 
with metastatic or locally advanced solid tumors.”
! Trial
EMR100070-002 is “a
Phase I
trial to investigate the tolerability, safety,
pharmacokinetics, biological, and clinical activity of avelumab in Japanese subjects with 
metastatic or locally advanced solid tumors, with expansion part in Asian subjects with gastric 
cancer.”
! Trial EMR100070-003 is “a Phase II, open-label, multicenter trial to investigate the clinical 
activity and safety of avelumab in subjects with Merkel cell carcinoma.”
3.3.1
Trial EMR100070-001
This trial consists of 2 parts, a dose-escalation phase and an expansion phase, which is performed 
in selected tumor indications.
A maximum of 60 subjects with advanced malignancies with no established therapy available were 
planned to be enrolled in the dose-escalation phase of this trial.  Avelumab was administered 
intravenously at the assigned dose level as a 1-hour intravenous (IV) infusion once every 2 weeks.
Dose escalation (3 + 3 design) was performed at the following dose levels: 
!
Dose level 1: 1.0 mg/kg (Cohort 1) 
!
Dose level 2: 3.0 mg/kg (Cohort 2)
!
Dose level 3: 10.0 mg/kg (Cohort 3)
!
Dose level 4: 20.0 mg/kg (Cohort 4)
 
 
 
 
 
 
 
 
 
  
 
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3.3.1.1
Safety Results
 
  
 
 
 
 
 
 
 
 
 
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Guidelines for the management of infusion-related reactions and severe hypersensitivity reaction 
according to the National Cancer Institute (NCI) are found in Sections 6.5.4.1 and 6.5.4.2, 
respectively. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf.
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3.3.2
Pharmacokinetic 
Draft PK assessments have been performed in ongoing studies EMR 100070-001 and 
EMR 100070-002. The preliminary results based on the data available as of 19 December 2014 
are presented under the individual trial headings.
3.3.2.1
Trial EMR100070-001
Pharmacokinetics following the first 1-hour infusion and dose proportionality of avelumab have 
been characterized in 57 Caucasian subjects treated in the dose escalation and expansion cohort of 
the Phase 1 Trial EMR100070-001 by standard non-compartmental analysis based on rich serum 
concentration-time data obtained over a complete dosing interval of 2 weeks (= tau). The analysis 
of these data revealed that the exposure parameters maximum concentration observed postdose 
(Cmax) and area under the concentration-time curve (AUCtau) increased with the doses in a linear 
fashion.
The apparent terminal half-life (t1/2) was 69 hours (mean) ± 21 hours (standard deviation) for 
1 mg/kg, 84 ± 22 hours for the 3 mg/kg, 106 ± 29 hours for 10 mg/kg, and 134 ± 74 hours for the 
20 mg/kg dose.  Taking into account the variability, the t1/2 of the 10 and 20 mg/kg doses can be 
regarded as similar, indicating that target mediated elimination does not increase at these doses. 
This implies that target occupancy is likely to be high at these two doses throughout the dosing 
interval. 
Trough concentrations (Cmin) were obtained for the majority of subjects enrolled in the trial. The 
median Cmin at the end of the first cycle after administration of the 10 mg/kg dose was 20 _g/mL 
(n=256).  This median Cmin increased during the subsequent cycles to 24 _g/mL (second cycle; 
n=233), 26 _g/mL (third cycle; n=167), and remained between 24 and 37 _g/mL during the 
subsequent cycles (n=22 to 114) indicative for no significant accumulation with the biweekly 
dosing scheme.  Median Cmin after the 3 mg/kg dose were 3.7_g/mL after the first dose, 3.9 _g/mL 
after the second dose and 8.3 _g/mL after the third dose (n=7 to 12), though some trough values 
below 1 _g/mL were observed, as well as antidrug antibodies in at least one subject in this dose 
group on day 85 of the treatment period, accompanied by loss of quantifiable exposure.  Median 
trough concentrations after the 20 mg/kg dose were 44, 70, and 77 _g/mL after the first, second,
and third dose, respectively (n=14 to19).
For the 10 mg/kg dose, the volume of distribution was 55 mL/kg (mean) ± 12 mL/kg (standard 
deviation) and total systemic clearance was low (0.38 mL/h/kg ± 0.11 mL/h/kg).
3.3.2.2
Trial EMR100070-002
 
 
 
 
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3.3.3
Clinical Pharmacodynamics
Receptor occupancy was measured in vitro by flow cytometry on peripheral blood CD3+ T-cells 
after spiking of human whole blood samples from eight healthy volunteers with avelumab over a 
concentration range of 0.003 to 10 `g/mL. In this assay, free receptors were measured in samples 
spiked over this range and compared with the amount of free receptors in the unspiked sample.  A 
50% receptor occupancy was observed at a drug concentration of 0.122 `g/mL ± 0.042 `g/mL 
(standard deviation) and a plateau indicating at least 95% receptor occupancy was reached in all 
donor blood samples at 1 `g/mL.
These in vitro data combined with PK data were confirmed in ex-vivo samples taken at Cmin after 
the first dose (Day 15) in a small number of subjects during the initial dose escalation part of the 
Phase 1b Trial EMR100070-001 (n=9). For doses of 10 mg/kg, target occupancy (TO) was greater 
than 90% for these 4 subjects, at trough serum levels ranging between 12.69 to 26.87 `g/mL. Also,
for doses of 3 mg/kg, available TO data for 2 subjects with trough levels ranging from 4.56 to 
6.99 `g/mL, showed greater than 90% TO at trough exposure levels. At dose level 1 mg/kg, 2 out 
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of 3 subjects displayed less than 90% TO at trough serum concentrations. Avelumab serum 
concentrations were below the quantification limit of 0.2 `g/mL in these two subjects.
Based on the observed avelumab serum concentrations in the EMR100070-001 Phase 1 clinical 
trial and the in vitro receptor occupancy data, trough concentrations were sufficient to achieve full 
target occupancy throughout the entire dosing interval in all of the subjects receiving the 10 mg/kg 
dose. After the 3 mg/kg dose, Cmin were insufficient in 3 of the 13 subjects to assure full target 
occupancy; therefore, in order to achieve target saturation during the whole treatment period in all 
subjects, the dose of 10 mg/kg every two weeks was selected as the dose for further investigation 
in the Phase 1b expansion cohorts and for the subsequent clinical studies.
3.4
Rationale for the Current Clinical Trial
The evaluation of an anti-PD-L1 antibody as second-line therapy for the treatment of metastatic
NSCLC is supported by
! the expression of PD-L1 by NSCLC tumor cells and by adjacent immune infiltrates, 
! the clinical activity reported for avelumab and 
 
 
! the existing need for better therapies that improve survival and maintain quality of life in 
patients with NSCLC no longer responding to platinum-based therapy.
3.5
Summary of the Overall Benefit and Risk
The benefit-risk 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.  An 
IDMC (see Section 2.3.1) will assess the benefit-risk ratio on an ongoing basis.  The trial shall be 
discontinued in the event of any new findings that indicate a relevant deterioration of the 
benefit-risk relationship that would render continuation of the trial unjustifiable.
The primary known risks of exposure to avelumab include: 
! infusion-related reactions and
! irAEs.
 
 
 
 
 
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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). 
As noted above (Section 3.2), trials with antibodies that block the PD-1 – PD-L1 interaction have 
been reported to produce objective response rates of 7% to 38% in patients with advanced or 
metastatic solid tumors (17-19), with response durations of 1 year or more for the majority of 
patients.
Furthermore, recent snapshot in Trial EMR100070-001 of subjects with NSCLC who had 
progressed after platinum-containing therapy (n=184 treated subjects with a minimum follow-up 
time of at least 13 weeks by the cut-off date of 15 October 2014) demonstrated an objective 
response rate (ORR) of 12.0% (22 of 184 subjects; 95% confidence interval [CI]: 7.6%, 17.5%), 
including 1 subject with complete response (CR) and 21 subjects with partial response (PR).  There 
were also 70 subjects with stable disease (SD), 68 subjects with progressive disease (PD), and 
24 subjects who were not evaluable.  
 
 
 
 
 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, and 
the applicable national regulatory requirements.
4
Trial Objectives
Primary
The primary objective is to demonstrate superiority with regard to overall survival (OS) of 
avelumab versus docetaxel in subjects with PD-L1+ (as determined by a companion diagnostic 
test under development) NSCLC after failure of a platinum-based doublet.
Secondary
Secondary objectives are as follows:
! To demonstrate superiority with regard to OS of avelumab versus docetaxel in the Full Analysis 
Set (FAS)
! To demonstrate superiority with regard to the ORR of avelumab versus docetaxel in PD-L1+
subjects
! To demonstrate superiority with regard to progression-free survival (PFS) of avelumab versus 
docetaxel in PD-L1+ subjects
! To demonstrate superiority with regard to the ORR of avelumab versus docetaxel in the FAS
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! To demonstrate superiority with regard to PFS of avelumab versus docetaxel in the FAS
! To compare the subject-reported outcomes / quality of life when treated with avelumab versus 
docetaxel using the EuroQOL 5-dimensions questionnaire (EQ-5D) and the European 
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and module 
QLQ-LC13 in the FAS
! To determine the safety and tolerability of avelumab
Exploratory objectives
Exploratory objectives are as follows:
 
 
 
 
 
 
 
 
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a multicenter, international, randomized, open-label, Phase III trial in subjects with locally 
advanced unresectable, metastatic, or recurrent NSCLC that has progressed after a platinum 
doublet.  
5.1.1
Overall Design
Approximately 750 subjects, among them approximately 522 PD-L1 assay positive subjects, are 
planned to be randomized in a 1:1 ratio to receive either avelumab at a dose of 10 mg/kg once 
every 2 weeks or docetaxel at a starting dose of 75 mg/m2 once every 3 weeks.  Subjects will be 
stratified according to PD-L1 assay status (positive versus negative expression in tumor cells) and
NSCLC histology (squamous cell versus non-squamous cell).
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Subjects will return to the clinic at regular intervals for assessments.  Tumor measurements by 
computed tomography (CT) scan or magnetic resonance imaging (MRI) will be performed every 
6 weeks from randomization until Week 55 (12 months) and then every 12 weeks thereafter to 
determine response to treatment.  A central imaging laboratory will be used to read and interpret 
all CT / MRI data.  Response will be evaluated using the RECIST 1.1 and as adjudicated by a 
blinded IERC.  Treatment will continue until 
! disease progression (see Section 5.5.1), 
! significant clinical deterioration (clinical progression, see Section 5.5.1), 
! unacceptable toxicity, or
! any criterion for withdrawal from the trial or trial drug is fulfilled (see Section 5.5).
For subjects receiving avelumab, treatment may continue past the initial determination of disease 
progression according to RECIST 1.1 if the subject’s performance status has remained stable, and 
if in the opinion of the Investigator, the subject will benefit from continued treatment and if other 
criteria are fulfilled as outlined in the protocol, that is, no new symptoms or worsening of existing 
symptoms and no decrease in performance score (see Section 6.2.1).
Subjects receiving avelumab who have experienced a CR should be treated for a maximum of 
24 months after confirmation, at the discretion of the Investigator.  If the Investigator believes that 
a subject may benefit from treatment beyond 24 months, it may be permissible after discussion 
with the Sponsor.  In 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 Medical Monitor.  In order to be eligible for re-treatment, 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 trial and will be treated and 
monitored according to the protocol and the “until progression” schedule in the Schedule of 
Assessments (see Appendix I).
Subjects assigned to docetaxel will be treated until disease progression, unacceptable toxicity, or 
any of the criteria for withdrawal from trial treatment is fulfilled as above an in Section 5.5.  
Subjects assigned to docetaxel will not be allowed to crossover to avelumab as long as superiority 
of avelumab versus docetaxel in terms of the primary objective has not been demonstrated in the 
planned interim or final analysis.
Assessments will be made by the Investigators for the purpose of subject management, but the
disease response 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 trial treatment and for efficacy and 
safety assessments (see Section 7.1.2).
The primary endpoint for the trial will be OS time, defined as the time from randomization to 
death.
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Safety endpoints include AEs, assessed throughout the trial and evaluated using the NCI-CTCAE
version 4.03 (CTCAE v 4.03), clinical laboratory assessments, vital signs, and electrocardiogram 
(ECG) parameters.
The final analysis will be conducted after 337 events (deaths) in PD-L1+ subjects have been 
observed  An interim analysis for efficacy will be performed after 75% of events (253 deaths) in 
PD-L1+ subjects have been observed, stopping for efficacy if the criteria are met. An IDMC will 
be convened to perform the evaluation at the interim analysis (see Section 2.3.1 for committee 
details).
5.1.2
Trial Endpoints
5.1.2.1
Primary Endpoints
The primary endpoint for the trial will be OS time, defined as the time from randomization to 
death.
5.1.2.2
Secondary Endpoints and Exploratory Endpoints
Secondary endpoints include
! PFS time according to RECIST 1.1 and as adjudicated by the IERC (see Section 2.3.2), 
! Best overall response (BOR) according to RECIST 1.1 and as adjudicated by the IERC (see 
Section 2.3.2),
! changes in subject-reported outcomes / quality of life as assessed by the EQ-5D, the EORTC 
QLQ-C30, and module QLQ-LC13 questionnaires, and 
! safety and tolerability of the trial drugs as measured by the incidence of AEs, SAEs, deaths, and 
laboratory abnormalities.
Exploratory endpoints include
 
 
 
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5.1.3
Trial Medication Administration and Schedule
The trial Schedule of Assessments is illustrated in Appendix I.
5.1.3.1
Avelumab
Subjects randomized to the avelumab arm will receive IV infusion of avelumab (10 mg/kg over 
1 hour) once every 2 weeks.  In order to mitigate infusion-related reactions, subjects will receive 
pretreatment with H1 blockers and acetaminophen 30 to 60 minutes prior to every avelumab
infusion.  Premedication with an antihistamine and with paracetamol (acetaminophen) 
approximately 30 to 60 minutes prior to each dose of avelumab is mandatory (for example, 
25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent).
The formulation and packaging information of avelumab is provided in Sections 6.1.1 and 6.6, 
respectively.
5.1.3.2
Docetaxel
Subjects randomized to the docetaxel arm will receive IV infusion of docetaxel (Hospira) 
according to the country approved label at a starting dose of 75 mg/m2 by IV infusion over 1 hour
once every 3 weeks until disease progression, unacceptable toxicity, or any of the criteria for 
withdrawal from trial treatment is fulfilled (Section 5.5).  
Additionally, in order to reduce the incidence and severity of fluid retention as well as the severity 
of hypersensitivity reactions, subjects will be administered dexamethasone 8 mg orally at 12, 3, 
and 1 hour(s) prior to each docetaxel infusion per docetaxel label instructions, or equivalent, per 
local institutional practice.
Patients assigned to docetaxel will not be allowed to crossover to avelumab as long as superiority 
of avelumab versus docetaxel in terms of the primary objective has not been demonstrated in the 
planned interim or final analysis.
The formulation of docetaxel is provided in Section 6.1.2.
5.1.4
Dose Modification and Adverse Drug Reactions Requiring 
Treatment Discontinuation
5.1.4.1
Dose Modification for Avelumab
The dose of avelumab will be calculated based on the weight of the subject determined within 
72 hours prior to the day of drug administration.  The dose of avelumab used for the previous 
administration can be repeated if the change in the subject’s weight is 10% or less of weight used 
for the last dose calculation.  
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 Sections
5.1.4.2 and 6.5.4.1.  There are to be no dose reductions.
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5.1.4.2
Adverse 
Drug 
Reactions 
Requiring 
Avelumab
Discontinuation or Modifications
The following adverse drug reactions (ADRs, see Section 7.4.1.1) 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 (Z 6 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management
! Transient (Z 24 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that 
resolves to Grade Z 1
! Single laboratory values out of normal range (excluding Grade M 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 Z 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
! Asymptomatic Grade M 3 drug-related amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis does not require dose delay or 
discontinuation.  The study Medical Monitor should be consulted for such abnormalities.
! Infusion should not be given if ECOG PS is M 3 on the day of trial treatment administration. 
Treatment should be discontinued if ECOG PS has not improved to Z 2 by the next scheduled 
treatment administration.  
Any Grade 2 ADR should be managed as follows:
! Infusion should not be given in case of ongoing Grade 2 ADR on the day of trial treatment 
administration.
Treatment can be resumed according to original schedule once ADR resolved to Grade Z 1. Up to 
2 subsequent study drug doses may be omitted. If more than two doses are skipped, treatment may 
be resumed after consultation with study Medical Monitor.
Infusion-related reactions, hypersensitivity reactions (Grades 1 to 4), tumor lysis syndrome, and 
irAEs should be handled according to guidelines in Sections 6.5.4.1, 6.5.4.2, 6.5.4.3, and 6.5.4.4,
respectively.
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5.1.4.3
Dose Modification for Docetaxel
Dose modifications (dose delays and dose changes) for docetaxel should be made in accordance 
with labeling instructions and local institutional guidelines.  Discontinuation of docetaxel due to 
ADRs should also be in accordance with the docetaxel label and local institutional practice.
5.2
Discussion of Trial Design
This is a Phase III, 2-arm, randomized, open-label trial to determine the efficacy and safety of 
avelumab compared with docetaxel in subjects with locally advanced unresectable or metastatic 
NSCLC that has progressed after a platinum doublet.  Approximately 70% of subjects randomized 
in the trial are expected to be PD-L1+, reflecting the prevalence of PD-L1 positivity in the 
underlying patient population, and leading to a high proportion of potential avelumab-responsive 
subjects and minimizing avelumab exposure to potentially non-responsive subjects. The dosing 
regimen is based upon the current ongoing Phase I trials.  
The primary endpoint of OS is usually the preferred endpoint (24) as it allows for a direct measure 
of patient benefit and is the most reliable cancer endpoint.  An open-label design is appropriate for 
this trial given the different schedules of the administration of the trial drugs and premedication 
regimens.  The endpoints of PFS and ORR will support the OS. 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit from continued treatment, despite initial evidence of PD (25); therefore, for 
subjects in receiving avelumab, treatment may continue past the initial determination of disease 
progression according to RECIST 1.1 if the subject’s ECOG PS has remained stable, and if in the 
opinion of the Investigator, the subject will benefit from continued treatment (see Section 6.2.1).
Docetaxel was chosen as the comparator as it is an approved therapy for NSCLC in the second-line 
setting. Docetaxel remains a standard of care for patients experiencing progression after first-line 
therapy in NSCLC based on superior PFS, OS, and quality of life when compared with best 
supportive care or other chemotherapy agents (26). Docetaxel and pemetrexed show similar PFS 
(2.9 months) and overall survival (8 months) with pemetrexed showing a better side effect profile 
(27, 28); however, pemetrexed has shown particular efficacy in patients with non-squamous 
histology and is increasingly being used in first-line regimens (29).  With this evolution of 
treatment paradigms, docetaxel remains the best option for patients with non-squamous histology 
who fail first-line therapy including maintenance and those with squamous histology where 
pemetrexed may not be as efficacious either as part of induction or maintenance. Erlotinib is 
another agent considered an option in the setting of progression after first-line therapy after 
demonstrating a PFS of 2.2 months and OS of 6.7 months (30). However, this was compared with
placebo and by indirect comparison the clinical endpoints appear inferior to chemotherapy. 
Docetaxel remains the best option in this setting because of its broad applicability and 
demonstrated clinical benefit.  Thus, it represents the ideal comparator for this trial.
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5.2.1
Inclusion of Special Populations
Not applicable.
5.2.2
Rationale for Exclusion of Subjects with Epidermal Growth 
Factor Receptor Mutation
Emerging data from a randomized Phase III trial in patients with non-squamous NSCLC who failed 
prior platinum-based therapy suggests that subjects with EGFR mutations who receive anti-PD1 
therapy may have different survival outcomes compared with patients with EGFR mutations who 
receive docetaxel. Data from the open-label CheckMate-057 trial that randomized 582 subjects
with advanced nonsquamous NSCLC after the failure of platinum-based doublet chemotherapy to 
nivolumab (anti-PD1) or docetaxel was presented at the annual meeting of the American Society 
of Clinical Oncology in 2015. In the overall population, the median OS was 12.2 months with 
nivolumab versus 9.4 months with docetaxel (HR=0.73; 95% CI, 0.59-0.89; p=0.00155). In this 
nivolumab study, 15% of subjects in the nivolumab group and 13% in the docetaxel group were 
EGFR-positive. Among the 82 subjects who were EGFR mutation positive, the HR for OS in 
nivolumab treated subjects versus docetaxel was 1.18 (95% CI 0.69, 2.00), while in the 
340 subjects who were not detected to have an EGFR mutation, the HR for OS in nivolumab versus
docetaxel treated subjects was 0.66 (95% CI 0.51, 0.86, see reference 31). These randomized data 
suggest that subjects with EGFR mutation may have different survival outcomes compared with
NSCLC subjects without an EGFR mutation when treated with anti-PD1.
The observation that subjects with EGFR mutation may have different clinical outcomes to 
immunotherapy with a checkpoint inhibitor is supported by emerging research regarding the 
potential correlation between mutational burden and response to immunotherapy. Data from the 
Cancer Genome Atlas Research Network have described NSCLC tumors with EGFR mutation to 
be associated with transversion low mutations and a lower mutational burden; whereas, 
transversion high mutations (often associated with smoking status) are associated with a higher 
mutation burden (32). In addition, Rizvi et al. have reported that in NSCLC, subjects with 
transversion high tumors respond better to pembrolizumab (anti-PD1) than subjects with 
transversion low tumors (ORR: 56% versus 17% [p=0.03]; PFS: median not reached versus
3.5 months, [p=0.0001], see reference 33). 
As a result of these emerging data, the inclusion of NSCLC subjects with EGFR mutation might 
introduce unwanted heterogeneity to the current avelumab EMR 100070-004 study; therefore, one
purpose of this amendment is to exclude further enrollment of NSCLC subjects with EGFR 
mutation to the study. For subjects with known EGFR mutation who have already been enrolled 
in the study, these subjects should consult with their physician and be informed when deciding 
whether or not to continue treatment based on this new information.
5.3
Selection of Trial Population
Subject enrollment will be randomized and managed by an IVRS (see Section 7.1.1).  Only persons 
meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial as subjects. 
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
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Investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consent following the procedure described in Section 9.2.  
5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. Signed written informed consent before any trial-related procedure is undertaken that is not 
part of the standard patient management
2.
Male or female subjects aged M 18 years
3.
Availability of a formalin-fixed, paraffin-embedded block containing tumor tissue or 
7 unstained tumor slides suitable for PD-L1 expression assessment
4.
Tumor determined to be evaluable for PD-L1 expression per the evaluation of a central 
laboratory 
5.
Subjects with histologically confirmed Stage IIIb/IV or recurrent NSCLC who have 
experienced disease progression
6.
Subjects must have progressed after an acceptable therapy defined as follows:
a.
Subjects must have progressed during or after a minimum of 2 cycles of 1 course of a 
platinum-based combination therapy administered for the treatment of metastatic disease.  
A history of continuation (use of a non-platinum agent from initial combination) or switch 
(use of a different agent) maintenance therapy is permitted provided there was no 
progression after the initial combination.  A switch of agents during treatment for the 
management of toxicities is also permitted provided there was no progression after the 
initial combination
OR
b. Subjects must have progressed within 6 months of completion of a platinum-based 
adjuvant, neoadjuvant, or definitive chemotherapy, or concomitant chemoradiation 
regimen for locally advanced disease
7. Subjects with non-squamous cell NSCLC of unknown EGFR mutation status will require 
testing (local laboratory, or central laboratory if local testing is not available).  Subjects with a 
tumor that harbors an activating EGFR mutation will not be eligible (see Exclusion Criterion 3)
8.
ECOG PS of 0 to 1 at trial entry 
9.
Estimated life expectancy of more than 12 weeks
10. Adequate hematological function defined by white blood cell (WBC) count M 2.5 × 109/L with 
absolute neutrophil count (ANC) M 1.5 × 109/L, lymphocyte count M 0.5 × 109/L, platelet count 
M 100 × 109/L, and hemoglobin M 9 g/dL (may have been transfused)
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11. Adequate hepatic function defined by a total bilirubin level Z 1.5 × the upper limit of normal 
(ULN) range and AST and alanine aminotransferase (ALT) levels Z 2.5 × ULN for all subjects
12. Adequate renal function defined by an estimated creatinine clearance > 30 mL/min according 
to the Cockcroft-Gault formula (or local institutional standard method)
13. 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 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.)  
All subjects who are randomized to the docetaxel arm are required to use effective 
contraception for up to 3 months after docetaxel treatment for women of childbearing potential 
and male subjects will be advised not to father a child during the 3 months after treatment with 
docetaxel.  Male subjects will be requested to seek advice on conservation of sperm prior to 
treatment.
5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. In the USA only, subjects with a squamous cell histology will be excluded
2. Systemic anticancer therapy administered after disease progression during or following a 
platinum-based combination
3. Subjects with non-squamous cell NSCLC whose disease harbors EGFR mutation(s) and / or 
anaplastic lymphoma kinase (ALK) rearrangement will not be eligible for this trial. Subjects 
of unknown ALK and / or EGFR mutation status will require testing at screening (local 
laboratory, or central laboratory if local testing is not available)
4. Prior therapy with any antibody / drug targeting T-cell coregulatory proteins (immune 
checkpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4). 
5. Concurrent anticancer treatment (for example, cytoreductive therapy, radiotherapy [with the 
exception of palliative bone-directed radiotherapy], immune therapy, or cytokine therapy 
except for erythropoietin)
6. Major surgery for any reason, except diagnostic biopsy, within 4 weeks of randomization and
/ or if the subject has not fully recovered from the surgery within 4 weeks of randomization
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7. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be 
tapered off these drugs before initiation of the trial treatment (with the exception of subjects
with adrenal insufficiency, who may continue corticosteroids at physiologic replacement dose, 
equivalent to Z 10 mg prednisone daily).
8. All subjects with brain metastases, except those meeting the following criteria:
a.
Brain metastases have been treated locally, and
b. 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)
9. Previous malignant disease (other than NSCLC) within the last 5 years with the exception of 
basal or squamous cell carcinoma of the skin or carcinoma in situ (bladder, cervical, colorectal, 
breast)
10. Prior organ transplantation, including allogeneic stem-cell transplantation 
11. Significant acute or chronic infections including, among others:
!
Known history of testing positive test for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome 
!
Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA if anti-HCV antibody screening test positive)
12. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent:
a.
Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not 
requiring immunosuppressive treatment are eligible
b. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids 
are administered only for the purpose of hormonal replacement and at doses Z 10 mg or 
equivalent prednisone per day
c.
Administration of steroids through a route known to result in a minimal systemic exposure 
(topical, intranasal, intro-ocular, or inhalation) are acceptable
13. Previous or ongoing administration of systemic steroids for the management of an acute 
allergic phenomenon is acceptable as long as it is anticipated that the administration of steroids 
will be completed in 14 days, or that the daily dose after 14 days will be Z 10 mg per day of 
equivalent prednisone
14. Known severe hypersensitivity reactions to monoclonal antibodies (Grade M 3 NCI-CTCAE v 
4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially 
controlled asthma)
15. History of hypersensitivity reaction to taxanes
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16. History of hypersensitivity to Polysorbate 80 that led to unacceptable toxicity requiring 
treatment cessation
17. Persisting toxicity related to prior therapy of Grade > 1 NCI-CTCAE v 4.03 (except 
neuropathy, see exclusion criterion #18)
18. Neuropathy M Grade 3
19. Pregnancy or lactation
20. Known alcohol or drug abuse
21. 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 M II), or serious uncontrolled cardiac arrhythmia requiring medication 
22. 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
23. Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent
24. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except 
for administration of inactivated vaccines (for example, inactivated influenza vaccines)
25. Legal incapacity or limited legal capacity
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 randomized before treatment start after verification of fulfilling all inclusion criteria without 
matching any exclusion criterion.
5.5
Criteria for Subject Withdrawal
5.5.1
Criteria for Withdrawal from Trial Treatment
Subjects will be withdrawn from trial treatment for any of the following reasons:
! PD per RECIST 1.1 (subjects receiving avelumab treatment may continue past the initial 
determination of disease progression if the subject’s ECOG PS has remained stable, and if in 
the opinion of the Investigator, the subject will benefit from continued treatment, see Section 
6.2.1)
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! Significant clinical deterioration (clinical progression), defined as new symptoms that are 
deemed by the Investigator to be clinically significant or significant worsening of existing 
symptoms
! Unacceptable toxicity
! Withdrawal of consent
! 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 M 3 ADRs as defined in Section 5.1.4.2
! Occurrence of AEs, resulting in the discontinuation of the trial 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 if considered necessary by 
the Investigator or Sponsor
! Noncompliance (see Section 6.9)
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; however, 
subjects will continue to be followed for survival
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 withdrawal from the trial, the assessments scheduled for the last visit (End-of-Treatment 
visit) should be performed (see Section 7.1.3), if possible, with focus on the most relevant 
assessments. In any case, the appropriate End-of-Treatment electronic case report form (eCRF) 
visit must be completed. In case of withdrawal, subjects will be asked to continue safety and 
survival follow-up, which includes the collection of data on survival, subject-reported outcomes / 
quality of life questionnaires, and subsequent anticancer therapy.
If a subject is withdrawn prior to progression for any reason, the subject will not be replaced.
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5.6
Premature Discontinuation of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
! New information leading to unfavorable benefit-risk judgment of the trial drug, for example,
due to
 evidence of inefficacy of the trial 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 trial drug
! After the interim analysis, the IDMC declares superior efficacy in the avelumab treatment arm 
compared with those randomized to receive docetaxel and recommends that the trial be stopped 
early
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 follow-up will continue 
until 5 years after the last subject receives the last dose of avelumab.
The Sponsor may terminate the study at any time once access to IMP for subjects still benefitting 
is provisioned via a roll over study, expanded access, marketed product or another mechanism of 
access as appropriate.
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 investigational drug is avelumab and 
the comparator drug is docetaxel.
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6.1
Description of Investigational Medicinal Product
6.1.1
Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration. It is presented 
at a concentration of 20 mg/mL in single-use glass vials closed with a rubber stopper and sealed 
with an aluminum polypropylene flip-off seal.
6.1.2
Docetaxel
Docetaxel is a white to almost-white powder with an empirical formula of C43H53NO14a3H2O and 
a molecular weight of 861.9.  Docetaxel is supplied commercially (Hospira, Lake Forest, Illinois) 
as 20 mg/2 mL and 160/16 mL in polysorbate 80/dehydrated alcohol suspension.  
6.2
Dosage and Administration
6.2.1
Avelumab Dosage and Administration
Subjects will receive an IV infusion of avelumab at a dose of 10 mg/kg (over the duration of 1 hour) 
following pretreatment with H1 blockers and acetaminophen 30 to 60 minutes prior to each 
avelumab infusion, once every 2 weeks (refer to Appendix I).  Premedication with an antihistamine 
and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to each dose of 
avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol 
[acetaminophen] IV or oral equivalent). 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 within 72 hours prior to the day of drug administration.  The dose 
of avelumab used for the previous administration can be repeated if the change in the subject’s 
weight is 10% or less of weight used for the last dose calculation.    Complete blood count and 
core chemistry samples must be drawn and results reviewed within 48 hours prior to dose 
administration.  Subjects will receive avelumab once every 2 weeks until the criteria in Sections 
5.5 through 5.7 are met.
For subjects receiving avelumab, treatment may continue past the initial determination of disease 
progression per RECIST 1.1 as long the following criteria are met:
! Investigator-assessed clinical benefit, without any rapid disease progression
! Tolerance of trial drug
! Stable ECOG PS
! Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (for example, central nervous system metastases).
In addition, if disease progression is due to brain metastasis, subjects may continue avelumab 
treatment after the local treatment of the brain lesions provided that the above criteria are met in 
addition to the following:
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! 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 Z 10 mg daily prednisone 
(or equivalent).
The decision to continue treatment should be discussed with the Medical Monitor and documented 
in the trial records.
A radiographic assessment should be performed within 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the subject is clinically deteriorating 
and unlikely to receive any benefit from continued treatment with avelumab.
If the Investigator feels that the subject continues to achieve clinical benefit by continuing 
treatment, the subject should remain on the trial and continue to receive monitoring according to 
the Schedule of Assessments (Appendix I).
For subjects who continue avelumab trial therapy beyond progression, further progression is 
defined as an additional 10% increase in tumor burden volume from time of initial PD. This 
includes an increase in the sum of all target lesions and / or the development of new measurable 
lesions. Treatment should be discontinued permanently upon documentation of further disease 
progression.
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm). Any new lesion considered nonmeasureable at the time of initial progression may become 
measureable and therefore included in the tumor burden volume if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15 mm).
Additionally, subjects receiving avelumab who have experienced a CR should be treated for a 
maximum of 24 months after confirmation, at the discretion of the Investigator.  If the Investigator 
believes that a subject may benefit from treatment beyond 24 months, it may be permissible after 
discussion with the Sponsor.  In 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 Medical Monitor.  In order to be eligible for re-treatment, 
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 trial and will be treated 
and monitored according to the protocol and the “until progression” schedule in the Schedule of 
Assessments (see Appendix I).
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6.2.2
Docetaxel Dosage and Administration
The starting dose of docetaxel for this trial is 75 mg/m2 as per the country approved labeling 
instructions.  Docetaxel should be administered at the clinic as a 1-hour IV infusion once every 
3 weeks in accordance to the label instructions and per local administration guidelines.  
Additionally, subjects will be administered dexamethasone 8 mg orally at 12, 3, and 1 hour(s) prior 
to each docetaxel infusion per docetaxel label instructions, or equivalent, per local institutional 
practice.
Dexamethasone will be prescribed locally according to local standards.  Docetaxel will be provided 
to trial sites through IVRS.
Subjects assigned to docetaxel will not be allowed to crossover to avelumab as long as superiority 
of avelumab versus docetaxel in terms of the primary objective has not been demonstrated in the 
planned interim or final analysis.
6.3
Assignment to Treatment Groups
Once the subject has provided a signed Informed Consent Form (ICF) and meets inclusion and 
exclusion criteria, the Investigator or delegate will request the trial treatment assignment using the 
IVRS. Qualified subjects will be randomized at a 1:1 ratio to receive either avelumab or docetaxel. 
The trial is fully controlled by the IVRS, which assigns treatment individual (unique) vial numbers
for each subject.  The vial number is linked via the Good Manufacturing Practice (GMP) qualified
system to the corresponding treatment as well as to the subject.
Allocation of subjects will be stratified according to PD-L1 assay status (positive versus negative
expression in tumor cells) and NSCLC histology (squamous cell versus non-squamous cell). This 
stratified randomization will be centrally allocated across all trial sites via the IVRS.
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.
6.4
Other Drugs to be Used in the Trial
Subjects randomized to receive avelumab will receive pretreatment with H1 blockers and 
acetaminophen 30 to 60 minutes prior to each avelumab infusion.  Premedication with an 
antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to each 
dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 500-650 mg 
paracetamol [acetaminophen] IV or oral equivalent).  This regimen may be modified based on 
local treatment standards and guidelines as appropriate.
Subjects randomized to receive docetaxel will receive pretreatment with dexamethasone 8 mg 
orally at 12, 3, and 1 hour(s) prior to each docetaxel infusion per docetaxel label instructions, or 
equivalent, per local institutional practice.
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Immediate access to an Intensive Care Unit (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 M 2 infusion-related, allergic, or anaphylactoid
reactions.  Following avelumab infusions, subjects must be observed for 2 hours post infusion for 
potential infusion-related 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 trial 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. The assessment of PD 
will be made according to RECIST 1.1 (1) and not based on the necessity for palliative bone 
directed-radiotherapy.
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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 including:
! Cytoreductive therapy
! Radiotherapy [with the exception of palliative bone-directed radiotherapy, or radiotherapy 
administered on superficial lesions], 
! Immune therapy, or 
! Cytokine therapy except for erythropoietin, 
! Concurrent systemic therapy with steroids or other immunosuppressive agents, 
! Use of any investigational drug within 28 days before randomization. 
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 or the management of irAEs is allowed)
Note:  The use of systemic corticosteroids for subjects randomized to receive docetaxel is per 
Investigator’s discretion and is to be based on local and institutional guidelines.
! Growth factors for subjects randomized to receive avelumab (granulocyte colony stimulating 
factor or granulocyte macrophage colony stimulating factor). Exception: Erythropoietin and 
darbepoietin alpha may be prescribed at the Investigator’s discretion
! For subjects randomized to docetaxel, use of concomitant strong cytochrome P450 3A4 
(CYP3A4) inhibitors should be avoided
(for example, ketoconazole, itraconazole, 
clarithromycin, 
atazanavir, 
indinavir, 
nefazodone, 
nelfinavir, 
ritonavir, 
saquinavir, 
telithromycin, and voriconazole).  For more information on CYP3A4 substrates, Investigators 
are directed to the following URL: http://medicine.iupui.edu/clinpharm/ddis/
! Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except 
for administration of inactivated vaccines (for example, inactivated influenza vaccines)
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).  The subject should complete the End-of-Treatment visit 
(Section 7.1.3) and be followed for survival according to Section 7.1.5.
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 or docetaxel as 
required. These might include analgesics, antinausea medications, antihistamines, diuretics, 
anti-anxiety medications, and medication for pain management, including narcotic agents.
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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 (or within 28 days 
before randomization):
! Major surgery (excluding prior diagnostic biopsy)
! Herbal remedies with immunostimulating properties (for example, mistletoe extract) or known 
to potentially interfere with major organ function (for example, hypericin)
! Subjects should not abuse alcohol or other drugs during the trial
6.5.4
Special Precautions
As a routine precaution, subjects randomized to the avelumab arm must be observed for 2 hours 
post infusion, in an area with resuscitation equipment and emergency agents. At all times during 
avelumab or docetaxel 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 M 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 first manifest 
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 antinuclear antibodies (ANAs) or antineutrophil cytoplasmic antibodies (ANCAs).
See Section 6.5.4.4 details on the management of irAEs.
6.5.4.1
Infusion-Related Reactions
A. Symptoms
!
Fever
!
Chills
!
Rigors
!
Diaphoresis
!
Headache
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B. Management according to Table 6.1
Table 6.1
Treatment Modification for Symptoms of Infusion-Related Reactions 
Caused by Avelumab
NCI-CTCAE Grade 
Treatment Modification for Avelumab
Grade 1 – mild
! Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
! Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening.
! The total infusion time for avelumab should not exceed 
120 minutes.
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 hours.
! Stop avelumab infusion.
! Resume infusion at 50% of previous rate once infusion-
related reaction has resolved or decreased to at least 
Grade 1 in severity, and monitor closely for any 
worsening.
Grade 3 or Grade 4 – severe or life-threatening
! Grade 3: Prolonged (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.  If an infusion reaction occurs, all details about drug preparation and infusion must be 
recorded.
6.5.4.2
Severe Hypersensitivity Reactions and Flu-Like Symptoms
If hypersensitivity reaction occurs, the subject must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council (United Kingdom) can be found at 
https://www.resus.org.uk/pages/reaction.pdf. Subjects should be instructed to report any delayed 
reactions to the Investigator immediately.
A. Symptoms
!
Impaired airway
!
Decreased oxygen saturation (< 92%)
!
Confusion
!
Lethargy
!
Hypotension
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!
Pale / clammy skin
!
Cyanosis
B. Management
!
Epinephrine injection and dexamethasone infusion
!
Subject should be placed on monitor immediately 
!
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 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 6.1) published by Howard et al (34).
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Figure 6.1
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 6.2.
Table 6.2
Management of Immune-Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea / Colitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Diarrhea: < 4 stools/day over Baseline
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment 
(e.g., loperamide)
Close monitoring for worsening symptoms
Educate subject to report worsening immediately
If worsens:
Treat as Grade 2 or 3/4 
Grade 2
Diarrhea: 4 to 6 stools per day over 
Baseline; i.v. fluids indicated < 24 
hours; not interfering with ADL
Colitis: abdominal pain; blood in stool 
Delay avelumab therapy
Symptomatic treatment
If improves to Grade 1: 
Resume avelumab therapy
If persists > 5 to 7 days or recur:
0.5 to 1.0 mg/kg/day methylprednisolone or 
equivalent 
When symptoms improve to Grade 1, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy per 
protocol.
If worsens or persists > 3 to 5 days with oral 
steroids:
Treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): M 7 stools per day 
over Baseline; incontinence; i.v. fluids 
M 24 hrs; interfering with ADL
Colitis (Grade 3):  severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Discontinue avelumab therapy 
per protocol
1.0 to 2.0 mg/kg/day 
methylprednisolone i.v. or  
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade 1, then taper over at 
least 1 month
If persists > 3 to 5 days, or recurs after 
improvement:
Add infliximab 5 mg/kg (if no contraindication), 
Note: Infliximab should not be used in cases of 
perforation or sepsis 
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Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Management
Follow-up
Grade 1 to 2 
Covering Z 30% body surface area 
Symptomatic therapy (for 
example, antihistamines, topical 
steroids) 
Continue avelumab therapy
If persists > 1 to 2 weeks or recurs: 
Consider skin biopsy 
Delay avelumab therapy
Consider 0.5 to 1.0 mg/kg/day methylprednisolone 
i.v. or oral equivalent. Once improving, taper 
steroids over at least 1 month, consider 
prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy
If worsens: 
Treat as Grade 3 to 4 
Grade 3 to 4
Covering > 30% body surface area; life 
threatening consequences 
Delay or discontinue  avelumab  
therapy
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day 
methylprednisolone i.v. or i.v.
equivalent 
If improves to Grade 1: 
Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic 
infections 
Resume avelumab therapy
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Radiographic changes only 
Consider delay of avelumab
therapy 
Monitor for symptoms every 
2 to 3 days 
Consider Pulmonary and 
Infectious Disease consults 
Re-image at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4 
Grade 2
Mild to moderate new symptoms 
Delay avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily, 
consider hospitalization 
1.0 mg/kg/day methyl-
prednisolone i.v. or oral 
equivalent 
Consider bronchoscopy, lung 
biopsy 
Re-image every 1 to 3 days 
If improves: 
When symptoms return to near baseline, taper 
steroids over at least 1 month and then resume 
avelumab  therapy and consider prophylactic 
antibiotics
If not improving after 2 weeks or worsening: 
Treat as Grade 3 to 4 
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Grade of Pneumonitis
(NCI-CTCAE v4)
Management
Follow-up
Grade 3 to 4
Severe new symptoms; New / worsening 
hypoxia; life-threatening 
Discontinue avelumab therapy
Hospitalize 
Pulmonary and Infectious 
Disease consults
2 to 4 mg/kg/day 
methylprednisolone i.v. or i.v.
equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to baseline: 
Taper steroids over at least 6 weeks 
If not improving after 48 hours or worsening: 
Add additional immunosuppression (for example,
infliximab, cyclophosphamide, 
i.v. immunoglobulin, or mycophenolate mofetil) 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Management
Follow-up
Grade 1
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and / or total bilirubin > ULN to
1.5 x ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4 
Grade 2
AST or ALT > 3.0 to Z 5 x ULN and /
or total bilirubin > 1.5 to Z 3 x ULN 
Delay avelumab therapy
Increase frequency of 
monitoring to every 3 days 
If returns to baseline: 
Resume routine monitoring, resume avelumab
therapy
If elevations persist > 5 to 7 days or worsen: 
0.5 to 1 mg/kg/day methylprednisolone or oral 
equivalent and when LFT returns to Grade 1 or 
Baseline, taper steroids over at least 1 month, 
consider prophylactic antibiotics for opportunistic 
infections, and resume avelumab therapy
Grade 3 to 4
AST or ALT > 5 x ULN and / or total 
bilirubin > 3 x ULN 
Discontinue avelumab therapy 
Increase frequency of 
monitoring to every 1 to 2 days 
1.0 to 2.0 mg/kg/day 
methylprednisolone i.v. or i.v.
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult gastroenterologist
Consider obtaining MRI/CT 
scan of liver and liver biopsy if 
clinically warranted
If returns to Grade 2: 
Taper steroids over at least 1 month 
If does not improve in > 3 to 5 days, worsens or 
rebounds: 
Add mycophenolate mofetil 1 gram (g) twice daily 
If no response within an additional 3 to 5 days, 
consider other immunosuppressants per local 
guidelines 
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Cardiac irAEs
Myocarditis
Management
Follow-up
New onset of cardiac signs or symptoms 
and / or new laboratory cardiac 
biomarker elevations (e.g. troponin, 
creatine kinase-MB, brain natriuretic 
peptide) or cardiac imaging 
abnormalities suggestive of myocarditis
Withhold avelumab therapy.
Hospitalize.
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management.
Cardiology consult to establish 
etiology and rule out immune-
mediated myocarditis.
Guideline based supportive 
treatment as per cardiology 
consult.a
Consider myocardial biopsy if 
recommended per cardiology 
consult.
If symptoms improve and immune-mediated 
etiology is ruled out, re-start avelumab therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-mediated 
etiology is suspected or confirmed following 
cardiology consult, manage as immune-mediated 
myocarditis.
Immune-mediated myocarditis 
Permanently discontinue 
avelumab.
Guideline based supportive 
treatment as appropriate as per 
cardiology consult.a
Methylprednisolone 1 to 
2 mg/kg/day.
Once improving, taper steroids over at least 
1 month and add prophylactic antibiotics for 
opportunistic infections.
If no improvement or worsening, consider 
additional immunosuppressants (e.g. azathioprine, 
cyclosporine A).
a Local guidelines, or eg. European Society of Cardiology or American Heart Association guidelines
European Society of Cardiology guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
American Heart Association guidelines website:
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Management
Follow-up
Asymptomatic TSH abnormality
Continue avelumab therapy  
If TSH < 0.5 x LLN, or TSH > 2 x ULN, or consistently out of range in 
2 subsequent measurements: include T4 at subsequent cycles as clinically indicated; 
consider endocrinology consult.
Symptomatic endocrinopathy 
Evaluate endocrine function 
Consider pituitary scan 
Symptomatic with abnormal lab
/ pituitary scan: 
If improves (with or without hormone 
replacement): 
Taper steroids over at least 1 month and consider 
prophylactic antibiotics for opportunistic 
infections.
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Delay avelumab therapy
1 to 2 mg/kg/day 
methylprednisolone iv or by 
mouth equivalent 
Initiate appropriate hormone 
therapy 
Endocrinology consult to 
distinguish (differentiate) 
between primary from 
secondary dysfunction. No 
abnormal lab/pituitary MRI 
scan but symptoms persist: 
Repeat labs in 1 to 3 
weeks/MRI in 1 month
Resume avelumab therapy 
Subjects with adrenal insufficiency may need to 
continue steroids with mineralocorticoid 
component 
Suspicion of adrenal crisis (for example,
severe dehydration, hypotension, shock 
out of proportion to current illness)
Delay or discontinue avelumab therapy 
Rule out sepsis 
Stress dose of i.v. steroids with mineralocorticoid activity 
i.v. fluids 
Consult endocrinologist 
If adrenal crisis ruled out, then treat as above for symptomatic endocrinopathy 
ADL=activities of daily living, ALT=alanine aminotransferase, AST=aspartate aminotransferase, CT=computed tomography; 
irAE=immune-related adverse event, IV=intravenous, LFT=liver function test, LLN=lower limit of normal, MRI=magnetic 
resonance imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Event, 
NSAID=nonsteroidal anti-inflammatory drugs, T4=free thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of 
normal.
6.6
Packaging and Labeling
Avelumab is formulated as a 20.0 mg/mL solution and is supplied by the Sponsor in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal.
Packaging and labeling will be in accordance with applicable local regulatory requirements and 
applicable GMP guidelines. Avelumab will be packed in boxes each containing 1 vial. The 
information on the trial 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.
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.
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Avelumab drug product must be stored at 2°C to 8°C until use, with a temperature log maintained 
daily.
All medication boxes supplied to each 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). 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 trial 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.
Storage, handling, preparation, and disposal of docetaxel should be according to the package insert.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring accountability for trial drug (avelumab or docetaxel), 
including reconciliation of drugs and maintenance of drug records.
! Upon receipt of trial 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 trial 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 Medical Monitor at each monitoring visit.
! Trial drug accountability records will include:
 confirmation of trial drug delivery to the trial site;
 the inventory at the site of trial 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 trial drug; and
 dates, quantities, batch numbers, expiry dates and (for trial drug prepared at the site) 
formulation, as well as the subjects’ trial numbers.
! 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 trial drug provided by the Sponsor was fully reconciled.
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Unused trial drug must not be discarded or used for any purpose other than the present trial. Any 
trial drug that has been dispensed to a subject must not be redispensed to a different subject.
The Sponsor’s Monitor will periodically collect the trial 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 trial drug is not used
! after the expiry date, and
! after the retest date unless the trial drug is reanalyzed and its retest date extended.
This is to be closely monitored by the Clinical Trial Monitor.
6.9
Assessment of Investigational Medicinal Product Compliance
In this trial, subjects will receive trial treatment at the investigational site. Well-trained medical 
staff will monitor and perform the trial drug administration. The information of each trial drug 
administration including the date, time, and dose of trial drug will be recorded on the eCRF. The 
Investigator will make sure that the information entered into the eCRF regarding drug 
administration is accurate for each subject. Any reason for noncompliance should be documented.
Noncompliance is defined as a subject missing > 1 infusion of trial treatment for nonmedical 
reasons (see Section 5.5.1). If 1 infusion is missed and the interval between the subsequent 
infusion and the last administered treatment is longer than 4 weeks for nonmedical reasons, the 
criteria of insufficient compliance are met as well.
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6.10
Method of Blinding
This is an open-label trial; thus, trial treatment is not blinded.  However, Investigators and trial site 
personnel will be blinded to the results of the PD-L1 expression determination.  Details of this 
blinding will be provided in the Study Manual.
6.11
Emergency Unblinding
Not applicable.
6.12
Treatment of Overdose
An overdose is defined as any dose M 10% than the planned calculated dose for that particular 
administration as described in this clinical trial protocol. Any overdose must be recorded in the 
trial 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 trial drug.
In the case of an overdose of docetaxel, subjects should receive therapeutic granulocyte colony-
stimulating factor per package insert as soon as possible after the overdose is discovered.
6.13
Medical Care of Subjects After End of Treatment
After a subject has stopped trial treatment, usual treatment will be administered, if required, in 
accordance with the trial site’s standard of care and generally accepted medical practice and 
depending on the subject’s individual medical needs.
Upon withdrawal from trial treatment, subjects may receive whatever care they and their 
physicians agree upon. Subjects will be followed for survival and AEs as specified in Section 
7.1.5.
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.
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7.1.1
Screening and Baseline Procedures and Assessments
During the Screening period and before any trial-related investigations and assessments are started, 
subjects will be asked to sign the ICF.  The Screening procedures and Baseline assessments will 
be completed within 28 days of signing the ICF before randomization.  Failure to establish 
eligibility within 28 days would result in screening failure and the subject will be excluded from 
the trial; however, subjects can be re-entered in the trial based on the Investigator’s judgment
within 6 weeks of signing the ICF. In this case, a new ICF will be required to be signed by the 
subject.
Tumor tissue must be available within 10 calendar days after the subject has signed the ICF in 
order to establish the PD-L1 status of the tumor.  Tumor tissue can be archival tissue or resulting 
from a screening biopsy of the subject if no archival tissue is available (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 assessments for this protocol will be 
permitted to participate in the protocol provided they meet all other inclusion criteria and no 
exclusion criteria.
Randomization cannot occur until PD-L1 expression has been determined by a companion 
diagnostic test under development and performed centrally (Investigators and trial site 
personnel will be blinded to the results of the PD-L1 expression determination).
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 
NSCLC, previous and ongoing (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 physical examination, including recording body height
and weight, vital signs, 12-lead ECG, and a determination of the ECOG PS (Appendix II).  With 
the use of a validated electronic tablet or validated site pad, subjects will also complete 
subject-reported outcomes/ quality of life questionnaires.
The Screening laboratory examination includes hematology, hemostaseology, full serum 
chemistry (including core chemistry), and full urinalysis (dipstick plus microscopic evaluation).
Adrenocorticotropic hormone (ACTH), ANA, ANCA, rheumatoid factor (RF), free thyroxine 
(T4), and thyroid-stimulating hormone (TSH) will also be assessed at Screening for all subjects.  
Additionally, HBV surface antigen and anti-HCV tests must be performed at screening to exclude 
hepatitis infection. If the anti-HCV antibody test is positive, infection should be confirmed by an 
HCV RNA test.  
During Screening, a serum P-human chorionic gonadotropin (P-HCG) pregnancy test will be 
performed for females of childbearing potential and blood hepatitis B virus and hepatitis C virus
will be performed (local laboratory) for all Screening subjects as these conditions are trial entry 
exclusion criteria (see Section 5.3.2). Females who are postmenopausal (age-related amenorrhea 
M 12 consecutive months and increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who 
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have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If 
necessary to confirm postmenopausal status, FSH will be drawn at Screening.
The tumor evaluation (type and staging, etc) will be performed using CT scan or MRI (if MRI is 
used, CT of chest is mandatory in all countries except Germany, in which case a MRI of the chest 
is allowed) 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 6 weeks prior to randomization. A bone scan 
should be done at Screening as clinically indicated.
The blood samples for Baseline
and
as well as for 
 
assessments (optional) will be collected before or on Day 1 before trial treatment starts for subjects 
randomized to receive avelumab.  
Subject eligibility will need to be confirmed by the CRO before the first administration of the trial
drug.
7.1.2
Treatment Period
In this trial, the treatment will be given until PD, significant clinical deterioration (clinical 
progression), unacceptable toxicity, or any criterion for withdrawal from the trial or trial drug is 
fulfilled (see Section 5.5.1). For subjects receiving avelumab, treatment may continue past the 
initial determination of disease progression according to RECIST 1.1 if the subject’s ECOG PS
has remained stable, and if in the opinion of the Investigator, the subject will benefit from 
continued treatment (see Section 6.2.1).  Additionally, subjects receiving avelumab who have 
experienced a CR should be treated for a maximum of 24 months after confirmation, at the 
discretion of the Investigator.  If the Investigator believes that a subject may benefit from treatment 
beyond 24 months, it may be permissible after discussion with the Sponsor.  In 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 Medical Monitor.  
In order to be eligible for re-treatment, 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 trial and will be treated and monitored according to the protocol and the “until 
progression” schedule in the Schedule of Assessments (see Appendix I).
The treatment should start within 4 days after randomization.  While on trial treatment, subjects 
will be asked to visit the trial site either 
! once every 2 weeks for subjects randomized to receive avelumab, or 
! once every 3 weeks for subjects randomized to receive docetaxel. 
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 the scheduled day (-5 days).
Subjects will receive either
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! avelumab by IV infusion following pretreatment with H1 blockers (diphenhydramine 25 to 
50 mg IV, or equivalent), and acetaminophen 500 to 650 mg (oral or IV), once every 2 weeks
(see Section 6.2.1), or
! docetaxel by IV infusion following pretreatment with dexamethasone 8 mg orally at 12, 3, and 
1 hour(s) prior to each docetaxel infusion (see Section 6.2.2).
During the treatment period, the following assessments will be performed (see Appendix I for the 
detailed schedule):
! With the use of a validated electronic tablet or validated site pad, subject-reported outcomes/ 
quality of life questionnaires will be completed by the subject after randomization (before the 
first administration of the trial treatment) then prior to administration of trial treatment and 
before any trial-related procedures (including collection of biological samples) at 
 Week 1 (treatment administration 1), Week 3 (treatment administration 2), Week 7
(treatment administration 4), and Week 13 (treatment administration 7) for subjects receiving 
avelumab,
 Week 1 (treatment administration 1), Week 4 (treatment administration 2), Week 7
(treatment administration 3), and Week 13 (treatment administration 5) for subjects receiving 
docetaxel, and
 every 6 weeks thereafter while on treatment for all subjects
! 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 trial visit thereafter.
! Physical examinations will be performed at each visit until Week 13 and every 6 weeks 
thereafter.  
! Vital signs and body weight will be assessed in each visit.
! The laboratory hematology, hemostaseology, and core serum chemistry tests will be assessed 
at each visit (complete blood count and core chemistry samples must be drawn and results 
reviewed within 48 hours prior to dose administration). Full serum chemistry (which includes 
core serum chemistry) will be assessed at Weeks 3, 5, and 13 for subjects randomized to 
avelumab, Weeks 4, 7, and 13 for subjects randomized to docetaxel, and then every 6 weeks 
thereafter for all subjects. A basic urinalysis (dipstick) will be performed at each treatment 
visit.  If the basic urinalysis is abnormal, a full urinalysis should be performed.
! A urine or serum P-HCG pregnancy test will be performed according to the Schedules of 
Assessments (Table 12.1 or Table 12.3 as appropriate) before administration of the trial drug
for females of childbearing potential.  Results of the most recent pregnancy test should be 
available prior to the next dosing of trial drug.
! Tumor evaluation for all subjects (see Section 7.3) will be performed every 6 weeks from 
randomization until Week 55 (12 months) and then every 12 weeks thereafter, with a tumor 
assessment visiting time window of 5 days prior to the scheduled tumor assessment day 
(-5 days).
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! ACTH, ANA, ANCA, RF, T4, and TSH will be measured according to the Schedules of 
Assessments (Table 12.1 or Table 12.3 as appropriate) and if clinically indicated for all subjects. 
 
 
 
 
 
 
 
 
 
 
7.1.3
End-of-Treatment
Discontinuation visit 
Any subject who experiences an AE that mandates discontinuation of trial treatment should have 
a Discontinuation visit as soon as possible after the decision to discontinue trial treatment (at least 
within 7 days). For all these subjects, the Discontinuation visit will include the following (see
Appendix I):
! Subject-reported outcomes / quality of life questionnaires will be completed with the use of a 
validated electronic tablet or validated site pad
! Documentation of AEs and concomitant medication
! Physical examination, including vital signs and body weight
! 12-lead ECGs
! Laboratory hematology, hemostaseology, full serum chemistry, and basic urinalysis
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! ECOG PS
Once the Discontinuation visit has been performed, subjects must return for the End-of-Treatment 
visit within 28 days (± 5 days) after discontinuation.
End-of-Treatment visit
The End-of-Treatment visit is scheduled 4 weeks (28 days ± 5 days) after the last administration 
of trial treatment, 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):
! Subject-reported outcomes / quality of life questionnaires will be completed with the use of a 
validated electronic tablet or validated site pad
! AEs, concomitant medications, and ECOG PS
! Physical examination including vital signs and body weight
! 12-lead ECGs
! Laboratory hematology, hemostaseology, full serum chemistry, and full urinalysis (dipstick 
plus microscopic evaluation)
! Urine or serum P-HCG pregnancy test (in females of childbearing potential)
! Tumor evaluation (only to be performed if no disease progression was documented previously)
! T4 and TSH levels
 
7.1.4
Safety Follow-up
All subjects will have a subsequent visit scheduled 12 weeks (± 2 weeks) after the last 
administration of trial treatment. The visit will include the following full assessment of safety 
parameters (refer to Appendix I):
! After the End-of-Treatment visit only treatment related AEs have to be documented until the 
Safety Follow-up visit
! 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
! Laboratory testing consisting of the following will be assessed:
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 Hematology, hemostaseology, core serum chemistry, and basic urinalysis (dipstick only)
 T4 and TSH levels
 
! A urine or serum P-HCG pregnancy test (in females of childbearing potential) will be conducted
7.1.5
Long-term Follow-up
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.” Any SAE assessed as related to the IMP must be reported whenever it occurs, 
irrespective of the time elapsed since the last administration of the IMP.
Subjects without PD according to RECIST 1.1 at the End-of-Treatment visit will be followed up 
for disease progression (CT / MRI scans every 6 weeks [± 5 days] until Week 55 (12 months) after 
the first study drug administration, then every 12 weeks thereafter using the same procedures and 
review as while on treatment) until disease progression, lost to follow-up, or withdrawal of 
informed consent. 
After the End-of-Treatment visit, subjects will be followed quarterly (that is, every 3 months 
± 1 week) for survival (including assessment of any further tumor therapy).  The survival follow-up 
will continue until 5 years after the last subject receives the last dose of avelumab.
7.1.6
Blood Draws for Clinical Assessments
The overall amount of blood to be drawn from a single subject with a body weight M 70 kg (154 lbs) 
must not exceed 120 mL/day and 550 mL in an 8-week period for safety laboratory testing, 
pregnancy testing,
.
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 recorded:
! Subject identifier
! Date of birth
! Sex
! Race
! Ethnicity
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7.2.2
Diagnosis of Non-Small Cell Lung Cancer
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 PD-L1 expression as determined by 
t and
performed centrally [Investigators and trial site personnel will be blinded to the results of the 
PD-L1 expression determination], Section 7.6 for details), 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;
! smoking history;
! current cancer signs and symptoms and side effects from current and previous anticancer 
treatments; and
! current cancer disease status.
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 (including herbal medications) taken and procedures carried out within 28 days 
prior to Screening
For the trial entry, all of 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 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 (Screening only) will be recorded.
7.2.5
CT or MRI Scans for Tumor Assessment at Baseline
Baseline imaging will be performed within 28 days prior to randomization in order to establish 
Baseline disease status of target and nontarget lesions according to RECIST 1.1. Acceptable 
modalities include CT scans (chest, abdomen, and pelvis), CT chest with contrast (or chest MRI 
in Germany) together with MRI of the abdomen and pelvis or positron emission tomography / CT 
scans. The use of IV contrast is preferred unless there is a history of allergy or other risk in the 
opinion of the Investigator (chest X-ray is not acceptable and other imaging modalities may be 
performed at the discretion of the Investigator and as clinically indicated). Bone scans should be 
performed if clinically indicated. Baseline tumor burden should be determined as outlined in 
Section 7.3.  A brain CT / MRI scan is required at Screening if one has not been performed within 
6 weeks prior to randomization.  In general, lesions detected at Screening / Baseline need to be 
followed using the same imaging methodology and preferably the same imaging equipment at 
subsequent tumor evaluation visits.
7.2.6
Cardiac Assessments
A 12-lead ECG will be recorded at Screening and at the Early Discontinuation / End-of-Treatment
visit 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 will 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
Radiographic images and physical findings (physical assessments) used for the local determination 
of disease progression will be read centrally and reviewed by a blinded IERC. The IERC will 
make a determination as to whether the criteria for tumor response or progression according to 
RECIST 1.1 have been met.  
For each subject, tumor response assessment will be performed by CT scan or MRI (if MRI is 
used, CT of chest is mandatory in all countries except Germany, in which case a MRI of the chest 
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is allowed) imaging of the chest / abdomen / pelvis (plus other regions 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 (except for brain 
scans, unless clinically indicated). In general, lesions detected at Baseline need to be followed 
using the same imaging methodology and preferably the same imaging equipment at subsequent 
tumor evaluation visits.
A brain CT / MRI scan is required at Screening if not performed within 6 weeks prior to 
randomization.  Brain CT / MRI scans should be performed after Screening, if clinically indicated 
by development of new specific symptoms. A bone scan should be done as clinically indicated at 
Screening and beyond. 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 must 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).
Treatment decisions will be made by the Investigator based on the Investigator’s assessment of 
tumor status.
For efficacy determination, 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, as described in RECIST 1.1 [1]).
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 RECIST 1.1 (1).
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 4 weeks after the initial documentation of CR or PR. Confirmation of PR can be confirmed 
at an assessment later than the next assessment after the initial documentation of PR.
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. Subjects who withdraw from the trial for clinical or symptomatic 
deterioration before objective documentation of PD will be requested to undergo appropriate 
imaging to confirm PD. Every effort should be made to confirm a clinical diagnosis of PD by 
imaging.
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7.4
Assessment of Safety
The safety profile of the trial treatments 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). Given the intended mechanism of action of avelumab, particular 
attention will be given to AEs that may follow the enhanced T-cell activation, such as dermatitis, 
colitis, hepatitis, uveitis, or other immune-related reactions. Ophthalmologic examinations should 
be considered, when clinically indicated, for signs or symptoms of uveitis.
The reporting period for AEs is described in Section 7.4.1.3.
The safety assessments will be performed according to the Schedule of Assessments (refer to 
Appendix I).
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
AE
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of 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 4.03 (publication date: 14 June 2010). This is a 
descriptive terminology that can be used for AE reporting.
A general grading (severity / intensity; hereafter referred to as severity) scale is provided at the 
beginning of the referenced document, and specific event grades are also provided.
If a particular AE severity is not specifically graded by the guidance document, the Investigator is 
to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment.
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The 5 general grades are
Grade 1:
Mild
Grade 2:
Moderate
Grade 3:
Severe
Grade 4:
Life-threatening 
Grade 5:
Death 
According to the Sponsor’s convention, any clinical AE with severity of Grade 4 or 5 must also 
be reported as an SAE; however, a laboratory abnormality of Grade 4, such as anemia or 
neutropenia, is considered serious only if the condition meets one of the serious criteria described 
below.  If death occurs, the primary cause of death (or 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 a 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 trial treatment
using the following definitions. Decisive factors for the assessment of causal relationship of an 
AE to trial treatment include, but may not be limited to, temporal relationship between the AE and 
treatment administration, known side effects of trial treatment, medical history, concomitant 
medication, course of the underlying disease, trial procedures.
Not related: Not reasonably related to the trial treatment avelumab / docetaxel. The AE could 
not medically (pharmacologically / clinically) be attributed to the trial treatment in 
this clinical trial protocol. A reasonable alternative explanation must be available.
Related:
Reasonably related to the trial treatment avelumab / docetaxel.
The AE could 
medically (pharmacologically / clinically) be attributed to the trial treatment. 
Abnormal laboratory findings and other abnormal investigational findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation, or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality 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)
Adverse drug reactions are defined in this trial as any AEs suspected to be related to trial treatment
by the Investigator and / or Sponsor.
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Serious Adverse Events (SAE)
A SAE is any untoward medical occurrence that at any dose
! results in death,
! is life-threatening (NOTE: The term “life-threatening” refers to an event in which the subject 
is at risk of death at the time of the event; not an event that hypothetically might have caused
death if it was 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.
Note: 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 above. 
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 trial drug is 
also considered a SAE, 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.
AEs / SAEs observed in association with disease progression
Disease progression recorded in the course of efficacy assessments only, but without any adverse 
signs and symptoms should not be reported as AEs.
However, if adverse signs or symptoms occur in association with disease progression then these 
should be recorded, and reported as SAEs if meeting any seriousness criteria.
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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). 
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit 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. 
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 causal relationship with the 
trial treatment, any other potential causal factors, any treatment given or other action taken 
(including dose modification or discontinuation of the trial 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 and Monitoring Conventions.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent) and continues through the trial’s 
End-of-Treatment visit, defined as 28 days (± 5 days) after last trial drug administration.  After the 
End-of-Treatment visit only treatment related AEs have to be documented until the Safety 
Follow-up visit, defined as 12 weeks (± 2 weeks) after the last trial treatment administration.
Any SAE suspected to be related to the trial treatment must be reported whenever it occurs, 
irrespective of the time elapsed since the last administration.
7.4.1.4
Procedure for Reporting Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (that is, within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or designee in writing. All written reports should be transmitted using the SAE Report 
Form, which must be completed by the Investigator following specific completion instructions. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone. 
In these cases, a written report must be sent immediately thereafter by fax or e-mail.
Reporting procedures and timelines are the same for any new information on a previously reported 
SAE (= follow-up).
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Names, addresses, telephone, and fax numbers for SAE reporting will be included in the trial 
specific SAE report form.
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). In all cases, the information provided 
on the SAE report form must be consistent with the data about the event recorded in the eCRF.  
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 
or designee may have on the AE within the same timelines as those noted above for initial reports.  
This is necessary to ensure a 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 Clinical Trial Monitor, although 
in exceptional circumstances, the Global Drug Safety department may contact the Investigator 
directly to obtain further information or to discuss the 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 or designee will inform the Investigator of 
“findings that could adversely affect the safety of subjects, impact the conduct of the trial, or alter 
the IEC / IRB approval / favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (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 the 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.
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7.4.1.6
Monitoring of Subjects with Adverse Events
Adverse events are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) 
and are assessed for final outcome at the End-of-Treatment visit. After the End-of-Treatment visit, 
only treatment related AEs have to be documented until the Safety Follow-up visit, defined as 
12 weeks (± 2 weeks) after the last trial treatment administration.
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.
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 to be 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 to pregnancies 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. If an abnormal outcome occurs, the SAE Report Form will be used if the subject 
sustains an event, and the Parent-Child / Fetus Adverse Event Report Form, if 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 the trial drug immediately. The Sponsor or designee must be notified without 
delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
It is essential that the Sponsor or designee be provided with a list of laboratory normal ranges 
before shipment of trial drug. Any change in laboratory normal ranges during the trial will 
additionally be forwarded to the CRO and the Sponsor.
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Blood samples will be taken from nonfasted subjects.  All routine laboratory analyses will be 
performed at a laboratory facility local to the trial site and relevant results must be available and 
checked before administration of trial treatment (details to be provided in the Laboratory Manual).  
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 7.1 will be taken from nonfasted 
subjects during the Screening phase (28 days prior to randomization), during the treatment period
as specified in Table 7.1 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 7.1 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 7.1
Required Full Laboratory Safety Tests
Full Chemistry
Core Chemistrya
Hematology
Albumin
Alkaline phosphatase
Absolute lymphocyte count
Alkaline phosphatase
ALT
ANC
ALT
AST
Hematocrit
Amylase
BUN / total urea
Hemoglobin
AST
Calcium
Platelet count
GGT
Chloride
RBC count
BUN / total urea
Creatinine
WBC count and differential count
Calcium
Glucose
Reticulocytes
Chloride
Phosphorus/Phosphates
MCH
Cholesterol
Magnesium
Mean corpuscular volume
Creatine kinase
Potassium
MCHC
Creatinine
Sodium
CRP
Total bilirubin
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 trial drug.
Potassium
Sodium
Total bilirubin
Total protein
Uric acid
Triglycerides
ACTH, ANA, ANCA, RF, TSH, and T4
As indicated in the Schedules of Assessments 
(Table 12.1 and Table 12.3 as appropriate) and if 
clinically indicated.
Hormone
FSH (yes / no if applicable)
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-glutamyltransferase, 
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.
a Core serum chemistries.
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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 (Appendix I) and documented in the eCRF.
Body weight will be measured at Screening and at subsequent visits as indicated in the Schedule 
of Assessments (Appendix I) 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, a serum P-HCG pregnancy test will be carried out 
during the Screening phase. A urine or serum P-HCG test will be performed according to the 
Schedules of Assessments (Table 12.1 or Table 12.3 as appropriate). Results of the most recent 
pregnancy test should be available prior to the next dosing of trial drug. Subjects who are 
postmenopausal (age-related amenorrhea M 12 consecutive months and FSH > 40 mIU/mL), or 
who have undergone hysterectomy or bilateral oophorectomy are exempt from pregnancy testing.
 
 
 
 
  
 
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Germline DNA will be investigated on DNA extracted from whole blood. For this purpose, an 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.7
Other Assessments
7.7.1
Subject-Reported Outcomes / Quality of Life
Subject-reported outcomes / quality of life will be assessed by the EQ-5D, EORTC QLQ-C30, and 
module QLQ-LC13.  Questionnaires will be completed by the subject at Screening, Day 1 (Week 
1), Weeks 3 and 7 prior to trial treatment administration and then every 6 weeks thereafter while 
on trial treatment for subjects randomized to receive avelumab and Day 1 (Week 1), Weeks 4 and 
7 and then every 6 weeks thereafter while on trial treatment for subjects randomized to receive 
docetaxel.  Subject-reported outcomes will also be assessed at the Early Discontinuation / End-of-
Treatment visit (details will be provided in the Study Manual).    
The subject-reported outcomes / quality of life questionnaires should be completed by the subject 
prior to any of the other trial-related assessments being performed, that is, physical examinations, 
blood draws, trial treatment administration, etc.  Subjects will use a validated electronic tablet or
validated site pad to record their responses to these questionnaires.
In rare and extenuating 
circumstances when an electronic tablet or site pad is not available or not working properly, 
collection on validated paper questionnaires may be allowed to ensure data are collected and not 
lost.
Data will be collected by the CRO and housed in a database.  Analysis of the questionnaires will 
be described in the SAP.
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8
Statistics
8.1
Sample Size
The following assumptions with regard to the primary endpoint of OS time in the PD-L1+ subjects 
are made for the sample size calculation:
! Hazard ratio (HR) of 0.70 corresponding to an increase in median OS time from 8 months in 
the control arm to 11.43 months in the investigational arm
! 1:1 randomization
! Alpha = 0.025 (1-sided)
! Power = 90%
! Uniform accrual over a period of 10 months 
! A follow-up time of 11 months after randomization of the last subject
! An expected drop-out rate of 5% 
! An interim analysis for efficacy after 75% of the planned events (deaths) PD-L1+ subjects have 
been observed, with an O’Brien-Fleming stopping boundary
A sample size of approximately 522 PD-L1+ subjects is planned in order to observe 337 events 
(deaths) at the final analysis.  Calculations were performed using ADDPLAN V 6.01, Aptiv 
Solutions.  The 75% interim analysis will be performed when 253 events have been observed.  An 
IDMC (see Section 2.3.1) will be convened to perform the evaluation at the interim analysis in 
order to safeguard the Sponsor’s personnel from unblinded trial results.
To ensure that the overall FAS is representative of the underlying patient population, the trial will 
enroll PD-L1 evaluable subjects without predetermining the ratio between PD-L1+ and PD-L1 
negative subjects; therefore, the total number of subjects enrolled in the trial is unknown, but can 
be estimated based on a prevalence estimate of PD-L1+ subjects from the NSCLC expansion 
cohort of Trial EMR100070-001, which was conducted in a similar patient population. 
 
 
 
 
8.2
Randomization
Qualified subjects will be randomized at a 1:1 ratio to receive either avelumab or docetaxel using
stratified permuted block randomization with variable block length via the IVRS.  Randomization
will be stratified according to PD-L1 assay status (positive versus negative expression in tumor 
cells) and NSCLC histology (squamous cell versus non-squamous cell).  The purpose of 
stratification is to ensure balanced distribution of prognostic factors between treatment arms.  
Randomization will occur upon completion of the Screening procedures and determination of 
subject eligibility, using the IVRS as described in Section 6.3.
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8.3
Endpoints
8.3.1
Primary Endpoint
The primary endpoint of the trial is the OS, defined as the time (in months) from randomization to 
the date of death, regardless of the actual cause of the subject’s death.  
The survival follow-up will continue until 5 years after the last subject receives the last dose of 
avelumab.  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, 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.
8.3.2
Secondary Endpoints
8.3.2.1
Progression-Free Survival
The PFS will be determined according to RECIST 1.1 as adjudicated by an IERC (see Section 
2.3.2). It is defined as the time from date of randomization until date of the first documentation of 
objective PD or death by any cause (whichever occurs first).  The PFS data will be censored on 
the date of the last adequate tumor assessment for subjects who do not have an event (PD or death), 
for subjects who start new anticancer treatment prior to an event, or for subjects with an event after 
two or more consecutive missing tumor assessments. Subjects who do not have a Baseline tumor 
assessment or who do not have any post-Baseline tumor assessments will be censored on the date 
of randomization unless death occurred on or before the time of the second planned tumor 
assessment, in which case the death will be considered an event.
The censoring and event date options to be considered for the PFS are presented in Table 8.1.  
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Table 8.1
General Censoring Rules for Progression-free Survival
Scenario
Date of event/censoring
Outcome
No baseline assessment
Start date
Censored a
PD or death  12 weeks after last tumor 
assessment or  12 weeks after start date
Date of PD or death
Event
PD or death > 12 weeks after the last 
adequate tumor assessment 
Date of last adequate tumor 
assessment b documenting 
no PD before new 
anticancer therapy is given 
or missed assessments
Censored
No PD
Date of last adequate tumor 
assessment b documenting 
no PD before new 
anticancer therapy is given 
or missed assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information 
is 
ignored. 
Outcome is derived based on 
documented 
progression 
only.
New anticancer therapy given 
Date of last adequate tumor 
assessment b documenting 
no PD before new 
anticancer therapy is given 
or missed assessments 
Censored
PD=progressive disease.
a However if the patient dies 12 weeks after start date the death is an event with date on death date
b  If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate 
assessment should be measured from the date of randomization; if the criteria were met the censoring will be 
on the date of randomization.
The PFS time according to Investigator assessment will be derived in the same way as the PFS 
time according to the IERC.
8.3.2.2
Best Overall Response
The confirmed BOR will be determined according to RECIST 1.1 (1) and as adjudicated by an 
IERC (see Section 2.3.2).  It is defined as the best response obtained among all tumor assessment 
visits after the date of randomization until documented disease progression.
Details of 
determination of tumor response date at each time point will be provided in the IERC charter. 
Only tumor assessments performed before the start of any further anticancer treatment will be 
considered in the assessment of BOR. Clinical deterioration will not be considered as documented 
disease progression.
For a BOR of PR or CR, confirmation of the response according to RECIST 1.1 will be required, 
preferably at the regularly scheduled 6-week assessment interval, but no sooner than 4 weeks after 
the initial documentation of CR or PR.  Confirmation of PR or CR can be confirmed at an 
assessment later than the next assessment after the initial documentation of PR or CR, respectively.  
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A BOR of SD requires that a time point overall response of SD has been determined at a time point
at least 6 weeks after randomization.
The ORR is defined as the proportion of all randomized subjects with a confirmed BOR of PR or 
CR according to RECIST 1.1 and as adjudicated by the IERC.
The confirmed BOR according to Investigator assessment will be derived in the same way as the 
BOR according to the IERC.
8.3.2.3
Changes in Subject-Reported Outcomes / Quality of Life
Changes in subject-reported outcomes / quality of life will be assessed by the EQ-5D, the EORTC 
QLQ-C30, and module QLQ-LC13 questionnaires.
The QLQ-LC13 comprises 13 questions incorporated into 1 multi-item scale designed to evaluate 
dyspnea and a series of single items assessing different types of pain, as well as, cough, 
hemoptysis, dysphagia, sore mouth, alopecia, and peripheral neuropathy.  For each domain and 
item, a linear transformation was applied to standardize the raw score to a range from 0 to 100, 
with 100 representing the best possible function / quality of life, and highest burden of symptoms 
for symptom domains and single items.  
8.3.3
Safety Endpoints
Safety endpoints include AEs, clinical laboratory assessments, vital signs, physical examination, 
ECG parameters, and ECOG PS as described in Section 7.4.
8.3.4
Exploratory Endpoints 
Exploratory endpoints include
 
 
 
 
 
 
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8.4
Analysis Sets
Screening Analysis Set
The screening analysis set includes all subjects who signed the ICF.
Full Analysis Set / Intention-to-Treat (ITT) Analysis Set
The Full Analysis Set (FAS) / ITT analysis set will include all subjects who were randomly 
assigned to trial treatment. Analyses performed on the FAS will take into account subjects’ 
allocation to treatment groups as randomized.
PD-L1+ FAS
The PD-L1+ FAS will include all PD-L1+ subjects who were randomly assigned to trial treatment. 
Analyses performed on the PD-L1+ FAS will take into account subjects’ allocation to treatment 
groups as randomized.
The primary analysis population will be the subjects with PD-L1+ tumors in the FAS.
Safety Analysis Set  
The Safety analysis set will include all subjects who were administered at least 1 dose of the trial
medication. Analyses performed on the Safety analysis set will consider subjects as treated.
PD-L1+ Safety Analysis Set  
The PD-L1+ Safety analysis set will include all PD-L1+ subjects who were administered at least 
1 dose of the trial medication. Analyses performed on the PD-L1+ Safety analysis set will consider 
subjects as treated.
Subgroup Analysis Sets 
Analysis of efficacy variables will also be performed on subgroups of interest, which will be
specified in the SAP.
Subject assignment per the IVRS will be used to determine the PD-L1+ subset. 
8.5
Description of Statistical Analyses
8.5.1
General Considerations
Full details of the planned analyses will be described in the trial SAP.
Baseline characteristics summary and the efficacy analysis will be performed on the PD-L1+ FAS
and the FAS, with the primary analysis population being the PD-L1+ FAS.  Analyses performed 
on the FAS will take into account subjects’ allocation to treatment groups as randomized.  Analyses 
performed on the safety population will consider subjects as treated.
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All safety and efficacy endpoints will be summarized by treatment group.  
In order to provide overall estimates of treatment effects, data will be pooled across trial centers.  
The “center” factor will not be considered in statistical models or for subgroup analyses due to the 
high number of participating centers in contrast to the anticipated small number of subjects 
randomized at each center.
In general, descriptive summaries will be presented for the efficacy and safety variables collected.  
Continuous variables will be summarized using mean, standard deviation, minimum, median, and 
maximum.  Categorical variables will be summarized using frequency counts and percentages.    
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.
A hierarchical testing strategy will be applied to perform confirmatory analysis of primary 
endpoint OS and the key secondary efficacy endpoints as follows:
1. OS in the PD-L1+ subset of the FAS; 
2. OS in the FAS;
3. BOR in the PD-L1+ subset of the FAS;
4. PFS in the PD-L1+ subset of the FAS;
5. BOR in the FAS;
6. PFS in the FAS.
Statistical testing of each of the hypotheses 2 through 6 will be performed at the same nominal 
significance level as for hypothesis 1 (one-sided alpha of 0.0100 and 0.0219 at the interim and the 
final analysis, respectively) if, and only if, the preceding null hypothesis in terms of the hierarchical 
order was rejected. 
All sensitivity analyses are regarded as purely exploratory; therefore, no formal adjustment for 
multiplicity will be undertaken for these sensitivity analyses.
For the safety analysis, Baseline is defined as the last measurement before the first trial drug 
administration.  For the efficacy analysis, Baseline is defined as the last measurement prior to 
randomization. If such a value is missing, the last measurement prior to the first trial drug 
administration will be used as the baseline measurement for the efficacy analysis except for 
analyses of tumor assessments data where the baseline assessment would be considered missing.
Statistical analyses will be performed using SAS® version 9.2 or higher.
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8.5.2
Analysis of Primary Endpoint
Primary Analysis
The primary endpoint of this trial is OS.  The primary analysis population will be the PD-L1+ 
FAS.  It will compare the OS time between the two treatment groups, and will be performed using 
a one-sided stratified log rank test (overall  = 2.5%). The stratification factors are those used for 
randomization as captured via the IVRS (PD-L1 assay status: positive versus negative expression 
in tumor cells; and NSCLC histology: squamous cell versus non-squamous cell). For analysis 
purposes, the subjects in the previously used strata non-squamous cell EGFR normal and 
non-squamous cell EGFR activating mutations will be combined into the stratum non-squamous 
cell.
The final analysis will be conducted after 337 events (deaths) in PD-L1+ subjects have been 
observed.  An interim analysis for efficacy will be performed after 75% of events (253 deaths) in 
PD-L1+ subjects have been observed, stopping for efficacy if the criteria are met.
The following null hypothesis will be tested:
H0: %A(t) = &%B(t), & M 1, versus H1: %A(t)=&%B(t), & < 1,
where %(t) represents the hazard at time t and & the unknown constant of proportionality of hazards 
in treatment groups A (avelumab) and B (docetaxel).
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by the 
randomization strata to calculate the hazard ratio and its 95% CI. Each stratum will define a 
separate Baseline hazard function.  Ties will be handled by replacing the proportional hazards 
model by the discrete logistic model.
Based on the O’Brien-Fleming efficacy stopping boundary,  level will be 0.0100 (one-sided) at 
the 75% interim analysis, and 0.0219 (one-sided) at the final analysis.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group together 
with a summary of associated statistics including the median survival time with two-sided 95% 
CIs. In particular, 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 primary analysis performed as described above will be repeated on the FAS as part of the 
hierarchical testing strategy as described in Section 8.5.1.
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Sensitivity Analyses
The following sensitivity analyses will be performed to explore the robustness of the primary 
confirmatory analysis. These analyses are regarded as purely exploratory. Additional sensitivity 
analyses may be specified in the trial SAP. The sensitivity analyses will include the following:
! The proportional hazards assumption for the primary analysis will be visually checked by 
plotting log(-log(survival)) versus log(time) by treatment arm
! An unstratified analysis will be performed to compare the OS time and to estimate the treatment 
effect
! The primary analysis will be repeated using strata according to eCRF instead of IVRS data
! The pattern of censoring with regard to OS time will be analyzed by treatment arm 
distinguishing between administrative censoring (that is, censoring imposed by the cut-off date) 
and censoring due to subjects being lost to follow-up.
Time of Follow-Up
A Kaplan-Meier plot will be created for both treatment groups to compare the duration of 
follow-up for overall survival using the following censoring rules (reversing the OS censoring and 
event indicators):
Table 8.2
Censoring Rules for Duration of Overall Survival Follow-up
Date of Event / Censoring
Censoring
Subjects alive or lost to follow-up
Time from randomization to last date known to be alive
No 
Subjects who died
Time from randomization to date of death
Yes
8.5.3
Analysis of Secondary Endpoints 
Secondary efficacy analyses will be performed on the FAS set and the PD-L1+ FAS.  Details will 
be provided in the trial SAP. 
Based on the hierarchical testing strategy described in Section 8.5.1, if the one-sided p-value from 
the stratified log-rank test of the primary endpoint OS is below 0.0100 and 0.0219 at the interim 
and the final analysis, respectively, the secondary endpoints will be tested with the specified order 
within the hierarchical testing procedure at the same nominal significance level as the primary 
endpoint (one-sided alpha of 0.0100 and 0.0219 at the interim and the final analysis, respectively) 
if, and only if, the preceding null hypothesis within the specified hierarchical order was rejected. 
For the secondary endpoint analysis of PFS time according to RECIST 1.1 and as adjudicated by 
the IERC, the statistical analysis will be the same as described for the primary analysis of OS time.
For the secondary endpoint analysis of BOR according to RECIST 1.1 and as adjudicated by the 
IERC, the ORR in terms of having a confirmed BOR of CR or PR will be calculated along with
corresponding two-sided exact Clopper-Pearson 95% CIs for the 2 treatment groups. The Cochran-
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Mantel-Haenszel test will be performed with the randomization strata taking into account to 
compare the ORR between the 2 treatment groups.
For PFS and BOR, the following sensitivity analyses will be performed to assess the robustness of 
the primary analysis results. These analyses are regarded as purely exploratory. 
1. PFS and BOR according to Investigator assessment will be analyzed
2. An unstratified analysis will be performed
3. For PFS, the frequencies of event types and reasons for censoring will be assessed by treatment 
arm
4. For PFS time, all deaths will be considered events based on IERC assessment and counting all 
PD and deaths as events without considering the censoring rule for PD or death as described 
in Table 8.1;
5. PFS based on IERC assessment and initiation of subsequent anticancer therapies will not be 
used as a censoring reason for PFS
8.5.4
Analysis of Exploratory Endpoints
 
 
 
 
 
 
 
 
 
 
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8.5.5
Safety Analyses
The extent of exposure to trial drugs (avelumab or docetaxel) will be characterized by duration 
(weeks), number of administrations, cumulative dose (mg/kg or mg/m2), dose intensity 
(mg/kg/week or mg/m2/week), relative dose intensity (actual dose given / planned dose), and 
number of dose delays.
Safety analyses will be performed on the Safety analysis set and the PD-L1+ Safety analysis set. 
The safety endpoints will be tabulated using descriptive statistics.
Safety assessments will be based on review of the incidence of AEs including AESIs, ADRs, and 
changes in vital signs, ECGs, body weight, and laboratory values (hematology and serum 
chemistry).
The on-treatment period is defined as the time from the first trial 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.
AEs
All AEs will be coded according to the MedDRA. Severity of AEs will be graded using the 
NCI-CTCAE v 4.03 toxicity grading scale. 
The incidence of TEAEs, regardless of attribution, and TEAEs defined as possibly related to trial
treatment will be summarized by Preferred Term and System Organ Class for each treatment arm, 
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and described in terms of intensity and relationship to trial treatment. Treatment-emergent AEs 
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.
All premature terminations will be summarized by primary reason for treatment discontinuation / 
withdrawal.
Laboratory variables 
Laboratory results will be classified by grade according to NCI-CTCAE.  Summaries of laboratory 
results by visit will be provided.  The worst on-treatment grades during the treatment period will 
be summarized.  Shifts in toxicity grading from Baseline to highest grade during the on-treatment 
period will be displayed.  Results for variables that are not part of NCI-CTCAE will be presented 
as below, within, or above normal limits.  Only subjects with post-Baseline laboratory values will 
be included in these analyses. Further details of analyses for all the laboratory parameters will be 
provided in the SAP.
Physical examination (including vital signs and 12-lead ECGs)
Physical examination data, including vital signs (body temperature, respiratory rate, heart rate, and 
blood pressure) and 12-lead ECGs recorded according to the Schedule of Assessments (Appendix 
I) will be presented. 
Further details of safety analyses will be provided in the SAP.
8.5.6
Subgroup Analyses
Subgroup analyses will be performed on the primary endpoint and secondary efficacy endpoints
with the subgroups, which will be specified in the SAP. Specifically, the subgroup analysis by 
PD-L1 status (positive versus negative expression in tumor cells) will be performed on the FAS
for the primary and secondary efficacy endpoints. The HR and its corresponding 95% CI will be 
computed per subgroup level. To assess the heterogeneity of treatment effects across the subgroup 
levels, a Cox regression model will be fitted with the event time as the dependent variable; 
subgroup, treatment, and with and without the treatment-by-subgroup interaction as explanatory 
variables. A p-value for the interaction test (Likelihood Ratio test) will be provided together with 
the HR and corresponding 95% CI of the interaction model parameter. For the secondary endpoint 
of BOR, analogous analyses will be performed using a logistic regression model.
All the subgroup analyses will be exploratory; no adjustment for multiplicity will be performed. 
In the case of a low number of subjects within a category (< 25 subjects, which is about 5% of the 
randomized PD-L1+ population), the categories will be pooled.
8.6
Interim Analysis
An IDMC will be formed and will be responsible for periodic evaluations of the trial as well as the 
evaluation of the interim and the final analysis. For this trial there will be 1 interim analysis that
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will be conducted after 75% of the events (deaths) in PD-L1+ subjects have been observed, that 
is, after 253 events have occurred.  The primary endpoint, OS, key secondary endpoints analysis 
including PFS and BOR, and safety analysis will be conducted in this interim analysis. The interim 
analysis of efficacy endpoints will be conducted on the FAS, with the primary analysis population 
being the PD-L1+ subset of the FAS. The IDMC will also be presented with subject disposition, 
subject background, Baseline disease and demographic information, along with safety information. 
Details of the IDMC mission, composition, and operations will be provided in the IDMC charter. 
An independent statistical provider will perform the interim analyses to support the IDMC. Results 
from the interim analyses will be transmitted from this group to the IDMC only and trial staff 
involved with the day to day management of the trial, as well as any Sponsor staff, will not have 
access to this interim information. 
After 253 events have been observed in the PD-L1+ subjects, the independent statistical group will 
prepare the outputs in agreement with the IDMC charter and transmit the analyses, tabulations,
and listings to the IDMC for the meeting.  The independent support IDMC statistician will be 
available at the IDMC meeting should any questions from the IDMC members arise regarding the 
data and / or analyses. 
The hierarchical testing strategy will be employed for the interim analysis. If the one-sided p-value 
from the stratified log-rank test of OS is below 0.0100, the treatment difference will be claimed as 
statistically significant and the secondary endpoints will be tested within the hierarchical testing 
strategy at the same nominal significance level.  If, at the time of this interim analysis, the OS of 
avelumab assigned subjects is shown to be superior to that of those randomized to the docetaxel 
group with a p-value of < 0.0100 the IDMC may declare superior efficacy in the avelumab
treatment arm compared with those randomized to receive docetaxel and recommend that the trial
be stopped early. This interim analysis of OS will be performed in a manner identical to the final 
efficacy analysis.
An IDMC charter will provide details about the conduct of the IDMC meeting and decision making 
rules.
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 USA FDA introduced a regulation (21 Code of Federal Regulations, 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 trial drug (named “covered trials” 
by the FDA), the Investigator and all sub-Investigators are obliged to disclose any financial interest 
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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.
 
 
 
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.
Where the information is provided by the Investigator, the ICF must be signed and personally 
dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing, and inspection purposes. A copy of the signed and dated information and 
ICF should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the Sponsor or designee and be submitted again to the IEC / IRB for 
review and favorable opinion. The agreed, revised information will be provided to each subject in 
the trial for signing and dating. The Investigator will explain the changes to the previous version.
9.3
Subject Identification and Privacy
A unique subject number will be assigned to each subject at inclusion by the IVRS system, 
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. 
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The subject’s original medical data that are reviewed at the site during source data verification by 
the Clinical Trial Monitor, audits, and Health Authority inspections will be kept strictly 
confidential.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the Sponsor or designee. The 
Emergency Medical Support card is based on the need to provide clinical trial subjects with a way 
of identifying themselves as participating in a clinical trial, and subsequently to give health care 
providers access to the information about this participation that may be needed to determine the 
course of the subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical trial.
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 or designee 
will provide 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.
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The trial must not start at a site before the Sponsor or designee has obtained written confirmation 
of favorable opinion / approval from the concerned IEC / IRB. The IEC / IRB will be asked to 
provide documentation of the date of the meeting at which the favorable opinion / approval was 
given, and of the members and voting members present at the meeting. Written evidence of 
favorable opinion / approval that clearly identifies the 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
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! Height
! Weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the trial)
! Tumor disease information
! Trial identification 
! 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 trial 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 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 
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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.
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 Clinical Trial 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 trial 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.
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial. Any publications and presentations of the results (abstracts in journals or 
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newspapers, oral presentations, etc), either in whole or in part, by Investigators or their 
representatives will require presubmission review by the Sponsor.
The Sponsor will not suppress or veto publications, but maintains the right to delay publication in
order to protect intellectual property rights.
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11
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12
Appendices
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Appendix I
Schedules of Assessments
Table 12.1
Avelumab Arm
Measure
Screening /
Baseline 
Assessments
Treatment Phasea
Discontinuation
(x) / End-of-
Treatment Visit
(X)
Safety 
Follow-up 
Visit
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Up to 7 / 28 Days 
(± 5 days) after 
Last Treatmentc,d
12 Weeks 
(± 2 weeks)  
after Last 
Treatment
Every 
3 monthsb
(± 1 week)  
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Written informed consent
X
PD-L1 tumor expression level / 
Tumor tissue (biopsy)e
X
Inclusion / exclusion criteria
X
Medical history / smoking historyf
X
Demographic data
X
HBV and HCV testing
X
Subject-reported outcomes / 
quality of life assessmentsg
X
X
X
X
X
6-weekly
x/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
Xh
X
X
X
X
X
X
X
2-weekly
x/X
X
Enrollment (if eligible)i
X
12-lead ECGj
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
2-weekly
X
Full serum chemistryl
X
X
X
X
6-weekly
x/X
Urinalysism
X
X
X
X
X
X
X
X
2-weekly
x/X
X
P-HCG pregnancy testn
X
X
X
X
X
4-weekly
- /X
X
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Measure
Screening /
Baseline 
Assessments
Treatment Phasea
Discontinuation
(x) / End-of-
Treatment Visit
(X)
Safety 
Follow-up 
Visit
Long-term 
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
V6
V7
Until 
Progression
Up to 7 / 28 Days 
(± 5 days) after 
Last Treatmentc,d
12 Weeks 
(± 2 weeks)  
after Last 
Treatment
Every 
3 monthsb
(± 1 week)  
W1
W3
W5
W7
W9
W11
W13
D1
D15
D29
D43
D57
D71
D85
Tumor evaluation / staging (CT 
Scan / MRI / other established 
methods)o,p
X
X
X
6 weekly up 
to 12 months 
then 
12 weeklyo,p
- /X
X
Documentation of AEs and 
concomitant medicationq
X
X
X
X
X
X
X
X
2-weekly
x/X
X
Xb
ACTH, ANA, ANCA, and RF 
X
As clinically indicated
T4 and TSH
X
X
X
6-weekly
- /X
X
Pretreatment and trial drug 
administrationr
X
X
X
X
X
X
X
2-weekly
ACTH=adrenocorticotropic hormone,
, ADR=adverse drug reaction; AE=adverse events, ALT=alanine aminotransferase, ANA=antinuclear antibody, 
ANCA=antineutrophil cytoplasmic antibody, AST=aspartate aminotransferase, P-HCG=P-human chorionic gonadotropin, BUN=blood urea nitrogen, CR= complete response, 
CT=computed tomography, D=Day, ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, HBV=hepatitis B virus, HCV=hepatitis C 
virus, ICF=Informed Consent Form, IV=intravenous, MRI=magnetic resonance imaging, NSCLC=non-small cell lung cancer; PD-L1=programmed death-ligand 1, 
, PR=partial response, RECIST=Response Evaluation Criteria in Solid Tumors version 1.1, RF=rheumatoid factor, T4=free thyroxine, TSH=thyroid-
stimulating hormone, V=visit, W=Week.
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.  Complete blood count and core chemistry 
samples must also be drawn and results reviewed within 48 hours prior to dose administration.
b
Subjects with an SAE ongoing at the Safety follow-up must be monitored and followed up by the Investigator until stabilization or until the outcome is known, unless the subject 
is documented as “lost to follow-up.”  Any SAE assessed as related to IMP must be reported whenever it occurs, irrespective of the time elapsed since the last administration of 
IMP.  Subjects without progressive disease at End-of-Treatment visit will be followed up for disease progression (CT / MRI scans every 6 weeks [± 5 days]) until 12 months 
after the first study drug administration, then every 12 weeks.  In addition, survival information (including assessment of any further anticancer therapy) will be collected 
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quarterly (that is, every 3 months ± 1 week).  The survival follow-up will continue until 5 years after the last subject receives the last dose of avelumab (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.
 
 
 
f
Medical history should include history of NSCLC, previous and ongoing medications, smoking history, and Baseline medical condition.
g
The subject-reported outcomes / quality of life questionnaires (EQ-5D, EORTC QLQ-C30, and module QLQ-LC13) should be completed using a validated electronic tablet or 
validated site pad by all subjects prior to any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, 
etc.
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 / End-of-Treatment visit.
k
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).
l
Full chemistry panel, which includes core serum chemistry, and other laboratory studies are detailed in Table 7.1.  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 each visit indicated prior to 
administration of trial drug.  If the basic urinalysis is abnormal, then a full urinalysis should be performed.
n
P-HCG should be determined from serum at Screening and from a urine or serum sample thereafter. Results of the most recent pregnancy test should be available prior to 
dosing of trial drug.
o
In general, the tumor visit time window is 5 days prior to the scheduled tumor assessment. 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 
4 weeks after the initial documentation of CR or PR. Confirmation of PR can be confirmed at an assessment later than the next assessment after the initial documentation of 
PR.  A CT scan or MRI should always be used (if MRI is used, CT of chest is mandatory in all countries except Germany, in which case a MRI of the chest is allowed).
p
A brain CT / MRI scan is required at Screening if not performed within 6 weeks prior to randomization, and beyond as clinically indicated.  A bone scan should be done as 
clinically indicated at Screening and beyond. Bone metastases detected at Screening need to be followed at the tumor evaluation visits.
q
Adverse events and concomitant medications will be documented at each trial visit. The AE reporting period for safety surveillance begins when the subject is initially included 
in the trial (date of first signature of informed consent) and continues through the trial’s End of Treatment visit, defined as 28 days (± 5 days) after last trial drug administration.  
After the End of Treatment visit only treatment related AEs have to be documented until the Safety Follow up visit, defined as 12 weeks (± 2 weeks) after the last trial treatment 
administration.
r
Subjects must receive pretreatment with H1 blockers and acetaminophen 30 to 60 minutes prior to infusion of avelumab (10 mg/kg IV over 1 hour). Premedication with an 
antihistamine and with paracetamol (acetaminophen) approximately 30 to 60 minutes prior to each dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine 
and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent).
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Appendix I
Schedule of Assessments 
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Appendix I
Schedule of Assessments 
Table 12.3
Docetaxel Arm
Measure
Screening /
Baseline 
Assessments
Treatment Phasea
Discontinuation (x) / 
End-of-Treatment 
Visit (X)
Safety 
Follow-up 
Visit
Long-term
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
Until 
Progression
Up to 7 / 28 Days 
(± 5 days) after Last 
Treatmentc,d
12 Weeks
(± 2 weeks)
after Last 
Treatment
Every  
3 monthsb
(± 1 week)  
W1
W4
W7
W10
W13
D1
D22
D43
D64
D85
Written informed consent
X
PD-L1 tumor expression level / 
Tumor tissue (biopsy)e
X
Inclusion / exclusion criteria
X
Medical history / smoking 
historyf
X
Demographic data
X
HBV and HCV testing
X
Subject-reported outcomes / 
quality of lifeg
X
X
X
X
X
6-weekly
x/X
Physical examination, including 
height at Screening
X
X
X
X
X
X
6-weekly
x/X
X
Vital signs
X
X
X
X
X
X
3-weekly
x/X
X
Weight
X
X
X
X
X
X
3-weekly
x/X
X
ECOG PS
Xh
X
X
X
X
X
3-weekly
x/X
X
Enrollment (if eligible)i
X
ECGj
X
x/X
Hematology and hemostaseology
X
X
X
X
X
X
3-weekly
x/X
X
Core serum chemistryk
X
X
3-weekly
X
Full serum chemistryl
X
X
X
X
6-weekly
x/X
Urinalysism
X
X
X
X
X
X
3-weekly
x/X
X
P-HCG pregnancy testn
X
X
X
X
X
X
3-weekly
- /X
X
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Measure
Screening /
Baseline 
Assessments
Treatment Phasea
Discontinuation (x) / 
End-of-Treatment 
Visit (X)
Safety 
Follow-up 
Visit
Long-term
Follow-upb
Day -28 to 
Randomization
V1
V2
V3
V4
V5
Until 
Progression
Up to 7 / 28 Days 
(± 5 days) after Last 
Treatmentc,d
12 Weeks
(± 2 weeks)
after Last 
Treatment
Every  
3 monthsb
(± 1 week)  
W1
W4
W7
W10
W13
D1
D22
D43
D64
D85
Tumor evaluation / staging (CT 
Scan / MRI / other established 
methods)o,p
X
X
X
6 weekly up 
to 
12 months 
then 
12 weeklyo,p
- /X
X
Documentation of AEs and 
concomitant medicationq
X
X
X
X
X
X
3-weekly
x/X
X
Xb
Pretreatment and trial drug 
administrationr
X
X
X
X
X
3-weekly
ACTH, ANA, ANCA, and RF 
X
As clinically indicated
T4 and TSHs
X
X
Week 25 
and as 
indicated
- /X
X
ACTH=adrenocorticotropic hormone, ADR=adverse drug reaction; AE=adverse events, ALT=alanine aminotransferase, ANA=antinuclear antibody, ANCA=antineutrophil 
cytoplasmic antibody, AST=aspartate aminotransferase, P-HCG=P-human chorionic gonadotropin, BUN=blood urea nitrogen, CR= complete response, CT=computed tomography, 
D=Day, ECG=electrocardiogram, ECOG PS=Eastern Cooperative Oncology Group Performance Status, HBV=hepatitis B virus, HCV=hepatitis C virus, ICF=Informed Consent 
Form, IV=intravenous, MRI=magnetic resonance imaging, NSCLC=non-small cell lung cancer; PD-L1=programmed death-ligand 1, PR=partial response, RECIST=Response 
Evaluation Criteria in Solid Tumors version 1.1, RF=rheumatoid factor, T4=free thyroxine, TSH=thyroid-stimulating hormone, V=visit, W=Week.
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.  Complete blood count and core chemistry 
samples must also be drawn and results reviewed within 48 hours prior to dose administration.
b
Subjects with an SAE ongoing at the Safety follow-up must be monitored and followed up by the Investigator until stabilization or until the outcome is known, unless the subject 
is documented as “lost to follow-up.”  Any SAE assessed as related to IMP must be reported whenever it occurs, irrespective of the time elapsed since the last administration of 
IMP.  Subjects without progressive disease at End-of-Treatment visit will be followed up for disease progression (CT / MRI scans every 6 weeks [± 5 days]) until 12 months 
after the first study drug administration, then every 12 weeks.  In addition, survival information (including assessment of any further anticancer therapy) will be collected 
quarterly (that is, every 3 months ± 1 week).  The survival follow-up will continue until 5 years after the last subject receives the last dose of avelumab (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.
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f
Medical history should include history of NSCLC, previous medications, smoking history, and Baseline medical condition.
g
The subject-reported outcomes / quality of life assessments (EQ-5D, EORTC QLQ-C30, and module QLQ-LC13) should be completed using a validated electronic tablet or 
validated site pad by all subjects prior to any of the other trial-related assessments being performed, that is, physical examinations, blood draws, trial treatment administration, 
etc.
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 / End-of-Treatment visit.
k
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). 
l
Full chemistry panel, which includes core serum chemistry, and other laboratory studies are detailed in Table 7.1.  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 each visit indicated prior to 
administration of trial drug.  If the basic urinalysis is abnormal, then a full urinalysis should be performed.
n
P-HCG should be determined from serum at Screening and from a urine or serum sample thereafter.  Results of the most recent pregnancy test should be available prior to next 
dosing of trial drug.
o
In general, the tumor visit time window is 5 days prior to the scheduled tumor assessment.  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 
4 weeks after the initial documentation of CR or PR.  Confirmation of PR can be confirmed at an assessment later than the next assessment after the initial documentation of 
PR.  A CT scan or MRI should always be used (if MRI is used, CT of chest is mandatory in all countries except Germany, in which case a MRI of the chest is allowed). 
p
A brain CT / MRI scan is required at Screening if not performed within 6 weeks prior to randomization, and beyond as clinically indicated.  A bone scan should be done as 
clinically indicated at Screening and beyond.  Bone metastases detected at Screening need to be followed at the tumor evaluation visits.
q
Adverse events and concomitant medications will be documented at each trial visit. The AE reporting period for safety surveillance begins when the subject is initially included 
in the trial (date of first signature of informed consent) and continues through the trial’s End of Treatment visit, defined as 28 days (± 5 days) after last trial drug administration.  
After the End of Treatment visit only treatment related AEs have to be documented until the Safety Follow up visit, defined as 12 weeks (± 2 weeks) after the last trial treatment 
administration.
r
Subjects will be administered dexamethasone 8 mg orally at 12, 3, and 1 hour(s) prior to each docetaxel infusion per docetaxel label instructions, or equivalent, per local 
institutional practice.  
s
Blood samples for T4 and TSH will be collected at the times indicated from all subjects.
 
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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 MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and Response 
Criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55. (38)
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Appendix III
Guidance on Contraception
Birth control methods considered as highly effective
Aligned with the Clinical Trials Facilitation Group (CTFG 2014) “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 Vasectomized 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.  Abstinence 
needs to be in line with the preferred and usual lifestyle of the subject.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
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Appendix IV Protocol Amendments and List of Changes
Previous Protocol Amendments
Amendment 
Number
Submission to 
Health Authority
(Yes/No/
Notification only)
Date
Region or Country
Included in the 
current document     
(Y/N)
Amendment 0.1
No
18 December 2014
Japan
No
Amendment 1
Yes
5 May 2015
Global
Yes
Amendment 2
Yes
10 July 2015
Global
Yes
Amendment 2.1
No
10 July 2015
Japan
No
Amendment 2.2
No
04 August 2015
Czech Republic
No
Amendment 2.3
No
04 August 2015
Japan
No
Amendment 2.4
No
06 November 2015
Korea
Yes
Amendment 3
Yes
15 November 2016
Global
Yes
Amendment 4
FDA only
29 November 2016
Global
Yes
The purpose of this amendment (Protocol Version 6.0, Amendment 5, 10 January 2017) is to:
! Correct an administrative error in Table 6.2 that suggested for cardiac myocarditis that 
hospitalization was only required in the presence of life-threatening cardiac decompensation
! Add language clarifying that quality of life questionnaires are completed on a validated 
electronic tablet or validated site pad
! Make minor administrative changes for consistency throughout the protocol
This amendment is considered as non-substantial as only administrative changes were made.
List of Changes
Main changes to the clinical trial protocol text are presented in the table below (updates in minor 
typographical/grammatical errors are not noted).  
Additions and amended text are shown in bold. If the original clinical trial protocol text was 
already bold, changes are shown in bold and underlined, deletions are marked using strike through.
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Comparison of Current version (Version 6.0) with Clinical Trial Protocol Version 5.0, Amendment 4, 29 November 
2016
Change
Section
Pages
Previous Wording
New Wording
Rationale
Added 
“approximately” 
to the number of 
PD-L1+ subjects 
Synopsis – Trial 
design and plan
5.1.1  Overall Design
15 
46
Approximately 750 subjects, among them 
522 PD-L1 assay positive subjects, ...
Approximately 750 subjects, among them 
approximately 522 PD-L1 assay positive 
subjects, ...
To provide some 
flexibility to avoid 
enrolling 
more 
subjects 
than 
necessary
Clarified that 
after 12 months 
from first 
administration, 
scans would be 
every 12 weeks
Synopsis – Trial 
design and plan
5.1.1  Overall Design
16 
47
Tumor 
measurements 
by 
computed 
tomography (CT) scan or magnetic 
resonance 
imaging 
(MRI) 
will 
be 
performed 
every 
6
weeks 
from 
randomization to determine response to 
treatment.  
Tumor 
measurements 
by 
computed 
tomography (CT) scan or magnetic 
resonance 
imaging 
(MRI) 
will 
be 
performed 
every 
6 
weeks 
from 
randomization 
until 
Week 
55 
(12 months) and then every 12 weeks 
thereafter
to determine response to 
treatment.  
For 
clarification 
and 
internal 
consistency
Added 
“approximately” 
to the number of 
PD-L1+ subjects
Synopsis – Planned 
number of subjects
17
Approximately 750
subjects will be 
randomized.  Accrual will proceed up to a 
target number of 522 PD-L1+ subjects.
Approximately 750
subjects will be 
randomized.  Accrual will proceed up to a 
target 
number 
of 
approximately
522 PD-L1+ subjects.
To provide some 
flexibility to avoid 
enrolling 
more 
subjects 
than 
necessary
Added statement 
that subjects will 
use an electronic 
tablet or site pad 
to complete 
subject-reported 
outcomes / 
quality of life 
questionnaires 
Synopsis – Schedule 
of visits and 
assessment
(Screening / Baseline 
assessments)
18
•  Subjects will complete subject-reported 
outcomes / quality of life questionnaires
•  Subjects With the use of a validated 
electronic tablet or validated site pad, 
subjects will complete subject-reported 
outcomes / quality of life questionnaires
To 
provide 
additional 
guidance 
and 
clarity
Clarified that 
after 12 months 
from first 
administration, 
scans would be 
Synopsis – Schedule 
of visits and 
assessments
(Treatment period) 
19
•  Tumor responses will be assessed every 
6 weeks from randomization (within 
5 days prior to the scheduled tumor 
assessment), per RECIST 1.1 while on 
trial.
•  Tumor responses will be assessed every 
6 weeks from randomization (within 
5 days prior to the scheduled tumor 
assessment), per RECIST 1.1 until 
Week 55 (12 months) and then every 
For 
clarification 
and 
internal 
consistency
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Change
Section
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Previous Wording
New Wording
Rationale
every 12 weeks
12 weeks thereafter while on trial.
Added statement 
that subjects will 
use an electronic 
tablet or site pad 
to complete 
subject-reported 
outcomes / 
quality of life 
questionnaires 
Synopsis – Schedule 
visits and 
assessments 
(Treatment period)
20
•  Subject-reported outcomes / quality of 
life questionnaires will be completed by 
the subject after randomization (before 
the first administration of the trial 
treatment) then prior to administration of 
trial treatment and before any trial-related 
procedures ...
•  Subject With the use of a validated 
electronic tablet or validated site pad, 
subject-reported outcomes / quality of 
life questionnaires will be completed by 
the subject after randomization (before 
the first administration of the trial 
treatment) then prior to administration of 
trial treatment and before any trial-related 
procedures ...
To 
provide 
additional 
guidance 
and 
clarity
Added statement 
that subjects will 
use an electronic 
tablet or site pad 
to complete 
subject-reported 
outcomes / 
quality of life 
questionnaires 
Synopsis – Schedule 
visits and assessment
(Follow-up phase)
21
During these two visits there will be a full 
assessment 
of 
safety 
parameters 
(including 
ECG 
at 
the 
Early 
Discontinuation 
/ 
End-of-Treatment 
visit), subject-reported outcomes / quality 
of 
life 
(Discontinuation 
/ 
End-of-Treatment visit),
 
(End-of-Treatment visit only) ...
During these two visits there will be a full 
assessment 
of 
safety 
parameters 
(including 
ECG 
at 
the 
Early 
Discontinuation / End-of-Treatment visit 
using a validated electronic tablet or 
validated site pad), subject-reported 
outcomes 
/ 
quality 
of 
life 
(Discontinuation 
/ 
End-of-Treatment 
visit), 
 (End-of-Treatment 
visit only) ...
To 
provide 
additional 
guidance 
and 
clarity
Added the word 
“approximately” 
to the number 
PD-L1+ subjects 
and total number 
of subjects
Synopsis – Statistical 
methods (includes 
sample size 
calculation)
30
A sample size of 522 PD-L1+ subjects is 
planned in order to observe 337 events 
(deaths) at the final analysis.  The total 
number of randomized subjects is 
expected to be 750 subjects, based on an 
estimated prevalence of approximately 
70% PD-L1+ subjects.  
A 
sample 
size 
of 
approximately
522 PD-L1+ subjects is planned in order 
to observe 337 events (deaths) at the final 
analysis.  The total number of randomized 
subjects is expected to be approximately 
750 subjects, based on an estimated 
prevalence 
of 
approximately 
70%
PD-L1+ subjects.  
To provide some 
flexibility to avoid 
enrolling 
more 
subjects 
than 
necessary
Made correction 
in management 
of Cardiac irAEs 
(Myocarditis)
6.5.4.4  Immune-
Related Adverse 
Events
71
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
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
Hospitalize 
In the presence of life threatening cardiac 
To correct error 
that suggested to 
hospitalize only in 
the presence of 
life-threatening 
cardiac 
decompensation
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Change
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Pages
Previous Wording
New Wording
Rationale
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management
Added statement 
that subjects will 
use an electronic 
tablet or site pad 
to complete 
subject-reported 
outcomes / 
quality of life 
questionnaires 
7.1.1  Screening and 
Baseline Procedures 
and Assessments
76
During Screening, subjects will undergo a 
physical 
examination, 
including 
recording body height and weight, vital 
signs, 12-lead ECG, and a determination 
of the ECOG PS (Appendix II).  
Subject-reported outcomes/ quality of life 
questionnaires.
During Screening, subjects will undergo a 
physical 
examination, 
including 
recording body height and weight, vital 
signs, 12-lead ECG, and a determination 
of the ECOG PS (Appendix II).  Subject
With the use of a validated electronic 
tablet or validated site pad, subjects 
will also complete subject-reported 
outcomes/ quality of life questionnaires.
To 
provide 
additional 
guidance 
and 
clarity
Added statement 
that subjects will 
use an electronic 
tablet or site pad 
to complete 
subject-reported 
outcomes / 
quality of life 
questionnaires 
7.1.2  Treatment 
Period
78
•  Subject-reported outcomes/ quality of 
life questionnaires will be completed by 
the subject after randomization (before 
the first administration of the trial 
treatment) then prior to administration of 
trial treatment and before any trial-related 
procedures 
(including 
collection 
of 
biological samples) at ...
•  Subject With the use of a validated 
electronic tablet or validated site pad, 
subject-reported outcomes/ quality of life 
questionnaires will be completed by the 
subject after randomization (before the 
first administration of the trial treatment) 
then prior to administration of trial 
treatment and before any trial-related 
procedures 
(including 
collection 
of 
biological samples) at ...
To 
provide 
additional 
guidance 
and 
clarity
Added statement 
that subjects will 
use an electronic 
tablet or site pad 
to complete 
subject-reported 
outcomes / 
quality of life 
questionnaires 
7.1.3  End-of-
Treatment –
Discontinuation visit
End-of-Treatment 
visit
79 
80
•  Subject-reported outcomes / quality of 
life questionnaires will be completed 
•  Subject-reported outcomes / quality of 
life questionnaires will be completed
with the use of a validated electronic 
tablet or validated site pad
To 
provide 
additional 
guidance 
and 
clarity
Added statement
that subjects will 
use an electronic 
tablet or site pad 
to complete 
7.7.1  Subject-
Reported Outcomes / 
Quality of Life
96
The subject-reported outcomes / quality 
of 
life 
questionnaires 
should 
be 
completed by the subject prior to any of 
the other trial-related assessments being 
performed, that is, physical examinations, 
The subject-reported outcomes / quality 
of 
life 
questionnaires 
should 
be 
completed by the subject prior to any of 
the other trial-related assessments being 
performed, that is, physical examinations, 
To 
provide 
additional 
guidance 
and 
clarity
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Change
Section
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Previous Wording
New Wording
Rationale
subject-reported 
outcomes / 
quality of life 
questionnaires 
blood 
draws, 
trial 
treatment 
administration, etc.  Subjects may use a 
site pad to record their responses to these 
questionnaires.
blood 
draws, 
trial 
treatment 
administration, etc.  Subjects may use a
will use a validated electronic tablet or
validated
site pad to record their 
responses to these questionnaires.  In 
rare and extenuating circumstances 
when a validated electronic tablet or 
validated site pad is not available or not 
working 
properly, 
collection 
on 
validated paper questionnaires may be 
allowed to ensure data are collected 
and not lost.
Added 
“approximately” 
to the number of 
PD-L1+ subjects
8.1  Sample Size
97
A sample size of 522 PD-L1+ subjects is 
planned in order to observe 337 events 
(deaths) at the final analysis.  Calculations 
were performed using ADDPLAN V
6.01, Aptiv Solutions.  The 75% interim 
analysis will be performed when 253 
events have been observed.  An IDMC 
(see Section 2.3.1) will be convened to 
perform the evaluation at the interim 
analysis in order to safeguard the 
Sponsor’s personnel from unblinded trial 
results.
A 
sample 
size 
of 
approximately
522 PD-L1+ subjects is planned in order 
to observe 337 events (deaths) at the final 
analysis.  Calculations were performed 
using 
ADDPLAN 
V
6.01, 
Aptiv 
Solutions.  The 75% interim analysis will 
be performed when 253 events have been 
observed.  An IDMC (see Section 2.3.1) 
will be convened to perform the 
evaluation at the interim analysis in order 
to safeguard the Sponsor’s personnel 
from unblinded trial results.
To provide some 
flexibility to 
avoid enrolling 
more subjects 
than necessary
Added statement 
that subjects will 
use an electronic 
tablet or site pad 
to complete 
subject-reported 
outcomes / 
quality of life 
questionnaires
Appendix 1 –
Table 12.1, 
footnote “g”
Appendix 1 –
Table 12.3, 
footnote “g”
120
125
g  The subject-reported outcomes / quality 
of life assessments (EQ-5D, EORTC 
QLQ-C30, and module QLQ-LC13) 
should be completed by all subjects prior 
to 
any 
of 
the 
other 
trial-related 
assessments being performed, that is, 
physical examinations, blood draws, trial 
treatment administration, etc.
g  The subject-reported outcomes / quality 
of life assessments (EQ-5D, EORTC 
QLQ-C30, and module QLQ-LC13) 
should be completed using a validated 
electronic tablet or validated site pad
by all subjects prior to any of the other 
trial-related 
assessments 
being 
performed, that is, physical examinations, 
blood 
draws, 
trial 
treatment 
administration, etc.
To 
provide 
additional 
guidance 
and 
clarity
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Correction to Table 6.2
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
Hospitalize.
In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility experienced 
in advanced heart failure and 
arrhythmia management.
Cardiology consult to establish 
etiology and rule out immune-
mediated myocarditis.
Guideline based supportive 
treatment as per cardiology 
consult.a
Consider myocardial biopsy if 
recommended per cardiology 
consult.
If symptoms improve and immune-mediated 
etiology is ruled out, re-start avelumab therapy.
If symptoms do not improve/worsen, viral 
myocarditis is excluded, and immune-mediated 
etiology is suspected or confirmed following 
cardiology consult, manage as immune-mediated 
myocarditis.
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Appendix V
Signature Pages and Responsible Persons for the Trial
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Signature Page – Principal Investigator
Title
A Phase III open-label, multicenter trial of avelumab
(MSB0010718C) versus docetaxel in subjects with 
non-small cell lung cancer that has progressed after 
a platinum-containing doublet
IND Number
IND 
EudraCT Number
2014-005060-15
Clinical Trial Protocol Date / Version
10 January 2017 / Version 6.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council for Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials to 
obtain and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such information 
solely for the purpose of complying with the regulatory requirements. I therefore agree to supply 
the Sponsor with any necessary information regarding ownership interest and financial ties 
including those of my spouse and dependent children, and to provide updates as necessary to meet 
Health Authority requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
Fax number:
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Further Sponsor Responsible Persons
Name, academic degree
Function
Senior Expert Statistician, 
Institution
Merck KGaA
Address
Frankfurter Str. 250 
64293 Darmstadt, Germany
Telephone number
Fax number
E-mail address
Name, academic degree
Function
Institution
EMD Serono Research & Development Institute, Inc.
Address
One Technology Place, Rockland, MA 02370, USA
Telephone number
Fax number
E-mail address
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