Clinical trial NCT02603419
Conditions: Hodgkins Lymphoma
Keywords: classical Hodgkins Lymphoma (relapsed/refractory) post-allogeneic HSCT anti PD-L1 Phase 1 PK Receptor occupancy Immunophenotypic biomarkers
Sponsor: Pfizer
Start date: 2016-03-10; Completion date: 2019-04-11
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1b, open-label, multi-center study comprising a lead-in phase and an expansion phase. The lead-in phase is a multiple-dose, randomized, parallel-arm, pharmacokinetic and pharmacodynamic study of avelumab as a single agent in adult patients with cHL. Patients enrolled in the lead-in phase of this study are required to have relapsed following a prior autologous or allogeneic HSCT, or to be ineligible for HSCT. Based on the preliminary TO, safety, and efficacy results from the lead-in phase, the expansion phase will evaluate the anti-tumor activity and safety of single-agent avelumab utilizing an intra-patient dose escalation paradigm based on two of the dosing regimens studied in the lead-in phase in 40 cHL patients in whom an allogeneic HSCT has failed.

Detailed description:

Arms: arm 1: X1 mg IV every 2 weeks arm 2: X2 mg IV every 2 weeks arm 3: X3 mg IV every 3 weeks arm 4: X4 mg IV every 2 weeks arm 5: X5 mg IV every 2 weeks arm 6: X1 mg IV every 2 weeks followed by X1 or X4 mg every 2 weeks
Interventions: intervention 1: Avelumab intervention 2: Avelumab intervention 3: Avelumab intervention 4: Avelumab intervention 5: Avelumab intervention 6: Avelumab
Intervention descriptions: intervention 1: Anti-PD-L1 antibody at X1 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression. intervention 2: Anti-PD-L1 antibody at X2 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression. intervention 3: Anti-PD-L1 antibody at X3 mg IV every 3 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression intervention 4: Anti-PD-L1 antibody at X3 mg IV every 2 weeks to optimize dosing for expansion. Treatment with avelumab will continue until disease progression intervention 5: Anti-PD-L1 antibody at X mg IV every 2 weeks. Treatment with avelumab will continue until disease progression intervention 6: Anti-PD-L1 antibody at X1 mg IV every 2 weeks which can be escalated to X4 mg every 2 weeks based on safety and efficacy. Treatment with avelumab will continue until disease progression.

Protocol documents:
Prot_000.pdf: 
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A PHASE 1 PHARMACOKINETIC−PHARMACODYNAMIC STUDY OF 
AVELUMAB (MSB0010718C) IN PATIENTS WITH PREVIOUSLY TREATED 
ADVANCED STAGE CLASSICAL HODGKIN’S LYMPHOMA
JAVELIN HODGKIN’S
Compound:
MSB0010718C
Compound Name:
Avelumab
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2015-002636-41
Protocol Number:
B9991007
Phase:
1
CCI


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Document History
Document
Version Date
Summary of Changes
Protocol Amendment 4
13 November 
2017

Added Section 3.1.3, Safety Stopping 
Rules, in Section 3, Study Design.

Added Section 9.4.1, Safety Stopping 
Rules, in Section 9.4, Safety 
Analysis.
Protocol Amendment 3
09 May 2017
Major changes to the expansion phase:

Target population: only patients 
relapsing following a prior allogeneic
hematopoietic stem cell transplant
(HSCT) will be enrolled in the study, 
given the high response rate observed 
in the lead-in phase and the lack of 
licensed therapy for this subset of 
patients.

Biopsy: introduction of baseline and 
on-treatment mandatory biopsies to 
ensure availability of tumor material,
to assess pharmacodynamic effects, 
mechanism of action and patient 
stratification related to response.

Criteria of disease response: change
from Response Criteria for Malignant 
Lymphoma (Cheson et al., 2007) to 
Lugano Classification (Cheson et al., 
2014) to reflect change in current 
clinical practice.

Study Design: introduction of an 
intra-patient dose escalation design as 
described below.
The Protocol Summary was extensively
modified to reflect changes introduced 
throughout the protocol.
In the Schedules of Activities for the 2-week 
and 3-week cycles in the lead-in phase the 
following changes were implemented:

Footnote 2: Follow-up after last dose 


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was modified to indicate that conduct 
of safety assessments would be 
discontinued in the event of start of 
new anti-cancer therapy for 
consistency with other avelumab 
protocols. 

Footnote 8: Contraception Check was 
added at the Day 30 Follow-up Visit 
to align to standard language from 
avelumab IBv7.

Footnote 10: Blood chemistry, text 
was added to clarify Day 7 
requirements, for consistency to the 
table.

Footnote 12: Pregnancy Test was 
added at the Day 30 Follow-up Visit 
to align to standard language from
avelumab IBv7.

Footnote 13: Urinalysis: the request 
for 24-hour urine collection was 
removed for consistency with other 
avelumab protocols. 

Footnote 14: 12-Lead ECG: text was 
modified for clarity.

Footnote 15: Tumor assessment was 
modified to more accurately reflect 
the assessment schedule as outlined 
in the Response Criteria for 
Malignant Lymphoma clinical 
guidelines (Cheson et al., 2007). 

Footnote 18: Randomization, text 
was deleted to align to the new study 
design.
A new Schedules of Activities table and 
companion footnotes were added to outline 
the updated plans for the expansion phase.
In the Pharmacokinetic and 
Pharmacodynamic Sampling Schedules for 
2-week cycles and 3-week cycles in the 


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lead-in phase, the following changes were 
implemented:

Footnote 1 was modified to clarify 
that PK samples need to be collected 
up to cycle 20. 

Footnote 3 was modified to clarify 
the conditions for and timing of 
biopsies, as well as management of 
biopsy samples.

Footnote 4 was modified to clarify 
that Anti-Avelumab 
Antibodies/Neutralizing Antibodies
need to be collected up to cycle 20
and at the End of Treatment. 
A new Pharmacokinetic and 
Pharmacodynamic Sampling Schedule table 
and companion footnotes were added to 
outline the updated plans for the expansion 
phase. 
In Section 1, Introduction, the description of 
the target population of the study was
changed to reflect change in the expansion
phase design.  Furthermore a paragraph to 
describe the role of allogeneic stem cell 
transplant in Hodgkin’s Lymphoma was
added.
In Section 1.3.1, Avelumab 
(MSB0010718C), avelumab safety summary 
information were updated to align to 
standard language from avelumab IBv7.  
Table 1 and 2 were deleted.
In Section 1.4, Rationale for Studying 
Avelumab in Hodgkin’s Lymphoma 
information approval status and response 
data for pembrolizumab and nivolumab were 
updated in line with the current prescribing 
information. In addition updated information 


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from the nivolumab Checkmate 205 and 
039 studies in Hodgkin’s Lymphoma, a new 
paragraph describing results from a phase 
1/1b study with ipilimumab in patients 
relapsing after allogeneic hematopoietic stem 
cell transplant (HSCT) and updated 
information on one study on nivolumab in 
patients with Hodgkin’s Lymphoma
relapsing after allogeneic HSCT were
introduced. 
In Section 1.5.1, Avelumab Dosing 
Regimens the title was changed to Lead-in 
Phase.  In addition Table 3 was renumbered 
as Table 1.
Section 1.5.2, Preliminary Results of the 
Lead-in Phase, 1.5.3 Rationale for the 
Exploration of Fixed Dosing vs Body 
Weight-Based Dosing and 1.5.4 Rationale 
for the Dose regimens in the Expansion 
Phase were added.  Table 2 was also added.
In Section 2, Study Objectives and 
Endpoints, the objectives and endpoints were 
updated and detailed in separate lead-in and
expansion phase sections.
In Section 2.2 Endpoints (Lead-in Phase), 
Disease Control was added as a secondary 
endpoint; 
In Section 3.1, Study Overview, in Section 
3.1.1, Study Phases and in Section 3.1.2,
Criteria for Intra-Patient Dose Escalation text 
was modified to reflect the fact the lead-in 
phase completed enrollment, the study 
design for the expansion phase was modified 
from the evaluation of three dose regimens 
identified in the lead-in phase in both 
post-autologous HSCT patients and 
post-allogeneic HSCT patients to evaluation 
of an intra-patient dose-escalation regimen in 
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post-allogenic HSCT patients (up to 40 in 
total) only.
In Section 3.1, Study Overview, text 
referring to maximum number of cycles was 
deleted as there is no specified duration of 
patient treatment. 
In Section 3.1.1. Table 4 was renumbered as 
Table 3.
In Section 4.1, Inclusion criteria, the 
following changes were implemented:

Inclusion criterion 1 was modified to 
indicate that enrollment into the 
expansion phase is restricted to 
patients with a prior allogeneic HSCT
with a donor chimerism >20%.

Inclusion criterion 3 was modified to 
indicate response assessment criteria 
to be used in the lead-in and 
expansion phases.

Inclusion criterion 8 was modified to 
clarify biopsy requirements for the 
expansion phase.

Inclusion criterion 13, the 
requirement for two contraception 
methods was updated from 60 days 
after the last dose to 30 days after the 
last dose to align to standard 
language from avelumab IBv7.

Multiple additional minor changes 
were introduced for clarity and to 
align language with the avelumab 
program standards. 
In Section 4.2, Exclusion criteria, the 
following changes were implemented:

Exclusion criterion 1, text was 
modified to provide improved 
guidance for the selection of patients 


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with prior allogeneic HSCT, 
especially with respect to current 
immunosuppressive therapy, prior 
and current Graft Versus Host 
Disease (GVHD) and timing from 
prior Donor Lymphocyte Infusion 
(DLI).

Exclusion criterion 2, text was added 
to clarify patient eligibility guidance 
with respect to prior anti-PD-1 or 
anti-PD-L1 therapy in the expansion 
phase. 

Exclusion criterion 16, the 
requirement for two contraception 
methods was updated from 60 days 
after the last dose to 30 days after the 
last dose to align to standard 
language from avelumab IBv7.

Multiple additional minor changes 
were introduced to align language
with the avelumab program 
standards. 
In Section 4.3.1, Contraception, the 
requirement of contraception methods to be 
used was updated from 60 days after the last 
dose to 30 days after the last dose to align to 
standard language from avelumab IBv7.
In Section 5.1, Allocation to Treatment, text 
was added to describe the use of Interactive 
Response Technology system in the 
expansion phase. 
In Section 5.4.1, Avelumab, text was added 
to describe the use of prophylactic steroids 
and to refer to appropriate section of dose 
modification due to irAEs and GVHD.  In 
addition text was modified to allow
avelumab dose reductions.
In Section 5.4.1, Avelumab, text relative to 


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the time windows permitted for infusions and 
text relative to the design of the lead in phase 
was deleted because redundant.
In Section 5.4.1.1, Treatment After Initial 
Evidence of Disease Progression, text was 
modified to align to Pfizer standard text. 
In Section 5.4.1.2, Treatment After Complete 
Response, text was modified to clarify 
treatment for patients achieving CR.
In Section 5.4.3, Recommended Dose 
Modifications, text was modified to allow 
avelumab dose reductions.
In Section 5.4.3.2, Avelumab Infusion 
Omissions for Drug Related Toxicity, Table
5 was renumbered as Table 4. In Table 4, 
Hypersensitivity Reactions section was 
removed for consistency to other part of the 
protocol and in Other non-hematologic 
toxicities and laboratory abnormalities, text 
in Grade 2 and Grade 3 sections was updated 
for consistency with other protocol sections. 
In Section 5.4.4, Special Precautions for 
Avelumab Administration, text referring to
the prophylactic use of steroids was added.
In addition text describing allergic reactions
was deleted to align to avelumab standard.
In Section 5.4.4.1, Management of 
Avelumab Infusion Related Reactions Table 
6 was renumbered as Table 5.  In Table 5, 
Modification for Symptoms of 
Infusion-related Reactions Caused By 
Avelumab, text was modified to align to 
standard language from avelumab IBv7 and 
additional text was added to detail 
management of infusion-related reactions 
(IRRs), including the use of corticosteroids 
for both IRR treatment and prophylaxis.
In Section 5.4.4.1, Management of 
Avelumab Infusion-Related Reactions, text 


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limiting total infusion time to ≤120 minutes 
was removed for consistency with avelumab 
program guidelines.
In Section 5.4.4.2, Management of 
Avelumab Related Tumor Lysis Syndrome,
Figure 1 was renumbered as Figure 3.
Section 5.3.4.2 Management of Avelumab 
related Severe Hypersensitivity Reactions 
and Flu like Symptoms was deleted to align 
to avelumab standard language.
In Section 5.4.4.3, Management of 
Avelumab Immune-Related Adverse Events, 
Table 7 was renumbered as Table 6.  In 
Table 6, Management of Avelumab 
Immune-Related Adverse Events text was 
modified to align to standard language from
avelumab IBv7.
In Section 5.4.4.4, Management of Acute or 
Chronic Graft-versus-Host-Disease, text 
describing the management of patients 
developing GVHD during the expansion 
phase was added.
In Section 5.4.5, Dose Reduction, text was 
modified to allow avelumab dose reduction.
Section 5.7.2, Concomitant Surgery was 
updated to clarify timing of major surgery 
and interventional procedures respect to 
avelumab therapy. 
In Section 5.7.4, Other Prohibited 
Concomitant Medications and Therapies, 
Clarification about Steroid Use, “short term 
treatment of irAEs” was removed to align 
with Table 6; text describing prophylactic 
use of steroids was also added.
In Section 7.1.1 Pregnancy Testing, language 
was updated to align with the Schedule of 
Activities.
In Section 7.1.3, Laboratory Safety 


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Assessment, Table 8 was renumbered as 
Table 7.  Table 7, Required Laboratory 
Tests, was updated to remove 24 hour urine 
collection and Erythrocyte Sedimentation 
Rate to align to avelumab standards;
clarifications for hepatitis tests were also 
added.
Section 7.4, Biomarker and 
Pharmacodynamic Assessments was 
extensively modified to clarify guidance on 
biopsy collection and management, to 
specify new biomarker assays included in the 
expansion phase, and to present in summary 
form the biomarker analyses planned for the 
lead-in and expansion phases of the study.  
In addition Table 9 was renumbered as 
Table 8 and Table 8, Biomarker Collection 
and Analysis, was updated to reflect changes
in Biomarker Assessment.
Section 7.5, Disease Response Assessment 
was extensively modified to clarify 
assessment schedules and response 
determination criteria for the lead-in and 
expansion phases of the study.  Furthermore,
the requirement for confirmation of response 
was deleted in accordance with the Response 
Criteria for Malignant Lymphoma (Cheson 
et al., 2007) and with the Lugano 
Classification (Cheson et al., 2014).
Section 7.5.1, Blinded Independent Central 
Review for Disease Assessment (Expansion 
phase), was added to indicate requirement 
for central review for disease assessment in 
the expansion phase.
In Section 7.6.1, Markers of Drug Response, 
the last paragraph was deleted as it conflicted 
with prior text in this section and text was 
added to reflect the new requirements for the 
updated study design of the expansion phase.
Section 9.1, Analysis Sets, was updated for 
correctness.


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Section 9.2.1, Sample Size Determination 
was updated to reflect that the lead-in phase
completed enrollment and to address changes 
in the study design of the expansion phase.
Table 9, Sample Size and Exact 95% CIs for 
ORR - Post-allogeneic HSCT cohort was 
added.
Section 9.2.2, Efficacy Analysis was updated 
to reflect the new study design of the 
expansion phase.
In Section 16, References, bibliographical 
information on Investigator’s Brochure for 
avelumab was updated, full bibliographical 
information was added for KEYTRUDA 
USPI, Sarina et al. 2010, Cheson et al. 2007, 
Cheson et al. 2014, Barrington et al. 2014, 
Davids MS et al. 2016, Sala E et al. 2014, 
Timmerman J et al 2016, BAVENCIO USPI, 
Wang et al. 2009, Gangadhar et al. 2015, 
Zhao et al. 2016 and Yared et al. 2016.
Appendix 1 was modified to update 
abbreviations.
Appendix 2, the title was modified to 
indicate that Appendix 2 is to be used for the
tumor assessment in the lead-in phase. 
Appendix 3 was added given that Lugano 
Classification (Cheson et al., 2014) response 
criteria are to be used for tumor assessment 
in the expansion phase. 
Appendix 6 was added to detail all the 
possible treatments for IRR.
Other minor typographical errors have been 
fixed throughout the protocol for further 
clarification.
Protocol Amendment 2
15 JULY 2016
The following are changes to the protocol:
In the Schedule of Assessments, Section 8.2, 


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the time period for reporting of AEs (serious 
and non-serious) has been extended from 
30 to 90 calendar days.
In the Schedule of Activities table, Section 
7.1.3, and Table 8, urine albumin test, ANA, 
ANCA and RF assessments have been 
removed.
In the footnotes of the Schedule of Activities 
table, the 48-hour (Day 3) post-dose PK 
sample has been removed.
In the footnotes of the Schedule of Activities 
table for the 3-week dosing, 3 time points (ie, 
Cycle 3 Day 1, Cycle 3 Day 7, and Cycle 3 
Day 14) were removed to reflect the blood 
chemistry assessments being performed 
weekly in the first 6 weeks of treatment.
In the footnotes of the Schedule of Activities, 
Inclusion Criterion 12, and Section 7.1.1, 
“urine or serum” was added for the 
Pregnancy Test. 
Section 1.4 has been modified to include: 1) 
new data regarding the use of PD-1/PD-L1 
inhibitors in the cHL population and 2) risk 
language for GVHD in the post-allo-HSCT
setting. 
In Section 4.1, Inclusion Criterion 1 has been 
modified to provide additional clarity on the 
patient population being studied.
In Section 4.1, Inclusion Criterion 7 has been 
modified to include CSF and/or transfusion 
support for adequate bone marrow 
functioning.
In Section 4.1, Inclusion Criterion 9 has been
modified to include a lower estimated 
creatinine clearance of 30 mL/min in 
keeping with avelumab program standard.
In Section 4.1, Inclusion Criterion 14 has 
been modified to include clarification 
regarding the exclusion of adult individuals 


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who lack the capacity to provide informed 
consent.
In Section 4.2, Exclusion Criterion 1 has 
been modified to allow patients with prior 
allo-HSCT in both the lead in and expansion 
phases of the study. 
In Section 4.2, Exclusion Criterion 1 has 
been modified to add additional criteria for 
patients who had prior allo-HSCT that are at 
higher risk for GVHD.
In Section 4.2, Exclusion Criterion 3 has 
been modified to remove the statement 
“Systemic anti-cancer therapy 2 weeks of 
study entry”.
In Section 4.2, Exclusion Criterion 9 has 
been modified to remove the statement “any 
history of anaphylaxis, or uncontrolled 
asthma (that is, 3 or more features of 
partially controlled asthma)”.
In Section 4.2, Exclusion Criterion 11 has 
been modified for further clarification adding 
the statement “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”.
In Section 4.2, Exclusion Criterion 12 has 
been modified to remove “deep vein 
thrombosis”.
In Section 4.2., Exclusion Criterion 18 has 
been removed.
In Section 4.2., Exclusion Criterion 19 has 
been modified to remove “(for example, 
inactivated influenza vaccines)”.
In Section 4.3.1, The duration of 
contraception for sexually active male
patients was changed from 28 to 60 days 


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after the last dose.
In Section 5.4.1, the statement regarding 
weight loss or gain of >10% was removed 
since the dose (10 mg/kg) will be calculated 
for each visit for patients randomized to 
Cohort E. 
In Section 5.4.3.2, Table 5 has been modified 
to allow patients with Grade 2 hematologic 
abnormalities continue with dosing and 
Grade 3 hematologic abnormalities hold 
treatment until resolution to Grade 1 or 
baseline.
In Section 5.4.3.2, Table 5 has been modified 
to remove the statement “Upon the second 
occurrence of the same Grade 2 toxicity 
(except for hormone deficiencies that can be 
managed by replacement therapy), the 
treatment must be permanently discontinued” 
under Grade 2 “Other Non-hematologic 
toxicities”.
Section 5.4.4.1, Table 6 has been modified to 
remove “The total infusion time for 
avelumab should not exceed 120 minutes”
Section 5.4.4.5 “Management of Acute or 
Chronic Graft versus Host Disease” has been 
added to the protocol. 
Section 5.7.1 has been modified to allow the 
use of Hematopoietic Growth Factors 
throughout the study.In Section 7.1.2, 
reference to “including baseline signs and 
symptoms” was removed.
In Section 7.6.1, additional sample times for 
banked blood biospecimens were included to 
make consistent with the Schedule of 
Assessments.
In Section 8.13, “legally acceptable 


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representative” was removed.
Section 12.2, an updated reference is 
included for the Declaration of Helsinki.
Section 16 “References” includes new 
literature supporting the investigation in cHL 
and the risk of GVHD.
Appendix 3 “1994 Consensus Conference on 
Acute GVHD Grading” was added.
Appendix 4 “National Institutes of Health 
Consensus Development Project on Criteria 
for Clinical Trials in Chronic 
Graft-versus-Host Disease” was added.
Protocol Amendment 1 
– Reissue
24 
NOVEMBER 
2015
The following are changes to the protocol
On the title page, an extra “0” is removed 
from the drug name in the title of the 
protocol.
The Schedule of Assessments was modified 
to remove the window for the End of 
Treatment/Withdrawal visit. 
The Schedule of Assessments includes a 
Physical Examination assessment at Day 1 of 
Cycle 1. 
The Schedule of Assessments includes a 
modification of the Thyroid function Tests 
and ACTH to include sampling at Day 1 of 
Cycles 3 and 6 and every 6 weeks thereafter.
The Schedule of Assessments includes a 
clarification with the Tumor Assessments to 
include every 6 weeks until Week 12, then 
every 12 weeks.
The Schedule of Assessments includes a 
modification with the Hematology and 
Coagulation to include assessments weekly 
through Cycles 1 and 2, and then at Day 1 of 
every cycle throughout the duration of the 
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“All patients” is removed from the 
Pregnancy Test footnote of the Schedule of 
Assessments.
In the Schedule of Assessments, appropriate 
reference to “Table 8” is included in 
Hematology and Coagulation and Blood 
Chemistry footnotes.
The Schedule of Assessments for the De 
Novo Tumor biopsy assessment in the 
PK/PD Sampling Schedule was revised to 
make consistent with the footnotes for both 
the 2-week and 3-week cycles. 
Reference to footnote 5 in the Schedule of 
Assessments for the Anti-Avelumab 
Antibodies and Neutralizing Antibodies in 
the in the PK/PD Sampling Schedule was 
removed for the End of Treatment / 
Withdrawal sample. 
In Section 5.5, replaced reference to dosage 
and administration instructions with 
Investigational Product Manual.
In Table 8, added Erythrocyte Sedimentation 
Rate to the Hematology assessments.
 
 
In the References Section, correction of the 
date for Reference #15.
Protocol Amendment 1
30 OCTOBER 
2015
The following are changes to the original 
Protocol:
The primary endpoint was revised to include 
CD14+ monocytes and is reflected in the 
Protocol Summary, Protocol Sections 2.2, 
7.4 and Table 9.
The dosing cohorts and dosing cohort names 
were revised to make consistent with Table 4 
throughout the Protocol including the 
Protocol Summary, Protocol Sections 1.5.1, 
3.1 and Table 3. 
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The Schedule of Assessments for Banked 
Blood Biospecimen was revised to include a 
sample at Day 1 of Cycle 3 for 2 week cycles 
and Day 7 of Cycle 2 for 3 week cycles. 
The timing of assessments for Immune Cell 
Phenotyping, 
 
 
 
 
. 
The Schedule of Assessments for the De 
Novo Tumor biopsy assessment was revised 
to include clarification for the sample 
collection in the footnotes of the PK/PD 
Sampling Schedule for both the 2 week and 3 
week cycles and in Protocol Section 7.4. 
The ECG on Day 1 of cycles greater than or 
equal to 3 was removed from the Schedule of 
Activities tables.
Original protocol
20 JULY 2015
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................22
LIST OF FIGURES .................................................................................................................23
APPENDICES .........................................................................................................................23
PROTOCOL SUMMARY.......................................................................................................24
SCHEDULE OF ACTIVITIES................................................................................................35
1. INTRODUCTION ...............................................................................................................54
1.1. Mechanism of Action/Indication.............................................................................54
1.2. Background and Rationale ......................................................................................54
1.3. Pharmaceutical and Therapeutic Background.........................................................56
1.3.1. Avelumab (MSB0010718C).......................................................................56
1.4. Rationale for Studying Avelumab in Hodgkin’s Lymphoma .................................59
1.5. Rationale for Avelumab Starting Dose ...................................................................62
1.5.1. Lead-In Phase .............................................................................................62
1.5.2. Preliminary Results of the Lead-in Phase...................................................63
1.5.3. Rationale for the Exploration of Fixed Dosing vs Body Weight-
Based Dosing ...................................................................................................65
1.5.4. Rationale for the Dosing Regimens in the Expansion Phase......................66
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................67
2.1. Objectives (Lead-in Phase) .....................................................................................67
2.2. Endpoints (Lead-in Phase) ......................................................................................68
2.3. Objectives (Expansion Phase).................................................................................69
2.4. Endpoints (Expansion Phase)..................................................................................70
3. STUDY DESIGN.................................................................................................................71
3.1. Study Overview.......................................................................................................71
3.1.1. Study Phases ...............................................................................................73
3.1.2. Criteria for Intra-Patient Dose Escalation...................................................74
3.1.3. Safety Stopping Rules.................................................................................74
4. PATIENT SELECTION......................................................................................................75
4.1. Inclusion Criteria.....................................................................................................75
4.2. Exclusion Criteria....................................................................................................77
4.3. Lifestyle Guidelines ................................................................................................80


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4.3.1. Contraception..............................................................................................80
4.4. Sponsor’s Qualified Medical Personnel..................................................................81
5. STUDY TREATMENTS.....................................................................................................82
5.1. Allocation to Treatment ..........................................................................................82
5.2. Patient Compliance .................................................................................................82
5.3. Investigational Product Supply ...............................................................................82
5.3.1. Formulation and Packaging........................................................................82
5.3.1.1. Avelumab ..................................................................................82
5.3.2. Preparation and Dispensing........................................................................83
5.3.2.1. Avelumab ..................................................................................83
5.4. Administration.........................................................................................................83
5.4.1. Avelumab....................................................................................................83
5.4.1.1. Treatment After Initial Evidence of Disease Progression.........84
5.4.1.2. Treatment After Complete Response ........................................85
5.4.2. Food Requirements.....................................................................................85
5.4.3. Recommended Dose Modifications............................................................85
5.4.3.1. Avelumab Dosing Interruptions in Case of Drug-Related 
Toxicity..............................................................................................86
5.4.3.2. Avelumab Infusion Omissions for Drug-Related Toxicity.......86
5.4.4. Special Precautions for Avelumab Administration ....................................87
5.4.4.1. Management of Avelumab Infusion-Related Reactions ...........88
5.4.4.2. Management of Avelumab-Related Tumor Lysis 
Syndrome...........................................................................................90
5.4.4.3. Management of Avelumab Immune-Related Adverse 
Events ................................................................................................92
5.4.4.4. Management of Acute or Chronic Graft versus Host 
Disease (GVHD) ...............................................................................99
5.4.5. Dose Reductions .......................................................................................100
5.5. Investigational Product Storage and Accountability.............................................100
5.6. Investigational Product Accountability.................................................................101
5.6.1. Destruction of Investigational Product Supplies ......................................101
5.7. Concomitant Treatment(s).....................................................................................101
5.7.1. Hematopoietic Growth Factors.................................................................102


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5.7.2. Concomitant Surgery................................................................................102
5.7.3. Concomitant Radiotherapy.......................................................................102
5.7.4. Other Prohibited Concomitant Medications and Therapies......................102
5.8. Rescue Medications and Supportive Care.............................................................103
5.8.1. Supportive Care Guidelines......................................................................103
6. STUDY PROCEDURES ...................................................................................................104
6.1. Screening...............................................................................................................104
6.2. Treatment Period...................................................................................................104
6.3. Follow-up Visit .....................................................................................................104
6.4. Patient Withdrawal................................................................................................104
7. ASSESSMENTS................................................................................................................105
7.1. Safety Assessment.................................................................................................106
7.1.1. Pregnancy Testing ....................................................................................106
7.1.2. Adverse Events.........................................................................................106
7.1.3. Laboratory Safety Assessment .................................................................106
7.1.4. Vital Signs and Physical Examination......................................................108
7.1.5. (12-Lead) Electrocardiogram....................................................................108
7.2. Pharmacokinetics Assessments.............................................................................109
7.2.1. Blood Sample Collection for Pharmacokinetic analysis of Avelumab ....109
7.3. Immunogenicity Assessment.................................................................................109
7.4. Biomarker and Pharmacodynamic Assessments...................................................109
7.5. Disease Response Assessment ..............................................................................112
7.5.1. Blinded Independent Central Review for Disease Assessment 
(Expansion Phase)..........................................................................................112
7.6. Banked Biospecimens ...........................................................................................113
7.6.1. Markers of Drug Response.......................................................................113
7.6.2. Additional Research..................................................................................114
8. ADVERSE EVENT REPORTING....................................................................................115
8.1. Adverse Events......................................................................................................115
8.2. Reporting Period ...................................................................................................115
8.3. Definition of an Adverse Event.............................................................................115
8.3.1. Avelumab Adverse Event of Special Interest...........................................116


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8.4. Medication Errors..................................................................................................117
8.5. Abnormal Test Findings........................................................................................117
8.6. Serious Adverse Events.........................................................................................118
8.6.1. Protocol-Specified Serious Adverse Events.............................................118
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................119
8.7. Hospitalization ......................................................................................................120
8.8. Severity Assessment..............................................................................................121
8.9. Causality Assessment............................................................................................121
8.10. Exposure During Pregnancy................................................................................122
8.11. Occupational Exposure .......................................................................................123
8.12. Withdrawal Due to Adverse Events (See also the Section on Patient 
Withdrawal).............................................................................................................123
8.13. Eliciting Adverse Event Information ..................................................................123
8.14. Reporting Requirements......................................................................................123
8.14.1. Serious Adverse Event Reporting Requirements ...................................124
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................124
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............124
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................124
9.1. Analysis Sets .........................................................................................................125
9.2. Statistical Methods and Properties ........................................................................126
9.2.1. Sample Size Determination ......................................................................126
9.2.2. Efficacy Analysis......................................................................................126
9.3. Analysis of Pharmacokinetics and Pharmacodynamics ........................................127
9.3.1. Analysis of Pharmacokinetics...................................................................127
9.3.1.1. Avelumab Pharmacokinetic Analysis .....................................127
9.3.2. Analysis of Pharmacodynamics................................................................128
9.3.2.1. Analysis of Biomarker Endpoints ...........................................128
9.3.3. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling ..............................128
9.3.4. Immunogenicity Assessment....................................................................128
9.4. Safety Analysis......................................................................................................129
9.4.1. Safety Stopping Rules...............................................................................129
9.4.2. Adverse Events .........................................................................................129


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9.4.3. Laboratory Test Abnormalities.................................................................130
9.4.4. Electrocardiograms...................................................................................130
9.6. Data Monitoring Committee .................................................................................131
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................131
11. DATA HANDLING AND RECORD KEEPING ...........................................................132
11.1. Case Report Forms/Electronic Data Record .......................................................132
11.2. Record Retention.................................................................................................132
12. ETHICS............................................................................................................................133
12.1. Institutional Review Board/Ethics Committee....................................................133
12.2. Ethical Conduct of the Study ..............................................................................133
12.3. Patient Information and Consent.........................................................................133
12.4. Patient Recruitment.............................................................................................134
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................134
13. DEFINITION OF END OF TRIAL.................................................................................134
13.1. End of Trial in a Member State...........................................................................134
13.2. End of Trial in All Other Participating Countries...............................................134
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................135
15. PUBLICATION OF STUDY RESULTS........................................................................135
15.1. Communication of Results by Pfizer ..................................................................135
15.2. Publications by Investigators ..............................................................................136
16. REFERENCES ................................................................................................................137
LIST OF TABLES
Table 1.
Simulated Median Ctrough (μg/mL) and 95% Prediction Interval (PI) for 
Proposed Avelumab Dosing Regimens ................................................................63
Table 2.
Preliminary Efficacy Data from the Lead-In Phase..............................................64
Table 3.
Avelumab Dosing Cohorts for the Lead In Phase ................................................73
Table 4.
Avelumab Infusion Omissions for Drug-Related Toxicity ..................................86
Table 5.
Treatment Modification for Symptoms of Infusion Related Reactions 
Caused by Avelumab............................................................................................88
Table 6.
Management of Avelumab Immune Related Adverse Events..............................92
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Table 7.
Required Laboratory Tests .................................................................................107
Table 8.
Biomarker Collections and Analyses..................................................................111
Table 9.
Sample Size and Exact 95% CIs for ORR - Post-allogeneic HSCT cohort .......126
Table 10.
Safety Stopping Rules.........................................................................................129
LIST OF FIGURES
Figure 1.
B9991007 Study Design for the Lead-In and Expansion Ph................................72
Figure 2.
B9991007 Study Design for the Expansion Phase ...............................................73
Figure 3.
Assessment and Initial Management of Tumor Lysis Syndrome (TLS) ..............91
APPENDICES
Appendix 1. Abbreviations....................................................................................................142
Appendix 2. Response Criteria for Malignant Lymphoma (Lead-in Phase) .........................146
Appendix 3. The Lugano Classification- (Expansion Phase)................................................147
Appendix 4. Consensus Conference on Acute GVHD Grading29 .........................................149
Appendix 5. National Institutes of Health Consensus Development Project on Criteria 
for Clinical Trials in Chronic Graft-versus-Host Disease: I.  The 2014 
Diagnosis and Staging Working Group report30.................................................150
Appendix 6. Treatment Recommendations for Symptoms of Avelumab 
Infusion-Related Reactions.................................................................................154


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PROTOCOL SUMMARY
Background and Rationale:
Hodgkin’s lymphoma is a B-cell malignancy and is a lymphoma involving peripheral lymph 
nodes, which may also impact organs including liver, lung as well as bone marrow.  
Hodgkin’s lymphoma affects approximately 9,000 new patients each year and represents 
approximately 12% of all lymphomas seen in the United States.1 Classical Hodgkin’s
lymphoma (cHL) and nodular lymphocyte-predominant Hodgkin’s lymphoma are the two 
main types of Hodgkin’s lymphoma.  cHL accounts for most (~95%) Hodgkin’s Lymphoma 
diagnosed.2  The standard initial treatment for patients with newly diagnosed cHL includes
chemotherapy or combined modality therapy, followed by restaging with Positron Emission 
Tomography-Computerized Tomography (PET-CT) to assess treatment.  While patients with 
cHL commonly respond well to initial therapy, a subset of patients (~25%) continue to 
experience relapsed disease and have very poor prognosis.3  
cHL is defined by the subclassifications of: nodular sclerosis (60-80% of Hodgkin’s
lymphoma cases), mixed cellularity (25-30% of cases), lymphocyte-rich (5%) and 
lymphocyte-depleted (1%), depending upon histology and phenotype of the tumor cells.2
Hodgkin’s lymphoma tumor cells represent less than 2% of cells in the tissue.  
Mononucleated Hodgkin’s and bi- or multi-nucleated Reed-Sternberg cells (HRS) are the 
malignant cells in cHL.13,14  
Chromosome 9p24.1 amplification, which contains the PD-L1 gene, is frequent in cHL.19 It 
is thought that this leads to an overexpression of PD-L1 on the surface of the HRS.  PD-L1 
on the surface of these tumor cells is thought to be responsible in part for the 
down-modulation of potentially cytotoxic anti-tumor T cells, which express PD-1.  PD-L1 on 
HRS cells may also be capable of down modulating the activity of other cell types expressing 
PD-1, such as natural killer (NK) cells, which might otherwise be capable of mediating
antibody-dependent cell-mediated cytotoxicity (ADCC) through therapeutic antibodies 
targeting to the HRS cells.  Avelumab may block the binding of PD-1 on these key 
anti-tumor effector cells to PD-L1 on HRS, thereby restoring anti-tumor immunity, while at
the same time stimulating NK directed ADCC toward HRS.  It is not clear at this time if 
other mechanisms may also inhibit immune cells in this disease, such as PD-L2, another 
ligand for PD-1.  However, this may be mitigated by the direct tumor targeting properties of 
avelumab through the ADCC mechanism.  Therefore, cHL has been chosen as a potentially 
responsive tumor type for this study.
For those patients who are refractory to standard initial therapy, immunomodulation via 
PD-L1 inhibition may provide clinical benefit.  PD-L1 blockade may reverse the inhibition of 
tumor-infiltrating cytotoxic CD8+ T cells mediated by the HRS, restore anti-tumor immunity,
and directly target the HRS through activating the innate immune system.
Blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach for cHL.  
Preliminary data suggests that PD-1 blockade in specific hematologic malignancies is a safe 
and effective therapeutic strategy.6,7,8  Nivolumab, a high-affinity, fully human anti-PD-1 
monoclonal antibody (mAb)has been granted accelerated approval for the treatment of cHL 


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that has relapsed or progressed following autologous hematopoietic stem cell transplantation 
(HSCT) and post-transplantation brentuximab vedotin.9,37  In a cohort of 95 patients from 
two studies (Checkmate 025 and 039), an objective response rate (ORR) of 65% (95%
Confidence Intervals (CI): 55, 75) was reported in 62 patients, including: 7 (7%) with a 
complete response (CR) and 55 (58 %) with a partial response (PR).The median duration of 
response was 8.7 months (95% CI: 6.8, not evaluable).  The other PD-1 inhibitor 
pembrolizumab has also been granted accelerated approval for adult and pediatric patients 
with refractory cHL, or those who have relapsed following three or more lines of therapy.  
Approval was based on data from 210 adult cHL patients enrolled in a multicenter, 
non-randomized, open-label clinical trial. Patients had refractory or relapsed disease after 
autologous HSCT (129 patients) and/or Brentuximab Vedotin (175 patients), and received a 
median of four prior systemic therapies (range: 1, 12). With a median follow-up of 
9.4 months (range: 1-15), the ORR was 69% (95% CI: 62, 75). This included PR in 47% of 
patients and CR in 22%.  The estimated median response duration was 11.1 months (range 
0 to 11.1).38
While these results are encouraging, there is room for improvement with therapies able to 
increase the ORR. 
Due to the potential risk of checkpoint inhibitors-induced Graft-Versus-Host Disease 
(GVHD), patients with a prior allogeneic hematopoietic stem cell transplantation 
(allo-HSCT) were excluded from the nivolumab studies, while pembrolizumab, although 
excluding only patients who had received an allo-HSCT in the past 5 years or greater than 
5 years but with symptoms of GVHD, did not enroll any patient with a prior allo-HSCT.  As 
a result, only limited data are available for the use of checkpoint inhibitors in post allo-HSCT
patients, principally from case reports and small patient series. The potential to enhance the 
graft-versus-lymphoma response in post-allo-HSCT patients, however, provides a rational 
basis for the use of checkpoint inhibitors in this subgroup of cHL patients, despite the risk of 
checkpoint-induced GVHD.
This study comprises a lead-in phase followed by an expansion phase. The lead-in phase 
evaluates different avelumab dose regimens in relapsed or refractory cHL patients who had 
received either an autologous HSCT or an allo-HSCT or were ineligible for HSCT.  Based on 
the preliminary target occupancy (TO), safety, and efficacy results from the lead-in phase 
(see Section 1.5.1), the expansion phase will further evaluate a dose-escalation regimen in 
patients in whom allo-HSCT has failed. 
Study Objectives (Lead-in Phase)
Primary Objective

To characterize the pharmacokinetics (PK) of different dosing regimens of avelumab 
and its relation to target occupancy (TO) in peripheral blood of patients with classical 
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Secondary Objectives
•
To evaluate the overall safety and tolerability of different dosing regimens of 
avelumab.
•
To assess the immunogenicity of different dosing regimens of avelumab.
•
To evaluate the effect of different dosing regimens of avelumab on pharmacodynamic 
biomarkers of tumor immunophenotype and anti-tumor immune response.
•
To evaluate the anti-tumor activity of avelumab in patients with cHL.
Study Endpoints (Lead-in Phase)
Primary Endpoints
•
Percent TO by dose/schedule in peripheral blood immune cells, including CD14+ 
monocytes and CD3+ T cells.
•
Pharmacokinetic parameters of avelumab including, but not limited to, Cmax, Tmax, 
AUClast, Tlast, AUC sd,τ, t1/2, AUCsd,inf, CL, and Volume of distribution (Vz) as data 
permit.  Multiple Dose (MD)  - Css,max, Tss,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss,
Rac (AUCss,τ /AUCsd,τ) and Rss (AUCss,τ /AUCsd,inf) as data permit.
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Secondary Endpoints
•
Adverse Events as characterized by type, severity (as graded by National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.4.03), 
timing, seriousness, and relationship to study therapy.
•
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v. 4.03), and timing.
•
Anti-drug antibodies (ADAs; neutralizing antibodies) and serum titers against 
avelumab.
•
Phenotype, quantity, and localization of tumor infiltrating lymphocytes (TILs) in 
tumor biopsy tissue by immunohistochemistry (IHC).
•
Relative expression of transcripts associated with immune activation and regulation in 
tumor biopsy tissue by gene expression profiling.
•
Phenotype, relative proportions, activation state and PD-L1 expression of peripheral 
blood T cell subsets by flow cytometry.
•
Objective response according to Response Criteria for Malignant Lymphoma42 per 
Investigator assessment.
•
Disease control (DC), time to tumor response (TTR), duration of response (DR), 
progression-free survival (PFS) per Investigator assessment.
Study Objectives (Expansion Phase)
Primary Objective 
•
To evaluate the objective response rate (ORR) of avelumab in patients with relapsed 
or refractory cHL who have previously been treated with an allogeneic HSCT.
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Secondary Objectives
•
To evaluate the overall anti-tumor activity of avelumab.
•
To evaluate the overall safety profile of avelumab.
•
To evaluate the incidence and severity of acute and chronic GVHD.
•
To characterize the pharmacokinetics of avelumab.
•
To assess the immunogenicity of avelumab.
•
To evaluate the phenotype and quantity of TILs and correlate these findings with 
anti-tumor activity.
Endpoints (Expansion Phase)
Primary Endpoint
•
Objective response defined by the Lugano Classification43 as evaluated by the blinded 
independent central review (BICR).
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Secondary Endpoints
•
Objective response defined by the Lugano Classification43 as evaluated by 
Investigator’s assessment.
•
Time to tumor response (TTR), duration of response (DR), Disease Control (DC) and 
progression-free survival (PFS) according to the Lugano Classification43 by BICR 
and by Investigator’s assessment, as well as overall survival (OS).
•
Adverse Events and laboratory abnormalities as graded by National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4.03; timing, 
seriousness, and relationship to study therapy.
•
Acute GVHD, as defined by the modified Seattle Glucksberg criteria (Consensus 
Conference on Acute GVHD Grading Criteria-Appendix 4), and chronic GVHD, as 
defined by the NIH Consensus Development Project (Appendix 5).
•
Pharmacokinetic parameters of avelumab including, but not limited to, Cmax, Tmax, 
AUC sd,τ, t1/2, CL, and Vz as data permit.  Multiple Dose (MD) - Css,max, Tss,max, 
AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss as data permit.
•
Anti-drug antibodies (ADAs; neutralizing antibodies) and serum titers against 
avelumab.
•
Phenotype, quantity, and localization of TILs in tumor biopsy tissue determined by 
IHC.
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Study Design:
This is a Phase 1b, open-label, multi-center study comprising a lead-in phase and an 
expansion phase.  The lead-in phase is a multiple-dose, randomized, parallel-arm,
pharmacokinetic and pharmacodynamic study of avelumab as a single agent in adult patients 
with cHL.  Patients enrolled in the lead-in phase of this study are required to have relapsed 
following a prior autologous or allogeneic HSCT, or to be ineligible for HSCT. Based on the 
preliminary TO, safety, and efficacy results from the lead-in phase, the expansion phase will 
evaluate the anti-tumor activity and safety of single-agent avelumab utilizing an intra-patient 
dose escalation paradigm based on two of the dosing regimens studied in the lead-in phase in 
40 cHL patients in whom an allogeneic HSCT has failed. 
Lead-in Phase
In the lead-in phase of the study, which completed enrollment on November 29, 2016, a total 
of 31 patients were randomized across 5 treatment cohorts in a ratio of 1:1:1:1:1, The 
5 treatment cohorts are: 70 mg every 2 weeks (Q2W) (Cohort A), 350 mg Q2W (Cohort B), 
500 mg every 3 weeks (Q3W) (Cohort C), 500 mg Q2W (Cohort D), and 10 mg/kg Q2W 
(Cohort E). Each cohort enrolled 6 patients, except Cohort B in which 7 patients were 
randomized, but 1 was never dosed. The goal of the lead-in phase was to determine the
doses and schedules of avelumab that provide greater than 90% TO over the dosing interval 
and to identify a dose regimen for use in the dose expansion phase. 
For patients not achieving >90% TO after C1D1, the dose could be escalated to 10 mg/kg 
(Treatment Cohort E) starting at C2D1, after Cycle 1 assessment of TO.
Rationale for the Dosing regimens in the Expansion Phase
Based on the lead-in phase data, which includes safety, an assessment of the number of 
patients achieving >90% TO following 1 treatment cycle, and clinical activity that met the 
predefined criteria (observing at least 3 objective responses per the Response Criteria for 
Malignant Lymphoma42 (Appendix 2) in each given cohort), two dose regimens (70 mg Q2W 
and 500 mg Q2W) were selected in the expansion phase for the intra-patient dose escalation 
design outlined below.
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As described in Section 1.5.2, TO, safety, and efficacy data from the lead-in phase were 
similar across all the dose regimens tested, including a dose as low as 70 mg Q2W (~1/10 of 
the dose used in other studies across the avelumab program), with no evidence of a 
dose-response relationship either in the entire population, or in the post-allo HSCT cohort. 
Although the TO was >90% at all the regimens tested in the lead-in phase, peripheral TO 
may over-estimate TO within the tumor itself. Therefore, although responses were observed 
across the broad range of dose regimens tested, it is not clear whether the frequency, depth, 
and durability of the responses will be more optimal at higher doses. Given that the 
peripheral TO has the a priori potential to differ from the intra-tumoral TO, and the potential 
for life-threatening checkpoint-induced GVHD, patients will start the expansion phase with a 
70 mg Q2W ‘test’ dosing regimen of avelumab, the lowest exposure tested in the lead-in 
phase. 
Although there is no evidence that checkpoint-induced GVHD is dose/exposure dependent, 
starting patients on the lowest tested dose is expected to minimize the risk of 
checkpoint-induced GVHD, while also providing for the possibility that higher doses may 
capture responses that are not achieved at lower doses.  Patients will be monitored for safety 
and efficacy at the test dose level.
Given that 70 mg Q2W is the lowest dose tested, and the therapeutic activity at this low dose 
might not be optimal, patients not achieving a CR may be dose escalated to the higher dose 
(500 mg Q2W) as detailed below.  A target dosing regimen of 500 mg Q2W (~8x the 
exposure of 70 mg Q2W), provides an exposure intermediate between that of the highest
(10 mg/kg Q2W) and lowest tested (70 mg Q2W) in the lead-in phase.  A dose-response 
relationship has not been observed for either safety or efficacy in the lead-in phase. 
However, given the relatively small sample size and the potential life-threatening clinical 
sequelae of high-grade GVHD, patients will escalate to a dose which is almost a log higher 
than the test dose while at the same time being lower than the 10 mg/kg Q2W which is used 
in other studies across the avelumab program.
Expansion Phase
In this phase, an intra-patient dose-escalation design will be utilized as follows: all patients 
will commence dosing at 70 mg Q2W, the lowest dose that showed clinical activity, and will 
be monitored for safety and efficacy. Following 3 cycles of treatment at 70 mg Q2W, 
patients who at the 6-week tumor assessment achieve a CR will continue at the same dose 
regimen.  Patients achieving a PR at 6 weeks will continue at 70 mg Q2W for an additional 
3 cycles, and if the 12-week tumor assessment still shows a PR, patients will be dose 
escalated to 500 mg Q2W.  Patients who at the 6-week tumor assessment achieve a stable 
disease (SD), will be dose escalated to 500 mg Q2W.  Additionally, those patients who at the 
6-week assessment are considered to have initial evidence of disease progression as 
confirmed by BICR but in the opinion of the Investigator are still experiencing clinical 
benefit (as defined in Section 5.4.1.1), may continue treatment with study drug at the 
Investigator’s discretion and following discussion with the Sponsor.  Such patients may be 
considered for escalation to 500 mg Q2W. Dose escalation to 500 mg Q2W after the 6 or the 
12 week tumor assessment, will be only permitted so long as there is no clinical evidence of 


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GVHD or treatment-related Grade 2 AEs with a duration of more than 14 days. Patients 
with progressive disease (PD) at 6 weeks in the absence of clinical benefit will be 
permanently discontinued from study treatment.
Patients with GVHD of any grade (other than Grade 1 GVHD of the skin requiring topical 
therapy only) must be permanently discontinued from the study treatment.
Disease responses will be assessed by a BICR according to processes defined in the Study 
Manual. Intra-patient dose escalation decisions will be made following discussion between 
the Investigator and the Sponsor and will be informed by the BICR disease response 
assessment-see Section 7.5.1.
Study Treatment:
Avelumab will be administered as a 1-hour intravenous (IV) infusion once every 2 weeks or 
3 weeks, with or without food, on a continuous dosing schedule.  Treatment with 
investigational product will continue until disease progression, patient refusal, or 
unacceptable toxicity, patient is lost to follow-up, or until the study is terminated by the 
Sponsor, whichever occurs first (see Section 6.4).
Patients will be monitored closely for toxicity, and in the event of significant toxicity, dosing
of avelumab may be delayed, reduced or permanently discontinued. Avelumab treatment 
modification for drug-related toxicities, including immune-related adverse events (irAEs) 
infusion-related AEs and GVHD are described in Section 5.4.3, Section 5.4.4 and
Section 5.4.5.
Every effort should be made to administer avelumab on the planned dose and schedule.  See 
STUDY DESIGN section for details of the lead-in and expansion phase study treatments.
Statistical Methods:  
Percent PD-L1 target occupancy will be calculated by dose/schedule in peripheral blood 
CD14+ monocytes and CD3+ T cells and will be summarized descriptively (n, mean,
standard deviation (SD), coefficient of variation (CV), median, minimum, maximum, 
geometric mean, its associated CV, and 95% confidence interval) by dose, cycle, day and 
nominal time. 
Standard plasma PK parameters for avelumab will be estimated using non-compartmental 
analysis.  For avelumab, standard PK parameters will include Cmax, Tmax, AUC0-τ, t1/2, 
plasma clearance (CL), and volume of distribution (Vz) and others, as data permit.  
Avelumab plasma concentrations and PK parameters will be summarized descriptively 
(n, mean, SD, CV, median, minimum, maximum, geometric mean, its associated CV, and 
95% confidence interval) by treatment cohort, cycle, day and nominal time. 


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For the lead-in phase of the study, the evaluation of the anti-tumor activity of avelumab is a 
secondary objective.  For the expansion phase, evaluation of the anti-tumor activity, as 
measured by the objective response rate, is the primary objective.  Efficacy will be 
summarized by treatment cohort for all patients randomized in the lead-in phase, and for all 
patients who received at least one dose of study treatment in the expansion phase.
In the expansion phase, tumor-related endopoints will be summarized separately based on 
BICR assessment and based on Investigator assessment.
For statistical analysis, ‘start date’ refers to the date of randomization for patients enrolled in 
the lead-in phase, and to the date of the first dose of study treatment for patients enrolled in 
the expansion phase.
Objective response (OR) is defined as complete response (CR) or partial response (PR) 
according to the Response Criteria for Malignant Lymphoma42 (Appendix 2 for the lead-in 
phase) and to the Lugano Classification43 (Appendix 3 for the expansion phase) from ‘start 
date’” until disease progression or death due to any cause. OR rate (ORR) is the proportion 
of patients with OR.
Time to Tumor Response (TTR) is defined, for patients with an objective response per the 
Response Criteria for Malignant Lymphoma42 (Appendix 2 for the lead-in phase) and per the 
Lugano Classification43 (Appendix 3 for the expansion phase), as the time from ‘start date’ to 
the first documentation of objective tumor response (CR or PR) .
Duration of Response (DR) is defined, for patients with an objective response per the 
Response Criteria for Malignant Lymphoma42 (Appendix 2 for the lead-in phase) and per the 
Lugano Classification43 (Appendix 3 for the expansion phase), as the time from the first 
documentation of objective tumor response (CR or PR) to the first documentation of 
objective progression of disease (PD) or to death due to any cause, whichever occurs first.  
Censoring rules for DR will follow those described below for PFS.
Disease Control (DC) is defined as the best overall response of CR, PR, or SD.  To qualify as 
a best overall response of SD, at least one SD assessment must be observed ≥6 weeks after 
start date and before disease progression. DC rate (DCR) is the proportion of patients with 
DC.
Progression Free Survival (PFS) is defined as the time from ‘start date’ to the date of the first 
documentation of objective progression of disease (PD) or death due to any cause, whichever 
occurs first.  PFS data will be censored on the date of the last adequate tumor assessment for 
patients who do not have an event (PD or death), for patients who start new anti-cancer 
treatment prior to an event, or for patients with an event after two or more missing tumor 
assessments.  Patients who do not have a baseline tumor assessment or who do not have any 
post-baseline tumor assessments will be censored on the ‘start date’ unless death occurred on 
or before the time of the second planned tumor assessment in which case the death will be 
considered an event.
OS in the expansion phase is defined as the time from the ‘start date’ to the date of death due 
to any cause. Patients last known to be alive will be censored at the date of the last contact.


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ORR will be estimated and the corresponding exact 2-sided 95% confidence interval will be 
reported.  TTR will be summarized using simple descriptive statistics (eg, median and range).
DCR will be summarized by frequency counts and percentages.  DR, PFS, and OS will be 
analysed using Kaplan-Meier methods. Median DR, median PFS, and median OS and 
associated 95% confidence intervals will be reported.
Sample Size Determination
In the lead-in phase, a total of 31 patients were randomized across 5 different treatment 
cohorts. Based on results from the lead-in phase, a dose escalation design has been planned 
for the expansion phase, which will enroll approximately 40 patients in whom allogeneic 
HSCT has failed. 
Approximately 70 patients will be enrolled into this study in total.
The 6 patients per treatment cohort in the lead-in phase are used to enable the initial 
estimation of TO; based on the historical data, with observed mean TO of 90%, the 
corresponding 95% confidence interval is 88.98% to 91.02%, assuming a standard deviation 
of 1.27%. With 40 treated patients in the expansion phase, ORR can be estimated with a 
standard error not exceeding 0.079.


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SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to the Assessments section of the 
protocol for detailed information on each assessment required for compliance with the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the Schedule of Activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the patient.
SCHEDULE OF ACTIVITIES (2-Week Cycles, for Lead-In Phase)
Protocol Activities
Screening
Study Treatment
(1 cycle = 14 days)
Post-Treatment
Cycle 1
Cycle 2
Cycles 3
28 Days Prior 
to 
Randomization
Day 1 
Day 
2[20]
Day 7 
(2 
days)
Day 1 
(3 days)
Day 2 Day 7 
(2 
days)
Day 1
(3 days)
End of Treatment
/Withdrawal[1]
Follow-up
After
Last Dose 
(Day 30 3,
Day 60 3, 
and Day 90 3)[2]
Clinical Assessments
Informed Consent[3]
X
Medical/Oncological History[4]
X
Baseline Signs/Symptoms[5]
X
Physical Examination[6]
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Vital Signs[7]
X
X
X
X
X
X
X
X
Contraception Check[8]
X
X
X
X
X
X
Laboratory Studies
Hematology[9]
X
X
X
X
X
X
X
X
Blood Chemistry[10]
X
X
X
X
X
X
X
X
Coagulation[9]
X
X
X
X
X
X
X
X
Thyroid Function Tests and 
ACTH[11] 
X
X
(Cycles 3 
and 6 and 
Q6 weeks 
thereafter)
X
X


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Protocol Activities
Screening
Study Treatment
(1 cycle = 14 days)
Post-Treatment
Cycle 1
Cycle 2
Cycles 3
28 Days Prior 
to 
Randomization
Day 1 
Day 
2[20]
Day 7 
(2 
days)
Day 1 
(3 days)
Day 2 Day 7 
(2 
days)
Day 1
(3 days)
End of Treatment
/Withdrawal[1]
Follow-up
After
Last Dose 
(Day 30 3,
Day 60 3, 
and Day 90 3)[2]
HBV, HCV
X
Pregnancy Test[12]
X
X
X
X
X
X
Urinalysis[13]
X
X
X
X
X
12-Lead ECG[14]
X
X
X
X
Disease Assessments
Tumor Assessments[15]
X
X (Q6W until W12, then Q12W)
X
X
Other Clinical Assessments
Adverse Events[16]
X
X
X
X
Concomitant 
Medications/Treatments[17]
X
X
X
X
Randomization and Study 
Treatment[18]
Avelumab[19]
X
X
X
Pharmacokinetics
See table below
Biomarkers
See table below
Footnotes for Schedule of Activities
1.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if performed 
within the prior 6 weeks.
2.
Follow-up After Last Dose: To occur at least up to 90 days (on Days 30 3, 60 3, and 90 3) after the last dose of study treatment.  All safety assessments are to 
continue through this period as noted in the Schedule of Activities.  Safety assessments will cease if new anti-cancer therapy is initiated during this follow-up period.  
3.
Informed Consent: Must be obtained prior to undergoing any trial-specific procedure.
4.
Medical/Oncological History: To include information on prior systemic therapy regimens, surgery, and radiation therapy.
5.
Baseline Signs/Symptoms: To be recorded predose for all patients on Cycle 1 Day 1.  Patients will be asked about any signs and symptoms experienced within the 14 days 
prior to randomization.
6.
Physical Examination: Includes an examination of major body systems, assessment of ECOG performance status, and weight (height included at Screening only).
7.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in supine or sitting position.


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Footnotes for Schedule of Activities
8.
Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to use 2 highly effective 
contraception methods consistently and correctly and document such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the 
patient to call immediately if one or both selected contraception methods are discontinued, whenever one menstrual cycle is missed or if pregnancy is known or suspected 
in the patient or the patient’s partner. Contraception checks will be routinely repeated at every treatment cycle during the active treatment period, at the End of 
Treatment/Withdrawal visit, and at the Day 30 Follow-up Visit.
9.
Hematology and Coagulation: Required tests are listed in Table 7.  Will be performed at screening prior to the first dose of study treatment, weekly through Cycles 1 and 
2, and then at Day 1 of every cycle throughout the duration of the study.  May also be performed when clinically indicated. 
10. Blood Chemistry: Full chemistry panel (required tests are listed in Table 7) is required at Screening, on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 7 Day 1, then 
every 6 weeks thereafter and at End of Treatment/Withdrawal.  Core chemistry panel (required tests are listed in Table 7) is required on Cycle 3 Day 1, Cycle 5 Day 1, 
Cycle 6 Day 1, Cycle 8 Day 1, then every 2 weeks (Q2 Week Schedule) thereafter. In addition a Core chemistry panel will be performed also at Day 7 through Cycles 1
and 2.  If full and core chemistry panels are scheduled at the same visit, then only the full chemistry panel will be performed.  For patients with documented liver 
involvement at study entry, ALT, AST, total bilirubin, and alkaline phosphatase tests will be performed weekly in the first 6 weeks of treatment, ie, Cycle 1 Day 1, Cycle 1 
Day 7, Cycle 2 Day 1, Cycle 2 Day 7, Cycle 3 Day 1, Cycle 3 Day 7, then on Day 1 of each cycle thereafter.  
11. ACTH and Thyroid Function Tests: ACTH, Free T4, TSH.  Performed at screening, Cycle 3 Day 1, Cycle 6 Day 1, every 6 weeks thereafter, EOT, and 30, 60, 90 days 
after last dose of study treatment, and if clinically indicated.  Test should additionally be performed in cases of suspected hypoadrenalism or hypopituitarism. See 
Section 7.1.3 in the full protocol for a list of the required Laboratory Tests.
12. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on two occasions 
prior to starting study therapy: once at the start of screening and at the baseline visit immediately before the administration of avelumab.  Following a negative pregnancy 
result at screening, appropriate contraception must be commenced.  Urine or serum pregnancy tests will also be routinely repeated at every treatment cycle during the active 
treatment period, at the End of Treatment/Withdrawal visit, at the Day 30 Follow-up Visit, and additionally whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Urine pregnancy tests may also be repeated as per request of institutional review board /ethics committee (IRB/IECs) or if required by 
local regulations (see Section 7.1.1).
13. Urinalysis: Dipstick is acceptable. Will be performed at screening, Day 1 of every cycle throughout the duration of the study, and at the End of Treatment/Withdrawal.
14. 12-Lead ECG: All patients require a single ECG measurement at screening.  On-treatment ECGs will be performed on Day 1 of Cycles 1 and 2 only before avelumab 
infusion and at the end of avelumab infusion and at End of Treatment.  At each time point, three (3) consecutive 12-lead ECGs (triplicates) will be performed 
approximately 2 minutes apart to determine mean QTc (average of triplicates).  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment 
should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  Additional triplicate ECGs may be performed as 
clinically indicated.  If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should be obtained at time of 
the event.  If the mean QTcF is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Clinically significant 
findings seen on follow-up ECGs should be recorded as adverse events.  
15. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging will include neck, chest, abdomen, and pelvis PET-CT at baseline and 
may additionally include CT with contrast or MRI if one of these two modalities (the same type of scan as baseline) will be continued for disease assessments; an 
additional PET-CT will be performed at 6 weeks and subsequently as clinically indicated.  Imaging for tumor assessments will be conducted at screening, 6 weeks, 
12 weeks and at 12-week intervals thereafter until documented disease progression regardless of initiation of subsequent anti-cancer therapy.  Additional tumor assessments 
should also be conducted whenever disease progression is suspected (eg, symptomatic deterioration), at End of Treatment/Withdrawal (if not done in the previous 6 weeks)
and at follow-up visits.
Assessment of response will be made using the Response Criteria for Malignant Lymphoma42 s Appendix 2.


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Footnotes for Schedule of Activities
16. Adverse Events: For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 
90 calendar days after the last administration of the investigational product.  SAEs occurring to a patient after the active reporting period has ended should be reported to 
the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to 
investigational product are to be reported to the Sponsor.  See Section 8.2.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the time the patient has taken at least 1 dose of investigational product through and 
including 90 calendar days after the last administration of the study drug.  If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends at 
the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.  See Section 8.
17. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment up to 90 days after the 
last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), the 
drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
18. Randomization: Patient number and treatment cohort allocation via interactive response technology (IRT) operated by the Sponsor.  In the lead-in phase, doses will be 
randomly assigned, with patients randomized in a 1:1:1:1:1 allocation to 5 different treatment cohorts.  Required information: site, patient identifiers and demographic 
information.  Study treatment should begin on or within 3 days after randomization.  
19. Study Treatment: Avelumab at the assigned dose level will be given as a 1-hour intravenous infusion every 2 weeks.  Patients with disease progression who are 
continuing to derive clinical benefit from study treatment may be eligible to continue with avelumab, provided that the treating physician has determined that the 
benefit/risk for doing so is favorable.
20. Day 2 Assessments: Refer to Pharmacokinetic and Pharmacodynamic Sampling Schedule for assessments performed on Day 2.


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SCHEDULE OF ACTIVITIES (3-Week Cycles, for Lead-In Phase)
Protocol Activities
Screening
Study Treatment
(1 cycle = 21 days)
Post-Treatment
Cycle 1
Cycle 2
Cycles 3
28 Days Prior 
to 
Randomization
Day 1 Day 2
[20]
Day 7
(2 
days)
Day 14
(2 days)
Day 1 
(3 
days)
Day 2
Day 7 
(2 days)
Day 14 
(2 days)
Day 1
(3 days)
End of 
Treatment
/Withdrawal 
[1]
Follow-up
After
Last Dose (Day 30 
3,
Day 60 3, Day 90 
3)[2]
Clinical Assessments
Informed Consent[3]
X
Medical/Oncological History[4]
X
Baseline Signs/Symptoms[5]
X
Physical Examination[6]
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Vital Signs[7]
X
X
X
X
X
X
X
X
Contraception Check[8]
X
X
X
X
X
X
Laboratory Studies
Hematology[9]
X
X
X
X
X
X
X
X
X
X
Blood Chemistry[10]
X
X
X
X
X
X
X
X
X
X
Coagulation[9]
X
X
X
X
X
X
X
X
X
X
Thyroid Function Tests and 
ACTH[11]
X
X 
(Cycles 3 
and 6 and 
Q6 weeks 
thereafter)
X
X
HBV, HCV
X
Pregnancy Test[12]
X
X
X
X
X
X
Urinalysis[13]
X
X
X
X
X
12-Lead ECG[14]
X
X
X
X
Disease Assessments
Tumor Assessments[15]
X
X (Q6W until W12, then Q12W)
X
X
Other Clinical Assessments
Adverse Events[16]
X
X
X
X


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Protocol Activities
Screening
Study Treatment
(1 cycle = 21 days)
Post-Treatment
Cycle 1
Cycle 2
Cycles 3
28 Days Prior 
to 
Randomization
Day 1 Day 2
[20]
Day 7
(2 
days)
Day 14
(2 days)
Day 1 
(3 
days)
Day 2
Day 7 
(2 days)
Day 14 
(2 days)
Day 1
(3 days)
End of 
Treatment
/Withdrawal 
[1]
Follow-up
After
Last Dose (Day 30 
3,
Day 60 3, Day 90 
3)[2]
Concomitant 
Medications/Subsequent 
Treatments[17]
X
X
X
X
Randomization and Study 
Treatment[18]
Avelumab[19]
X
X
X
Pharmacokinetics
See table below
Biomarkers
See table below
Footnotes for Schedule of Activities
1.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if performed within 
the prior 6 weeks.
2.
Follow-up After Last Dose: To occur at least up to 90 days (on Days 30 3, 60 3, and 90 3) after the last dose of study treatment. All safety assessments are to continue 
through this period as noted in the Schedule of Activities.  Safety assessments will cease if new anti-cancer therapy is initiated during this follow-up period.  
3.
Informed Consent: Must be obtained prior to undergoing any trial-specific procedure.
4.
Medical/Oncological History: To include information on prior systemic therapy regimens, surgery, and radiation therapy.
5.
Baseline Signs/Symptoms: To be recorded pre-dose for all patients, on Cycle 1 Day 1.  Patients will be asked about any signs and symptoms experienced within the 14 days 
prior to randomization.
6.
Physical Examination: Includes an examination of major body systems, assessment of ECOG performance status, and weight (height included at Screening only).
7.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in supine or sitting position.
8.
Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to use 2 highly effective contraception 
methods consistently and correctly and document such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call 
immediately if one or both selected contraception methods are discontinued, whenever one menstrual cycle is missed or if pregnancy is known or suspected in the patient or the 
patient’s partner. Contraception checks will be routinely repeated at every treatment cycle during the active treatment period, at the End of Treatment/Withdrawal visit, and at 
the Day 30 Follow-up Visit.
9.
Hematology and Coagulation: Required tests are listed in Table 7.  Will be performed at screening prior to the first dose of study treatment and weekly through Cycles 1 and 
2, then Day 1 of every cycle throughout the duration of the study.  May also be performed when clinically indicated.  


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Footnotes for Schedule of Activities
10. Blood Chemistry: Full chemistry panel (required tests are listed in Table 7 is required at Screening, on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 7 Day 1, then 
every 6 weeks thereafter and at End of Treatment/Withdrawal.  Core chemistry panel (required tests are listed in Table 7) is required on, Cycle 3 Day 1, Cycle 5 Day 1, Cycle 6 
Day 1, Cycle 8 Day 1, then every 3 weeks (Q3 Week Schedule) thereafter. In addition a Core chemistry panel will be performed at Day 7 and Day 14 through Cycles 1 and 2. 
If full and core chemistry panels are scheduled at the same visit, then only the full chemistry panel will be performed.  For patients with documented liver involvement at study 
entry, ALT, AST, total bilirubin, and alkaline phosphatase tests will be performed weekly in the first 6 weeks of treatment, ie, Cycle 1 Day 1, Cycle 1 Day 7, Cycle 1 Day 14, 
Cycle 2 Day 1, Cycle 2 Day 7, Cycle 2 Day 14, then on Day 1 of each cycle thereafter.  
11. ACTH and Thyroid Function Tests: ACTH, Free T4, TSH.  Performed at screening, Cycle 3 Day 1, Cycle 6 Day 1, every 6 weeks thereafter, EOT, and 30, 60, 90 days after 
last dose of study treatment and if clinically indicated.  Test should additionally be performed in cases of suspected hypoadrenalism or hypopituitarism.  See Section 7.1.3 in 
the full protocol for a list of the required Laboratory Tests.
12. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on two occasions 
prior to starting study therapy: once at the start of screening (all patients) and at the baseline visit immediately before the administration of avelumab.  Following a negative 
pregnancy result at screening, appropriate contraception must be commenced.  Urine or serum pregnancy tests will also be routinely repeated at every cycle during the active 
treatment period, at the End of Treatment/Withdrawal visit, at the Day 30 Follow-up Visit and additionally whenever one menstrual cycle is missed or when potential 
pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations (see Section 7.1.1).
13. Urinalysis: Dipstick is acceptable Will be performed prior to screening, Day 1 of every cycle throughout the duration of the study and at End of Treatment/Withdrawal.
14. 12-Lead ECG: All patients require a single ECG measurement at screening.  On-treatment ECGs will be performed on Day 1 of Cycles 1 and 2 only before avelumab infusion 
and at the end of avelumab infusion and at End of Treatment.  At each time point, three (3) consecutive 12-lead ECGs (triplicates) will be performed approximately 2 minutes 
apart to determine mean QTc (average of triplicates).  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment should be performed prior to 
blood sample collection, such that the blood sample is collected at the nominal time.  Additional triplicate ECGs may be performed as clinically indicated.  If a patient 
experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should be obtained at time of the event.  If the mean QTcF is 
prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Clinically significant findings seen on follow-up ECGs 
should be recorded as adverse events.  
15. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging will include neck, chest, abdomen, and pelvis PET-CT at baseline and 
may additionally include CT with contrast or MRI if one of these two modalities (the same type of scan as baseline) will be continued for disease assessments; an additional 
PET-CT will be performed at 6 weeks and subsequently as clinically indicated Imaging for tumor assessments will be conducted at screening, 6 weeks, 12 weeks, and at 
12-week intervals thereafter until documented disease progression regardless of initiation of subsequent anti-cancer therapy. Additional tumor assessments should also be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration), at End of Treatment/Withdrawal (if not done in the previous 6 weeks) and at follow-up 
visits Assessment of response will be made using Response Criteria for Malignant Lymphoma.42  See Appendix 2).  
16. Adverse Events: For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 
90 calendar days after the last administration of the investigational product.  SAEs occurring to a patient after the active reporting period has ended should be reported to the 
Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to 
investigational product are to be reported to the Sponsor.  See Section 8.2.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the time the patient has taken at least 1 dose of investigational product through and 
including 90 calendar days after the last administration of the study drug..  If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends at the 
time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.  See Section 8.
17. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment up to 90 days after the last 
dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), the drugs 
used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).


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Footnotes for Schedule of Activities
18. Randomization: Patient number and dose level allocation via interactive response technology (IRT) operated by the Sponsor.  In the lead-in phase, doses will be randomly 
assigned, with patients randomized in a 1:1:1:1:1 allocation to 5 different treatment cohorts. Required information: site, patient identifiers and demographic information.  
Study treatment should begin on or within 3 days after randomization.  
19. Study Treatment: Avelumab at the assigned dose level will be given as a 1-hour intravenous infusion every 3 weeks.  Patients with disease progression who are continuing to 
derive clinical benefit from study treatment may be eligible to continue with avelumab, provided that the treating physician has determined that the benefit/risk for doing so is 
favorable.
20. Day 2 Assessments: Refer to Pharmacokinetic and Pharmacodynamic Sampling Schedule for assessments performed on Day 2.


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SCHEDULE OF ACTIVITIES (Expansion Phase)
Protocol Activities
Screening
Study Treatment
70 mg Q2W and 500 mg Q2W = 1 cycle: 14 days
Post-Treatment
28 Days 
Prior to 
first dose 
of study 
treatment
End of 
Treatment
/Withdrawal 
[1]
Follow-up 
After
Last Dose 
(Day 30 3,
Day 60 3, 
Day 90 
3)[2]
Long-term 
Follow-up
Every 12 
weeks 14 
days[3]
All Cycles
Cycles 1-3 
Cycles 4-6 
(patients who 
escalate to 500 
mg Q2W at 
Cycle 4)
Cycles 7-9 
(patients who 
escalate to 500 
mg Q2W at 
Cycle 7)
Day 1 (3 days 
for all but 
Cycle 1)
Day 7 (2 
days)
Day 7 (2 
days)
Day 7 (2 
days)
Clinical Assessments
Informed Consent[4]
X
Medical/Oncological
History [5]
X
Baseline 
Signs/Symptoms[6]
X
Physical Examination[7]
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
Vital Signs[8]
X
X
X
X
X
X
X
Contraception Check[9]
X
X
X
X
Laboratory Studies
Hematology[10]
X
X
X
X
X
X
X
Blood Chemistry[11]
X
X
X
X
X
X
X
Coagulation[10]
X
X
X
X
X
X
X
Thyroid Function Tests 
and ACTH[12] 
X
Cycle 3, Cycle 6, 
and Q6W 
thereafter
X
X
HBV, HCV
X
Pregnancy Test[13]
X
X
X
X


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Protocol Activities
Screening
Study Treatment
70 mg Q2W and 500 mg Q2W = 1 cycle: 14 days
Post-Treatment
28 Days 
Prior to 
first dose 
of study 
treatment
End of 
Treatment
/Withdrawal 
[1]
Follow-up 
After
Last Dose 
(Day 30 3,
Day 60 3, 
Day 90 
3)[2]
Long-term 
Follow-up
Every 12 
weeks 14 
days[3]
All Cycles
Cycles 1-3 
Cycles 4-6 
(patients who 
escalate to 500 
mg Q2W at 
Cycle 4)
Cycles 7-9 
(patients who 
escalate to 500 
mg Q2W at 
Cycle 7)
Day 1 (3 days 
for all but 
Cycle 1)
Day 7 (2 
days)
Day 7 (2 
days)
Day 7 (2 
days)
Urinalysis[14]
X
X
X
X
12-Lead ECG[15]
X
Cycle 1, Cycle 2
Cycle 4
Cycle 7
X
Tumor Assessments[16]
X
X (Q6W until W12, then Q12W for one year after start of study treatment, and then every Q24W until documented 
disease progression by BICR assessment, regardless of initiation of subsequent anti-cancer therapy)
Other Clinical 
Assessments
Adverse Events[17]
X
X
X
X
X
X
X
Concomitant 
Medications/Treatments[18]
X
X
X
X
X
X
X
Avelumab[19]
X
Subsequent anti-cancer 
treatments
X
X
Survival update[20]
X
Pharmacokinetics
See Table Below
Biomarkers
See Table Below
Footnotes for Schedule of Activities
1.
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if performed 
within the prior 6 weeks.
2.
Follow-up After Last Dose: To occur at least up to 90 days (on Days 30 3, 60 3, and 90 3) after the last dose of study treatment.  All safety assessments are to 
continue through this period as noted in the Schedule of Activities.  Safety assessments will cease if new anti-cancer therapy is initiated during this follow-up period.  


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3.
Long Term Follow-up: Beyond the 90 days until the end of the study, all patients will be followed every 12 weeks (+/-14 days) for survival and new anticancer treatment 
within the long-term follow-up  
4.
Informed Consent: Must be obtained prior to undergoing any trial-specific procedure.
5.
Medical/Oncological History: To include information on prior systemic therapy regimens, surgery, and radiation therapy.
6.
Baseline Signs/Symptoms: To be recorded predose for all patients on Cycle 1 Day 1.  Patients will be asked about any signs and symptoms experienced within the 14 days 
prior to first dose of study treatment 
7.
Physical Examination: Includes on Day 1 of each cycle an examination of major body systems and assessment of ECOG performance status and weight (height included 
at Screening only).  An abbreviated physical exam will be conducted on Day 7 of Cycles 1, 2 and 3, on Day 7 of Cycles 4, 5 and 6 for patients who are escalated to 500 mg 
Q2W at Cycle 4 and on Day 7 of cycles 7, 8, and 9 for patients who are escalated to 500 mg Q2W at week at Cycle 7. Particular attention must be paid to signs and 
symptoms of GVHD.
8.
Vital Signs: Blood pressure (BP) and pulse rate to be recorded in supine or sitting position.
9.
Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet the criteria for 
correct use of 2 of the selected methods of contraception.  The investigator or his or her designee will discuss with the patient the need to use 2 highly effective 
contraception methods consistently and correctly and document such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the 
patient to call immediately if one or both selected contraception methods are discontinued, whenever one menstrual cycle is missed or if pregnancy is known or suspected 
in the patient or the patient’s partner. Contraception checks will be routinely repeated at every treatment cycle during the active treatment period, at the End of 
Treatment/Withdrawal visit, at the Day 30 Follow-up Visit.
10. Hematology and Coagulation: Required tests are listed in Table 7.  Will be performed at screening prior to the first dose of study treatment, at Day 1 and Day 7 through 
Cycles 1, 2 and 3 and on Day 7 of Cycles 4, 5 and 6 for patients who escalate to 500 mg Q2W at Cycle 4 and on day 7 of Cycle 7, 8 and 9 for patients who escalate to 
500 mg Q2W at Cycle 7, and then at Day 1 of every cycle throughout the duration of the study, at End of Treatment/Withdrawal, at Day 30, Day 60 and Day 90 Follow-up 
after last dose, and at other times if clinically indicated.
11. Blood Chemistry: Full chemistry panel (required tests are listed in Table 7) is required at Screening, on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 7 Day 1, then 
every 6 weeks, at End of Treatment/Withdrawal, at the 30-day Follow-up after last dose, and at other times if clinically indicated.  Core chemistry panel (required tests are 
listed in Table 7) is required on Day 7 through Cycle 1, 2 and 3 and on Day 7 of Cycles 4, 5 and 6 for patients who escalate to 500 mg Q2W at Cycle 4 and on Day 7 of 
Cycles 7, 8 and 9 for patients who escalate to 500 mg Q2W at Cycle 7, at Cycle 3 Day 1, Cycle 5 Day 1, Cycle 6 Day 1, Cycle 8 Day 1, then every 2 weeks thereafter, and 
at the Day 60 and Day 90 Follow-up after last dose.  If full and core chemistry panels are scheduled at the same visit, then only the full chemistry panel will be performed.  
For patients with documented liver involvement at study entry, ALT, AST, total bilirubin, and alkaline phosphatase tests will be performed weekly in the first 6 weeks of 
treatment, ie, Cycle 1 Day 1, Cycle 1 Day 7, Cycle 2 Day 1, Cycle 2 Day 7, Cycle 3 Day 1, Cycle 3 Day 7, then on Day 1 of each cycle thereafter.  
12. ACTH and Thyroid Function Tests: ACTH, Free T4, TSH.  Performed at screening, Cycle 3 Day 1, Cycle 6 Day 1, every 6 weeks thereafter, EOT, and 30, 60, 90 days 
after last dose of study treatment, and if clinically indicated.  Test should additionally be performed in cases of suspected hypoadrenalism or hypopituitarism.  See 
Section 7.1.3 in the full protocol for a list of the required Laboratory Tests.
13. Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL human chorionic gonadotropin , will 
be performed on two occasions prior to starting study therapy: once at the start of screening and at the baseline visit immediately before the administration of avelumab.  
Following a negative pregnancy result at screening, appropriate contraception must be commenced.  Urine or serum pregnancy tests will also be routinely repeated at every 
treatment cycle during the active treatment period, at the End of Treatment/Withdrawal visit, at the Day 30 Follow-up Visit, and additionally whenever one menstrual cycle 
is missed or when potential pregnancy is otherwise suspected.  Urine pregnancy tests may also be repeated as per request of institutional review board /ethics committee 
(IRB/IECs) or if required by local regulations (see Section 7.1.1).
14. Urinalysis: Dipstick is acceptable.  Will be performed at screening, Day 1 of every cycle throughout the duration of the study and at the End of Treatment/Withdrawal.


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15. 12-Lead ECG: All patients require a single ECG measurement at screening.  On-treatment ECGs will be performed on Day 1 of Cycles 1 and 2 only before avelumab 
infusion and at the end of avelumab infusion and at End of Treatment.  At each time point, three (3) consecutive 12-lead ECGs (triplicates) will be performed 
approximately 2 minutes apart to determine mean QTc (average of triplicates).  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment 
should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  Additional triplicate ECGs may be performed as 
clinically indicated.  If a patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should be obtained at time of 
the event.  If the mean QTcF is prolonged (>500 msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation.  Clinically significant 
findings seen on follow-up ECGs should be recorded as adverse events.  
16. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging will include neck, chest, abdomen, and pelvis PET-CT.  CT with 
contrast or MRI may be additionally performed, if clinically indicated.  Imaging for tumor assessments will be conducted at screening, 6 weeks, 12 weeks, at 12-week 
intervals thereafter for one year from start of study treatment and every 24 weeks thereafter until documented disease progression by BICR assessment, regardless of 
initiation of subsequent anti-cancer therapy.  Additional tumor assessments should also be conducted whenever disease progression is suspected (eg, symptomatic 
deterioration) and at End of Treatment/Withdrawal (if not done in the previous 12 weeks). For patient achieving a CR, a CT with contrast or MRI can be used instead of 
the PET-CT for tumor assessment until progression of disease which will require a PET-CT to be documented.
Disease responses will be assessed real-time by a Blinded Independent Central Review (BICR) according to processes defined in the Study Manual. The 6-week 
and the 12-week tumor assessment may be performed up to one week before the scheduled time so that images can undergo BICR review before Cycle 4 and 
Cycle 7.
Assessment of response will be made using the Lugano Classification43 (Appendix 3).
17. Adverse Events: For SAEs, the active reporting period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 
90 calendar days after the last administration of the investigational product.  SAEs occurring to a patient after the active reporting period has ended should be reported to 
the Sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to 
investigational product are to be reported to the Sponsor.  See Section 8.2.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the time the patient has taken at least 1 dose of investigational product through and 
including 90 calendar days after the last administration of the study drug.  If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends at 
the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.  See Section 8.
18. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment up to 90 days after the 
last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), the 
drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
19. Study treatment: Avelumab at the assigned dose level will be given as a 1-hour intravenous infusion every 2 weeks.  The dose of 70 mg Q2W will be initially tested for 
safety and efficacy.  Following 3 cycles of treatment, patients who at the 6-week tumor assessment achieve a CR will continue at the same dosing regimen.  Patients 
achieving a PR at 6 weeks will continue at 70 mg Q2W for 3 additional cycles, and if the 12-week tumor assessment still shows a PR, patients will be dose escalated to 
500 mg Q2W.  Patients who at the 6-week tumor assessment achieve a SD will be dose escalated to 500 mg Q2W. In addition those patients who at the 6-week assessment 
are considered to have initial evidence of disease progression as confirmed by BICR but in the opinion of the Investigator are still experiencing clinical benefit (as defined 
in Section 5.4.1.1) may continue treatment with study drug at the Investigator’s discretion and following discussion with the Sponsor. Such patients may be considered for 
escalation to 500 mg Q2W.  Dose escalation to 500 mg Q2W after the 6-week or the 12-week tumor assessment, will be only permitted so long as there is no clinical 
evidence of GVHD or treatment-related Grade ≥2 AEs with a duration of more than 14 days.  Patients with PD at 6 weeks in the absence of clinical benefit will be 
permanently discontinued from study treatment.
20. Survival Assessment: Beyond Day 90, post treatment survival status will be collected every 12 weeks ±14 days until deaths.  This includes the collection of information 
on subsequent anti-cancer therapies.  Telephone communication is acceptable.


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Pharmacokinetic and Pharmacodynamic Sampling Schedule (2-Week Cycles, for Lead-In Phase)
Protocol Activities
Screening
Study Treatment (1 cycle = 14 days)
Post-Treatment
Cycle 1
Cycle 2
Cycles ≥3
≤28 Days Prior 
to 
Randomization
Day 1
Day 2 Day 7 (±2 
days)
Day 1
Day 2
Day 7 
(±2 days)
Day 1 (±3 days)
End of Treatment / 
Withdrawal 
Follow-up
After
Last Dose (Day 30 ±3,
Day 60 ±3, Day 90 ±3)
Pharmacokinetics[1]
X
X
X
X
X
X
X (Prior to dosing 
in Cycles 3, 4, 6, 8,
then Q12W up to 
cycle 20)
Banked Blood Biospecimen[2]
X
X 
De Novo Tumor Biopsy[3]
X (optional)
X (Cycle 3; 
optional) 
X (optional)
Anti-Avelumab Antibodies 
/Neutralizing Antibodies[4]
X
X
X (Cycles 3, 4, 6, 8,
then Q12W up to 
cycle 20)
X
Target Occupancy[5]
(whole blood)
X
X
X
X
X
X
X (Cycles 3, 4)
X
Immune Cell Phenotyping[6]
(whole blood)
X
X
X
X (Cycles 3, 4, 7, 
10)
X
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Footnotes for Schedule of Activities
1.
Pharmacokinetics: Serial PK samples will be collected on Day 1 of Cycles 1 and 2.  A 3.5 mL blood sample will be collected at pre-dose (0), 1, 6, 24 (Day 2), and 144 
(Day 7) hours post-dose.  Thereafter, a 3.5 mL blood sample will be collected pre-dose on Day 1 of Cycles 3, 4, 6, 8, and every 12 weeks up to cycle 20.
2.
Banked Blood Biospecimen:  A 4-mL blood sample will be collected at Screening and Day 1 (+/- 3 days) of Cycle 3 to be retained for potential 
pharmacogenomic/biomarker analyses related to drug response, unless prohibited by local regulations or ethics committee decision. 
 
 
3.
De Novo Tumor Biopsy: pre-treatment baseline, on-treatment, (at study Day 1 (±2 days) of Cycle 3, and/or end of treatment /disease progression de novo (ie, fresh) tumor 
biopsies (lymph node or bone marrow) are optional in the lead-in phase.  If conducted, a baseline biopsy must be collected within 28 days prior to randomization.  Tumor 
tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted.  A portion of the de novo
biopsy(ies) should be formalin-fixed and paraffin-embedded and a portion of the de novo biopsy should be added to RNAlater solution (see Study Manual).  The resulting 
FFPE tissue block(s) and tumor sample in RNAlater should be submitted to the Central Laboratory.  An archival FFPE tumor tissue block either from initial diagnosis, or 
from a tumor biopsy that was obtained no more than 6 months prior to enrollment and after which the patient had not received any systemic anti-cancer therapy prior to 
enrollment may be submitted in place of a baseline de novo biopsy
4.
Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): One blood sample (3.5 mL) for anti-avelumab antibodies will be 
collected pre-dose on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 and every 12 weeks up to cycle 20 and for the End of Treatment/Withdrawal.  All samples should be drawn within 
2 hours before start of avelumab infusion.  Follow up samples are only collected in patients who are ADA positive at end of treatment.  All the samples that are positive for 
ADA may also undergo characterization for Nab.  
5.
Target Occupancy: A 3-mL whole blood sample will be collected on Days 1 (pre-dose), 2, and 7 of Cycles 1 and 2, Day 1 (pre-dose) of Cycles 3 and 4 and at End of 
Treatment/Withdrawal.  PD-L1 occupancy by avelumab on immune cells will be measured using flow cytometry.
6.
Immune Cell Phenotyping: A 6-mL whole blood sample will be collected at screening, Day 1 (pre-dose) of Cycle 1, Day 1 of Cycles 2, 3, 4, 7, 10 and at End of Treatment/ 
Withdrawal.  Immune cell phenotypes associated with anti-tumor immunity and immune regulation will be measured by flow cytometry.
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Pharmacokinetic and Pharmacodynamic Sampling Schedule (3-Week Cycles, for Lead-In Phase)
Protocol Activities
Screening
Study Treatment (1 cycle = 21 days)
Post-Treatment
Cycle 1
Cycle 2
Cycles ≥3
≤28 Days Prior 
to 
Randomization 
Day 1 Day 2 Day 7 
(±2 
days)
Day 14  
(±2 
days)
Day 1 Day 2
Day 7 
(±2 days)
Day 14 (±2 
days)
Day 1 (±3 days)
End of 
Treatment / 
Withdrawal 
Follow-up
Day 90 Days 
After Last Dose 
(Day 30 ±3, Day 
60 ±3, 
Day 90 ±3) 
Pharmacokinetics[1]
X
X
X
X
X
X
X
X
X (Prior to dosing of 
Cycles 3, 4, 6, 8, then 
Q12W up to cycle 20)
Banked Blood 
Biospecimen[2]
X
X
De Novo Tumor Biopsy[3]
X (optional)
X
(optional)
X (optional)
Anti-Avelumab Antibodies /
Neutralizing Antibodies [4]
X
X
X (Cycles 3, 4, 6, 8,
then Q12W up to cycle 
20)
X
Target Occupancy[5]
(whole blood)
X
X
X
X
X
X
X
X
X (Cycle 3, 4)
X
Immune Cell Phenotyping[6]
(whole blood)
X
X
X
X
X (Cycle 3, 5, 7))
X
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1.
Pharmacokinetics: Serial PK samples will be collected on Day 1 of Cycles 1 and 2.  A 3.5 mL blood sample will be collected at pre-dose (0), and 1, 6, 24 (Day 2), 144 
(Day 7), and 312 (Day 14) hours post dose.  Thereafter, a 3.5 mL blood sample will be collected pre-dose on Day 1 of Cycles 3, 4, 6, 8 and every 12 weeks up to cycle 20.
2.
Banked Blood Biospecimen: A 4-mL blood sample will be collected at the Screening and Day 7 (+/-2) of Cycle 2 to be retained for potential pharmacogenomic/biomarker 
analyses related to drug response, unless prohibited by local regulations or ethics committee decision.  
 
 
3.
De Novo Tumor Biopsy: Pre-treatment baseline, on-treatment, (at study Day 7 (±2 days) of Cycle 2, and/or end of treatment /disease progression de novo (ie, fresh) tumor 
biopsies (lymph node or bone marrow) are optional in the lead-in phase.  If conducted, a baseline biopsy must be collected within 28 days prior to randomization.  Tumor 
tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted. A portion of the de novo
biopsy(ies) should be formalin-fixed and paraffin-embedded and a portion of the de novo biopsy should be added to RNAlater (see Study Manual). The resulting FFPE 
tissue block(s) and tumor sample in RNAlater should be submitted to the Central Laboratory. An archival FFPE tumor tissue block either from initial diagnosis or from a 
tumor biopsy that was obtained no more than 6 months prior to enrollment and after which the patient had not received any systemic anti-cancer therapy prior to enrollment 
may be submitted in place of a baseline de novo biopsy. 
4.
Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): One blood sample (3.5 mL) for anti-avelumab antibodies will be 
collected pre-dose on Day 1 of Cycles 1, 2, 3, 4, 6 and 8 and at the end of treatment visit.  Subsequently, testing should be performed approximately every 12 weeks up to 
cycle 20. All samples should be drawn within 2 hours before start of avelumab infusion.  Additional samples for anti-avelumab antibodies will be collected at End of 
Treatment/Withdrawal.  Follow up samples are only collected in patients who are ADA positive at end of treatment.  All the samples that are positive for ADA may also 
undergo characterization for Nab.  
5.
Target Occupancy: A 3 mL whole blood sample will be collected on Days 1 (pre-dose), 2, 7, 14 of Cycles 1 and 2, Day 1(pre-dose) of Cycles 3, 4 and at End of 
Treatment/Withdrawal.  PD-L1 occupancy by avelumab on immune cells will be measured using flow cytometry.
6.
Immune Cell Phenotyping: A 6 mL whole blood sample will be collected at screening and Day 1 (pre-dose) and Day 14 of Cycle 1, Day 7 of Cycle 2, Day 1 (pre-dose) of 
Cycle 3, 5, 7; and at End of Treatment/Withdrawal.  Immune cell phenotypes associated with anti-tumor immunity and immune regulation will be measured by flow 
cytometry.
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Pharmacokinetic and Pharmacodynamic Sampling Schedule (Expansion Phase)
Protocol Activities
Screening
Study Treatment (1 cycle = 14 days)
Post-Treatment
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4
≤28 Days Prior 
to 
First dose of 
study treatment
Day 1
Day 7  
Day 1
Day 7 
Day 1
Day 1   
End of 
Treatment / 
Withdrawal 
Follow-up 
After Last 
Dose (Day
30 ±3,
Day 60 ±3, 
Day 90 ±3)
Visit Window
(±3 days) (±3 days)
(±3 days)
(±3 days)
(±3 days)
(±7 days)
Pharmacokinetics[1]
X
X
X
X
X
X (Prior to dosing on Cycle 4, 7 & 13 for 
all patients)
Banked Blood Biospecimen[2]
X
Mandatory De Novo Tumor 
Biopsy[3]
X
X (Cycle 3 Day 7  
±7 days)
Optional De Novo Tumor 
Biopsy[3]
As clinically indicated throughout 
At week 12/24 following tumor assessment scan
X
Anti-Avelumab Antibodies 
and Neutralizing Antibodies[4]
X
X
X
X (Prior to dosing on Cycle 4,  7, & 13 
for all patients)
X
X
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Footnotes for Schedule of Activities
1.
Pharmacokinetics: Blood samples (3.5-mL whole blood at each time point) will be collected from all patients in the study at pre-dose and 1 hour post-infusion (ie, at the end 
of infusion) on Day 1 of Cycles 1, 2 and 3.  Blood samples will also be collected on Day 7 of Cycles 1 and 2.  Thereafter, a 3.5 mL blood sample will be collected pre-dose 
on Day 1 of Cycle 4, 7, and 13 and prior to dosing after the first dose of study treatment.
2.
Banked Blood Biospecimen: A 4-mL blood sample (Prep D1) will be collected at Day 1 (pre-dose) of Cycle 1 to be retained for potential biomarker analyses related to drug 
response, unless prohibited by local regulations or ethics committee decision.  
 
 
 
.
3.
De Novo Tumor Biopsy: For the expansion phase, patients must consent to undergo a pre-treatment and an on-treatment biopsy assuming lesions to be biopsied may be 
safely accessed and sampled.  De novo (ie, fresh) tumor biopsy is mandatory at baseline and at Day 7 (+/- 7 days) of Cycle 3, following the tumor assessment scan during 
week 6, and assuming lesions for biopsy can be accessed safely.  Baseline biopsy must be collected within 28 days prior to first dose of study treatment, but where possible 
upon completion of screening activities.  If an archival FFPE block is available from a biopsy taken within 3 months of first dose of study treatment, and there has been no 
intervening systemic anti-cancer therapy, this can substitute for the baseline de novo sample. Where possible, the on-treatment biopsy should be performed close to the 
6 week tumor response scan, and before Cycle 4 dosing.  An optional de novo tumor sample is particularly encouraged following the 12 or 24-week scans, in patients who 
dose escalate at Cycle 4 or 7, respectively, and can also be collected from all subjects as clinically indicated and/or at End of Treatment if a patient discontinues due to 
disease progression.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material) is not adequate and should not be submitted.
Note, if a biopsy is completed on the same day as CT scan, it must be completed after the scan so that full tumor assessment information is available.  A portion of the de 
novo biopsy(ies) should be formalin-fixed and paraffin-embedded, and tissue permitting, a second portion should be prepared as fresh-frozen (details for sample collection, 
processing, storage and shipping will be provided in the Study Manual). The resulting FFPE and frozen tissue block(s) should be submitted to the Central Laboratory.  In the 
event a de novo biopsy cannot be safely obtained, submission of an archival FFPE tumor tissue block or slides from the closest time point that is within 6 months of first dose 
of study treatment must be provided.
4.
Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): One blood sample (3.5 mL) for anti-avelumab antibodies will be 
collected pre-dose on Day 1 of Cycles 1, 2, 3, 4, 7 and 13 after the first dose of study treatment.  All samples should be drawn within 2 hours before start of avelumab 
infusion.  Additional samples for anti-avelumab antibodies will be collected at the End of Treatment/Withdrawal.  Follow up samples for ADA will also be collected on 
Day 30, 60 and 90 follow up visits after the last dose of avelumab.  All the samples that are positive for ADA may also undergo characterization for Nab.  
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1. INTRODUCTION
This is a Phase 1b dose-finding study to evaluate the pharmacokinetics, pharmacodynamics, 
and preliminary antitumor activity of avelumab (MSB00100718C) in adult patients with 
relapsed or refractory classical Hodgkin’s Lymphoma (cHL). The primary purpose of the 
lead-in phase of this study is to assess the pharmacokinetics, biological activity, and early 
signs of efficacy of various avelumab dosing regimens in patients with relapsed or refractory 
cHL in whom a prior autologous or allogeneic HSCT (allo-HSCT) has failed, or who are 
ineligible for HSCT.  The primary purpose of the expansion phase of the study is to evaluate 
the anti-tumor activity of select dose regimen(s) of avelumab in patients with relapsed or 
refractory cHL in whom a prior allogeneic HSCT has failed. 
1.1. Mechanism of Action/Indication
Avelumab (also referred to as MSB0010718C) is a fully human IgG1 antibody directed 
against programmed death ligand 1 (PD-L1), a 290 amino acid type I transmembrane protein 
encoded by the Cd274 gene on human chromosome 9. Avelumab binds PD-L1 and blocks 
the interaction between PD-L1 and its receptors programmed death 1 (PD-1) and 
B7.1 (CD80).  This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, 
resulting in the restoration of cytotoxic T cell response.  PD-L1 (also called B7-H1 and 
CD274) is expressed on resting and activated T cells, B cells, macrophages, dendritic cells, 
and mast cells.11
In vivo anti-tumor effects were found to be primarily mediated by CD8+ T cells as evidenced 
by the observation that in vivo depletion of this cell type completely abrogated the anti-tumor 
efficacy of avelumab.  The contribution of ADCC as a potential mechanism of anti-tumor 
activity was further demonstrated in vivo using a deglycosylated version of avelumab to 
abrogate fragment crystalline (Fc) receptor binding or via the systemic depletion of natural 
killer (NK) cells.  In both settings, loss of in vivo ADCC potential significantly reduced the 
anti-tumor activity.
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator’s Brochure.15
1.2. Background and Rationale
Hodgkin’s lymphoma is a B-cell malignancy and is one of the most common lymphomas 
involving peripheral lymph nodes and may impact organs including liver, lung as well as 
bone marrow.  Hodgkin’s lymphoma affects approximately 9,000 new patients each year and 
represents approximately 12% of all lymphomas seen in the United States.1  Classical 
Hodgkin’s lymphoma (cHL) and nodular lymphocyte-predominant Hodgkin’s lymphoma are 
the two main types of Hodgkin’s lymphoma. cHL accounts for most (~95%) Hodgkin’s
Lymphoma diagnosed.2 The standard initial treatment for patients with newly diagnosed 
cHL includes chemotherapy or combined modality therapy, followed by restaging with 
PET/CT to assess treatment.  While patients with Hodgkin’s Lymphoma commonly respond 
well to initial therapy, a subset of patients (~25%) continue to experience relapsed disease
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cHL is defined by the subclassifications of: nodular sclerosis (60-80% of Hodgkin’s
lymphoma cases), mixed cellularity (25-30% of cases), lymphocyte-rich (5%) and 
lymphocyte-depleted (1%), depending upon histology and phenotype of the tumor cells.  
Hodgkin’s lymphoma tumor cells represent less than 2% of cells in the tissue.
Mononucleated Hodgkin’s and bi- or multi-nucleated Reed-Sternberg cells (HRS) are the
malignant cells in cHL.13,14 In approximately 40% of Hodgkin’s lymphoma cases, the tumor 
cells are infected by Epstein Barr virus.10  
The unique cellular composition of Hodgkin’s lymphoma provides a number of opportunities 
to target either the malignant HRS cell or the inflammatory tumor microenvironment.  HRS 
cells appear to orchestrate their microenvironment in many ways to evade host immune 
attack by recruiting immune bystander cells, such as non-neoplastic helper T lymphocytes, 
macrophages, mast cells, and eosinophils.22,23,24,25 HRS cells are commonly surrounded by 
CD4+ T-lymphocytes (both the Th1 and the Th2 type).  These regulatory T-cells may play a 
pathogenic role in cHL, since they could contrast the potential cytotoxic effect of CD8+ cells 
against HRS cells. Moreover, HRS cells secrete cytokines and chemokines creating a mobile 
microenvironment and utilize receptor signaling pathways to preserve their high proliferative 
capacity and anti-apoptotic phenotype.26
The programmed death 1 (PD-1) pathway functions as a barrier to limit T-cell–mediated 
immune responses.  PD-1 ligands, such as PD-L1, induce PD-1 signaling and associated 
T-cell “exhaustion,” a reversible inhibition of T-cell activation and proliferation.27 In 
addition, several pathways are constitutively activated in cHL, including NF-kB, JAK/STAT 
and aberrant expression of receptor tyrosine kinases.  In approximately 40% of classical 
Hodgkin’s lymphoma cases, encoding of SOCS1 is inactivated by mutations in the 
JAK/STAT pathway.20 The chromosomal region 9p24 includes PD-L1 and several genes 
residing within this region have been postulated to be a factor in cHL.4,5 Thus, 
PD-L1 expression may play a role in HRS cells avoiding immunosurveillance in
cHL.
With regard to current treatments, early-stage cHL is generally treated with four cycles of 
chemotherapy using ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed 
by radiation therapy.  Advanced-stage cHL is usually treated with six to eight cycles of 
ABVD, followed by radiation to residual masses.  Current treatment algorithms for cHL 
patients who relapse after ABVD incorporate a platinum-based regimen followed by high 
dose chemotherapy with autologous HSCT.  If non-responsive to the platinum-based 
regimen, a gemcitabine-based regimen could then be administered, and if response does not 
follow this regimen (transplant ineligible), then a third-line treatment could include 
brentuximab vedotin or an investigational agent.
Brentuximab vedotin was approved by the U.S. Food and Drug Administration (FDA) in 
2011 for the treatment of patients with HL after failure of autologous Hematopoietic Stem 
Cell Transplant (HSCT) or after failure of at least two prior multi-agent chemotherapy 
regimens in patients who are not candidates for autologous HSCT.  This agent is an 
antibody-drug conjugate that contains a monoclonal antibody targeting CD30 linked to an 
antimitotic agent.  After attaching to the cell surface receptor CD30, brentuximab vedotin 


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internalizes into the target cell where it delivers the active component of the drug.  Although 
brentuximab has a high response rate, it is frequently not curative and patients may then 
relapse.  Therefore, there is need for additional therapies in relapsed cHL.
Allogeneic HSCT may also be an option for selected patients with relapsed/refractory cHL. 
The use of reduced intensity conditioning regimens has improved OS and reduced the 
non-relapse mortality of this approach, consequently the percentage of patients with cHL 
undergoing an allogeneic HSCT has increased.  However, the prognosis of these patients 
remains poor with an expected 2-year PFS ranging from 18% to 39%.46 Management of 
patients relapsing after allogeneic HSCT remains challenging and although different 
approaches have been reported (eg, reduction of immunosuppression, donor lymphocyte 
infusion, a second allogeneic HSCT, and clinical trials) there is no standard therapy for this 
patient population, which remains an area of high unmet medical need. 
1.3. Pharmaceutical and Therapeutic Background
1.3.1. Avelumab (MSB0010718C)
The investigational product in the present clinical trial is avelumab (MSB0010718C), a fully 
human monoclonal antibody of the immunoglobulin (Ig) G1 isotype.
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.16  For complete details of the in vitro and nonclinical studies, refer 
to avelumab Investigator’s Brochure (IB).15
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in Phase 1, 2 and 3 clinical protocols in a variety of cancers, including non-small cell 
lung cancer, gastric cancer, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, 
urothelial cancer, head and neck cancer, and Hodgkin’s and non-Hodgkin’s Lymphomas, as 
single agent or in combination with chemotherapy, tyrosine kinase inhibitors, radiotherapy, 
or other immune modulating agents. 
The safety profile of avelumab administered intravenously (IV) as single agent at a dose of 
10 mg/kg every 2 weeks (Q2W) has been characterized primarily in 1738 adult patients from 
studies EMR100070-001 in various solid tumors (N=1650) and EMR100070-003 Part A in 
Merkel cell carcinoma (N=88). Study EMR100070-001 consists of 2 parts, a dose escalation 
phase and a dose expansion phase, which is performed in selected tumor types. 
As of 09 June 2016, a total of 53 patients were treated in the dose escalation phase of the 
EMR100070-001 study, with 4, 13, 15, and 21 patients treated with avelumab doses of 1, 3, 
10, and 20 mg/kg Q2W, respectively.  None of the patients treated with doses up to 10 mg/kg 
experienced a dose limiting toxicity (DLT), and the 10 mg/kg dose of avelumab was thus 
considered a safe and well tolerated dose for further investigation in the dose expansion 
cohorts.  One DLT (a Grade 3 immune related adverse event characterized by increased 
creatine kinase, myositis, and myocarditis) was observed in 1 patient at the dose of 20 mg/kg.


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The dose expansion phase of study EMR100070-001 included patients with non-small cell 
lung cancer, gastric cancer, breast cancer, colorectal cancer, castration resistant prostate 
cancer, adrenocortical carcinoma, melanoma, mesothelioma, urothelial carcinoma, ovarian 
cancer, renal cell carcinoma, and squamous cell cancer of the head and neck. Study 
EMR100070-003 Part A was conducted in patients with Merkel cell carcinoma. 
A summary of pooled safety data from patients treated at 10 mg/kg Q2W in studies
EMR100070- 001 and EMR100070-003 (N=1738) is provided here. 
Treatment-emergent adverse events (TEAEs) were observed in 1697 (97.6%) patients, with 
the most frequent (10%) being fatigue (32.4%), nausea (25.1%), diarrhea (18.9%), 
constipation (18.4%), decreased appetite (18.4%), infusion related reaction (17.1%), weight 
decreased (16.6%), vomiting (16.2%), anemia (14.9%), abdominal pain (14.4%), cough 
(13.8%), pyrexia (13.6%), dyspnea (13.2%), edema peripheral (11.9%), back pain (11.8%), 
and arthralgia (10.4%).
Treatment-related TEAEs were observed in 1164 (67.0%) patients, and the most frequent 
(5%) were fatigue (17.7%), infusion related reaction (17.0%), nausea (8.6%), diarrhea 
(7.1%), chills (6.7%), pyrexia (6.1%), decreased appetite (5.2%), and hypothyroidism 
(5.0%). 
A total of 177 patients (10.2%) experienced Grade 3 treatment-related TEAEs, and the most 
frequent (0.5%) were fatigue (1.0%), lipase increased (1.0%), Gamma-Glutamyl
Transferase (GGT) increased (0.6%), infusion related reaction (0.6%), and AST increased 
(0.5%).
A total of 777 (44.7%) patients had at least 1 serious TEAE.  Treatment-related serious 
TEAEs were reported in 108 (6.2%) patients, with the most frequent (0.2%) being infusion
related reaction (0.9%), pneumonitis (0.6%), pyrexia (0.3%), adrenal insufficiency (0.3%), 
and hypothyroidism, diarrhea, vomiting, autoimmune disorder, autoimmune hepatitis, 
transaminases increased, dyspnea, and colitis (0.2% each). 
There were 911 deaths (52.4%) in the pooled safety data set.  The majority of deaths were 
due to progressive disease (744, 42.8%).  There were 59 (3.4%) deaths attributed to TEAEs 
not related to trial treatment, and 4 deaths (0.2%) attributed to a treatment-related TEAE by 
the investigator and which occurred up to 30 days after the last dose of avelumab: 
pneumonitis (1 case), acute liver failure (1 case), respiratory distress (in the context of sepsis)
(1 case), and autoimmune hepatitis with hepatic failure (1 case). In addition, 1 patient died 
with acute respiratory failure (in the context of lung cancer progression) considered related to 
avelumab by the investigator 37 days after the last dose of avelumab.  The cause of death was 
marked as “other” or “unknown” in 17 (1.0%) and 83 (4.8%) of cases, respectively.
A total of 244 patients (14.0%) permanently discontinued avelumab treatment due to TEAEs, 
including 107 patients (6.2%) discontinuing because of treatment-related TEAEs.  The most 
frequent treatment related TEAEs leading to treatment discontinuation were infusion related 
reaction (1.8%), GGT increased (0.4%), and diarrhea, fatigue, autoimmune disorder, ALT 
increased, blood creatine phosphokinase (CPK) increased, lipase increased, arthralgia, and 
pneumonitis (0.2% each).


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Immune-related adverse events (irAEs): in the pooled safety data (N=1738), a total of 
247 patients (14.2%) experienced irAEs, defined as adverse events requiring use of 
corticosteroids (and/or hormonal therapy for endocrinopathies), and no clear alternate 
etiology. The median time to first onset of an irAE was 11.7 weeks. The most frequent 
irAEs were thyroid disorders including hypothyroidism (5.2%), hyperthyroidism (0.4%) and 
thyroiditis (0.2%), immune-related rash (5.2%), immune-related colitis (1.5%), 
immune-related pneumonitis (1.2%), immune-related hepatitis (0.9%), adrenal insufficiency
(0.5%) and immune-related myositis (0.5%). In addition, irAEs reported in 0.1% of patients 
in the pooled safety dataset included: type 1 diabetes mellitus, immune-related nephritis/renal 
dysfunction, hypopituitarism, uveitis and Guillain-Barre Syndrome. The majority of irAEs 
were Grade 1 or Grade 2 in severity, with 39 (2.2%) being of Grade 3 severity. Fatal 
outcome was reported in 1 patient (0.1%) with immune-related pneumonitis, and 2 patients 
(0.1%) with immune-related hepatitis.  Other relevant irAEs reported with avelumab outside 
the pooled safety dataset included 1 case of fatal immune-related myocarditis in Study 
B9991002 (avelumab in combination with axitinib for RCC), 1 case of non-fatal 
immune-related myocarditis in the 20 mg/kg cohort of the dose escalation phase of Study 
EMR100070-001, and 2 patients with non-fatal graft versus host disease (GVHD) in Study 
B9991007 (avelumab in patients with classical Hodgkin’s lymphoma).
Infusion-related reactions (IRRs): a total of 439 patients (25.3%) experienced at least 1 IRR, 
defined as a TEAE coded under the PTs of infusion related reaction, drug hypersensitivity, 
hypersensitivity, anaphylactic reaction, type I hypersensitivity, chills, pyrexia, back pain, 
dyspnea, hypotension, flushing, and abdominal pain according to a predefined case 
definition. The most common PTs that met the definition for an IRR included: infusion 
related reaction (17.0%), chills (5.4%), and pyrexia (3.6%). Most of the events were of 
Grade 1 or Grade 2 severity.  Grade 3 IRRs occurred in 12 patients (0.7%) including 
3 patients (0.2%) who experienced Grade 4 IRRs.  No Grade 5 IRRs were reported.  In most 
cases, the first occurrence of an IRR was related to the first infusion, with only 6 patients 
experiencing the first IRR at the fifth or later infusion. All Grade 3 IRRs occurred with the 
first (7 patients) or second (5 patients) infusion. Overall, 21.6% of patients had 1 IRR, 
2.6% of patients had 2 IRRs, 14 patients (0.8%) had 3 IRRs, and 3 patients had >3 IRRs.  
IRR recurrence after the fourth infusion was rare (15 patients) and all recurrent IRRs were of
Grade 1 or 2 severity. In 35 patients (2.0%), treatment was permanently discontinued 
because of an IRR.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the avelumab IB.15
Avelumab pharmacokinetics: Avelumab pharmacokinetics and dose proportionality 
following the first 1-hour infusion have been characterized in 57 Caucasian patients treated 
in the dose escalation and expansion cohorts of Study EMR 100070-001 by standard 
non-compartmental analysis.  This analysis revealed that the exposure parameters of Cmax
and AUCτ increased in a dose proportionate fashion across the 1, 3, 10 and 20 mg/kg doses.  
Apparent half-life tended to increase with dose, likely due to target mediated disposition at 
lower doses, but terminal half-life of 10 and 20 mg/kg doses were similar (106-134 hours).  


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This likely indicates target mediated elimination does not increase at these two doses and 
target occupancy is very high. 
Target occupancy on peripheral blood CD3+ T-cells was investigated in human blood in 
vitro by flow cytometry after spiking of whole blood samples from eight healthy volunteers 
with avelumab over a concentration of 0.003-10 g/mL.  Fifty percent (50%) receptor 
occupancy was observed at a drug concentration of 0.122 g/mL 0.042 g/mL with a 
plateau indicating at least 95% receptor occupancy reached in all blood samples at 1 g/mL. 
PK profiles obtained from the dose escalation phase of Trial EMR 100070-001 found all 
patients at 10 mg/kg dose reached or exceeded the serum level (median Ctrough 20-37 µg/mL) 
of avelumab required for >90% TO.  For patients treated with 3 mg/kg of avelumab, 10 of 
13 patients reached the required serum level (3.7-8.3 µg/mL).
Complete information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab IB.15
1.4. Rationale for Studying Avelumab in Hodgkin’s Lymphoma
Attempts to selectively manipulate components of the immune system involved in tumor 
immune surveillance and anti-tumor responses have led to the development of immune 
checkpoint inhibitors targeting molecules such as programmed death 1 (PD-1) and its ligand 
(PD-L1). Engagement of PD-1 by its ligands PD-L1 and PD-L2 leads to decreased T cell 
proliferation, cytotoxicity, and an increased susceptibility to apoptosis. Blockade of the 
PD-1/PD-L1 axis has been shown to enhance anti-tumor responses in a range of different 
indications and clinical trials.38
Immunomodulation through the inhibition of the PD-1/PD-L1 and PD-L2 or the 
PD-1/PD-L1 interactions has the potential to provide durable clinical benefit in some patients 
who are refractory to standard-of-care therapy.38,40  Selective blockade of the PD-1/PD-L1
interaction with avelumab may, in principle, exert its anti-tumor effects though two distinct 
mechanisms: (i) direct tumor cell targeting through engagement of the innate immune system 
via the intact antibody-dependent cell-mediated cytotoxicity (ADCC) functionality that has 
been specifically edited out of all other PD-1 and PD-L1 checkpoint inhibitors currently in 
the clinic, and (ii) indirectly through impacting the immune system by reversing the 
inhibition of ‘exhausted’ tumor-infiltrating cytotoxic CD8+ T cells, and restoring anti-tumor 
immunity. 
Hodgkin’s lymphoma has a distinct targetable genetic abnormality in that the majority of 
patients have a genetic alteration involving copy number increases and amplification of 
chromosome 9p24.1. This region typically encodes the PD-L1, PD-L2, and JAK2 genes.19  
The presence of abnormalities in this genetic locus leads to the overexpression of the PD-L1
and PD-L2 protein at the surface of malignant Reed-Sternberg (RS) cells.  PD-L1 expressed 
at the surface of RS cells is thought to be responsible for the functional suppression of the 
activity of cytotoxic anti-tumor T cells expressing the PD-1 receptor.


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PD-L1 ligand expressed on RS cells may also down-modulate the activity of other cell types 
expressing the PD-1 receptor, including natural killer (NK) cells, which might otherwise be 
capable of mediating ADCC through IgG1 isotype therapeutic antibodies that target RS cells.  
Avelumab may block the binding of the PD-1 receptor on key anti-tumor effector cells to 
PD-L1 ligand expressed on RS cells, thereby restoring the anti-tumor immune response, 
while also potentiating NK-directed ADCC activity directed at RS cells. 
It is currently not known whether molecules other than PD-L1 contribute to the inhibition of 
infiltrating immune cells in cHL. In particular, the functional significance of PD-L2, the 
other ligand for PD-1, in contributing to the disease phenotype of cHL remains unclear. If 
PD-L2 does have an important role in driving the cHL disease phenotype, it might be 
expected that an anti-PD-L1 inhibitor would be less efficacious than a PD-1 inhibitor, which 
blocks the molecular interactions with both the PD-L1 and PD-L2 ligands. However, even if 
PD-L2 does make a significant contribution to the cHL disease phenotype, anti-PD-L1 agents 
like avelumab which leave the PD-L2 ligand functionally intact may, in principle, still be 
effective through their potential to mediate ADCC activity and direct kill of malignant HRS 
cells.
Emerging clinical data suggests that checkpoint blockade with anti-PD-1/PD-L1 agents may 
offer an effective therapeutic option in a broad selection of lymphoid malignancies, 
especially in those such as cHL that harbor the 9p24.1 genetic abnormality. Lymphoid 
malignancies such as cHL which have the 9p24.1 alteration have been found to have a higher 
response rate to checkpoint inhibition than those, such as non-Hodgkin’s lymphoma (NHL) 
indications, which lack this genetic change.6,7,8 Nivolumab, a high-affinity, fully human 
anti-PD-1 monoclonal antibody (mAb) has been has been granted accelerated approval for 
the treatment of cHL that has relapsed or progressed following autologous HSCT and 
post-transplantation brentuximab vedotin.9,37  In a cohort of 95 patients from two studies 
(Checkmate 205 and 039), an ORR of 65% (95% CI: 55, 75) was reported in 62 patients, 
including: 7 (7%) with a complete response (CR) and 55 (58 %) with a partial response (PR).  
The median duration of response was 8.7 months (6.8, not evaluable). In addition an update 
of the arm B from study Checkmate 205 enrolling patients treated with Brentuximab Vedotin 
after failing an autologous HSCT was presented at the 2016 ASH congress:  at data cut-off 
(April 2016) with median duration of follow-up of 15.4 months (range 1.9—18.5),
80 patients had been treated in that cohort.  Independent Radiologic Review Committee 
(IRRC)-assessed ORR for patients in 205B was 68% (95% CI, 56%, 78%).  CR and PR rates 
per IRRC were 8% (3%, 16%) and 60% (48%, 71%), respectively.  With longer follow-up, 
the median duration of response was prolonged to 13.1 months (95% CI, 8.7, not reached; 
range, 0.0, 14.2+). The median duration of CR (DOCR) was not reached (95% CI, 4.6, not 
available [NA]; range, 0.7+, 10.4+) and the median duration of PR was 13.1 months 
(95% CI, 7.79, NA; range, 0.0, 13.4+). IRRC median PFS was 14.8 months (95% CI, 
11.3 months, NA); 12-month PFS was 54.6% (95% CI, 40.9%, 66.4%), and 12-month overall
survival (OS) was 94.9% (median OS not reached).  Of 37 patients (46%) who discontinued 
nivolumab, the most common reasons were disease progression (n = 19 [24%]), allogeneic 
stem cell transplant (n = 7 [9%]) and adverse events (n = 5 [6%]).47


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The other PD-1 inhibitor pembrolizumab has also been granted accelerated approval for adult 
and pediatric patients with refractory cHL, or those who have relapsed after three or more 
lines of therapy.  Approval was based on data from 210 adult cHL patients enrolled in a 
multicenter, non-randomized, open-label clinical trial.  Patients had refractory or relapsed 
disease after autologous HSCT (129 patients) and/or Brentuximab Vedotin (175 patients), 
and received a median of four prior systemic therapies (range: 1, 12). With a median 
follow-up of 9.4 months (range: 1-15), the ORR was 69% (95% CI: 62, 75). This included 
PR in 47% of patients and CR in 22%. The estimated median response duration was 
11.1 months (range 0 to 11.1).38
While these results are encouraging, there is room for improvement with therapies that 
increase the ORR.
Due to the potential risk of checkpoint inhibitors-induced Graft-Versus-Host Disease 
(GVHD), patients with a prior allo-HSCT were excluded from the nivolumab studies, while
pembrolizumab, although excluding only patients who had received an allo-HSCT in the past 
5 years or greater than 5 years but with symptoms of GVHD, did not enroll any patient with a 
prior allo-HSCT.  As a result, only limited data are available for the use of checkpoint 
inhibitors in post-allo-HSCT patients. The potential to enhance the graft-versus-lymphoma 
response in post-allo-HSCT patients, however, provides a rational basis for the use of 
checkpoint inhibitors in this subgroup of cHL patients despite the risk of inducing GVHD.31
GVHD is a common and potentially life-threatening complication of allo-HSCT. It is 
immunologically-mediated and contributes to the high morbidity and mortality of 
allo-HSCT.32 GVHD has several clinical manifestations, and these may emerge both as a 
result of the disease, and its treatment. Several recent case reports and patient series indicate 
that checkpoint inhibitors may be efficacious in the post-allo-HSCT setting and that 
GVHD-related toxicities may be effectively managed. The observed efficacy and rapid 
kinetics of the responses following treatment of post-allo-HSCT patients with checkpoint 
inhibitors confirms that checkpoint inhibition has the potential to enhance the 
T-cell-mediated graft-versus-lymphoma response. 
A Phase 1/1b multicenter, investigator-initiated study testing the safety and efficacy of 
ipilimumab in 28 patients with hematologic malignancies relapsing following allo-HSCT 
(including 7 patients with cHL) has been reported.45  GVHD that precluded further 
administration of ipilimumab was observed in 14% of the patients including: 3 cases of 
chronic GVHD of the liver, and 1 case of Grade 2 acute GVHD of the gut, both of which 
resolved with glucocorticoids. Immune-related adverse events, including one death, were 
observed in 21% of patients.  ORR was 32% and with a median follow-up of 15 months 
(range 8-27) the 1-year OS rate was 49%, demonstrating that CTLA-4 blockade with 
ipilimumab can induce clinically significant remissions in patients with recurrent 
malignancies following HSCT.


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In a published study of 20 post-allo-HSCT cHL patients treated with nivolumab,33 the ORR 
was 95% with CR and PR rates of 42% (95%CI= 21, 67; n=8) and 52% (95%CI= 29, 76;
n=10), respectively.  Acute GVHD (30%, 95%CI=9.9, 50.1) developed in 6 patients for two 
of them it was fatal. At a median follow-up of 370 days (range 24-486), median PFS and OS 
have not been reached.  The efficacy of nivolumab in the post-allo HSCT patient population 
has been shown also other published case reports.34,52  A case of fatal GVHD following 
treatment with the checkpoint inhibitor pembrolizumab has also been reported.35  In both the
nivolumab and the pembrolizumab product labels, a warning describing the increased risk of 
GVHD and GVHD-related fatality in patients that received an allogeneic HSCT after being 
previously treated with a checkpoint inhibitor is reported.37,38 The nivolumab label also 
reports a warning describing the increased risk of hepatic veno-occlusive disease (VOD) in 
the same patient population.37 Overall, however, the benefit/risk assessment in patients that 
have previously failed allo-HSCT favors the testing of these agents in the post-allo-HSCT
setting, as there are no effective treatments available for these patients, and their life 
expectancy is very poor.36
1.5. Rationale for Avelumab Starting Dose
1.5.1. Lead-In Phase
The avelumab dosing regimens investigated in the lead-in phase of this study were 10 mg/kg 
every 2 weeks (Q2W), 500 mg Q2W, 500 mg every 3 weeks (Q3W), 350 mg Q2W, and 
70 mg Q2W administered as 1-hour intravenous infusions.  Of note, the currently used 
clinical dosing regimen in the clinical development of avelumab is 10 mg/kg Q2W.  The 
specific dosing regimens were chosen to explore the influence of: 1) different nominal doses; 
2) dosing frequency (Q2W vs. Q3W); and 3) fixed dosing vs body weight-based dosing on 
avelumab PK and the TO time course.  The purpose of exploring the different dosing 
attributes is to gain insight on the regimens that would provide greater than 90% TO over the 
entire dosing interval.  Moreover, this study was designed to identify pharmacodynamic (PD) 
markers that provide evidence of in vivo pharmacological activity, providing further support 
for selection of doses exhibiting sufficient target coverage (eg, tumor gene expression, T-cell 
infiltration).
The proposed treatment cohorts were enrolled in parallel.  The plasma exposures of the 
different dose levels being investigated are not expected to exceed 10 mg/kg Q2W, the 
current clinically used dosing regimen.  Since there was no expectation of a dose-related 
safety concern and a dose escalation design may confound results of the PD time-course 
(ie, carry over effect) for the different dosing regimens tested, a parallel design was 
implemented.
The preliminary TO data from clinical studies suggest >90% TO is required for clinical 
benefit.  Based on in-vitro evidence, 90% receptor occupancy is reached in blood samples at 
avelumab concentrations greater than 1 g/mL.  In a dose escalation phase of a Phase Ib 
study (Trial EMR100070-001), all patients at the current recommended dose of avelumab, 
10 mg/kg, reached or exceeded the serum level (median Ctrough) of avelumab required for 
>90% TO.  Moreover, PK simulations indicated that a 10 mg/kg Q2W dosing regimen 
provides >90% TO over the entire dosing interval for the majority of patients (Table 1).


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Avelumab plasma exposures in the dosing regimens to be investigated in this study are 
expected to be less than those obtained from a 10 mg/kg Q2W dosing regimen.  However, 
each dosing regimen is expected to provide median trough plasma concentrations (Ctrough) 
greater than 1 g/mL for the majority of the dosing interval (Table 1), and thus >90% TO is 
expected to be reached in all blood samples.  However, given the inherent variability in 
avelumab PK and the corresponding variability in TO, it is uncertain whether or not a lower 
exposure (ie, lower dose and/or longer dosing interval) may provide a similar therapeutic 
benefit to that observed with 10 mg/kg.  The purpose of exploring the different dosing 
attributes is to gain insight on the dosing regimen(s) that would provide greater than 90% TO 
over the entire dosing interval.  For patients not achieving >90% TO in Cycle 1, the dose 
may be escalated to 10 mg/kg (Treatment Cohort E) starting at C2D1, after C1 assessment of 
TO.
The doses chosen for this study will help characterize the dose-exposure-response profile.  
The protocol restricts the dosing regimens to provide exposures yielding a mean TO
>90% over the dosing interval based on simulations (Table 1).  There is approximately a 
40% difference in exposure between 350 (Cohort B) and 500 mg Q2W (Cohort D) dosing 
regimens.  Based on simulations (Table 1), the median trough concentrations for 350 mg 
Q2W yields median trough exposures that are approximately half of the 10 mg/kg dosing 
regimen, whereas the 500 mg Q2W median exposures are between 10 mg/kg and 350 mg. 
Moreover, this study is designed to identify pharmacodynamic (PD) markers that provide 
evidence of in vivo pharmacological activity, providing further support for selection of doses 
exhibiting sufficient target coverage. 
Table 1.
Simulated Median Ctrough (g/mL) and 95% Prediction Interval (PI) for 
Proposed Avelumab Dosing Regimens
Cohort - dosing regimen
Median Ctrough
Lower 95% PI
Upper 95% PI
A - 70 mg Q2 weeks
2.6
0.98
6.2
B - 350 mg Q2 weeks
13.6
5.2
31.8
C - 500 mg Q3 weeks
7.0
1.7
20.3
D - 500 mg Q2 weeks
20.2
7.0
45.4
E - 10 mg/kg Q2 weeks
27.3
9.9
63.9
1.5.2. Preliminary Results of the Lead-in Phase
From March to November 2016, a total of 31 patients were enrolled in the lead-in phase of 
the study and 30 received avelumab treatment. The majority of patients were male (80.6%) 
or caucasian (71.0%). The median age was 38 years (range 22 to 81).
A total of 13 patients had received a prior stem cell transplant: 5 patients had previously 
received an autologous HSCT, and 8 patients a prior allogeneic HSCT. The remaining 
19 were ineligible for HSCT.  As of the cutoff date of 09 February 2017, 14 (45.2%) patients 
were still on treatment, 17 (54.8%) patients had discontinued, and 1 patient was randomized 
but never dosed.  Out of the 17 patients who discontinued study treatment, 6 (19.4%) did so
due to progressive disease, and 5 (16.1%) due to an adverse event (Grade 3 GVHD in 
2 patients, Grade 3 infusion related reaction in 2 patients and Grade 3 elevated liver function 


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tests in 1 patient); 1 patient was discontinued due to physician decision, 1 because was not 
meeting the eligibility criteria anymore, and 4 for other reasons.
Overall, the median duration of study treatment was 14 weeks (range 2.0-46.1), for a median 
of 6 infusions (range 1-23). 
Preliminary efficacy data from the lead-in phase are shown in Table 2.
Table 2.
Preliminary Efficacy Data from the Lead-In Phase
All patients
Best Overall 
Response
70 mg
Q2W (N=6)
350 mg
Q2W (N=7)
500 mg
Q3W (N=6)
500 mg
Q2W (N=6)
10 mg/kg
Q2W (N=6)
Total
(N=31)
n (%)
CR
1
0
1
0
0
2 (6.5%)
PR
3
1
4
3
4
15 (48.4%)
SD
0
4
1
0
0
5 (16.1%)
PD
0
0
0
1
2
6 (19.4%)
NE
2
2
0
2
0
6 (19.4)
ORR n (%)
(95% CI)
4 (66.7)
1 (14.3)
5 (83.3)
3 (50)
4 (66.7)
17 (54.8)
(36.0, 72.7)
Post-allo patients
Best Overall 
Response
70 mg
Q2W (N=1)
350 mg
Q2W (N=2)
500 mg
Q3W (N=2)
500 mg
Q2W (N=2)
10 mg/kg
Q2W (N=1)
Total
(N=8)
n (%)
CR
0
0
1
0
0
1 (12.5)
PR
1
0
1
2
1
5 (62.5)
SD
0
0
0
0
0
0
PD
0
0
0
0
0
0
NE
0
1
0
0
0
1 (12.5)
ORR n (%)
(95% CI)
1 (100)
0
1 (100)
2 (100)
1 (100)
6 (75)
(34.9-96.8)
Source: Output for PRJB999 Submission (B9991007) Protocol (B9991007_LEADIN) 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NE=not evaluable
Of the 5 patients that relapsed after an autologous HSCT, 1 patient (20%) achieved a PR in 
the 500 mg Q3W cohort.


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Safety: Treatment-Related Adverse Events (TRAEs) were reported in a total of 24 (80.0%) 
patients, and were of Grade 3 severity in 11 (36.7%) of the patients; no Grade 5 AEs were
reported.  Of the 11 patients who experienced a Grade3 AE, 4 were in the 70 mg Q2W 
cohort, 1 in the 350 mg Q2W, 3 in the 500 mg Q2W, 2 in the 500 mg Q3W, and 1 in the 
10 mg/kg Q2W cohort. The most common (10 %) TRAEs of any grade were 
infusion-related reaction (IRR; 26.7%), nausea (20.0%), rash (20.0%), and fatigue (13.3%). 
There was no clinically significant difference between the safety profiles of the different 
dosing cohorts.
Two of the 8 post-allo HSCT patients developed Grade 3 acute GVHD of the liver (28%):
1 patient each in the 70 mg Q2W and 500 Q3W cohorts, respectively. 
The first patient with acute GVHD was a 31-year old female who received an allogeneic 
HSCT from a related donor in 2011.  In May 2016, after receiving a total of two doses of 
avelumab 70 mg Q2W, she developed Grade 3 acute GVHD of the liver which ultimately 
completely resolved following permanent discontinuation of avelumab, and prolonged
immunosuppressive therapy (including high dose steroids, basiliximab, infliximab, 
tacrolimus, sirolimus, mycophenolate mofetil and ruxolitinib). The patient achieved a partial 
response approximately 6 weeks after receiving the first dose of avelumab, which matured 
into a complete response in August 2016 (approximately 4 months after the first dose of 
avelumab). The CR lasted until January 2017 (approximately 9 months later her first dose of 
avelumab), at which point progressive disease was documented.
The second patient with acute GVHD was a 30-year old male who received an allogeneic 
HSCT from a unrelated donor in 2014.  In June 2016, after receiving a single dose of 
avelumab 500 mg Q3W, he developed Grade 3 acute GVHD of the liver associated with 
biliary sepsis and Grade 4 thrombocytopenia. The patient was treated with high dose steroids 
and rituximab, until complete resolution of the event.  The patient achieved a CR 
approximately 6 weeks following the single dose of avelumab.  At the time of data cutoff this 
response was still ongoing.
Of the 30 patients treated in the lead-in phase, 8 (26.7%) experienced at least 1 IRR; 
2 (33.3%) each in the 70 mg Q2W, 500 mg Q2W, and 10 mg/kg Q2W cohorts, respectively, 
and 1 (16.7%) each in the 350 mg Q2W and 500 mg Q3W cohorts, respectively.  Most of the 
IRRs were Grade 2, while 2 (6.7%) patients (1 each in the 70 mg Q2W and 500 mg Q2W 
cohorts, respectively) experienced a Grade 3 IRR which led to treatment discontinuation.  
Preliminary TO data analysis from the lead-in phase showed that >90% TO was observed
throughout the dosing interval for all dosing regimens tested.
1.5.3. Rationale for the Exploration of Fixed Dosing vs Body Weight-Based Dosing
To date, avelumab has been administered at the clinically active, safe, and tolerable dose of 
10 mg/kg Q2W to more than 1,700 patients across multiple (predominantly solid tumors) 
indications.  Furthermore, the 10 mg/kg Q2W avelumab dosing regimen has been granted 
accelerated approval by the US Food and Drug Administration (FDA) for Merkel cell 
carcinoma48. Avelumab was originally dosed on a mg/kg basis in order to reduce the 


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inter-subject variability in drug exposure. However, emerging data for inhibitory 
monoclonal antibodies, including the marketed PD-1 and PD-L1 immune checkpoint 
inhibitors nivolumab, pembrolizumab, and atezolizumab, reveal that body weight-based 
dosing regimens do not result in less variability in measures of exposure as compared with
fixed (ie, body-weight independent) dosing regimens.49-51 Additionally, fixed dosing has less 
potential for dispensing errors, shorter dose preparation times, and greater ease of 
administration.
Population PK analysis was conducted based on acquired PK data across three single-agent 
avelumab studies incorporating patients with 14 different types of cancer. PK simulations 
suggest that exposures to avelumab across the available range of body weights are less 
variable for fixed dosing, as compared with body weight based dosing, although exposures 
were similar near the population median weight. Low-weight subjects tended towards 
marginally lower exposures relative to the rest of the population when weight-based dosing 
was used, and marginally higher exposures when flat dosing was applied. However, these 
exposure differences are not expected to be clinically meaningful.  Furthermore, the fixed 
doses chosen for this study are expected to result in serum concentrations (Ctrough >1 g/mL)
required to maintain avelumab serum concentrations at >90% TO throughout the entire Q2W 
dosing interval across all weight categories.
Therefore, in this clinical trial, a fixed dosing regimen will be utilized for avelumab, with the 
avelumab dose of 70 mg administered as 1-hour IV infusions Q2W, and with the potential to 
increase the dose to 500 mg Q2W. 
1.5.4. Rationale for the Dosing Regimens in the Expansion Phase
Given the high ORR (6/8=75%) observed in the post-allo HSCT cohort, the poor prognosis 
of patients with cHL relapsing after an allo-HSCT, and the lack of approved therapies in this 
setting, the expansion phase will enroll only patients in whom allogeneic HSCT has failed.
Based on the lead-in phase data, which includes safety, an assessment of the number of 
patients achieving >90% TO following 1 treatment cycle, and clinical activity that met the 
predefined criteria (observing at least 3 objective responses per the Response Criteria for 
Malignant Lymphoma42 (Appendix 2) in each given cohort), two dose regimens (70 mg Q2W 
and 500 mg Q2W) were selected in the expansion phase for the intra-patient dose escalation
design as outlined below.  As described in Section 1.5.2, TO, safety, and efficacy data from 
the lead-in phase were similar across all the dose regimens tested, including a dose as low as 
70 mg Q2W (~1/10 of the dose used in other studies across the avelumab program), with no 
evidence of a dose-response relationship either in the entire population, or in the post-allo 
HSCT cohort. Although the TO was >90% at all the regimens tested in the lead-in phase, 
peripheral TO may over-estimate TO within the tumor itself. Therefore, although responses 
were observed across the broad range of dose regimens tested, it is not clear whether the 
frequency, depth, and durability of the responses will be more optimal at higher doses. 
Given that the peripheral TO has the a priori potential to differ from the intra-tumoral TO, 
and the potential for life-threatening checkpoint-induced GVHD, patients will start the 
expansion phase with a 70 mg Q2W ‘test’ dosing regimen of avelumab, the lowest exposure 
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Although there is no evidence that checkpoint- induced GVHD is dose/exposure dependent, 
starting patients on the lowest tested dose is expected to minimize the risk of 
checkpoint-induced GVHD, while also providing for the possibility that higher doses may 
capture responses that are not achieved at lower doses.  Patients will be monitored for safety 
and efficacy at the test dose level
Given that 70 mg Q2W is the lowest dose tested, and the therapeutic activity at this low dose 
might not be optimal, patients not achieving a CR may be dose escalated to the higher dose 
(500 mg Q2W) as detailed below.  A target dosing regimen of 500 mg Q2W (~8x the 
exposure of 70 mg Q2W), provides an exposure intermediate between that of the highest 
(10 mg/kg Q2W) and lowest tested (70 mg Q2W) in the lead-in phase.  A dose-response 
relationship has not been observed for either safety or efficacy in the lead-in phase. 
However, given the relatively small sample size and the potential life-threatening clinical 
sequelae of high-grade GVHD, patients will escalate to a dose which is almost a log higher 
than the test dose while at the same time being lower than the 10 mg/kg Q2W which is used 
in other studies across the avelumab program.
All patients will commence dosing at 70 mg Q2W, the lowest dose that showed clinical
activity, and will be monitored for safety and efficacy.  Following 3 cycles of treatment at 
70 mg Q2W, patients who at the 6-week tumor assessment achieve a CR will continue at the 
same dose regimen.  Patients achieving a PR at 6 weeks will continue at 70 mg Q2W for an 
additional 3 cycles, and if the 12-week tumor assessment still shows a PR, patients will be 
dose escalated to 500 mg Q2W.  Patients who at the 6-week tumor assessment achieve a SD,
will be dose escalated to 500 mg Q2W. Additionally, those patients who at the 6-week 
assessment are considered to have initial evidence of disease progression as confirmed by 
BICR but in the opinion of the Investigator are still experiencing clinical benefit (as defined 
in Section 5.4.1.1), may continue treatment with study drug at the Investigator’s discretion 
and following discussion with the Sponsor. Such patients may be considered for escalation 
to 500 mg Q2W. Dose escalation to 500 mg Q2W after the 6 or the 12-week tumor 
assessment, will be only permitted so long as there is no clinical evidence of GVHD or 
treatment-related Grade 2 AEs with a duration of more than 14 days. Patients with PD at 
6 weeks in the absence of clinical benefit will be permanently discontinued from study 
treatment.
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives (Lead-in Phase)
Primary Objective

To characterize the pharmacokinetics (PK) of different dosing regimens of avelumab 
and its relation to target occupancy (TO) in peripheral blood of patients with cHL.
Secondary Objectives

To evaluate the overall safety and tolerability of different dosing regimens of 
avelumab.


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•
To assess the immunogenicity of different dosing regimens of avelumab.
•
To evaluate the effect of different dosing regimens of avelumab on pharmacodynamic
biomarkers of tumor immunophenotype and anti-tumor immune response.
•
To evaluate the anti-tumor activity of avelumab in patients with cHL.
2.2. Endpoints (Lead-in Phase)
Primary Endpoints
•
Percent TO by dose/schedule in peripheral blood immune cells, including CD14+ 
monocytes and CD3+ T cells;
•
Pharmacokinetic parameters of avelumab including, but not limited to, Cmax, Tmax, 
AUClast, Tlast, AUC sd,τ, t1/2, AUCsd,inf, CL, and Vz as data permit.  Multiple Dose 
(MD) - Css,max, Tss,max, AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss, Rac (AUCss,τ /AUCsd,τ) 
and Rss (AUCss,τ /AUCsd,inf) as data permit.
Secondary Endpoints
•
Adverse Events as characterized by type, severity (as graded by National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03), 
timing, seriousness, and relationship to study therapy.
•
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v. 4.03), and timing.
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•
Anti-drug antibodies (ADAs; neutralizing antibodies) and serum titers against 
avelumab.
•
Phenotype, quantity, and localization of TILs in tumor biopsy tissue by IHC.
•
Relative expression of transcripts associated with immune activation and regulation in 
tumor biopsy tissue by gene expression profiling.
•
Phenotype, relative proportions, activation state and PD-L1 expression of peripheral 
blood T cell subsets by flow cytometry.
•
Objective response according to Response Criteria for Malignant Lymphoma42 per 
Investigator assessment.
•
Disease control (DC), time to tumor response (TTR), duration of response (DR), 
progression-free survival (PFS) per Investigator assessment.
2.3. Objectives (Expansion Phase)
Primary Objective
•
To evaluate the objective response rate (ORR) of avelumab in patients with relapsed 
or refractory cHL who have previously been treated with an allogeneic HSCT.
Secondary Objectives
•
To evaluate the overall anti-tumor activity of avelumab.
•
To evaluate the overall safety profile of avelumab.
•
To evaluate the incidence and severity of acute and chronic GVHD.
•
To characterize the pharmacokinetics of avelumab.
•
To assess the immunogenicity of avelumab.
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•
To evaluate the phenotype and quantity of TILs and correlate these findings with 
anti-tumor activity.
2.4. Endpoints (Expansion Phase)
Primary Endpoint
Objective response defined by the Lugano Classification43 as evaluated by the blinded 
independent central review (BICR).
Secondary Endpoints
•
Objective response as defined by the Lugano Classification43 and evaluated by 
Investigator’s assessment.
•
Time to tumor response (TTR), duration of response (DR), Disease Control (DC) and 
progression-free survival (PFS) according to the Lugano Classification43 by BICR 
and by Investigator’s assessment, as well as overall survival (OS).
•
AEs and laboratory abnormalities as graded by National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v.4.03; timing, 
seriousness, and relationship to study therapy.
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•
Acute GVHD as defined by the modified Seattle Glucksberg criteria (Consensus 
Conference on Acute GVHD Grading Criteria-Appendix 4) and Chronic GVHD as 
defined by the NIH Consensus Development Project (Appendix 5).
•
Pharmacokinetic parameters of avelumab including, but not limited to, Cmax, Tmax, 
AUC sd,τ, t1/2, CL, and Vz as data permit.  Multiple Dose (MD) - Css,max, Tss,max, 
AUCss,τ, t1/2, Css,min, Css,av, CL, and Vss as data permit.
•
Anti-drug antibodies (ADAs; neutralizing antibodies) and serum titers against 
avelumab.
•
Phenotype, quantity, and localization of TILs in tumor biopsy tissue determined by 
IHC.
3. STUDY DESIGN
3.1. Study Overview
This is a Phase 1b, open-label, multi-center study comprising a lead-in phase and an
expansion phase in patients with relapsed/refractory cHL.
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The lead-in is a multiple-dose, randomized, parallel-arm, pharmacokinetic and 
pharmacodynamic study of avelumab as a single agent in adult patients with cHL. Patients 
enrolled in the lead-in phase of the study were required to have relapsed following a prior 
autologous or allogeneic HSCT, or to be ineligible for HSCT.
In the lead-in phase of the study, which completed enrollment on November 29, 2016,a total 
of 31 patients were randomized across 5 treatment cohorts in a 1:1:1:1:1 ratio.  The 
5 treatment cohorts were: 70 mg Q2W (Cohort A), 350 mg Q2W (Cohort B), 500 mg 
Q3W (Cohort C), 500 mg Q2W (Cohort D), and 10 mg/kg Q2W (Cohort E).  Each cohort 
enrolled 6 patients, except Cohort B in which 7 patients were randomized, but 1 was never 
dosed. The primary objective for the lead-in phase was to determine the doses and schedules 
of avelumab that provide >90% TO over the dosing interval and to identify a dose regimen 
for use in the dose expansion phase.  For patients not achieving >90% TO after C1D1, the 
dose could be escalated to 10 mg/kg (Treatment Cohort E) starting at C2D1, after Cycle 1 
assessment of TO.
The study design for the lead-in and expansion phases is detailed in Figure 1.
Figure 1.
B9991007 Study Design for the Lead-In and Expansion Ph
Based on the preliminary TO, safety, and efficacy results from the lead-in phase, the 
expansion phase will evaluate the anti-tumor activity and safety of single-agent avelumab 
utilizing an intra-patient dose escalation paradigm based on two of the dosing regimens 
studied in the lead-in phase in 40 cHL patients in whom an allogeneic HSCT has failed. 
The study design for the expansion phase is shown in Figure 2. 


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Figure 2.
B9991007 Study Design for the Expansion Phase
Approximately 70 patients are expected to be enrolled into the study. Treatment with 
investigational product will continue until disease progression, patient refusal, or 
unacceptable toxicity, patient is lost to follow-up, or until the study is terminated by the 
Sponsor, whichever occurs first (see Section 6.4).
3.1.1. Study Phases
Lead-in Phase: 
Patients were randomized to one of the 5 treatment cohorts as stipulated in Table 3 below.
Table 3.
Avelumab Dosing Cohorts for the Lead In Phase
Cohort
Dose
Schedule
N
A
70 mg
Q2W
6
B
350 mg
Q2W
7
C
500 mg
Q3W
6
D
500 mg
Q2W
6
E
10 mg/kg
Q2W
6


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Expansion Phase:
In this phase, an intra patient dose-escalation design will be utilized as follows: all patients 
will commence dosing at 70 mg Q2W, the lowest dose that showed clinical activity, and will 
be monitored for safety and efficacy.  Following 3 cycles of treatment at 70 mg Q2W, 
patients who at the 6-week tumor assessment achieve a CR will continue at the same dose 
regimen.  Patients achieving a PR at 6 weeks will continue at 70 mg Q2W for an additional 
3 cycles, and if the 12-week tumor assessment still shows a PR, patients will be dose 
escalated to 500 mg Q2W.  Patients who at the 6-week tumor assessment achieve a SD, will 
be dose escalated to 500 mg Q2W.  Additionally, those patients who at the 6-week 
assessment are considered to have initial evidence of disease progression as confirmed by 
BICR but in the opinion of the Investigator are still experiencing clinical benefit (as defined 
in Section 5.4.1.1), may continue treatment with study drug at the Investigator’s discretion 
and following discussion with the Sponsor.  Such patients may be considered for escalation 
to 500 mg Q2W. Dose escalation to 500 mg Q2W after the 6 or the 12-week tumor 
assessment, will be only permitted so long as there is no clinical evidence of GVHD or 
treatment-related Grade 2 AEs with a duration of more than 14 days.  Patients with PD at 
6 weeks in the absence of clinical benefit will be permanently discontinued from study 
treatment.
Patients with GVHD of any grade (other than Grade 1 GVHD of the skin requiring topical 
therapy only) must be permanently discontinued from the study treatment.
Disease responses will be assessed by a Blinded Independent Central Review (BICR), 
according to processes defined in the Study Manual.  Intra-patient dose escalation decisions 
will be made following discussion between the Investigator and the Sponsor and will be 
informed by the BICR disease response assessment-see Section 7.5.1.
3.1.2. Criteria for Intra-Patient Dose Escalation
The 5 different treatment cohorts in the lead-in phase were randomized in parallel.  To ensure 
patients at all dose levels achieved the target level of ≥90% TO, the dose could be escalated
to 10 mg/kg (Treatment Cohort E) starting at C2D1, after C1 assessment of TO. Criteria for 
Intra-Patient Dose escalation in the expansion phase have been detailed in Section 3.1.1.
3.1.3. Safety Stopping Rules
The safety stopping rules will be based on the observed incidence of acute GVHD Grade 3, 
acute GVHD-related mortality and Grade 4 irAEs, within 16 weeks from start of study 
treatment for each patient in the lead-in phase and expansion phase.  Two formal evaluations 
of safety will be performed:

16 weeks after 15 patients have received the first dose of study treatment.

16 weeks after 30 patients have received the first dose of study treatment.


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The statistical stopping criteria (see Section 9.4.1) was determined based on the following 
clinical thresholds:
1. Acute GVHD Grade 3 <33% (Grade 3 liver GVHD must be confirmed by biopsy).
2. Acute GVHD-related mortality 20%.
3. irAEs Grade 4 <15%.
Events from patients who did not meet the criteria for a minimum of 16 weeks follow-up will 
also be considered in the evaluation.  The study will stop if the stopping boundary is crossed 
for any of the 3 event categories.
4. PATIENT SELECTION
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol.
4.1. Inclusion Criteria
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Histological confirmation of classical Hodgkin’s Lymphoma (cHL) with relapsed or 
refractory disease who, for the lead-in phase, either have had a prior autologous or 
allogeneic HSCT or are not eligible for HSCT, and , for the expansion phase, have 
had a prior allogeneic HSCT. In the expansion phase there must be a documented 
CD3+ donor chimerism of 20%.
2. Patients must be off previous cHL therapy for at least 28 days prior to randomization
in the lead-in phase/first dose of study treatment in the expansion phase.
3. At least 1 fluorodeoxyglucose (FDG)-PET-avid (Deauville 4/5)21 measurable lesion 
>1.5 cm on PET-CT scan as defined by the Response Criteria for Malignant 
Lymphoma42 (Appendix 2 for the lead-in phase) and the Lugano Classification43
(Appendix 3 for the expansion phase) that has not previously been irradiated. 
4. Age 18 years. 
5. Estimated life expectancy of at least 3 months.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.


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7. Adequate bone marrow function including: 
a.
Absolute neutrophil count (ANC) 1,000/mm3 or 1.0 x 109/L (may have 
received G-CSF support); 
b. Platelets 50,000/mm3 or 50 x 109/L; 
c.
Hemoglobin 8.0 g/dL (>4.9 mmol/L) (may have been transfused).
8. Expansion phase: De novo tumor biopsy and archival tumor tissue:
a.
A de novo baseline biopsy and consent for an on-treatment tumor biopsy that is 
not the only measurable lesion is required within 28 days prior to the first dose of 
study treatment and following the first 6-week scan respectively, unless collecting 
either biopsy is considered to constitute an unacceptable clinical risk to the 
patient.  Provision of a formalin-fixed paraffin-embedded (FFPE) tumor tissue 
block is required for the de novo tumor biopsy.  In the event the patient has an 
archival tumor tissue sample obtained within 3 months of the first dose of study 
treatment, and there has been no intervening systemic anti-cancer therapy, this 
can substitute for the baseline de novo sample.  Provision of an FFPE tumor tissue
block, or of at least 15 (but preferably 20) freshly cut unstained slides (if block is 
unavailable) is required in the event that an archival tumor tissue specimen is 
provided. 
b. If a de novo biopsy is unadvisable due to an unacceptable clinical risk to the 
patient, an archival tumor tissue sample from the closest time point that is within 
6 months of the first dose of study treatment must be provided. Provision of an 
FFPE tumor tissue block, or of at least 15, (but preferably 20) unstained slides (if 
block is unavailable) is required in the event that an archival tumor tissue 
specimen is provided. 
9. Adequate Renal Function: Estimated creatinine clearance 30 mL/min as calculated 
using the Cockcroft-Gault (CG) formula or by 24-hour urine collection for creatinine 
clearance or according to local institutional standard method.
10. Adequate Liver Function, defined by:
a.
Total serum bilirubin 1.5 x upper limit of normal range (ULN);
b. Aspartate and Alanine aminotransferase (AST and ALT) levels 2.5 x ULN.
11. International Normalized Ratio (INR) or prothrombin time (PT) <1.5 x ULN.
12. Serum or urine pregnancy test (for females of childbearing potential) negative at 
screening.


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13. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective method(s) of contraception 
throughout the study and for at least 30 days after the last dose of assigned treatment. 
Female patients who are not of childbearing potential (ie, meet at least one of the 
following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;
Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; a serum follicle-stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal women. 
14. Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study. As inclusion of 
adult patients for whom consent must be provided by a legally authorized 
representative is not appropriate for this research, this protocol excludes adult 
individuals who lack capacity to consent for themselves.
15. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests and other study procedures. 
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Patients with prior allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)
who have had: 
a.
Lead-in phase: allo-HSCT performed <12 months prior to randomization.  
Expansion phase: allo-HSCT performed ≤4 months prior to the first dose of 
study treatment. NOTE: Patients who have had allo-HSCT performed >4 months 
prior to the first dose of study treatment must have discontinued all 
immunosuppressive therapy, and must have no clinical evidence of GVHD; or
b. Immunosuppressive treatment for acute or chronic GVHD within 3 months prior 
to randomization for the lead-in phase or prior to the first dose of study treatment 
for the expansion phase (with the exception of those patients who required 
15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day 
oral prednisone or equivalent must have discontinued it within 7 days prior to first 
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c.
Acute Grade 3 or Grade 4 GVHD at any time in the past (as defined by the 
modified Seattle Glucksberg criteria (Consensus Conference on Acute GVHD 
Grading Criteria29) (Appendix 4); or
d. Prior chronic GVHD (as defined by the NIH Consensus Development Project30) 
(Appendix 5) that persisted for >6 months and required systemic 
immunosuppression (with the exception of those patients who required 
15 mg/day oral prednisone or equivalent). Patients who required 15 mg/day 
oral prednisone or equivalent must have discontinued it within 7 days prior to the 
first dose of study treatment; or
e.
A donor lymphocyte infusion (DLI) within 3 months prior to randomization for 
the lead-in phase or first dose of study treatment for the expansion phase.
2. Prior therapy with an anti-PD-1 or anti-PD-L1 mAb.
a.
Lead-in Phase: May be enrolled if patient stopped prior anti-PD1 or anti-PD-L1
therapy more than one year prior to randomization and had a documented prior 
response.
b. Expansion Phase: Prior therapy with an anti-PD-1 or anti-PD-L1 agent following
allo-HSCT is prohibited unless the therapy was stopped more than one year prior 
to the first dose of study treatment, and the patient had a documented prior 
response. NOTE: Prior therapy with an anti-PD-1 or anti-PD-L1 agent prior to 
allo-HSCT is permitted with no time limits and irrespective of a documented 
response. 
c.
Patients with a history of Grade 3 anti-PD-1 or anti-PD-L1-related immune 
toxicity are not eligible.
3. Persisting toxicity related to prior therapy NCI CTCAE v4.03 Grade >1. Note that 
alopecia, sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a 
safety risk to the patient based on the investigator’s judgment are acceptable.
4. Major surgery within 4 weeks or radiation therapy within 14 days prior to study entry. 
5. Prior palliative radiotherapy (10 fractions) to lesion(s) is permitted as long as there 
is at least one lesion evaluable for anti-tumor activity and prior radiotherapy that has 
been completed at least 48 hours prior to the first dose of study treatment.
6. Diagnosis of prior immunodeficiency or organ transplant requiring 
immunosuppressive therapy, or known human immunodeficiency virus (HIV) or 
acquired immunodeficiency syndrome (AIDS)-related illness.


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7. Current or prior use of immunosuppressive medication within 7 days prior to 
randomization in the lead in phase/first dose of study treatment in the expansion 
phase, except the following:
a.
Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection).
b. Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or 
equivalent for the treatment of adrenal insufficiency.
c.
Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).
8. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agents.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible.
9. Prior severe hypersensitivity reactions to the investigational product or any 
component of its formulation, including known severe hypersensitivity reactions to 
other monoclonal antibodies (Grade 3 NCI-CTCAE v 4.03).
10. Active infection requiring systemic therapy.
11. 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. Clinically significant cardiovascular disease, either active or within 6 months prior to
randomization for the lead-in phase or the first dose of study treatment for the 
expansion phase: cerebral vascular accident/stroke, myocardial infarction, unstable 
angina, congestive heart failure (New York Heart Association Classification 
Class II), or serious cardiac arrhythmia requiring medication. 
13. Diagnosis of any other malignancy within 5 years prior to randomization for the 
lead-in phase or first dose of study treatment for the expansion phase, except for:
adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the 
breast or cervix, or low-grade (Gleason 6) prostate cancer on surveillance without 
any plans for treatment intervention (eg, surgery, radiation, or castration).
14. Participation in other studies involving investigational drug(s) within 4 weeks prior to 
study entry.
15. Patients who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.


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16. Pregnant female patients; breastfeeding female patients; male patients able to father
children and female patients of childbearing potential who are unwilling or unable to 
use 2 highly effective methods of contraception as outlined in this protocol for the 
duration of the study and for at least 30 days after the last dose of investigational 
product. 
17. Other severe acute or chronic medical conditions including but not limited to colitis, 
inflammatory bowel disease, pneumonitis, or pulmonary fibrosis, or psychiatric 
conditions, recent (within the past year) or active suicidal ideation or behavior, or 
laboratory abnormality that may increase the risk associated with study participation 
or investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient 
inappropriate for entry into this study.
18. Vaccination with live vaccine within 4 weeks of the first dose of avelumab is 
prohibited except for administration of inactivated vaccines.
4.3. Lifestyle Guidelines
4.3.1. Contraception
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive avelumab for which the teratogenic risk is currently 
unknown.
Two (2) methods of highly effective contraception must be used throughout the study and 
continued for at least 30 days after the last dose.  The Investigator or his or her designee, in 
consultation with the patient, will select two appropriate methods of contraception for the 
individual patient and his/her partner from the list of permitted contraception methods (see 
below), and instruct the patient in their consistent and correct use.  Patients need to affirm 
that they meet the criteria for correct use of 2 of the selected methods of contraception.  The 
Investigator or his or her designee will discuss with the patient the need to use 2 highly 
effective contraception methods consistently and correctly according to the Schedule of 
Activities and document such conversation in the patient’s chart.  In addition, the 
Investigator or his or her designee will instruct the patient to call immediately if one or both 
selected contraception methods are discontinued, or if pregnancy is known or suspected in 
the patient or to the patient’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the patient plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper containing intrauterine device (IUD).


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3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
6. Female partner who meets the criteria for non-childbearing potential, defined as:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause.  Status may be confirmed by having a serum 
follicle-stimulating hormone (FSH) level within the laboratory’s reference range 
for postmenopausal women.
All sexually active male patients must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 30 days after the last
dose.
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the Sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site.


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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH)
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated or packaged) in 
a way different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use (ICH E6 1.33).
5.1. Allocation to Treatment
In the Lead-in phase, an Interactive Response Technology (IRT) System/Interactive Web 
Response (IWR) was used to randomize patients to treatment cohorts.
The Expansion phase is not randomized.  Therefore in this phase the IRT will be used to 
assign patient number, record visits, and dispense drug.
In both the lead-in phase and the expansion phase, patients must receive their first dose of 
avelumab within 3 days of drug assignment by the IRT. 
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, protocol 
number, the patient number and the date of birth of the patient.  The site personnel will then 
be provided with a treatment assignment and/or dispensable unit (DU) or container number 
when drug is being supplied via the IRT.  The IRT system will provide a confirmation report 
containing the patient number and DU or container number assigned.  The confirmation 
report must be stored in the site’s files.  There is a 24 hours-a-day, 365 days-a-year IRT 
helpdesk available for any questions or issues.  The study specific IRT reference manual will 
provide the contact information and further details on the use of the IRT. 
5.2. Patient Compliance
The site will complete required dosage Preparation Record located in the study manual.  The 
use of the Preparation Record is preferred but it does not preclude the use of an existing 
appropriate clinical site documentation system.  The existing clinical site’s documentation 
system should capture all pertinent/required information on the preparation and 
administration of the dose.  This may be used in place of the Preparation Record after 
approval from the Sponsor’s monitor. 
5.3. Investigational Product Supply
5.3.1. Formulation and Packaging
5.3.1.1. Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20 mg/mL solution and will be supplied by the Sponsor in single-use glass 
vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal.


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Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practices (GMP) guidelines.  Avelumab will be packed 
in boxes each containing one 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 monitoring devices.
5.3.2. Preparation and Dispensing
5.3.2.1. Avelumab
Avelumab will be dosed at the investigational site.
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.
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 Dosage and Administration Instruction. 
Avelumab must not be used for any purpose other than the trial. The administration of trial 
investigational product to patients 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.
See the Dosage and Administration Instruction for instructions on how to prepare the 
investigational product for administration.  Investigational product should be prepared and 
dispensed by an appropriately qualified and experienced member of the study staff 
(eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as allowed by local, 
state, and institutional guidance.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
biotherapeutic agents.
5.4. Administration
All trial treatment will be administered on an outpatient basis.
5.4.1. Avelumab
The Study Manual contains specific instructions for avelumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.


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Avelumab will be administered on Day 1 of each cycle and all procedures/assessments will 
be completed as described in the Schedule of Activities table.  Avelumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons.
Avelumab will be administered as a 1-hour IV infusion once every 2 weeks or 3 weeks.  In 
order to mitigate infusion-related reactions, a 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 may be modified based on local treatment 
standards and guidelines, as appropriate.  Prophylactic steroids are permitted after Cycle 1 
under specific circumstances as described in Section 5.4.4.1.  Sites should make every effort 
to target infusion timing to be as close to 1 hour as possible.  The exact duration of infusion 
should be recorded in both source documents and CRFs.  Possible modifications of the 
infusion rate for the management of infusion-related reactions are described in
Section 5.4.4.1.
A cycle is defined as the time from Day 1 dose to the next Day 1 dose.  If there are no 
treatment delays, a cycle will be 2 weeks for Q2W dosing and 3 weeks for Q3W dosing 
regimens.
Avelumab dose reduction for toxicity management is permitted as detailed in Section 5.4.5. 
No other dose reduction for toxicity management is permitted but next cycle administration 
may be omitted due to persisting toxicity as described in Section 5.4.3.1, and Section 5.4.3.2.
Further details on avelumab dose modifications due to infusion related reactions, tumor lysis 
syndrome, irAEs and GVHD can be found in Section 5.4.4.1, Section 5.4.4.2, Section 5.4.4.3
and Section 5.4.4.4, respectively.
5.4.1.1. Treatment After Initial Evidence of Disease Progression
The response kinetics observed with immunotherapeutic agents such as PD-1/PD-L1 axis 
inhibitors may in some instances result in an apparent initial increase in disease burden prior 
to any objective response being clearly discernable. Consequently, in the presence of 
apparent clinical benefit in the context of early evidence of radiologic disease progression, it 
may, in select cases, and following an individualized assessment of overall risk/benefit, be 
appropriate to consider treatment continuation with avelumab accompanied by radiologic and 
clinical monitoring. 
In the event of evidence of radiological progression, patients may continue to receive 
avelumab if they are clinically stable as defined by the following criteria: 

Absence of clinical signs and symptoms of disease progression.

Absence of clinically significant decline in laboratory values.

No decline in ECOG performance status.


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
Absence of progressive tumor at critical anatomical sites (eg, cord compression)
requiring urgent alternative medical intervention.
If the patient remains clinically stable and repeat imaging at 6 weeks or earlier, no longer 
shows PD but rather a CR, PR, or SD compared to baseline, treatment with avelumab may be 
continued.  In determining whether the tumor burden has increased or decreased, all lesions
should be taken into consideration (refer to the Study Manual). 
If repeat imaging at 6 weeks or earlier confirms PD, then treatment with avelumab should be 
discontinued.  However, according to the Investigator’s clinical judgment and following 
discussion between the Investigator and the Sponsor, if a patient continues to experience
clinical benefit, continued treatment with avelumab may be considered.  The Investigator’s 
decision to continue treatment should be based on the overall risk-benefit assessment and the 
patient’s clinical condition, including performance status, clinical signs, symptoms, adverse 
events, laboratory data and availability of alternative therapies. 
Prior to treatment continuation, the patient must be re-consented via an informed consent 
addendum and informed that in continuing to receive the investigational product on study,
they may be foregoing the opportunity of being treated with alternative approved or 
investigational therapies that have the potential to provide clinical benefit.
Treatment with avelumab should be permanently discontinued if the patient is found to have 
further disease progression according to the Response Criteria for Malignant Lymphoma(42)
in the lead-in phase or to the Lugano Classification(43) in the expansion phase at the next 
tumor assessment or if there is evidence of further clinical disease progression. 
Patients who stop avelumab treatment for reasons other than disease progression and then go 
on to experience disease progression will be eligible for re-treatment with avelumab at the 
discretion of the Investigator and after discussion with the Sponsor if 1) no cancer treatment 
was administered since the last dose of avelumab, 2) the patient does not meet the safety 
withdrawal criteria, and 3) the trial is still open.  Patients will resume avelumab therapy at the 
same dose and schedule applied at the time of discontinuation 
5.4.1.2. Treatment After Complete Response
Patients achieving CR will continue on treatment with investigational product until disease 
progression, patient refusal, or unacceptable toxicity, patient is lost to follow-up, or until the 
study is terminated by the Sponsor, whichever occurs first (see Section 6.4).
5.4.2. Food Requirements 
Avelumab may be administered without regard to food.
5.4.3. Recommended Dose Modifications
Every effort should be made to administer study treatment on the planned dose and schedule.


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In the event of significant toxicity, dosing may be delayed as described below.  In the event 
of multiple toxicities, dose modification should be based on the worst toxicity observed.  
Patients are to be instructed to notify Investigators at the first occurrence of any adverse 
symptom.  In addition to dose modifications, investigators are encouraged to employ best 
supportive care according to local institutional clinical practices and according to the 
guidance for selected adverse events provided below.
Avelumab dose reduction for toxicity management is permitted only as detailed in 
Section 5.4.5. No other dose reduction for toxicity management is permitted, but dosing
interruptions are allowed for toxicity, as outlined in Section 5.4.3.1, Section 5.4.3.2 and
Section 5.4.4.  Intrapatient dose escalations may be permitted as described in Section 3.1.2.
5.4.3.1. Avelumab Dosing Interruptions in Case of Drug-Related Toxicity
Recommended avelumab infusion interruptions in case of drug-related toxicity are shown 
below in Table 4.  Consider consulting with Sponsor’s Medical Monitor for drug-related 
toxicities.  Always consult with the Sponsor’s Medical Monitor for Grades 3 and 
4 drug-related toxicities.
5.4.3.2. Avelumab Infusion Omissions for Drug-Related Toxicity
Recommendations for avelumab infusion omissions in case of drug-related toxicity are 
shown in Table 4.
Table 4.
Avelumab Infusion Omissions for Drug-Related Toxicity
Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Treatment Modification
Hematologic 
Abnormalities
Grade 1
Continue as per schedule.
Grade 2
Continue as per schedule.
Grade 3
Hold treatment for up to 4 weeks (for every 2-week dosing) 
and for up to 6 weeks (for every 3-week dosing) until 
Grade 1 or baseline, then re-challenge at the same dose.
Permanent discontinuation if recurrence to Grade 3.
(Unless resolves to Grade 1 or baseline within 7 days 
following appropriate medical management).
Grade 4
Permanent discontinuation.
(Unless resolves to Grade 1 or baseline within 7 days 
following appropriate medical management).
Infusion-Related 
Reaction 
Grades 1-4
See Section 5.4.4.1 and Table 5
Tumor Lysis Syndrome
Grades 1-4
See Section 5.4.4.2 and Figure 3
Immune-related AE 
(irAE)
Grades 1-4
See Section 5.4.4.3 and Table 6
Other Non-hematologic
Toxicities and 
Laboratory 
Abnormalities
Grade 1
Continue as per schedule 


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Toxicity
NCI CTCAE 
Severity Grade
Avelumab
Treatment Modification
Other Non-hematologic
Toxicities and 
Laboratory 
Abnormalities
Grade 2
If toxicity resolves to Grade 1 by the last day of the 
current cycle, treatment may continue.
If toxicity does not resolve to Grade 1 by the last day of 
the current cycle despite optimal treatment, next cycle 
infusion should be omitted. 
If after 2 weeks of dose holding, the event has not resolved 
to Grade 1, the patient should permanently discontinue 
treatment.
Exceptions are:
Hormone deficiencies that can be managed by replacement 
therapy as described in Table 6.
Other Non-hematologic
Toxicities and 
Laboratory 
Abnormalities 
Grade 3
Permanent discontinuation.
Exceptions are:
Transient (6 hours) flu-like symptoms or fever, which is 
controlled with medical management.
Transient (24 hours) fatigue, local reactions, headache that 
resolves to Grade 1.
Nausea and vomiting controlled by medical therapy.
Amylase or lipase abnormality that is not associated with 
symptoms or clinical manifestations of pancreatitis.
Tumor flare phenomenon defined as local pain, irritation, or 
rash localized at sites of known or suspected tumor.
Laboratory abnormality that does not require medical 
intervention or hospitalization
Single laboratory values out of normal range that are 
unlikely related to avelumab treatment as assessed by the 
Investigator, do not have any clinical correlate, and resolve 
to Grade 1 within 7 days with adequate medical 
management.
Grade 4
Permanent discontinuation.
Exceptions are:
Laboratory abnormality that does not require medical 
intervention or hospitalization
Single laboratory values out of normal range that are 
unlikely related to avelumab treatment as assessed by the 
Investigator, do not have any clinical correlate, and resolve 
within 7 days with adequate medical management.
5.4.4. Special Precautions for Avelumab Administration
In order to mitigate avelumab infusion-related reactions, a premedication regimen of 25 to 
50 mg IV or oral equivalent diphenhydramine and 650 mg IV or oral equivalent 
acetaminophen/paracetamol (as per local practice) is mandatory approximately 30 to 
60 minutes prior to each dose of avelumab.  This regimen may be modified based on local 


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treatment standards and guidelines, as appropriate.  However, prophylactic administration of 
corticosteroids is permitted only in the conditions described in Table 5.
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications 
(IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access.
Following avelumab infusions, patients must be observed for 2 hours post-infusion for 
potential infusion-related reactions.  Patients should be instructed to report any delayed 
reactions to the Investigator immediately.
Treatment recommendations for the management of infusion-related reactions, and tumor 
lysis syndrome are outlined in Sections 5.4.4.1, and 5.4.4.2, respectively.
Treatment recommendations for the management of irAEs and GVHD are outlined in
Section 5.4.4.1 and Section 5.4.4.3.
5.4.4.1. Management of Avelumab Infusion-Related Reactions
Since avelumab is administered IV, infusion-related reactions may occur (with symptoms 
such as fever, chills, rigors, diaphoresis, and headache).  Treatment of the infusion-related 
reaction and modifications of avelumab infusion are mainly dependent upon severity, as 
indicated in Table 5. 
Table 5.
Treatment Modification for Symptoms of Infusion Related Reactions 
Caused by Avelumab
NCI CTCAE Grade  
Treatment Modification for Avelumab
Grade 1 – mild
Mild transient reaction; infusion interruption not indicated; 
intervention not indicated.
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening
Grade 2 –moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for 24 hours.
Temporarily discontinue avelumab infusion.
Resume infusion at 50% of previous rate as soon as 
infusion-related reaction has resolved or decreased to at 
least Grade 1 in severity, and monitor closely for any 
recurrence or worsening.
If a Grade 2 infusion-related reaction does not improve 
or worsens following implementation of the 
modifications indicated above (including reducing the 
infusion rate by 50%), treatment should be commenced 
based on the specific symptoms (see Appendix 6), and 
the infusion should not be resumed for that cycle. 
At the next cycle, consider the addition of an 
H2-blocker, meperidine, or ibuprofen to the mandatory 
premedication. 


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Recurrent Grade 2 – moderate
In the event of further recurrence, in spite of 
implementation of all measures indicated above, 
hydrocortisone 100 mg IV may be added to the 
premedication schema outlined above following 
discussion with the Sponsor.
Grade 3 – severe 
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical sequelae.
Recurrent Grade 3 - severe
Stop the avelumab infusion immediately and disconnect 
infusion tubing from the subject
If IV fluids to maintain blood pressure, or prolonged 
administration of steroids, or inotropic agents, or 
administration of oxygen to maintain peripheral 
saturations are required, or the symptoms persist for 
more than 48 hours: 

permanently discontinue avelumab treatment 
If none of the conditions listed above applies, 

consider resuming avelumab treatment if the 
risk/benefit assessment for the individual 
patient is positive and upon discussion with 
the Sponsor. 

if the decision is made to resume treatment, 
the  infusion rate must be reduced by 50% 
AND hydrocortisone 200 mg IV must be 
added to the standard premedication .
Stop the avelumab infusion immediately and disconnect 
the infusion tubing from the patient.
Subjects have to be withdrawn immediately from
avelumab treatment and must not receive any
further avelumab treatment .
Grade 4 – life-threatening
Grade 4: Life-threatening consequences; urgent intervention 
indicated.
Stop the avelumab infusion immediately and disconnect
the infusion tubing from the patient.
Subjects have to be withdrawn immediately from
avelumab treatment and must not receive any
further avelumab treatment
In addition, if premedication with hydrocortisone is necessary it should be added for at least the subsequent 2 cycles of 
avelumab therapy.  In the case of patients requiring hydrocortisone and in whom the dose of avelumab is escalated from 
70 mg Q2W to 500 mg Q2W, hydrocortisone should be added to the premedication schema for at least a total of 3 cycles
at 500 mg Q2W.  
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% due to an infusion-related 
reaction, it must remain so for all subsequent infusions.


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5.4.4.2. Management of Avelumab-Related Tumor Lysis Syndrome
Avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), so there is a 
potential risk of tumor lysis syndrome.  Should this occur, patients should be treated as per 
local guidelines and the management algorithm (Figure 3) published by Howard et al.


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Figure 3.
Assessment and Initial Management of Tumor Lysis Syndrome (TLS)
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia


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5.4.4.3. Management of Avelumab 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 v. 4.03):

Grade 1 to 2: treat symptomatically or with moderate-dose steroids, more frequent 
monitoring;

Grade 1 to 2 (persistent): manage similar to Grade 3 to 4 AE;

Grade 3 to 4: treat with high-dose corticosteroids.
Treatment of irAEs should follow guidelines set forth in Table 6.
Table 6.
Management of Avelumab Immune Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea / Colitis
(NCI v4)
Initial Management 
Follow-up Management
Grade 1
Diarrhea: <4 stools/day over 
baseline;
Colitis: asymptomatic 
Continue avelumab therapy
Symptomatic treatment 
(eg, loperamide)
Close monitoring for worsening 
symptoms
Educate patient to report worsening 
immediately
If worsens:
Treat as Grade 2, 3 or 4.
Grade 2
Diarrhea: 4 to 6 stools per day over 
baseline; IV fluids indicated 
<24 hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy
Symptomatic treatment
If improves to Grade 1: 
Resume avelumab therapy
If persists >5-7 days or recurs:
Treat as Grade 3 or 4
Grade 3 to 4
Diarrhea (Grade 3): 7 stools per 
day over baseline; incontinence; IV 
fluids 24 hours; interfering with 
ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, perforation
Withhold avelumab for Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent grade 3.
1.0 to 2.0 mg/kg/day prednisone
IV or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy
If improves: 
Continue steroids until Grade 1, 
then taper over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3).
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication), Note: Infliximab 
should not be used in cases of 
perforation or sepsis


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Dermatological irAEs
Grade of Rash
(NCI CTCAE v4)
Initial Management
Follow-up Management
Grade 1 to 2
Covering 30% body surface area 
Continue avelumab therapy 
Symptomatic therapy 
(eg, antihistamines, topical 
steroids) 
If persists >1 to 2 weeks or recurs: 
Withhold avelumab therapy
Consider skin biopsy 
Consider 0.5 to 1.0 mg/kg/day 
prednisone or equivalent.  Once 
improving, taper steroids over at 
least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume avelumab therapy following 
steroids taper
If worsens: 
Treat as Grade 3 to 4
Grade 3 to 4
Grade 3: Covering >30% body 
surface area;
Grade 4: life threatening 
consequences 
Withhold avelumab for Grade 3
Permanently discontinue for 
Grade 4 or recurrent Grade 3
Consider skin biopsy 
Dermatology consult 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
If improves to Grade 1: 
Taper steroids over at least 
1 month; resume avelumab therapy
following steroids taper (for initial 
Grade 3)
Pulmonary irAEs
Grade of Pneumonitis
(NCI CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding avelumab 
therapy 
Monitor for symptoms every 2 to 
3 days
Consider Pulmonary and 
Infectious Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4


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Grade 2
Mild to moderate new symptoms
Withhold avelumab therapy
Pulmonary and Infectious 
Disease consults
Monitor symptoms daily, 
consider hospitalization 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to 
Grade 1,  taper steroids over at 
least 1 month and then resume 
avelumab therapy 
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia; 
Grade 4:Llife-threatening 
Permanently discontinue 
avelumab therapy
Hospitalize 
Pulmonary and Infectious 
Disease consults
1.0 to 2.0 mg/kg/day prednisone 
or equivalent 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, lung 
biopsy 
If improves to Grade 1: 
Taper steroids over at least 1 month
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression 
(eg, infliximab, cyclophosphamide, 
intravenous immunoglobulin, or 
mycophenolate mofetil) 
Hepatic irAEs
Liver Function Tests (LFTs) 
Increase
(NCI CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or total bilirubin 
>ULN to 1.5 x ULN 
Continue avelumab therapy
Continue liver function monitoring 
If worsens: 
Treat as Grade 2 or 3 to 4
Grade 2
AST or ALT >3.0 to 5 x ULN 
and/or total bilirubin >1.5 to 3 x 
ULN 
Withhold avelumab therapy
Increase frequency of monitoring 
to every 3 days   
If returns to Grade 1: 
Resume routine monitoring, resume 
avelumab therapy
If elevations persist >5 to 7 days or 
worsen : 
Treat as Grade 3 to 4
Grade 3 to 4
AST or ALT >5 x ULN and/or total 
bilirubin >3 x ULN 
Permanently discontinue 
avelumab therapy 
Increase frequency of monitoring 
to every 1 to 2 days 
1.0 to 2.0 mg/kg/day prednisone 
or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
If returns to Grade 1: 
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram 
(g) twice daily 
If no response within an additional 
3 to 5 days, consider other


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Consult 
gastroenterologist/hepatologist
Consider obtaining MRI/CT scan 
of liver and liver biopsy if 
clinically warranted
immunosuppressants per local 
guidelines 
Renal irAEs
Grade of Creatinine Increased 
(NCI CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 1.5 
x ULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased >1.5 and 
6 x ULN
Withhold avelumab therapy
Increase frequency of monitoring to 
every 3 days
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
If returns to Grade 1:
Taper steroids over at least 1 month, 
and resume avelumab therapy 
following steroids taper.
If worsens: 
Treat as Grade 4.
Grade 4
Creatinine increased >6 x ULN
Permanently discontinue avelumab 
therapy
Monitor creatinine daily
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections
Consider renal biopsy
Nephrology consult
If returns to Grade 1:
Taper steroids over at least 1 month.
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I diabetes 
mellitus)
Continue avelumab therapy 
Endocrinology consult if needed
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate. 
Rule-out secondary 
endocrinopathies (ie,
hypopituitarism / hypophysitis)
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.


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Grade 3 or Grade 4 endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I diabetes 
mellitus)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 
treatment (for hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
Rule-out secondary 
endocrinopathies (ie,
hypopituitarism / hypophysitis)
Resume avelumab once 
symptoms and/or laboratory tests 
improve to Grade 1 (with or 
without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate.
Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or 
adrenal insufficiency is 
confirmed (ie, subnormal serum 
FT4 with inappropriately low 
TSH and/or low serum cortisol 
with inappropriately low 
ACTH):

Refer to endocrinologist for 
dynamic testing as indicated 
and measurement of other 
hormones (FSH, LH, 
GH/IGF-1, PRL, 
testosterone in men, 
estrogens in women) 

Hormone 
replacement/suppressive 
therapy as appropriate 

Perform pituitary MRI and 
visual field examination as 
indicated
If hypophysitis confirmed:

Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month

Withhold avelumab if 
moderate, severe or 
life-threatening symptoms of 
hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 
mg/kg/day prednisone or 
equivalent) followed by 
corticosteroids taper during 
at least 1 month.

Add prophylactic antibiotics 
for opportunistic infections.
Resume avelumab once symptoms 
and hormone tests improve to 
Grade 1 (with or without hormone 
replacement).
In addition, for hypophysitis with 
abnormal MRI, resume avelumab 
only once shrinkage of the pituitary 
gland on MRI/CT scan is 
documented. 
Continue hormone 
replacement/suppression therapy as 
appropriate.


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Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management 
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations 
(eg, BNP, troponin, CK-MB) 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 appropriate per 
cardiology consult.*
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 per 
cardiology consult.*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections 
Once improving, taper steroids over 
at least 1 month and add 
prophylactic antibiotics for 
opportunistic infections.
If no improvement or worsening, 
consider additional 
immunosuppressants (eg, 
azathioprine, cyclosporine A).
*Local guidelines, or eg. ESC or AHA guidelines 
ESC guidelines website:  https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001


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Other irAEs
Grade of other irAEs
(NCI CTCAE v4)
Initial Management 
Follow-up Management 
Grade 2 or Grade 3 clinical signs or 
symptoms suggestive of a potential 
irAE
Withhold avelumab therapy 
pending clinical investigation
If irAE is ruled out, manage as 
appropriate according to the 
diagnosis and consider re-starting 
avelumab therapy
If irAE is confirmed, treat as 
Grade 2 or 3 irAE.
Recurrence of same Grade 3 irAEs
Permanently discontinue 
avelumab therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult as appropriate.
If improves to Grade 1: 
Taper steroids over at least 1 month.
Grade 4 
Permanently discontinue 
avelumab therapy
1.0to 2.0 mg/kg/day
prednisone or equivalent and/or 
other immunosuppressant as 
needed
Add prophylactic antibiotics for 
opportunistic infections 
Specialty consult.
If improves to Grade 1: 
Taper steroids over at least 1 month
Requirement for 10 mg per day or 
greater prednisone or equivalent for 
more than 12 weeks for reasons 
other than hormonal replacement for 
adrenal insufficiency
Persistent Grade 2 or 3 irAE lasting 
12 weeks or longer
Permanently discontinue 
avelumab therapy
Specialty consult.
ACTH=adrenocorticotropic hormone; ADL=activities of daily living, ALT=alanine aminotransferase, 
AST=aspartate aminotransferase; BNP_B-type natriuretic peptide; CK-MB_creatine kinase MB; 
CT=computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like 
growth factor 1;, irAE=immune-related adverse event, IV=intravenous, LH=luteinizing hormone; LLN=lower 
limit of normal, MRI=magnetic resonance imaging, NCI-CTCAE=National Cancer Institute-Common 
Terminology Criteria for Adverse Events, NSAIDs=nonsteroidal anti-inflammatory drugs, PRL=prolactin;
T4=thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of normal.


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5.4.4.4. Management of Acute or Chronic Graft versus Host Disease (GVHD)
Lead-in Phase 
In the event that GVHD is diagnosed, avelumab should be immediately and permanently
discontinued.
Expansion Phase 
Patients with GVHD of any grade must be permanently discontinued from the study 
treatment with the following exception: in the event of Grade 1 GVHD of the skin requiring 
topical therapy only, treatment with avelumab must be withheld until complete resolution of 
the GVHD, at which point treatment with avelumab may be resumed.

If the event occurs during the first 6 weeks of the 70 mg Q2W dosing regimen and 
subsequently recovers, avelumab therapy must be resumed at the 70 mg Q2W dosing 
level and the dose must not be escalated to 500 mg Q2W (irrespective of the findings 
of the 6-week tumor assessment). 

If the event occurs during the first 12 weeks of the 70 mg Q2W, in a patient who 
achieves a PR at 6 week and continues on the same dosing regimen until Week 12, 
and subsequently recovers, avelumab therapy may be resumed only at the 70 mg 
Q2W dosing regimen without escalation to 500 mg Q2W (irrespective of the findings 
12-week tumor assessment).

If the event occurs in a patient while on 500 mg Q2W and then recovers, avelumab 
therapy may be resumed only at the 70 mg Q2W dosing regimen.
In the event of GVHD recurrence, the patient must be permanently discontinued from 
avelumab.
Any patient developing GVHD should be treated per local institutional guidelines, and 
immunosuppressive therapy and other appropriate medical interventions commenced as 
clinically indicated.  The immunosuppression resulting from the treatment of GVHD 
increases the risk of life-threatening infection, and appropriate anti-microbial and anti-viral 
prophylactic therapy must be initiated.
It is not known whether checkpoint inhibitor-induced GVHD is more aggressive than 
conventional GVHD, and whether checkpoint inhibitor-induced GVHD should consequently 
be managed more aggressively than GVHD that occurs in the absence of checkpoint 
inhibition. 
Early diagnosis of GVHD and close monitoring of the response to GVHD therapy is essential 
to prevent the progression and complications of GVHD, and to reduce the risk of mortality. 
The long-term goal of GVHD management is the development of immunological tolerance, 
which is indicated by the successful withdrawal of immunosuppressive treatment without 
recurrence of GVHD, or a clinically significant GVHD exacerbation. 


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The management of GVHD should occur within the context of an interdisciplinary team that 
includes the treating physician, a transplant specialist, and a microbiologist (to guide the 
selection of appropriate anti-microbial and anti-viral prophylaxis). 
Liver function (including bilirubin, alkaline phosphatase, AST, and ALT) should be closely 
monitored, especially when hepatic GVHD is suspected, and the indication for a liver biopsy, 
and abdominal imaging should be reviewed at appropriate intervals. 
In the case of hepatic GVHD, other potential underlying causes of cholestatic disease should 
be excluded, and the medications reviewed to identify other potential contributory or 
exacerbating factors. 
The Sponsor’s Medical Monitor must be informed within 24 hours if GVHD is suspected. 
5.4.5. Dose Reductions
Avelumab dose reduction for toxicity management is only permitted as follows:

Those patients who, following dose-escalation at the 500 mg Q2W experience any 
treatment related Grade 2 AEs lasting more than 14 days, will reduce their avelumab 
dose and continue treatment at the 70 mg Q2W dosing regimen. 

Additionally those patients who develop Grade 1 skin GVHD requiring topical 
therapy only while on 500 mg Q2W, will have their avelumab dose reduced to 70 mg 
Q2W as detailed in Section 5.4.4.4.
No other dose reduction for toxicity management is permitted, but next cycle administration 
may be omitted due to persisting toxicity as described in Section 5.4.3.1, Section 5.4.3.2 and
Section 5.4.4. 
5.5. Investigational Product Storage and Accountability
The Investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational product is stored in a secured area with controlled access, under specified 
storage conditions and in accordance with applicable regulatory requirements. 
Investigational product should be stored in its original container and in accordance with the 
label.  See the Investigational Product Manual for the storage conditions of the prepared 
product.
Storage conditions stated in the SRSD (ie, Investigator Brochure) will be superseded by the 
storage conditions stated in the labeling. 
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 


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for excursions should be documented.  The operation of the temperature monitoring device 
and storage unit (for example, refrigerator), as applicable, should be regularly inspected to 
ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product. It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions.
5.6. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.
5.6.1. Destruction of Investigational Product Supplies 
The Sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
Medications or vaccinations specifically prohibited in the exclusion criteria are also not 
allowed during the active treatment period, except for administration of the inactivated 
influenza vaccine.
If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from study therapy or 
medication/vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the patient’s primary physician.  However, the 
decision to continue the patient on study therapy or medication/vaccination schedule requires 
the mutual agreement of the Investigator, the Sponsor, and the patient. 


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Concomitant treatment considered necessary for the patient’s wellbeing may be given at the 
discretion of the treating physician.
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatment and up to 90 days after the last dose of 
study treatment.  All concomitant medications should be recorded in the CRF including 
supportive care drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat 
adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
Concurrent anticancer therapy with agents other than avelumab is not allowed.  Medications 
intended solely for supportive care (ie, antiemetics, analgesics, megestrol acetate for 
anorexia) are allowed.
Recommended medications to treat infusion-related reactions, tumor lysis syndrome 
immune-related adverse events, and GVHD are reported in Sections 5.4.4.1, 5.4.4.2, 5.4.4.3
and 5.4.4.4, respectively.
5.7.1. Hematopoietic Growth Factors
Primary prophylactic use of granulocyte-colony stimulating factors is permitted during the 
study. They may also be used to treat treatment emergent neutropenia as indicated by the 
current American Society of Clinical Oncology guidelines.18
Use of erythropoietic growth factors is allowed during the study.
5.7.2. Concomitant Surgery 
No formal studies of the effect of avelumab on wound healing have been conducted; 
however, caution is advised based on the mechanism of action.  If a major surgery or an 
interventional procedure (eg, endoscopy, biopsy) is required, treatment with avelumab must 
be interrupted at least 24 hours before the procedure.  Patients may resume avelumab as soon 
as the wound has completely healed and if there are no wound healing complications (eg, 
delayed healing, wound infection or fistula).
5.7.3. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain, the sites of bone disease should be present at baseline, otherwise, bone 
pain requiring radiotherapy will be considered as a sign of disease progression. 
5.7.4. Other Prohibited Concomitant Medications and Therapies
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy. 


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
Immunotherapy not specified in this protocol. 

Investigational agents other than avelumab. 

Radiation therapy (with the exception noted above in the Concomitant Radiotherapy 
Section 5.7.3).

Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs (see 
Table 6).  See below Clarification about Steroid Use.

Other experimental pharmaceutical products.

Any vaccine therapies for the prevention of infectious disease (eg, human papilloma 
virus vaccine) except for inactivated vaccines.

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or 
known to potentially interfere with major organ function (eg, hypericin).
Clarifications about Steroid Use: Data indicate that corticosteroids have an adverse effect 
on T cell function and that they inhibit and damage lymphocytes.12,17  Furthermore, as with 
all immunotherapies intended to augment cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit of the 
proposed study treatment.  However, studies with anti-CTLA4 compounds indicate that 
short-term use of steroids may be employed without compromising clinical outcomes.  
Therefore, the use of steroids during this trial is restricted as follows:
Therapeutic use: for the treatment of infusion-related reactions steroids are permitted 
according to the modalities indicated in Table 5.

Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
10 mg prednisone daily is acceptable.

Prophylactic use: prior to CT or magnetic resonance imaging (MRI), steroids are
permitted; prophylactic use for the prevention of acute infusion-related reactions is 
permitted only as described in Table 5.
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.8. Rescue Medications and Supportive Care
5.8.1. Supportive Care Guidelines
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below: 

Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.


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
Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in Table 6.

Anti-inflammatory or narcotic analgesics may be offered as needed.  
Acetaminophen/paracetamol to a maximum total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited.

Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, warfarin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed. 
6. STUDY PROCEDURES 
6.1. Screening
For screening procedures see Schedule of Activities (SOA).
6.2. Treatment Period
For treatment period procedures, see Schedule of Activities and Section 7.
6.3. Follow-up Visit
For follow-up procedures see Schedule of Activities and Section 7.
6.4. Patient Withdrawal
Patients may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the Investigator or Sponsor for safety or behavioral reasons, or 
the inability of the patient to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity;


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


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7.1. Safety Assessment
Safety assessments will be performed at the time points described in the Schedule of 
Activities and include collection of adverse events (AEs), serious adverse events (SAEs), 
vital signs and physical examination, electrocardiogram (ECG [12-lead]), laboratory 
assessments, including pregnancy tests and verification of concomitant treatments.
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting study treatment, once at the start of screening and once at the 
baseline visit immediately before investigational product administration.  Following a 
negative pregnancy test result at screening, appropriate contraception must be commenced 
and another negative pregnancy test result will then be required at the baseline visit before 
the patient may receive the investigational product.  Pregnancy tests (urine or serum) will 
also be routinely repeated at every treatment cycle during the active treatment period, at the 
end of study treatment visit, at the Day 30 Follow-up Visit, and additionally whenever 
1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  In the case 
of a positive hCG test, the patient will be withdrawn from treatment and will be withdrawn 
from the study.  Additional pregnancy tests may also be undertaken if requested by IRB/ECs
or if required by local regulations.
7.1.2. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by the 
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] 
(version 4.03) timing, seriousness, and relatedness.
Adverse events that occur during the study will be recorded on the adverse events CRF page.
7.1.3. Laboratory Safety Assessment
Hematology, blood chemistry, and urinalysis will be collected at the time points described in 
the Schedule of Activities (SOA) and analyzed at local laboratories.  They may also be 
performed when clinically indicated.  The required laboratory tests are listed in Table 7.
If a full and core chemistry panel are scheduled at the same visit, then only the full chemistry 
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Table 7.
Required Laboratory Tests
Hematology
Chemistry Panel
(* denotes core 
chemistry test)
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT*
Urine dipstick for 
protein, glucose, blood
PT or INR
For female 
patients of 
childbearing 
potential, serum 
or urine 
Platelets
AST*
PTT or aPTT
WBC
Alkaline Phosphatase*
Absolute Neutrophils
Sodium*
Absolute Lymphocytes
Potassium*
Absolute Monocytes
Magnesium*
Absolute Eosinophils
Chloride*
Absolute Basophils
Total Calcium*
Total Bilirubin* °
BUN or Urea*
Creatinine*
Glucose (non-fasted)*
Phosphorus or Phosphate*
Albumin
Total Protein
Uric Acid
Amylase
Gamma 
glutamyltransferase 
(GGT)
Cholesterol
Creatine kinase
C-reactive protein (CRP) 
Lactate dehydrogenase 
(LDH)
Lipase
Triglycerides
Thyroid Function Tests:
TSH, free T4
Other Tests: 
ACTH
HBsAg, HBsAb, HBcAb, 
HCV Ab
° For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyltransferase, 
prothrombin time (PT)/INR, alkaline phosphatase, and acetaminophen levels.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin 
time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, 
GGT=gamma-glutamyltransferase, , HBsAg=Hepatitis B surface antigen, HbsAb=Hepatitis B surface 
antibody, HbcAb= Hepatitis B core antibody, HCV Ab= Hepatitis C virus antibody, INR=international 
normalized ratio, LDH=lactate dehydrogenase, TSH=thyroid-stimulating hormone, WBC=white blood cells


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7.1.4. Vital Signs and Physical Examination
Patients will have a physical examination to include examination of the body systems, 
weight, vital signs, assessment of ECOG performance status, and height; height will be 
measured at screening only.
7.1.5. (12-Lead) Electrocardiogram
Single ECG measurements will be obtained at screening (all patients).  On-study triplicate 
ECGs will be performed on Day 1 of Cycles 1 and 2, before avelumab infusion, and at the 
end of avelumab infusion and at End of Treatment.  When coinciding with blood sample 
draws for PK, ECG assessment should be performed prior to blood sample collection such 
that the blood sample is collected at the nominal time. 
Triplicate 12-lead (with a 10-second rhythm strip) tracing will be used for all on-treatment 
ECGs and at End of Treatment.  It is preferable that the machine used has a capacity to 
calculate the standard intervals automatically.  At each time point (see Schedule of 
Activities), 3 consecutive ECGs (triplicates) will be performed at approximately 2 minutes 
apart to determine the mean QTc interval (average of triplicates).  If the mean QTc is 
prolonged (>500 msec, ie, CTCAE Grade 3), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate.  If manual reading verifies a QTc of
>500 msec, immediate correction for reversible causes (including electrolyte abnormalities, 
hypoxia and concomitant medications for drugs with the potential to prolong the QTc 
interval) should be performed.  In addition, repeat ECGs should be immediately performed 
hourly for at least 3 hours until the QTc interval falls below 500 msec.  If QTc interval 
reverts to less than 500 msec, and in the judgment of the investigator(s) and Sponsor is 
determined to be due to cause(s) other than investigational product, treatment may be 
continued with regular ECG monitoring.  If in that timeframe the QTc intervals rise above 
500 msec the investigational product will be held until the QTc interval decreases to 
500 msec.  Patients will then restart the investigational product at the next lowest dose level.  
If the QTc interval has still not decreased to 500 msec after 2 weeks, or if at any time a 
patient has a QTc interval >515 msec or becomes symptomatic, the patient will be removed 
from the study.  Additional triplicate ECGs may be performed as clinically indicated.
An electronic reading of prolonged QTc must be confirmed by manual reading.  Prior to 
concluding that an episode of prolongation of the QTc interval is due to investigational 
product, thorough consideration should be given to potential precipitating factors (eg, change 
in patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist.
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, 
or stroke), an ECG (triplicate) should be obtained at the time of the event.  Clinically 
significant findings seen on follow-up ECGs should be recorded as adverse events. 


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7.2. Pharmacokinetics Assessments
7.2.1. Blood Sample Collection for Pharmacokinetic analysis of Avelumab
Where noted in the Schedule of Activities blood samples will be collected at approximately 
the same time as other assessments wherever possible. 
At each sampling time point, 3.5-mL of blood for avelumab PK will be collected as outlined 
in the Pharmacokinetic and Pharmacodynamic Sampling Schedule table.  PK sampling 
schedule may be modified based on emerging PK data. 
In addition to samples collected at the scheduled times, an additional blood sample may be 
collected from patients experiencing unexpected and/or serious AE’s and the date and time of 
blood sample collection and of last dosing prior to PK collection documented in the CRF.
Where noted in the Schedule of Activities, blood samples for avelumab concentrations will 
be collected at approximately the same time as other assessments such as pharmacodynamic 
samples whenever possible.  When PK sampling coincides with ECGs, PK samples should 
be taken after the ECG is performed. 
All efforts will be made to obtain the pharmacokinetic samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60-minute sample) will be considered protocol compliant, and the exact time 
of the sample collection noted on the CRF.  If a scheduled blood sample collection cannot be 
completed for any reason, the missed sample time may be rescheduled with agreement of the 
clinical investigator, patient, and Sponsor.
PK samples will be assayed for avelumab using a validated analytical method in compliance 
with Pfizer standard operating procedures.  Details regarding the collection, processing, 
storage and shipping of the blood samples will be provided in the Study Manual.
7.3. Immunogenicity Assessment
3.5 mL of blood will be collected for evaluation of immunogenicity of avelumab.  
Immunogenicity blood samples will be assayed for anti-avelumab antibodies using a 
validated analytical method.  All of the samples that are positive for ADA may also undergo 
characterization for Nabs.  Additional details regarding the collection, processing, storage, 
and shipping of the blood samples will be provided in the Study Manual.
7.4. Biomarker and Pharmacodynamic Assessments
Tissue samples (including peripheral blood 
and biopsies where appropriate and 
as indicated) will be collected pre- and post-avelumab administration from all patients 
participating in the study.  De novo biopsies will be optional in the lead-in phase and 
mandatory in the dose expansion phase, assuming that the lesions to be biopsied can be 
safely accessed and sampled.
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De novo biopsies will be collected at baseline during the screening period and on treatment 
as detailed in the Schedule of Activities.  Patients who have an archival sample obtained 
within 3 months of the first dose of study drug and who have not received any intervening 
systemic anti-cancer therapy may submit this sample in lieu of a baseline de novo sample.  It 
is strongly preferred that the 6-week on-treatment sample is collected prior to a potential dose 
escalation at Cycle 4.  In the event a de novo biopsy cannot be safely accessed and sampled, 
an archival sample obtained within 6 months of enrollment must be submitted.  Optional de 
novo biopsies can be collected at any time during the treatment phase as clinically indicated.  
In patients who have readily accessible lesions and who dose escalate to 500 mg Q2W at 
Cycle 4 or Cycle 7, an on-treatment biopsy at the time of the 12 or 24 -week tumor 
assessment scan, respectively, is desirable, but non-mandatory. An attempt should be made 
to collect archival tissue from patients in the lead-in phase who elect not to provide a baseline 
de novo biopsy.  In this instance, an archival FFPE tumor tissue block from initial diagnosis 
or a previously obtained tumor biopsy of a disease lesion obtained within 6 months of 
enrollment and only if the patient has received no intervening systemic anti-cancer treatment 
during this period may be submitted. Tumor tissue from cytologic sampling (eg, fine needle 
aspiration, including FFPE cell pellet material) is not adequate and should not be submitted.  
Mandatory de novo biopsy(ies) should be processed to an FFPE block. Material-permitting, 
a second portion of the mandatory de novo biopsy(ies) should be processed to a fresh frozen 
block (see Study Manual for instructions on collection, processing, and shipping).  The 
resulting FFPE, and fresh frozen blocks should be submitted to the Central Laboratory.
Biomarker evaluation will be performed on biopsies, peripheral blood,
.  Biopsy 
tissue will be submitted to analysis by immunohistochemistry to assess target expression, 
phenotypes of infiltrating immune cells and markers associated with immune activation and 
tolerance.  Tumor tissue will also be submitted to RNA, 
 
  Target occupancy on immune cells including, but not limited to, CD14+ 
monocytes and CD3+ T cells will be evaluated in the peripheral blood by flow cytometry in 
the lead-in phase only.  Peripheral blood will also be submitted for immune cell profiling by 
flow cytometry,
  
 
 
 
Refer to the specific lead-in or expansion phase Schedule of Activities for details pertaining 
to specific days of sample collection and to the Lab Manual for details of sample preparation, 
storage and shipment.  Note: while many biomarker collections are common to both the 
lead-in and expansion phases, some analyses are unique to one phase or the other, and, in 
addition, timepoints may differ between the two phases.  The optional de novo tumor biopsy 
collections in the lead-in phase and mandatory and optional collections in the expansion 
phase are detailed above and in the SOA.
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Table 8.
Biomarker Collections and Analyses
Biomarker
Phase
Sample Type
Analysis
Target Occupancy
Lead-in only
Whole Blood
PD-L1 occupancy by avelumab on 
immune cells including CD14+ 
monocytes and CD3+ T cells by flow 
cytometry
Immune Cell Phenotypes
Lead-in: T cell subsets
Expansion: TBNK and NK 
subsets
Whole Blood
Immune cell phenotypes associated 
with anti-tumor immunity and immune 
regulation by flow cytometry
 
 
 
 
 
Immuno-phenotypic Markers
Tumor Biopsy
Markers associated with immune cell 
phenotypes, regulation and activity by 
immunohistochemistry or 
immunofluorescence
Transcriptional Profile
Optional Biopsy in Lead-in;
Mandatory pre- and on-treatment 
Biopsy in Expansion Phase
Tumor Biopsy (RNA)
RNA will be analyzed for expression 
profile of immune- and tumor-related 
transcripts
 
 
 
 
 
 
 
 
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7.5. Disease Response Assessment
Lead-in Phase
In the lead-in phase, tumor assessments includes all known or suspected disease sites.  
Imaging will include: neck, chest, abdomen, and pelvis PET-CT at baseline and at 6 weeks.  
Additionally PET-CT scans may be performed as clinically indicated.  Following the 6-week 
disease assessments, CT or MRI may be used, as long as one of these modalities was also 
performed at baseline and the same type of scan is used in the subsequent tumor assessments.  
The CT scan should be performed with contrast agents unless contraindicated.  Imaging for 
tumor assessments will be conducted at screening, 6 weeks, 12 weeks and at 12-week 
intervals thereafter until documented disease progression regardless of initiation of 
subsequent anti-cancer therapy.  Additional tumor assessments should also be conducted
whenever disease progression is suspected (eg, symptomatic deterioration) and at End of 
Treatment/Withdrawal (if not done in the previous 6 weeks) and at follow-up visits.
Responses will be assessed using the Response Criteria for Malignant Lymphoma42
(Appendix 2).
All patient files and radiologic images must be available for source verification and for 
potential peer review. Imaging data from patients in the lead-in phase are being collected 
and retained by an independent radiology vendor.  At the discretion of the Sponsor, these 
may be read by an independent radiologist.
Expansion Phase
In 2014, updated guidelines for initial evaluation, staging and response assessment of 
Hodgkin and Non-Hodgkin Lymphoma formally incorporating FDG PET-CT into standard 
staging for FDG-avid lymphoma were published. These guidelines will be used in the 
expansion phase since they represent the current standard of practice.  For the expansion 
phase, tumor assessments will be evaluated using PET-CT at all timepoints. CT with 
contrast or MRI may be additionally performed if clinically indicated.  Imaging for tumor 
assessment will be conducted at: screening, 6 weeks, 12 weeks, and at 12-week intervals 
thereafter for one year from the start of study treatment, and every 24 weeks thereafter until 
documented disease progression by BICR assessment, regardless of the initiation of 
subsequent anti-cancer therapy.  Additional tumor assessments should be conducted
whenever disease progression is suspected (eg, symptomatic deterioration) and at the End of 
Treatment/Withdrawal (if not done in the previous 6 weeks). For patients achieving a CR, a 
CT with contrast or MRI may be used instead of the PET-CT for tumor assessment until 
disease progression, which will require PET-CT documentation.  Response assessment will 
be made using the Lugano Classification43 (Appendix 3), in association with the Deauville 
5 point scale.
7.5.1. Blinded Independent Central Review for Disease Assessment (Expansion Phase)
In the expansion phase disease responses will be assessed by a Blinded Independent Central 
Review (BICR) according to the process defined in the Study Manual.


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The PET-CT imaging collected for all patients from screening to the 6 week assessment and 
those collected at the 12 week assessment for patients in PR at 6 week will be submitted to
the BICR for real-time expedited review. Intra-patient dose escalation decisions will be 
made following discussion between the Investigator and the Sponsor and will be informed by 
the BICR disease response assessment. Due to the time-sensitive nature of this process, the 
6-week and the 12-week tumor assessment may be performed up to one week prior to the 
scheduled time, so that images can undergo BICR review before Cycle 4 and Cycle 7. 
For investigator-assessed progressive disease, real-time expedited BICR review will be also 
performed to inform the Investigator’s decision of whether treatment should be discontinued. 
Upon investigator-assessed disease progression, all radiographic images collected for a 
patient from screening onwards will be submitted to the BICR for expedited review. Every 
effort should be made to keep the patient on study treatment until the BICR has completed
the radiographic image review, unless treatment continuation is contraindicated (see Study 
Manual for details).
7.6. Banked Biospecimens 
7.6.1. Markers of Drug Response 
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic (RNA), protein, and metabolite variation patterns of patients who respond well 
and those who respond poorly to treatment may help to better define the most appropriate 
group of patients in which to target a given treatment.
 
 
 
 
 
 
. 
To protect patients’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the patient’s study identification (ID) number.  Samples will be kept in a 
facility accessible only by swiping a badge.  Data will be stored on password-protected 
computer systems.  The key between the code and the patient’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information.  Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/patient information sheet; any other uses require additional ethical approval.  
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
postmarketing research.  Patients can withdraw their consent for the use of their 
biospecimens at any time by making a request to the investigator, in which case any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
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continue to be stored to protect the integrity of existing analyses.  It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants.  Patients are notified in the informed 
consent document/patient information sheet that their results will not be given to them, unless 
required by local laws or regulations, in which case results will be returned via the 
investigator.  Results will not be provided to family members or other physicians, nor will 
they be recorded in the patient’s medical record.  There is no intention to contact patients 
after completion of the clinical study.
A 4-mL blood biospecimen Prep D1 (K2 edetic acid [ethylenediaminetetraacetic 
acid][EDTA] whole blood collection optimized for DNA analysis) will be collected at 
baseline and Day 1 of Cycle 3 (for Lead-in phase every 2-week dosing) baseline and Day 7 
of Cycle 2 (for Lead-in phase every 3-week dosing), and baseline only (pre-dose Day 1of 
Cycle 1) for Expansion phase to be retained for potential pharmacogenomic/biomarker 
analyses related to drug response, unless prohibited by local regulations or ethics committee 
decision.  For example, putative safety biomarkers, drug-metabolizing enzyme genes, 
drug-transport protein genes, or genes thought to be related to the mechanism of drug action 
may be examined.
The banked biospecimen will be collected from all patients unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage, and 
shipment instructions are provided in a separate study manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Patients will be advised in the informed consent document/patient information sheet that they 
will not be compensated in this event.
7.6.2. Additional Research
Unless prohibited by local regulations or ethics committee decision, patients will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:

Investigations of the disease under study in the clinical study, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 
Patients need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Markers of Drug Response Section will be used.  Patients may 
still participate in the clinical study if they elect not to allow their banked biospecimens to be 
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8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious AE that is 
determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 90 calendar days after the last 
administration of the investigational product.  SAEs occurring to a patient after the active 
reporting period has ended should be reported to the Sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
Sponsor.
AEs (serious and non-serious) should be recorded on the CRF from the time the patient has 
taken at least 1 dose of investigational product through and including 90 calendar days after 
the last administration of the study drug.
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs
ends at the time the new treatment is started.  Death must be reported if it occurs during the 
SAE reporting period after the last dose of investigational product, irrespective of any 
intervening treatment.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:

Abnormal test findings;


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
Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasations;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure;

Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs.
8.3.1. Avelumab Adverse Event of Special Interest
Any AE that is suspected to be a potential irAE is considered an AE of special interest 
(AESI).  Specific guidance for the management of irAEs is provided in Section 5.4.4.3 and 
Table 6.  AESIs are reported according to the general AE reporting rules specified in 
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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the Sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving patient exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page.
The guidance on reporting of medication errors also applies to the reporting of overdose.
For purposes of this study, an overdose of avelumab is defined as an increase 5% than the 
planned avelumab dose for that particular administration. 
There is no specific treatment for avelumab overdose.  In the event of overdose, the patient 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided as clinically indicated.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

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Merely repeating an abnormal test, in the absence of any of the above conditions does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period. Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE. If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE) Grade 5 (see the section on 
Severity Assessment).
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).


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8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase(AST) and/or alanine aminotransferase(ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions. Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value 2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 × ULN or not available;

For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above:

For patients with preexisting AST or ALT baseline values above the normal range,
AST or ALT value 2 times the baseline values and 3 × ULN, or 8 × ULN
(whichever is smaller);
Concurrent with

For patients with pre-existing values of total bilirubin above the normal range: Total 
bilirubin level increased from baseline by an amount of at least 1 × ULN or if the 
value reaches 3 × ULN (whichever is smaller).
The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered. In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyltransferase, prothrombin time
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug,
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected. Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted. All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for LFT abnormalities identified at the time, should be considered potential Hy’s 
law cases irrespective of availability of all the results of the investigations performed to 
determine etiology of the abnormal LFTs. Such potential Hy’s law cases should be reported 
as SAEs.


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8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.


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Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
GRADE
Clinical Description of Severity
0
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. For example headache may be severe (interferes significantly with the 
patient’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product,”
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.


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8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form. In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for
the termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;


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
Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See also the Section on Patient Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient.  In addition, each study patient/legally acceptable representative will be 
questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.


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8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This time frame 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a patient death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan, which will be maintained by the Sponsor.  
This document may modify the plans outlined in the protocol; however, any major 
modification of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 


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9.1. Analysis Sets 

Full Analysis Set.
For the lead-in phase the full analysis set includes all randomized patients.  Patients 
will be classified according to the treatment assigned at randomization.

For the expansion phase: the full analysis set includes all patients who receive at least 
one dose of study drug.  Patients will be classified according to the study treatment 
actually received.  Safety Analysis Set.
For the lead-in phase the safety analysis set includes all patients who received at least 
1 dose of study treatment.  Patients will be classified according to the treatment 
assigned at randomization unless the incorrect treatment was received throughout the 
dosing period in which case patients will be classified according to the first treatment 
received.
For the expansion phase the safety analysis set is identical to the full analysis set.

Target Occupancy Analysis Set.

The TO analysis set includes patients in the safety analysis set who have at least one 
Receptor Occupancy blood sample collected both pre and post Cycle 1 Day 1 dose.

Immunogenicity Analysis Set.
The immunogenicity analysis set includes patients in the safety analysis set who have 
at least 1 ADA sample collected.

PK Analysis Sets.
The PK parameter analysis set includes patients in the safety analysis set who have
sufficient information to estimate at least 1 of the PK parameters of interest.
The PK concentration analysis set includes all randomized patients who receive at 
least 1 dose of study treatment and have at least 1 analyte concentration.

Biomarker Analysis Set(s).
The biomarker analysis set is a subset of the safety analysis set and will include 
patients who have at least one biomarker sample.  Analysis sets will be defined 
separately for whole blood, plasma, and tumor biopsy biomarkers.
All other statistical analysis sets will be documented in the Statistical Analysis Plan (SAP).


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9.2. Statistical Methods and Properties
9.2.1. Sample Size Determination
In the lead-in phase, 31 patients were randomized in a 1:1:1:1:1 ratio and approximately 
40 patients will be enrolled in the expansion phase. In total, the study will enroll 
approximately 70 patients.
Lead-in Phase
In the lead-in phase, a total of 31 patients were randomized across 5 different treatment 
cohorts. The 6 patients per treatment cohort in the lead-in phase will be used to enable the 
initial estimation of TO; based on the historical data, with observed mean TO of 90%, the 
corresponding 95% confidence interval will be 88.98% to 91.02%, assuming a standard 
deviation of 1.27%. 
Expansion Phase
Approximately 40 patients will be enrolled in the post-allogeneic HSCT cohort.
With 40 treated patients, ORR can be estimated with a standard error not exceeding 0.079. 
Table 9 provides 95% confidence intervals for ORR based on different possible observed 
responses in the post-allogeneic HSCT cohort.
Table 9.
Sample Size and Exact 95% CIs for ORR - Post-allogeneic HSCT cohort
Number of Patients in 
the Post-allogeneic 
HSCT Cohort
Number of 
Observed 
Responses
Observed ORR
95% CI for True ORR
40
16
40%
(24.86%, 56.67%)
20
50%
(33.80%, 66.20%)
24
60%
(43.33%, 75.14%)
28
70%
(53.47%, 83.44%)
32
80%
(64.35%, 90.95%)
9.2.2. Efficacy Analysis
Efficacy will be summarized by treatment cohort based on the full analysis set, separately for 
each phase of the study. The evaluation of anti-tumor activity will be based on the Response 
Criteria for Malignant Lymphoma42 (Appendix 2) for patients enrolled in the lead-in phase 
and on the Lugano Classification43 (Appendix 2) for patients enrolled in the expansion phase.
In the expansion phase, tumor-related endpoints will be summarized separately based on 
BICR assessment and based on Investigator assessment.
In what follows ‘start date’ refers to date of randomization for patients enrolled in the lead-in 
phase and to date of first dose of study treatment for patients enrolled in the expansion phase.


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Objective response (OR) is defined as complete response (CR) or partial response (PR) from 
‘start date’ until disease progression or death due to any cause.  OR rate (ORR) is the 
proportion of patients with OR.
Time to Tumor Response (TTR) is defined, for patients with an objective response as the 
time from ‘start date’ to the first documentation of objective tumor response (CR or PR).
Duration of Response (DR) is defined, for patients with an objective response, as the time 
from the first documentation of objective tumor response (CR or PR) to the first 
documentation of objective progression of disease (PD) or to death due to any cause, 
whichever occurs first.  Censoring rules for DR will follow those described below for PFS.
Disease Control (DC) is defined as the best overall response of CR, PR, or SD.  To qualify as 
a best overall response of SD, at least one SD assessment must be observed 6 weeks after 
start date and before disease progression. DC rate (DCR) is the proportion of patients with 
DC.
Progression Free Survival (PFS) is defined as the time from ’start date’ to the date of the first 
documentation of objective progression of disease (PD) or death due to any cause, whichever 
occurs first.  PFS data will be censored on the date of the last adequate tumor assessment for 
patients who do not have an event (PD or death), for patients who start new anti-cancer 
treatment prior to an event, or for patients with an event after two or more missing tumor 
assessments.  Patients who do not have a baseline tumor assessment or who do not have any 
post-baseline tumor assessments will be censored on ‘start date’ unless death occurred on or 
before the time of the second planned tumor assessment in which case the death will be 
considered an event.
OS is defined as the time from ’start date’ to the date of death due to any cause.  Patients last 
known to be alive will be censored at date of last contact.
ORR will be estimated and the corresponding exact 2-sided 95% confidence interval will be 
reported.  TTR will be summarized using simple descriptive statistics (eg, median and range).  
DC will be summarized by frequency counts and percentages.  DR, PFS, and OS will be 
analysed using Kaplan-Meier methods; median DR, median PFS, and median OS and 
associated 95% confidence intervals will be reported.
9.3. Analysis of Pharmacokinetics and Pharmacodynamics 
9.3.1. Analysis of Pharmacokinetics
9.3.1.1. Avelumab Pharmacokinetic Analysis
Standard plasma PK parameters for avelumab will be estimated using non-compartmental 
analysis.  For avelumab, standard PK parameters will include Cmax, Tmax, AUC0-τ, t1/2, plasma 
clearance (CL), and volume of distribution (Vz) and other PK parameters, as data permit.  
Dose normalized parameters (eg, CDN-Cmax, DN-AUC) will be reported as appropriate.  
Descriptive statistics for the PK parameters for avelumab will be provided by dose, cycle and 
day of assessment in tabular form.


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Avelumab plasma concentrations and PK parameters will be summarized descriptively 
(n, mean, SD, CV, median, minimum, maximum, geometric mean, its associated CV, and 
95% confidence interval) by cohort, cycle, day and nominal time.  Individual patient and 
median profiles of the avelumab concentration-time data will be plotted by cohort, cycle and 
day using nominal times.  Median avelumab profiles will be presented on both linear-linear 
and log-linear scales.
9.3.2. Analysis of Pharmacodynamics
Percent PD-L1 TO will be summarized descriptively (n, mean, SD, CV, median, minimum, 
maximum, geometric mean, its associated CV, and 95% confidence interval) by dose, cycle, 
day and nominal time. Mean PD-L1 TO before the second cycle (at the expected Ctrough) will 
be used to decide which dose to move forward into the expansion phase of the protocol.  
Decision criteria are outlined in Section 3.1.
9.3.2.1. Analysis of Biomarker Endpoints
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, coefficient of variation percent, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate.  
Appropriate change from baseline measurements will be provided.  For discrete measurement 
biomarkers, frequencies and percentages of categorical biomarker measures will be 
determined at baseline and on-treatment/post-treatment time points, as appropriate; shift 
tables may also be provided. 
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Wilcoxon signed-rank test, Wilcoxon rank-sum test, correlation/linear 
regression, box-and-whisker plots, etc.  The statistical approaches will examine correlations 
of biomarker results (eg, PD-L1) with pharmacokinetic parameters and measures of efficacy, 
such as tumor response and progression free survival.
9.3.3. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab exposure and TO, biomarkers or significant safety/efficacy
endpoints.  The results of these analyses, if performed, may be reported separately.
9.3.4. Immunogenicity Assessment
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized by cohort and for the entire population in the study.  For 
patients with positive ADA, the magnitude (titer), time of onset, and duration of ADA 
response will also be described, if data permit.


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Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials.
9.4. Safety Analysis
Safety will be summarized by treatment cohort based on the safety analysis set, separately for 
each phase of the study.
9.4.1. Safety Stopping Rules
Based on the clinical thresholds described in Section 3.1.3, the trial will be stopped if given 
the data there is at least 70% probability that the toxicity rate is above the clinical threshold 
for any of the event categories.
Table 10.
Safety Stopping Rules
Patients
Gr 3 acute GVHD *
GVHD-related deaths
Gr 4 irAEs (excluding acute 
GVHD)
15
6/15 (40%)
4/15 (27%)
3/15 (20%)
20
8/20 (40%)
5/20 (25%)
4/20 (20%)
25
10/25 (40%)
6/25 (24%)
5/25 (20%)
30
12/30 (40%)
8/30 (27%)
6/30 (20%)
35
13/35 (37%)
9/35 (26%)
7/35 (20%)
40
15/40 (38%)
10/40 (25%)
8/40 (20%)
* Grade 3 liver GVHD must be confirmed by biopsy.
Only patients meeting eligibility criteria will be included in the evaluation.  As such, one 
patient in the lead-in phase who met exclusion criterion 1 related to GVHD will be excluded.
Two formal evaluations will be conducted at the following time points:  

16 weeks after 15 patients have received the first dose of study treatment.

16 weeks after 30 patients have received the first dose of study treatment.
Events from patients who at the time of the formal evaluation have not yet been followed for 
16 weeks from first dose of study treatment will also be considered in the evaluation.  The 
study will stop if the stopping boundary is crossed for any of the 3 event categories.
9.4.2. Adverse Events 
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 (http://ctep.info.nih.gov/reporting/ctc.html). 


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The frequency of patients experiencing treatment emergent adverse events corresponding to 
body systems and MedDRA preferred term will be reported.  Adverse events will be graded 
by worst NCI CTCAE v4.03 Grade.  Adverse events will be summarized by cycle and by 
relatedness to trial treatment. 
Emphasis in the analysis will be placed on AEs classified as treatment emergent.  Adverse 
events leading to death or discontinuation of trial treatment, events classified as NCI CTCAE 
v4.03 Grade 3 or higher, trial drug-related events, and serious adverse events will be 
summarized.
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study drug, action taken, and clinical 
outcome. 
9.4.3. Laboratory Test Abnormalities
Laboratory data will be summarized by treatment cohort and separately for each phase of the 
study. 
The laboratory results will be graded according to the NCI CTCAE v4.03 severity grade.  
The number and percentage of patients who experienced laboratory test abnormalities will be 
summarized according to worst grade for each laboratory test. 
For laboratory tests without NCI CTCAE grade definitions, results will be categorized as 
normal (within normal ranges), abnormal, or not done. 
Shift tables will be provided to examine the distribution of laboratory abnormalities.
9.4.4. Electrocardiograms
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, and QTc. 
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment. Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post-baseline corrected QT interval. 


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Shift tables will be provided for baseline vs worst on treatment corrected QT.  Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment.  Patients 
experiencing clinically-relevant morphological ECG changes will be summarized (including 
frequency and percentage).
 
9.6. Data Monitoring Committee
An external Data Monitoring Committee will not be established for the study. For the 
purpose of this protocol, Pfizer procedures for periodic safety review will be applied by an 
internal safety review team with medical and statistical capabilities to review individual and 
summary data collected in the safety and clinical databases, including surveillance for serious 
adverse events (SAEs) according to regulatory guidelines.
Discussions between the investigators and the Sponsor of AEs and laboratory test 
abnormalities seen at each dose level in an ongoing manner at regular teleconferences and/or 
meetings to determine the safety profile and make a benefit/risk assessment to decide if 
further patient enrollment at one or more avelumab dose levels is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
CCI


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It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry.
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to ICH guidelines, according to local regulations, or 
as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 


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Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg, 
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
on any Sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, address and other identifiable data will be replaced by a numerical code consisting of 
a numbering system provided by Pfizer in order to de-identify trial patients. The study site 
will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws.
The informed consent document(s) must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.


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The informed consent document(s) used during the informed consent process must be 
reviewed and approved by the Sponsor, approved by the IRB/IEC before use, and available 
for inspection. 
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each patient before any study-specific activity is performed.  The Investigator 
will retain the original of each patient's signed consent document.
12.4. Patient Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA)) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries
End of Trial in all other participating countries is defined as Last Patient Last Visit.


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, or investigational safety problems, or at the discretion of 
Pfizer.  In addition, Pfizer retains the right to discontinue development of avelumab at any 
time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
Investigator.  After notification, the Investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 1 month.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final patient was examined or received 
an intervention for the purposes of final collection of data for the primary outcome, whether 
the clinical study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 


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Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues.


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Appendix 1. Abbreviations
Abbreviation
Term
Ab
Antibody
ABVD
Doxorubicin, bleomycin, vinblastine, dacarbazine
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse event
AIDS
Acquired immunodeficiency syndrome
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
Allogeneic-HSCT
Allo-HSCT
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Area under the curve
BP
Blood pressure
BUN
Blood urea nitrogen
BICR
Blinded independent central review
C
Cycle
C
Concentration
cHL
Classic Hodgkin’s Lymphoma
CI
Confidence interval
CL
Clearance
CNS
Central nervous system
CPK
Creatine phosphokinase
CR
Complete response
CRF
Case report form
CSA
Clinical study agreement
CSF
Cerebrospinal fluid
CSR
Clinical study report
CT
Computed tomography
CTA
Clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
D
Day
DC
Disease control
DLI
Donor lymphocyte infusion
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
DR
Duration of Response
DU
Dispensable unit
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group


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Abbreviation
Term
EDP
Exposure during pregnancy
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
eg
For example
etc
‘And other things’ or ‘and so forth’
EudraCT
European Clinical Trials Database
EU
European Union
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
FDG
Fluorodeoxyglucose
FFPE
Formalin-fixed paraffin-embedded 
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
GVHD
Graft-versus-host disease
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HR
Heart rate
HRS
Hodgkin and Reed-Sternberg
HSCT
Hematopoietic stem cell transplant
IB
Investigator’s brochure
ICH
International Conference on Harmonisation
ID
Identification
ie
That is
IHC
Immunohistochemistry
IND
Investigational New Drug application
INR
International Normalized Ratio
irAE
Immune related adverse event
IRB
Institutional Review Board
IRR
Infusion related reaction
IRRC
Independent radiologic review committee
IRT
Interactive response technology
IUD
Intrauterine device
IV
Intravenous
JAK
Janus kinase
K2EDTA
Dipotassium ethylene diamine tetraacetic acid
LFT
Liver function test
LPD
Local product document
LVEF
Left ventricular ejection fraction
NSAID
Non-steroidal anti-inflammatory drug
mAb
Monoclonal antibody


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Abbreviation
Term
MD
Multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic resonance imaging
N/A
Not applicable
NCI 
National Cancer Institute 
NHL
Non-Hodgkin Lymphoma
NK
Natural killer
ORR
Objective response rate
OS
Overall survival
PCD
Primary completion date
PD
Pharmacodynamics
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression-Free Survival
PK
Pharmacokinetics
PR
Partial response
PS
Performance status
PT
Prothrombin time
PTT
Partial thromboplastin time
Q2W
Every 2 weeks
Q3W
Every 3 weeks
QD
Every day
QT
Time between the start of the Q wave and the end of the T wave
RNA
Ribonucleic acid
RR
Respiratory rate
RS
Reed-Sternberg
SOA
Schedule of activities
SAE
Serious adverse event
SAP
Statistical analysis plan
HSCT
Stem cell transplantation
SD
Single dose
SIB
Suicidal ideation and behavior
SRSD
Single reference safety document
STAT
Signal Transducer and Activator of Transcription
T
Time
T1/2
Terminal elimination half-life
TEAE
Treatment emergent adverse event
TBR
Tumor background ratio
TCR
T cell receptor
TIL
Tumor infiltrating lymphocyte
TO
Target Occupancy
TTR
Time to tumor response
ULN
Upper limit of normal


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Abbreviation
Term
US
United States
Vz
Volume of distribution
VOD
Veno-occlusive disease
WBC
White blood cell
WES
Whole exome-sequencing


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Appendix 2. Response Criteria for Malignant Lymphoma (Lead-in Phase)
From the International Workshop to Standardize Response Criteria for Lymphomas42
Complete Response (CR): Complete disappearance of all detectable clinical and 
radiographic evidence of disease and disappearance of all disease related symptoms if present 
before therapy and normalization of those biochemical abnormalities (for example LDH) 
definitely assignable to the lymphoma.  All lymph nodes must have regressed to normal size 
(less than or equal to 1.5 cm in greatest diameter if >1.5 cm before therapy).  Previously 
involved nodes that were 1.1 to 1.5 cm in greatest diameter must have decreased to less than 
or equal to 1 cm or by more than 75 percent in the sum of the products of the greatest 
diameters.  The spleen, if considered to be enlarged before therapy, must have regressed in 
size and not be palpable on physical examination.  The bone marrow must show no evidence 
of disease by histology.  Flow cytometry, molecular or cytogenetic studies will not be used to 
determine response.  Response must persist for 1 month.  For FDG-avid or PET positive 
lesions prior to therapy; mass of any size is permitted if the current scan is PET negative.  
For variably FDG-avid or PET negative lesions; regression to normal size on CT is required. 
Partial Response (PR): 50% decreased in the sum of products of the greatest diameters
(SPD) of 6 largest dominant nodes or nodal masses.  No increase in size of nodes, liver or 
spleen and no new sites of disease.  Splenic and hepatic nodules must regress by 50% in the 
SPD.  Bone marrow is irrelevant for determination of a PR.  No new sites of disease should 
be observed.  For FDG-avid or PET positive lesions prior to therapy; one or more PET 
positive at previously involved site is permitted.  For variably FDG-avid or PET negative 
lesions; regression on CT is required.
Progressive Disease (PD): 50% increase from nadir in the SPD of any previously 
identified abnormal node for PRs or non-responders.  Appearance of any new lesion during 
or at the end of therapy. 
Stable Disease (SD): is defined as less than a PR but not progressive disease.  ALL 
assessment of clinical response will be made according to the NHL guidelines.
Relapsed disease requires the following: Appearance of any new lesion or increase by 
50% in the size of the previously involved sites.  Greater than or equal to 50% increase in 
greatest diameter of any previously identified node >1 cm in its shortest axis or in the SPD of 
more than one node.
The major criteria for judging response will include physical examination and examination of 
blood and bone marrow.  All laboratory studies that are abnormal prior to study will be 
repeated to document the degree of maximal response.


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Page 147
Appendix 3. The Lugano Classification- (Expansion Phase)
From the Recommendations of Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification43:


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Appendix 4. Consensus Conference on Acute GVHD Grading29  


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Appendix 5. National Institutes of Health Consensus Development Project on Criteria 
for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and 
Staging Working Group report30


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Appendix 6. Treatment Recommendations for Symptoms of Avelumab 
Infusion-Related Reactions
The following treatment recommendations for symptoms of avelumab infusion-related
reactions may be modified based on local treatment standards and guidelines, as appropriate.
For Grade 1 Symptoms: (Mild reaction; infusion interruption not indicated; intervention not
indicated)

Decrease the avelumab infusion rate by 50% and monitor closely for any worsening.

Remain at bedside and monitor patient until recovery from symptoms.
For Grade 2 Symptoms: (Moderate reaction; Therapy or infusion interruption indicated but
responds promptly to symptomatic treatment (eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated for 24 hours.)

Temporarily discontinue avelumab infusion.

Treat based on emerging symptoms.  Treatment may include:

Normal saline IV;

H1 blockers, such as diphenhydramine 25 to 50 mg IV (or equivalent);

H2 blockers, such as ranitidine 50 mg IV (or equivalent);

NSAIDs, such as ibuprofen 600 mg (or equivalent);

Meperidine 12.5 to 50 mg IV;

Corticosteroids, such as hydrocortisone 100 to 500 mg IV (or equivalent);

Bronchodilators.

Remain at bedside and monitor patient until resolution of symptoms.

Resume avelumab infusion at 50% of previous rate as soon as infusion related 
reaction has resolved or decreased to at least Grade 1 in severity, and monitor closely 
for any recurrence or worsening.
For Grade 3 or Grade 4 Symptoms: (Severe reaction; Grade 3: prolonged [eg, not rapidly
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of
symptoms following initial improvement; hospitalization indicated for clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]; Grade 4: life-threatening consequences; urgent
intervention indicated).


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Page 155

Stop the avelumab infusion immediately and disconnect infusion tubing from the 
patient.

Begin an IV infusion of normal saline, and treat the patient with one or more of the 
following:

Airway maintenance;

Oxygen;

Bronchodilators;

Epinephrine 0.01 mg/kg of a 1:1,000 (1 mg/mL) solution IM, up to a maximum 
dose of 0.5 mg;

H1 blockers, such as diphenhydramine 25 to 50 mg IV (or equivalent);

H2 blockers, such as ranitidine 50 mg IV (or equivalent);

Corticosteroids, such as hydrocortisone 100 to 500 mg IV (or equivalent).

Remain at bedside and monitor patient until recovery from symptoms. 

Patients have to be withdrawn immediately from avelumab treatment and must not 
receive any further avelumab treatment.

SAP_001.pdf: 
Avelumab 
B9991007 (MSB0010718C) Statistical Analysis Plan
Page 1 
A PHASE 1 PHARMACOKINETIC PHARMACODYNAMIC STUDY OF 
AVELUMAB (MSB00100718C) IN PATIENTS WITH PREVIOUSLY TREATED 
ADVANCED STAGE CLASSICAL HODGKIN’S LYMPHOMA 
JAVELIN HODGKIN’S
STATISTICAL ANALYSIS PLAN - B9991007 
Compounds:
MSB0010718C
Compound Name:
Avelumab
Version:
V3
Date:
09-Apr-2018


Avelumab 
B9991007 (MSB0010718C) Statistical Analysis Plan
Page 2 
TABLE OF CONTENTS 
LIST OF TABLES .....................................................................................................................6 
APPENDICES ...........................................................................................................................6 
1. VERSION HISTORY ............................................................................................................7 
2. INTRODUCTION ...............................................................................................................10 
2.1. Study Objectives .....................................................................................................10 
2.2. Study Design ...........................................................................................................12 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................13 
3.1. Primary Endpoints ...................................................................................................13 
3.2. Secondary Endpoints ...............................................................................................15 
3.2.1. Safety endpoints ..........................................................................................15 
3.2.2. Efficacy endpoints ......................................................................................15 
3.2.3. Pharmacokinetic endpoints .........................................................................16 
3.2.4. Immunogenicity endpoints .........................................................................16 
3.2.5. Biomarker endpoints ...................................................................................16 
 
3.4. Baseline Variables ...................................................................................................18 
3.4.1. Study drug, study treatment and baseline definitions .................................18 
3.4.2. Baseline characteristics ...............................................................................19 
3.5. Safety Endpoints .....................................................................................................20 
3.5.1. Adverse events ............................................................................................20 
4. ANALYSIS SETS ...............................................................................................................20 
4.1. Full Analysis Set .....................................................................................................20 
4.2. Safety Analysis Set ..................................................................................................20 
4.3. Other Analysis Set ...................................................................................................21 
4.3.1. Target Occupancy analysis set ....................................................................21 
4.3.2. PK analysis set ............................................................................................21 
4.3.3. Biomarker analysis set ................................................................................21 
4.3.4. Immunogenicity analysis set .......................................................................21 
5. GENERAL METHODOLOGY AND CONVENTIONS ....................................................21 
5.1. Hypotheses and Decision Rules ..............................................................................21 
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B9991007 (MSB0010718C) Statistical Analysis Plan
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5.1.1. Hypotheses and sample size determination ................................................21 
5.1.2. Decision rules .............................................................................................22 
5.2. General Methods .....................................................................................................23 
5.2.1. Data handling after the cut-off date ............................................................24 
5.2.2. Pooling of centers .......................................................................................24 
5.2.3. Presentation of continuous and qualitative variables ..................................25 
5.2.4. Definition of study day ...............................................................................25 
5.2.5. Definition of start of new anti-cancer drug therapy ....................................25 
5.2.6. Definition of start of new anti-cancer therapy ............................................25 
5.2.7. Definition of on-treatment period ...............................................................26 
5.2.8. Standard derivations and reporting conventions .........................................26 
5.2.9. Unscheduled visits ......................................................................................27 
5.2.10. Adequate baseline tumor assessment ........................................................27 
5.2.11. Adequate post-baseline tumor assessment................................................27 
5.3. Methods to Manage Missing Data ..........................................................................27 
5.3.1. Missing data ................................................................................................27 
5.3.1.1. Pharmacokinetic concentrations ................................................27 
5.3.1.2. Pharmacokinetic parameters .....................................................28 
5.3.2. Handling of incomplete dates .....................................................................28 
5.3.2.1. Disease history ..........................................................................28 
5.3.2.2. Adverse events ..........................................................................29 
5.3.2.3. Prior and concomitant medications ...........................................29 
5.3.2.4. Exposure ....................................................................................30 
5.3.3. Imputation rules for date of last contact and efficacy assessments ............30 
5.3.3.1. Date of last contact ....................................................................30 
5.3.3.2. Death date ..................................................................................31 
5.3.3.3. Tumor assessments ....................................................................31 
5.3.3.4. Date of start of new anti-cancer therapy ...................................31 
6. ANALYSES AND SUMMARIES ......................................................................................33 
6.1. Primary Endpoints ...................................................................................................33 
6.1.1. Percent TO (Lead-in Phase) ........................................................................33 
6.1.1.1. Primary analysis ........................................................................33 
6.1.2. Objective Response by BICR Assessment (Expansion Phase) ..................34 


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6.1.2.1. Primary analysis ........................................................................34 
6.2. Secondary Endpoint(s) ............................................................................................36 
6.2.1. Safety endpoints ..........................................................................................36 
6.2.2. Efficacy endpoints ......................................................................................36 
6.2.2.1. Tumor shrinkage from baseline .................................................37 
6.2.2.2. Disease control ..........................................................................37 
6.2.2.3. Duration of response .................................................................37 
6.2.2.4. Time to response .......................................................................38 
6.2.2.5. Progression-free survival ...........................................................38 
6.2.2.6. Overall Survival ........................................................................40 
6.2.3. Pharmacokinetic endpoints .........................................................................41 
6.2.4. Population pharmacokinetic endpoints .......................................................43 
6.2.5. Biomarker endpoints ...................................................................................43 
6.2.5.1. IHC Analysis of PD-L1, CD8 and FoxP3 Expression in 
Tumor Biopsy ....................................................................................43 
6.2.5.2. RNA Expression Profiling of Tumor Biopsy Tissue by 
RNA Sequencing ...............................................................................44 
6.2.5.3. Relative Proportion of T Cell Subsets in the Peripheral 
Blood by Flow Cytometry .................................................................44 
6.2.6. Endpoints for Immunogenicity Data of Avelumab ....................................44 
6.2.6.1. Time to and Duration of ADA and nAb response .....................46 
6.2.6.2. ADA titer ...................................................................................47 
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity 
status ..................................................................................................47 
 
6.4. Subset Analyses .......................................................................................................49 
6.5. Baseline and Other Summaries and Analyses .........................................................50 
6.5.1. Baseline summaries ....................................................................................50 
6.5.1.1. Demographic characteristics .....................................................50 
6.5.1.2. Medical history ..........................................................................51 
6.5.1.3. Disease characteristics ...............................................................51 
6.5.1.4. Prior anti-cancer therapies .........................................................53 
6.5.1.5. Prior and concomitant immunosuppressive therapies ...............53 
6.5.2. Study conduct and patient disposition ........................................................54 
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6.5.2.1. Patient disposition .....................................................................54 
6.5.2.2. Protocol deviations ....................................................................55 
6.5.3. Study treatment compliance and exposure .................................................56 
6.5.3.1. Exposure to avelumab ...............................................................57 
6.5.3.2. Dose reductions .........................................................................59 
6.5.3.3. Dose delays ...............................................................................59 
6.5.3.4. Infusion rate reductions .............................................................59 
6.5.3.5. Infusion interruptions ................................................................60 
6.5.4. Concomitant medications and non-drug treatments ...................................60 
6.5.5. Subsequent anti-cancer therapies ................................................................61 
6.6. Safety Summaries and Analyses .............................................................................61 
6.6.1. Adverse events ............................................................................................61 
6.6.1.1. All adverse events .....................................................................62 
6.6.1.2. Adverse events leading to dose reduction .................................63 
6.6.1.3. Adverse events leading to interruption of study treatment .......63 
6.6.1.4. Adverse events leading to discontinuation of study 
treatment ............................................................................................64 
6.6.2. Deaths .........................................................................................................64 
6.6.3. Serious adverse events ................................................................................65 
6.6.4. Other significant adverse events .................................................................65 
6.6.5. Laboratory data ...........................................................................................66 
6.6.5.1. Hematology and chemistry parameters .....................................66 
6.6.5.2. Other laboratory parameters ......................................................69 
6.6.6. Vital signs ...................................................................................................70 
6.6.7. Electrocardiogram .......................................................................................70 
6.6.8. Physical examination ..................................................................................72 
6.6.9. ECOG performance status ..........................................................................72 
7. INTERIM ANALYSES .......................................................................................................72 
7.1. Introduction .............................................................................................................72 
7.2. Interim Analyses and Summaries ............................................................................72 
8. REFERENCES ....................................................................................................................73 
9. APPENDICES .....................................................................................................................74 


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LIST OF TABLES 
Table 1. 
Summary of Major Changes in SAP Amendments ................................................7 
Table 2. 
PK Parameters to be Determined for Avelumab ..................................................13 
Table 3. 
Biomarker Definition and Determination .............................................................16 
Table 4. 
Sample Size and Exact 95% CIs for ORR - Post-allogeneic HSCT cohort F ......22 
Table 5. 
Safety Stopping Rules...........................................................................................23 
Table 6. 
Summaries for each endpoint ...............................................................................24 
Table 7. 
Possible BOR Outcomes for Investigator vs BICR ..............................................36 
Table 8. 
Outcome and event dates for PFS and DR analyses .............................................39 
Table 9. 
PFS Censoring Reasons and Hierarchy ................................................................40 
Table 10. 
OS Censoring Reasons and Hierarchy ..................................................................41 
Table 11.  Patients Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ...................................................................................................................45 
Table 12.  Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) ...................................................................................................................46 
Table 13. 
Case Definition for irAEs .....................................................................................74 
Table 14. 
Case Definition for IRRs ......................................................................................76 
APPENDICES 
Appendix 1. Immune-Related Adverse Events ........................................................................74 
Appendix 2. Infusion Related Reactions .................................................................................76 


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1. VERSION HISTORY 
This Statistical Analysis Plan (SAP) for study B9991007 is based on the protocol amendment 
4 dated 13NOV2017.   
Table 1. 
Summary of Major Changes in SAP Amendments 
Version
Version Date
Summary of Changes
3
09-Apr-2018
Section 3.4.1 “Study drug, study treatment and baseline definitions” - Added the 
definition of baseline for biomarker analyses.
Section 5.1.2 “Decision Rules” - added safety stopping rules for the expansion 
phase, as per Protocol Amendment 4.
Section 5.3.3.1 “Date of last contact” - Withdrawal of consent date was added to 
the derivation of date of last contact. 
Section 6.1.2.1 “Primary Analysis” - Added analysis summary of concordance 
between BICR and Investigator for objective response and best overall response.
Section 6.2.2.5 “Progression Free Survival” - Expanded the analysis of Time of 
Follow-Up for PFS to include Kaplan-Meier estimates
Section 6.2.2.6 “Overall Survival” - Expanded the analysis of Time of Follow-Up 
for OS to include Kaplan-Meier estimates
Section 6.2.3 “Pharmacokinetic endpoints” - Clarified the PK analysis for Lead-in 
and Expansion phases.
Section 6.2.5 “Biomarker endpoints” – Added details on how data from patients
with more than one result at a visit for a specific biomarker analyte will be 
handled. 
Section 6.2.6 “Endpoints for immunogenicity data of avelumab” – provided 
further details for the analyses that will be performed including summaries of 
SAEs, AEs with grade ≥3, AEs leading to dose reduction of avelumab and AEs 
leading to discontinuation of avelumab by anti-drug antibody (ADA) status and, if 
data permits, neutralizing antibody (nAb) status. Added to Section 3.4.1 the 
baseline definition for immunogenicity analyses. 
Section 6.5.3.3 “Dose Delays” – Modified the grouping of delays for categorical 
analysis to be aligned with dosing window allowed per protocol.
Section 6.6.1 “Adverse events” and subsections – given the nature of immune-
related AEs (irAEs) and infusion related reactions (IRRs), removed the summaries 
of treatment-related irAEs and treatment-related IRRs; added summaries of AEs 
leading to dose reduction, AEs leading to interruption of study treatment and AEs 
leading to both dose reduction and interruption of study treatment. 
Appendix 1 “Immune-related Adverse Events” – provided additional ATC codes 
for concomitant medications in Step 4 of the case definition for irAEs; ATC code 
H02C was deleted from Step 4 since it reflects a group of drugs that is “anti-
corticosteroids” used to treat Cushing’s syndrome rather than “corticosteroids”.
Minor editorial and consistency changes throughout the document.
2
03-Aug-2017
Updated study design and analysis for expansion phase as per Protocol 
Amendment 3.
Section 2 “Introduction” – Changed the cut-off date for the primary analysis from 
12 months to 24 months after the last patient receives the first dose of study drug.


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Section 2.1 “Study Objectives” – Added primary, secondary 
objectives for the expansion phase according to Protocol Amendment 3.
Section 2.2 “Study Design” – Added design for expansion phase according to 
Protocol Amendment 3.
Section 3.1 “Primary Endpoints” – added primary endpoint for expansion phase 
according to Protocol Amendment 3.
Section 3.2 “Secondary Endpoints” – added secondary safety, efficacy, PK, 
immunogenicity, biomarker endpoints for expansion phase according to Protocol 
Amendment 3.
Section 3.4.1 “Study drug, study treatment and baseline definitions” – Added 
Cohort F for expansion phase (avelumab 70 mg IV Q2W) according to Protocol 
Amendment 3; provided further detail for definition of start and end dates of study 
treatment; added definition of baseline for the non-randomized expansion phase of 
the study; changed heart rate to RR in the references for derivations since the ECG 
CRF collects RR rather than heart rate.
Section 4.1 “Full Analysis Set” – Added definition of full analysis set for the non-
randomized expansion phase as per Protocol Amendment 3.
Section 4.3.1. “Target Occupancy analysis set” – Changed the definition of the 
analysis set to include only patients with at least one receptor occupancy sample 
both pre- and post- Cycle 1 Day 1 dose.
Section 4.3.3. “Biomarker analysis set” – provided further details for the selection 
of patients to be included in each of the biomarker analysis sets.
Section 5.1.1. “Hypotheses and sample size determination” – Modified according 
to specifications in Protocol Amendment 3.
Section 5.2. “General Methods” - Added Cohort F for expansion phase (avelumab 
70 mg IV) according to Protocol Amendment 3 and provided the details for the 
summaries across treatment groups and phases for each endpoint (Table 5); the 
associated wording is also added to each subsection of Section 6 “Analyses and 
Summaries” for the relevant endpoint.
Section 5.2.5. “Definition of start of new anti-cancer drug therapy” – Section 
added.
Section 5.2.6. “Definition of start of new anti-cancer therapy” – Section added.
Section 5.2.8. “Standard derivations and reporting conventions” – Removed 
derivation of BSA since no drug in this study is administered based on BSA.
Section 5.2.10. “Adequate baseline tumor assessment” – Section added.
Section 5.2.11. “Adequate post-baseline tumor assessment” – Section added.
Section 5.3.2.4. “Exposure” – Imputation rules updated with regards to 
comparison with start date of study drug.
Section 5.3.3.2. “Death date” – Imputation rules simplified to be based on the 
derived date of last contact.
Section 5.3.3.4. “Date of start of new anti-cancer therapy” – Section added.
Section 6.1.2. “Objective Response by BICR (Expansion Phase)” – Section added
according to Protocol Amendment 3.
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Section 6.2.2. “Efficacy endpoints” – Section updated to reflect the different 
criteria of response evaluation in the lead-in and expansion phase, as per Protocol 
Amendment 3.
Section 6.2.2.1. “Tumor shrinkage” – Index Lesions changed to Largest Dominant 
Masses, to correctly reflect the updated CRF (as per Cheson 2007).
Section 6.2.2.3. “Duration of response” – 18 months added to the pre-specified 
time points where DR rate will be estimated given the increase in the minimum 
follow-up for all patients at the time of the cut-off for the primary analysis. 
Section 6.2.2.5. “Progression-free survival” – updated to reflect the tumor 
assessment schedule in the expansion phase, as per Protocol Amendment 3. 
Outcome and Event Dates for PFS and DR Analyses as well as Reason for 
Censoring have been updated with more details; 18 months added to the pre-
specified time points where PFS rate will be estimated given the increase in the 
minimum follow-up for all patients at the time of the cut-off for the primary 
analysis
Section 6.2.2.6. “Overall Survival” – Section added to reflect the additional 
endpoint in the expansion phase, as per Protocol Amendment 3.
Section 6.4. “Subset Analyses” – Added subgroup analyses of efficacy endpoints 
by prior stem cell transplant type.
Section 6.5.1.1. “Demographic characteristics” – Updated Geographic Regions,
removed BSA.
Section 6.5.1.2 “Medical history” – Added a listing for prior stem cell transplant 
details.
Section 6.5.1.3 “Disease characteristics” – variables updated to reflect the updated 
CRF, including prior transplant details.
Section 6.5.1.5. “Prior and concomitant immunosuppressive therapies” – Section 
added.
Section 6.5.2. “Study conduct and patient disposition” – Study phases will not be 
analyzed together.
Section 6.5.2.1. “Patient disposition” – Added the analyses for the non-
randomized expansion phase.
Section 6.5.3. “Study treatment compliance and exposure” and subsections –
Added Cohort F according to Protocol Amendment 3 and provided further details 
for derivations.
Section 6.5.3.3. “Dose delays” – Added formula for the calculation of dose delays 
and updated delays categories.
Section 6.5.3.5. “Infusion interruptions” – Section added.
Section 6.5.4 “Concomitant medications and non-drug treatments” – added 
summaries for pre-medications.
Section 6.5.5. “Subsequent anti-cancer therapies” – Updated references to CRF 
forms to reflect the updated CRF.
Section 6.6. “Safety Summaries and Analyses” and subsections – updated the 
definition and analyses for IRRs and irAEs and added Appendix 1 and 2 with the 
algorithms for derivation of IRRs and irAEs. Section 6.6.1.1. “All adverse events” 
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– Added analysis of GVHD as per Protocol Amendment 3.
Section 6.6.5 “Laboratory data” and subsections – provided the formula for 
corrected calcium in SI units and corrected the descriptors associated with the 
eDISH plot.
Section 6.6.6. “Vital signs” – Schedule of assessment for expansion phase added 
as per Protocol Amendment 3.
Removed confirmation of response throughout the document, as per Cheson 
Criteria 2007 and Protocol Amendment 3.
Minor additional editorial changes.
1
18- Sep-2015
Not applicable (N/A)
2. INTRODUCTION 
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991007.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment. 
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (i.e., 
biopsy data from the central laboratory, pharmacokinetic (PK) data, and biomarker data). The 
primary analysis of Target Receptor Occupancy (TO) will include all data up to a analysis 
cut-off date corresponding to 1 cycle of treatment (2-week or 3-week, depends on treatment 
cycle) after the last patient is randomized.   The primary analysis for the Clinical Study 
Report will include all data up to an analysis cut-off date corresponding to 24 months after 
the last patient receives the first dose of study drug.  The final analysis of the data will 
be performed after last patient last visit (LPLV).  
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes. 
Throughout this document ‘start date’ refers to date of randomization for patients enrolled in 
the lead-in phase, and first dose of study treatment for patients enrolled in the expansion 
phase.  
2.1. Study Objectives 
Primary Objectives 
Lead-in Phase 
x
To characterize the pharmacokinetics (PK) of different dosing regimens of avelumab and 
its relation to target occupancy (TO) in peripheral blood of patients with Classic 
Hodgkin’s Lymphoma (cHL). 


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Expansion Phase 
x
To evaluate the objective response rate (ORR) of avelumab in patients with relapsed or 
refractory cHL who have previously been treated with an allogeneic Hematopoietic Stem 
Cell Transplant (HSCT). 
Secondary Objectives 
Lead-in Phase 
x
To evaluate the overall safety and tolerability of different dosing regimens of avelumab.  
x
To assess the immunogenicity of different dosing regimens of avelumab. 
x
To evaluate the effect of different dosing regimens of avelumab on pharmacodynamics 
biomarkers of tumor immunophenotype and anti-tumor immune response. 
x
To evaluate the anti-tumor activity of avelumab in patients with cHL. 
Expansion Phase 
x
To evaluate the overall anti-tumor activity of avelumab. 
x
To evaluate the overall safety profile of avelumab. 
x
To evaluate the incidence and severity of acute and chronic GVHD.
x
To characterize the pharmacokinetics of avelumab. 
x
To assess the immunogenicity of avelumab. 
x
To evaluate the phenotype and quantity of TILs and correlate these findings with 
antitumor activity. 
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2.2. Study Design 
This is a Phase 1b, open-label, multi-center study comprising a lead-in phase and an 
expansion phase in patients with relapsed/refractory cHL. 
Lead-in Phase 
The lead-in is a multiple-dose, randomized, parallel-arm, pharmacokinetic and 
pharmacodynamic study of avelumab administered intravenously (IV) as a single agent in 
adult patients with cHL.  Patients enrolled in the lead-in phase of the study are required to 
have relapsed following a prior autologous or allogeneic HSCT, or to be ineligible for HSCT. 
In the lead-in phase of the study, a total of approximately 30 patients will be randomized 
across 5 treatment cohorts in a ratio of 1:1:1:1:1, with 6 patients per treatment cohort.  The 
5 treatment cohorts will be 70 mg every 2 weeks (Q2W) (Cohort A), 350 mg Q2W 
(Cohort B), 500 mg every 3 weeks (Q3W) (Cohort C), 500 mg Q2W (Cohort D), and 
10 mg/kg Q2W (Cohort E). The goal of the lead-in phase is to determine the doses and 
schedules of avelumab that provide greater than 90% TO over the dosing interval and to 
identify a dose regimen for use in the dose expansion phase. 
Expansion Phase 
Based on the preliminary TO, safety, and efficacy results from the lead-in phase, the 
expansion phase will evaluate the anti-tumor activity and safety of single-agent avelumab 
utilizing an intra-patient dose escalation paradigm based on two of the dosing regimens 
studied in the lead-in phase in 40 cHL patients in whom an allogeneic HSCT has failed.   
CCI


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In the expansion phase all patients will commence dosing at 70 mg Q2W and will be 
monitored for safety and efficacy. Following 3 cycles of treatment at 70 mg Q2W,  
x
patients who achieve a CR at the 6-week tumor assessment will continue dosing at 70 mg 
Q2W;  
x
patients who achieve a PR at the 6-week tumor assessment will continue dosing at 70 mg 
Q2W for an additional 3 cycles (6 weeks);  
-
if the 12-week tumor assessment still shows a PR, patients will be dose escalated to 
500 mg Q2W;  
x
patients who achieve a SD at the 6-week tumor assessment, will be dose escalated to 500 
mg Q2W. 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoints 
Lead-in Phase 
x
Percent TO by dose/schedule in peripheral blood immune cells, including CD14+ 
monocytes and CD3+ T cells. 
Percent TO is defined as the percentage of target receptors occupied by avelumab in 
peripheral blood immune cells, including, but not limited to monocytes.  
x
Pharmacokinetic parameters of avelumab including, but not limited to, Cmax, Tmax,
AUClast, Tlast, AUCsd,τ, t1/2, AUCsd,inf, CL, and Vz as data permit. Multiple Dose (MD) - 
Css,max, Tss,max, AUCss, τ, t1/2, Css,min, Css,av, CL and Vss ,Rac (AUCss, τ /AUCsd, τ) and Rss
(AUCss, τ /AUCsd,inf) as data permit.  
Table 2. 
PK Parameters to be Determined for Avelumab  
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time 
profile from time zero((pre-dose) to the 
time of the last quantifiable concentration 
(Clast)
Linear/Log trapezoidal method
AUCsd,W
AUCss,W
Area under the plasma concentration-time 
profile from time zero ((pre-dose) to the 
next dose (after single dose(sd) and at 
steady state (ss))
Linear/Log trapezoidal method
Cmax
Maximum observed plasma concentration 
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of first 
occurrence
Tss, max
Time for Cmax at steady state 
Observed directly from data as time of first 
occurrence at steady state


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Parameter
Definition
Method of Determination
t½
a
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate constant 
calculated by a linear regression of the 
log-linear concentration-time curve.  Only 
those data points judged to describe the 
terminal log-linear decline were used in the 
regression.
Ctrough
Pre-dose concentration during multiple 
dosing
Observed directly from data
Css, av
Pre-dose concentration during multiple 
dosing
AUCss / τ
CL
Clearance
Dose / AUCτ for steady state
Vz
a
Volume of distribution
Dose / (AUCτ ·kel) for steady state
Rac
Accumulation ratio
AUCss,W / AUCsd,W
Rss
Steady state accumulation ratio
AUCss,W/AUCsd,inf
Cmax(dn)
Dose normalized Cmax
Cmax / Dose
Tlast
The last time point of the last quantifiable 
concentration (Clast)
Observed directly from data
C ss,max
Maximum observed plasma concentration 
at steady state
Observed directly from data
AUC sd,inf
Area under the plasma concentration-time 
profile from time zero to infinity, after 
single dose.
Linear/Log trapezoidal method
C ss,max
Maximum observed plasma concentration 
at steady state
Observed directly from data
C ss,min
Minimum observed plasma concentration at 
steady state
Observed directly from data
a If data permit
Expansion Phase 
x
Objective response defined by the Lugano Classification (Cheson et al., 2014) as 
evaluated by the blinded independent central review (BICR). 
OR is defined as complete response (CR) or partial response (PR) according to the 
Lugano Classification (Cheson et al., 2014) from ‘start date’ until documented disease 
progression. 


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3.2. Secondary Endpoints 
3.2.1. Safety endpoints 
Lead-in Phase and Expansion Phase
x
Adverse Events as characterized by type, severity (as graded by National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.03), timing, 
seriousness, and relationship to study therapy. 
AEs will be graded by the investigator according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) 
x
Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v.
4.03), and timing. 
Expansion Phase
x
Acute GVHD as defined by the modified Seattle Glucksberg criteria (Consensus 
Conference on Acute GVHD Grading Criteria) and Chronic GVHD as defined by the 
NIH Consensus Development Project.
3.2.2. Efficacy endpoints 
Lead-in Phase
x
Objective response according to Response Criteria for Malignant Lymphoma (Cheson et 
al., 2007) per Investigator assessment. 
x
Disease control (DC), time to tumor response (TTR), duration of response (DR), 
progression-free survival (PFS) per Investigator assessment. 
Expansion Phase 
x
Objective response as defined by the Lugano Classification (Cheson et al., 2014) and 
evaluated by Investigator’s assessment.
x
Time to tumor response (TTR), duration of response (DR), Disease Control (DC) and 
progression-free survival (PFS) according to the Lugano Classification (Cheson et al., 
2014) by BICR and by Investigator’s assessment, as well as overall survival (OS). 
OR is defined as complete response (CR) or partial response (PR) according to Response 
Criteria for Malignant Lymphoma  (Cheson et al., 2007) (Lead-in Phase) or Lugano 
Classification  (Cheson et al., 2014) (Expansion Phase) from ‘start date’ until first 
documentation of progressive disease (PD).  
DR is defined, for patients with OR, as the time from first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.   


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DC is defined as CR, PR or SD. Criterion for SD must have been met at least 6 weeks 
after the ‘start date’. 
TTR is defined, for patients with an OR, as the time from the ‘start date’ to the first 
documentation of objective response (CR or PR).  
PFS is defined as the time from ‘start date’ to the date of the first documentation of PD or 
death due to any cause, whichever occurs first. 
OS is defined as the time from ‘start date’ to the date of death due to any cause. 
3.2.3. Pharmacokinetic endpoints 
Expansion Phase 
x
Pharmacokinetic parameters of avelumab including, but not limited to, Cmax, Tmax,
AUCsd,W, t1/2, CL, and Vz as data permit.  Multiple Dose (MD) - Css,max, Tss,max, AUCss,W,
t1/2, Css,min, Css,av, CL, and Vss as data permit. 
Definition of PK parameters is provided in Table 2.
3.2.4. Immunogenicity endpoints 
Lead-in Phase and Expansion Phase
x
Anti-drug antibodies (ADAs; neutralizing antibodies) and serum titers against avelumab. 
3.2.5. Biomarker endpoints 
Lead-in Phase
x
Relative expression of transcripts associated with immune activation and regulation in 
tumor biopsy tissue by gene expression profiling. 
x
Phenotype, relative proportions, activation state and PD-L1 expression of peripheral 
blood T cell subsets by flow cytometry. 
Lead-in Phase and Expansion Phase
x
Phenotype, quantity, and localization of tumor infiltrating lymphocytes (TILs) in tumor 
biopsy tissue by immunohistochemistry (IHC). 
Table 3. 
Biomarker Definition and Determination 
Parameter
Definition
Method of Determination
Peripheral blood target 
occupancy
Occupancy of PD-L1 in peripheral blood 
immune cells by avelumab
Flow cytometry
Biopsy CD8, FoxP3, 
PD-L1 expression
Expression of immune- and target-related 
markers on immune cells, tumor cells and 
tumor vs stroma
Immunohistochemistry


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Biopsy expression of 
RNA transcripts 
Expression of immune- and pathway-related 
RNA transcripts
RNA Sequencing
Peripheral blood 
immune cell 
phenotypes
Relative proportion of T cell subsets 
Flow cytometry
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3.4. Baseline Variables 
3.4.1. Study drug, study treatment and baseline definitions 
In this study, ‘study drug’ refers to avelumab and ‘study treatment’ (or ‘treatment 
group’) refers to one of the following: 
Lead-in Phase
x
Cohort A:  avelumab 70 mg IV Q2W.  
x
Cohort B:  avelumab 350 mg IV Q2W. 
x
Cohort C:  avelumab 500 mg IV Q3W. 
x
Cohort D:  avelumab 500 mg IV Q2W.  
x
Cohort E:  avelumab 10 mg/kg IV Q2W. 
Expansion Phase 
x
Cohort F: avelumab 70 mg IV Q2W or avelumab 70 mg IV Q2W followed by avelumab 
500 mg Q2W 
As described in Section 2.2, patients enrolled in Cohort F initiate dosing with avelumab 
at 70 mg Q2W but intra-patient dose escalation to 500 mg Q2W may occur.
Start and end dates of study treatment:
The date/time of first dose of study treatment is the earliest date/time of non-zero dosing of 
the study drug. 
The date/time of last dose of study treatment is the latest date/time of non-zero dosing of the 
study drug. 
Definition of baseline:  
Definition of baseline for efficacy analyses in the lead-in phase (randomized) 
The last measurement prior to randomization will serve as the baseline measurement for 
efficacy analyses. If such a value is missing, the last measurement prior to the first dose of 
study treatment will be used as the baseline measurement except for analyses of tumor 
assessments data where the baseline assessment would be considered as missing.  
Definition of baseline for immunogenicity analyses 
The last available assessment prior to the start of treatment with avelumab is defined as 
‘baseline’ result or ‘baseline’ assessment.  If an assessment is planned to be performed prior 
to the first dose of avelumab in the protocol and the assessment is performed on the same day 
as the first dose of avelumab, it will be assumed that it was performed prior to avelumab 
administration, if assessment time point is not collected or is missing. 


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Definition of baseline for biomarker analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for biomarker analyses. For biomarkers that are planned to be 
measured on Cycle 1 Day 1, if the assessment time point is not collected or is missing, it will 
be assumed that the measurement was performed prior to first dose of study treatment. 
Definition of baseline for efficacy analyses in the expansion phase (non-randomized) and for 
safety analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety and efficacy (for the non-randomized phase)
analyses.  If an assessment is planned to be performed prior to the first dose of study 
treatment in the protocol and the assessment is performed on the same day as the first dose of 
study treatment, it will be assumed that it was performed prior to study treatment
administration, if assessment time point is not collected or is missing. If assessment time 
points are collected, the observed time point will be used to determine pre-dose on study day 
1 for baseline calculation. Unscheduled assessments will be used in the determination of 
baseline. However, if time is missing, an unscheduled assessment on study day 1 will be 
considered to have been obtained after study treatment administration. 
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection.  
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement. 
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point. 
3.4.2. Baseline characteristics 
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 
are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6.


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3.5. Safety Endpoints 
3.5.1. Adverse events 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period.  
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs) 
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendices 1 and 2, 
respectively. 
4. ANALYSIS SETS 
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures. 
Only patients who signed informed consent will be included in the analysis sets below. 
4.1. Full Analysis Set 
For the lead-in phase (randomized): The full analysis set (FAS) will include all randomized 
patients.  Patients will be classified according to the study treatment assigned at 
randomization. 
For the expansion phase (non-randomized): The FAS will include all patients who receive at 
least one dose of study drug.  Patients will be classified according to the study treatment 
actually received.  If a patient receives more than one treatment the patient will be classified 
according to the first study treatment received.  
4.2. Safety Analysis Set 
The safety analysis set will include all patients who receive at least one dose of study drug. 
Patients will be classified according to the study treatment assigned at randomization unless 
the incorrect treatment(s) was/were received throughout the dosing period in which case 
patients will be classified according to the first study treatment received. In the expansion 
phase, since non-randomized, the FAS and the safety analysis set are identical.  


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4.3. Other Analysis Set 
4.3.1. Target Occupancy analysis set 
The TO analysis set includes patients in the safety analysis set who have at least one 
Receptor Occupancy blood sample collected both pre and post Cycle 1 Day 1 dose. 
4.3.2. PK analysis set 
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for avelumab. 
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least one of the PK parameters of interest for avelumab. 
4.3.3. Biomarker analysis set  
The biomarker analysis set is a subset of the safety analysis set and will include patients who 
have at least one baseline biomarker sample.   
x
Whole Blood Biomarker Analysis Set: subjects in the biomarker analysis set who have at 
least one whole blood biomarker sample collected  
x
Plasma Biomarker Analysis Set: subjects in the biomarker analysis set who have at least 
one plasma biomarker sample collected  
x
Tumor Biopsy Biomarker Analysis Set: subjects in the biomarker analysis set who have 
provided at least one evaluable tumor biopsy sample.
4.3.4. Immunogenicity analysis set 
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb sample collected for avelumab. 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and sample size determination 
Lead-in Phase 
There is no formal hypothesis testing in this phase. Approximately 30 patients will be 
randomized in a 1:1:1:1:1 ratio across 5 treatment groups.  The 6 patients per treatment group
in the lead-in phase will be used to enable the initial estimation of TO; based on the historical 
data, with an observed mean TO of 90%, the corresponding 95% confidence interval (CI) 
will be 88.98% to 91.02%, assuming a standard deviation of 1.27%.  


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Expansion Phase 
There is no formal hypothesis testing in this phase. Approximately 40 patients will be 
enrolled. With 40 treated patients, ORR can be estimated with a standard error not exceeding 
0.079.
Table 4 provides 95% CIs for ORR based on different observed responses in the post-
allogeneic HSCT cohort. 
Table 4. 
Sample Size and Exact 95% CIs for ORR - Post-allogeneic HSCT cohort F 
Number of patients 
in Cohort F
Number of observed 
responders
Observed ORR
95% CI for True ORR
40
16
40%
(24.86%, 56.67%)
20
50%
(33.80%, 66.20%)
24
60%
(43.33%, 75.14%)
28
70%
(53.47%, 83.44%)
32
80%
(64.35%, 90.95%)
The study plans to enroll approximately 70 patients in total. 
5.1.2. Decision rules 
Lead-in Phase
A dose regimen studied in the lead-in phase may be selected for the expansion phase if, 
based on the data from the lead-in phase: 
x
greater than a mean 90% TO after 1 treatment cycle is achieved, and 
x
at least 3 objective responses per Response Criteria for Malignant Lymphoma are 
observed. 
Expansion Phase 
The safety stopping rules will be based on the observed incidence of acute GVHD Grade ≥3,
acute GVHD-related mortality and Grade ≥4 irAEs, within 16 weeks from start of study 
treatment for each patient in the expansion phase and each patient with prior allogeneic 
HSCT in the lead-in phase, according to the following clinical thresholds: 
1. Acute GVHD Grade ≥3 <33% (Grade 3 liver GVHD must be confirmed by biopsy).
2. Acute GVHD-related mortality ≤20%.
3. irAEs Grade ≥4 <15%.


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Using a Beta(0.5, 0.5) prior, the trial will be stopped if given the data the posterior 
probability that the toxicity rate is above the clinical threshold for any of the event categories 
is ≥70%. The following stopping rules are obtained using the beta-binomial posterior. 
Table 5. 
Safety Stopping Rules 
Number of 
Patients 
Gr ≥3 acute GVHD * 
GVHD-related deaths 
Gr ≥4 irAEs (excluding acute 
GVHD) 
15 
6/15 (40%) 
4/15 (27%) 
3/15 (20%) 
20 
8/20 (40%) 
5/20 (25%) 
4/20 (20%) 
25 
10/25 (40%) 
6/25 (24%) 
5/25 (20%) 
30 
12/30 (40%) 
8/30 (27%) 
6/30 (20%) 
35
13/35 (37%)
9/35 (26%)
7/35 (20%)
40
15/40 (38%)
10/40 (25%)
8/40 (20%)
* Grade 3 liver GVHD must be confirmed by biopsy. 
Only patients meeting eligibility criteria will be included in the evaluation. Events from 
patients who at the time of the formal evaluation have not yet been followed for 16 weeks 
from first dose of study treatment will also be considered in the evaluation. The study will 
stop if the stopping boundary is crossed for any of the 3 event categories. 
Two formal evaluations of safety will be performed: 
x
16 weeks after 15 patients have received the first dose of study treatment. 
x
16 weeks after 30 patients have received the first dose of study treatment. 
5.2. General Methods 
As described in Section 3.4, in this study ‘treatment group’ refers to one of the following:
Lead-in Phase
x
Cohort A:  avelumab 70 mg IV Q2W.  
x
Cohort B:  avelumab 350 mg IV Q2W. 
x
Cohort C:  avelumab 500 mg IV Q3W. 
x
Cohort D:  avelumab 500 mg IV Q2W.  
x
Cohort E:  avelumab 10 mg/kg IV Q2W. 


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Expansion Phase 
x
Cohort F: avelumab 70 mg IV Q2W or avelumab 70 mg IV Q2W followed by avelumab 
500 mg Q2W  
As described in Section 2.2, patients enrolled in Cohort F initiate dosing with avelumab 
at 70 mg Q2W but intra-patient dose escalation to 500 mg Q2W may occur 
Unless otherwise specified (see Table 6), all data will be analyzed by study phase and 
treatment group, and treatment groups in the lead-in phase will also be pooled together.   
Table 6. 
Summaries for each endpoint 
Endpoints
Lead-in by 
treatment group
Lead-in treatment 
groups pooled
Expansion
Lead-in and 
expansion treatment 
groups pooled
Efficacy 
9
9
9
Target Occupancy
9
Safety
9
9
9
PK
9
9
Immunogenicity
9
9
9
9
Biomarkers
9
9
9
9
Exposure
9
9
Demographic 
characteristics
9
9
9
9
Disease characteristics, 
prior anti-cancer 
therapies, prior and 
concomitant therapies
9
9
9
Disposition
9
9
9
5.2.1. Data handling after the cut-off date 
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of centers 
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients randomized/treated at each center. 


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5.2.3. Presentation of continuous and qualitative variables 
Continuous variables will be summarized using descriptive statistics i.e., number of non-
missing values and number of missing values [i.e., n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3).  
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore counts of missing observations will be included in the denominator and presented 
as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified. 
5.2.4. Definition of study day 
Start day of study treatment is the day of the first dose of study treatment. 
The study day for assessments occurring on or after the start of study treatment (e.g., adverse 
event onset, tumor measurement) will be calculated as: 
Study day = Date of the assessment/event - start of study treatment + 1.  
The study day for assessments occurring prior to the first dose of study treatment (e.g.,
baseline characteristics, medical history) will be negative and calculated as: 
Study day = Date of the assessment/event - start of study treatment. 
The study day will be displayed in all relevant data listings. 
5.2.5. Definition of start of new anti-cancer drug therapy 
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of start of new anti-cancer therapy 
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.2 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment for the expansion phase or after the date of randomization for the lead-in phase 
amongst the following: 


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x
Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages 
x
Start date of radiation therapy recorded in ‘Concomitant Radiation Therapy’, and 
‘Follow-up Radiation Therapy’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’ 
x
Surgery date recorded in ‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages
when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially Resected’.  
When start date of anti-cancer therapy is missing or partially missing, the imputation rules 
described in Section 5.3.3.4 should be applied using ‘Follow-up Cancer Therapy’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘Concomitant Surgery’, 
and ‘Follow-up Surgery’ eCRF pages.
5.2.7. Definition of on-treatment period 
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). 
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized. 
5.2.8. Standard derivations and reporting conventions 
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days. 
Demographics and physical measurements: 
x
Age [years]:  
-
(date of given informed consent - date of birth + 1) / 365.25 
-
In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth) 
-
In case only year of birth is given: Age [years]: (year of given informed consent - 
year of birth) 
The integer part of the calculated age will be used for reporting purposes.  
x
BMI (kg/m2) = weight (kg)/[height (m)]2
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 


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rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. E.g., 5.1 to 5.4 will be rounded to an integer of 5, and 
5.5 to 5.9 will be rounded to an integer of 6. 
5.2.9. Unscheduled visits 
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits. 
5.2.10. Adequate baseline tumor assessment 
Adequate baseline is defined using the following criteria: 
x
All baseline assessments must be within 28 days prior to and including the ‘start date’.
x
All documented lesions must have non-missing assessments (i.e. non missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions). 
5.2.11. Adequate post-baseline tumor assessment 
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, or PD can be determined (see Section 6.1.2.1).  Time points where the response is 
not evaluable (NE) or no assessment was performed will not be used for determining the 
censoring date. 
5.3. Methods to Manage Missing Data 
5.3.1. Missing data 
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used. 
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged. 
Missing statistics, e.g. when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’.  
5.3.1.1. Pharmacokinetic concentrations 
Concentrations Below the Limit of Quantification 
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented.  The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 


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BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures. 
Deviations, Missing Concentrations and Anomalous Values 
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true: 
1. A concentration has been reported as ND (i.e., not done) or NS (i.e., no sample); 
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist. 
Summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data. 
5.3.1.2. Pharmacokinetic parameters 
Actual PK sampling time will be used for the derivation of PK parameters.  If a PK 
parameter cannot be derived from a patient’s concentration data, the parameter will be coded 
as NC (i.e., not calculated).  NC values will not be generated beyond the day that a patient 
discontinues. 
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (i.e., analysis of variance), PK parameters coded as NC will also be set to 
missing. 
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables and the 
parameter will not be included in the calculation of summary statistics or statistical analyses. 
5.3.2. Handling of incomplete dates 
5.3.2.1. Disease history 
Incomplete dates for disease history (e.g., initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
x
If the day is missing, it will be imputed to the 15th day of the month.  
x
If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st.
x
If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st.  
x
If the date is completely missing, no imputation will be performed. 


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


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x
In all other cases the incomplete medication stop date will not be imputed.  
5.3.2.4. Exposure 
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows: 
x
If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date 
x
If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then
imputed last dose date is: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date)  
= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date) 
= min (EOT date, death date), for all other cases. 
5.3.3. Imputation rules for date of last contact and efficacy assessments 
5.3.3.1. Date of last contact 
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following: 
x
All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments) 
x
Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation 
x
AE start and end dates 
x
Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’)
x
Study drug start and end dates 
x
Randomization date 
x
Withdrawal of consent date 
x
Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up). 
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date. 


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5.3.3.2. Death date 
Missing or partial death dates will be imputed based on the last contact date: 
x
If the date is missing it will be imputed as the day after the date of last contact  
x
If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following: 
-
Missing day:  
 
1st day of the month and year of death 
-
Missing day and month: 
January 1st of the year of death
5.3.3.3. Tumor assessments 
All investigation dates (e.g., X-ray, CT scan) must be completed with day, month and year. 
If there are multiple scan dates associated with an evaluation, i.e., radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 
associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment. 
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates 
(e.g., X-ray, CT-scan).   
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used.  
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment.  If both a previous and following assessments are not available, this 
assessment will not be used for any calculations. 
5.3.3.4. Date of start of new anti-cancer therapy 
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment. 
x
The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is 
o
completely missing then it will be ignored in the imputations below 
o
partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy 


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o
partially missing with only month and year  available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy 
x
For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below.  
x
If the start date of new anti-cancer therapy is completely or partially missing then the 
imputed start date of new anti-cancer therapy is derived as follows: 
o
Start date of new anti-cancer therapy is completely missing 
Imputed start date = min [max(PD date + 1, last dose of study treatment + 1), end date 
of new anti-cancer therapy] 
o
Only year (YYYY) for start of anti-cancer therapy is available 
IF YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]  THEN imputed start date = 31DECYYYY;  
ELSE IF YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
ELSE IF YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]  
THEN imputed start date = 01JANYYYY 
o
Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available 
IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY ; 
ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]); 


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ELSE IF 
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM > Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]  
THEN  
imputed start date = 01 MMM YYYY; 
ELSE IF 
YYYY < Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = DAY (Last day of MMM) MMM YYYY; 
ELSE IF 
YYYY > Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] 
THEN  
imputed start date = 01 MMM YYYY. 
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology.  
Unless otherwise specified, all data will be analyzed by study phase and treatment group, and
treatment groups in the lead-in phase will also be pooled together.   
6.1. Primary Endpoints  
6.1.1. Percent TO (Lead-in Phase) 
6.1.1.1. Primary analysis 
The following analyses will be based on the TO analysis set for patients in the lead-in phase.  
Percent TO will be summarized by treatment group; treatment groups in the lead-in phase 
will not be pooled together. 
Percent PD-L1 TO will be summarized descriptively (n, mean, SD, CV, median, minimum, 
maximum, geometric mean, its associated CV, and 95% CI) by treatment group, cycle, day 
and nominal time.  Mean PD-L1 TO before the second cycle (at the expected Ctrough), 
together with safety and clinical activity, will be used to decide which dose to move forward 
into the expansion phase of the study. 


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Presentation of Percent PD-L1 TO data will include: 
x
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of percent TO 
will be presented in tabular form by treatment group, cycle, day and nominal time.  
x
Linear-linear plots of mean and median percent TO by nominal time will be presented for
TO sampling days by treatment group, cycle, and study day. Similar plots will be 
presented for each individual patient percent TO.  Patients who have undergone intra-
patient dose reduction or escalation will be excluded from the median percent TO plots. 
x
Box plots for percent TO will be generated. Individual data points, the geometric mean 
and the median of the parameter in each treatment will be overlaid on the box plots.  If a 
treatment group has limited evaluable TO data (n<4), matchstick plots showing changes 
in percent TO in individual patients will then be generated. The geometric mean of the 
parameter in each treatment will be overlaid in the plots.   
Percent TO will be plotted for each treatment group using a box-whisker plot by cycle and 
day within cycle in order to assess the attainment of a steady-state pharmacodynamic effect. 
6.1.2. Objective Response by BICR Assessment (Expansion Phase) 
6.1.2.1. Primary analysis 
The following analyses will be based on the FAS.   Assessment of response will be made 
using the Lugano Classification (Cheson et al., 2014). Assessments below refer to BICR 
assessment.  Similar analyses will be repeated using investigator assessment as secondary 
analysis.   
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the ‘start date’ until the first documentation of PD, 
according to the following rules. Only tumor assessments performed on or before the start of 
any further anti-cancer therapies will be considered in the assessment of BOR.  Clinical 
deterioration will not be considered as documentation of disease progression. 
BOR: 
x
CR = one objective status of CR documented before first documentation of PD. 
x
PR = one objective status of PR documented before first documentation of PD (and not 
qualifying for CR). 
x
SD = at least one SD assessment (or better) ≥ 6 weeks after ‘start date’ and before first 
documentation of PD (and not qualifying for CR or PR).  
x
PD = first documentation of PD ≤ 12 weeks after ‘start date’ (and not qualifying for CR, 
PR, SD). NE:  all other cases.   
x
NE:  all other cases. 
An objective status of PR or SD cannot follow one of CR.   


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Objective Response (OR) is defined as BOR of CR or PR according to the Lugano 
Classification (Cheson et al., 2014). 
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set. 
ORR by treatment group will also be calculated along with the 2-sided 95% CI using the 
Clopper-Pearson method (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option).  
In addition, the frequency (number and percentage) of patients with a BOR of CR, PR, SD, 
PD, and NE will be tabulated. Patients with BOR of NE will be summarized by reason for 
having NE status. The following reasons will be used: 
x
No baseline assessment  
x
No post-baseline assessments due to death  
x
No post-baseline assessments due to other reasons 
x
All post-baseline assessments have overall response NE 
x
New anti-cancer therapy started before first post-baseline assessment 
x
SD of insufficient duration  (<6 weeks after the ‘start date’) 
x
PD too late (>12 weeks after the ‘start date’) 
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD too early’ (ie, SD of insufficient duration). 
BICR vs Investigator Assessment: 
Table 7 outlines the possible BOR outcomes by investigator and BICR.  


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Table 7. 
Possible BOR Outcomes for Investigator vs BICR 
BOR
BICR Assessment
CR
PR
SD
PD
NE
Investigator 
Assessment
CR
n11
n12
n13
n14
n15
PR
n21
n22
n23
n24
n25
SD
n31
n32
n33
n34
n35
PD
n41
n42
n43
n44
n45
NE
n51
n52
n53
n54
n55
is the number of agreements on BOR between BICR and Investigator  
for i ≠ j is the number of disagreements on BOR between BICR and Investigator 
N=
  
The following measures of concordance will be calculated for each treatment group: 
x
Concordance rate for BOR = 
x
Concordance rate for response =  
Concordance rates are calculated for each treatment group and, for each metric, the 
difference in concordance between the experimental and control groups are used to evaluate 
potential bias.  If the concordance is similar across the treatment groups then this suggests the 
absence of evaluation bias favoring a particular treatment group. 
6.2. Secondary Endpoint(s) 
6.2.1. Safety endpoints 
Refer to Section 6.6. 
6.2.2. Efficacy endpoints 
The following analyses will be based on the FAS. Data will be analyzed by study phase and 
treatment group; treatment groups in the lead-in phase will also be pooled together.  
Assessment of response will be made using the Response Criteria for Malignant Lymphoma 
(Cheson et al., 2007) for the Lead-in Phase and the Lugano Classification (Cheson et al., 
2014) for the expansion phase. Tumor-related endpoints will be analyzed based on 
investigator assessment for the Lead-in Phase, and separately based on BICR assessments 
and based on investigator assessment for the Expansion Phase.  


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6.2.2.1. Tumor shrinkage from baseline
Tumor shrinkage will be summarized as the percent change from baseline in the Sum of the 
Product of the Diameters (SPD) for Largest Dominant Masses per time point. It will be 
derived as: 
x
((SPD at week XX – SPD at baseline)/ SPD at baseline) × 100 
The maximum reduction in SPD from baseline will be derived across all the post-baseline 
assessments until documented disease progression, excluding assessments after start of 
subsequent anti-cancer therapy, as: 
x
Minimum of ((SPD at week XX – SPD at baseline)/ SPD at baseline) × 100 
A waterfall plot of maximum percent reduction in the SPD for Largest Dominant Masses 
from baseline will be created by treatment group. These plots will display the best percentage 
change from baseline in SPD for each patient with measurable disease at baseline and at least 
one post-baseline assessment. 
6.2.2.2. Disease control 
Disease Control (DC) is defined as BOR of CR, PR or SD.   DC rate (DCR) is the proportion 
of patients with DC. 
DCR will be summarized by frequency counts and percentages. 
6.2.2.3. Duration of response 
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are as described for PFS 
in Table 8.
 
DR (months) = [date of event or censoring– first date of OR +1]/30.4375 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with 2-sided 
95% CIs.  In particular, the DR rate at 3, 6, 12, and 18 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley 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 (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided. 


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6.2.2.4. Time to response 
Time to response (TTR) is defined, for patients with OR, as the time from the ‘start date’ to
the first documentation of objective response (CR or PR).  
 
TTR (in months) = [first date of OR – ‘start date’ +1]/30.4375 
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3). 
6.2.2.5. Progression-free survival 
Progression-Free Survival (PFS) is defined as the time from the ‘start date’ to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.    
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.   Patients who do not have an adequate baseline tumor assessment or who do 
not have an adequate post-baseline tumor assessment will be censored on the ‘start date’
unless death occurred on or before the time of the second planned tumor assessment (i.e. ≤ 12
weeks after the ‘start date’) in which case the death will be considered an event.  
In the lead-in phase antitumor activity will be assessed through radiological tumor 
assessments conducted at screening, 6 weeks, 12 weeks, and at 12-week intervals thereafter 
until PD regardless of initiation of subsequent anti-cancer therapy.  In the expansion phase, 
antitumor activity will be assessed through radiological tumor assessments conducted at 
screening, 6 weeks, 12 weeks, and at 12-week intervals thereafter for one year from the start 
of study treatment, and every 24 weeks thereafter until PD by BICR assessment, regardless 
of the initiation of subsequent anti-cancer therapy. 
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 8.   
 
PFS (months) = [date of event or censoring– ‘start date’ +1]/30.4375 


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Table 8. 
Outcome and event dates for PFS and DR analyses 
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
‘start date’ a
Censored a
PD or death 
- After at most one missing or 
inadequate post-baseline tumor 
assessment, OR
- ≤ 12 weeks after the ‘start date’
Date of PD or death
Event
PD or death 
- after 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
No PD and no death
Date of last adequate tumor
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression
Not applicable
Information is ignored. 
Outcome is derived based 
on documented progression 
only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment b documenting no PD
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a However if the patient dies ≤12 weeks after the ‘start date’ the death is an event with date on death date
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the ‘start date’; if the criteria were met the censoring will be on the ‘start 
date’
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided 
95% CIs.  In particular, the PFS rate at 3, 6, 9, 12, and 18 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley 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 (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 
to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 9 following the hierarchy shown. 


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Table 9. 
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy. 
Start of new anti-cancer therapy
3
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/’start date’
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Subject refused further follow-up] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
Time of Follow-Up for PFS 
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment group. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment groups reversing the PFS censoring and event 
indicators. Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
group together with a summary of associated statistics including the median time of follow-
up for PFS with 2-sided 95% CIs.   In particular, the rate at 3, 6, 9, 12 and 18 months will be 
estimated with corresponding 2-sided 95% CIs. 
6.2.2.6. Overall Survival 
Overall survival (OS) is defined as the time from the ‘start date’ to the date of death due to 
any cause. Patients last known to be alive will be censored at date of last contact. 
 
OS (months) = [date of death or censoring– ‘start date’ +1]/30.4375 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rate at 3, 6, 9, 12, 18 and 24 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley 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 (conftype=loglog default option in SAS Proc LIFETEST) with back transformation 


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to a CI on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.  
Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 10 following the hierarchy shown. 
Table 10. OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ ‘start date’ OR 
End of study (EOS) = Subject refused further follow-up] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 14 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS 
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators. Kaplan-Meier 
estimates (product-limit estimates) will be presented by treatment group together with a 
summary of associated statistics including the median time of follow-up for OS with 2-sided 
95% CIs.  In particular, the rate at 3, 6, 9, 12, 18, and 24 months will be estimated with 
corresponding 2-sided 95% CIs. 
6.2.3. Pharmacokinetic endpoints 
The following pharmacokinetic analyses will be based on the PK analyses set. Data will be 
analyzed by study phase and treatment group; treatment groups in the lead-in phase will not 
be pooled together.  
Additionally, in the expansion phase, PK data will be summarized separately by dose (i.e. PK 
data following 70 mg Q2W will be summarized separately from PK data following 500 mg 
Q2W). 
Ctrough and Cmax for avelumab will be summarized descriptively (n, mean, SD, CV, median,
minimum, maximum, geometric mean, its associated CV, and 95% CI) by treatment group, 
cycle, and day. Other standard parameters will be calculated as data permit, including, but 
not limited to: following Single Dose (SD):  Tmax, AUClast, Tlast, AUC sd,W, t1/2, CL, and Vz, and 
following multiple Dose (MD) - Tss,max, AUCss,W, t1/2, Css,av, CL, and Vss. In the lead-in phase, 
parameters Rac (AUCss,W/AUCsd,W) and Rss (AUCss,W/AUCsd,inf) will also be determined, as data 
permit. 


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Dose normalized parameters (e.g., CDN- Cmax, CDN- Ctrough) will be reported as appropriate. 
The trough concentrations for avelumab will be plotted for each dose using a box whisker 
plot by cycle and day in order to assess the attainment of steady state. 
Pharmacokinetic parameters for avelumab will be taken from observed values or derived 
from plasma concentration-time data as described in Section 3.2.3.
Presentation of pharmacokinetic data will include: 
x
Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of plasma 
concentrations will be presented in tabular form by treatment group, dose level, cycle, 
day and nominal time. Additionally similar descriptive statistics will also be generated 
for dose-normalized avelumab pharmacokinetic parameters. 
x
Linear-linear and log-linear plots of mean and median plasma concentrations by nominal 
time for avelumab will be presented for PK sampling days by treatment group, cycle, and 
study day. Similar plots will be presented for each individual patient’s concentrations. In 
the lead-in phase, patients who have undergone intrapatient dose reduction or escalation 
will be excluded from the median plasma concentration-time plots. In the expansion 
phase, mean and median concertation-time plots will be generated separately for data 
from patients who stay on the 70 mg Q2W dosing regimen, those who dose-escalate to 
500 mg Q2W in Cycle 3 and those who dose escalate to 500 mg Q2W in Cycle 7. 
x
Pharmacokinetic parameters for avelumab will be listed and summarized by treatment 
group/dose level, cycle and study day using descriptive statistics (n, mean, SD, %CV, 
median, minimum, maximum, geometric mean and its associated %CV, and 95% CI).
For Tmax, the range (min, max) will also be provided. PK parameters with zero values will 
be excluded from the calculation of geometric means and its associated %CV. In the 
lead-in phase, if an intrapatient dose escalation or reduction occurs, dose-dependent PK 
parameters (AUC and Cmax) for that patient may be dose-normalized when it is known 
that the drug exhibits linear PK within the dose range and other PK parameters will be 
reported as estimated; or may only be included in descriptive statistics and summary plots 
up to the time of the dose change. In addition, dose-normalized Cmax and AUC 
parameters will be summarized (as described above) using data pooled across treatment 
groups in which different avelumab doses were administered. In the expansion phase, 
summary statistics will be presented separately by cycle and day for patients receiving 70 
mg Q2W and those receiving 500 mg Q2W. 
x
Box plots for AUC and Cmax for avelumab will be generated. Individual data points, the 
geometric mean and the median of the parameter in each treatment will be overlaid on the 
box plots. If a treatment group has limited evaluable PK data (n<4), matchstick plots 
showing changes in AUC and Cmax for each drug in individual patients will then be 
generated. The geometric mean of the parameter in each treatment will be overlaid in the 
plots. In the lead-in phase, box plots for dose-normalized avelumab  Cmax and AUC 
parameters will be created using data pooled across treatment groups in which different 
avelumab doses were administered. Box plots for AUC and Cmax from patients in the 
expansion phase will only be presented on data up to Cycle 3. 


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x
Ctrough and Cmaxfor avelumab will be plotted for each treatment group using a box-
whisker plot by cycle and day within cycle in order to assess the attainment of steady-
state. For the lead-in phase, data from patients who undergo intrapatient dose escalation 
or reduction will be excluded from these plots. For the expansion cohort, Ctrough data will 
be presented separately for patients receiving 70 mg Q2W and those receiving 500 mg 
Q2W. 
6.2.4. Population pharmacokinetic endpoints 
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab exposure and biomarkers or significant safety/efficacy 
endpoints. The results of these analyses, if performed, may be reported separately. 
6.2.5. Biomarker endpoints 
The following biomarker analyses will be based on the biomarker analyses set.  Data will be 
analyzed by study phase and treatment group; treatment groups in the lead-in phase will also 
be pooled together. In addition, biomarker endpoints will be presented pooling together the 
lead-in and expansion phases. 
If a patient has more than one result at a visit for a specific biomarker analyte, then: 
x
For continuous data, the duplicate results will be averaged, and the average used in the 
analysis; 
x
For non-continuous data (eg, identified genes), the study team will select the record 
appropriate for analysis.  A flag will be added to the data sets indicating which record 
was selected for analysis.   
6.2.5.1. IHC Analysis of PD-L1, CD8 and FoxP3 Expression in Tumor Biopsy 
x
The absolute number and percent positive of cells expressing PD-L1, CD8 and FoxP3 in 
the tumor, in the stroma and the tumor/stroma ratio of these marker positive cells by IHC 
will be summarized using descriptive statistics . 
x
The ratio of cells expressing biologically relevant pairs of these markers in each region 
by IHC (for example, the ratio of CD8+/FoxP3+ cells in the tumor) will be summarized 
using descriptive statistics.
x
Correlation of the absolute numbers and percent positive cells by region, the ratio of 
expression by region and the ratio of marker pairs at baseline with efficacy measures such 
as tumor shrinkage, time to response or PFS will be evaluated. 
x
Correlation of the change in absolute numbers and percent positive cells by region, the 
ratio of expression by region and the ratio of marker pairs from baseline to time of on 
study tumor biopsy with efficacy measures such as tumor shrinkage, time to response or 
PFS will be evaluated. 


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6.2.5.2. RNA Expression Profiling of Tumor Biopsy Tissue by RNA Sequencing 
x
Abundance of immune- and pathway-related RNA transcripts and enrichment of related 
gene sets at baseline as well as correlation of gene set enrichment with efficacy measures 
such as tumor shrinkage, time to response or PFS will be evaluated. 
x
Change in expression of immune- and pathway-related RNA transcripts and enrichment 
of related gene sets between baseline and time of on study tumor biopsy as well as 
correlation of change in gene expression and gene set enrichment with efficacy measures 
such as tumor shrinkage, time to response or PFS will be evaluated. 
6.2.5.3. Relative Proportion of T Cell Subsets in the Peripheral Blood by Flow 
Cytometry 
x
Relative proportion of naïve, memory and regulatory T cell subsets at baseline will be 
summarized using descriptive statistics.  
x
Change in proportions of T cell subsets in response to dosing with avelumab will be 
summarized using descriptive statistics. 
x
Correlation of baseline and changes in relative proportions of T cell subsets with efficacy 
measures such as tumor shrinkage, time to response or PFS will be evaluated.
6.2.6. Endpoints for Immunogenicity Data of Avelumab  
All analyses described below are performed by study phase and treatment group; treatment 
groups in the lead-in phase will also be pooled together. In addition, immunogenicity 
endpoints will be presented pooling together the lead-in and expansion phases.
In the lead-in phase, blood samples for avelumab immunogenicity testing will be collected 
pre-dose on Day 1 of Cycles 1, 2, 3, 4, 6 and 8, and every 12 weeks up to cycle 20. 
Additional samples for anti-avelumab antibodies will be collected at the End of Treatment 
visit. Follow up samples are only collected in patients who are ADA positive at end of 
treatment. In the dose-expansion phase, blood samples for avelumab immunogenicity testing 
will be collected pre-dose on Day 1 of Cycles 1, 2, 3, 4, 7 and 13, and at Day 30, 60 and 90 
follow up visits. Additional samples for anti-avelumab antibodies will be collected at the End 
of Treatment visit. 
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.  As of the 
finalization of this SAP, the nAb assay is not yet available, therefore the analyses of nAb data 
described in the following sections will only be conducted contingent upon assay and data 
availability at the time of reporting.  
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 11.   


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Table 11.  Patients Characterized Based on Anti-Drug Antibody Results (ADA Status) 
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
ADA never-positive 
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint)
Number of patients with at least one 
valid ADA result at any time point
ADA ever-positive 
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint)
Number of patients with at least one 
valid ADA result at any time point
Baseline ADA 
positive
A positive ADA result at baseline
Number of patients with valid baseline 
ADA result
Treatment-boosted 
ADA
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result
Treatment-induced 
ADA
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive past-baseline 
ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Transient ADA 
response
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Persistent ADA 
response
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
ADA: anti-drug antibody, NR = not reportable. 
Patients will be characterized into different nAb categories based on the criteria in Table 12.
For nAb, treatment-boosted is not applicable since no titer result is available. 


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Table 12.  Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
nAb never-positive 
No positive nAb results at any time point
Number of patients with at least one 
valid ADA result at any time point
nAb ever-positive 
At least one positive nAb result at any time 
point
Number of patients with at least one 
valid ADA result at any time point
Baseline nAb 
positive
A positive nAb result at baseline
Number of patients with valid baseline 
ADA result
Treatment-induced 
nAb
Patient is not nAb positive at baseline and  has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive past-
baseline ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
Transient nAb 
response
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive.
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR)
Persistent nAb 
response
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result. 
The number and percentage of patients in each ADA and nAb category will be summarized.  
6.2.6.1. Time to and Duration of ADA and nAb response  
The ADA and nAb analyses described below will include patients with treatment-induced 
ADA or nAb, respectively.   
Time (weeks) to ADA response is defined as: 
(Date of first positive ADA result – date of first dose of avelumab + 1)/7.  
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3). 
Duration (weeks) of ADA response is defined as: 
(Date of last positive ADA result – date of first positive ADA result + 1)/7.  
Duration of ADA response will be censored if:  
x
the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or 


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x
the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (End of Treatment visit) is after the cut-off date. 
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result.  
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-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 will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2011) (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided 
As data permit, the analyses described above will be repeated for patients with treatment-
induced nAb.  
6.2.6.2. ADA titer 
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated. The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory.  
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided. The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks. In this categorization, the censoring in duration of ADA response is ignored.  
6.2.6.3. Analysis of PK, safety and efficacy by immunogenicity status 
The following ADA and nAb status will be used for the analyses described below. 
ADA
x
ADA ever-positive versus ADA never-positive  
x
ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive 


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nAb  
x
nAb ever-positive versus nAb never-positive  
x
nAb: treatment-induced nAb versus nAb never-positive or baseline nAb positive 
Data listings will include immunogenicity data together with relevant PK, safety and efficacy 
data. 
PK parameters and immunogenicity status 
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax.
Blood samples for avelumab PK will be collected where noted in the Schedule of Activities 
section of the protocol. 
Ctrough and Cmax will be summarized descriptively (n, mean, SD, CV, median, minimum, 
maximum, geometric mean, its associated CV, and 95% CI) by nominal time and ADA 
status. Linear-linear and log-linear plots of mean and median for Ctrough and Cmax over 
nominal time and by ADA status will be presented.  
Among patients with treatment-induced ADA, analyses will be conducted to assess whether 
Ctrough and Cmax have any changes before and after the first positive ADA assessment. To be 
included in this analysis, patients must have the same PK parameter available both before 
and after the first positive ADA assessment.  Relative PK day will be calculated as: 
(PK assessment nominal day) – (first positive ADA assessment nominal day). 
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is
collected on Day 1 of Cycle 2 and the first positive ADA result is observed on Day 1 of 
Cycle 3, then the relative PK day for this Ctrough is -14  for 2-week cycles and -21 for 3-week 
cycles. Linear-linear and log-linear plots of mean and median for Ctrough and Cmax over 
relative PK day will be presented.  
As data permit, the analyses described above will be repeated for nAb. 
Safety and immunogenicity status 
The following analyses will include patients in the immunogenicity analysis set. 
The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status. 
x
TEAEs, by SOC and PT  
x
TEAEs leading to dose reduction of avelumab, by SOC and PT


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x
TEAEs leading to discontinuation of avelumab, by SOC and PT
x
Grade ≥ 3 TEAEs, by SOC and PT
x
SAEs, by SOC and PT
x
IRRs, by PT 
For patients who had at least one IRR and have treatment-induced ADA, time related to first 
onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later) will be summarized 
taking into account whether the  IRR occurred on or after the first ADA positive assessment 
or whether the IRR occurred before the first ADA positive assessment.   
As data permit, the analyses described above will be repeated for nAb. 
Efficacy and immunogenicity status 
For the ADA ever-positive patients, a listing will be prepared with patient ID, start and stop 
of avelumab treatment, date of first positive ADA result, time to ADA response, duration of 
ADA response, date of last ADA positive result, BOR, DR, PFS time or censoring time and 
reason for censoring, and OS time or censoring time and reason for censoring.   If applicable, 
date of first positive nAb result, time to nAb response, duration of nAb response, date of last 
nAb positive result will also be presented.  In the expansion phase, tumor-related endpoints 
will be presented based on BICR assessment and based on Investigator assessment.  
For the ADA ever-positive patients, the percent change from baseline in target lesions as well 
as the first occurrence of a new lesion and patient off avelumab treatment will be displayed 
against time point (weeks) in a line plot. Additional symbols will indicate the first and last 
ADA positive result and, if applicable, the first and last nAb positive result.  In the dose-
expansion phase, plot will be presented separately based on BICR assessment and based on 
Investigator assessment. 
6.4. Subset Analyses 
In the lead-in phase, OR and DR (if applicable) will be summarized by prior HSCT type 
(Allogeneic or Syngeneic vs. other) for each treatment group and for all treatment groups 
pooled together.  
CCI


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6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline summaries 
The following analyses will be based on the FAS. Unless otherwise specified, data will be 
analyzed by study phase and treatment group; treatment groups in the lead-in phase will also 
be pooled together. 
6.5.1.1. Demographic characteristics 
Demographic characteristics and physical measurements will be summarized by study phase 
and treatment group using the following information from the ‘Screening/Baseline Visit’ 
eCRF pages. Demographic characteristics will also be presented pooling together treatment 
groups in the lead-in phase and the lead-in and expansion phases. 
x
Demographic characteristics  
x
Gender: Male, Female  
x
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Unknown 
x
Ethnic origin: Hispanic/Latino (Yes/No) 
x
Age (years): summary statistics  
x
Age categories :  

< 65 years, ≥ 65 years 

< 65, 65-<75, 75-<85, ≥ 85 years 
x
Pooled Geographical Region (as applicable):

North America  

Europe 

Asia 

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the 
overall randomized/treated population) 
x
Geographic Region (as applicable): 

North America 

Latin America 

Western Europe 

Eastern Europe 


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
Middle East 

Australasia

Asia 

Africa 
x
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4
x
Physical measurements 
x
Height (cm) 
x
Weight (kg) 
x
Body Mass Index (BMI) (kg/m2) 
Center codes will be used for the determination of the patient’s geographic region.
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), and ECOG performance status. 
6.5.1.2. Medical history 
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order. 
Prior stem cell transplant details will only be listed. 
6.5.1.3. Disease characteristics 
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Use’ and 
‘Transplant Details’ eCRF pages will be summarized. Summary statistics will be presented 
for the following. 
From the ‘Primary Diagnosis’ eCRF page: 
x
Site of primary tumor 
x
Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page) 


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x
Time since initial diagnosis to ‘start date’ (months), defined as (‘start date’ – date of 
initial diagnosis)/30.4375 
x
Time since diagnosis of local/regional recurrence of disease (months), defined as (‘start
date’ – date of diagnosis of local/regional recurrence of disease)/30.4375 
x
Hodgkin’s Lymphoma stage and substage at initial diagnosis 
x
Current Hodgkin’s Lymphoma stage and substage
From the ‘Substance Use’ eCRF page: 
x
Smoking history 
x
Never smoker vs current vs former smoker  
x
Smoking exposure (pack-years): 0, <20, 20-<40, ≥40 and summary statistics
x
Years since quitting: never smoker, current smoker, <5, 5-<10, ≥10 and summary 
statistics 
Specifications for computation: 
x
Cigarette equivalents are calculated as follows: one cigar is regarded equivalent to 5 
cigarettes and 1 pipe is regarded equivalent to 3 cigarettes 
x
Duration of nicotine consumption [years]: 
(end of nicotine consumption – start of nicotine consumption + 1) / 365.25 
x
Pack-years: 
x
calculate cigarette equivalents per day using the conversion factors given above 
x
convert to packs per day where 20 cigarettes are regarded as 1 pack 
x
pack-years = packs per day × duration of nicotine consumption [years] 
From the ‘Transplant Details’ eCRF page:
x
Transplant Type (Allogeneic or Syngeneic, Autologous, No Prior Stem Cell Transplant, 
Unknown) 
x
Donor-Receptor Relatedness (Related, Unrelated, Unknown) 
x
HLA Compatibility (HLA-matched, HLA-unmatched, HLA-haploidentical, Unknown) 
x
Stem Cell Source (Bone marrow, Peripheral blood, Cord Blood, Unknown) 
x
Type of Conditioning (Myeloablative, Reduced-intensity, Unknown) 
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ and ‘Substance Use’ eCRF pages) and derived variables as above.


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6.5.1.4. Prior anti-cancer therapies 
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Surgery’ eCRF pages. 
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated: 
x
Patients with at least one type of prior anti-cancer therapy 
x
Patients with at least one prior anti-cancer drug therapy 
x
Patients with at least one prior anti-cancer radiotherapy 
x
Patients with at least one prior anti-cancer surgery 
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following: 
x
At least one prior anti-cancer drug therapy 
x
Number of prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4
x
Prior anti-cancer immune therapy (including PD-1, PD-L1, anti-CTLA4, others) 
x
Best response: CR, PR, SD, PD, Unknown, Not applicable. Best response is derived from 
the last treatment regimen.
The prior anti-cancer drug therapies will also be summarized based on the number and 
percentage of patients by the drug class and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. The summary will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used. 
Prior anti-cancer therapies will be included in the listings that follow with a flag to identify 
prior therapies. These will include the patient identification number, and all the relevant 
collected data-fields on the corresponding eCRF pages. 
x
Listing of anti-cancer drug therapies  
x
Listing of anti-cancer radiotherapy  
x
Listing of anti-cancer surgeries 
6.5.1.5. Prior and concomitant immunosuppressive therapies 
The prior and concomitant immunosuppressive therapies are collected under the ‘Prior 
Immunosuppressive Therapy’ and ‘Concomitant Immunosuppressive Therapy’ eCRF pages. 
The immunosuppressive therapies will be summarized based on the number and percentage 
of patients by the drug class and preferred term. A patient will be counted only once within a 


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given drug class and within a given drug name, even if he/she received the same medication 
at different times. The summary will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used.
Immunosuppressive therapies will be included in the listing of immunosuppressive therapies 
with a flag to identify prior and concomitant therapies. These will include the patient 
identification number, and all the relevant collected data-fields on the corresponding eCRF 
pages. 
6.5.2. Study conduct and patient disposition 
The following analyses will be performed based on the FAS. Data will be analyzed by study 
phase and treatment group; treatment groups in the lead-in phase will also be pooled 
together. 
6.5.2.1. Patient disposition 
Lead-in Phase 
The percentages below will be calculated based on the number of patients in the FAS. 
x
Total number of patients screened overall 
x
Number of patients who discontinued from the study prior to randomization overall and 
by the main reason for discontinuation 
x
Number and percentage of randomized patients in each of the analysis sets defined in 
Section 4
x
Number and percentage of randomized patients with study drug ongoing 
x
Number and percentage of randomized patients who discontinued study drug overall and 
by the main reason for discontinuation of study drug 
x
Number and percentage of patients who entered follow-up
x
Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation 
x
Number and percentage of patients who entered long-term follow-up
x
Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation.
The results of the randomization algorithm (according to IRT) will be summarized as 
follows: 
x
Number and percentage of randomized patients overall, by region (Europe, EEA 
(required by EudraCT), North America, Latin America, Middle East, Asia, Australasia,
Africa), by country within region 


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x
Number and percentage of randomized patients by center
x
Cross tabulation: patients randomized (Cohort A/ Cohort B/ Cohort C/ Cohort D/ Cohort 
E/ not randomized) vs. patients treated (Cohort A/ Cohort B/ Cohort C/ Cohort D/ Cohort 
E/ not treated)
Expansion Phase 
The percentages below will be calculated based on the number of patients in the FAS. 
x
Total number of patients screened overall
x
Number of patients who discontinued from the study prior to treatment with study drug 
overall and by the main reason for discontinuation
x
Number and percentage of treated patients in each of the analysis sets defined in Section 
4
x
Number and percentage of patients  with study drug ongoing 
x
Number and percentage of patients who discontinued study drug overall and by the main 
reason for discontinuation of study drug 
x
Number and percentage of patients who entered follow-up
x
Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation 
x
Number and percentage of patients who entered long-term follow-up
x
Number and percentage of patients who discontinued long-term follow-up overall and by 
the main reason for discontinuation
In addition the following will be summarized: 
x
Number and percentage of treated patients overall, by region (Europe, EEA (required by 
EudraCT), North America, Latin America, Middle East, Asia, Australasia, Africa), by 
country within region 
x
Number and percentage of treated patients by center
6.5.2.2. Protocol deviations 
All protocol violations that impact the safety of the patients and/or the conduct of the study 
and/or its evaluation will be reported. These include: 
x
Patients who are dosed on the study despite not satisfying the inclusion criteria
x
Patients who develop withdrawal criteria whilst on the study but are not withdrawn


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x
Patients who receive the wrong treatment or an incorrect dose
x
Patients who receive an excluded concomitant medication
x
Deviations from GCP.
The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study treatment compliance and exposure 
The following analyses will be based on the safety analysis set by treatment group. 
For Cycle X, actual cycle start date for each patient is 
x
the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the
patient received study treatment on that visit (i.e., any study drug with dose>0 at that 
visit)
x
the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (i.e., all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit. 
Actual cycle end date for each patient is,  
x
for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day;
x
for the last cycle, actual cycle end date = actual cycle start date + d (in days) – 1 day 
where d=14 for Q2W schedule, and d=21 for Q3W schedule. 
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of study drug should be included.  
Exposure may be summarized (overall) as dose received (cumulative dose, actual dose 
intensity) and as dose received relative to intended dose (relative dose intensity [RDI]).   
The derivations below are provided assuming 1 cycle = 3 weeks for Cohort C and 1 cycle = 2 
weeks for all the other cohorts, and for the following study drugs (administered alone or in 
combination): 
x
Cohort A: Avelumab administered as a 1-hour IV infusion at a dose of 70 mg once every 
2 weeks in 2-week cycles.  
x
Cohort B: Avelumab administered as a 1-hour IV infusion at a dose of 350 mg once 
every 2 weeks in 2-week cycles.  


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x
Cohort C: Avelumab administered as a 1-hour IV infusion at a dose of 500 mg once 
every 3 weeks in 3-week cycles.  
x
Cohort D: Avelumab administered as a 1-hour IV infusion at a dose of 500 mg once 
every 2 weeks in 2-week cycles.  
x
Cohort E: Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg once 
every 2 weeks in 2-week cycles.  
x
Cohort F: Avelumab administered as a 1-hour IV infusion at a dose of 70 mg once every 
2 weeks with the possibility of intra-patient dose escalation to avelumab administered as 
a 1-hour IV infusion at a dose of 500 mg once every 2 weeks in 2-week cycles (see 
Section 2.2).
6.5.3.1. Exposure to avelumab  
The dose level for avelumab is calculated as actual dose administered/weight (mg/kg) for 
Cohort E, and as actual dose administered (mg) for all the other cohorts. The last available 
weight of the patient on or prior to the day of dosing will be used. 
Intended duration of treatment with avelumab (weeks) =
(end date–date of first dose of study drug +1)/7,  
where end date = start date of last cycle with non-zero dose of study drug + d – 1
and where d=14 for Q2W schedule, and d=21 for Q3W schedule. 
Duration of exposure to avelumab (weeks) =  
(last dose date of avelumab – first dose date of avelumab + d)/7   
where d=14 for Q2W schedule, and d=21 for Q3W schedule.
Cumulative dose in a cycle or overall is the sum of the actual doses of avelumab received in 
a cycle or overall, respectively.   
Actual Dose Intensity (DI)
For Cohort E: 
x
Overall actual DI (mg/kg/2-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/2].   
For Cohort C: 
x
Overall actual DI (mg/3-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/3].   


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For all the other cohorts: 
x
Overall actual DI (mg/2-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/2].  
Relative Dose Intensity (RDI)   
For Cohort E: 
x
Intended DI (mg/kg/2-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 2-weeks in a cycle] = [10 (mg/kg)] / [1 (2-week cycle)]  = 10 (mg/kg/2-week 
cycle) 
x
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [10 (mg/kg/2-week cycle)]  
For Cohort C:
x
Intended DI (mg/3-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 3-weeks in a cycle] = [500 mg] / [1 (3-week cycle)]  = 500 (mg/3-week cycle) 
x
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [500 (mg/3-week cycle)]  
For Cohort F: 
x
For patients that do not undergo dose escalation, then  
o
Intended DI (mg/2-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 2-weeks in a cycle] = [70 mg] / [1 (2-week cycle)]  = 70 (mg/2-week 
cycle) 
o
Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [70 (mg/2-week cycle)]  
x
For patients that undergo dose escalation, then 
o
Intended DI (mg/2-week cycle) = [(n1×70 (mg) + n2×500 (mg))/(n1+n2)] / [intended 
number of 2-weeks in a cycle] = [n1×70 (mg) + n2×500 (mg)] / [1 (2-week cycle)] = 
[(n1×70 + n2×500)/(n1+n2)] (mg /2-week cycle)   
o
Overall RDI (%) = 100 × [overall actual DI] / [intended DI]   
       where,  
o
n1 = (date of first administration of the higher dose – 1)/14 
o
n2 = intended duration of treatment with avelumab (weeks)/2 – n1
o
n1+n2= intended duration of treatment with avelumab (weeks)/2 


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For all the other cohorts: 
x
Intended DI (mg/2-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 2-weeks in a cycle] = [k mg] / [1 (2-week cycle)]  = k (mg/2-week cycle) 
x
Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [k (mg/2-week cycle)]  
where k=70 for Cohort A, 350 for Cohort B, 500 for Cohort D. 
6.5.3.2. Dose reductions  
Dose reduction is defined as actual non-zero dose < 90% of the planned dose.  
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized. 
6.5.3.3. Dose delays  
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses. 
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – d. 
where d=14 for Q2W schedule, and d=21 for Q3W schedule.
Dose delays will be grouped into the following categories:  
x
No delay  
x
1-3 days delay
x
4-6 days delay
x
7 or more days delay 
For example, for avelumab administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16 or 17, this is considered as 1-3 days delay.   
No delay and 1-3 days delay will also be summarized together.  
The number and percentage of patients with delayed study drug administration and maximum 
length of delay, i.e., the worst case of delay if patients have multiple dose delays will be 
summarized.  
6.5.3.4. Infusion rate reductions 
The number and percentage of patients with at least one infusion rate reduction of ≥50%
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized.


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6.5.3.5. Infusion interruptions 
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (i.e., for a visit more than one infusion start time and infusion end time are recorded). 
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant medications and non-drug treatments 
The following analyses will be based on the safety analysis set. Data will be analyzed by 
study phase and treatment group; treatment groups in the lead-in phase will also be pooled 
together. 
Concomitant medications are medications, other than study medications, which started 
prior to first dose date of study treatment and continued on on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study medications and pre-medications for study drug, which are started before the first dose 
of study treatment.  
Prior and concomitant medications will be summarized from the ‘General Concomitant 
Medications’ eCRF page. Pre-medications for study drug will also be summarized separately 
from the ‘Pre-Medication Treatment’ eCRF page. 
Summary of prior medications, summary of concomitant medications and summary of pre-
medications will include the number and percentage of patients by Anatomical Therapeutic 
Chemical (ATC) Classification level 2 and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. If any prior or concomitant medication is classified into 
multiple ATC classes, the medication will be summarized separately under each of these 
ATC classes. The summary tables will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. In case any 
specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category. 
A listing of prior medications and a listing of concomitant medications will be created with 
the relevant information collected on the ‘General Concomitant Medications’ eCRF page.  A 
listing of pre-medications will be created with the relevant information collected on the ‘Pre-
Medication Treatment’ eCRF page.
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’. 
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page.


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6.5.5. Subsequent anti-cancer therapies 
The following analyses will be based on the FAS. Data will be analyzed by study phase and 
treatment group; treatment groups in the lead-in phase will also be pooled together. 
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer Therapy’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, 
‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages.  
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages.  
6.6. Safety Summaries and Analyses 
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of 
AEs and other safety parameters will be based on the safety analysis set. Data will be 
analyzed by study phase and treatment group; treatment groups in the lead-in phase will also 
be pooled together.  
All summaries described below by SOC and PT may further be presented by PT in 
decreasing frequency based on the frequencies observed in the Cohort A for the Lead-in 
Phase and in the Cohort F for the Expansion phase.
6.6.1. Adverse events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period as defined in Section 3.5.1.
All analyses described in the following sections will be based on TEAEs (started during the 
on-treatment period) if not otherwise specified. The AE listings will include all AEs (whether 
treatment-emergent or not). AEs outside the on-treatment period will be flagged in the 
listings. 
x
Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (i.e., no answer to the question 
‘Relationship with study treatment’).
x
Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).
x
Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction
of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
= Dose reduced).
x
Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 


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between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).   IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.
x
Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).
x
Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5). 
x
Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs,
documented in the Safety Review Plan and finalized for analysis of the current studies 
data prior to DB lock)
x
Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
Safety Review Plan and finalized for analysis of the current studies data prior to DB lock.
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment group, primary SOC 
and PT in decreasing frequency based on the frequencies observed for the Cohort A for the 
Lead-in Phase and in the Cohort F for the Expansion phase.  
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity. 
6.6.1.1. All adverse events 
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the  latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category.  
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed.  
The following tables will be created:  
x
The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment group: 
-
TEAEs
-
TEAEs, Grade ≥ 3


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-
Related TEAEs 
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to dose reduction of avelumab 
-
TEAEs leading to interruption of avelumab
-
TEAEs leading to discontinuation of avelumab 
-
Related TEAEs leading to discontinuation of avelumab
-
Serious TEAEs 
-
Related Serious TEAEs  
-
TEAEs leading to death 
-
Related TEAEs leading to death 
-
irAEs 
-
IRRs 
x
TEAEs by SOC and PT and worst grade 
x
Related TEAEs by SOC and PT and worst grade 
x
TEAEs leading to death by SOC and PT 
x
Related TEAEs leading to death by SOC and PT 
x
TEAEs Excluding SAEs, with frequency ≥ 5% in any treatment group by SOC and PT
x
Graft Versus Host Disease (GVHD) by SOC and PT. Information recorded in the 
“Adverse Events” and in the “Graft Versus Host Disease Assessment” eCRF will be 
combined in the summary tables and listings for GVHD.
6.6.1.2. Adverse events leading to dose reduction 
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment group: 
x
TEAEs leading to dose reduction of avelumab by SOC and PT
The listing of all AEs leading to dose reduction will also be provided with the relevant 
information.  
6.6.1.3. Adverse events leading to interruption of study treatment 
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).   IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay).  


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As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding  
x
IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.3). These IRRs will be considered as IRRs leading to 
interruption of infusion.
x
IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.3).
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment group: 
x
TEAEs leading to interruption of avelumab by SOC and PT 
The listing of all AEs leading to interruption of study treatment will also be provided with the 
relevant information. 
In addition, the frequency (number and percentage) of patients with each of the following 
will be presented for TEAEs leading to interruption of each study drug by treatment group: 
x
TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT
This summary will take into account PTs with both actions as defined in Section 6.6.1, even
though the actions may be captured for different PT records (ie, different onset for the PT 
with action “drug interrupted” and the PT with action “dose reduced”.  
6.6.1.4. Adverse events leading to discontinuation of study treatment  
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of study treatment, by treatment 
group: 
x
TEAEs leading to discontinuation of avelumab by SOC and PT
x
Related TEAEs leading to discontinuation of avelumab by SOC and PT.
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information.  
6.6.2. Deaths 
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’
eCRFs, by treatment group.   
x
All deaths 
x
Deaths within 30 days after last dose of study treatment 


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x
Reason for Death  
-
Disease progression 
-
Study treatment toxicity
-
AE not related to study treatment 
-
Unknown
-
Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information: 
x
AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5),  
x
Flag for death within 30 days of last dose of study treatment.
6.6.3. Serious adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group: 
x
SAEs by SOC and PT 
x
Related SAEs by SOC and PT
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period. 
6.6.4. Other significant adverse events 
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group: 
x
irAEs leading to death, by Cluster and PT
x
irAEs, by Cluster and PT 
x
irAEs, Grade ≥ 3, by Cluster and PT
x
irAEs leading to discontinuation of avelumab, by Cluster and PT 
x
Serious irAEs, by Cluster and PT
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period.  
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group: 


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x
IRRs leading to death, by PT
x
IRRs, by PT 
x
IRRs, Grade ≥ 3, by PT
x
IRRs leading to discontinuation of avelumab, by PT 
x
Serious IRRs, by PT 
x
Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later) 
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period. 
6.6.5. Laboratory data 
6.6.5.1. Hematology and chemistry parameters 
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (e.g., hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges).  
Quantitative data will be summarized using simple descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each 
nominal visit over time (unscheduled measurements would therefore not be included in these 
summaries as described in Section 5.2.9). End of Treatment visit laboratory results will be 
summarized separately. The changes computed will be the differences from baseline. 
Qualitative data based on reference ranges will be described according to the categories (i.e., 
Low, Normal, High).  
Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 will be 
described using the worst grade. For those parameters which are graded with two toxicities 
such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (e.g., hypokalemia) grades at baseline and post baseline will be set to 
0 when the variables are derived for summarizing high direction toxicity (e.g.,
hyperkalemia), and vice versa.   
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows:  
Derived differential absolute count = (WBC count) × (Differential %value / 100) 


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If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows:  
x
Lymphocyte count decreased:   
-
derived absolute count does not meet Grade 2-4 criteria, and 
-
% value < % LLN value, and 
-
derived absolute count  ≥ 800/mm3
x
Neutrophil count decreased  
-
derived absolute count does not meet Grade 2-4 criteria, and 
-
% value < % LLN value, and 
-
derived absolute count  ≥ 1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows 
 
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L]) 
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.    
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment group: 
x
ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
x
AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN
x
(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN 
x
TBILI ≥ 2×ULN 
x
Concurrent  ALT ≥ 3×ULN and TBILI ≥ 2×ULN
x
Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN 
x
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN  
x
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN 


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x
Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or
missing)
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, i.e., a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages.  
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying 
x
peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at
ALT=3×ULN and total bilirubin =2×ULN.
x
peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at
AST=3×ULN and total bilirubin =2×ULN .
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with a post-
baseline TBILI ≥ 2×ULN, ALT≥ 3×ULN or AST ≥ 3×ULN will be provided. 
Parameters with NCI-CTC grades available:  
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period.  The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (i.e. those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived). 
x
The summary of laboratory parameters by CTCAE grade table will include number and 
percentage of patients with Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4),
laboratory abnormalities during the on-treatment period.
x
The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary.  
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, i.e.: 
x
Hematology:  
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased). 
x
Serum Chemistry: 
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin


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increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase (CPK increased), Potassium (hypokalemia/hyperkalemia),Sodium (hyponatremia/ 
hypernatremia), Magnesium (hypomagnesemia/hypermagnesemia), Calcium 
(hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), Gamma 
Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), Phosphates 
(hypophosphatemia), Triglycerides (hypertriglyceridemia). 
Parameters with NCI-CTC grades not available: 
Hematology and chemistry evaluations which cannot be graded per CTCAE criteria will be 
summarized as frequency (number and percentage) of patients with:  
x
shifts from baseline normal to at least one result above normal during on-treatment period  
x
shifts from baseline normal to at least one result below normal during on-treatment 
period 
In this study, these apply to the following parameters:  
x
Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils. 
x
Serum Chemistry: Chloride, Total Urea, Uric Acid, Total Protein, C-Reactive Protein, 
Lactate Dehydrogenase (LDH).
6.6.5.2. Other laboratory parameters 
All other parameters collected on the eCRF will be listed in dedicated listings presenting all 
corresponding collected information on the eCRF.  
x
Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time 
(INR). 
x
Urinalysis: all urinalysis parameters. 
x
Other parameters: hormone, and immunology parameters. 
x
Pregnancy test. 
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests.  
In addition, listings of abnormal values will be provided for hematology, chemistry, 
urinalysis, coagulation parameters. If there is at least one abnormal assessment for any 
parameter, all the data for that laboratory parameter will be included into the listing.  
For all tests not mentioned above but present in the clinical data, a listing of patients with at 
least one result for the relevant test will be provided. 


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6.6.6. Vital signs 
Both in the Lead-in and in the Expansion phases, weight for the purposes of dose calculation 
will be recorded at screening and within 3 days pre-dose Day 1 of each cycle. Weight will 
also be collected at End of Treatment. Height will be measured at screening only. In the 
Expansion phase only, weight will be recorded also on Day 7 of Cycles 1 through 3 for all 
patients, on Day 7 of Cycles 4 thought 6 for patients who escalate to 500 mg Q2W at Cycle 
4, and on Day 7 of Cycles 7 through 9 for patients who escalate to 500 mg Q2W at Cycle 7. 
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign assessments will be listed, and those collected outside the on-treatment period 
will be flagged in the listing.  
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline. 
6.6.7. Electrocardiogram 
ECG summaries will include all ECG assessments from the on-treatment period.  All ECG 
assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing.  QTcB and QTcF will be derived based on RR and QT (see below).  The 
average of the replicate measurements should be determined after the derivation of the 
individual parameter at each time point. 
Selecting Primary QT Correction for Heart Rate 
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as  
RR
QT
QTcB  
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF  
, 
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.   
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions.  If QTcB and 


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QTcF methods do not adequately correct for HR and there are a sufficient number of patients 
(e.g. >30) with baseline ECGs, an alternate correction to achieve the goal of getting 
uncorrelated QTc and RR is based on a linear regression methods which yields, theoretically, 
uncorrelated QTc and RR. 
Linear regression method: 
x
Fit a model QT = a + b × RR to baseline data  
x
Use the estimated slope,  
^b , to correct QT 
x
Corrected QT for heart rate will be computed as follows: 
QTcP = QT + 
^b × (1- RR ) 
Data will be summarized using QTcF and QTcB. However, if these are not appropriate for 
the data set due to an observed large correlation between corrected QT and HR using the 
baseline assessments, the results will also be summarized using QTcP.   
ECG Summaries 
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment group, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category. 
x
Pearson correlation between QT and HR, QTc (QTcB, QTcF and, if applicable, QTcP) 
and HR using individual (non-averaged) baseline assessments  
x
For each of the ECG parameters (HR, and QT, QTc, QRS, PR intervals), descriptive 
statistics at baseline, at each post-baseline time point and changes from baseline at each 
post-baseline time point  
x
Frequency (number and percentage) of patients with notable ECG values according to the 
following categories:            
- 
QT/QTc increase from baseline >30 ms,  >60 ms 
- 
QT/QTc > 450 ms, > 480 ms, > 500 ms 
- 
HR ≤ 50 bpm and decrease from baseline ≥ 20 bpm
- 
HR ≥ 120 bpm and increase from baseline ≥ 20 bpm
- 
PR ≥ 220 ms and increase from baseline ≥ 20 ms
- 
QRS ≥ 120 ms 
Patients with notable ECG interval values and qualitative ECG abnormalities will be listed 
for each patient and time point and the corresponding notable values and abnormality 
findings will be included in the listings. 


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Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG changes and the shift table analysis of notable QT parameters. 
6.6.8. Physical examination 
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system.
6.6.9. ECOG performance status 
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment group. ECOG performance status with shift from ECOG=0 or 1 to 
ECOG 2 or higher will also be presented in a data listing. 
7. INTERIM ANALYSES 
There is no formal interim analysis planned for this study.   
7.1. Introduction 
Not Applicable. 
7.2. Interim Analyses and Summaries 
Not Applicable. 


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8. REFERENCES 
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982. 
2.
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht et al. Revised Response 
Criteria for Malignant Lymphoma. J Clin Oncol. 2007 25:579-586.
3.
Cheson DB, Fisher RI, Barrington SF, Cavalli F, Schwartz LH et al. Recommendations 
of Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification. J Clin Oncol. 2014 32:3059-3067. 
4.
Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall 
5.
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika; 26, 404-413. 
6.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience   
7.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.


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9. APPENDICES 
Appendix 1. Immune-Related Adverse Events 
The MedDRA PTs and clusters for irAEs are defined in the Safety Review Plan (SRP) for 
avelumab. 
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 13.
This case definition is hierarchical, i.e., each step is only checked for patients and events that 
have already met the prior step.   
Table 13. Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE
matches the list then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs if 
A) OR B) below are met then the AE is in for the 
next step
A) conmed ATC code is in (H02A, H02B, D07, 
A01AC, S01BA, S01BB, L04AA,  L04AB,  
L04AC,   L04AD,  L04AX, A07EA) and AE PT 
is in any of the irAE clusters.
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters  associated with 
“Immune-mediated endocrinopathies”
C) conmed ATC code is A10A and AE PT is in the 
irAE cluster associated with “Immune-mediated 
endocrinopathies: Type I Diabetes Mellitus”


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


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Appendix 2. Infusion Related Reactions 
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered.  
x
All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
infusion) and the event resolved with end date within 2 days after onset.  
x
All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
the infusion) or the day after the study drug infusion (irrespective of  resolution date). 
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab.  
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 14.
Table 14. Case Definition for IRRs 
Condition
Selection criterion
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)]  then AE is classified as an IRR
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list
2
x
AE onset date = date of infusion of study drug AND
x
AE timing related to study drug (‘DURING’, ‘AFTER’) AND
x
AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND
x
AE  end date – AE onset date <=2 
3
PT is included in the ‘IRRs CORE’ list 
4A
x
AE onset date = date of infusion of study drug AND
x
AE timing related to study drug in (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion