Clinical trial NCT02952586
Conditions: Squamous Cell Carcinoma of the Head and Neck
Sponsor: Pfizer
Start date: 2016-11-28; Completion date: 2020-08-25
Enrollment: 697 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3 randomized, placebo controlled study to evaluate the safety and anti-tumor activity of Avelumab in combination with standard of care chemoradiation (SoC CRT) versus SoC CRT alone in front-line treatment of patients with locally advanced head and neck cancer.

Detailed description:

Arms: arm 1: * Avelumab 10 mg/kg IV: Day 1 of the Lead-in Phase; Days 8, 25, and 39 of the CRT Phase; and Q2W for 12 months during the Maintenance Phase
* Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase
* Intensity Modulated Radiation Therapy (IMRT) 70 Gy/35 fractions/7 weeks; 1 fraction per day, 5 fractions/week for 7 weeks during the CRT Phase arm 2: * Placebo IV matching avelumab: Days 1 of the Lead-in Phase; Days 8, 25, and 39 of the CRT Phase; Q2W for 12 months during the Maintenance Phase
* Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase
* IMRT 70 Gy/35 fractions/7 weeks; 1 fraction per day, 5 fractions/week for 7 weeks during the CRT Phase
Interventions: intervention 1: Avelumab intervention 2: Chemoradiation
Intervention descriptions: intervention 1: Avelumab + SOC Chemoradiation intervention 2: Cisplatin + Radiation Therapy

Protocol documents:
Prot_000.pdf: 
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JAVELIN HEAD AND NECK 100 
A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF AVELUMAB IN 
COMBINATION WITH STANDARD OF CARE CHEMORADIOTHERAPY 
(CISPLATIN PLUS DEFINITIVE RADIATION THERAPY) VERSUS STANDARD
OF CARE CHEMORADIOTHERAPY IN THE FRONT-LINE TREATMENT OF
PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF 
THE HEAD AND NECK 
Compound:
MSB0010718C
Compound Name:
Avelumab
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-001456-21
Protocol Number:
B9991016
Phase:
3
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
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Document History
Document
Version Date
Summary of Changes
Amendment 3
31 Jul 2019
Major changes:
•
The Protocol Summary and Section 9.1 were
revised to reflect the changes resulting from the 
update in the timing of the interim analysis from a 
PFS information fraction of 60% to 75%. The 
increase in information fraction from 60% to 75% 
will allow for an interim analysis with more 
mature data.
•
Section 9.1, 9.3.2.1, and 9.6 were revised to 
reflect the changes resulting from the increase in 
the number of interim analyses for OS from
3 to 4. 
Other changes:
•
Footnote 7 of the Screening, Lead-In Phase, and 
Definitive Treatment (Chemoradiotherapy) Phase 
SOA and footnote 6 of the Maintenance Phase, 
EOT/Withdrawal, and Short-/Long Term 
Follow-up Periods SOA were updated to reflect 
that laboratory assessments could be collected
and results reviewed on Friday (up to 1 business 
day) prior to avelumab administration the 
following Monday.
•
 
 
 
 
 
 
•
Section 5.5.1, clarified that laboratory draws and 
assessment of results up to 1 business day prior to 
study drug administration is acceptable and not 
considered a protocol deviation.
•
Section 5.5.2.2, footnote 7 of the Screening, 
Lead-In Phase and Definitive Treatment 
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(Chemoradiotherapy) Phase SOA, and footnote 6 
of the Maintenance Phase, EOT/Withdrawal, and 
Short-/Long Term Follow-up Periods SOA were 
updated to allow laboratory samples collected on 
Friday before administration of cisplatin on the 
following Monday. 
•
Section 7.5.1 language was updated to reflect that 
tumor tissue collected (via slides) in China were 
not retained and were examined for PD-L1 
expression and CD8 lymphocyte infiltration by 
immunochemistry, tumor mutational burden and 
immune repertoire by TCR analysis.
•
 
 
 
 
 
 
 
 
 
 
•
Footnotes 21 and 22 of the Screening, 
Lead-In Phase, and Definitive Treatment 
(Chemoradiotherapy) Phase SOA, footnote 18 
of the Maintenance Phase, EOT/Withdrawal, 
and Short-/Long Term Follow-up Periods 
SOA were also updated.
•
Section 3.8 and Footnote 17 of the Screening, 
Lead-In Phase, and Definitive Treatment 
(Chemoradiotherapy) Phase SOA, footnote 15 of 
the Maintenance Phase, EOT/Withdrawal, and 
Short-/Long Term Follow-up Periods SOA were 
updated to clarify that PRO assessments should 
coincide scheduled clinic visits, do not require an 
additional trip to the clinic, and will be completed 
in the clinic.
•
Footnote 2 of the SOA for the Maintenance 
Phase, EOT/Withdrawal Visit, and 
Short-/Long-Term Follow-Up Periods was 
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clarified to distinguish imaging and assessment 
requirements for patients who complete the 
maintenance phase and continue into the 
follow-up period from those patients who 
discontinue early from the study and refuse 
follow up.
•
Footnotes 3 and 14 of the Maintenance Phase, 
EOT/Withdrawal, and Short-/Long Term 
Follow-up Periods SOA were updated to allow 
for additional collections of survival information.
•
Section 4.1 and IC #8 updated to include the 
minimum age for entry for patients in Taiwan and 
Korea.
 
 
 
 
•
Section 12.2, compliance language was updated 
to remove incorrect dates and versions.
Amendment 2
22 March 2018
This country specific change concerns the addition of 
Appendix 11 to capture some operational items not 
included in the mandatory contract format for France 
(ie, French “Contrat Unique”), which Pfizer includes 
in standard contract language for other countries. 
The items included do not impact the conduct of the 
trial, the safety or integrity of the subject, or use of 
their data. The information being added relates to 
requirements for: 
1. GCP Training
2. Investigational Product
3. Inspections
Amendment 1
30 January 2018
Major changes:
•
Inclusion Criterion (IC) No. 2 was clarified to 
include patients with HPV-positive 
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oropharyngeal disease T4 OR N2c OR N3 per 
TNM guidelines for head and neck sites. 
Section 1.2.3.4 and Section 1.3, were updated 
accordingly.
•
Inclusion Criterion (IC) No. 8 was updated to 
include patients with a creatinine clearance of at 
least 60 ml/min if this value is described in the 
contra-indications for cisplatin as per country’s 
local labeling. 
•
Inclusion Criterion (IC) No. 11 and Exclusion 
No 14 were updated as per the new guideline on 
Lifestyle, requiring the use of two methods of 
contraception (at least one of which is considered 
to be highly effective). Section 4.3 was updated 
to include new lifestyle guidelines. 
•
Exclusion Criterion (IC) No. 3 was updated to 
exclude patients with prior malignancy requiring 
tumor-directed therapy within the last 2 years 
prior to enrollment, or concurrent malignancy 
associated with clinical instability. Exceptions 
for disease within the 2 years are specified.
•
 
 
 
 
 
•
Sections 1.2.2, Avelumab clinical experience, 
1.2.3.3, rationale for avelumab dose, 5.4.6.6, 
Table 5 and 5.4.6.9 Table 6 were updated as per 
Avelumab Investigator Brochure version 7.
Other changes:
•
Section 3.1, study design was updated to include 
clarification for possible extension of CRT phase. 
The 14 days mandatory interval between two 
consecutive doses of avelumab/placebo was 
removed. 
•
Sections 3.2 and 7.8, Tumor assessments, were
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updated to include high resolution PET/CT and 
clarify that baseline scans obtained within 
28 days prior to randomization, are acceptable. 

Section 5.4.1.4, compliance criteria, was further 
clarified for radiotherapy. 

Section 5.4.2 cisplatin dosing, was updated to 
include requirement for dosing calculation based 
on actual weight in accordance with ASCO 
guidelines for obese patients. Guidance for split 
dose provided.

Section 5.4.3.2. Avelumab.  Text was added to 
clarify that, for weight changes 10%, the 
decision on whether to recalculate the avelumab 
dose will be made in accordance with local 
practices.

Section 5.5.1.4, special precautions for 
avelumab/placebo, was updated to include new 
guidance for required premedication and for 
observation post infusion (30 min).

Section 5.5.1 text was clarified to better define 
the beginning of maintenance and allowed 3 days 
visit window except for C1D1.

Section 5.5.1.5, management of 
avelumab/placebo infusion related reactions, 
updated to include guidance for infusion rate 
reduction.

Sections 5.5.2.2.1 and section 5.5.2.3, updated to 
allow administration of the 3rd cisplatin infusion 
any time up to 5 days after the end of radiation 
therapy. 

Section 5.5.2.2.2, cisplatin related ototoxicity, 
updated to include audiogram requirements in 
accordance with country specific label.

Section 5.8, concomitant treatments, updated to 
include reporting period of up to 90 days after last 
dose of study treatment or until the start of a new 


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therapy, whichever comes first. 
•
Section 5.8.2, Hematopoietic Growth Factors,
updated to clarify that the use of erythropoietin is 
prohibited during radiation therapy and that CSF 
administration for the management of 
treatment-emergent neutropenia requires 
consultation and approval from sponsor.
•
The Schedule of Activities (SoA), Table 2 for 
Screening/Lead-in phase and CRT phase 
assessments and table 3 for maintenance/ 
EOT/withdrawal visit/ follow up periods 
assessments, were updated to include relevant 
changes and clarifications and specify the 
requirement that laboratory assessments must be 
performed and results reviewed by the treating 
physician prior to study drug administration. 
HPV status (P16) assessed prior to screening is 
allowed and baseline nasopharyngoscopy is 
strongly recommended.
•
Appendix 8, appropriate chemotherapy dosing for 
obese adults with cancer as per ASCO guidelines 
added, clarifying BSA calculation.
 
•
Typos and inconsistencies were corrected; 
references and abbreviation list were updated.
Original 
protocol
20 Jun 2016
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...................................................................................................................15
LIST OF FIGURES .................................................................................................................15
APPENDICES .........................................................................................................................16
PROTOCOL SUMMARY.......................................................................................................17
SCHEDULE OF ACTIVITIES................................................................................................29
1. INTRODUCTION ...............................................................................................................41
1.1. Mechanism of Action/Indication.............................................................................41
1.2. Background and Rationale ......................................................................................41
1.2.1. Head and Neck Cancer ...............................................................................41
1.2.2. Avelumab Clinical Experience...................................................................42
1.2.2.1. Clinical Experience in Patients with Carcinomas Treated 
with Platinum-Based Chemotherapy.................................................46
1.2.2.2. Pharmacokinetics of Avelumab in Humans..............................47
1.2.3. Study Rationale...........................................................................................47
1.2.3.1. Rationale for Combining Avelumab with 
Chemoradiotherapy ...........................................................................47
1.2.3.2. Rationale for Chemoradiotherapy Dose....................................49
1.2.3.3. Rationale for Avelumab Dose and Schedule in Regards to 
CRT Regimens to be Evaluated ........................................................50
1.2.3.4. Rationale for Selected Patient Population.................................51
1.2.3.5. Rationale for Stratification Factors ...........................................51
1.2.3.6. Rationale for Endpoints.............................................................52
1.3. Summary of Benefit/Risk Assessment....................................................................52
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................54
2.1. Objectives................................................................................................................54
2.2. Endpoints.................................................................................................................55
3. STUDY DESIGN.................................................................................................................56
3.1. Overall Study Design ..............................................................................................56
3.2. Tumor Assessments.................................................................................................59
3.3. Tumor Related Endpoints and Definitions..............................................................60
3.4. Surgical Salvage of Residual Disease after Completion of the CRT Phase............61
3.5. Safety Assessments .................................................................................................63


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3.6. Pharmacokinetic/Immunogenicity Assessments.....................................................63
3.7. Biomarker Assessments ..........................................................................................63
3.8. Patient-Reported Outcomes.....................................................................................63
3.8.1. NCCN-FHNSI-22.......................................................................................64
3.8.2. EQ-5D-5L...................................................................................................64
64
64
4. PATIENT SELECTION......................................................................................................65
4.1. Inclusion Criteria.....................................................................................................65
4.2. Exclusion Criteria....................................................................................................67
4.3. Lifestyle Guidelines ................................................................................................68
4.4. Sponsor’s Qualified Medical Personnel..................................................................69
5. STUDY TREATMENTS.....................................................................................................70
5.1. Allocation to Treatment ..........................................................................................71
5.2. Breaking the Blind ..................................................................................................71
5.3. Patient Compliance .................................................................................................72
5.4. Investigational Product/Study Treatments Supplies ...............................................72
5.4.1. Radiation Therapy to the Primary Lesion and Neck (IMRT).....................72
5.4.1.1. Dose Specificiations..................................................................72
5.4.1.2. Technical Factors ......................................................................72
5.4.1.3. Documentation Requirements for IMRT ..................................73
5.4.1.4. Compliance Criteria ..................................................................73
5.4.2. Cisplatin......................................................................................................73
5.4.2.1. Formulation ...............................................................................74
5.4.2.2. Administration...........................................................................74
5.4.2.3. Storage and Stability .................................................................74
5.4.2.4. Adverse Events..........................................................................74
5.4.2.5. Supply........................................................................................74
5.4.3. Avelumab/Placebo......................................................................................75
5.4.3.1. Dosage Form and Packaging.....................................................75
5.4.3.2. Preparation and Dispensing.......................................................75
5.5. Administration.........................................................................................................76
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5.5.1. Avelumab/Placebo......................................................................................76
5.5.1.1. Treatment After Initial Evidence of Radiological Disease 
Progression ........................................................................................77
5.5.1.2. Recommended Dose Modifications ..........................................78
5.5.1.3. Dosing Delays ...........................................................................78
5.5.1.4. Special Precautions for Avelumab/placebo Administration .....79
5.5.1.5. Management of Avelumab/placebo Infusion-Related
Reactions ...........................................................................................80
5.5.1.6. Management of Avelumab/Placebo-related Severe 
Hypersensitivity Reactions and Flu-like Symptoms .........................81
5.5.1.7. Management of Investigational Product-Related Tumor 
Lysis Syndrome.................................................................................82
5.5.1.8. Management of Avelumab/placebo Immune-Related 
Adverse Events..................................................................................84
5.5.2. Cisplatin......................................................................................................92
5.5.2.1. Management of Cisplatin Toxicities and Pretreatment 
Guidelines..........................................................................................92
5.5.2.2. Cisplatin Dose Modifications for Toxicity During 
Concurrent Radiation.........................................................................93
5.5.2.3. Cisplatin Dosing Delays............................................................96
5.5.2.4. Concurrent Radiation Therapy Adverse Events........................96
5.5.3. Food Requirements.....................................................................................96
5.6. Investigational Product Storage ..............................................................................96
5.7. Investigational Product Accountability...................................................................98
5.7.1. Destruction of Investigational Product Supplies ........................................98
5.8. Concomitant Treatment(s).......................................................................................98
5.8.1. Hematopoietic Growth Factors...................................................................99
5.8.2. Concomitant Surgery..................................................................................99
5.8.2.1. Primary treatment neck dissection ............................................99
5.8.2.2. Other Surgery ............................................................................99
5.8.3. Other Prohibited Concomitant Medications and Treatments .....................99
5.9. Rescue Medications and Supportive Care.............................................................100
5.9.1. Supportive Care Guidelines......................................................................100
5.10. Potential for Drug-Drug Interactions with Cisplatin...........................................101


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6. STUDY PROCEDURES ...................................................................................................101
6.1. Screening...............................................................................................................102
6.2. Study Treatment Period.........................................................................................102
6.2.1. Tumor Biospecimens................................................................................102
6.2.1.1. Mandatory Tumor Tissue........................................................102
6.2.1.2. Optional Tumor Tissue – Lead-In Phase.................................102
6.2.1.3. De Novo Tumor Tissue – Maintenance Phase........................102
6.2.1.4. De Novo Tumor Tissue – End of Treatment/Withdrawal.......102
6.3. End of Treatment, Short- and Long-term Follow-up Visits..................................103
6.4. Patient Withdrawal................................................................................................103
7. ASSESSMENTS................................................................................................................104
7.1. Assessment of Progression....................................................................................104
7.2. Safety Assessments ...............................................................................................105
7.2.1. Pregnancy Testing ....................................................................................105
7.2.2. Adverse Events.........................................................................................106
7.2.3. Laboratory Safety Assessments................................................................106
7.2.4. Physical Examinations and Vital Signs....................................................107
7.2.5. 12-Lead Electrocardiograms.....................................................................108
7.3. Pharmacokinetics Assessments.............................................................................109
7.3.1. Blood for PK Analysis of Avelumab........................................................109
7.3.2. Blood for PK Analysis of Cisplatin..........................................................110
7.4. Immunogenicity Assessments...............................................................................110
7.4.1. Immunogenicity Assessment of Avelumab..............................................110
7.5. Translational and Pharmacodynamic Assesments ................................................110
7.5.1. Tumor Biospecimens................................................................................111
.111
111
113
7.7. Patient-Reported Outcomes Assessments .............................................................113
7.8. Tumor Response Assessment................................................................................113
8. ADVERSE EVENT REPORTING....................................................................................114
8.1. Adverse Events......................................................................................................114
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8.2. Reporting Period ...................................................................................................115
8.3. Definition of an Adverse Event.............................................................................115
8.4. Medication Errors..................................................................................................116
8.5. Abnormal Test Findings........................................................................................117
8.6. Serious Adverse Events.........................................................................................117
8.6.1. Protocol-Specified Serious Adverse Events.............................................118
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................118
8.7. Hospitalization ......................................................................................................119
8.8. Severity Assessment..............................................................................................120
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. Sample Size Determination...................................................................................125
9.2. Analysis Populations.............................................................................................125
9.2.1. Full Analysis Set.......................................................................................125
9.2.2. Per-Protocol Analysis Set.........................................................................126
9.2.3. Safety Analysis Set...................................................................................126
9.2.4. Pharmacokinetics Analysis Set.................................................................126
9.2.5. Immunogenicity Analysis Set...................................................................126
9.2.6. Biomarker Analysis Set............................................................................126
9.3. Efficacy Analysis ..................................................................................................126
9.3.1. Analysis of the Primary Endpoint.............................................................126
9.3.2. Analysis of Secondary Endpoints.............................................................127
9.3.2.1. Overall Survival ......................................................................127


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9.3.2.2. Pathologic Complete Response...............................................128
9.3.2.3. Objective Response.................................................................128
9.3.2.4. Duration of Response..............................................................128
9.3.2.5. Locoregional Failure ...............................................................128
9.3.2.6. Distant Metastatic Failure .......................................................129
9.3.2.7. Neck Dissection.......................................................................129
9.3.2.8. Patient-Reported Outcomes.....................................................129
9.3.2.9. Analysis of Pharmacokinetics .................................................130
9.3.2.10. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling................131
9.3.2.11. Immunogenicity Analysis .....................................................131
131
9.5. Safety Analysis......................................................................................................131
9.5.1. Adverse Events.........................................................................................132
9.5.2. Laboratory Abnormalities.........................................................................132
9.5.3. Electrocardiograms...................................................................................132
9.6. Interim Analysis ....................................................................................................133
9.7. Data Monitoring Committee .................................................................................134
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................135
11. DATA HANDLING AND RECORD KEEPING ...........................................................135
11.1. Case Report Forms/Electronic Data Record .......................................................135
11.2. Record Retention.................................................................................................136
12. ETHICS............................................................................................................................136
12.1. Institutional Review Board/Ethics Committee....................................................136
12.2. Ethical Conduct of the Study ..............................................................................137
The study will be conducted in accordance with the protocol, the most current, 
legal and regulatory requirements, and the general principles set forth in the 
International Ethical Guidelines for Biomedical Research Involving Human 
Subjects (Council for International Organizations of Medical Sciences 2002), 
ICH Guideline for GCP, and the Declaration of Helsinki.......................................137
12.3. Patient Information and Consent.........................................................................137
12.4. Patient Recruitment.............................................................................................138
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................138
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13. DEFINITION OF END OF TRIAL.................................................................................138
13.1. End of Trial in a Member State...........................................................................138
13.2. End of Trial in All Other Participating Countries...............................................138
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................138
15. PUBLICATION OF STUDY RESULTS........................................................................139
15.1. Communication of Results by Pfizer ..................................................................139
15.2. Publications by Investigators ..............................................................................139
16. REFERENCES ................................................................................................................141


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LIST OF TABLES
Table 1.
Chemoradiation and Avelumab/Placebo Treatment Schedule .............................23
Table 2.
SCHEDULE OF ACTIVITIES – Screening, Lead-in Phase, and Definitive 
Treatment (Chemoradiotherapy) Phase ................................................................30
Table 3.
SCHEDULE OF ACTIVITIES – Maintenance Phase, End of 
Treatment/Withdrawal, and Short-/Long-Term Follow-up Periods.....................36
Table 4.
Chemoradiation and Avelumab/Placebo Treatment Schedule .............................58
Table 5.
Treatment Modifications for Avelumab/placebo-Related Toxicity – to be 
followed only when the AE is deemed related to avelumab/placebo...................79
Table 6.
Treatment Modification for Symptoms of Avelumab/Placebo 
Infusion-Related Reactions...................................................................................81
Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related................85
Table 8.
Cisplatin Dose Levels...........................................................................................94
Table 9.
Cisplatin Dose Modifications Due to Hematological Toxicity ............................94
Table 10.
Cisplatin Dose Modification Due to Decreased Creatinine Clearance.................95
Table 11.
Cisplatin Dose Modifications Due to Neurologic Toxicity..................................95
Table 12.
Required Laboratory Tests .................................................................................107
LIST OF FIGURES
Figure 1
Study Design.........................................................................................................22
Figure 2
Algorithm for Evaluation of Regional Lymph Nodes Following Definitive 
CRT.......................................................................................................................26
Figure 3
Study Design.........................................................................................................57
Figure 4
Algorithm for Evaluation of Regional Lymph Nodes Following Definitive 
CRT.......................................................................................................................62
Figure 5
Assessment and Initial Management of Tumor Lysis Syndrome (TLS) ..............83


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APPENDICES
Appendix 1. Abbreviations....................................................................................................147
Appendix 2. ECOG Performance Status................................................................................152
Appendix 3. Modifications to Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 Guidelines Specific to Study B9991016..........................................153
Appendix 4. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Guidelines...........................................................................................................155
Appendix 5. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................160
Appendix 6. NCCN FHNSI-22..............................................................................................161
Appendix 7. EuroQol EQ-5D-5L...........................................................................................162
Appendix 8. Appropriate Chemotherapy Dosing For Obese Adult Patients With 
Cancer: ASCO Clinical Practice Guideline........................................................165
 
..166
 
167
Appendix 11. France Appendix.............................................................................................168
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PROTOCOL SUMMARY
Background
Head and neck cancers, including cancers of the oral cavity, nasopharynx, pharynx, and 
larynx, account for approximately 5% of cancers worldwide (excluding non-melanoma skin 
cancers).9  Approximately 680,000 new cases of head and neck cancer were diagnosed in 
2012 with 370,000 deaths attributed to this disease; of these new cases reported, almost 
140,000 were in Europe, and over 90% were squamous cell histology.10  In the US, it is 
estimated that over 61,000 people will be diagnosed with head and neck cancer in 2016 and 
over 13,000 will die from this cancer.62 Head and neck cancers are predominately squamous 
carcinomas.  Squamous cell carcinomas of the head and neck (SCCHN) involving the oral 
cavity, larynx, oropharynx, and hypopharynx account for 75% SCCHN overall and are 
closely associated with alcohol and tobacco use.  SCCHN of the oropharynx is also closely 
associated with human papillomavirus (HPV) type 16 infection.11  In the past 2 decades, 
HPV-positive oropharyngeal cancers have increased dramatically especially in North 
America, underscoring an important role in HPV infection and oropharyngeal cancer.12
Although the incidence of HPV-negative SCCHN has decreased, consistent with decreasing 
use of tobacco products worldwide, the curability of HPV-negative tumors remains 
suboptimal.43
Of newly diagnosed patients with SCCHN, approximately 60% present with locally or 
regionally advanced disease.10,13  Depending on the tumor site, stage, and resectability, 
locoregional failure rates can range between 35% and 65%.  With a median PFS of 1.9 years 
and reported 3-year PFS rate of 61.2%, this disease will ultimately recur locally in a large 
proportion of treated patients, with distant metastases developing in 10% to 30% of these 
patients.13,44,57 Currently available treatment options for both locoregional and distant 
recurrences are limited.  Outcomes for both groups of recurrences are abysmal, and the 
limited number of patients who are eligible for potentially curative treatment for locoregional 
disease recurrence are exposed to a high degree of morbidity.
Study Rationale
There are emerging data supporting the rationale for combinations of immune checkpoint 
inhibitors with chemotherapy.18,19  Chemotherapy has been shown to have 
immunostimulatory properties by stimulating the release of neoantigens and adjuvants by 
dying cells, increasing susceptibility to immune attack, and preferentially reducing 
immunosuppressive cells such as T regulatory cells.20,21,22,23  
Several immune checkpoint inhibitors have been combined with chemotherapy agents.  The 
addition of ipilimumab to dacarbazine led to an improvement in PFS and OS in previously 
untreated melanoma compared to dacarbazine alone.25  Ipilimumab was combined with 
platinum doublet chemotherapy in small cell as well as non-small cell lung cancer (NSCLC) 
with encouraging results.26,27  Single-arm studies investigating the combination of 
programmed death protein 1 (PD-1) blockers (pembrolizumab, nivolumab) as well as a 
programmed death-ligand 1 (PD-L1) blocker (atezolizumab) with platinum doublet 
chemotherapy demonstrated acceptable safety profiles with early evidence of clinical activity 


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which appears to be higher than expected for platinum doublet therapy alone, particularly for 
atezolizumab.27,28,29,30,31 Randomized Phase 3 studies in the first-line treatment of NSCLC 
patients are currently investigating the addition of pembrolizumab and atezolizumab to 
platinum-based chemotherapy.
In addition to the data supporting combining immune checkpoint inhibitors with 
chemotherapy, a strong body of evidence supports the combination of radiation therapy with 
immunotherapy such as a PD-L1 inhibitor.34,35  Radiation therapy (RT) in combination with 
avelumab was found to be highly synergistic, capable of causing complete regression of 
established tumors with the potential to generate antitumor immune memory.17
There are currently several studies ongoing evaluating immune checkpoint inhibitor agents in 
later lines of treatment for SCCHN patients.  These trials have demonstrated activity in this 
tumor type for this class of drugs when used as single agents for patients with recurrent or 
metastatic disease.  Nivolumab, in the CheckMate – 141 study in platinum-refractory patients 
in the recurrent or metastatic setting, has demonstrated an improved OS relative to alternative 
investigator-choice chemotherapy at 7.5 (95% confidence interval [CI]: 5.5 – 9.1) vs. 5.1
(95% CI: 4.0 – 6.0) months (HR 0.70 [97.73% CI: 0.51 – 0.96]), and was stopped early by 
the data monitoring committee (DMC).  Updates presented at the American Society of 
Clinical Oncology (ASCO) 2016 Annual Meeting described the activity in subgroups of 
patients with tumors that were p16 positive (N=63 HR 0.56, 95% CI: 0.32 - 0.99) or negative 
(N=50, HR 0.73, 95% CI: 0.42 - 1.25) and those whose tumors were positive for PD-L1 
staining at 1% (HR: 055; 95%CI: 0.36-0.83) vs. 1% (HR: 0.89 95% CI: 0.54-1.45).59  Also 
at ASCO, updated efficacy data for pembrolizumab in recurrent/metastatic SCCHN 
(KEYNOTE-012) was presented.  An overall objective response rate (ORR) of 18% (34/192; 
95% CI: 13-24%) was observed, with ORR of 24% (11/45, 95% CI: 13 - 40%) and 16% 
(23/147, 95% CI: 10 – 23%) in HPV-positive and HPV-negative patients, respectively.  
However, the limited number of patients evaluated and overlapping 95% CIs preclude 
definitive conclusions regarding any role HPV or PD-L1 status may play in response to 
checkpoint inhibitor treatments.  Additionally, it should be noted that both HPV groups had 
the same (n=4) number of patients with CR in the KEYNOTE-12 update.  Median time to 
response was 2 months, but several patients took substantially longer to respond 
(range: 2 - 17 months).  Median OS was 8 months (95% CI: 6 – 10 months) in these heavily 
pretreated patients with 38% alive at 12 months.60,61  These trials provide strong early 
evidence that SCCHN represents a tumor type that is responsive to this class of agents.  
Collectively, these data, the strong scientific rationale for radiation (which increases 
PDL-1 expression) and immune checkpoint inhibitor combinations, and the poor patient 
options if disease control is not obtained in front-line therapy, persuasively argue for 
progressing an immune checkpoint inhibiting agent into combination therapy with definitive 
chemoradiotherapy (CRT) to provide an optimized, multimodality approach to treat this 
disease and help patients avoid the high morbidity and mortality associated with disease 
progression.  This combination can potentially overcome the treatment resistance that 
patients experience, in particular for HPV-negative tumors.43


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Study Objectives and Endpoints
Primary Objective
To demonstrate that treatment with avelumab in combination with standard of care (SOC) 
CRT is superior to SOC CRT alone in prolonging progression-free survival (PFS) in 
front-line patients with high-risk (as defined in Inclusion Criterion 2 [Section 4.1]), locally 
advanced SCCHN who are candidates for definitive CRT with cisplatin. 
Secondary Objectives
•
To compare the overall survival (OS) of avelumab in combination with SOC CRT vs 
SOC CRT alone.
•
To evaluate the anti-tumor activity of avelumab in combination with SOC CRT and 
SOC CRT alone.
•
To evaluate the overall safety and tolerability profile of avelumab in combination
with SOC CRT and SOC CRT alone.
•
To evaluate the pharmacokinetics (PK) of avelumab.
•
To evaluate the PK of cisplatin (total and free).
•
To assess avelumab anti-drug antibodies (ADAs).
•
To evaluate the effect of avelumab in combination with SOC CRT and SOC CRT
alone on patient-reported outcomes (PROs) of disease-related symptoms and 
health-related quality of life.
•
To evaluate candidate immune-related predictive biomarkers of sensitivity or 
insensitivity to treatment with avelumab in combination with SOC CRT in 
pre-treatment tumor samples (eg, PD-L1 expression).
•
To evaluate candidate immune-related predictive biomarkers of sensitivity or 
insensitivity to treatment with avelumab in combination with SOC CRT in tumor 
samples (eg, PD-L1 expression) after one dose of avelumab in patients who provide 
this optional biopsy.
 
 
 
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Primary Endpoint
•
PFS per modified Response Evaluation Criteria in Solid Tumors (RECIST) version 
(v)1.1 (see Appendix 3 for specific modifications, including pathologic confirmation) 
by investigator assessment.
Secondary Endpoints
•
OS.
•
Antitumor Activity: Pathologic complete response in any resected specimens, neck 
dissection. 
•
Antitumor Activity: Locoregional failure, objective response, distant metastatic 
failure, and duration of response, per modified RECIST v1.1 (Appendix 3) by 
investigator assessment.
•
Safety: Adverse events and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; 
vital signs (blood pressure, pulse rate).
•
Pharmacokinetics:
•
Maximum concentrations (Cmax) and trough concentrations (Ctrough) for avelumab.
•
Area under the concentration-time curve extrapolated to infinity (AUCinf), Cmax, 
clearance (CL), time to maximum plasma concentration (Tmax), elimination 
half-life (t1/2), and volume of distribution (Vz) for cisplatin (total and free), as data 
permit.
•
Immunogenicity: Incidence of ADA (neutralizing antibody) against avelumab.
•
Patient-Reported Outcomes: Disease-related symptoms and Health-Related Quality 
of Life as measured by the National Cancer Comprehensive Network (NCCN) Head 
and Neck Symptom Index-22 items (FHNSI-22), and the EuroQoL Group 
5-Dimension 5-Level Self-Report Questionnaire (EQ-5D-5L).
•
Biomarkers: Tumor tissue biomarkers including, but not limited to, PD-L1 expression 
and tumor-infiltrating CD8+ T-lymphocytes.
C
C
I


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Study Design
This is a Phase 3, international, multicenter, randomized, double-blind, parallel, 2-arm study 
in patients with previously untreated, histologically confirmed, locally advanced SCCHN 
(oral cavity, oropharynx, larynx, or hypopharynx) who are candidates for definitive CRT 
with cisplatin.  The study is designed with the primary objective of demonstrating that 
treatment with avelumab in combination with SOC CRT is superior to SOC CRT alone in 
prolonging PFS. 
One interim analysis for the assessment of PFS will be conducted to allow early stopping of 
the study for futility or to demonstrate early superiority of avelumab in combination with 
SOC CRT compared to SOC CRT alone, and to assess the safety of avelumab in combination 
with SOC CRT. 
A total of approximately 640 patients will be randomized in a 1:1 ratio to either Arm A 
(avelumab + SOC CRT) or Arm B (placebo + SOC CRT).  Randomization will be stratified 
by tumor (T) stage (<T4 vs T4), nodal (N) stage (N0/N1/N2a/N2b vs N2c/N3), and HPV 
status (positive vs negative) as measured by p16 expression by IHC.
The specific study treatments to be administered in each treatment arm are described in the 
STUDY TREATMENTS section below. 
The study design is illustrated in Figure 1.
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Figure 1
Study Design
a.
Patients with LA SCCHN (oral cavity, oropharynx, larynx, or hypopharynx) eligible for front-line 
treatment: HPV negative disease stage III, IVa, IVb; non-oropharyngeal HPV positive disease stage III, 
IVa, IVb; HPV positive oropharyngeal disease T4 OR N2cOR N3 (staging per TNM [tumor, node, 
metastases] guidelines for head and neck sites AJCC 7th Edition).  (Note: entry criteria for patients with 
HPV-positive tumors are different than for patients with HPV-negative tumors).
b.
Avelumab or placebo IV to be administered on Day 1 of the Lead-in Phase (1 week prior to the start of the 
CRT Phase) and on Days 8, 25, and 39 during the CRT Phase. 
c.
SOC CRT = IMRT (70 Gy/35 fractions/7 weeks; 1 fraction per day, 5 fractions/week) for 7 weeks + 
cisplatin (100 mg/m2 Days 1, 22, 43) during the CRT Phase.
d.
Maintenance Phase to start after completion of the CRT Phase and continue for 12 months.
e.
Patients will continue treatment until confirmed disease progression as assessed by Investigator per 
modified RECIST v1.1.
AJCC = American Joint Committee on Cancer; CRT = chemoradiotherapy; HPV = human papillomavirus; 
IMRT = intensity-modulated radiation therapy; LA = locally advanced; Q2W = every 2 weeks; 
RECIST = Response Evaluation Criteria in Solid Tumors; SCCHN = squamous cell carcinoma of the head and 
neck; SOC = standard of care.
There will be 3 treatment phases in this study: 

Lead-in Phase: On Day 1 of the Lead-in Phase of the study, patients will receive a 
single dose of avelumab or matching placebo, administered 7 days prior to initiation 
of the CRT Phase; 

CRT Phase: Avelumab or matching placebo will be administered on Days 8, 25, and 
39 in conjunction with SOC CRT starting on Day 1 of the CRT phase; 

Maintenance Phase: Following completion of the CRT Phase, avelumab or matching 
placebo will be administered every 2 weeks (Q2W) for 12 months during the 
Maintenance Phase. 
The treatment schedule is described in the following table.


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Table 1.
Chemoradiation and Avelumab/Placebo Treatment Schedule
Lead-in Phase 
(7 days)a
CRT Phase 
(63 days)
Maintenance 
Phaseb
-- Day --
----------------  Day  ----------------
1
1
8
15
22 25 29
36
39 43
IMRT (70 Gy/35 fractions/
7 weeks; 1 fraction per day,
5 fractions/week 
[Monday – Friday])
XXXX XXX
Cisplatin (100 mg/m2 Q3W)
X
X
X
Avelumab (10 mg/kg) or placebo
X
X
Xc
X
Q2W
a.
Lead-in Phase to start 7 days prior to initiation of CRT Phase. 
b.
Maintenance Phase to start after completion of the CRT Phase (ie, 2 weeks following completion of CRT) 
and be 12 months in duration.  CRT phase may be extended as required for patient recovery from CRT; 
however, it is hypothesized that patients will receive maximal benefit from beginning maintenance as close 
to the scheduled time as possible.
c.
Day 25 dose of avelumab/placebo during the CRT Phase may be administered between Day 24 and Day 29. 
Cisplatin should be administered on a Monday or Tuesday to maximize overlap with IMRT. 
CRT = Chemoradiotherapy; IMRT = intensity-modulated radiation therapy; Q2W = every 2 weeks; 
Q3W = every 3 weeks.
Tumor Assessments

Tumor assessments will be completed on the schedule detailed below using a 
modification of RECIST v1.1.  The modification is required in head and neck cancer 
assessment as these tumors are fairly unique in their accessibility for thorough clinical 
evaluation and biopsy.  Furthermore, the extensive mucosal surface which is available 
for clinical evaluation of tumor response or recurrence may indicate tumor status 
changes that may not be present or as clear on radiographic imaging alone.  
Conversely, radiographic changes that could be suggestive of tumor progression or 
recurrence can reflect radiation therapy changes.  Taken collectively, this has given 
rise to the clinical practice of using biopsies to directly assess tumor recurrence in this 
patient population.  Therefore, RECIST was modified for this protocol to recognize 
this practice and better confirm (through direct pathologic ascertainment) when tumor 
recurrence has occurred.

Radiographic and clinical evaluations will be conducted with the same schedule in 
both treatment arms of the study.  The investigator will assess antitumor activity 
based on radiological assessments and clinical evaluation of patients using modified 
RECIST v1.1 (see Appendix 3) at baseline, 12 weeks after the completion of CRT,
every 16 weeks (Q16W) thereafter for 48 months (208 weeks), and every 24 weeks 
(Q24W) thereafter until confirmed disease progression per modified RECIST v1.1 


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and regardless of discontinuation of study treatment or initiation of subsequent 
anti-cancer therapy. 

Radiological tumor assessments will also be conducted whenever disease progression 
is suspected (eg, symptomatic deterioration or physical exam findings suggestive of 
mucosal recurrence). 

Locoregional disease progression per modified RECIST v1.1 requires that 
radiographic changes suggestive of disease progression are confirmed by biopsy.  
Pathologic confirmation of progression will verify that radiographic changes 
represent true tumor progression and not radiation effects or non-malignant contrast 
enhancement.

When disease progression occurs for distant metastases per RECIST v1.1, 
confirmation of pathology is recommended unless medically contraindicated or if the 
lesion location is too high risk for biopsy.

If a patient withdraws from study treatment for a reason other than disease 
progression per modified RECIST v1.1, radiological tumor assessments are to 
continue until disease progression per modified RECIST v1.1, even if a new 
anti-cancer therapy is initiated. 

A head and neck computed tomography (CT) or magnetic resonance imaging (MRI), 
chest CT, and PET scan are required at baseline and at 12 weeks after the completion 
of CRT.  High resolution PET/CT does not require additional CT thorax/neck/brain.
MRI brain may be performed if clinically indicated. Subsequent PET scans may be 
performed during the Maintenance Phase in the absence of clinical or CT complete 
resolution of nodal disease (described in Section 3.3) or at the investigator’s 
discretion.
Surgical Salvage of Residual Disease after Completion of the CRT Phase
Treatment of residual disease at the primary site will be determined by the investigator and 
the clinical situation (see Figure 2).  If treatment at the primary site is necessary after 
completion of CRT, study treatment has failed and the patient will discontinue treatment.  
Surgical resection, re-irradiation, chemotherapy, or palliative care may be performed per 
institutional policy.  If the primary site is cleared of residual disease, yet residual disease at 
the cervical nodal basin is suggested by imaging/clinical evaluation, then selective neck 
dissection will be performed unless a cytologic sampling of the node is negative.  Residual 
disease in the neck is not considered treatment failure if surgical salvage is completed within 
140 days of completion of CRT.  A primary treatment neck dissection after completion of the 
CRT Phase will be defined as a neck dissection performed for residual disease and within 
20 weeks (140 days) after completion of CRT.  Patients who undergo such a primary 
treatment neck dissection will remain on study treatment. 


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Positive neck specimens removed within 140 days of completion of CRT will be considered 
part of the initial treatment plan and not considered as failures of initial management; 
positive specimens upon neck dissection beyond 140 days will be considered regional 
failures.  Such consolidation neck dissections after completion of the CRT Phase will 
encompass only the areas (typically only levels 2 and 3) initially involved in the side of the 
neck in question.  The extent of neck dissections performed for nodal recurrence, nodal 
progression, and/or salvage of disease at the primary will be determined by the treating 
surgeon. 
If a neck dissection is required, then the treating surgeon is required to contact the surgical 
Principal Investigator (PI) of this study, Dr. 
 prior to the surgery 
to discuss the clinical and radiologic findings as well as the planned surgery itself.  Notes 
from the surgery, as well as the pathology report from the neck dissection, must also be 
submitted to Dr. 
 for review when they become available, but no later than 6 weeks 
following the procedure.
In the case of negative PET in patients who did not achieve clinical or CT/MRI-based 
radiological nodal complete response (CR) at the tumor assessment performed 12 weeks 
following completion of CRT, follow-up PET scans are recommended every 4 months 
(Q16W) with the CT imaging for 24 months (104 weeks), then every 6 months (Q24W) in 
Years 3-5, as well as careful recording of the clinical dimensions of the residual abnormality.  
CT imaging should be obtained as described in the Schedule of Activities beyond Year 5.
PPD
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Figure 2
Algorithm for Evaluation of Regional Lymph Nodes Following Definitive 
CRT
a.
High risk = perceived risk of residual disease is high, such as sub-optimally treated patients due to 
premature cessation of treatment, unplanned treatment interruptions. 
b.
Low risk = perceived risk of residual nodal disease is low, such as low burden disease without treatment 
interruption.
c.
Ongoing clinical and imaging observation until residuum is <1 to 1.5 cm or stable for >6 months.
d.
In the case of positive biopsy, the surgical PI (Dr. 
]) must be contacted prior to 
performing the surgery to discuss the clinical and radiological findings as well as the planned surgery itself. 
e.
If biopsy is negative but there is high clinical/radiologic suspicion of disease, consider rebiopsy and contact 
the surgical PI (Dr. 
]) for discussion.
CRT = chemoradiotherapy; CT = computed tomography; IMRT = intensity-modulated radiation therapy; 
PET = positron emission tomography; PI = (surgical) principal investigator.
Safety Assessments
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the Schedule of Activities table. 
Pharmacokinetic/Immunogenicity Assessments
Samples for PK and immunogenicity analyses will be collected as described in the Schedule 
of Activities table. 
PPD
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Biomarker Assessments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate biomarkers that are potentially predictive of treatment benefit with the 
combination of avelumab and SOC CRT.  In addition, biomarker studies of tumor and blood 
biospecimens will be carried out to help further understand the mechanism of action, as well
as potential mechanisms of resistance, to the combination of avelumab with SOC CRT.  
Tumor and blood biospecimens as required for the various analyses will be collected as 
described in the Schedule of Activities table.
Study Treatments

Arm A: Avelumab + SOC CRT:

Avelumab 10 mg/kg intravenously (IV): Day 1 of the Lead-in Phase; Days 8, 25, 
and 39 of the CRT Phase; and Q2W for 12 months during the Maintenance Phase.

Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase.

Intensity Modulated Radiation Therapy (IMRT) 70 Gy/35 fractions/7 weeks; 
1 fraction per day, 5 fractions/week for 7 weeks during the CRT Phase.

Arm B: Placebo + SOC CRT:

Placebo IV matching avelumab: Days 1 of the Lead-in Phase; Days 8, 25, and 
39 of the CRT Phase; Q2W for 12 months during the Maintenance Phase.

Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase.

IMRT 70 Gy/35 fractions/7 weeks; 1 fraction per day, 5 fractions/week for 
7 weeks during the CRT Phase.
Statistical Methods:
The primary endpoint of the study is PFS per modified RECIST v1.1 by investigator 
assessment.  PFS is defined as the time from the date of randomization to the date of the first 
documentation of objective progressive disease (PD) per modified RECIST v1.1 or death due 
to any cause, whichever occurs first.
Two hundred eighty-nine (289) PFS events will be required to have at least 90% power to 
detect a hazard ratio of 0.68 using a 1-sided log-rank test at a significance level of 0.025, and 
a 2-look group-sequential design with Lan-DeMets (O’Brien-Fleming) -spending function 
to determine the efficacy boundary and a Gamma Family (-7) -spending function to 
determine the non-binding futility boundary.


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The sample size of 640 patients for this study is determined based on the assumptions that the 
median PFS for patients in Arm B is 33 months43,44 and that combination treatment including 
avelumab (Arm A) is expected to increase the median PFS to 48.5 months, corresponding to 
a hazard ratio (HR) of 0.68 under the exponential model assumption.  The sample size 
further assumes a 15% drop-out rate within each treatment arm and a non-uniform patient 
accrual over a 22-month period.  The data cutoff date for the primary PFS analysis will occur 
after the target number of events has been reached and the last patient randomized in the 
study has been followed for at least 24 months after randomization.
The primary analysis of PFS will include all patients who are randomized.  A stratified 
log-rank test (1-sided) stratified by randomization stratification factors will be used at the 
interim and/or final analyses with the overall significance level preserved at 0.025 (1-sided).  
PFS times associated with each treatment arm will be summarized using the Kaplan-Meier 
method and displayed graphically where appropriate.  Confidence intervals (CIs) for the 25th, 
50th, and 75th percentiles will be reported.  The stratified Cox proportional hazards model will 
be fitted to compute the treatment hazard ratios and the corresponding 95% CIs.
For the primary analysis, PFS data will be censored on the date of the last adequate tumor 
assessment for patients who do not have an event (PD per modified RECIST v1.1 or death); 
the analysis will consider any PD per modified RECIST v1.1 or death as an event regardless 
of the number of prior missing tumor assessments or timing of the event with respect to 
initiation of anti-cancer therapy.
A sensitivity analysis for PFS will be performed using the methodology outlined for the 
primary analysis of PFS above but defining PD as per standard RECIST v1.1.  Summary of 
discordance of PD (event and timing) as well as reasons for discordance between assessment 
of PFS per modified RECIST v1.1 and standard RECIST v1.1 will be provided for each 
treatment arm. 


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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 
procedure and assessment required for compliance with the protocol.
If deemed clinically necessary, the investigator may schedule visits in addition to those listed 
in the Schedule of Activities table (unplanned visits) at any time to conduct evaluations or 
assessments required to protect the well-being of the patient.


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Table 2.
SCHEDULE OF ACTIVITIES – Screening, Lead-in Phase, and Definitive Treatment (Chemoradiotherapy) Phase
Visit Identifiers1
-- Screening --
----------------------------------- Study Treatment -----------------------------------
Protocol Activities
Lead-in Phase
Chemoradiotherapy (CRT) Phase ([2] days for each visit)
28 Days Prior to 
Randomization18
Day 1
(7 days prior to 
initiation of CRT Phase)
------ Day ------
1
8
15
22
25
29
36
39
43
50 - 63*
Clinical Assessments
Informed Consent2
X
Medical/Oncological History
X
Baseline Signs/Symptoms3
X
Physical Examination4
X
X
X
X
X
Contraception Check5
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Vital Signs6
X
X
X
X
X
X
X
X
Laboratory Studies
Hematology7
X
X
X
X
X
X
X
X
Blood Chemistry7,8
X
X8
X8
X8
X8
X8
X8
X8
Coagulation7
X
X
If clinically indicated
Thyroid Function and ACTH Tests9
X
Pregnancy Test10
X
X
X
X
X
X
X
X
Urinalysis11
X
If clinically indicated
HBV, HCV Tests
X
If clinically indicated
12-Lead ECG12
X
X
if clinically indicated
Disease Assessments
HPV status (measured by p16 
status)13
X
Tumor Assessments (including 
scans)14
X


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Table 2.
SCHEDULE OF ACTIVITIES – Screening, Lead-in Phase, and Definitive Treatment (Chemoradiotherapy) Phase
Visit Identifiers1
-- Screening --
----------------------------------- Study Treatment -----------------------------------
Protocol Activities
Lead-in Phase
Chemoradiotherapy (CRT) Phase ([±2] days for each visit)
≤28 Days Prior to 
Randomization18
Day 1
(7 days prior to 
initiation of CRT Phase)
------ Day ------
1
8
15
22
25
29
36
39
43
50 - 63*
Other Clinical Assessments
Adverse Events15
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications/Treatments16
X
X
X
X
X
X
X
X
X
X
X
X
Patient-Reported Outcomes 
(NCCN-FHNSI-22, EQ-5D-5L, 
)17
X
X
X 
Randomization and Study Treatment18
IMRT (70 Gy/35 fractions/
7 weeks; 
1 fraction per day,5 fractions/week 
X→
X→
X→
X→
→
X→
X→
→
X→
Cisplatin (100 mg/m2 Q3W)18
X
X
X
Avelumab or Placebo Q2W18
X
X
X
X
Other Samplings
Avelumab Pharmacokinetics19
X
X
X
Cisplatin Pharmacokinetics20
X
Banked Blood Biospecimens21
X
X
X
X
Mandatory Tumor Tissue22
X
Optional De Novo Biopsy23
X
Anti-Avelumab Antibodies and 
Neutralizing Antibodies24
X
X
X
* A 2-week observation period will follow completion of CRT therapy.
ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed and 
paraffin-embedded HBV = hepatitis B virus; HCV = hepatitis C virus; HPV = human papillomavirus; 
 
 PK = pharmacokinetics; Q2W = every 2 weeks, Q3W = every 3 weeks; Q12W = every 12 weeks. 
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Footnotes for Schedule of Activities FOR SCREENING, LEAD-IN PHASE AND CRT PHASE  
1.
Visit Identifiers: All assessments should be performed prior to dosing with study treatments unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headers where applicable.  
2.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure.
3.
Baseline Signs/Symptoms: To be recorded pre-dose on Day 1 of the Lead-in Phase.  Patients will be asked about any signs and symptoms experienced 
within the 14 days prior to randomization.  Baseline signs and symptoms should be recorded in the medical history case report form (CRF) page.
4.
Physical Examination: Includes an examination of major body systems including height (screening only), and weight and whole nasopharyngeal area.  
(nasopharyngoscopy strongly recommended).
5.
Contraception Check: 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 contraception methods (at least one of which is 
considered to be highly effective as defined in Section 4.3) consistently and correctly and document such conversation in the patient’s chart.  The 
contraception check is an opportunity to confirm that contraception, if assigned, is used consistently and correctly.  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. 
6.
Vital Signs: vital signs to include blood pressure and pulse rate.  Blood pressure and pulse rate should be taken before any other assessments (eg, PK, 
laboratory blood draws), prior to receipt of study treatment with the patient in the seated position after the patient has been sitting quietly for at least 
5 minutes.
7.
Hematology, Blood Chemistry (full panel), and Coagulation: Results from the Screening assessments may be used for Day 1 of the Lead-in Phase if they 
were performed within 7 days prior to the visit.  All assessments may also be performed when clinically indicated.  Full chemistry panel is required at 
screening only.  Laboratory assessments may be performed and results reviewed by the treating physician up to 1 business day prior to study drug 
administration.
8.
Blood Chemistry (core panel): Core chemistry panel is required on Day 1 of the Lead-in Phase; and Days 1, 8, 22, 25, 39, and 43 of the CRT Phase.  Core 
panel must be performed, and results reviewed by the treating physician prior to study drug administration. When an infusion is shifted towards another 
day, chemistry panel will be shifted accordingly; additional assessments whenever clinically indicated. 
9.
Thyroid Function and ACTH Tests: Free T4, TSH, and ACTH tests will be performed at Screening and every 8 weeks thereafter. Additional tests should 
be performed when clinically indicated.
10. Serum/Urine Pregnancy Test: For 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 treatment: once at the start of screening and once on the Day 1 of the Lead-in Phase immediately before 
avelumab/placebo administration.  Additional pregnancy tests (serum or urine) will also be routinely repeated prior to avelumab/placebo dosing during the 
CRT Phase and Maintenance Phases.  In addition, pregnancy tests will be performed whenever one menstrual cycle is missed or when potential pregnancy 
is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by Institutional Review Board (IRB)/Ethics Committees (ECs) or if 
required by local regulations.  Results of the pregnancy test should be evaluable prior to each dosing.
11. Urinalysis: Required only at Screening.  To be performed as clinically indicated at other time points.


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12. 12-Lead Electrocardiogram (ECG): All patients require a single ECG measurement at screening.  Triplicate ECGs will be collected in at least 30 patients 
in each treatment arm.  In these patients, on-treatment triplicate ECGs will be performed on the day of avelumab/placebo administration (ie, Day 1 of the 
Lead-in Phase, and Days 8, 25, and 39 of the CRT Phase; if the avelumab/placebo dosing day is shifted for patient scheduling reasons, the ECG assessment 
should be shifted also).  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) prior to avelumab/placebo administration and at the end of infusion.  Additional single ECGs may be performed as 
clinically indicated.  Clinically significant findings seen on ECGs during the treatment period should be recorded as adverse events.
13. HPV status will be determined per institutional standard using p16 immunohistochemistry (IHC).  HPV status (p16) assessed prior to screening window is 
allowed for study.
14. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  Imaging at screening (baseline) and at 12 weeks following 
completion of CRT must include a head and neck computed tomography [CT] or magnetic resonance imaging [MRI], chest CT, and Positron Emission 
Tomography (PET) scan. High resolution PET/CT does not require additional CT thorax/neck/brain.  MRI brain may be performed if clinically indicated. 
Other areas may be scanned as clinically indicated.  The CT and MRI scans should be performed with contrast agents unless contraindicated for medical 
reasons.  The same imaging technique(s) used to characterize each identified and reported lesion at baseline will be employed in the following tumor 
assessments.  At minimum, the CT modality used at baseline will be the expected imaging technique for follow-up.  Any clinical progression concern 
warranting a biopsy must have supporting imaging (ie, CT, MRI, PET, or digital photograph) archived for documentation purposes.  Additional imaging 
modalities may also be employed if clinically required.  Radiographic and clinical evaluations will be conducted with the same schedule in both treatment 
arms of the study. The investigator will assess antitumor activity based on radiological assessments and clinical evaluation of patients using modified 
RECIST v1.1 at baseline, 12 weeks after the completion of CRT, every 16 weeks thereafter for 48 months (208 weeks), and every 24 weeks thereafter until 
confirmed disease progression per modified RECIST v1.1 and regardless of discontinuation of study treatment or initiation of subsequent anti-cancer 
therapy.  Radiological tumor assessments will also be conducted whenever disease progression is suspected (eg, symptomatic deterioration or physical exam 
findings suggestive of mucosal recurrence).  The assessment performed 12 weeks after completion of the CRT is to include CT and PET for all patients and 
MRI also if clinically appropriate to delineate the extent of the local tumor.  Subsequent scans are to include CT of the head and neck and thorax.  In the 
case of negative PET in patients who did not achieve clinical or CT/MRI-based radiological nodal CR at the tumor assessment performed 12 weeks 
following completion of CRT, follow-up PET scans are recommended every 4 months (16 weeks) with the CT imaging for 24 months (104 weeks), then 
every 6 months (24 weeks) in Years 3-5. CT imaging should be obtained as described herein beyond Year 5. All radiographic images will be collected and 
stored for possible future objective verification by an independent third-party core imaging laboratory (central review) as described in the Study Manual.  
Photographs of clinical progression will also be collected for potential future review. Baseline tumor assessments should be done within 28 days prior to 
randomization. 
15. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  For serious adverse events (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 study treatment, through and including 90 calendar days after the last administration of the study treatment.  
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 study treatment are to be reported to the sponsor. 
AEs (serious and non-serious) should be recorded on the Case Report Form (CRF) from the time the patient has initiated any study treatment through and 
including 90 calendar days after the last administration of study treatment. 
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 study treatment, irrespective of any intervening treatment.


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16. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded for all patients from 28 days prior to the start of study 
treatment and up to 90 days after the last dose of study treatment or until the start of new therapy, whichever comes first.  All concomitant medications and 
non-drug supportive interventions should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis, infusion 
reaction prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions). 
17. Patient-Reported Outcomes: All scheduled assessments of the NCCN FHNSI-22, EQ-5D-5L, 
must be completed in the clinic by the 
patient prior to any other study or medical procedures - these cannot be taken home.  PRO assessments should be conducted during scheduled clinic visits
(Q16W through 48 months) and do not require additional clinic visits. Subsequent PRO assessments will be Q24W until PD.
 
 
18. Randomization: An interactive voice and web response system (IVRS) will be used for randomization to a treatment arm.  Required information: site and 
patient identifiers, and demographic information.  Patients meeting all entry criteria will be randomized and will be administered the first dose of study 
treatment preferably on the day of randomization, but no later than 3 days after randomization.
Study Treatment: 
Arm A: Avelumab + SOC CRT
Arm B: Placebo + SOC CRT 
In both treatment arms, study treatment will be initiated with a Lead-in avelumab/placebo Phase followed by a Chemoradiotherapy (CRT) Phase and a 
Maintenance Phase.  In both arms, BSA must be calculated prior to each cisplatin administration and patient must be weighed prior to each 
avelumab/placebo administration.  Specific therapies to be administered include the following:
•
Lead-in Phase: avelumab 10 mg/kg (Arm A) or placebo (Arm B) administered on Day 1 (7 days prior to the start of the CRT phase).
•
CRT Phase: avelumab 10 mg/kg (Arm A) or placebo (Arm B) administered on Days 8, 25, and 39 in combination with cisplatin 100 mg/m2 on 
Days 1, 22, and 43 plus intensity modulated-radiation therapy (IMRT) 70 Gy/35 fractions/7 weeks; 1 fraction/day, 5 fractions/week.
Cisplatin should be administered on a Monday or Tuesday if feasible to maximize overlap with IMRT. The Day 43 dose of cisplatin can be 
given any time up to 5 days after the end of radiation therapy.
•
Maintenance Phase: avelumab 10 mg/kg (Arm A) or placebo (Arm B) administered Q2W for 12 months.  The Maintenance Phase starts following 
completion of CRT Phase (ie, 2 weeks following completion of CRT).
Patient weight should be verified prior to dose calculation for each of the study treatments.
See Section 5.5.1.5 and 5.5.2.1 for mandatory premedications to be administered with avelumab/placebo and cisplatin, respectively.
19. Avelumab Pharmacokinetics: Blood samples (3.5 mL) for avelumab PK will be collected in all patients: pre-dose (within 2 hours before the start of 
avelumab/placebo infusion) and at the end of infusion (immediately before until 10 minutes after the end of avelumab/placebo infusion) on Days 1 of the 
Lead-in Phase and Days 8, and 25 of the CRT Phase.
20. Cisplatin Pharmacokinetics: Blood Samples (5 ml) for cisplatin PK (total and free) will be collected in a total of 24 patients (12 patients in Arm A and 
12 patients in Arm B) at selected sites at pre-dose, mid-infusion, end of infusion (immediately before the end of cisplatin infusion), and 3, 4, and 24 hours 
post start of cisplatin infusion on Day 1 of the CRT Phase.
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21.
 
 
 
22. Mandatory Tumor Tissue: An archival formalin fixed, paraffin embedded (FFPE) tumor tissue block from the most recent tumor resection or biopsy must 
be provided for all patients enrolled in the study and submitted to the Central Laboratory prior to randomization.  If an FFPE tissue block cannot be 
provided, 15 unstained slides (10 minimum) will be acceptable. Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell 
pellet material), is not adequate and should not be submitted.  Tumor tissue collected in China (via slides) will not be retained and will be examined for PD-
L1 expression and CD8 lymphocyte infiltration by immunochemistry, tumor mutational burden, and immune repertoire by TCR analysis.
23. Optional De Novo Tumor Biopsy – Lead-in Phase: An optional tumor biopsy, to be collected 4 to 7 days following the single dose of avelumab in the 
Lead-in Phase, is requested for analysis of potential biomarkers of response.  The de novo biopsy should be FFPE per routine (see Study Manual), and the 
resulting tissue block(s) submitted to the central laboratory.
24. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): One blood sample (3.5 mL at each time point) for ADA 
will be collected at pre-dose on Day 1 of the Lead-in Phase, and Days 8, and 25 of the CRT Phase.  All samples should be drawn within 2 hours before the 
start of avelumab or placebo infusion.  All samples that are positive for ADA may also undergo characterization for Nab.
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Table 3.
SCHEDULE OF ACTIVITIES – Maintenance Phase, End of Treatment/Withdrawal, and Short-/Long-Term 
Follow-up Periods
Visit Identifiers1 -- Study Treatment --
------------------------------------ Post-Treatment ------------------------------------
Protocol Activities
Maintenance Phase*
(1 cycle = 4 weeks)
End of Treatment 
(EOT)/
Withdrawal
(+3 days)2
Follow-up3
Day 1
(3 days)
Day 15
(3 days)
Short-Term (after last dose or EOT/Withdrawal Visit)
Long-Term
(+ 14 days)
30 days
(3 days)
90 days Follow-up 
Telephone Contact*
(3 days)
Documentation
Physical Examination4
X
X
Contraception Check 
X
X
X
ECOG Performance Status
X
X
X
Vital Signs5
X
X
X
Laboratory Studies
Hematology & Blood Chemistry6
X
X
X
X
Coagulation6
If clinically indicated
X
If clinically indicated
Thyroid Function Tests and 
ACTH7
X (then Q8W)
X
X
Pregnancy Test8
X
X
X
X
Urinalysis9
If clinically indicated
X
If clinically indicated
12-lead ECG10
If clinically indicated
X
Disease Assessments
Tumor Assessments (including 
scans)11
X (12 weeks after completion of CRT, then Q16W for 48 months, then Q24W until PD per modified RECIST v1.1;
additional assessment to be performed at the EOT/Withdrawal Visit)
Other Clinical Assessments
Adverse Events12
X
X
X
X
Concomitant 
Medications/Treatments13
X
X
X
X
Initiation of New Systemic 
Anticancer Treatment
X
X
X
X
Survival Assessment14
X


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Table 3.
SCHEDULE OF ACTIVITIES – Maintenance Phase, End of Treatment/Withdrawal, and Short-/Long-Term 
Follow-up Periods
Visit Identifiers1 -- Study Treatment --
------------------------------------ Post-Treatment ------------------------------------
Protocol Activities
Maintenance Phase*
(1 cycle = 4 weeks)
End of Treatment 
(EOT)/
Withdrawal
(+3 days)2
Follow-up3
Day 1
(±3 days)
Day 15
(±3 days)
Short-Term (after last dose or EOT/Withdrawal Visit)
Long-Term
(+ 14 days)
30 days
(±3 days)
90 days Follow-up 
Telephone Contact*
(±3 days)
Patient-Reported Outcomes 
NCCN FHNSI-22, EQ-5D-5L, 
, and
5
X (Day 1 Cycle 1 and Day 1 Cycle 3 of the Maintenance Phase, 
then Q16W for 48 months, then Q24W until PD per modified RECIST v1.1;
additional assessment to be performed at the EOT/Withdrawal Visit)
Study Treatments
Avelumab or Placebo16
X
X
Other Samplings
Avelumab Pharmacokinetics17
X
X
X
Banked Blood Biospecimens18
X (Cycle 1 
Day 15 
only)
X
De Novo Tumor Biopsy19
X
X
Anti Avelumab Antibodies and 
Neutralizing Antibodies20
X
X
X
ACTH = adrenocorticotropic hormone; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed and 
paraffin-embedded HBV = hepatitis B virus; HCV = hepatitis C virus; HPV = human papillomavirus; 
, 
 PK = pharmacokinetics; Q2W = every 2 weeks; Q12W = every 12 weeks; Q16W = every 16 weeks; 
Q24W = every 24 weeks. 
* Maintenance Phase: Maintenance Phase to start following completion of the CRT Phase and to be 12 months in duration.  Study assessment window of 
±3 days starting from C1D15.  CRT phase may be extended as required for patient recovery from CRT; however, it is hypothesized that patients will receive 
maximal benefit from beginning maintenance as close to the scheduled time as possible.
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Footnotes for Schedule of Activities FOR MAINTENANCE PHASE, END OF TREATMENT/WITHDRAWAL, AND SHORT-/LONG-TERM 
FOLLOW-UP PERIODS
1.
Visit Identifiers: Acceptable time windows for performing each assessment are described in the column headers.  
2.
End of Treatment/Withdrawal: Visit to be performed within 3 days following the last dose of study treatment received.  Obtain these assessments if not 
completed within 7 days prior to the EoT/Withdrawal visit, except for tumor assessments and patient-reported outcome questionnaire assessments, which 
need not be repeated if they have been performed within the prior 6 and 4 weeks, respectively. Patients who complete the maintenance phase and proceed to 
follow up will follow the prespecified timelines described in the table above. EoT/Early withdrawal imaging (if more than 6 weeks ago) and questionnaire 
assessments (if more than 4 weeks ago) relate only to patients who discontinue early, and refuse follow up.
3.
Short- and Long-Term Follow-up: All patients will be followed for safety with evaluations at 30 days after the last study treatment administration or until 
the time of initiation of new systemic anticancer treatment.  The Day 90 Short-Term Follow-up Visit will be conducted as a phone call.  If any concern 
arises, the patient will be called in for a follow-up visit within 5 calendar days for appropriate assessments (as per the investigator’s medical judgement).
Beyond the Day 90 Short-Term Follow-up Visit, all patients will be followed every 16 weeks (Q16W) for survival (additional survival follow up 
information may be requested) and new systemic anticancer treatment within the long-term follow-up period.  Patients who refuse to return to the site for 
evaluations should be contacted by telephone as an alternative.  
4.
Physical Examination: Includes an examination of major body systems and weight. 
5.
Vital Signs: Vital signs to include blood pressure and pulse rate.  Blood pressure and pulse rate should be taken with the patient in the seated position after 
the patient has been sitting quietly for at least 5 minutes.
6.
Hematology, Blood Chemistry, and Coagulation: Hematology and core blood chemistry to be performed prior to each administration of 
avelumab/placebo, and at the EOT/Withdrawal and 30-day Short Term Follow-Up visits.  Coagulation to be performed when clinically indicated. Full 
chemistry panel is required at End of Treatment/Withdrawal. All laboratory assessments may be performed and results reviewed by the treating physician 
up to 1 business day prior to study drug administration. 
7.
Thyroid Function Tests: Free T4, TSH, and ACTH will be performed on Day 1 and then every 8 weeks thereafter during the Maintenance Phase, and at 
the End of Treatment/Withdrawal and 30-day Short Term Follow-up visits after the last administration of study treatment unless performed in the prior 
8 weeks.  
8.
Serum/Urine 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 prior to each avelumab/placebo administration during the Maintenance Phase, and at the End of Treatment/Withdrawal and 30-day Short Term 
Follow-up visits, and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests 
may also be undertaken if requested by Institutional Review Board (IRB)/Ethics Committees (ECs) or if required by local regulations.
9.
Urinalysis: Required only at the End Of Treatment/Withdrawal.  To be performed as clinically indicated at other time points.
10. 12-Lead Electrocardiogram (ECG): Additional single ECG measurements may be performed as clinically indicated.  For End of Treatment/Withdrawal, a 
single ECG measurement will be obtained for all patients.  Clinically significant findings seen on ECGs should be recorded as adverse events. 


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11. Tumor Assessments: Tumor assessments will include all known or suspected disease sites.  The CT and MRI scans should be performed with contrast 
agents unless contraindicated for medical reasons.  The same imaging technique(s) used to characterize each identified and reported lesion at baseline will 
be employed in the following tumor assessments.  At minimum, the CT modality used at baseline will be the expected imaging technique for follow-up.  
Additional imaging modalities may also be employed if clinically required. Radiographic and clinical evaluations will be conducted with the same schedule 
in both treatment arms of the study. The investigator will assess antitumor activity based on radiological assessments and clinical evaluation of patients 
using modified RECIST v1.1 12 weeks after the completion of CRT, every 16 weeks thereafter for 48 months (208 weeks), and every 24 weeks thereafter 
until confirmed disease progression per modified RECIST v1.1 and regardless of discontinuation of study treatment or initiation of subsequent anti-cancer 
therapy. Radiological tumor assessments will also be conducted whenever disease progression is suspected (eg, symptomatic deterioration or physical exam 
findings suggestive of mucosal recurrence).  The assessment performed 12 weeks after completion of the CRT is to include CT and PET for all patients and 
MRI also if clinically appropriate to delineate the extent of the local tumor. Subsequent scans are to include CT of the head and neck and thorax.  In the 
case of negative PET in patients who did not achieve clinical or CT/MRI-based radiological nodal CR at the tumor assessment performed 12 weeks 
following completion of CRT, follow-up PET scans are recommended every 4 months (16 weeks) with the CT imaging for 24 months (104 weeks), then 
every 6 months (24 weeks) in Years 3-5.  CT imaging should be obtained as described herein beyond Year 5. The time window for tumor assessments is 
±1 week except for the assessment at week 12 which cannot be done earlier but up to one week later. 
12. Adverse Events: Adverse events (AE) should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03.  For serious adverse events (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 study treatment, through and including 90 calendar days after the last administration of the study treatment.  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 study treatment are to be reported to the sponsor.
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 study treatment 
through and including 90 calendar days after the last administration of the study treatment. 
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 study treatment, irrespective of any intervening treatment.
13. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded for all patients from 28 days prior to the start of study 
treatment and up to 90 days after the last dose of study treatment or until the start of new therapy, whichever comes first.  All concomitant medications and 
non-drug supportive interventions should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis, infusion 
reactions prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions). 
14. Survival Assessment: All patients will be followed for survival and subsequent anticancer therapies every 16 weeks until death, end of the study, or patient 
withdrawal of consent, whichever comes first.  For patients refusing to return to the site, a telephone follow-up call is acceptable. Additional survival 
information may be requested in preparation for interim and final analyses.
15. Patient-Reported Outcomes: All scheduled assessments of the NCCN FHNSI-22, EQ-5D-5L, 
 must be completed in the clinic by the 
patient prior to any other study or medical procedures - these cannot be taken home. PRO assessments should be conducted during scheduled clinic visits 
(Q16W through 48 months) and do not require additional clinic visits. Subsequent PRO assessments will be Q24W until PD. 
 
  
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16. Study Treatment: 
Arm A: Avelumab + SOC CRT
Arm B: Placebo + SOC CRT 
•
Maintenance phase: avelumab 10 mg/kg (Arm A) or placebo (Arm B) administered Q2W for 12 months.  The Maintenance Phase starts following 
completion of CRT Phase.
Patient weight should be verified prior to dose calculation for each of the study treatments.
During the Maintenance Phase, avelumab/placebo may be administered up to 3 days before or after the scheduled treatment day of each cycle for 
administrative reasons, except for C1D1. Maintenance C1D1 is defined as the day when the first avelumab/placebo is given; therefore there is no window 
required as it defines the beginning of maintenance whenever the infusion is given.
17. Avelumab Pharmacokinetics: Blood samples (3.5 mL) for avelumab PK will be collected in all patients: pre-dose (within 2 hours before the start of 
avelumab/placebo infusion) and at the end of infusion (immediately before the end until 10 minutes after avelumab/placebo infusion) on Day 1 of Cycles 1 
and 2 of the Maintenance Phase.  Thereafter, a pre-dose sample will be taken every 3 cycles (eg, Cycles, 5, 8, 11) while a patient remains on treatment.  A 
single sample will be taken at both EOT and 30 days post-EOT.
18.
 
 
 
 
 
19. De Novo Tumor Biopsy: A de novo (ie, fresh biopsy) tumor sample should also be collected at the End of Treatment/Withdrawal visit, unless clinically 
contraindicated or no tumor remains.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including formalin fixed, paraffin embedded [FFPE] 
cell pellet material), is not adequate and should not be submitted.  The de novo biopsy should be formalin-fixed and paraffin-embedded as per routine (see 
Study Manual), and the resulting FFPE tissue block(s) should be submitted to the Central Laboratory.  For patients who, during the course of the study, 
undergo a clinically-indicate tumor resection procedure, a tumor sample from the procedure should be collected and submitted to the Central Laboratory.  
The tumor sample obtained during the Maintenance Phase should be FFPE as per routine (see Study Manual) and the resulting FFPE tissue block(s) should 
be submitted to the Central Laboratory.
20. Anti-Avelumab ADAs and Nab: One blood sample (3.5 mL) for anti-avelumab antibodies will be collected at on Day 1 of Cycles 1 and 2 of the 
Maintenance Phase.  All samples should be drawn within 2 hours before the start of avelumab or placebo infusion.  Thereafter a pre-dose sample will be 
taken every 3 cycles (eg, Cycles 5, 8, 11) while a patient remains on treatment.  A single sample will be taken at both EOT and 30 days post-EOT.  All 
samples that are positive for ADA may also undergo characterization for Nab.
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1. INTRODUCTION 
1.1. Mechanism of Action/Indication
Avelumab1 (also referred to as MSB0010718C) is a fully human immunoglobulin (Ig) G1 
antibody directed against programmed death ligand 1 (PD-L1).  Avelumab binds PD-L1 and 
blocks the interaction between PD-L1 and its receptors programmed death 1 (PD-1) and 
B7-1.  This removes the suppressive effects of PD-L1 on anti-tumor CD8+ T cells, resulting 
in the restoration of a cytotoxic T-cell response.  In addition, avelumab may mediate 
antibody-dependent cell-mediated cytotoxicity (ADCC) in certain settings via engagement of 
activating FcRs on cytotoxic natural killer cells and macrophages. 
Radiation therapy is a core treatment modality in cancer therapeutics.  Ionizing radiation 
causes cell death through the generation of free oxygen radicals, DNA double strand breaks 
and resulting mitotic catastrophe.  The tumor is targeted, and normal tissue relatively spared 
through physical means including imaging based target identification and the use of intensity 
modulated radiation therapy that enable radiation treatment planning to limit normal tissue 
dosing.  Cisplatin is added to the definitive radiation therapy in the treatment of head and 
neck cancers as a radiation sensitizing agent and has proven effective at improving OS, by, 
on average, 6.5% at 5 years.36  
The dominant mode of action of cisplatin appears to be inhibition of the incorporation of 
deoxyribonucleic acid (DNA) precursors, although protein and RNA synthesis are also 
inhibited.  Although this drug seems to act as an alkylating agent, there are data to indicate 
that its mode and sites of action are different from those of nitrogen mustard and the standard 
alkylating agents.37
The mechanism of action of avelumab is further described in Section 1.2.2. 
The indication under study is the front-line therapy of patients with locally advanced 
squamous cell carcinoma of the head and neck (SCCHN, oral cavity, oropharynx, larynx, or 
hypopharynx) who are eligible for definitive chemoradiotherapy (CRT) with cisplatin.
1.2. Background and Rationale
1.2.1. Head and Neck Cancer
Head and neck cancers, including cancers of the oral cavity, nasopharynx, pharynx, and 
larynx, account for approximately 5% of cancers worldwide (excluding non-melanoma skin 
cancers).9  Approximately 680,000 new cases of head and neck cancer were diagnosed in 
2012 with 370,000 deaths attributed to this disease; of these new cases reported, almost 
140,000 were in Europe, and over 90% were squamous cell histology.10  In the US, it is 
estimated that over 61,000 people will be diagnosed with head and neck cancer in 2016 and 
over 13,000 will die from this cancer.62  Head and neck cancers are predominately squamous 
                                                
1 Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-L1 monoclonal 
antibody (MSB0010718C)


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carcinomas.  SCCHN involving the oral cavity, larynx, oropharynx, and hypopharynx 
account for 75% SCCHN overall and are closely associated with alcohol and tobacco use.  
SCCHN of the oropharynx is also closely associated with HPV type 16 infection.11  In the 
past 2 decades, HPV-positive oropharyngeal cancers have increased dramatically especially 
in North America, underscoring an important role in HPV infection and oropharyngeal 
cancer.12 Although the incidence of HPV-negative SCCHN has decreased, consistent with 
decreasing use of tobacco products worldwide, the curability of HPV-negative tumors 
remains suboptiomal.43
Of newly-diagnosed patients with SCCHN, approximately 60% present with locally or 
regionally advanced disease.10,13 Combination modality therapy is generally employed for 
these patients and may include surgery with adjuvant radiotherapy for early stage disease 
and/or concurrent CRT which is standard for more advanced disease.10,14  The most widely 
used standard regimen used in this setting consists of 100 mg/m2 cisplatin administered every 
3 weeks (Q3W), combined with ~70 Gy radiation delivered in 1.8-2.0 Gy daily fractions.  
Although associated with increased local control rates and overall survival (OS) compared to 
radiotherapy alone, this combination is also associated with increased toxicity.  Additionally, 
depending on the tumor site, stage, and resectability, locoregional failure rates can range 
between 35% and 65%.10,13  With a median PFS of 1.9 years and reported 3-year PFS rate of 
61.2%, this disease will ultimately recur locally in a large proportion of treated patients, with 
distant metastases developing in 10% to 30% of these patients.13,44,57 Currently available 
treatment options for both locoregional and distant recurrences are limited. Outcomes for 
both groups of recurrences are abysmal, and the limited number of patients who are eligible 
for potentially curative treatment for locoregional disease, are exposed to a high degree of 
morbidity.
Treatment options for patients with recurrent SCCHN are limited to palliative chemotherapy 
and, in patients suitable for more aggressive treatment, combination systemic chemotherapy 
regimens.10  Response rates to single-agent chemotherapy range from 15% to 35%, with a 
median OS of 6 months. With combination therapy, response rates vary from 26% to 36% 
with a median OS of 10.1 months.  Recently presented data on single agent PD-1 blockage in 
the cisplatin refractory group (progression within 6 months of prior cisplatin therapy) is 
encouraging relative to chemotherapy, but median OS is still only 7.5 months.55  Thus, the 
primary treatment of the presenting SCCHN is critical for both the prevention of highly 
morbid secondary local therapy and the prevention of metastatic disease.  There remains an 
unmet medical need for improved therapy for high–risk locally advanced SCCHN. 
1.2.2. Avelumab Clinical Experience
Avelumab (MSB0010718C) is a fully human monoclonal antibody (mAb) of the 
immunoglobulin (Ig) G1 isotype.
PD-L1 is expressed by a variety of human tumors, both by the tumor cells, as well as by the 
immune cells that are present in the tumor microenvironment.1 High levels of PD-L1 
expression have been found to be associated with disease progression, increased metastases, 
poor response to treatment, and decreased survival in a number of human cancers.1
Importantly, anti-PD-L1 blockade has demonstrated therapeutic efficacy in a variety of 


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murine tumor models as monotherapy and has shown synergistic effect in the combination 
therapy setting.2,3,4,5,6,7,8
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 programmed death ligand 2 (PD-L2)/PD-1 
pathway intact to promote peripheral self-tolerance.15,16
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial cancer, and 
Hodgkin’s Lymphoma, as single agent or in combination with chemotherapy, tyrosine kinase 
inhibitors, 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.
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%). 


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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 glutamyltransferase 
(GGT) increased (0.6%), infusion related reaction (0.6%), and aspartate aminotransferase 
(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, alanine 
aminotransferase (ALT) increased, blood creatinine phosphokinase (CPK) increased, lipase 
increased, arthralgia, and pneumonitis (0.2% each).
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 


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the pooled safety dataset included 1 case of fatal immune-related myocarditis in Study 
B9991002 (avelumab in combination with axitinib for renal cell carcinoma (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.
As required per protocol, the first eDMC review occurred after 30 patients had been 
randomized, treated, and followed for at least 12 weeks. At the time of the data cutoff a total 
of 78 patients had been randomized and 77 had received at least one dose of study treatment.  
The eDMC reviewed unblinded data.  The Sponsor does not have access to 
unblinded data/data summarized by treatment arm.  The eDMC recommended that the study 
proceed after reviewing unblinded safety data.  The DMC had no requests for changes to the 
protocol or study conduct.
Of the 78 patients randomized in the study, 75 patients (96.2%) had entered the CRT phase, 
49 (62.8%) finished cisplatin treatment phase and 26 (33.3%) were ongoing.  Amongst the 
72 patients who started cisplatin the median number of cisplatin infusions received was 
2 (range: 1.0-3.0).
Patients that came off of protocol therapy during the CRT phase all completed SOC CRT off 
protocol, with the exception of a single patient who, for personal reasons, elected to stop all 
therapy against medical advice.  For the patients who completed IMRT, the median total dose 
of IMRT was the protocol expected dose of 70 Gy (range: 40.0-70.0) (the individual who had 
40 Gy on study completed IMRT to 70 Gy off of study).  Overall AE profile was consistent 
with the known AE profile of CRT.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the avelumab investigator’s brochure.


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1.2.2.1. Clinical Experience in Patients with Carcinomas Treated with Platinum-Based 
Chemotherapy
Avelumab is being evaluated in patients with SCCHN in a tumor-specific expansion cohort 
of study EMR100070-001. In this expansion cohort, 93 recurrent or metastatic SCCHN 
patients, who have received 1 line of platinum-based chemotherapy, or are ineligible for 
platinum-based treatment, have received at least 1 dose of avelumab. 
The overall safety profile among the 93 patients enrolled in the SCCHN cohort of Study 
EMR100070-001 was comparable to the safety profile described above.
In the SCCHN cohort, TEAEs were reported in 78.5% of patients and treatment-related 
TEAEs were reported in 44.1%.  Four Grade 3 treatment-related TEAEs were reported in 
3 (3.2%) patients and included one event each of dyspnea, vomiting, diarrhea, and 
hypophosphatemia.  There were no Grade 5 events in the SCCHN cohort. 
Immune-mediated TEAE assessed as related to avelumab by the investigators were reported 
in 3 (3.2%) patients and included hypothyroidism in 2 patients and hyperthyroidism in 
1 patient.  IRR were reported at a lower rate in the SCCHN cohort (8.6%) compared to the 
pooled expansion cohort (16.2%).  There were no Grade 3 infusion-related reactions 
reported in the SCCHN cohort.  The overall rate of TEAEs leading to treatment 
discontinuation in the SCCHN was 5.4% compared to 13.5% in the pooled expansion cohort 
and there were no TEAEs leading to treatment discontinuation that were assessed by the 
investigators as related to avelumab.
For the SCCHN expansion cohort, the efficacy data are still immature; however, as of 
9 September 2015 for the 22 patients with at least 13 weeks of follow-up from start of 
avelumab treatment, the response rate (including unconfirmed partial response [PR]) was 
18.2% (4/22 patients).
For the NSCLC expansion cohort, 6 months after start of avelumab treatment of the last 
patient in this expansion cohort (15 January 2015), the response rate (including confirmed 
and unconfirmed complete response [CR] and PR) was 14.1% (26/184 patients). The median 
progression-free survival (PFS) for the NSCLC cohort was 11.6 weeks (95% CI: 8.4 to 
13.7 weeks). The median OS was 8.4 months. 
For the ovarian cancer expansion cohort, 13 weeks (13 February 2015) after start of 
avelumab treatment of the last patient included in the interim analysis of this expansion 
cohort, the response rate (including confirmed and unconfirmed CR and PR) was 10.7% 
(8/75 patients).  The median PFS for the ovarian cancer cohort was 11.4 weeks (95% CI: 6.3 
to 12.0 weeks).
In summary, preliminary data from the ongoing EMR100070-001 study in SCCHN patients 
who have received 1 line of platinum-based chemotherapy or who were platinum ineligible 
demonstrate that avelumab has antitumor activity in SCCHN.  Further, avelumab has also 
shown antitumor activity in NSCLC and ovarian cancer in patients who had disease 
progression after prior platinum-based therapy.


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1.2.2.2. Pharmacokinetics of Avelumab in Humans
Avelumab pharmacokinetics and dose proportionality following the first 1-hour infusion 
have been characterized in 77 Caucasian patients treated in the dose escalation and expansion 
cohorts of Trial EMR100070-001 by standard non-compartmental analysis.  This analysis 
revealed that the exposure parameters of maximum concentration (Cmax) and area under the 
concentration-time curve to the end of the dosing period (AUCτ) increased in a dose 
proportionate fashion for the 10 and 20 mg/kg doses.  The half-life of avelumab tended to 
increase with dose, likely due to target mediated disposition at lower doses (1 and 3 mg/kg), 
but terminal half-life of 10 mg/kg (102 28 hours) and 20 mg/kg (120 42 hours) doses 
were similar, taking into account the PK variability.  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 8 healthy volunteers with 
avelumab over a concentration range 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.
Pharmacokinetic profiles obtained during the dose escalation phase of Trial EMR100070-001 
were utilized to investigate whether this concentration of at least 1 g/mL was achieved 
throughout the dosing interval. The median standard deviation trough concentration 
(Ctrough) at the end of the first cycle after administration of the 10 mg/kg dose is 
21 12 μg/mL (n=283). This median Ctrough increases during the subsequent cycles to 
25 16 μg/mL (second cycle) (n=269), 27 17 g/mL (third cycle) (n=202), and remains 
between 27 and 36 g/mL during the subsequent cycles (n=55–171).
Complete information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab Investigator’s Brochure (IB).17
1.2.3. Study Rationale
1.2.3.1. Rationale for Combining Avelumab with Chemoradiotherapy
There are emerging data supporting the rationale for combinations of immune checkpoint 
inhibitors with chemotherapy.18,19  Chemotherapy has been shown to have 
immunostimulatory properties by stimulating the release of neoantigens and adjuvants by 
dying cells, increasing susceptibility to immune attack, and preferentially reducing 
immunosuppressive cells such as T regulatory cells.20,21,22,23  Certain chemotherapy agents 
including platinum-based agents are mutagenic.24  Therefore, treatment with chemotherapy 
may create a pro-immunogenic, hypermutated state that may be optimal for activity of 
immune checkpoint inhibitors.  In preclinical studies, the combination of avelumab with 
chemotherapy (gemcitabine, oxaliplatin, 5-fluorouracil) showed improved anti-tumor activity 
over single-agent chemotherapy.17  
Several immune checkpoint inhibitors have been combined with chemotherapy agents.  The 
addition of ipilimumab to dacarbazine led to an improvement in PFS and OS in previously 
untreated melanoma compared to dacarbazine alone.25  Ipilimumab was combined with 


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platinum doublet chemotherapy in small cell as well as NSCLC with encouraging results.26,27  
Single-arm studies investigating the combination of PD-1 blockers (pembrolizumab, 
nivolumab) as well as a PD-L1 blocker (atezolizumab) with platinum doublet chemotherapy 
demonstrated acceptable safety profiles with early evidence of clinical activity which appears 
to be higher than expected for platinum doublet therapy alone, particularly for 
atezolizumab.27,28,29,30,31  Randomized Phase 3 studies in the first-line treatment of NSCLC 
patients are currently investigating the addition of pembrolizumab and atezolizumab to 
platinum-based chemotherapy.
There is also emerging evidence indicating that the response to chemotherapy is partly 
dependent on an immunological reaction against tumor cell death during treatment with 
chemotherapy.32,33  Some chemotherapy agents have been shown to mediate "immunogenic" 
cancer cell death by activation of the immune system via release of high-mobility- group 
box 1 (HMGB1) and subsequent immune cell activation.  These data suggest that there may 
also be a therapeutic interaction between chemotherapy and avelumab that may provide 
additional clinical benefit to that anticipated between radiation therapy (RT) and avelumab, 
as discussed below.
In addition to the data supporting combining immune checkpoint inhibitors with 
chemotherapy, a strong body of evidence supports the combination of RT with 
immunotherapy such as a PD-L1 inhibitor.34,35  Radiation alone can modify the immune 
response in several ways to allow for synergistic effects when combined with 
immunotherapy, including 1) enhancement of major histocomopatibility complex (MHC) 
class I surface expression, calreticulin expression, and release of HMGB1; 2) enhancement of 
Fas cell surface receptor (FAS) surface expression; 3) activation of dendritic cells and 
enhancement of cross-presentation of tumor antigens; 4) increased density of 
tumor-infiltrating lymphocytes; and 5) the modulation of immune checkpoint molecule 
expression.35  When combined with checkpoint blockade immunotherapies such as 
anti-cytotoxic T-lymphocyte associated protein (CTLA-4) and anti-PD-L1, improved local 
and systemic disease control was observed in several preclinical studies.  Additionally, 
treatment with low doses of fractionated radiotherapy was demonstrated to lead to the 
upregulation of PD-L1 expression on tumor cells secondary to CD8+ T-cell production of 
intereferon (IFN)-and inhibit the antitumor response.  Concomitant administration of an 
anti-PD-L1 mAb resulted in enhanced efficacy of radiotherapy in several mouse models of 
melanoma, colorectal, and breast cancer.35  In particular, RT in combination with avelumab 
was found to be highly synergistic, capable of causing complete regression of established 
tumors with the potential to generate antitumor immune memory.17
There are currently several studies ongoing evaluating immune checkpoint inhibitor agents in 
later lines of treatment for SCCHN patients.  These trials have demonstrated activity in this 
tumor type for this class of drugs when used as single agents for patients with recurrent or 
metastatic disease.  Nivolumab, in the CheckMate-141 study in platinum-refractory patients 
in the recurrent or metastatic setting, has demonstrated an improved OS relative to alternative 
investigator-choice chemotherapy at 7.5 (95% confidence interval [CI]: 5.5 – 9.1) vs 5.1 
(95% CI: 4.0 – 6.0) months (HR 0.70, 97.73% CI: 0.51 – 0.96) and was stopped early by the 
data monitoring committee (DMC).  Updates presented at the ASCO 2016 Annual Meeting 
described the activity in subgroups of patients with tumors that were p16 positive (N=63 HR 


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0.56, 95% CI: 0.32 - 0.99) or negative (N=50, HR 0.73, 95% CI: 0.42 - 1.25) and those 
whose tumors were positive for PD-L1 staining at 1% (HR: 055; 95%CI: 0.36-0.83) vs. 
1% (HR: 0.89 95% CI: 0.54-1.45).59  Also at ASCO, updated efficacy data for 
pembrolizumab in recurrent/metastatic SCCHN (KEYNOTE-012) was presented.  An overall 
objective response rate (ORR) of 18% (34/192; 95% CI: 13-24%) was observed, with ORR 
of 24% (11/45, 95% CI: 13 - 40%) and 16% (23/147, 95% CI: 10 – 23%) in HPV-positive 
and HPV-negative patients, respectively.  However, the limited number of patients evaluated 
and overlapping 95% CIs preclude definitive conclusions regarding any role HPV or PD-L1 
status may play in response to checkpoint inhibitor treatments.  Additionally, it should be 
noted that both HPV groups had the same (n=4) number of patients with CR in the 
KEYNOTE-012 update.  Median time to response was 2 months, but several patients took 
substantially longer to respond (range: 2 - 17 months).  Median OS was 8 months (95% CI: 
6 – 10 months) in these heavily pretreated patients with 38% alive at 12 months.60,61  These 
trials provide strong early evidence that SCCHN represents a tumor type that is responsive to 
this class of agents.  Collectively, these data, the strong scientific rationale for radiation 
(which increases PDL-1 expression) and immune checkpoint inhibitor combinations, and the 
poor patient options if disease control is not obtained in front-line therapy, persuasively argue 
for progressing an immune checkpoint inhibiting agent into combination therapy with 
definitive CRT to provide an optimized, multimodality approach to treat this disease and help 
patients avoid the high morbidity and mortality associated with disease progression.  This 
combination can potentially overcome the treatment resistance that patients experience, in 
particular for HPV-negative tumors.43
1.2.3.2. Rationale for Chemoradiotherapy Dose
Definitive locoregional therapy combined with systemic chemotherapy is the current SOC 
for locally-advanced SCCHN based upon multiple randomized trials.10,13,44  Definitive 
radiation therapy treats the extent of local tumor, including any involved lymph nodes, and is 
combined with concurrent chemotherapy.  Radiation therapy dose for areas of gross tumor is 
defined by the maximally tolerated dose to the surrounding normal tissue and is commonly 
noted as 70 Gy/35 fractions/7 weeks; 1 fraction/day, 5 fractions/week.36  The optimal 
chemotherapy regimen is not defined, but cisplatin is the most commonly used agent and is 
known to be a radiosensitizing agent.  The delivery of chemotherapy in conjunction with 
radiation (vs. induction or adjuvant alone) is well supported by the individual patient data 
meta-analysis, MACH-NC (Meta-analysis of Chemotherapy in Head and Neck cancer), 
which reviewed almost 16,500 patients’ data and demonstrated an HR of 0.81 of CRT vs. 
definitive radiation alone, producing an absolute survival advantage of 6.5% at 5 years.  This 
was limited to concurrent chemotherapy and not shown for either induction or adjuvant.  
Thus, definitive radiation therapy with cisplatin administered Q3W at 100 mg/m2 is 
considered a SOC and is commonly used in clinical trials as such.
Complete information for cisplatin may be found in the SRSD, which for this study is the 
cisplatin package insert.37


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1.2.3.3. Rationale for Avelumab Dose and Schedule in Regards to CRT Regimens to be 
Evaluated
In this clinical trial, the avelumab dose will be 10 mg/kg administered as 1-hour IV infusions.  
Avelumab (or placebo) will be administered on Day 1 of the Lead-in Phase; Days 8, 25, and 
39 in conjunction with SOC CRT during the CRT Phase; and Q2W for 12 months during the 
Maintenance Phase. 
Avelumab 10 mg/kg Q2W is the recommended dosing regimen and has been administered to 
a total of 1738 patients in the ongoing dose-expansion phase of Study EMR100070-001 
(see Section 1.2.2 for details). 
1.2.3.3.1. Rationale for Concurrent Administration of Avelumab with CRT Followed by 
Maintenance with Avelumab
The combination of avelumab and radiation therapy with concurrent cisplatin has not been 
evaluated in nonclinical pharmacology, pharmacokinetics and metabolism, or toxicology 
studies.  However, a strong scientific rationale exists for combining avelumab with radiation 
therapy.17,18,19 The combination of anti-PD-L1 with commonly used cancer treatments, such 
as cytotoxic agents and RT, resulted in an improved anti-tumor activity in animal models as 
noted previously.  In particular, radiation therapy in combination with avelumab was found 
to be highly synergistic, capable of causing complete regression of established tumors with 
the potential to generate anti-tumor immune memory.17  
Multiple lines of evidence suggest that following immune checkpoint inhibition therapy 
(anti-PD-1, PD-L1, CTLA-4, or a combination thereof), T-cell mobilization and proliferation 
is evident in the periphery by approximately 14 days post-treatment and intratumorally by a 
median of 39 days post-treatment.38 Dosing avelumab 7 days prior to initiation of CRT 
(Day 1 of Lead-in Phase) may effectively activate and initiate expansion of T-cell 
populations which are receptive/reactive to antigens released by CRT and protect these 
sensitive T-cell populations from radiation by mobilizing them to the periphery, thereby 
maximizing the potential antitumoral response upon administration of CRT on Day 8 of the 
CRT Phase.
There is preclinical evidence of enhanced efficacy of PD-L1 agents with radiation when 
given concurrently that is greater than the benefit seen in the models when PD-L1 therapy is 
only initiated at the conclusion of RT; however, there is still benefit when the therapies are 
given sequentially over tumor control with RT alone.35,39 Therefore, the maximize potential 
benefit of the addition of avelumab to CRT, avelumab will be delivered in all 3 treatment 
settings where benefit may be achieved: the 1) Lead-in Phase, 2) CRT Phase, and 
3) Maintenance Phase.
The ideal schedule is neither known, nor are there studies that define the optimal length of 
maintenance therapy in this front-line treatment setting.  Also, in the metastatic setting, 
treatment duration is not well studied.  Most PD-1/PD-L1 regimens have been arbitrarily 
limited at 2 years of treatment.  Anecdotal evidence exists for long duration of response after 
discontinuation of treatment, as well as responses after re-treatment in patients who have 
progressed after initial benefit.  There are data supporting the concept of immune response 


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induction with the initial treatments, and then the maintenance phase prolongs and supports 
the immune memory development.58  Thus, a schedule was designed to dose avelumab for a 
sufficient length of time to enrich the likelihood of patient response, without being overly 
extended in the Maintenance Phase for multiple years as a substantial number of patients 
might have already achieved maximal response within the year of maintenance. 
1.2.3.4. Rationale for Selected Patient Population 
This study is designed to determine the effect of avelumab in combination with SOC CRT 
compared to SOC CRT alone for patients with high-risk disease and a relatively poor 
prognosis with current SOC.  The proposed patient population will include patients with 
previously untreated locally advanced SCCHN in the following stages: HPV-negative 
SCCHN patients with Stage III, IVa, or IVb disease, HPV-positive SCCHN patients from 
non-oropharyngeal sites with stage III, IVa, or IVb disease and high risk HPV-positive 
SCCHN patients with oropharyngeal SCCHN as evidenced by T4 or N2c or N3 disease. 
Although patients with an HPV-positive oropharyngeal tumor have an overall better 
prognosis than patients with an HPV-negative tumor and the same stage, the most advanced 
stages of HPV-positive locoregional disease, still carry a poor outcome with current SOC. 
Therefore, HPV-positive SCCHN patients with oropharyngeal T4or N2cor or N3 disease will 
be included, as SCCHN patients with these stages of disease are still considered high risk and 
with a poor prognosis based on a systematic review by ICON-S (International Collaboration 
on Oropharyngeal Cancer Network for Staging).40,41 HPV-related disease in other primary 
tumor locations is much less common and there are insufficient data to indicate that 
prognosis would be altered. These subgroups of patients are at highest risk for recurrence 
and therefore, represent appropriate populations for a clinical trial investigating additional 
treatment over SOC.
1.2.3.5. Rationale for Stratification Factors
The selection of randomization stratification factors for this study took into consideration 
both the size of the study and the prognostic impact of the factors on the primary endpoint.  
Tumor stage and nodal stage were selected as the randomization stratification factors for this 
study as each factor confers a different prognostic outcome for patients, which correlates 
directly with PFS.42
HPV status in oropharyngeal cancer is associated with a different prognostic outcome under 
current treatment SOC.41 Thus, this trial will only enroll patients with high-risk 
HPV-positive disease who have poor prognosis with current SOC. There are currently no 
data as to whether HPV status itself will impact responsiveness to immune checkpoint 
inhibition in combination with SOC CRT in this indication, although emerging response data 
from studies of single-agent immune checkpoint blockade in the recurrent/metastatic setting 
do not suggests such a difference.  As described previously, pembrolizumab was reported to 
have approximately a 25% ORR in the recurrent/metastatic setting, with ORRs of 
approximately 21% and 27% in patients with HPV-positive and HPV-negative disease, 
respectively.  No difference in response between patients with HPV-positive vs 
HPV-negative tumors were observed, although the overall number of patients evaluated in 
this study was small.  These data from the recurrent/metastatic treatment setting have limited 
applicability, as they do not account for the radiation impact, and are limited overall.  


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Preclinical data are equally uninformative.  Thus, stratifying on the basis of HPV status will 
ensure equal distribution of HPV-positive SCCHN patients in each treatment arm should any 
differential impact of immune checkpoint inhibition with SOC CRT exist.
1.2.3.6. Rationale for Endpoints
Cancers of the head and neck region are somewhat unusual in their relative accessibility for 
direct observation of response or recurrence that may not be as clear on radiologic imaging.  
Disease recurrence may be visible on inspection of the head and neck mucosal surfaces that 
does not cause any radiologically visible changes.  Conversely, radiologic changes may occur 
that arise as a consequence of acute tissue response to local therapy (ie, CRT) that are
radiographically indistinguishable from tumor progression changes.  This patient population 
is also at higher risk at developing second primary malignancies due to the common etiologic 
risks of tobacco and excessive alcohol intake.  Therefore, tumor-related endpoints in this 
study will be based on Response Evaluation Criteria in Solid Tumors (RECIST) version 
(v)1.1 modified with respect to the definition of what constitutes progressive disease (PD) as 
detailed in Section 3.2, Section 9 and Appendix 3.  Broadly, locoregional disease progression 
requires biopsy confirmation and biopsies are strongly recommended to confirm a diagnosis 
of distant metastatic progression.  Per current standard patterns of care, neck dissection 
completed with 140 days following completion of CRT is considered part of the definitive 
management of the tumor and not as a disease progression event. 
1.3. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The benefit-risk relationship has been carefully considered in the planning of the trial.  
Avelumab has demonstrated clinical activity in patients with advanced solid tumors in an 
expansion cohort of an ongoing Phase 1 Trial EMR 100070-001.  The clinical safety data 
with single-agent avelumab in patients with advanced solid tumors available to date suggest 
an acceptable safety profile of the compound and no differences in the overall safety profile 
for patients with SCCHN relative to all patients.  Most of the observed events were either in 
line with those expected in patients with advanced solid tumors or with those observed with 
other antibodies blocking the PD-1/PD-L1 axis (see Section 1.2.2.1).  Infusion-related 
reactions including hypersensitivity and irAEs/autoimmune disorders have been identified as 
important risks for avelumab.  Respective risk mitigation measures have been implemented 
in all ongoing clinical studies with avelumab, including this clinical trial protocol.  These 
include guidelines for treatment interruption and discontinuation in case of irAEs, as well as 
mandatory pre-treatment with a histamine H1 receptor (H1) blocker and acetaminophen.  
Risk mitigation measures for AEs associated with CRT are discussed in their respective 
sections.
As reported by Ang et al. from Study RTOG0522, among patients with previously untreated 
Stage III to IV squamous cell carcinoma of the oropharynx, hypopharynx, or larynx treated 
with combination of radiotherapy over 6 weeks, and cisplatin (100 mg/m2 on Days 1 and 22
of radiotherapy) (N=447), Grade 3-4 treatment-related toxicities were reported in 87% of 


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patients.44  The most commonly reported Grade 3-4 non-hematological toxicities involved 
the gastrointestinal tract and included adverse events of dysphagia (57%), radiation mucositis 
(33%), mucositis/stomatitis of pharynx (24%), dehydration (15%), nausea (14%), and 
vomiting (9%). Skin reactions inside the portal were reported in 79% of patients (all severity 
grades) with 15% of patients experiencing Grade 3/4 events.  The most frequently reported 
hematological toxicities included leukopenia (19%), neutrophil count decreased (16%), and 
lymphopenia (13%).43,44
The safety profile, consistent with Study RTOG0522, was reported among 361 patients 
treated on Study RTOG0129 with newly diagnosed stage III to IV carcinoma of the oral 
cavity, oropharynx, hypopharynx, or larynx treated with a combination of radiotherapy 
(standard fractionation [70 Gy in 35 fractions over 7 weeks]) in combination with cisplatin 
100 mg/m2 once every 3 weeks for 3 cycles. Grade 3 to 5 toxicities were reported in 
approximately 80% of patients.  The most common Grade 3 to 5 toxicities reported were 
gastrointestinal (approximately 60%), including radiation mucositis, dysphagia, nausea, 
vomiting, and dehydration.  Blood/bone marrow toxicities were reported in approximately 
40% of patients most notably leukopenia/neutropenia.  Overall radiation dermatitis (all 
severity grades) was reported in approximately 70% of patients with severe radiation 
dermatitis (all Grade 3) was reported in 8% of patients.45
The safety profile of avelumab is described in Section 1.2.2.1 of this document and the 
Avelumab Investigator’s Brochure, version 7.0.17  Identified risks include immune-mediated 
reactions and infusion-related reactions.  No events of mucositis have been reported among 
1738 patients from the Pooled Safety Dataset.  Grade 3 to 4 neutropenia and leukopenia were 
reported in 1% of patients.  Severe immune-related rash was uncommon with avelumab 
treatment (0.1%).
Additional safety concerns are not expected from combining avelumab with radiotherapy, 
given their distinct mechanisms of action and toxicity profiles, consistent with the existing 
literature on concurrent immunotherapy with radiation therapy. A retrospective analysis by 
Barker et al described findings among 29 patients treated with ipilimumab (median dose 
10 mg/kg) for melanoma who underwent non-brain radiotherapy (median dose 30 Gy) 
between the first and last doses of ipilimumab.  In this study, the rates of local adverse events 
(AEs) or systemic immune-related irAEs were not increased with the concurrent treatment of 
ipilimumab and radiotherapy.46
In a Phase 1/2 study in metastatic castration-resistant prostate cancer, patients received 
ipilimumab 10 mg/kg, with (n=34) or without (n=16) radiotherapy.  Grade 3/4 
treatment-related AEs were reported in 38% and 63% of patients treated with and without 
concurrent radiotherapy respectively.  Similarly, Grade 3/4 irAEs were reported in 18% and 
63% of patients, respectively.  No increased toxicity was noted among patients treated with 
ipilimumab and concurrent radiotherapy.47
Given the distinct safety profile and mostly non-overlapping toxicities, no significant 
increased risk is anticipated from the combination of avelumab with CRT including cisplatin 
for the treatment of locally-advanced SCCHN.  The potential for benefit is significant given 


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the strong preclinical interaction between radiation and immune checkpoint inhibitors as well 
as the data showing activity as single agents, which in the frontline setting could result in 
enhanced localregional tumor control and improved PFS and OS. As described previously, 
treatment options for patients with recurrent SCCHN are limited and associated with severe 
toxicities; response rates are low, ranging between 15% and 36% with a median OS of 6 to 
10.1 months.  Improved treatment for locally-advanced, high-risk SCCHN to prevent 
locoregional relapse and distant metastases is critical for successful management of this 
multidimensional disease and therefore testing of multimodality therapy is appropriate with 
an acceptable risk-benefit profile for patients. 
The Sponsor plans to closely monitor the safety profile for new emerging safety risks or 
increased frequency or severity of anticipated risks based on a review of aggregate data.
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives
Primary Objective
To demonstrate that treatment with avelumab in combination with SOC CRT is superior to 
SOC CRT alone in prolonging PFS in front-line patients with high risk (as defined in 
Inclusion Criterion 2 [Section 4.1]), locally advanced SCCHN who are candidates for 
definitive CRT with cisplatin. 
Secondary Objectives

To compare the OS of avelumab in combination with SOC CRT vs SOC CRT alone.

To evaluate the anti-tumor activity of avelumab in combination with SOC CRT and 
SOC CRT alone.

To evaluate the overall safety and tolerability profile of avelumab in combination 
with SOC CRT and SOC CRT alone.

To evaluate the PK of avelumab.

To evaluate the PK of cisplatin (total and free). 

To assess avelumab ADAs. 

To evaluate the effect of avelumab in combination with SOC CRT and SOC CRT 
alone on patient-reported outcomes (PROs) of disease-related symptoms and 
health-related quality of life.

To evaluate candidate immune-related predictive biomarkers of sensitivity or 
insensitivity to treatment with avelumab in combination with SOC CRT in 
pre-treatment tumor samples (eg, PD-L1 expression).


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•
To evaluate candidate immune-related predictive biomarkers of sensitivity or 
insensitivity to treatment with avelumab in combination with SOC CRT in tumor 
samples (eg, PD-L1 expression) after one dose of avelumab in patients who provide 
this optional biopsy.
 
 
 
 
 
 
2.2. Endpoints
Primary Endpoint
•
PFS per modified RECIST v1.1 (see Appendix 3 for specific modifications, including 
pathologic confirmation) by investigator assessment. 
Secondary Endpoints
•
OS.
•
Antitumor activity: Pathologic complete response in any resected specimens, neck 
dissection.
•
Antitumor activity: Locoregional failure, objective response, distant metastatic 
failure, and duration of response, per modified RECIST v1.1 by investigator 
assessment.
•
Safety: Adverse events and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03; 
vital signs (blood pressure, pulse rate).
•
Pharmacokinetics:
•
Cmax and Ctrough for avelumab;
•
Area under the concentration-time curve extrapolated to infinity (AUCinf), Cmax, 
clearance (CL), time to maximum plasma concentration (Tmax), elimination 
CCI


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half-life (t1/2), and volume of distribution (Vz) for cisplatin (total and free), as data 
permit.
•
Immunogenicity: ADA (neutralizing antibody) against avelumab.
•
Patient-Reported Outcomes: Disease-related symptoms and Health-Related Quality 
of Life as measured by the National Cancer Comprehensive Network (NCCN) Head 
and Neck Symptom Index-22 items (FHNSI-22), and the EuroQoL 
Group 5-Dimension 5- Level Self-Report Questionnaire (EQ-5D-5L).
•
Biomarkers: Tumor tissue biomarkers including but not limited to, PD-L1 expression 
and tumor-infiltrating CD8+ T-lymphocytes.
 
 
3. STUDY DESIGN
3.1. Overall Study Design
This is a Phase 3, international, multicenter, randomized, double-blind, parallel, 2-arm study 
in patients with previously untreated, histologically confirmed locally advanced SCCHN 
(oral cavity, oropharynx, larynx, or hypopharynx) who are candidates for definitive CRT 
with cisplatin. 
The study is designed with the primary objective of demonstrating that treatment with 
avelumab in combination with SOC CRT is superior to SOC CRT alone in prolonging PFS. 
One interim analysis for the assessment of PFS will be conducted to allow early stopping of 
the study for futility or to demonstrate early superiority of avelumab in combination with 
SOC CRT compared to SOC CRT alone, and to assess the safety of avelumab in combination 
with SOC CRT. 
A total of approximately 640 patients will be randomized in a 1:1 ratio to either Arm A 
(avelumab + SOC CRT) or Arm B (placebo + SOC CRT).  Randomization will be stratified 
by tumor (T) stage (<T4 vs T4), nodal (N) stage (N0/N1/N2a/N2b vs N2c/N3), and HPV 
status (positive vs negative) as measured by p16 expression by IHC. 
The study schematic is provided in Figure 3.
CCI


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Figure 3
Study Design
a.
Patients with LA SCCHN (oral cavity, oropharynx, larynx, or hypopharynx) eligible for front-line 
treatment: HPV negative disease stage III, IVa, IVb; non-oropharyngeal HPV positive disease stage III, 
IVa, IVb; HPV positive oropharyngeal disease T4 OR N2cOR N3 (staging per TNM [tumor, node, 
metastases] guidelines for head and neck sites AJCC 7th Edition).  (Note: entry criteria for patients with 
HPV-positive tumors are different than for HPV-negative tumors).
b.
Avelumab or placebo IV to be administered on Day 1 of the Lead-in Phase (1 week prior to the start of the 
CRT Phase), and on Days 8, 25, and 39 during the CRT Phase. 
c.
SOC CRT = IMRT (70 Gy/35 fractions/7weeks; 1 fraction/day, 5 fractions/week) for 7 weeks + cisplatin 
(100 mg/m2 Days 1, 22, 43) during the CRT Phase.
d.
Maintenance Phase to start after completion of the CRT Phase and continue for 12 months.
e.
Patients will continue treatment until confirmed disease progression as assessed by Investigator per 
modified RECIST v1.1.
AJCC = American Joint Committee on Cancer; CRT = chemoradiotherapy; HPV = human papillomavirus; 
IMRT = intensity-modulated radiation therapy; LA = locally advanced; Q2W = every 2 weeks; 
RECIST = Response Evaluation Criteria in Solid Tumors; SCCHN = squamous cell carcinoma of the head and 
neck; SOC = standard of care.
There will be 3 treatment phases in this study. 

Lead-in Phase: On Day 1 of the Lead-in Phase of the study, patients will receive a 
single dose of avelumab or matching placebo, administered 7 days prior to initiation 
of the CRT Phase; 

CRT Phase: Avelumab or matching placebo will be administered on Days 8, 25, and 
39 in conjunction with SOC CRT starting on Day 1 of the CRT Phase;

Maintenance Phase: Following completion of the CRT Phase, avelumab or matching 
placebo will be administered Q2W for 12 months during the Maintenance Phase. 
The treatment schedule is described in the following table.


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Table 4.
Chemoradiation and Avelumab/Placebo Treatment Schedule
Lead-in Phase 
(7 days)a
CRT Phase 
(63 days)
Maintenance 
Phaseb
-- Day --
----------------  Day  ----------------
1
1
8
15
22 25 29
36
39 43
IMRT (70 Gy/35 fractions/7 
weeks; 1 fraction per day,
5 fractions/week 
[Monday – Friday])
X→X→X→X →X→X→→X→
Cisplatin (100 mg/m2 Q3W)
X
X
X
Avelumab (10 mg/kg) or placebo
X
X
Xc
X
Q2W
a.
Lead-in Phase to start 7 days prior to initiation of CRT Phase. 
b.
Maintenance Phase to start after completion of the CRT Phase (ie, 2 weeks following completion of CRT) 
and be 12 months in duration. CRT phase may be extended as required for patient recovery from CRT; 
however, it is hypothesized that patients will receive maximal benefit from beginning maintenance as close 
to the scheduled time as possible. 
c.
Day 25 dose of avelumab/placebo during the CRT Phase may be administered between Day 24 and Day 29.
Cisplatin should be administered on a Monday or Tuesday if feasible to maximize overlap with IMRT. 
CRT = Chemoradiotherapy; IMRT = intensity-modulated radiation therapy; Q2W = every 2 weeks; 
Q3W = every 3 weeks.
NOTE: The study consists of 3 study treatments: avelumab/placebo as study treatment 1; 
cisplatin as study treatment 2; IMRT as study treatment 3. Cisplatin is not to be considered 
concomitant medication. 
Patients who meet all study entry criteria will be randomized 1:1 to study treatment (Arm A 
or Arm B).  Patients will receive study treatment until completion of the protocol-defined 
treatment period (ie, 12 months following completion of CRT Phase), PD per modified 
RECIST v1.1, patient withdrawal of consent, patient lost to follow-up, or until unacceptable 
toxicity occurs, or until the study is terminated by the Sponsor, whichever occurs first. 
If a patient starts a new anti-cancer therapy prior to disease progression per modified 
RECIST v1.1, tumor assessments should be continued per Schedule of Activities (unless not 
feasible) until PD per modified RECIST v1.1 or death. 
All patients will be followed for survival until death, end of the study, or patient withdrawal 
of consent, whichever comes first, regardless of initiation of new cancer therapy.  All patients 
will be followed for safety with evaluations through 90 days after the last study treatment 
administration or until the time of initiation of new systemic anticancer treatment.  The 
Day 90 Short-Term Follow-up Visit will be conducted as a phone call.  If any concern arises, 
the patient will be called in for a follow-up visit within 5 calendar days of the initial phone 
call for appropriate assessment (as per the investigator’s medical judgement).  Beyond the 
Day 90 Short-Term Follow-up Visit, all patients will be followed every 16 weeks (Q16W) 
for survival and new systemic anticancer treatment within the long-term follow-up period.  


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Patients who refuse to return to the site for evaluations should be contacted by telephone as 
an alternative.
3.2. Tumor Assessments 

Tumor assessments will be completed on the schedule detailed below using a 
modification of RECIST v1.1.  The modification is required in head and neck cancer 
assessment as these tumors are fairly unique in their accessibility for thorough clinical 
evaluation and biopsy.  Furthermore, the extensive mucosal surface which is available 
for clinical evaluation of tumor response or recurrence may indicate tumor status 
changes that may not be present or as clear on radiographic imaging alone.  
Conversely, radiographic changes that could be suggestive of tumor progression or 
recurrence can reflect radiation therapy changes.  Taken collectively, this has given 
rise to the clinical practice of using biopsies to directly assess tumor recurrence in this 
patient population.  Therefore, RECIST was modified for this protocol to recognize 
this practice and better confirm (through direct pathologic ascertainment) when tumor 
recurrence has occurred.

Radiographic and clinical evaluations will be conducted with the same schedule in 
both treatment arms of the study.  The investigator will assess antitumor activity 
based on radiological assessments and clinical evaluation of patients using modified 
RECIST v1.1 (see Appendix 3) at baseline, 12 weeks after the completion of CRT, 
every 16 weeks (Q16W) thereafter for 48 months (208 weeks), and every 24 weeks 
(Q24W) thereafter until confirmed disease progression per modified RECIST v1.1 
and regardless of discontinuation of study treatment or initiation of subsequent 
anti-cancer therapy. 

Radiological tumor assessments will also be conducted whenever disease progression 
is suspected (eg, symptomatic deterioration or physical exam findings suggestive of 
mucosal recurrence). 

Locoregional disease progression per modified RECIST v1.1 requires that 
radiographic changes suggestive of disease progression are confirmed by biopsy.  
Pathologic confirmation of progression will verify that radiographic changes 
represent true tumor progression and not radiation effects or non-malignant contrast 
enhancement.

When disease progression occurs for distant metastases per RECIST v1.1, 
confirmation of pathology is recommended unless medically contraindicated or if the 
lesion location is too high risk for biopsy.

If a patient withdraws from study treatment for a reason other than disease 
progression per modified RECIST v1.1, radiological tumor assessments are to 
continue until disease progression per modified RECIST v1.1 even if a new 
anti-cancer therapy is initiated. 


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
A head and neck CT or MRI, chest CT, and PET scan are required at baseline and at 
12 weeks after completion of CRT.  High resolution PET/CT does not require 
additional CT thorax/neck/brain.  MRI brain may be performed if clinically indicated. 
Subsequent PET scans may be performed during the Maintenance Phase in the 
absence of clinical or CT complete resolution of nodal disease (described in 
Section 3.3) or at the investigator’s discretion. Baseline tumor assessments should be 
done within 28 days prior to randomization. 
3.3. Tumor Related Endpoints and Definitions 
Tumor related endpoints in this study will be based on RECIST v1.1 modified with respect to 
the definition of what constitutes progressive disease (PD) as follows.  Any of the following 
will constitute PD per modified RECIST v1.1:  

Locoregional disease progression per RECIST v1.1 which is subsequently confirmed 
by pathology.  Pathologic confirmation of progression will verify that radiographic 
changes represent true tumor progression and not radiation effects or non-malignant 
contrast enhancement.

Locoregional clinically detectable progression that is confirmed by pathology.

Surgical removal (salvage) of primary tumor with tumor present on final pathology.

Salvage neck dissection >20 weeks (140 days) after completion of CRT with tumor 
present on final pathology.

Metastatic (distant metastases) disease progression per RECIST v1.1.  Confirmation 
of pathology is recommended unless medically contraindicated or lesion location too 
high risk for biopsy.
Pathologic evaluation of resected or biopsied specimens must be completed by a trained and 
medically qualified expert (eg, specialty board certified pathologist). 
Pathologic complete response is defined as the absence of histologically identifiable 
residual cancer in any resected specimen. 
Local failure is defined as residual or recurrent viable tumor on pathologic evaluation from 
the site of original tumor location.  Presence of tumor is required for declaration of a 
progression event which requires identification of viable tumor cells on final pathology.  
Tumor reappearing within the initial and immediately adjoining anatomical region of the 
primary will be considered local recurrence.
Regional failure is defined as residual or recurrent viable tumor on pathologic evaluation 
from the regional lymph node basins (eg, neck nodes).  Presence of tumor is required for 
declaration of a progression event which requires identification of viable tumor cells on final 
pathology.


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Distant metastatic disease is defined as new tumor identified at a site distant from the head 
and neck anatomic region or draining lymph nodes.  Biopsy of any presumed distant 
metastatic disease is strongly recommended.  A solitary, speculated lung mass/nodule is a
second primary neoplasm and is not a disease progression event unless proven otherwise by 
biopsy in a patient with a smoking history.  Multiple lung nodules/masses are considered 
distant metastases from the index cancer and constitute a disease progression event unless 
proven otherwise by biopsy.
Irradiation of the primary tumor and radiographically enlarged lymph nodes is considered 
part of the treatment under investigation in this clinical trial and therefore these target lesions 
remain evaluable lesions for response assessment.
It is expected that the status of the primary tumor is assessed thoroughly at the beginning of 
the surgical procedure before undertaking nodal dissection.  Presence of persistent disease at 
the primary site, confirmed by frozen section will be considered disease progression. 
Neck dissection parameters are described in Section 3.4 and will consist of a selective neck 
dissection unless a cytologic sampling of the nodes that appear enlarged is negative.
Positive neck specimens removed within 140 days after completion of CRT will be 
considered part of the initial treatment plan and not considered as failures of initial 
management; positive specimens upon neck dissection beyond 140 days will be considered 
regional failures. 
3.4. Surgical Salvage of Residual Disease after Completion of the CRT Phase
Treatment of residual disease at the primary site will be determined by the investigator and 
the clinical situation (see Figure 4).  If treatment at the primary site is necessary after 
completion of CRT, study treatment has failed and the patient will discontinue the study 
treatment.  Surgical resection, re-irradiation, chemotherapy, or palliative care may be 
performed per institutional policy.  If the primary site is cleared of residual disease yet 
residual disease at the cervical nodal basin is suggested by imaging/clinical evaluation, then 
selective neck dissection will be performed unless a cytologic sampling of the node is 
negative.  Residual disease in the neck is not considered a treatment failure if surgical 
salvage is completed within 140 days of completion of CRT.  A primary treatment neck 
dissection after completion of the CRT Phase will be defined as a neck dissection performed 
for residual disease and within 20 weeks (140 days) of completion of CRT.  Patients who 
undergo such a primary treatment neck dissection will not be considered experiencing a 
disease progression event and remain on study treatment, regardless whether neck specimens 
are positive or negative. 
Positive specimens removed within 140 days of completion of CRT will be considered part 
of the initial treatment plan and not considered failures of initial management; positive 
specimens upon neck dissection beyond 140 days will be considered regional failures.  Such 
consolidation neck dissections after completion of the CRT Phase will encompass only the 
areas (typically only levels 2 and 3) initially involved in the side of the neck in question.  The 
extent of neck dissections performed for nodal recurrence or nodal progression, and/or 
salvage of disease at the primary will be determined by the treating surgeon. 


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If a neck dissection is required, then the treating surgeon is required to contact the surgical 
Principal Investigator (PI) of this study, Dr. 
) prior to the surgery 
to discuss the clinical and radiologic findings as well as the planned surgery itself.  Notes 
from the surgery, as well as the pathology report from the neck dissection, must also be 
submitted to Dr. 
 for review when they become available, but no later than 6 weeks 
following the procedure.
In the case of negative PET in patients who did not achieve clinical or CT/MRI-based 
radiological nodal CR at the tumor assessment performed 12 weeks following completion of 
CRT, follow-up PET scans are recommended every 4 months (Q16W) with the CT imaging 
for 24 months, then every 6 months (Q24W) in Years 3-5, as well as careful recording of the 
clinical dimensions of the residual abnormality.  CT imaging should be obtained as described 
in the Schedule of Activities beyond Year 5.
Figure 4
Algorithm for Evaluation of Regional Lymph Nodes Following Definitive 
CRT
a.
High risk = perceived risk of residual disease is high, such as sub-optimally treated patients due to 
premature cessation of treatment, unplanned treatment interruptions. 
b.
Low risk = perceived risk of residual nodal disease is low, such as low burden disease without treatment 
interruption.
c.
Ongoing clinical and imaging observation until residuum is <1 to 1.5 cm or stable for >6 months.
d.
In the case of positive biopsy, the surgical PI (Dr. 
]) must be contacted prior to 
performing the surgery to discuss the clinical and radiological findings as well as the planned surgery itself. 
e.
If biopsy is negative but there is high clinical/radiologic suspicion of disease, consider re-biopsy and 
contact the surgical PI (Dr. 
]) for discussion.
CRT = chemoradiotherapy; CT = computed tomography; IMRT = intensity-modulated radiation therapy; 
PET = positron emission tomography; PI = (surgical) principal investigator.
PPD
PPD
PPD
PPD


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3.5. Safety Assessments 
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the Schedule of Activities table. 
3.6. Pharmacokinetic/Immunogenicity Assessments 
Samples for PK and immunogenicity analyses will be collected as described in the Schedule 
of Activities table. 
3.7. Biomarker Assessments 
A key objective of the biomarker analyses that will be performed in this study is to 
investigate biomarkers that are potentially predictive of treatment benefit with the 
combination of avelumab and SOC CRT.  In addition, biomarker studies of tumor and blood 
biospecimens will be carried out to help further understand the mechanism of action, as well 
as potential mechanisms of resistance, to the combination of avelumab with SOC CRT.  
Tumor and blood biospecimens as required for the various analyses will be collected as 
described in the Schedule of Activities table.
3.8. Patient-Reported Outcomes
Patient-Reported Outcomes (PRO) will be assessed using the NCCN FHNSI-2248 and the 
EQ-5D-5L49
  The maximum 
number of questions to be answered at any assessment is 30, so PRO collection is not 
expected to be burdensome to patients.  The EQ-5D-5L will be administered to assess overall 
quality of life and to produce the utility values used for the economic model.  The NCCN 
FHNSI-22 will be administered specifically to capture head and neck related (disease-related 
[DRS]) physical (DRS-P) and emotional symptoms (DRS-E), treatment side effects (TSE), 
and functional well-being (FWB), with a focus on the item “I can swallow naturally and 
easily.”  
 
The EQ-5D-5L, FHNSI-22, 
will be administered on Day 1 of the Lead-in Phase 
(baseline); Days 1 and 29 of the CRT Phase; on Day 1 Cycle 1 and Day 1 Cycle 3 during the 
Maintenance Phase; then Q16W for 48 months, then Q24W until PD per modified 
RECIST v1.1.  
 
 
 
 
CCI
CCI
CCI
CCI
CCI


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3.8.1. NCCN-FHNSI-22
The NCCN FHNSI-22 was developed using methods consistent with the Food and Drug 
Administration (FDA) PRO guidance50 and surveyed input from patients with advanced 
cancers and physician experts.48  The FHNSI-22 questionnaire is specifically designed to be a 
stand-alone instrument to measure disease symptoms, treatment side effects and overall 
quality of life in patients with head and neck cancer. 
Responses on the FHNSI-22 questionnaire are used to calculate a total score and scores for 
four subscales: TSE, DRS-P, DRS-E, and FWB.  The questionnaire contains 22 items with 
5-point Likert scales ranging from ‘not at all’ to ‘very much’.  Higher scores mean better 
symptomatology, quality of life or functioning.  The expected questionnaire completion time 
is about 5 minutes.
3.8.2. EQ-5D-5L
The EuroQol EQ-5D-5L is a patient-completed questionnaire designed to assess health status 
in terms of a single index value or utility score.49  There are 2 components to the EuroQol 
EQ-5D-5L: a descriptive system in which individuals rate their level of problems (none, 
slight, moderate, severe, extreme/unable) in 5 areas (mobility, self- care, usual activities, 
pain/discomfort, and anxiety/depression) and a Visual Analogue Scale (VAS) in which 
patients rate their overall health status from 0 (worst imaginable) to 100 (best imaginable).  
Published weights are available that allow for the creation of a single summary score for the 
5 Likert scale items.  The expected questionnaire completion time is about 3 minutes or less.
 
 
 
 
 
 
 
  
 
 
 
CCI
CCI


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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 nonmedical 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:
4. Histological diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, 
hypopharynx, or larynx with tissue available.
5. High-risk disease as defined by American Joint Committee on Cancer [AJCC] Guidelines 
7th Edition:42

HPV-negative disease, Stage III, IVa, IVb per tumor/nodes/metastasis (TNM) 
guidelines for head and neck sites; or

Non-oropharyngeal HPV-positive disease, Stage III, IVa, IVb per TNM guidelines 
for head and neck sites; or

HPV-positive oropharyngeal disease T4 OR N2c OR N3 per TNM guidelines for 
head and neck sites.
where HPV status will be determined per institutional standard using p16 
immunohistochemistry (IHC). 
6. No prior therapy for advanced stage SCCHN; eligible for definitive CRT with curative 
intent.
7. Available tumor samples for submission or willing to undergo further tumor biopsies:

Availability of a formalin-fixed paraffin-embedded (FFPE) tumor tissue block from 
primary tumor or nodal biopsy.  If an FFPE tissue block cannot be provided, 
15 unstained slides (10 minimum) will be acceptable.
8. Age 18 years (20 years in Japan and Taiwan, and 19 years in Korea).
9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 
0 or 1 (Appendix 2).


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10. Adequate bone marrow function, including:

Absolute Neutrophil Count (ANC) 1,800/L or 1.8 x 109/L.

Platelets 100,000/µL or 100 x 109/L.

Hemoglobin 9 g/dL (may have been transfused).
11. Adequate renal function, including:

Estimated creatinine clearance 50 mL/min as calculated using the Cockcroft-Gault 
(CG) equation OR; 

A creatinine clearance of at least 60 ml/min if this value is described in the 
contra-indications for cisplatin as per country’s local labeling. 
12. Adequate liver function, including:

Total serum bilirubin 1.5 x upper limit of normal (ULN).

Aspartate and alanine aminotransferase (AST and ALT) 2.5 x ULN. 
13. Pregnancy test (for patients of childbearing potential) negative at screening. 
14. Male patients able to father children and female patients of childbearing potential and at 
risk for pregnancy must agree to use two methods of contraception (at least one of which 
is considered to be highly effective as defined in Section 4.3) throughout the study and 
for at least 6 months after the last dose of cisplatin and 30 days after the last dose of 
avelumab/placebo (whichever is later). 
Female patients who are not of childbearing potential (ie, meeting at least one of the 
following criteria):

have undergone a documented hysterectomy and/or bilateral oophorectomy;

have medically confirmed ovarian failure; 

have 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 a serum follicle-stimulating hormone (FSH) level 
consistent with the post-menopausal state. 
15. Evidence of a signed and dated informed consent document indicating that the patient (or 
a legally acceptable representative, as allowed by local guideline/practice) has been 
informed of all pertinent aspects of the study.


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16. 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. Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-CTLA-4 antibody (including ipilimumab), or any other antibody or drug specifically 
targeting T cell co-stimulation or immune checkpoint pathways.
2. Major surgery 4 weeks prior to randomization. 
3. Prior malignancy (other than the current Head and Neck cancer or in situ disease) 
requiring tumor-directed therapy within the last 2 years prior to enrollment, or concurrent 
malignancy associated with clinical instability.  Exceptions for disease within the 2 years 
are superficial esophageal cancer (TIS or T1a) fully resected by endoscopy, prostate 
cancer (Gleason score 6) either curatively treated or deemed to not require treatment, 
ductal in situ carcinoma of the breast that has completed curative treatment, adequately 
treated basal cell or squamous cell skin cancer. 
4. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent.  Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid disease 
not requiring immunosuppressive treatment are eligible.
5. Any of the following in the 6 months prior to randomization: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive 
heart failure, cerebrovascular accident, transient ischemic attack, or symptomatic 
pulmonary embolism.
6. Active infection requiring systemic therapy.
7. Known prior severe hypersensitivity to investigational products or any component in the 
formulations, including known severe hypersensitivity reactions to mAbs, cisplatin, or 
platinum-related compounds (NCI CTCAE v4.03 Grade 3).
8. Use of immunosuppressive medication at time of randomization, 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;
c.
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication). 
9. Prior organ transplantation including allogenic stem-cell transplantation.


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10. Diagnosis of prior immunodeficiency or known human immunodeficiency virus (HIV) or 
acquired immunodeficiency syndrome (AIDS) related illness.
11. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV 
surface antigen or HCV RNA [ribonucleic acid] if anti-HCV antibody screening test 
positive).
12. Vaccination within 4 weeks prior to randomization except for administration of 
inactivated vaccines.
13. Current use of or anticipated need for treatment with other anti-cancer drugs.
14. Pregnant female patients, breastfeeding female patients, and male patients able to father 
children and female patients of childbearing potential who are unwilling or unable to use 
2 methods of contraception (at least one of which is considered to be highly effective) as 
outlined in the protocol for the duration of the study and for at least 6 months after the 
last dose of cisplatin and 30 days after the last dose of avelumab/placebo (whichever is 
later).
15. Other severe acute or chronic medical conditions including: immune colitis, 
inflammatory bowel disease, pneumonitis, pulmonary fibrosis, or psychiatric condition 
including recent (within the past year) or active suicidal ideation or behavior; or 
laboratory abnormality that may increase the risk associated with study participation or 
study treatment 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.
16. 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.
17. Participation in other interventional studies involving investigational drug(s) within 
4 weeks prior to randomization.
4.3. Lifestyle Guidelines 
In this study, male patients who are able to father children and female patients who are of 
childbearing potential will receive radiation and cisplatin and half of these patients will also 
receive avelumab.  The effect of avelumab on reproduction is unknown.  Cisplatin can cause 
fetal harm when administered to pregnant women.
Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy 
must agree to use 2 methods of contraception (at least one of which is considered to be 
highly effective with low user dependency as defined below) throughout the study and 
continue to do so for at least 6 months after the last dose of cisplatin and 30 days after the last 
dose of avelumab/placebo (whichever is later).  The investigator or his or her designee, in 


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consultation with the patient, will confirm the patient has selected 2 appropriate methods of 
contraception for the individual patient and his/her partner from the list of permitted 
contraception methods (see below) and will confirm the patient has been instructed 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 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 the patient’s partner. 
Highly effective contraception methods with low user dependency include (applies to female 
subjects at risk for pregnancy with their male partners):
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, inserted, injected, implanted).
2. Correctly placed intrauterine device (IUD) or intrauterine system (IUS).
3. Male sterilization with absence of sperm in the post-vasectomy ejaculate. 
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
Female patients of non-childbearing potential must 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; status may be confirmed with a serum FSH level consistent with the 
post-menopausal state.
All other female patients (including females with tubal ligations) will be considered to be of 
childbearing potential.
All sexually active male subjects 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 study treatment and continuing for at least 6 months after the last dose 
of cisplatin and 30 days after the last dose of avelumab/placebo (whichever is later).
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 supporting study portal.


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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.
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). 
In this study, the investigational products are all study treatments to be administered, namely, 
avelumab (MSB0010718C)/placebo and SOC CRT. The study treatments include the 
following:

Arm A: Avelumab + SOC CRT:

Avelumab 10 mg/kg IV: Day 1 of the Lead-in phase; Days 8, 25, and 39 of the 
CRT Phase; Q2W for 12 months during the Maintenance Phase.

Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase.

IMRT 70 Gy/35 fractions/7 weeks; 1 fraction/day, 5 fractions/week for 7 weeks 
during the CRT Phase.

Arm B: Placebo + SOC CRT:

Placebo IV matching avelumab: Days 1 of the Lead-in phase; Days 8, 25, and 39 
of the CRT Phase; Q2W for 12 months during the Maintenance Phase.

Cisplatin 100 mg/m2 IV: Days 1, 22, and 43 of the CRT Phase.

IMRT 70 Gy/35 fractions/7 weeks; 1 fraction/day, 5 fractions/week for 7 weeks 
during the CRT Phase.


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Note: The Day 25 dose of avelumab/placebo during the CRT Phase may be administered 
between Day 24 and Day 29. 
5.1. Allocation to Treatment
Patients will be randomized in a 1:1 ratio to either Arm A (avelumab + SOC CRT) or Arm B 
(placebo + SOC CRT). Randomization will be stratified by tumor stage (<T4 vs T4), nodal 
stage (N0/N1/N2a/N2b vs N2c/N3), and HPV status (positive vs negative) measured by 
p16 expression by IHC.
Assignment of patient number, patient enrollment, and allocation of study drug will be 
managed by the Interactive Response Technology (IRT) system (interactive web-based 
response [IWR]). At the time that a patient has signed informed consent and entered 
screening, the site should contact the IRT system to obtain the patient identification number.  
Once a patient has met all eligibility criteria, the site then contacts the IRT system to enroll 
the patient and to obtain the study drug allocation information.  Study treatment must be 
initiated preferably on the day of randomization, but no later than 3 days after randomization.
At the time of enrollment, site personnel (study coordinator or specified designee) will be 
required to enter into or select information from the IRT system including but not limited to 
the user’s identification (ID) and password, the protocol number, the patient number, and the 
date of birth of the patient.  The IRT system will then provide a treatment assignment 
(Arm A or Arm B) and dispensable unit (DU) or vial number.  The IRT system will also 
provide a confirmation report containing the patient number and DU or vial number assigned.  
The confirmation report must be stored in the site’s files. 
There is a 24-hour-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 system. 
5.2. Breaking the Blind
At all times, treatment and randomization information will be kept confidential and will not 
be released to the patient, investigator, the study staff, or the sponsor’s study team until 
following the conclusion of the study, with the exception described in this section. 
At the initiation of the study, the study site will be instructed on procedures for breaking the 
blind.  Blinding codes should be broken only in emergency situations for reasons of patient 
safety.  If a patient has an adverse event (AE) that may be considered immune mediated, 
treatment for the AE should be administered as if the patient is receiving avelumab.  
Whenever possible, the investigator should contact Pfizer before breaking the blind.  The 
method will be either a manual or electronic process.  When the blind for a patient has been 
broken, the reason must be fully documented.  If the blind is broken, the investigator should 
promptly inform the Pfizer Clinician or Medical Monitor.  The patient for whom the blind 
has been broken will be discontinued from the study treatment and undergo the 
post-treatment (End-of-Treatment [EOT]/Follow-up) procedures. 


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5.3. Patient Compliance
All doses of study treatments (avelumab or placebo and SOC CRT) will be administered at 
the investigational site by well-trained medical staff.
The information related to each trial drug administration, including the date, time, and dose 
of study drug, will be recorded on the electronic case report form (eCRF).  The Investigator 
will make sure that the information entered into the eCRF regarding drug administration is 
accurate for each patient.  Any reason for noncompliance should be documented.
Noncompliance is defined as a patient missing >1 infusion of any study treatment 
(avelumab/placebo or cisplatin) for non-medical reasons.  If 1 infusion is missed and the 
interval between the subsequent infusion and the last administered treatment is longer than 
4 weeks for nonmedical reasons, the criteria of insufficient compliance will have been met as 
well.  Non-compliance with radiation is defined in the Radiation Delivery Guidelines 
Document.
5.4. Investigational Product/Study Treatments Supplies
5.4.1. Radiation Therapy to the Primary Lesion and Neck (IMRT)
5.4.1.1. Dose Specificiations
Radiation therapy (RT) will be delivered using IMRT technique and will be delivered in 
35 fractions over 7 weeks, 5 fractions weekly either in one plan (simultaneous integrated 
boost [SIB]) or through separate plans, of cone-down boosts.  Detailed definitions of clinical 
target volumes to encompass gross disease with appropriate margin (clinical target volume 
[CTV]1), high risk sub-clinical disease sites (CTV2) and lower risk areas, as well as normal 
tissue maximal doses are detailed separately in the Radiation Delivery Guidelines Document.
For questions regarding IMRT, please contact Dr. 
or 
call
.
5.4.1.2. Technical Factors
5.4.1.2.1. Treatment Planning/Delivery
Megavoltage energy photon beam irradiation is required.  Any treatment planning and 
delivery system that has been credentialed for head and neck IMRT for cooperative group 
radiation studies (eg, NRG Oncology, Radiation Therapy Oncology Group [RTOG], or 
EORT) is acceptable.  See Radiation Delivery Guidelines Document for additional details.
5.4.1.2.2. Localization, Simulation, and Immobilization
Patients must have an immobilization device (eg, Aquaplast mask) made prior to treatment 
planning CT scan.
Although not mandatory, the treatment planning CT scan should be performed with IV 
contrast so that the major vessels of the neck are easily visualized.  However, when possible, 
fusion of respective diagnostic imaging such as PET/CT and/or MRI should be done to 
carefully delineate the gross tumor volume.  The treatment planning CT scan must be 
PPD
PPD


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performed with the immobilization device and in the treatment position.  Slice thickness 
should be 0.3 cm or less.
5.4.1.3. Documentation Requirements for IMRT 
Documentation requirements for IMRT are described in the Radiation Delivery Guidelines 
Document and include the following:

Pre-treatment radiation therapy planning CT scan;

All radiation treatment plans will undergo full, centralized, real-time quality 
assurance (QA), consisting of a rapid review prior to IMRT initiation and a full 
review of the delivered plan at the completion of therapy.  Details of the IMRT 
review and treatment plan submission process will be provided in the Radiation 
Delivery Guidelines Document;

All treatment plans are to be normalized to provide exactly 95% volume coverage of 
the PTV1 with 70 Gy.
5.4.1.4. Compliance Criteria
Treatment breaks must be clearly indicated in the treatment record along with the reason(s) 
for the treatment break(s).  Treatment breaks are highly discouraged; however, if necessary 
for severe acute toxicity, ideally should not exceed 5 treatment days at a time and 
10 treatment days in total. Treatment breaks should be allowed only for resolution of severe 
acute toxicity and/or for intercurrent illness.
Days that the RT department is closed, RT is not expected to be administered and this is not a
treatment break.  This includes all statutory holidays in that locale.  Over times of multiple, 
consecutive days of holidays, the site is encouraged but not required to “make up” the RT 
fractions through BID treatments, at least 6 hours apart, during the shortened treatment week. 
It is recognized that over the course of 35 treatment fractions in RT various factors aside 
from statutory holidays may result in RT not being delivered on a day that otherwise could be 
a potential RT treatment day.  It is expected that sites will attempt to keep the overall RT 
treatment duration as close to 7 weeks as possible, but inability to deliver the RT fraction to a 
patient on a given day is not a PD unless >2 consecutive regular treatment days (Mon-Fri) are 
missed.  Sites are encouraged to consider BID treatments, at least 6 hours apart, for making 
up missed RT fractions to maintain the overall treatment time.
RT delivered to the total dose of 70 Gy is a completed dose, regardless of delays in RT 
delivery.
5.4.2. Cisplatin 
All patients will receive cisplatin (100 mg/m2) administered IV on Days 1, 22, and 43 of the 
CRT Phase (note: cisplatin given within 48 hours of the scheduled days is acceptable).  The 
actual dose of cisplatin administered should be based on actual body surface area (BSA).


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In case of obesity (body mass index (BMI) >30 kg/m²), actual BSA will still be used 
according to the ASCO recommendation published in the Journal of Clinical Oncology, 
2012: Appropriate Chemotherapy Dosing for Obese Patients with Cancer (Appendix 8).
Cisplatin is to be given on a Q3W schedule of 100 mg/m² (a weekly dosing schedule is not 
allowed on protocol) on Day 1, 22 and 43 of the CRT phase. The 100 mg/m² dose may be 
split over 2 to 4 consecutive days (eg, 50 mg/m² on 2 consecutive days up to 25 mg/m² over
4 consecutive days) if that is the institutional standard way of delivering the Q3W cisplatin 
dosing. It is recognized that some patients will not be able to receive the 3rd dose of cisplatin 
and this is not a protocol deviation. 
Complete information for cisplatin may be found in the SRSD, which for this study is the 
cisplatin package insert.37
5.4.2.1. Formulation
Each vial contains 10 mg of cis-diamminedichloridoplatinum, 19 mg of sodium chloride, 
100 mg of mannitol, and hydrochloric acid for pH adjustment. One vial is reconstituted with 
10 mL of sterile water. The pH range will be 3.5 to 4.5. Cisplatin injection also is available 
from the manufacturer in aqueous solution, each ml containing 1 mg cisplatin and 19 mg 
sodium chloride (NaCl) and hydrogen chloride (HCl) or sodium hydroxide (NaOH) to adjust 
pH.
5.4.2.2. Administration
Cisplatin is highly emetogenic.  After administering appropriate antiemetics 
(see Section 5.5.2.1), cisplatin will be infused over 60-120 minutes for the 100 mg/m2 dose 
along with vigorous hydration per local standard of care.  Please refer to the study 
Investigational Product (IP) manual for further details regarding cisplatin administration.
5.4.2.3. Storage and Stability
Please refer to the study IP manual for cisplatin storage and stability data. 
5.4.2.4. Adverse Events
Refer to the cisplatin package insert for safety data.
5.4.2.5. Supply
Cisplatin is commercially available.  The Sponsor will provide cisplatin to individual study 
sites as required. The use of drug(s) or combination of drugs in this protocol meets the 
criteria described under Title 21 Code of Federal Regulations (CFR) 312.2(b) for 
Investigational New Drug (IND) exemption.


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5.4.3. Avelumab/Placebo
5.4.3.1. Dosage Form and Packaging
Avelumab/placebo will be supplied for the study by Pfizer Global Clinical Supply, 
Worldwide Research and Development.  Drug supplies will be shipped to the study sites with 
a Drug Shipment and Proof of Receipt form.  This form will be completed, filed, and the 
shipment confirmed as directed on the bottom of the Drug Shipment and Proof of Receipt 
form.  The Investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and usage 
of investigational products in accordance with the protocol and any applicable laws and 
regulations.
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  It is 
presented at a concentration of 20 mg/mL with a nominal volume of 10 mL in glass vials 
closed with a rubber stopper and sealed with an aluminum polypropylene flip-off seal.  Each 
vial is intended for single-use only.
The placebo for avelumab is a sterile, clear, and colorless solution for IV administration 
presented with a nominal volume of 10 mL in matching glass vials.  Each vial is intended for 
single-use only.
Packaging and labeling of avelumab/placebo will be blinded to all investigative personnel in 
accordance with applicable local regulatory requirements and applicable Good 
Manufacturing Practice (GMP) guidelines.  Avelumab/placebo will be packed in boxes each 
containing one vial.  The information on the trial drug will be in accordance with approved 
submission documents. 
Avelumab/placebo will be shipped in transport cool containers (2C to 8C) with temperature 
monitoring devices.
5.4.3.2. Preparation and Dispensing
Avelumab 10 mg/kg or placebo will be administered on Day 1 of the Lead-in Phase and 
Day 8, Day 25, and Day 39 of the CRT Phase after all procedures/assessments have been 
completed as described in the Schedule of Activities (excluding IMRT).  Avelumab/placebo 
or cisplatin may be administered either before or after the RT fraction that is administered on 
the same day; however, it is preferred that administration of these agents occur prior to RT.  
See the dosage and administration instructions in the Investigational Product Manual for 
instructions on how to prepare the investigational products for administration.  
Investigational products 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 
study agents.


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The contents of the avelumab/placebo 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 and should be documented in case report 
forms (CRFs). 
For administration in this trial, avelumab/placebo 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 Investigational Product Manual.  Tubing with in-line, low protein 
binding 0.2 micron filter made of polyether sulfone (PES) must be used during 
administration.
The dose amount required to prepare the avelumab/placebo infusion solution will be based 
on the patient’s weight in kilograms (kg).  All patients should be weighed within 3 days prior 
to dosing for every cycle.  If the patient experienced a weight change of >10% compared to 
the weight that was used for the last dose calculation, the amount of study drug must be 
recalculated.  It is at the site’s discretion however, to recalculate the avelumab/placebo dose 
at weight changes below the threshold for mandatory recalculations. 
Avelumab/placebo must not be used for any purpose other than the trial.  The administration 
of trial drug to patients who have not been enrolled into the trial is not covered by the trial 
insurance.
Any unused portion of the avelumab/placebo solution should be discarded in biohazard waste 
disposal with final disposal by accepted local and national standards of incineration.
5.5. Administration
All study treatments (IMRT, cisplatin, and avelumab/placebo) will be administered at the 
investigational site on an outpatient basis. 
Avelumab/placebo or cisplatin can be given either before or after the RT fraction that is 
given on the same day; however, it is preferred that administration of these agents occur prior 
to RT.
5.5.1. Avelumab/Placebo 
On each of the days that avelumab/placebo is administered (see Schedule of Activities table 
for details), the investigational product will be administered after all procedures/assessments 
have been completed as described in the Schedule of Activities table. 
In order to mitigate infusion-related reactions, premedication should be administered as 
described in Section 5.5.1.4.  This may be modified based on local treatment standards and 
guidelines, as appropriate.  When investigational product and IMRT are administered on the 
same day, premedication should be timed relative to the infusion. 


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Avelumab/placebo will be administered as a 1-hour infusion.  Sites should make every effort 
to target the timing of avelumab/placebo infusion to be as close to 1 hour as possible.  
However, given the variability of infusion pumps from site to site, time windows of minus 
10 minutes and plus 20 minutes are permitted (ie, infusion time is 50-80 minutes).  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 5.5.1.5.
Avelumab/placebo dose reduction for toxicity management is not permitted; however, the 
next administration may be omitted due to persisting toxicity as described in Table 5, 
Table 6, and Table 7.  Patients experiencing toxicity may require treatment adjustment or 
discontinuation according to the guidelines specified in Table 5, Table 6, and Table 7.  
Laboratory draws may be performed and results reviewed by the treating physician up to 
1 business day before study drug administration. Laboratory draws taken 1 business day prior 
to infusion will not be considered a deviation.
During the Maintenance Phase, avelumab/placebo may be administered up to 3 days before 
or after the scheduled treatment day of each cycle for administrative reasons, except for 
C1D1.  Maintenance C1D1 is defined as the day when the first avelumab/placebo is given, 
therefore there is no window required as the delivery of this dose defines the beginning of 
maintenance, irrespective of when the infusion is given. 
Patients will receive trial treatment until completion of treatment per protocol, disease 
progression (PD) per modified RECIST v1.1 (Appendix 3), unacceptable toxicity, 
withdrawal of consent, patient is lost to follow-up, or until the study is terminated by the 
Sponsor, whichever occurs first. 
Patients who temporarily stop the study treatment(s) due to AE may resume treatments upon 
recovery as described in Table 5, Table 6, or Table 7.
5.5.1.1. Treatment After Initial Evidence of Radiological Disease Progression 
Immunotherapeutic agents such as avelumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
If radiologic imaging shows disease progression, assigned study treatment should be 
continued while awaiting pathological confirmation of disease progression per modified 
RECIST v1.1 unless the patient is clinically unstable and/or requires an urgent alternative 
intervention (eg, decompression of a spinal cord compression).  All locoregional disease 
recurrence or progression must be pathologically confirmed (see Appendix 3). 
If the patient has confirmed PD per modified RECIST v1.1 by investigator assessment, the 
patient should discontinue from investigational products. 


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5.5.1.2. Recommended Dose Modifications
Every effort should be made to administer the investigational products at the planned dose 
and schedule. 
No dose modifications of avelumab/placebo are permitted in this study, but the next infusion 
may be omitted based on persisting toxicity, as outlined in the next sections.
5.5.1.3. Dosing Delays
In the event of significant toxicity, dosing for the investigational products may be delayed or 
modified as described below.  In the event of multiple toxicities, dose delays 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 delays, 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.
Each of the 3 treatment components (IMRT, cisplatin, and avelumab) can cause significant 
toxicities, some of which may be overlapping.  Determining the main cause of a toxicity may 
rely on the temporal relationship of the event to one of the agents, specific characteristics or 
the likelihood of developing such a toxicity relative to patients receiving only that modality.  
Investigator judgment may be required to best determine which agent to hold or modify.  
Recommendations for the management of each agent’s toxicity are addressed individually in 
the following sections.
Both cisplatin and avelumab/placebo will be delayed appropriately if the IMRT is delayed.  
All treatment days in the Schedule of Activities table for the CRT Phase are predicated on 
radiation treatment days and neither systemic agent should be delivered in the CRT Phase if 
radiation is being held for toxicity management.
In case treatment interruption for one of the investigational drugs (cisplatin or 
avelumab/placebo) is required for drug-related toxicity, the dose of the other drug may also 
be modified or interrupted based on the guidance provided for toxicity management, product 
labeling, and institutional guidelines according to investigator’s best medical judgement.
5.5.1.3.1. Study Treatment Modifications for Avelumab/placebo Drug-Related Toxicity
Recommended avelumab/placebo treatment modifications in case of avelumab/placebo
drug-related toxicity are shown in Table 5.  These specific guidelines are applicable in cases 
which have a causality attributed to avelumab/placebo.  In cases where it is possible that an 
AE is related to both study treatments (avelumab/placebo and CRT), the guidelines for 
avelumab/placebo should be followed.


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Table 5.
Treatment Modifications for Avelumab/placebo-Related Toxicity – to be 
followed only when the AE is deemed related to avelumab/placebo. 
Toxicity
NCI 
CTCAE 
Severity 
Grade
Avelumab/placebo
Treatment Modification
Avelumab/placebo General 
Toxicity Management 
(other than infusion-related 
reaction/
hypersensitivity and irAEs)
Grade 1 

Continue as per schedule.
Grade 2

Continue as per schedule.
Grade 3

Withhold avelumab/placebo until recovery to Grade 1. 

Permanently discontinue avelumab/placebo if toxicity does 
not resolve to Grade 1 within 12 weeks of last 
administration or upon recurrence of the same Grade 3 ADR 
except for laboratory values out of normal range that do not 
have any clinical correlate.
Grade 4

Permanent discontinuation,
Exceptions are:

Laboratory values out of normal range that do not have any 
clinical correlate.
Infusion-related Reaction 
Grade 1-4

See Section 5.5.1.5 and Table 6.
Hypersensitivity reactions
Grade 3-4

See  Section 5.5.1.6 .
Immune-related AE (irAE)
Grade 1-4

See section 5.5.1.8 and Table 7
Tumor lysis syndrome
Grade 1-4

See section 5.5.1.7 and Figure 5.
5.5.1.4. Special Precautions for Avelumab/placebo Administration
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Avelumab/placebo 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.
In order to mitigate infusion-related reactions, patients have to be premedicated with an 
antihistamine and with paracetamol (acetaminophen) prior to the first 4 infusions of 
avelumab. Premedication should be administered for subsequent avelumab doses based upon 
clinical judgment and presence/severity of prior infusion reactions.
Following avelumab/placebo infusions, patients must be observed for 30 minutes post 
infusion for potential infusion related reactions. 


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Infusion of avelumab/placebo will be stopped in case of Grade 2 infusion-related, allergic, 
or anaphylactic reactions.  If an infusion/allergic reaction occurs, the patient must be treated 
according to the best available medical practice.  Patients should be instructed to report any 
delayed reactions to the Investigator immediately. 
Treatment recommendations for the management of infusion-related reactions, severe 
hypersensitivity reactions, and tumor lysis syndrome are outlined in Section 5.5.1.5, 
Section 5.5.1.6, and Section 5.5.1.7, respectively.
Investigators should also monitor patients closely for potential irAEs, which may become 
manifest at the earliest weeks of treatment.  Immune-related adverse events include 
pneumonitis, colitis, hepatitis, endocrinopathies including thyroid disorders 
(hyperthyroidism, hypothyroidism, thyroiditis), adrenal insufficiency, rash, nephritis and 
other immune-mediated reactions including eye disorders (uveitis, iritis), myositis, and 
myocarditis.  Treatment recommendations for the management of irAEs are outlined in 
Section 5.5.1.8.
5.5.1.5. Management of Avelumab/placebo Infusion-Related Reactions 
Avelumab/placebo infusion-related reactions may occur.  Symptoms may include fever, 
chills, rigors, diaphoresis, and headache). 
Treatment of the infusion-related reaction and modifications of the infusion rate and/or 
treatment interruption/discontinuation are mainly dependent upon severity, as indicated in 
Table 6. 


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Table 6.
Treatment Modification for Symptoms of Avelumab/Placebo 
Infusion-Related Reactions
NCI CTCAE Grade 
Treatment Modifications
Grade 1 – mild
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.

Decrease the investigational product 
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.

Stop investigational product 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.
Grade 3 or Grade 4 – severe or life-threatening
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
Grade 4: Life-threatening consequences; urgent 
intervention indicated.

Stop the investigational product infusion 
immediately and disconnect bag infusion 
tubing from the patient.

Investigational product treatment must be 
permanently discontinued.
IV=intravenous, NCI-CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Event, 
NSAIDs=nonsteroidal anti-inflammatory drugs.
*If avelumab/placebo infusion rate has been decreased by 50% due to an infusion reaction, it must remain 
decreased for the next scheduled infusion.  If no infusion reaction is observed at the next scheduled infusion, 
the infusion rate may be returned to baseline at subsequent infusions.
Additional Modifications for Patients with Grade 2 Avelumab/Placebo Infusion-Related 
Reactions: In the event of a Grade 2 infusion-related reaction that does not improve or 
worsens after implementation of the modifications indicated in Table 6 (including reducing 
the infusion rate by 50%), the Investigator may consider treatment with corticosteroids, and 
the infusion should not be resumed for that cycle.  At the next cycle, the Investigator may 
consider the addition of H2-blocker antihistamines (eg, famotidine or ranitidine), meperidine, 
or ibuprofen to the mandatory premedication.  
5.5.1.6. Management of Avelumab/Placebo-related Severe Hypersensitivity Reactions 
and Flu-like Symptoms 
Many mAb therapies can induce flu-like symptoms and hypersensitivity reactions, including 
impaired airway, decreased oxygen saturation (<92%), confusion, lethargy, hypotension, 
pale/clammy skin, and cyanosis.
Avelumab/placebo should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment if required.  Patient should be placed on 
monitor immediately and epinephrine injection and dexamethasone infusion should be 
available for immediate access.


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For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable nonsteroidal 
anti- inflammatory drugs (NSAID) dose (eg, ibuprofen 600 mg, naproxen sodium 500 mg) 
may be administered at Investigator discretion 2 hours before and 8 hours after the start of 
each dose of avelumab/placebo IV infusion.  Alternative treatments for fever (eg, 
paracetamol or ibuprofen) and rigors (eg, meperidine) may be given to patients at the 
discretion of the Investigator.
5.5.1.7. Management of Investigational Product-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 5) published by Howard et al.51


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Figure 5
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
Allopurinolor ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxinexposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia


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5.5.1.8. Management of Avelumab/placebo Immune-Related Adverse Events 
Because inhibition of PD-L1 stimulates the immune system, avelumab/placebo may cause 
toxicity by increasing the immune response, leading to inflammatory reactions collectively 
referred to as immune-related adverse events (irAEs). 
Immune-related adverse events described with this class of drugs include pneumonitis, 
colitis, hepatitis, endocrinopathies including thyroid disorders (hyperthyroidism, 
hypothyroidism, thyroiditis), adrenal insufficiency, rash, nephritis and renal dysfunction,  eye 
disorders (including uveitis, iritis), and other immune-mediated reactions including myositis 
and myocarditis.
Any AE which may have an underlying immune-mediated mechanism including those 
described above, and without other clear etiologies, should be considered immune-related 
and managed according to guidelines described in this section.
If a patient has an AE that may be considered immune mediated, treatment for the AE should 
be administered as if the patient is receiving avelumab. 
Treatment of irAEs is mainly dependent upon severity (NCI CTCAE grade v4.03):

Grade 1 or 2: treat symptomatically or with moderate-dose steroids, more frequent 
monitoring;

Grade 1 or 2 (persistent): manage similar to high grade AE (Grade 3 to 4);

Grade 3 or 4: treat with high-dose corticosteroids.
Treatment of irAEs should follow guidelines set forth in Table 7.


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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI CTCAE v4.03)
Initial management
Follow-up management
Grade 1
Diarrhea: <4 stools/day over 
baseline;
Colitis: asymptomatic 

Continue avelumab/placebo 
therapy

Symptomatic treatment 
(eg, loperamide)
Close monitoring for worsening 
symptoms
Educate patient to report worsening 
immediately
If worsens:

Treat as Grade 2 or 3 or 4 
Grade 2
Diarrhea: 4 to 6 stools per day 
over baseline; IV fluids 
indicated <24 hours; not 
interfering with activities of 
daily living (ADL)
Colitis: abdominal pain; blood in 
stool 

Withhold avelumab/placebo 
therapy

Symptomatic treatment
If improves to Grade 1: 

Resume avelumab/placebo 
therapy
If persists >5-7 days or recur:

Treat as Grade 3 to 4
Grade 3 to 4
Diarrhea (Grade 3): 7 stools per 
day over baseline; incontinence; 
IV fluids 24 hrs; interfering 
with ADL
Colitis (Grade 3): severe 
abdominal pain, medical 
intervention indicated, peritoneal 
signs
Grade 4: life-threatening, 
perforation

Withhold avelumab/placebo 
for Grade 3

Permanently discontinue 
avelumab/placebo for Grade 4 
or recurrent Grade 3

1.0 to 2.0 mg/kg/day
prednisone or equivalent

Add prophylactic antibiotics 
for opportunistic infections 

Consider lower endoscopy
If improves: 

Continue steroids until 
Grade 1, then taper over at least 
1 month; resume 
avelumab/placebo 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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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related
Dermatological irAEs
Severity of Rash
(NCI-CTCAE v4.03)
Initial management
Follow-up management
Grade 1 to 2 
Covering 30% body surface 
area 

Symptomatic therapy 
(eg, antihistamines, topical 
steroids) 

Continue avelumab/placebo 
therapy
If persists >1 to 2 weeks or recurs: 

Consider skin biopsy 

Withhold avelumab/placebo 
therapy

Consider 0.5 to 1.0 mg/kg/day 
prednisone or equivalent.  Once 
improving, taper steroids over at 
least 1 month, consider 
prophylactic antibiotics for 
opportunistic infections, and 
resume therapy following 
steroids taper.
If worsens: 

Treat as Grade 3 to 4 
Grade 3
Covering >30% body surface 
area 
Grade 4
Life-threatening consequences

Withhold avelumab/placebo 
for Grade 3

Permanently discontinue 
avelumab/placebo 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/placebo 
therapy following steroids taper 
(for initial Grade 3)
Pulmonary AEs
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Initial management
Follow-up management
Grade 1
Radiographic changes only 

Consider withholding 
avelumab/placebo therapy 

Monitor for symptoms every 
2 to 3 days 

Consider Pulmonary and 
Infectious Disease consults 
Re-image at least every 3 weeks
If worsens: 

Treat as Grade 2 or Grade 3 to 4 


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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related
Grade 2
Mild to moderate new symptoms

Withhold avelumab/placebo 
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-image every 1 to 3 days 
If improves: 

When symptoms return to 
Grade 1, taper steroids over at 
least 1 month and then resume 
avelumab/placebo therapy 
following steroids taper
If not improving after 2 weeks or 
worsening: 

Treat as Grade 3 to 4 
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia;
Grade 4: Life-threatening 

Permanently discontinue 
avelumab/placebo 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 (LFT) 
Increase
(NCI-CTCAE v4.03)
Initial management
Follow-up management
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN 

Continue avelumab/placebo 
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
3x ULN 

Withhold avelumab/placebo 
therapy

Increase frequency of 
monitoring to every 3 days

Permanently discontinue 
investigational product 
therapy if AST/ALT 
>3X ULN with concurrent 
elevation if total bilirubin 
>2X ULN without another 
obvious cause  
If returns to Grade 1: 

Resume routine monitoring, 
resume avelumab/placebo 
therapy
If elevations persist >5 to 7 days or 
worsen: 

Treat as Grade 3 to 4


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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related
Grade 3 to 4
AST or ALT >5 x ULN and/or 
total bilirubin >3 x ULN 

Permanently discontinue 
avelumab/placebo therapy 

Increase frequency of 
monitoring to every 1 to 
2 days 

1.0 to 2.0 mg/kg/day 
prednisone or equivalent

Add prophylactic antibiotics 
for opportunistic infections 

Consult gastroenterologist/ 
hepatologist

Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted
If returns to Grade 1: 

Taper steroids over at least 
1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds: 

Add mycophenolate mofetil 
1 gram (g) twice daily 

If no response within an 
additional 3 to 5 days, consider 
other immunosuppressants per 
local guidelines 
Renal irAEs
Grade of Creatinine Increased
(NCI-CTCAE v4.03)
Initial management
Follow-up management
Grade 1
Creatinine increased > ULN to 
1.5 x ULN

Continue avelumab/placebo 
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/placebo 
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/placebo therapy 
following steroids taper
If worsens:

Treat as Grade 4
Grade 4
Creatinine increased >6 x ULN

Permanently discontinue 
avelumab/placebo 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


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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related
Cardiac irAEs
Myocarditis
Initial management
Follow-up management
New onset of cardiac signs or
symptoms and/or new 
laboratory cardiac biomarker 
elevations (eg, troponin, 
CK-MB, BNP) or cardiac 
imaging abnormalities 
suggestive of myocarditis

Withhold avelumab/placebo 
therapy

Hospitalize

In the presence of life 
threatening cardiac 
decompensation, consider 
transfer to a facility 
experienced in advanced heart 
failure and arrhythmia 
management

Cardiology consult to establish 
etiology and rule-out 
immune-mediated myocarditis

Guideline based supportive 
treatment as per cardiology 
consult*

Consider myocardial biopsy if
recommended per cardiology 
consult

If symptoms improve and
immune-mediated etiology is 
ruled out, re-start 
avelumab/placebo 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/placebo

Guideline based supportive 
treatment as appropriate as 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

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
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/placebo 
therapy

Endocrinology consult if 
needed

Start thyroid hormone 
replacement therapy (for 
hypothyroidism), anti-thyroid 

Continue hormone 
replacement/suppression and 
monitoring of endocrine function 
as appropriate


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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related
treatment (for 
hyperthyroidism), 
corticosteroids (for adrenal 
insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.

Rule-out secondary 
endocrinopathies 
(ie, hypopituitarism/
hypophysitis)
Grade 3 or Grade 4
endocrinopathies
(hypothyroidism,
hyperthyroidism, adrenal
insufficiency, type I diabetes
mellitus)

Withhold avelumab/placebo 
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/placebo 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/placebo if 
Resume avelumab/placebo once 
symptoms and hormone tests improve 
to Grade 1 (with or without hormone
replacement)
In addition, for hypophysitis with 
abnormal MRI, resume 
avelumab/placebo only once 
shrinkage of the pituitary gland on 
MRI/CT scan is documented
Continue hormone
replacement/suppression therapy as 
appropriate


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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related
mild symptoms with normal 
MRI. Repeat the MRI in 
1 month

Withhold avelumab/placebo 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
Other irAEs (not described above)
Grade of other irAEs
(NCI-CTCAE v4.03)
Initial management
Follow-up management
Grade 2 or Grade 3 clinical signs
or symptoms suggestive of a
potential irAE
Withhold avelumab/placebo 
therapy pending clinical 
investigation
If irAE is ruled out, manage as
appropriate according to the diagnosis 
and consider re-starting
avelumab/placebo therapy If irAE is 
confirmed, treat as Grade 2 or 3 irAE.
Grade 2 irAE or first occurrence
of Grade 3 irAE
Withhold avelumab/placebo 
therapy

1.0 to 2.0 mg/kg/day 
prednisone or equivalent

Add prophylactic antibiotics 
for opportunistic infections

Specialty consult as 
appropriate
If improves to Grade 1:

Taper steroids over at least 
1 month and resume 
avelumab/placebo therapy
following steroids taper.
Recurrence of same Grade 3
irAEs

Permanently discontinue 
avelumab/placebo 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/placebo therapy

1.0 to 2.0 mg/kg/day
prednisone or equivalent 
and/or other 
immunosuppressant as needed
If improves to Grade 1:

Taper steroids over at least 
1 month


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Table 7.
Management of Avelumab/placebo Immune-Related Adverse Events – to 
be followed only when the Adverse Event is deemed immune related

Add prophylactic antibiotics 
for opportunistic infections

Specialty consult
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/placebo 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, 
MRI=magnetic resonance imaging, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria 
for Adverse Events, PRL=prolactin, T4=thyroxine, TSH=thyroid-stimulating hormone, ULN=upper limit of 
normal.
5.5.2. Cisplatin
Cisplatin 100 mg/m2 will be administered in 500 mL normal saline over a 60 – 120 minute 
infusion with an additional 1 to 1.5 L of fluid give post-hydration.  Efforts should be made to 
dose cisplatin on Mondays or Tuesdays to maximize overlap with radiation therapy.  See the 
IP manual for further details regarding cisplatin administration.
5.5.2.1. Management of Cisplatin Toxicities and Pretreatment Guidelines
High dose cisplatin is a highly emetogenic regimen with significant incidence of delayed 
nausea and vomiting.  Institutional or ASCO guidelines for highly emetogenic regimens
should be followed.  In the absence of such guidelines the following may be used:

For acute nausea and vomiting, premedication should include a 5-HT3 
(5-hydroxytryptamine 3) antagonist, such as granisetron 1 mg IV; ondansetron, up to 
to 16 mg IV; or palonosetron, 0.25 mg IV; plus a corticosteroid, such as 
dexamethasone, up to 20 mg IV. Palonosetron has a longer half life (40h) than the 
first generation 5HT3 antagonists. 

Breakthrough nausea and vomiting should be managed at the discretion of the 
medical oncologist or radiation oncologist. Delayed nausea and vomiting (greater 
than 24 hours after chemotherapy administration) may be managed by the addition of 
aprepitant concurrently or with metoclopramide and dexamethasone. Potential 
delayed nausea regimens include:

The neurokinin (NK)-1 antagonist, may be added for prevention of delayed 
emesis on the day of cisplatin administration and for two consecutive days 


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thereafter (80, 80), with a corticosteroid, such as dexamethasone on Days 1-4. 
Dexamethasone should be reduced on Day 1 to 12 mg and delivered at up to 8 mg 
total daily for the 3 days following cisplatin administration. A 5HT3 antagonist 
(eg, granisetron, ondansetron) may be also given for the 3 days following cisplatin 
administration, only if palonosetron was not given prior to chemotherapy.

Delayed emesis also may be managed by the addition of dexamethasone 8 mg 
administered twice daily (BID) x 2 days, followed by dexamethasone 
4 mg BID x 2 days, beginning on the day after chemotherapy; and oral 
metoclopramide 0.5 mg/kg (usually 20-40 mg) four times daily (QID) x 2-4 days. 
A 5HT3 antagonist (eg, granisetron, ondansetron) may also be given for up to 
3 days after cisplatin administration, only if palonosetron was not given prior to 
chemotherapy.
Patients must receive vigorous hydration and diuresis. A suggested regimen is prehydration 
with a 1 liter of D5NS (potassium chloride in 5% dextrose and sodium chloride) over 
2-4 hours and mannitol, 12.5 g IV bolus immediately prior to cisplatin. Then cisplatin, 
100 mg/m2, in 500-1000 mL normal saline (NS) is administered over 1-2 hours followed by 
an additional 1 to 1.5 liters of fluid. Any pre-existing dehydration must be corrected prior to 
cisplatin administration. Should extravasation occur, the treating physician should follow 
institutional guidelines for management.
Additional IV hydration and blood urea nitrogen (BUN)/creatinine check also should be 
considered, if necessary, later in the week after cisplatin administration, in order to address 
any dehydration or severe fluid/electrolyte imbalance. On the second and third day following 
cisplatin, patients should be encouraged to take at least 2 liters of fluid per day orally.  
Patients unable to orally self-hydrate should be considered for additional IV hydration on 
these days with NS.
5.5.2.2. Cisplatin Dose Modifications for Toxicity During Concurrent Radiation
Patients will be examined and graded for subjective/objective evidence of toxicity while 
receiving concurrent cisplatin with radiotherapy. 
Chemotherapy dosage modifications are based upon laboratory values obtained within the 
24 hours prior to cisplatin and non-hematologic toxicities during the week prior to a 
particular cisplatin dose. Laboratory draws can be performed 1 business day prior to cisplatin 
infusion ie, laboratory draws on Friday can be used for infusion on Monday providing that 
any abnormality compromising cisplatin infusion (eg neutropenia, creatinine increase) is 
re-assessed on the day of infusion. 
The dose modifications for cisplatin (below) are intended to be permanent (ie, if the patient’s 
dose is reduced to dose level -1, it remains at the reduced dose level for the remainder of the 
CRT Phase).  There will be no dose re-escalation for cisplatin.
The dose of cisplatin may be modified on Days 22 and/or 43 for the following toxicities:


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Table 8.
Cisplatin Dose Levels 
Cisplatin Starting Dose
Dose Level -1
Dose Level -2
100 mg/m2
75 mg/m2
50 mg/m2
5.5.2.2.1. Cisplatin-Related Hematologic Adverse Events
Chemotherapy must not be administered until the patient’s ANC is 1,000/mm3 and platelets 
are 75,000/mm3. If not, delay 7 days. Cisplatin should be held every week until the above 
ANC and platelet parameters are met.  Dose reductions when cisplatin is resumed after delay 
for low ANC or platelets will be as follows, based upon counts at time cisplatin was held. 
Table 9.
Cisplatin Dose Modifications Due to Hematological Toxicity
ANC
Platelets
Reduction
1000/mm3
75,000/mm3
None
<1000/mm3
or
<75,000/mm3
One dose level
If on Day 22, neutropenia or thrombocytopenia prevents administration of cisplatin, but there 
is no contraindication for avelumab/placebo, then avelumab/placebo may be given on Day 22 
and cisplatin on any day between Days 25 to 33 if ANC and platelet counts recover.  If 
avelumab/placebo is administered on Day 22, then the following dose of avelumab/placebo
should then be administered 14 days later on Day 36.  The Day 43 dose of cisplatin can be 
given any time up to 5 days after the end of radiation therapy.
5.5.2.2.2. Cisplatin-Related Non-Hematologic Adverse Events 
Neutropenic Fever
Temperature of 38.5C with ANC <1000/mm3 is an expected potential complication of 
concurrent chemotherapy and radiotherapy or chemotherapy alone.  If neutropenic fever is 
encountered, then the chemotherapy dose reduction will be determined by the weekly blood 
counts (see Table 9).
Renal Toxicity
Cisplatin dose should be based on the serum creatinine or creatinine clearance immediately 
prior to the second cisplatin dose using the following guidelines.  Note:  If creatinine is 
>1.5 mg/dL, creatine clearance must be calculated (Cockcroft-Gault) in order to make a dose 
adjustment.  If the calculated clearance is 50 mL/min, a 24-hour urine collection is not 
needed.  However, if the calculation is <50 mL/min, a 24-hour urine collection is required, 
and the cisplatin dose will be determined as described in Table 10.


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Table 10.
Cisplatin Dose Modification Due to Decreased Creatinine Clearance
Serum Creatinine
Creatinine Clearance
Cisplatin Dose
≤1.5 mg/dL
OR
>50 mL/min
100 mg/m2
>1.5 mg/dL
AND
40-50 mL/min
50 mg/m2
>1.5 mg/dL
AND
< 40 mL/min
Hold cisplatina
a.
Cisplatin should be held (but the RT continued) and the creatinine measured weekly, until it is 
<1.5 mg/dL or the creatinine clearance is >50 mL/min, and then the second dose of cisplatin should be given 
at the reduced dose of 50 mg/m2.
Neurologic (Neuropathy) Adverse Events:
Table 11.
Cisplatin Dose Modifications Due to Neurologic Toxicity
CTCAE Grade
Dose Reduction 
0 – 1
None
2
One dose level
3 – 4
Hold drug
Ototoxicity:
Should patients develop clinical evidence of ototoxicity, further audiometric evaluation is 
required. A neurologic deficit should be distinguished from a conductive loss from 
obstruction of the Eustachian tube leading to a middle ear effusion. Because no AE scale, 
including the CTCAE, v4.03, has been validated in terms of correlation with clinically 
relevant hearing loss, there are no protocol mandates requiring dose reduction for 
audiogram-determined sensorineural hearing loss without an analogous clinical high grade 
(>Grade 2) hearing loss.  However, for clinical Grade 3 or higher hearing loss, cisplatin 
should be held and for Grade 2 clinical hearing loss, one dose level reduction.
Dependent upon the requirements documented in each country’s cisplatin SmPC, patients 
may require a baseline audiogram and a second audiogram within 12 weeks after the 
completion of CRT to monitor for potential ototoxicity related to cisplatin administration.  
Audiograms are a requirement in France.  For other countries that may have this requirement 
for cisplatin administration, refer to the local cisplatin SmPC.
All Other Non-Hematologic Adverse Events Attributable to Cisplatin during Concurrent 
Radiation:
For Grade>2 toxicities (excluding lymphopenia, mucositis, or dysphagia), hold cisplatin, 
re-evaluate weekly until AE resolves to Grade 1, then restart cisplatin at one lower dose 
level.


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5.5.2.3. Cisplatin Dosing Delays
Cisplatin chemotherapy will be delayed appropriately if treatment course is delayed 
(ie, second and third courses are administered on the 22nd and 43rd day of radiation therapy.  
If the second dose of cisplatin is delayed more than 21 days because of hematologic, 
neurologic, renal, or other adverse events, that dose will be omitted. 
If the Day 22 dose of cisplatin cannot be administered due to toxicity, but there is no 
contraindication for avelumab/placebo, avelumab/placebo may then be given on Day 22 and 
cisplatin administered on any day between Day 25 to 33 if the toxicity resolves.  If 
avelumab/placebo is administered on Day 22, the following dose of avelumab/placebo should 
then be administered 14 days later on Day 36.  The Day 43 dose of cisplatin can be given any 
time up to 5 days after the end of radiation therapy. 
It is expected that approximately 30% of patients will not be able to receive the 3rd dose of 
cisplatin due to related toxicity and this is not a PD. 
5.5.2.4. Concurrent Radiation Therapy Adverse Events
Grade 3 or 4 (CTCAE v4.03) therapy-induced mucositis and/or dysphagia, which are 
enhanced by cisplatin, are expected to develop in about two thirds of patients.  Nutritional 
evaluation prior to the initiation of therapy for a prophylactic percutaneous endoscopic 
gastrostomy (PEG) tube placement is highly recommended.  Placement of a feeding tube 
should be recorded, as should use of a feeding tube during and after treatment (eg, greater 
than or less than 50% of nutrition by tube).  Other common radiation adverse events include: 
fatigue, weight loss, regional alopecia, xerostomia, hoarseness, transient ear discomfort, 
dysgeusia, and skin erythema and desquamation within the treatment fields.
Less common long-term treatment adverse events include: hypothyroidism, loss of hearing, 
chronic swallowing dysfunction requiring permanent feeding tube, and cervical fibrosis. 
Much less common radiation adverse events include: mandibular osteoradionecrosis 
(<5% incidence), and cervical myelopathy (<1% with restriction of spinal cord dose to 
45 Gy).
Treatment interruptions are allowed if there is symptomatic mucositis or skin reaction that, in 
the judgment of the clinician, warrants a break.  For chemotherapy-attributable AEs requiring 
a break in treatment, IMRT may continue if clinically appropriate. 
5.5.3. Food Requirements
All investigational products may be administered without regard to food.
5.6. Investigational Product Storage
The Investigator, or an approved representative, eg, pharmacist, will ensure that 
avelumab/placebo and cisplatin are stored in a secured area with controlled access under 
required storage conditions and in accordance with applicable regulatory requirements.


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Avelumab/placebo and cisplatin should be stored in its original container and in accordance 
with the label.  See the Investigational Product (IP) Manual for storage conditions of the 
avelumab/placebo product once diluted.  Reconstituted solution of cisplatin is stable for 
20 hours when stored at 27C (80.6)F and should be protected from light if not used within 
6 hours.  Cisplatin has been shown to react with aluminum needles, producing a black 
precipitate within 30 minutes.
Both avelumab and placebo must be stored in the refrigerator at 2- 8C (36- 46F).  Do 
not freeze.  Protect from light.  Do not shake vigorously.
Storage conditions stated in the SRSD (IB)17 for avelumab and SRSD for cisplatin (package 
insert)37 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 
for excursions should be available.  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 investigational products are briefly out of the temperature range described in the labeling 
are not considered excursions.  More specific details will be provided to the sites separately. 
All study drug supplies must be kept in a locked, limited access room.  Avelumab/placebo 
must not be used outside the context of this protocol.  Under no circumstances should the 
Investigator or other site personnel supply study drug to other Investigators, patients, or 
clinics, or allow supplies to be used other than directed by this protocol without prior 
authorization from the Sponsor.  The Investigator and or site staff must report any 
unacceptable condition of the investigational product to the site monitor.


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5.7. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.
Pfizer may supply drug accountability forms that must be used or may approve of standard 
institution forms.  In either case, the forms must identify the investigational product, 
including batch or code numbers, and account for its disposition on a patient by patient basis, 
including specific dates and quantities. 
The prescribed dose must be recorded in the patient’s medical records.  Drug dispensing 
needs to be verified and documented by a second individual and the forms must be signed by 
both the individual who dispensed the drug and the second individual who verified the 
dispensing.  Copies must be provided to Pfizer. 
5.7.1. Destruction of Investigational Product Supplies 
At the end of the trial, or at appropriate points during the trial, Pfizer will provide instructions 
as to disposition of any unused investigational product.  If Pfizer authorizes destruction at the 
trial 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.  Destruction must be adequately documented.  If drug destruction is not 
permitted locally, Pfizer should be contacted for further directions.
5.8. 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 inactivated vaccines 
(for example, the 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 may be required.  
The Investigator should consult with the Sponsor about individual cases.  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. 
Concomitant treatment considered necessary for the patient’s well-being may be given at 
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 or until the start of new therapy, whichever comes first.  All concomitant 
medications and non-drug supportive interventions should be recorded in the CRF including 
supportive care drugs (eg, antiemetic treatment and prophylaxis, infusion reaction 
prophylaxis), and the drugs used to treat adverse events or chronic diseases, and non-drug 
supportive interventions (eg, transfusions).


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Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
Recommended medications to treat infusion-related reactions, hypersensitivity reactions and 
flu-like symptoms, tumor lysis syndrome and immune-related events are reported in 
Section 5.5.1.5, Section 5.5.1.6, Section 5.5.1.7, and Section 5.5.1.8, respectively.
5.8.1. Hematopoietic Growth Factors
The use of Erythropoietin is prohibited during radiation therapy. 
Hematological toxicity related to cisplatin should follow the modifications as stipulated in 
Table 9 of the protocol which states that for ANC <1000/mm³ or platelets <75.000/mm³ the 
infusion should be held until recovery and the next dose should be one level down 
(75 mg/mm³). 
According to ASCO guidelines (Journal of Clinical oncology (JCO) 2012),63 colony 
stimulating factors (CSF) should not be routinely used for afebrile neutropenia and secondary 
prophylaxis should be recommended in case dose reduction or treatment delay may 
compromise treatment outcome. 
If the investigator deems the administration of CSF warranted, its use may be allowed after 
consultation with, and approval by, the Sponsor.
5.8.2. Concomitant Surgery
5.8.2.1. Primary treatment neck dissection
Neck dissections within 20 weeks (140 days) of the completion of CRT are considered part 
of the initial treatment plan as defined in Appendix 3. 
5.8.2.2. Other Surgery
In case of a surgical procedure, study treatment should be delayed.  If a surgical requirement 
is required during the CRT Phase, CRT administration is to be held until patient recovery, at 
which time investigator assessment of the appropriateness of continuing definitive CRT is 
required for study treatment re-initiation.  Re-initiation at any phase of study treatment 
should be discussed with the Sponsor. 
5.8.3. Other Prohibited Concomitant Medications and Treatments
Patients are prohibited from receiving the following therapies during the treatment (CRT and 
Maintenance) phases of this trial: 

Anti-cancer systemic chemotherapy or biological therapy or investigational agents 
other than avelumab.

Immunotherapy not specified in this protocol. 


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
Immunosuppressive drugs (ie, systemic corticosteroids or other immunosuppressants 
except for short term treatment of allergic reactions, toxicity management associated 
with cisplatin, or for the treatment of irAEs).  Topical and inhalation steroids are 
allowed.

Medications or vaccinations specifically prohibited in the exclusion criteria.

Any vaccine therapies for the prevention of infectious disease within 4 weeks of start 
of study treatment, except administration of the inactivated vaccine. 

Bisphosphonate or denosumab treatment unless it has been initiated more than 
14 days prior to receiving the first administration of avelumab. 

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin).

Vitamins used as anticancer treatments.
Clarifications About Steroid Use with Avelumab: Data indicate that corticosteroids have 
an adverse effect on T-cell function and that they inhibit and damage lymphocytes.52,53  
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.54  Therefore, the use of steroids during this trial is restricted as follows:  
Therapeutic use: for the treatment of infusion-related reactions and short term treatment of 
irAEs, steroids are permitted according to the modalities indicated in Section 5.5.1.8.

Steroid administration required for cisplatin administration should be completed per 
institutional practice.

Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
10 mg prednisone daily is acceptable.

Prophylactic use, eg, prophylactic use prior to CT or MRI.

There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.9. Rescue Medications and Supportive Care
5.9.1. 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: 


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
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.

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. See also ASCO 
guidelines for treatment of nausea and vomiting.56

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 5.

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, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time (PT)/international normalized ratio (INR) should be performed.
5.10. Potential for Drug-Drug Interactions with Cisplatin
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy. 
Cisplatin might reduce the absorption of phenytoin thereby leading to reduced control of 
epilepsy.  Per country’s product labeling, anti-seizure medication might have to be changed 
to an alternative that is not contra-indicated with cisplatin administration.
In a randomized trial in advanced ovarian cancer, response duration was adversely affected 
when pyridoxine was used in combination with altretamine (hexamethylmelamine) and 
cisplatin.37
6. STUDY PROCEDURES 
All patients must sign an informed consent prior to any study-specific procedures.
All assessments should be performed prior to dosing with IV study treatments unless 
otherwise indicated on the Schedule of Activities table.  Assessments can be performed 
before or after daily IMRT during the CRT Phase.  Acceptable time windows for performing 
each assessment are described in the column headers on the Schedule of Activities table 
where applicable. 


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6.1. Screening
For screening procedures, see Schedule of Activities table as well as the Assessments section 
(Section 7).
Following informed consent, patients who complete screening assessments and are 
determined to be eligible may be registered use the IRT system.  Screening assessments for 
eligibility MUST have already been completed before the patient is enrolled.  To allow for 
additional flexibility in scheduling patient visit and procedures, Screening and Lead-in 
Day 1 procedures may be completed on the same day (see Schedule of Activities table). 
6.2. Study Treatment Period
For all on-treatment activities, see Schedule of Activities table as well as the Assessments 
section (Section 7).
6.2.1. Tumor Biospecimens
6.2.1.1. Mandatory Tumor Tissue
An archival FFPE tumor tissue block from the most recent tumor resection or biopsy must be 
provided for all patients enrolled in the study and submitted to the Central Laboratory prior 
to randomization.  If an FFPE tissue block cannot be provided, 15 unstained slides 
(10 minimum) will be acceptable.  Tumor tissue from cytologic sampling (eg, fine-needle 
aspiration, including FFPE cell pellet material), is not adequate and should not be submitted.
6.2.1.2. Optional Tumor Tissue – Lead-In Phase
An optional tumor biopsy, to be collected 4 to 7 days following the single dose of avelumab 
in the Lead-in Phase, is requested for analysis of potential biomarkers of response.  The de 
novo biopsy should be FFPE as per routine (see Study Manual), and the resulting FFPE 
tissue block(s) should be submitted to the Central Laboratory. 
6.2.1.3. De Novo Tumor Tissue – Maintenance Phase
For patients who, during the course of the study, undergo a clinically-indicated tumor 
resection procedure, a tumor sample from the procedure should be collected and submitted to 
the Central Laboratory as an FFPE tissue block. 
6.2.1.4. De Novo Tumor Tissue – End of Treatment/Withdrawal
A de novo (ie, fresh biopsy) tumor sample should also be collected at the End of 
Treatment/Withdrawal visit, unless clinically contraindicated or no tumor remains. 
Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet 
material) is not adequate and should not be submitted.  The de novo biopsy should be FFPE 
as per routine (see Study Manual), and the resulting FFPE tissue block(s) should be 
submitted to the Central Laboratory. 


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6.3. End of Treatment, Short- and Long-term Follow-up Visits
For End of Treatment, Follow-up, and Long-term Survival procedures, see Schedule of 
Activities table as well as Assessments section (Section 7).
In patients receiving investigational product up to the time of End of Treatment visit, 
additional safety follow-up visit will be scheduled for 30 days after the last dose received 
(Day 30 3) and a follow-up phone call will be performed 90 days after the last dose 
received (Day 90 3 [telephone contact]).  If any concern arises during the follow-up phone 
call, the patient will be called in for a follow-up visit within 5 calendar days of the initial 
phone call for appropriate assessment (as per the investigator’s medical judgement). 
Patients continuing to experience treatment related toxicity following discontinuation of 
study treatment will continue to be followed at least every 4 weeks until resolution or 
determination, in the clinical judgment of the investigator, that no further improvement is 
expected.
6.4. Patient Withdrawal
Patients may withdraw from the study 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:

Disease progression per modified RECIST v1.1;

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is clearly attributed to one of the 
investigational products, then withdrawal from study treatment may be considered, 
dependent upon the treatment and specific toxicity.  If a patient cannot tolerate 
cisplatin, or has a toxicity-related treatment delay due to the radiation therapy, 
withdrawal from this study is neither required nor suggested;

Pregnancy;

Significant protocol violation (including radiation therapy protocol violations);

Lost to follow-up;

Patient refused further treatment;

Study terminated by sponsor;

Death.


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Reasons for withdrawal from study follow-up may include:

Study terminated by the 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.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  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 
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.
7.1. Assessment of Progression
For all suspected progression of disease that is detected clinically, but is not visible on 
radiographic imaging, direct imaging (ie, photographs) are required.  This requirement is in 
addition to the requirement for pathologic confirmation of progression.
Tissue (pathologic) confirmation of disease is expected and required on this protocol for all 
local and regional lymph node suspected progression of disease. It is highly recommended 
that all new distant lesions suspicious for metastatic disease are also biopsied and 
pathologically confirmed.  Good clinical judgment is expected to be utilized on biopsy 
ascertainment including, but not limited to, the situations below. 
The following are expectations for biopsy ascertainment on a patient.  If any of these 
conditions are met, it is expected that a biopsy will be performed, and the reason for biopsy 
and pathologic findings noted in the CRF.  If a biopsy is not performed, clinical rationale 
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
New or significantly increased lesions on imaging or clinical exam;

Mucosal ulceration;

Suspicious mucosal changes;

Suspicion of unresolved disease at the primary tumor location at the 12 week post 
CRT visit (primary treatment failure and a PD event if biopsy is positive);

Significant enlargement, or newly enlarged, regional lymph nodes on clinical exam or 
imaging;

Areas of PET-positive fludeoxyglucose (FDG)- uptake;

Change of clinical findings on regional lymph node (neck) exam with new 
enlargement of a lymph node or group of nodes, or changes in character of lymph 
node group to palpation (eg, becoming harder or decreased mobility on physical 
exam - such as feeling attached to overlying skin, subcutaneous tissue or muscles, or 
underlying bone or muscle).
7.2. Safety Assessments
Safety assessments will include collection of AEs, Serious Adverse Events (SAEs), vital 
signs, physical examination, electrocardiogram (ECG, 12-lead), and laboratory assessments 
(including pregnancy tests). Further details of these assessments are described in the 
Schedule of Activities table.
7.2.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL human chorionic gonadotropin (hCG) 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 Day 1 of the Lead –in Phase, immediately before 
administration of avelumab/placebo.  Following a negative pregnancy test result at screening, 
appropriate contraception must be commenced and another negative pregnancy result will 
then be required at Day 1 of the Lead-in Phase visit before the patient may receive the study 
treatment.  Pregnancy tests (serum or urine) will also be routinely repeated as described in 
the Schedule of Activities prior to each dose of study treatment during the active treatment 
period, at the End of Treatment visit, during the post-treatment safety follow-up visits up to 
at least 30 days after the last study treatment infusion, and additionally whenever 1 menstrual 
cycle is missed or when potential pregnancy is otherwise suspected.  In the case of a positive 
confirmed pregnancy, the patient will be withdrawn from administration of study treatment 
but may remain in the study. 
Additional pregnancy tests may also be undertaken if requested by institutional review 
boards (IRBs)/ethics committees (EC) or if required by local regulations.


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7.2.2. Adverse Events
Assessment of adverse events will include the type and severity (graded by 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.
Baseline signs and symptoms should be recorded in the medical history CRF page.
7.2.3. Laboratory Safety Assessments
Hematology, blood chemistry, and urinalysis will be collected at the time points described in 
the Schedule of Activities and analyzed at local laboratories.  They may also be performed 
when clinically indicated.  Abnormal laboratory test results should be repeated as soon as 
possible (preferably within 24-48 hours).  The required laboratory tests are listed in Table 12.


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Table 12.
Required Laboratory Tests
Hematology
Chemistry Panel
(*denotes core chemistry 
test)
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT*
Protein, glucose, blood PT or INR
For female 
patients of 
childbearing 
potential, serum 
or urine 
Platelets
AST*
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*
Phosphorus or Phosphate*
Albumin*
Total Protein*
Uric Acid
Amylase
Gamma glutamyl 
transferase (GGT)
Cholesterol
Creatine kinase
C-reactive protein (CRP)
Lactate dehydrogenase 
(LDH)
Lipase
Triglycerides
HBV, HCV serology
Thyroid Function Tests:
TSH, free T4
Other Tests: 
ACTH, 
° 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, GGT, 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, HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international 
normalized ratio, LDH=lactate dehydrogenase, PT=prothrombin time, TSH=thyroid-stimulating hormone, 
WBC=white blood cell
7.2.4. Physical Examinations and Vital Signs
Patients will have physical examinations to include major body systems, assessment of 
ECOG performance status, weight and height (height will be measured at screening only) at 
the time points described in the Schedule of Activities table. 
At baseline evaluation, nasopharyngoscopy is strongly recommended.


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Weight for the purposes of dose calculation will be recorded at screening and within 3 days 
prior to each dose of avelumab. Baseline weight is used for the Lead-in D1 dose calculation. 
Vital signs (blood pressure and pulse rate) will be also recorded as reported in the Schedule 
of Activities table. They should be taken before any other assessments (eg, PK, laboratory 
blood draws), prior to receipt of study treatment with the patient in the seated position after 
the patient has been sitting quietly for at least 5 minutes.
7.2.5. 12-Lead Electrocardiograms
All patients require a single ECG measurement at screening and at the 
End-of-Treatment/Withdrawal visit or when clinically indicated. Clinically significant 
findings seen on ECG during the treatment period should be recorded as adverse events.
Triplicate 12-lead (with a 10-second rhythm strip) tracing will be collected in approximately 
30 patients in each arm of the study.  It is preferable that the machine used has a capacity to 
calculate the standard intervals automatically.  In these patients, on-treatment triplicate ECGs 
will be performed on the day of avelumab/placebo administration (ie, Day 1 of the Lead-in 
Phase, and Days 8, 25, and 39 of the CRT Phase; if the avelumab/placebo dosing day is 
shifted for patient scheduling reasons, the ECG assessment should be shifted also).  At each 
time point (see the Schedule of Activities) 3 consecutive 12-lead ECGs (triplicates) will be 
performed approximately 2 minutes apart to determine mean QTc (average of triplicates) 
prior to avelumab/placebo administration and at the end of infusion.  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 a 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 as clinically indicated.  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 or have their dosing delayed as 
appropriate for specific investigational product.  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. 
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 a specialist.


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If a patient experiences any cardiac or neurologic AEs (especially syncope, dizziness, 
seizures, or stroke), an ECG in triplicate should be obtained at the time of the event. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (ie, the timing of the PK 
collections over rides the timing of the ECG collections).
Clinically significant findings seen on ECGs during the treatment period should be recorded 
as AEs. 
7.3. Pharmacokinetics Assessments
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing. If a scheduled blood sample collection cannot be completed for any reason, the 
missed sample may be re-scheduled with agreement of clinical investigators, patient and 
Sponsor.

Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site prior to initiation of the trial.

Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.

The samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor. On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulted in compromised 
sample integrity, will be considered a protocol deviation.

As part of understanding the pharmacokinetics of the study drug, samples may be 
used for further characterization and/or evaluation of the bioanalytical method.  These 
data will be used for internal exploratory purposes and will not be included in the 
clinical report. Samples collected for this purpose will be retained in accordance with 
local regulations and, if not used within this timeframe, will be destroyed. 
7.3.1. Blood for PK Analysis of Avelumab
Blood samples (3.5 mL whole blood) for PK analysis of avelumab will be collected in all 
patients into an appropriately labeled serum separator tube (SST) as outlined in the Schedule 
of Activities table.  PK sampling schedule may be modified based on emerging PK data.  
Blood for PK samples will be drawn from the contralateral arm of the drug infusion.


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7.3.2. Blood for PK Analysis of Cisplatin
Blood samples (5 mL whole blood at each time point) will be collected for PK analysis of 
cisplatin in a total of 24 patients (12 patients in Arm A and 12 patients in Arm B) at selected 
sites into appropriately labeled tubes as outlined in the Schedule of Activities table.  PK 
sampling schedule may be modified based on emerging PK data. Blood for PK samples will 
be drawn from the contralateral arm of the drug infusion.
7.4. Immunogenicity Assessments
The sample analysis will follow a tiered approach of screening, confirmation, and titer 
determination. Samples tested positive for ADA may be further analyzed for neutralizing 
antibodies (nAb). 
Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site prior to initiation of the trial in the 
Study Manual.
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
The samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor. On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulted in compromised 
sample integrity, will be considered a protocol deviation.
As part of understanding the immunogenicity of the study drug, samples may be used 
for further characterization and/or evaluation of the bioanalytical method. These data 
will be used for internal exploratory purposes and will not be included in the clinical 
report.  Samples collected for this purpose will be retained in accordance with local 
regulations and, if not used within this timeframe, will be destroyed. 
7.4.1. Immunogenicity Assessment of Avelumab
Blood samples (3.5 mL whole blood) will be collected for development of avelumab ADAs 
into an appropriately labeled SST.  This monitoring will take place at regular intervals during 
the treatment and follow-up periods as described in the Schedule of Activities table.  All 
samples that are positive for ADA may also undergo characterization for Nab.
7.5. Translational and Pharmacodynamic Assesments
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers that may identify those patients who benefit from treatment 
with the combination of avelumab and CRT.  In addition, analyses of sequentially obtained 
blood biomarkers will provide an opportunity to investigate pharmacodynamic effects.  
Samples collected at the End of Treatment/Withdrawal visit will also help understand 
potential acquired mechanisms of resistance to the drug combination.


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7.5.1. Tumor Biospecimens
Tumor biospecimens representing tissue samples from tumor resection or biopsy (see 
Section 6.2.1) will be used to analyze candidate DNA, RNA, or protein markers, or relevant 
signature of markers for their ability to identify those patients who are most likely to benefit 
from treatment with the study drugs. 
Markers that may be analyzed include but may not necessarily be limited to: PD-L1 
expression and tumor infiltrating CD8+ T lymphocytes by IHC; and/or tissue expression of 
FoxP3, PD-1, PD-L2; homologous recombination deficiency testing on tumor tissue.
Samples obtained during the Lead-in Phase (optional), Maintenance Phase (in patients who 
undergo a clinically-indicated tumor resection), and/or at the End of Treatment/Withdrawal 
visit (all patients) will be assessed in parallel with the mandatory pre-treatment 
biospecimens(s) to provide data on the changes in the tumor that accumulated over the course 
of therapy, including acquired mechanisms of resistance. Cytologic preparations, such as 
fine needle aspirate biopsies, are not acceptable. Tumor tissue collected (via slides) in China 
will not be retained and will be examined for PD-L1 expression and CD8 lymphocyte 
infiltration by immunochemistry, tumor mutational burden and immune repertoire by T-cell 
receptor (TCR) analysis.
Additional information on tissue collection procedures can be found in the Study Manual. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
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7.7. Patient-Reported Outcomes Assessments
The NCCN FHNSI-22 (Appendix 6), EQ-5D-5L (Appendix 7), 
 
will be administered at time points described in the Schedule of 
Activities in the clinic by the patient.  These questionnaires cannot be taken home. 
 
7.8. Tumor Response Assessment
Tumor assessments will include all known or suspected disease sites.  Imaging at screening 
(baseline) and at 12 weeks after completion of CRT must include a head and neck CT or 
MRI, chest CT, and PET scan.  High resolution PET/CT does not require additional 
CT thorax/neck/brain.  MRI brain may be performed if clinically indicated.  Other areas may 
be scanned as clinically indicated.  The CT and MRI scans should be performed with contrast 
agents unless contraindicated for medical reasons. The same imaging technique used to 
characterize each identified and reported lesion at baseline will be employed in the following 
tumor assessments.  At a minimum, the CT modality used at baseline will be the expected 
imaging technique for follow-up. Any clinical progression concern warranting a biopsy must 
have supporting imaging (ie, CT, MRI, PET, or digital photograph) archived for 
documentation purposes.  Additional imaging modalities may also be employed if clinically 
required.  Baseline tumor assessments should be done within 28 days prior to randomization. 
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Radiographic and clinical evaluations will be conducted with the same schedule in both 
treatment arms of the study.  The investigator will assess antitumor activity based on 
radiological assessments and clinical evaluation of patients using modified RECIST v1.1 
(Appendix 3) at screening (baseline), 12 weeks after the completion of CRT, every 16 weeks 
thereafter for 48 months (208 weeks), and every 24 weeks (Q24W) thereafter until confirmed 
disease progression per modified RECIST v1.1 and regardless of discontinuation of study 
treatment or initiation of subsequent anti-cancer therapy. 
The assessment performed 12 weeks after completion of the CRT is to include CT and PET 
for all patients and MRI also if clinically appropriate in patients who did not achieve clinical 
or CT/MRI-based radiological nodal CR at the tumor assessment performed 12 weeks 
following completion of CRT, and follow-up PET scans are recommend every 4 months 
(16 weeks) with the CT imaging for 24 months (104 weeks), then every 6 months (Q24W) in 
Years 3-5.  CT imaging should be obtained as described in the Schedule of Activities beyond 
Year 5. The time window for tumor assessments is 1 week except for the assessment at 
Week 12 which cannot be done earlier but can be done up to one week later.
Additional radiological tumor assessments will also be conducted whenever disease 
progression is suspected (eg, symptomatic deterioration or physical exam findings suggestive 
of mucosal recurrence).  See the Schedule of Activities.
If radiologic imaging shows progressive disease, assigned study treatment should be 
continued while awaiting pathologic confirmation of disease progression per modified 
RECIST v1.1 unless the patient is clinically unstable and/or requires an urgent alternative 
intervention (eg, decompression of a spinal cord compression).  All locoregional disease 
recurrence or progression must be pathologically confirmed (see Appendix 3).  The date of 
progression will be the date of the radiographic evaluation that showed progression which 
was subsequently confirmed by pathology.
All radiographic images will be collected and stored for possible future objective verification 
by an independent third-party core imaging laboratory (central review) as described in the 
Study Manual.  In addition any photographs of clinical progression concerns warranting 
biopsy will also be collected for potential future review. 
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 a 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.


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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 90 days after last administration of 
investigational product.

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;

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;


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
Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

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.
8.4. 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 AE(s) 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 or cisplatin is defined as any dose 
5% over the calculated dose for that particular administration.  Radiation dosing parameters 
are defined and limited in the Radiation Delivery Guidelines document. 


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There is no specific treatment for avelumab overdose.  In the event of overdose with 
avelumab, the patient should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided as clinically indicated.
An acute overdose of cisplatin may result in renal failure, liver failure, deafness, ocular 
toxicity (including detachment of the retina), significant myelosuppression, untreatable 
nausea and vomiting and/or neuritis. An overdose may be fatal.
There is no specific antidote in the event of an overdosage of cisplatin. Even if 
haemodialysis is initiated 4 hours after the overdose it has little effect on the elimination of 
cisplatin from the body following a strong and rapid fixation of cisplatin to proteins.
Treatment in the event of an overdose consists of general support measures.
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 or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
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;


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
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 Section 8.8 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). 
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in AST and/or 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 values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).


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Concurrent with:

For patients with preexisting 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-glutamyl 
transferase, 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 liver function test (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.
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;


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
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 pretreatment 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.
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
AEs will be reported using concise medical terminology (verbatim) as well as the grade from 
the CTCAE Version 4.03, http://ctep.cancer.gov/reporting.ctc.html) listed in the Cancer 
Therapy Evaluation Program. 
If required on the AE CRFs, the investigator will use the following definitions of severity in 
accordance with CTCAE Version 4.03 to describe the maximum intensity of the adverse 
event (Appendix 5).


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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, a 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.
For combination study treatment, causality assessment will be performed for each of the 
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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 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure 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.


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Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

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/ legally acceptable representative. 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 trial 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment.
This section describes the data analysis and statistical methods for this study.


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9.1. Sample Size Determination
The study is designed to test the following hypotheses:
        H0: HRPFS(A/B) 1 versus Ha: HRPFS(A/B) <1
Where HRPFS(A/B) represents the hazard ratio (HR) for PFS in Arm A vs Arm B. A 
stratified log-rank test stratified by randomization stratification factors will be used for 
analysis of PFS. 
Two hundred eighty-nine (289) PFS events will be required to have at least 90% power to 
detect a hazard ratio of 0.68 using a1-sided log-rank test at a significance level of 0.025, and 
a 2-look group-sequential design with Lan-DeMets (O’Brien-Fleming) -spending function 
to determine the efficacy boundary and a Gamma Family (-7) -spending function to 
determine the non-binding futility boundary.
The sample size of 640 patients for this study is determined based on the assumptions that the 
median PFS for patients in Arm B is 33 months43,44 and that combination treatment including 
avelumab (Arm A) is expected to increase the median PFS to 48.5 months, corresponding to 
a HR of 0.68 under the exponential model assumption. 
The sample size further assumes a 15% drop-out rate within each treatment arm and a 
non-uniform patient accrual over a 22-month period.  The data cutoff for the primary PFS 
analysis will occur after the target number of events has been reached and the last patient 
randomized in the study has been followed for at least 24 months after randomization.
The sample size of 640 patients will also allow the assessment of a difference in OS.  OS will 
be tested using a hierarchical testing procedure, provided the primary endpoint, PFS, is 
statistically significant favoring Arm A.  A total of 392 OS events will be required to have 
80% power to detect a HR of 0.75 using a 1-sided log-rank test at a significance level of 
0.025 and a 5-look group sequential design with Lan-DeMets (O’Brien-Fleming) -spending 
function to determine the efficacy boundary.  It is assumed that the median OS for patients in 
Arm B is 70 months,43,44 and that treatment with avelumab (Arm A) is expected to increase 
the median OS to 93 months, corresponding to a HR of 0.75 under the exponential model 
assumption.  The sample size further assumes a 5% drop-out rate for OS in each treatment 
arm, and a follow-up of approximately 106 months after the last patient is randomized.  The 
data cutoff for the final OS analysis will occur after the target number of deaths has been 
reached in the study.
9.2. Analysis Populations
9.2.1. Full Analysis Set
The full analysis set (FAS) will include all patients who are randomized.  Patients will be 
classified according to the treatment assigned at randomization.  The FAS will be the primary 
population for evaluating all efficacy endpoints and patient characteristics.


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9.2.2. Per-Protocol Analysis Set
The per-protocol analysis set is a subset of the FAS and will include patients who do not 
meet criteria that could impact the key objectives of the study.  These criteria will be 
pre-specified in the statistical analysis plan.  The per-protocol analysis set will be used for 
sensitivity analyses of the primary efficacy endpoint, PFS. 
9.2.3. Safety Analysis Set
The safety analysis set will include all patients who receive any study treatment.  Patients 
will be classified according to the treatment assigned at randomization unless the incorrect 
treatment(s) are received throughout the treatment period, in which case patients will be 
classified according to the first treatment received.  The safety analysis set will be the 
primary population for evaluating treatment administration/compliance and safety.
9.2.4. Pharmacokinetics Analysis Set
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least 1 concentration above the lower limit of quantitation (LLQ) for 
avelumab or cisplatin (total and free).
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least 1 of the PK parameters of interest for avelumab or cisplatin.
9.2.5. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least 1 ADA/Nab sample collected for avelumab in Arm A. 
9.2.6. Biomarker Analysis Set
The biomarker analysis set is a subset of the safety analysis set and will include patients who 
have at least 1 screening biomarker assessment.  Analysis sets will be defined separately for 
blood-based and tumor tissue-based biomarkers.
9.3. Efficacy Analysis
All analyses will be performed on the FAS unless otherwise specified.
All analyses will be performed by using SASVersion 9.1.3 or higher.
9.3.1. Analysis of the Primary Endpoint
PFS is defined as the time from the date of randomization to the date of the first 
documentation of objective PD per modified RECIST v1.1or death due to any cause, 
whichever occurs first.
The following will be considered events in the analysis of PFS:

Death due to any cause;


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
Locoregional disease progression per RECIST v1.1 which is subsequently confirmed 
by pathology;  

Locoregional clinically detectable progression that is confirmed by pathology;

Surgical removal (salvage) of primary tumor with tumor present on final pathology;

Salvage neck dissection >20 weeks (140 days) after completion of SOC CRT with 
tumor present on final pathology;

Metastatic (distant metastases) disease progression per RECIST v1.1. 
For the primary analysis, PFS data will be censored on the date of the last adequate tumor 
assessment for patients who do not have an event (PD per modified RECIST v1.1 or death); 
the analysis will consider any PD per modified RECIST v1.1 or death as an event regardless 
of the number of prior missing tumor assessments or timing of the event with respect to 
initiation of anti-cancer therapy. 
The primary analysis of PFS will be performed based on the FAS.  A stratified log-rank test 
(1-sided) stratified by randomization stratification factors will be used at the interim and/or 
final analyses with the overall significance level preserved at 0.025 (1-sided).  PFS times 
associated with each treatment arm will be summarized using the Kaplan-Meier method and 
displayed graphically where appropriate.  CIs for the 25th, 50th, and 75th percentiles will be 
reported.  The stratified Cox proportional hazards model will be fitted to compute the 
treatment hazard ratio and the corresponding 95% CI.
A sensitivity analysis for PFS will be performed using the methodology outlined for the 
primary analysis of PFS above but defining PD as per standard RECIST v1.1.  Summary of 
discordance of PD (event and timing) as well as reasons for discordance between assessment 
of PFS per modified RECIST v1.1 and standard RECIST v1.1 will be provided for each 
treatment arm. 
PFS based on modified RECIST v1.1 will also be evaluated based on the per-protocol 
analysis set as a sensitivity analysis using the methodology outlined for the primary analysis 
of PFS. 
Other sensitivity analyses will be pre-specified in the SAP.
9.3.2. Analysis of Secondary Endpoints
9.3.2.1. Overall Survival
OS is defined as the time from date of randomization to date of death due to any cause.  
Patients last known to be alive will be censored at date of last contact. 
OS will be hierarchically tested for significance at the time of PFS analyses, provided the 
primary endpoint, PFS, is statistically significant at the PFS interim or final analyses.  In 
addition, OS will be tested at 69% and 88% of the OS events and at the OS final analysis.  A 


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stratified log-rank test (1-sided) stratified by randomization stratification factors will be used 
at the interim and/or final analyses with the overall significance level preserved at 0.025 
(1-sided).  OS time associated with each treatment arm will be summarized using the 
Kaplan-Meier method and displayed graphically where appropriate.  CIs for the 25th, 50th, 
and 75th percentiles will be reported.  The Cox proportional hazards model will be fitted to 
compute the treatment hazard ratio and the corresponding 95% CI.
9.3.2.2. Pathologic Complete Response
Pathologic complete response is defined as the absence of histologically identifiable residual 
cancer in any resected specimen.  The pathogical complete response rate on each treatment 
arm will be estimated by dividing the number of patients with pathogical complete response 
recorded from randomization until PD per modified RECIST v1.1 or death due to any cause 
by the number of patients randomized to the respective treatment arm.  The corresponding 
exact 2-sided 95% CIs will be provided by treatment arm.
9.3.2.3. Objective Response
Objective response (OR) is defined as a CR or PR per RECIST v1.1 (Appendix 4) recorded 
from randomization until disease progression per modified RECIST v1.1 (Appendix 3) or 
death due to any cause.  A patient will be considered to have achieved an OR if the patient 
has a CR or PR which does not need to be confirmed at a subsequent assessment.  
Additionally, patients with inadequate data for tumor assessment (eg, no baseline assessment 
or no follow-up assessments) will be considered as non-responders in the ORR analysis.
The ORR on each treatment arm will be estimated by dividing the number of patients with 
OR (CR or PR) by the number of patients randomized to the respective treatment arm.  The 
corresponding exact 2-sided 95% CIs will be provided by treatment arm.  The CR rate and 
PR rate analyses will be performed similarly.  In addition, the best overall response for each 
patient will be summarized by treatment arm.
9.3.2.4. Duration of Response
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 PD per modified RECIST v1.1 or death due to any cause, whichever 
occurs first.  Censoring rules for DR will follow those described above for PFS.  DR will be 
summarized by treatment arm using Kaplan-Meier method and displayed graphically, where 
appropriate.  The median DR and 95% CI for the median will be provided for each treatment 
arm.
9.3.2.5. Locoregional Failure 
Locoregional failure (LRF) is defined as the time from the date of randomization to the date 
of the first documentation of locoregional recurrence or death due to any cause, whichever 
occurs first.  LRF will be summarized by treatment arm using Kaplan-Meier method and 
displayed graphically, where appropriate.  The median LRF and 95% CI for the median will 
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9.3.2.6. Distant Metastatic Failure 
Distant metastatic failure or distant metastasis (DM) is defined as the time from the date of 
randomization to the date of the first documentation of distant metastatic or death due to any 
cause, whichever occurs first.  DM will be summarized by treatment arm using Kaplan-Meier 
method and displayed graphically, where appropriate.  The median DM and 95% CI for the 
median will be provided for each treatment arm.
9.3.2.7. Neck Dissection
The rate of neck dissection on each treatment arm will be estimated by dividing the number 
of patients with neck dissection recorded from randomization until PD per modified RECIST 
v1.1 or death due to any cause by the number of patients randomized to the respective 
treatment arm.  The corresponding exact 2-sided 95% CIs will be provided by treatment arm.
The rate of pathologically-positive neck dissection and rate of pathologically-negative neck 
dissection will be analyzed in the same way as the rate of neck dissection. 
9.3.2.8. Patient-Reported Outcomes
The FAS will be used for the PRO analysis. 
NCCN-FHNSI-22 and EQ-5D-5L, will be scored according to their respective validation 
papers and user’s guides.  For the EQ-5D-5L, utility scores will be calculated using the 
published weights (tariffs) for the United Kingdom (UK).  Specific country weights may be 
applied for country specific analyses as needed. 
Summary statistics (mean and standard deviation [SD], median, range) of absolute scores 
will be reported for the total and subscales of the FHNSI-22, and the utility and VAS scores 
of the EQ-5D-5L..  The mean change of absolute scores from baseline (and 95% CI) will also 
be reported.  Line charts depicting the means and mean changes of items and subscales over 
time will be provided for each treatment arm. 
Symptoms of disease will be assessed using the DRS-P subscale of the NCCN-FHNSI-22 
with a focus on the single item ‘I can swallow easily and naturally’.  HRQoL will be assessed 
using the FWB subscale of the NCCN-FHNSI-22 and also the EQ-5D-5L. 
Treatment arms will be compared using percent of patients with improvement in swallowing, 
defined as a 1-point increase on the 5-point Likert scale maintained for 2 consecutive 
assessments, in the single ‘swallowing’ item of the FHNSI-22.  A chi-square test will be used 
for the analysis including patients in the FAS with a baseline score and at least one 
post-baseline assessment. 
Treatments arms will be compared based on time to deterioration (TTD) of 1) HRQol, 
2) disease-related symptoms-physical, and 3) ‘swallowing’.  TTD is defined as the time from 
randomization to deterioration where deterioration is defined, respectively, as 1) a 3 point 
decrease on the FWB scale for health-related quality of life (HRQoL), 2) a 3 point decrease 
on the DRS-P for symptoms of disease, and 3) a 1 point decrease on the ‘swallowing’ item of 
the FHNSI-22, in two consecutive assessments.  The time to event will be calculated using 


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the date of the baseline assessment and the date of first of the two consecutive assessments 
use to identify the event.  Note that a decline in FWB subscale of the FHNSI-22 represents a 
worsening in HRQol.  A decline in DRS-P score represents an increase in physical symptoms 
of disease.  A decline in the ‘swallowing’ item score represents a decrease in the ability to 
swallow naturally and easily. 
Patients will be censored at the last time when they completed a PRO assessment if they have 
not deteriorated prior to death, lost to follow-up or the last scheduled PRO assessment. 
TTD associated with each treatment arm will be summarized using the Kaplan-Meier method 
and displayed graphically where appropriate.  CIs for the 25th, 50th, and 75th percentiles will 
be reported.  The Cox proportional hazards model will be fitted to compute the treatment 
hazard ratios and the corresponding 95% CIs. 
Treatment arms will be compared based on mean scores of the FHNSI-22 total, subscales and 
the EQ-5D-5L utility and VAS scores obtained from repeated measures, mixed-effects 
regression models that contain the baseline score as a covariate.  Other exploratory PRO 
analyses may be performed subsequently.
9.3.2.9. Analysis of Pharmacokinetics
The central laboratory, analytical laboratories (eg, PK, ADA, NAb), and Pfizer clinical assay 
group (CAG) colleagues will be unblinded.  If the need arises for early analysis of the PK 
concentration analysis set (before database lock and release of the randomization codes for 
the study), a PK unblinding plan will be developed.  A PK analyst, who is not associated with 
the study team, will conduct the analysis to avoid unblinding of the study team.
9.3.2.9.1. Pharmacokinetic Analysis of Avelumab
Cmax and Ctrough for avelumab will be summarized descriptively (n, mean, SD, CV, median, 
minimum, maximum, geometric mean ratios, its associated CV, and 95% CI) by study phase, 
cycle (if applicable), and day.  The trough concentrations for avelumab will be plotted using 
a box-whisker plot by study phase, cycle (if applicable), and day in order to assess the 
attainment of steady-state in Arm A.
Additionally, avelumab PK will be evaluated following cisplatin dosing by comparing the 
overall geometric mean ratios of Cmax and Ctrough in only Arm A on Day 8 of the CRT Phase 
to Day 1 of the Lead-in Phase.
9.3.2.9.2. Pharmacokinetic Analysis of Cisplatin
Standard plasma PK parameters for cisplatin (total and free) will be estimated using 
non-compartmental and/or compartment methods, if needed.  Analyses will include Cmax, 
time to Tmax, AUCinf, t½, CL, and Vz as data permit.
Dose-normalized parameters (eg, CDN-Cmax, DN-AUCinf) will be reported as appropriate.  
Descriptive statistics for the PK parameters for cisplatin will be provided in tabular form.  
Cisplatin plasma concentrations will be summarized descriptively (n, mean, SD, CV, median, 


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minimum, maximum, geometric mean, its associated CV, and 95% CI) by nominal time.  
Individual patient and median profiles will be presented on both linear-linear and log-linear 
scales.
Additionally, cisplatin PK (total and free) will be evaluated following avelumab or placebo 
dosing by comparing the overall geometric mean ratios of Cmax and AUCinf on Day 1 of the 
CRT Phase in Arm A to Day 1 of the CRT Phase in Arm B.
9.3.2.10. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
PK and PD 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 efficacy and safety endpoints.  The results of these 
analyses, if performed, may be reported separately.
In addition, the relationship between exposure and efficacy and safety endpoints may be 
explored, as necessary, based on emerging efficacy and safety data.  The analysis details will 
be provided in the Population Modeling Analysis Plan.  The results of these modeling 
analyses may be reported separately from the clinical study report. The analyses will include 
subjects in both the FAS and the safety analysis set. 
9.3.2.11. Immunogenicity Analysis
All analyses will be performed on the immunogenicity analysis set.
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized by phase (Lead-in, CRT, or Maintenance) and overall.  
For patients with positive ADA, the magnitude (titer), time of onset, and duration of ADA 
response will also be described, if data permit. 
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.
 
9.5. Safety Analysis
The safety analysis set will be the primary population for safety evaluation.  Summaries of 
AEs and other safety parameters will be provided, by treatment arm, as appropriate.
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9.5.1. 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 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html).  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 severity grade, and will be summarized by relatedness to study 
treatment.
Emphasis in the analysis will be placed on AEs classified as treatment emergent.  Adverse 
events leading to death or discontinuation of study treatment, events classified as NCI 
CTCAE v4.03 Grade 3, trial drug-related events, and serious adverse events will be 
considered with special attention.  As appropriate, the difference in risk between treatment 
arms for AEs of clinical interest may be further assessed as described in the SAP.
Detailed information collected for each AE will include a description of the event, duration, 
whether the AE was serious, intensity, relationship to study treatment, action taken, and 
clinical outcome.  Acute toxicities and late toxicities will also be summarized separately.
9.5.2. Laboratory Abnormalities
Laboratory test results will be graded according to the NCI CTCAE v4.03 severity grade.  
The frequency of patients with laboratory test abnormalities will be summarized according to 
the worst grade for each laboratory test. 
For laboratory tests without an NCI CTCAE grade definition, 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.
9.5.3. Electrocardiograms
ECG measurements will be used for the statistical analysis and all data presentations.  
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, heart rate (HR), and RR, PR, QRS, QTc intervals. 
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. 
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 


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experiencing clinically relevant morphological ECG changes will be summarized (including 
frequency and percentage).
9.6. Interim Analysis
The interim analysis will be performed based on the FAS.  Any safety evaluation at the time 
of the interim analysis will be based on the safety analysis set.
The goals of the interim analysis for PFS are to allow early stopping of the study for futility 
or determination of superiority of Arm A compared to Arm B based on PFS. 
The study is designed to have 1 interim analysis and the final analysis based on the primary 
PFS endpoint.  A formal efficacy boundary (O’Brien-Fleming) for rejecting the null 
hypothesis is constructed by using the spending function methodology of Lan-DeMets.  To 
protect the integrity of the study and to preserve the type 1 error rate, a fraction of α (0.0097) 
for efficacy will be spent at the interim analysis and accounted for in the overall type 1 error 
rate if the interim analysis is performed exactly at the planned number of PFS events.  The 
nominal significance levels for the interim and final efficacy analyses of PFS will be 
determined by using the Lan-DeMets procedure with an O’Brien-Fleming stopping 
boundary.  The overall significance level for the efficacy analysis of PFS will be preserved at 
0.025 (1-sided test).  The futility boundary is non-binding and will be determined based on a 
Gamma Family (-7) β-spending function.
The interim analysis of PFS will be performed after all patients have been randomized in the 
study and approximately 217 PD events per modified RECIST v1.1 or deaths 
(75% information fraction) have occurred.  If the value of the test statistic exceeds the 
efficacy boundary (z <- 2.338, p <0.010), then superiority of Arm A compared to Arm B 
could be declared.  If the value of the test statistic exceeds the futility boundary (z >- 0.728, 
p >0.233), then the study may be stopped for futility.  Since the observed number of events at 
the interim analysis may not be exactly equal to the planned 217 PFS events, the efficacy and 
futility boundaries will be updated based on the actual number of observed events using the 
pre-specified -and -spending functions. 
If the results of the interim analysis indicate serious safety concerns, the sponsor, in 
conjunction with an external Data Monitoring Committee (E-DMC), will communicate with 
the Health Authorities regarding stopping the clinical trial.
OS will be compared between the 2 treatment arms using a hierarchical testing procedure, 
provided the primary endpoint, PFS, is statistically significant favoring Arm A. A maximum 
of 5 analyses are planned for OS: at the time of the interim analysis for PFS, at the time of 
the final analysis for PFS, after 270 deaths are observed, after 345 deaths are observed, and a 
final analysis for OS after 392 deaths are observed. An -spending function according to 
Lan-DeMets (O’Brien-Fleming) independent of the one used for the primary efficacy 
analysis will be used to preserve the 0.025 overall level of significance across the two 
hypotheses and the repeated testing of the OS hypotheses in the interim and the final 
analyses. The trial allows for the stopping of the study for a superior OS result, provided the 


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primary endpoint, PFS, has already been shown to be statistically significant favoring Arm 
A.
9.7. Data Monitoring Committee 
This study will use an E-DMC comprised of 2 independent clinicians and 1 independent 
statistician.
The E-DMC will be responsible for ongoing monitoring of the safety throughout the study, 
and the evaluation of efficacy at the interim analysis according to the charter. The 
recommendations made by the E-DMC to alter the conduct of the study will be forwarded to 
Pfizer for final decision.
Pfizer will forward such decisions, which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints, to regulatory authorities, as 
appropriate.
The E-DMC will review unblinded safety data.

The first review will occur after 30 patients have been randomized, treated, and 
followed for at least 12 weeks.  No patient enrollment hold is planned.  The E-DMC 
assessment will be conducted based on the available safety data of the first 30 patients 
treated and on all the available data of other patients treated up to the time of data 
cutoff.

Subsequent safety review will occur every 6 months thereafter, or as recommended 
by the E-DMC. 
In addition, the E-DMC will be informed of suspected unexpected serious adverse reactions 
(SUSARs) as soon as these are communicated to Health Authorities.
To ensure ongoing close monitoring of safety in the study, Pfizer clinical and safety teams 
perform routine monitoring of the incoming safety data and evaluate safety issues potentially 
impacting the product benefit-risk profile in a timely manner per the Safety Review Plan.  
The data reviewed includes weekly updates of AEs and laboratory assessments documented 
in the clinical database and SAE information reported in the Pfizer safety database.  Safety 
signals identified from review of clinical study safety data are escalated at any time to the 
multidisciplinary product Risk Management Committee.  In addition, if a requirement for 
further evaluation and assessment is identified, including possible need to review unblinded 
safety data, the clinical study team may escalate the issue to an internal Safety Review 
Committee. 
During the initial enrollment period, prior to the first formal E-DMC review of the safety 
data after 30 patients have been randomized, treated, and followed for at least 12 weeks, 
close monitoring and frequent communication between investigators and Sponsor clinical 
and safety personnel will be undertaken.  It is anticipated that such communication will be 


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approximately weekly and immediately upon any significant change in patient clinical status, 
AEs, laboratory abnormalities or other potential safety concerns. 
Relevant safety information is conveyed in a timely manner to regulatory authorities and 
relevant parties in accordance with international principles and prevailing regulations as well 
as to the EDMC.  The E-DMC chairperson, as well as Pfizer, has discretion to request ad-hoc 
meetings as judged necessary for safety evaluation.
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 IRB/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.
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 


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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 the 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 an independent third party arranged by Pfizer.  
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 


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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 the protocol, the most current, legal and 
regulatory requirements, and the general principles set forth in the International Ethical 
Guidelines for Biomedical Research Involving Human Subjects (Council for International 
Organizations of Medical Sciences 2002), ICH Guideline for GCP, and the Declaration of 
Helsinki.
12.3. Patient Information and Consent
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study 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 documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study patient or his or her legally acceptable 
representative is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a patient’s legally acceptable representative, the patient’s 
assent (affirmative agreement) must subsequently be obtained when the patient has the 
capacity to provide assent, as determined by the IRB/EC.  If the investigator determines that 
a patient’s decisional capacity is so limited he/she cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
patient’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study patient does not provide his or her own consent, the source documents 
must record why the patient did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the patient’s legally 
acceptable representative, the consent signer’s relationship to the study patient (eg, parent, 
spouse), and that the patient’s assent was obtained, or waived.  If assent is obtained verbally 
it must be documented in the source documents.


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The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative, when applicable, 
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 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.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab alone or the combination of avelumab plus SOC CRT 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.


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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 pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (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 
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 


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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, patient to the 
other requirements of this section.
For all publications relating to the study, the 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 
This is a list of abbreviations that may be used in the protocol. 
5HT3
5-Hydroxytryptamine3
ADA
Anti-Drug Antibody
ADCC
Antibody-Dependent Cell-Mediated
AE
Adverse Event
AIDS 
Acquired Immune Deficiency Syndrome
AJCC
American Joint Committee on Cancer
ALT 
Alanine aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST 
Aspartate Aminotransferase
AUCinf
Area Under the Concentration – Time Curve Extrapolated to Infinity
AUCτ
Area Under the Concentration – Time Curve to the End of the Dosing 
Period
BMI
Body Mass Index
BID
Twice Daily
BSA
Body Surface Area
BUN 
Blood Urea Nitrogen
CAG
Clinical Assay Group
CFR
Code of Federal Regulations
CG
Cockcroft-Gault
CI
Confidence Interval
CL
Clearance
Cmax
Maximum Concentration
CPK
Creatine Phosphokinase
CR
Complete Response
CRF
Case Report Form
CRP
c-Reactive Protein
CRT
Chemoradiotherapy
CSA
Clinical Study Agreement
CSF
Colony Stimulating Factor
CT
Computerized Tomography
CTA
Clinical Trial Application
CTCAE 
Common Terminology Criteria for Adverse Events (US NCI)
CTLA-4
Cytotoxic T-Lymphocyte-Associated Protein 4
Ctrough
Trough Concentration
CTV
Clinical Target Volume
CV
Coefficient of Variation
D5NS
Potassium Chloride in 5% Dextrose and Sodium
DDP
cis-diamminedichloridoplatinum 
DR
Duration of Response
DLT
Dose-Limiting Toxicity


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DM
Distant Metastatic Failure or Distant Metasis
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DRS
Disease-Related Symptoms
DRS-E
Disease-Related Symptoms – Emotional
DRS-P
Disease-Related Symptoms – Physical
DU
Dispensable Unit
EC
Ethics Committee
ECG 
Electrocardiogram
ECOG
Easter Cooperative Oncology Group
eCRF
Electronic Case Report Form
E-DMC
External Data Monitoring Committee
EDP
Exposure During Pregnancy
EOT
End of Treatment
EQ-5D-5L
EuroQoL Group 5-Dimension 5-Level Self-Report Questionnaire
EU
European Union
EudrCT
European Clinical Trials Database
FAS
Fas Cell Surface Receptor 
FAS
Full Analysis Set
FDA
Food and Drug Administration
FDG
Fludeosyglucose
FFPE
Formalin Fixed, Paraffin Embedded
FHNSI-11
FACT/NCCN Head/Neck Symptom Index-22
FSH
Follicle-Stimulating Hormone
FWB
Functional Well-Being
g
Gram
GCP 
Good Clinical Practice
GFR
Glomerular Filtration Rate
GGT
Gamma-Glutamyl Transferase
GMP
Good Manufacturing Practice
GVHD
Graft Versus Host Disease
H1
Histamine 1 Receptor
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin
HCl
Hydrogen Chloride
HCV
Hepatitis C Virus
HDPE
High Density Polyethylene
HMGB1
High-Mobility-Group Box 1
HIV 
Human Immunodeficiency Virus
HPV
Human papillomavirus
HR
Hazard Ratio
HRQoL
Health-Related Quality of Life
IB
Investigator’s Brochure
ICD
Informed Consent Document
ICH
International Committee Harmonization
CCI


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ICON-S
International Collaboration on Oropharyngeal Cancer Network for 
Staging 
ID
Identification
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMRT
Intensity-Modulated Radiation Therapy
IND
Investigational New Drug
INF
Interferon
INN
International Nonproprietary Name
INR 
International Normalized Ratio
IP
Investigational Product
irAE
Immune-Related Adverse Event
IRB 
Institutional Review Board
IRR
Infusion-related reaction
IRT
Interactive Response Technology
IUD
Intrauterine Device
IV
Intravenous
IWR
Interactive Web-Based Response
JCO
Journal of Clinical Oncology
kg
Kilogram
LA
Locally-Advanced
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLN
Lower Limit of Normal
LLQ
Lower Limit of Quantitation
LRF
Locoregional Failure
mAb
Monoclonal Antibody
MACH-NC
Meta-analysis of Chemotherapy in Head and Neck Cancer
MedDRA
Medical Dictionary for Regulatory Activities
MHC
Major Histocompatibility Complex
MRI 
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
N
Nodal (Stage)
N/A
Not Appliable
nAb
Neutralizing Antibody
NaCl
Sodium Chloride
NaOH
Sodium Hydroxide
NASBA
nucleic-acid sequence-based amplification
NCCN
National Cancer Comprehensive Network
NCI 
National Cancer Institute
NK-1
Neurokinin 1
NS
Normal Saline
NSAID
Nonsteroidal Anti-Inflammatory Drugs
NSCLC
Non-small Cell Lung Cancer
OR
Objective Response
ORR
Objective Response Rate


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OS 
Overall Survival
PBMC
Peripheral Blood Mononuclear Cell
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic
PD
Progressive Disease
PD-1
Programmed Death Protein-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death Ligand 2
PEG
Percutaneous Endoscopic Gastrostomy
PES
Polyether Sulfone
PET
Positron Emission Tomography
PFS
Progression-Free Survival
PK
Pharmacokinetics
PI
Principal Investigator
PR
Partial Response
PRO
Patient-Reported Outcome
PS
Performance Status
PT
Prothrombin Time
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
Q4W
Every 4 Weeks
Q16W
Every 16 Weeks
Q24W
Every 24 Weeks
QA
Quality Assurance
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RT
Radiation Therapy
RTOG
Radiation Therapy Oncology Group
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable Disease
SD
Standard Deviation
SIB
Simultaneous Integrated Boost
SOA
Schedule of Activities
SOC
Standard of Care
SRSD
Single Reference Safety Document
SST
Serum Separator Tube
SUSAR 
Suspected Unexpected Serious Adverse Reaction
T
Tumor (Stage)
TCR
T-cell receptor 
t½
Elimination half life
TEAE
Treatment-emergent Adverse Event
CCI


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TLS
Tumor Lysis Syndrome
Tmax
Time to maximum plasma concentration
TNM
Tumor, Node, Metastases (Staging)
TSE
Treatment Side Effects
TSH
Thyroid Stimulating Hormone
TTD
Time to Deterioration
TTR
Time to Tumor Response
UK
United Kingdom
ULN 
Upper Limit of Normal
US
United States
VAS
Visual Analogue Scale
Vd
Volume of Distribution
Vz
Volume of Distribution
v
Version
WBC 
White Blood Cell
WHO 
World Health Organization


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Appendix 2. ECOG Performance Status
Score
Definition
0
Fully active, able to carry on all pre-disease activities without restriction
1
Restricted in physically strenuous activity, but ambulatory and able to carry 
out work of a light or sedentary nature; eg, light house work or office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair
5
Dead


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Appendix 3. Modifications to Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 Guidelines Specific to Study B9991016
Tumor-related endpoints in this study will be based on Response Evaluation Criteria in Solid 
Tumors (RECIST) version (v)1.1 (Appendix 4) modified with respect to the definition of 
what constitutes progressive disease (PD) as follows.  Any of the following will constitute 
PD per modified RECIST v1.1:

Locoregional disease progression per RECIST v1.1 which is subsequently confirmed 
by pathology.  Pathologic confirmation of progression will verify that radiographic 
changes represent true tumor progression and not radiation effects or non-malignant 
contrast enhancement.

Locoregional clinically detectable progression that is confirmed by pathology.

Surgical removal (salvage) of primary tumor with tumor present on final pathology.

Salvage neck dissection >20 weeks (140 days) after completion of CRT with tumor 
present on final pathology.

Metastatic (distant metastases) disease progression per RECIST v1.1.  Confirmation 
of pathology is recommended unless medically contraindicated or lesion location too 
high risk for biopsy.
Pathologic evaluation of resected or biopsied specimens must be completed by a trained and 
medically qualified expert (eg, specialty board certified pathologist). 
Pathologic complete response is defined as the absence of histologically identifiable 
residual cancer in any resected specimen. 
Local failure is defined as residual or recurrent viable tumor on pathologic evaluation from 
the site of original tumor location.  Presence of tumor is required for declaration of a 
progression event which requires identification of viable tumor cells on final pathology.  
Tumor reappearing within the initial and immediately adjoining anatomical region of the 
primary will be considered local recurrence.
Regional failure is defined as residual or recurrent viable tumor on pathologic evaluation 
from the regional lymph node basins (eg, neck nodes).  Presence of tumor is required for 
declaration of a progression event which requires identification of viable tumor cells on final 
pathology.
Distant metastatic disease is defined as new tumor identified at a site distant from the head 
and neck anatomic region or draining lymph nodes.  Biopsy of any presumed distant 
metastatic disease is strongly recommended.  A solitary, speculated lung mass/nodule is a 
second primary neoplasm and is not a disease progression event unless proven otherwise by 
biopsy in a patient with a smoking history.  Multiple lung nodules/masses are considered 


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distant metastases from the index cancer and constitutes a disease progression event unless 
proven otherwise by biopsy.
Irradiation of the primary tumor and radiographically enlarged lymph nodes is considered 
part of the treatment under investigation in this clinical trial and therefore these target lesions 
remain evaluable lesions for response assessment.
It is expected that the status of the primary tumor is assessed thoroughly at the beginning of 
the surgical procedure before undertaking nodal dissection.  Presence of persistent disease at 
the primary site, confirmed by frozen section will be considered disease progression. 
Neck dissection parameters are described in Section 3.4 and will consist of a selective neck 
dissection unless a cytologic sampling of the nodes that appear enlarged is negative.
Positive neck specimens removed within 140 days after completion of CRT will be 
considered part of the initial treatment plan and not considered as failures of initial 
management; positive specimens upon neck dissection beyond 140 days will be considered 
regional failures. 


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 155
Appendix 4. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Guidelines
Adapted from E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.
CATEGORIZING LESIONS AT BASELINE
Measurable Lesions

Lesions that can be accurately measured in at least one dimension.

Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm).

Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.

Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.

Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions.
Non-Measurable Disease
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.

Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.

Previous local treatment: A previously irradiated lesion (or lesion patiented to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment.


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 156
Normal Sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions.

Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study.
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large target 
lesion splits, the sum of the parts is used.
Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-Target Disease
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).


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B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 157
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate.
Target Disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed.

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds.

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm.

Indeterminate.  Progression has not been documented, and

One or more target measurable lesions have not been assessed;
or

Assessment methods used were inconsistent with those used at baseline;
or

One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);
or

One or more target lesions were excised or irradiated and have not reappeared or 
increased.


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B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 158
Non-Target Disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits.

PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR.
If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status.
Objective/Patientive Progression
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 159
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in Table.
Objective Response Status at each Evaluation
Target Lesions
Non-Target Lesions
New Lesions
Tumor Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Indeterminate or 
Missing
No
PR
PR
Non-CR/Non-PD, 
Indeterminate or 
Missing
No
PR
SD
Non-CR/Non-PD,   
Indeterminate or 
Missing
No
SD
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any response
Yes or No
PD
Any response
PD
Yes or No
PD
Any response
Any response
Yes
PD
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest sum on study).  
For CR and PR, the patient’s best response assignment will depend on the achievement of 
both measurement.  Confirmation of CR or PR is not required as this trial is randomized and 
double-blinded.  In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval of 6 weeks.


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 160
Appendix 5. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study Reference 
Binder for this protocol.  Alternatively, the NCI CTCAE may be reviewed online at the 
following NCI website:
http://ctep.cancer.gov/reporting/ctc.html


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 161
Appendix 6. NCCN FHNSI-22
Do not copy for patient administration.


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 162
Appendix 7. EuroQol EQ-5D-5L
Do not copy for patient administration.


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B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 163


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 164


Avelumab MSB0010718C
B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 165
Appendix 8. Appropriate Chemotherapy Dosing For Obese Adult Patients With 
Cancer: ASCO Clinical Practice Guideline
Calculation Tools for Body Surface Area (BSA)
BSA Calculation Resources
Formula Name
Formula
Chemotherapy is usually dosed by square meter of body surface area (BSA).  BSA has been chosen rather than body weight 
as the basis for calculation for two reasons.  First, BSA has been demonstrated to provide a more accurate comparison of 
activity and toxicity for certain drugs.  Second, BSA can be more closely correlated with cardiac output, which determines 
the blood flow to the liver and kidneys, thus influencing drug elimination.
Boyd
BSA (m2) = 0.0003207 x Ht(cm) 0.3 x weight(g)(0.7285 – (0.0188 x 
LOG10weight(g)))
DuBois and DuBois
BSA(m2) = Wt(kg)0.425x Ht(cm)0.725 x 0.007184
Gehan and George
BSA(m2) = Wt(kg)0.51456x Ht(cm)0.42246x 0.0235
Haycock, et al.
BSA(m2) = Wt(kg)0.5378x Ht(cm)0.3964x 0.024265
Mosteller (Adults and Children)
BSA(m2) = SQR RT((Ht(cm) x Wt(kg))/3600)
or
BSA(m2) = SQR RT((Ht(in) x Wt(lb))/3131)
Please note: Calculators using these formulas are available online
This practice tool for physicians is a dosing table derived from an ASCO® practice guideline.
The practice 
guideline and this table are not intended to substitute for the independent professional judgment of the treating
physician. Practice guidelines do not account for individual variation among patients and may not reflect the
most recent evidence.  This table does not recommend any particular product or course of medical treatment.
Use of the practice guideline and this table is voluntary.  The full practice guideline and additional information 
are available at http://www.asco.org/guidelines/wbd.


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B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 166
 
 
 
 
 
 
 
 
 
 
CCI


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B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
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CCI


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B9991016
Final Protocol Amendment 3, 31 July 2019
PFIZER CONFIDENTIAL
Page 168
Appendix 11. France Appendix
This appendix applies to study sites located in France.
1. GCP Training
Prior to enrollment of any subjects, the investigator and any sub-investigators will complete 
the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) or 
training deemed equivalent by Pfizer.  Any investigators who later join the study will 
complete the Pfizer GCP Training or equivalent before performing study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials.
2. Investigational Product
No subjects or third-party payers will be charged for investigational product.
3. Inspections
The investigator(s) will notify Pfizer or its service provider immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with Pfizer or its service provider to prepare the study site for the inspection and will allow 
Pfizer or its service provider (if not prohibited by law) to be present during the inspection. 
The study site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the subject's medical records.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its service provider.  Before response 
submission to the regulatory authorities, the investigator will provide Pfizer or its service 
provider with an opportunity to review and comment on responses to any such findings.

SAP_001.pdf: 
Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan    
 
PFIZER CONFIDENTIAL 
Page 1 
 
B9991016 
A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF AVELUMAB IN 
COMBINATION WITH STANDARD OF CARE CHEMORADIOTHERAPY 
(CISPLATIN PLUS DEFINITIVE RADIATION THERAPY) VERSUS STANDARD 
OF CARE CHEMORADIOTHERAPY IN THE FRONT-LINE TREATMENT OF 
PATIENTS WITH LOCALLY ADVANCED SQUAMOUS CELL CARCINOMA OF 
THE HEAD AND NECK 
 
JAVELIN HEAD AND NECK 100 
 
STATISTICAL ANALYSIS PLAN – B9991016 
 
Compounds:  
MSB0010718C 
PF-06834635 
 
Compound Name: 
Avelumab 
 
Version: 
3.0 
Date: 
30-Aug-2019 
 
 
 
 
 


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CCI


Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan    
 
PFIZER CONFIDENTIAL 
Page 3 
5.1. Hypotheses and Decision Rules ..............................................................................22 
5.1.1. Hypotheses and sample size determination ................................................22 
5.1.2. Decision rules .............................................................................................23 
5.2. General Methods .....................................................................................................26 
5.2.1. Data handling after the cut-off date ............................................................26 
5.2.2. Pooling of centers .......................................................................................27 
5.2.3. Presentation of continuous and qualitative variables ..................................27 
5.2.4. Definition of study day ...............................................................................27 
5.2.5. Definition of start of new anti-cancer drug therapy ....................................27 
5.2.6. Definition of start of new anti-cancer therapy ............................................28 
5.2.7. Definition of on-treatment period ...............................................................28 
5.2.8. Standard derivations and reporting conventions .........................................28 
5.2.9. Unscheduled visits ......................................................................................29 
5.2.10. Adequate baseline tumor assessment ........................................................29 
5.2.11. Adequate post-baseline tumor assessment................................................29 
5.3. Methods to Manage Missing Data ..........................................................................29 
5.3.1. Missing data ................................................................................................29 
5.3.1.1. Pharmacokinetic concentrations ................................................30 
5.3.1.2. Pharmacokinetic parameters .....................................................30 
5.3.2. Handling of incomplete dates .....................................................................30 
5.3.2.1. Disease history ..........................................................................30 
5.3.2.2. Adverse events ..........................................................................31 
5.3.2.3. Prior and concomitant medications ...........................................31 
5.3.2.4. Exposure ....................................................................................32 
5.3.3. Imputation rules for date of last contact and efficacy assessments ............32 
5.3.3.1. Date of last contact ....................................................................32 
5.3.3.2. Death date ..................................................................................33 
5.3.3.3. Tumor assessments ....................................................................33 
5.3.3.4. Date of start of new anti-cancer therapy ...................................33 
6. ANALYSES AND SUMMARIES ......................................................................................35 
6.1. Primary Endpoints ...................................................................................................35 
6.1.1. Progression-free survival per modified RECIST v1.1 ................................35 
6.1.1.1. Primary analysis ........................................................................35 


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Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan    
 
PFIZER CONFIDENTIAL 
Page 5 
6.5.1. Baseline summaries ....................................................................................65 
6.5.1.1. Demographic characteristics .....................................................65 
6.5.1.2. Medical history ..........................................................................66 
6.5.1.3. Disease characteristics ...............................................................67 
6.5.2. Study conduct and patient disposition ........................................................67 
6.5.2.1. Patient disposition .....................................................................67 
6.5.2.2. Protocol deviations ....................................................................69 
6.5.3. Study treatment compliance and exposure .................................................69 
6.5.3.1. Exposure to avelumab or matching placebo .............................70 
6.5.3.2. Exposure to Cisplatin ................................................................72 
6.5.3.3. Exposure to IMRT .....................................................................73 
6.5.3.4. Dose reductions .........................................................................73 
6.5.3.5. Dose Delays ...............................................................................74 
6.5.3.6. Infusion rate reductions .............................................................74 
6.5.3.7. Infusion interruptions ................................................................75 
6.5.4. Concomitant medications and non-drug treatments ...................................75 
6.5.5. Subsequent anti-cancer therapies ................................................................76 
6.6. Safety Summaries and Analyses .............................................................................76 
6.6.1. Adverse events ............................................................................................76 
6.6.1.1. All adverse events .....................................................................77 
6.6.1.2. Adverse events leading to dose reduction .................................79 
6.6.1.3. Adverse events leading to interruption of study treatment .......79 
6.6.1.4. Adverse events leading to discontinuation of study 
treatment ............................................................................................80 
6.6.2. Deaths .........................................................................................................80 
6.6.3. Serious adverse events ................................................................................81 
6.6.4. Other significant adverse events .................................................................81 
6.6.5. Laboratory data ...........................................................................................83 
6.6.5.1. Hematology and chemistry parameters .....................................83 
6.6.5.2. Other laboratory parameters ......................................................86 
6.6.6. Vital signs ...................................................................................................87 
6.6.7. Electrocardiogram .......................................................................................87 
6.6.8. ECOG performance status ..........................................................................89 


Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan    
 
PFIZER CONFIDENTIAL 
Page 6 
7. INTERIM ANALYSES .......................................................................................................89 
7.1. Introduction .............................................................................................................89 
7.2. Interim Analyses and Summaries ............................................................................89 
7.2.1. Interim analysis for PFS .............................................................................89 
7.2.2. Interim analysis for OS ...............................................................................90 
8. REFERENCES ....................................................................................................................91 
9. APPENDICES .....................................................................................................................93 
 
LIST OF TABLES 
Table 1. 
Summary of Major Changes in SAP Amendments ................................................8 
Table 2. 
Chemoradiation and Avelumab/Placebo Treatment Schedule .............................14 
Table 3. 
PK Parameters to be Determined for Avelumab and Cisplatin ............................16 
Table 4. 
Biomarker Definition and Determination .............................................................17 
Table 5. 
Statistical Analyses by Analysis Set .....................................................................21 
Table 6. 
Power to Detect Specific Hazard Ratios for OS ...................................................23 
Table 7. 
Simulated cumulative probabilities to stop for futility at the interim or final 
PFS analysis ..........................................................................................................25 
Table 8. 
Simulated cumulative probabilities to stop for efficacy on overall survival 
at PFS interim analysis, final PFS analysis, third interim OS analysis, 
fourth interim OS analysis, or final OS analysis ..................................................26 
Table 9. 
Outcome and Event Dates for PFS Analyses .......................................................37 
Table 10. 
PFS Censoring Reasons and Hierarchy ................................................................38 
Table 11. 
OS Censoring Reasons and Hierarchy ..................................................................40 
Table 12. 
Outcome and Event Date for PFS Sensitivity Analysis (M1) ..............................41 
Table 13. 
Outcome and Event Date for PFS Sensitivity Analysis (S0) ................................42 
Table 14. 
Outcome and Event Date for PFS Sensitivity Analysis (S1) ................................42 
Table 15. 
Possible Outcomes per Modified RECIST v1.1 vs Standard RECIST v1.1 ........45 
Table 16.  Outcome and Event Dates for Time to LRF Analysis ............................................47 
Table 17.  Time to LRF Censoring Reasons and Hierarchy ....................................................48 
Table 18. 
Outcome and Event Dates for Time to DM analysis ............................................49 
Table 19. 
Time to DM Censoring Reasons and Hierarchy ...................................................50 
Table 20. 
Outcome and Event Dates for DR Analyses .........................................................53 
Table 21.  DR Censoring Reasons and Hierarchy .................................................................54 


Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan    
 
PFIZER CONFIDENTIAL 
Page 7 
Table 22.  Patients Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ...................................................................................................................59 
Table 23.  Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) ...................................................................................................................60 
Table 24. 
Case Definition for irAEs .....................................................................................93 
Table 25. 
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs ..............................................................95 
Table 26. 
Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets) ......................................................................................96 
Table 27. 
Derivation of Objective Status Based on Target and Non-Target Lesion 
Response Assuming No New Lesions ..................................................................99 
 
LIST OF FIGURES 
Figure 1. 
Study Design Schema ...........................................................................................13 
 
APPENDICES 
Appendix 1. Immune-Related Adverse Events ........................................................................93 
Appendix 2. Infusion Related Reactions .................................................................................95 
Appendix 3. Programmatic Derivation of Tumor Response Using RECIST v1.1 ..................97 
 


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Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 10 
Section 6.2.2.1 “Overall survival” - added that RCIs will be calculated for the 
analyses of OS; provided more details on analysis of Time of Follow-Up for 
OS. Section 6.2.2.2 “Sensitivity analyses for progression-free survival” - the 
plot of RMST versus tau was deleted as detailed summaries for the 3 different 
tau values will be provided.  PD was appropriately replaced with PFS in the 
analyses of concordance/discordance for PFS 
Section 6.2.2.9 “Duration of response” – added details regarding censoring for 
duration of response since “no adequate baseline assessment” which is used in 
censoring for PFS analyses is not applicable to analyses of duration of response 
for patients with objective response. 
Section 6.2.4 “Pharmacokinetic endpoint” – additional parameters included, if 
data permit. 
Section 6.2.7 “Endpoints for immunogenicity data of avelumab” - added details 
for the analysis of ADA and nAb. 
Section 6.4 “Subset Analyses” – pooled geographical region updated to 
consider Western Europe and Eastern Europe separately (instead of Europe 
combined); updated the p-value for the interaction test to be based on Wald’s 
test; removed forest plots for median DR by subgroup. 
Section 6.5.1.1 “Demographic characteristics” - pooled geographical region 
updated to consider Western Europe and Eastern Europe separately (instead of 
Europe combined); BSA added; randomization stratification factors and subsite 
of primary diagnosis removed since described in Section 6.4. 
Section 6.5.3 “Study treatment compliance and exposure” and subsections - by-
cycle and  week-based analyses of exposure were removed;   
formulas for actual dose intensity for avelumab and cisplatin were corrected to 
refer to intended duration of exposure; summaries of dose omissions were 
removed since the non-adherence to the treatment schedule will be described 
with dose delays and interruptions; added details for derivation and summary of 
dose delays. 
Section 6.6.1 “Adverse events” and subsections – updated definition of 
treatment-emergent adverse event. Given the nature of immune-related AEs 
(irAEs) and infusion related reactions (IRRs), removed the summaries of 
treatment-related irAEs and treatment-related IRRs; removed the requirement 
that all summaries by SOC and PT will be replicated by PT only.  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. 
Section 6.6.1.2 “Adverse events leading to dose reduction” and Section 6.6.1.3 
“Adverse events leading to interruption of study treatment” were added. 
Section 6.6.2 “Death” – deleted references to primary reason for death since not 
collected in the eCRF. 
Section 6.6.4 “Other significant adverse events” – nominal p-values for risk 
difference for Tier-1 events will not be calculated. 
Section 6.6.5 “Laboratory data” and subsections –added summary for patients 
with newly occurring or worsening laboratory abnormities; updated lab 
parameters that will be listed. 
Section 6.6.7 “Electrocardiogram” – Deleted the summary for patients with 
ECG abnormalities based on morphology since collected in a free text field..  
Section for “Physical Examination” was removed as data not collected in the 
eCRF (abnormal findings are reported as AEs). 
Section 8 ”References” – references updated. 
Appendix 1 “Immune-related Adverse Events” – updated the ATC codes for 
concomitant medications in Step 4 of the case definition for irAEs and added a 


Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 11 
statement regarding medical review if needed to refine the programmatic 
derivation. 
Minor editorial and consistency changes throughout the document. 
1 
21-Oct-2016 
Not applicable (N/A) 
 
2. INTRODUCTION 
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in study B9991016.  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. 
A separate SAP will cover the interim analyses for periodic safety review by the External 
Data Monitoring Committee (E-DMC). 
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie, 
intensity-modulated radiation therapy [IMRT] data, immunogenicity data, pharmacokinetic 
[PK] concentration data).  
The primary analysis will include all data up to a cut-off date which is determined by the 
number of progression-free survival (PFS) events by modified RECIST v1.1 and minimum 
follow-up of 24 months (104 weeks) after the last randomized patient required for the 
analysis of PFS. The cut-off date is determined once a data extract (before database lock) is 
available which indicates that the required number of events for PFS (289) and minimum 
follow-up of 24 months (104 weeks) is expected to occur by the cut-off date.  
Due to cleaning activities, the final number of events might deviate from the planned 
number. The data cut-off date will not be adjusted retrospectively in this case.   
2.1. Study Objectives 
Primary Objectives 
• To demonstrate that treatment with avelumab in combination with standard of care 
chemoradiotherapy (SOC CRT) is superior to SOC CRT alone in prolonging PFS in 
front-line patients with high risk, locally advanced squamous cell carcinoma of the head 
and neck (SCCHN) who are candidates for definitive CRT with cisplatin. 
Secondary Objectives 
• To compare the overall survival (OS) of avelumab in combination with SOC CRT vs 
SOC CRT alone; 
• To evaluate the anti-tumor activity of avelumab in combination with SOC CRT and SOC 
CRT alone; 
• To evaluate the overall safety and tolerability profile of avelumab in combination with 
SOC CRT and SOC CRT alone; 
• To evaluate the PK of avelumab; 


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Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 14 
The treatment schedule is described in Table 2. 
Table 2. 
Chemoradiation and Avelumab/Placebo Treatment Schedule 
Lead-in Phase  
(7 days)a 
CRT Phase  
(63 days) 
Maintenance 
Phaseb 
-- Day -- 
----------------  Day  ---------------- 
1 
1 
8 
15 
22 25 29 
36 39 43 
IMRT (70 Gy/35 fractions/7 
weeks; 1 fraction per day, 
5 fractions/week  
[Monday – Friday]) 
 
X→ X→ X→ X → X→ X→ → X→ 
 
Cisplatin (100 mg/m2 Q3W) 
 
X 
 
 
X  
 
 
 
X 
 
Avelumab (10 mg/kg) or placebo 
X 
 
X 
 
 Xc 
 
 
X 
 
Q2W 
a. 
Lead-in Phase to start 7 days prior to initiation of CRT Phase.  
b. Maintenance Phase to start after completion of the CRT Phase (ie, 2 weeks following completion of CRT) 
and be 12 months in duration.  CRT phase may be extended as required for patient recovery from CRT; 
however, it is hypothesized that patients will receive maximal benefit from beginning maintenance as close 
to the scheduled time as possible.  
c. 
Day 25 dose of avelumab/placebo during the CRT Phase may be administered between Day 24 and Day 29. 
Cisplatin should be administered on a Monday or Tuesday if feasible to maximize overlap with IMRT.  
CRT = Chemoradiotherapy; IMRT = intensity-modulated radiation therapy; Q2W = every 2 weeks; 
Q3W = every 3 weeks. 
The investigator will assess antitumor activity based on radiological assessments and clinical 
evaluation of patients using modified RECIST v1.1 at baseline, 12 weeks after the 
completion of CRT (ie, 10 weeks following completion of the CRT Phase of the study), 
every 16 weeks thereafter for 48 months (208 weeks), and every 24 weeks thereafter until 
confirmed disease progression per modified RECIST v1.1 and regardless of discontinuation 
of study treatment or initiation of subsequent anti-cancer therapy.  
 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint 
• PFS per modified RECIST v1.1 by investigator assessment. 
PFS is defined as the time from the date of randomization to the date of the first 
documentation of progressive disease (PD per modified RECIST v1.1) or death due to 
any cause, whichever occurs first.   
3.2. Secondary Endpoints 
3.2.1. Safety endpoints 
• Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. 


Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 15 
AEs will be graded by the investigator according to CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
• Vital signs (blood pressure, pulse rate). 
3.2.2. Efficacy endpoints 
• OS.  
OS is defined as the time from the date of randomization to the date of death due to any 
cause. 
• Antitumor activity: Pathologic complete response in any resected specimens, neck 
dissection. 
Pathologic complete response is defined as the absence of histologically identifiable 
residual cancer in any resected specimen. 
• Antitumor activity: Locoregional failure, objective response (OR), distant metastatic 
failure, and duration of response (DR), per modified RECIST v1.1 by investigator 
assessment. 
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the date of randomization until the date of the first documentation of PD per 
modified RECIST v1.1 or death due to any cause.  Response does not need to be 
confirmed at a subsequent assessment. 
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 per modified RECIST v1.1 
or death due to any cause.   
Time to locoregional failure is defined as the time from the date of randomization to the 
date of the first documentation of locoregional PD per RECIST v1.1 with pathologic 
confirmation, locoregional clinically detectable progression with pathologic 
confirmation, salvage of primary tumor with tumor present on final pathology, salvage 
neck dissection >20 weeks after completion of CRT with tumor present on final 
pathology or death due to any cause, whichever occurs first.   
Time to distant metastatic failure or distant metastasis is defined as the time from the date 
of randomization to the date of the first documentation of metastatic PD per RECIST 
v1.1 or death due to any cause, whichever occurs first. 
3.2.3. Patient reported outcomes  
• Disease-related symptoms and HRQoL as measured by the National Cancer 
Comprehensive Network (NCCN) Head and Neck Symptom Index-22 items (FHNSI-22), 
and the EuroQoL Group 5-Dimension 5- Level Self-Report Questionnaire (EQ-5D-5L). 
The NCCN FHNSI-22 was developed using methods consistent with the Food and Drug 
Administration (FDA) PRO guidance (FDA, 2009) and surveyed input from patients with 
advanced cancers and physician experts (Cella D, et al., 20116). The FHNSI-22 


Avelumab 
B9991016 (MSB0010718C, PF-06834635) Statistical Analysis Plan 
 
PFIZER CONFIDENTIAL 
Page 16 
questionnaire is specifically designed to be a stand-alone instrument to measure disease 
symptoms, treatment side effects and overall quality of life in patients with head and neck 
cancer. 
Responses on the FHNSI-22 questionnaire are used to calculate a total score and scores 
for four subscales: TSE, DRS-P, DRS-E, and FWB. The questionnaire contains 22 items 
with 5-point Likert scales ranging from ‘not at all’ to ‘very much’. Higher scores mean 
better symptomatology, quality of life or functioning.  
The EuroQol EQ-5D-5L is a patient-completed questionnaire designed to assess health 
status in terms of a single index value or utility score (Herdman M, et al., 201110). There 
are 2 components to the EuroQol EQ-5D-5L: a descriptive system in which individuals 
rate their level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas 
(mobility, self- care, usual activities, pain/discomfort, and anxiety/depression) and a 
Visual Analogue Scale (VAS) in which patients rate their overall health status from 0 
(worst imaginable) to 100 (best imaginable).  Published weights are available that allow 
for the creation of a single summary score for the 5 Likert scale items.  
 
3.2.4. Pharmacokinetic endpoints 
• Cmax and Ctrough for avelumab 
• Area under the concentration-time curve extrapolated to infinity (AUCinf), Cmax, clearance 
(CL), time to maximum plasma concentration (Tmax), elimination half-life (t1/2),and 
volume of distribution (Vz) for cisplatin (total and free), as data permit. 
Table 3. 
PK Parameters to be Determined for Avelumab and Cisplatin 
Parameter 
Definition 
Method of Determination 
AUCinf 
Area under the plasma concentration-time 
profile from time zero extrapolated to 
infinite time 
AUClast + (Clast/kel)  
where Clast is the predicted plasma 
concentration at the last quantifiable 
time point estimated from the log-linear 
regression analysis, and kel is the 
terminal phase rate constant calculated 
by linear regression of the log-linear 
concentration-time curve.  Only those 
data points judged to describe the 
terminal log-linear decline will be used 
in the regression. 
Cmax 
Maximum observed plasma concentration  
Observed directly from data 
Tmax 
Time for Cmax 
Observed directly from data as time of 
first occurrence 
t½a 
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. 


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Start and end dates of study treatment:  
The date/time of first dose of study treatment is the earliest date/time of the first non-zero 
dose date/time for each of the study drugs.  
The date/time of last dose of study treatment is the latest date/time of the last non-zero dose 
date/time for each of the study drugs. 
Start dates of study treatment within each treatment phase:  
• Lead-in Phase 
The start date/time of study treatment is the first dose date/time of avelumab or matching 
placebo across the Lead-in Phase visits.  
• CRT Phase 
The start date/time of study treatment is the earliest dose date/time of avelumab or 
matching placebo, cisplatin or IMRT across the CRT Phase visits.  
• Maintenance Phase 
The start date/time of study treatment is the earliest dose date/time of avelumab or 
matching placebo across the Maintenance Phase visits.  
 
Definition of baseline:  
Definition of baseline for efficacy and PRO analyses  
The last measurement prior to randomization will serve as the baseline measurement for 
efficacy and PRO analyses. If such a value is missing (since per protocol the first PRO 
assessment is planned to occur prior to dosing on Day 1 of the Lead-in Phase), 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. 
Definition of baseline for safety analyses 
The last available assessment prior to the start of study treatment is defined as ‘baseline’ 
value or ‘baseline’ assessment for safety 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 


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Page 19 
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 for approximately 30 
patients in each treatment arm 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. 
Definition of baseline for  biomarker analyses  
Baseline biomarker is the last biomarker assessment prior to the start of study treatment.  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, 
unless otherwise defined in the protocol.  
3.4.2. Baseline Characteristics 
Randomization is stratified by the following, as recorded in the Interactive Response 
Technology (IRT): 
• Tumor (T) stage (<T4 vs T4); 
• Nodal (N) stage (N0/N1/N2a/N2b vs N2c/N3); 
• HPV status (positive vs negative) as measured by p16 expression by IHC. 
The primary analyses of PFS and OS will be stratified by these randomization stratification 
factors. 
Other baseline characteristics (including demographics, physical measurements, and disease 
history) 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.  
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 Appendix 1 and 
Appendix 2, respectively. 
3-Tier Adverse Events 
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an adverse event or a group of 
adverse events. Except for select events in unique situations, studies do not employ formal 
adjudication procedures for the purpose of event classification. As such, safety analyses are 
generally considered as an exploratory analysis and its purpose is to generate hypotheses for 
further investigation. The 3-tier approach facilitates these exploratory analyses. 
Adverse events and clusters of adverse events, of any causality and treatment-related, will 
also be summarized following a 3-tier approach.  Under this approach, AEs are classified into 
1 of 3 tiers.   
Tier-1 events: These are pre-specified events or clusters of events of clinical importance and 
will be described in the Safety Review Plan (SRP).   
Tier-2 events: These are events that are not Tier-1 but are “common”.  A MedDRA PT is 
defined as a Tier-2 event if it is reported by  
a) at least 10% of patients with any grade in any treatment arm, or 
b) at least 5% of patients with Grade 3, 4 or 5 in any treatment arm.   
Tier-3 events: All other AEs that are classified neither as Tier-1 nor Tier-2. 
 


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• Patient did not meet inclusion criterion 5 or met any of exclusion criteria 1, 13 or 17; 
namely patient received any anti-cancer therapy for advanced stage SCCHN or 
immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 
antibody (including ipilimumab), or any other antibody or drug specifically targeting T 
cell co-stimulation or immune checkpoint pathways prior to randomization or patient 
received other non-protocol active anticancer therapy within 4 weeks prior to 
randomization.  
The list of patients who are excluded from the PP analysis set will be documented with the 
reason for exclusion. 
4.3.2. PK analysis sets 
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 or cisplatin (total and free).  
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 or cisplatin (total and 
free). 
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 screening biomarker assessment. For the optional tumor biopsy assessment, 
a second analysis set will include patients who have at least one dose of avelumab and who 
have at least one on-treatment biomarker assessment.  Analysis sets will be defined 
separately for blood-based and tumor tissue-based biomarkers. 
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 in Arm A. 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
5.1.1. Hypotheses and sample size determination 
The study is designed to test the following hypotheses: 
H01: HRPFS(A/B) ≥1, versus Ha1: HRPFS(A/B) <1 
where HRPFS(A/B) represents the hazard ratio for PFS in Arm A vs Arm B.   
Approximately 640 patients will be randomized to the treatment arms using a 1:1 
randomization, stratified by tumor stage (<T4 vs T4), nodal stage (N0/N1/N2a/N2b vs 
N2c/N3), and HPV status (positive vs negative) as measured by p16 expression by IHC.   
Two hundred eight-nine (289) PFS events per modified RECIST v1.1 will be required to 
have at least 90% power to detect a hazard ratio of 0.68 using a 1-sided log-rank test at a 


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significance level of 0.025, and a 2-look group-sequential design with Lan-DeMets (O’Brien-
Fleming) α-spending function to determine the efficacy boundary and a Gamma Family (-7) 
β-spending function to determine the non-binding futility boundary.  
The sample size for this study is determined based on the assumptions that the median PFS in 
Arm B is 33 months (Ang  KK, et al., 20102; Ang KK, et al., 20143) and that combination 
treatment with  avelumab + SOC CRT (Arm A) is expected to increase the median PFS to ≥ 
48.5 months, corresponding to a hazard ratio of 0.68 under the exponential model 
assumption.  The sample size further assumes a 15% drop-out rate within each treatment arm 
and a non-uniform patient accrual over a 22-month period.  The data cut-off for the primary 
PFS analysis will occur after the target number of events has been reached and the last 
patient randomized in the study has been followed for at least 24 months after randomization. 
The study will also include a formal comparison for OS.  The following hypotheses will be 
tested according to a testing strategy that preserves the overall type I error in the study as 
described in Section 5.1.2: 
H02: HROS(A/B) ≥1, versus Ha2: HROS(A/B) <1 
where HROS(A/B) represents the hazard ratio for OS in Arm A  vs Arm B.  
With 392 deaths, the study will have 80% cumulative power (unadjusted for the pre-testing, 
in the hierarchical procedure, of PFS) to detect a hazard ratio of 0.75 using a 1-sided log-rank 
test at a significance level of 0.025 and a 5-look group-sequential design with Lan-DeMets 
(O’Brien-Fleming) α-spending function to determine the efficacy boundary.  If the median 
OS in Arm B is 70 months (Ang KK, et al., 20102; Ang KK, et al., 20143), a hazard ratio of 
0.75 corresponds to an increase in median OS from 70 months in Arm B to 93 months in 
Arm A under the exponential model assumption.   
Table 6 summarizes the power to detect several hazard ratios and the estimated duration of 
the study based on the same number of patients that are planned to be enrolled in the study to 
meet the primary endpoint and assuming a 5% dropout rate for survival follow-up. These 
calculations are conditional on achieving statistical significance for the test of PFS.  
Table 6. 
Power to Detect Specific Hazard Ratios for OS 
HR under Ha2 
Power 
Calendar time (months) to 392 deaths under Ha2  
0.75 
80% 
127 
0.80 
58% 
124 
0.70 
93% 
131 
Simulations performed using EAST 6.4.1 with number of simulations = 10,000 and seed=7282016. 
 
5.1.2. Decision rules 
To protect the integrity of the study and to preserve the type I error rate, a fraction of alpha 
(0.0097) for PFS efficacy will be spent at the interim analysis and accounted for in the 
overall type I error rate if the interim analysis is performed exactly at the planned number of 


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PFS events. The nominal significance levels for the interim and final efficacy analyses of 
PFS will be determined by using the Lan-DeMets procedure with an O’Brien-Fleming 
stopping boundary. The overall significance level for the efficacy analysis of PFS will be 
preserved at 0.025 (1-sided). 
Two analyses will be performed for PFS: 
1) an interim analysis after all patients have been randomized in the study and at least 217 
(75%) of the 289 PFS events  have been documented  per modified RECIST v1.1, and 
2) the final analysis for PFS after all patients randomized in the study have been followed 
for 24 months and at least 289 PFS events  have been documented  per modified RECIST 
v1.1. 
If the value of the test statistic for PFS exceeds the efficacy boundary for a comparison 
(z< - 2.338, p < 0.010 if the IA is performed after exactly 217 events), then superiority of 
Arm A compared to Arm B could be declared. If the value of the test statistic for PFS 
exceeds the futility boundary (z> - 0.728, p > 0.233 if the IA is performed after exactly 217 
events), then the study may be stopped for futility. 
Since the observed number of events at the interim analysis  may not be exactly equal to the 
planned 217 PFS events, the efficacy and futility boundaries will be updated based on the 
actual number of observed events using the pre-specified α-and β-spending functions. 
Therefore, the observed Z-test statistic at the interim analysis will be compared with the 
updated efficacy and futility boundaries.  
If the study continues to final analysis, the p-value that will be used to declare statistical 
significance at the final analysis will be based on the actual number of PFS events 
documented at the cut-off date for the final analysis and the α already spent at the interim 
analysis. Therefore, if the interim analysis occurs after exactly 217 events, and the study 
continues until the final analysis, the observed p-value for the comparison will have to be 
< 0.022 to declare statistical significance. If the number of events in the final analysis 
deviates from the expected number of events, the final analysis criterion will be determined 
so that the overall significance level across all analyses is maintained at 1-sided 0.025. 
Based on the stopping boundaries defined above and the timing of interim analysis at 75% 
information fraction the design has the following operating characteristics. 


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Table 7. 
Simulated cumulative probabilities to stop for futility at the interim or final 
PFS analysis 
Scenario 
Look 
Number 
of PFS 
events 
Calendar Time 
(months) 
P(Reject H01) 
P(Reject Ha1) 
H01 is true (HR=1) 
Interim 
217 
34 
0.0093 
0.7679 
 
Final 
289 
44 
0.0246 
0.9754 
Ha1 is true (HR=0.68) 
Interim 
217 
38 
0.6917 
0.0197 
 
Final 
289 
51 
0.9010 
0.0990 
Simulations performed in EAST 6.4.1 with number of simulations = 10,000 and seed=7282016. 
 
The secondary OS endpoint will be analyzed using a hierarchical testing procedure, provided 
the primary endpoint PFS endpoint is statistically significant favoring Arm A.  An α-
spending function according to Lan-DeMets (O’Brien-Fleming) independent of the one used 
for the primary efficacy analysis will be used to preserve the 0.025 overall level of 
significance across the hypotheses and the repeated testing of the OS hypotheses in the 
interim and final analyses. The trial allows for the stopping of the study for a superior OS 
result, provided the primary PFS endpoint has already been shown to be statistically 
significant favoring Arm A.  
A maximum of five analyses are planned for OS:  
1) an interim analysis at the time of the interim analysis for PFS (provided PFS is 
significant);  
2) an interim analysis at the projected time of the final analysis for PFS (provided PFS is 
significant);  
3) an interim analysis  when 270 deaths are observed;  
4) an interim analysis  when 345 deaths are observed;  
5) a final analysis for OS when 392 deaths are observed. 
The exact nominal p-values that will need to be observed to declare statistical significance at 
the time of these analyses for OS will depend on the number of OS events that have been 
observed at the time of these analyses and the α for OS already spent at the time of earlier 
analyses. 


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If OS is tested alone, independent of the testing strategy for PFS, the design concerning 
overall survival analyses will have the following operating characteristics. These calculations 
are unadjusted for the pre-testing of PFS.   
Table 8. 
Simulated cumulative probabilities to stop for efficacy on overall survival at 
PFS interim analysis, final PFS analysis, third interim OS analysis, fourth 
interim OS analysis, or final OS analysis 
Scenario 
Look 
Number of 
deaths 
Calendar Time 
(months) 
P(Reject H0j) 
H02 is true (HR=1) 
Interim PFS 
139 
38 
<0.0001 
 
Final PFS 
198 
51 
0.0005 
 
3rd Interim OS 
270 
69 
0.0067 
 
4th Interim OS 
345 
93 
0.0160 
 
Final OS 
392 
112 
0.0247 
Ha2 is true (HR=0.75) 
Interim PFS 
122 
38 
0.0104 
 
Final PFS 
176 
51 
0.1060 
 
3rd Interim OS 
270 
78 
0.4613 
 
4th Interim OS 
345 
106 
0.6973 
 
Final OS 
392 
127 
0.8015 
Ha2 is true (HR=0.80) 
Interim PFS 
126 
38 
0.0037 
 
Final PFS 
181 
51 
0.0470 
 
3rd Interim OS 
270 
76 
0.2625 
 
4th Interim OS 
345 
103 
0.4738 
 
Final OS 
392 
124 
0.5825 
Interim and final PFS analyses calendar time expected at 38 and 51 months, respectively, under Ha1 (HR for 
PFS=0.68).   
Simulations performed in EAST 6.4.1 with number of simulations = 10,000 and randomization seed 
=7282016.  
 
5.2. General Methods 
As described in Section 3.4, in this study ‘treatment arm’ refers to one of the following: 
• Arm A = Avelumab + SOC CRT; 
• Arm B = Placebo + SOC CRT. 
Endpoints will be summarized based on the analysis sets described in Table 5 by treatment 
arm, unless otherwise specified.  
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. 


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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 at each center. 
5.2.3. Presentation of continuous and qualitative variables 
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, 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. 
Confidence intervals (CIs) may also be reported as noted in subsequent sections. 
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 (eg, 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 (eg, 
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. 


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5.2.6. Definition of start of new anti-cancer therapy 
The start date of new anti-cancer therapy is the earliest date after randomization amongst the 
following: 
• Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages 
• Start date of radiation therapy recorded in ‘Follow-up Radiation Therapy’ eCRF pages 
with ‘Treatment Intent’ = ‘Curative in intent’  
• 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’,  ‘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 will not be 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: 
• 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.  
• BMI (kg/m2) = weight (kg)/[height (m)]2 


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• BSA (m²) = ([height (cm) × weight (kg)] / 3600)0.5 
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 
rounding will be performed to closest integer / first decimal using the common mid-point 
between the two consecutive values. Eg, 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: 
• All baseline assessments must be within 28 days prior to and including the date of 
randomization; 
• All documented lesions must have non-missing assessments (ie, 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 uCR, 
uPR, SD, non-uCR/non-PD, or PD can be determined (see Section 6.2.2.8).  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, eg 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’.  


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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 
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 (ie, not done) or NS (ie, 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 or nominal 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 (ie, 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 (ie, 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 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 (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
• If the day is missing, it will be imputed to the 15th day of the month.  


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• If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st. 
• If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st.  
• If the date is completely missing, no imputation will be performed. 
5.3.2.2. Adverse events 
Incomplete AE-related dates will be imputed as follows: 
• If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment. 
• 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. 
• 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. 
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
• In all other cases the incomplete 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: 
• If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment. 
• If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015.  
• If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014. 


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• In all other cases the missing medication day or missing medication month will be 
replaced by 1. 
• Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date.  
• In all other cases the incomplete medication stop date will not be imputed.  
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: 
• 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; 
• 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: 
• All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments); 
• Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation; 
• AE start and end dates; 
• Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’); 
• Study drug start and end dates; 
• Randomization date; 
• Withdrawal of consent date; 


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• 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. 
5.3.3.2. Death date 
Missing or partial death dates will be imputed based on the last contact date: 
• If the date is missing it will be imputed as the day after the date of last contact  
• 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 (eg, X-ray, CT scan) must be completed with day, month and year. 
If there are multiple scan dates associated with an evaluation, ie, 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 (eg, 
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 sensitivity 
efficacy analyses and in the derivation of the end of on-treatment period.  PD date below 
refers to PD date by modified RECIST V1.1. 


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• 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 
- completely missing then it will be ignored in the imputations below 
- partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy 
- 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 
• 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.  
• 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: 
- 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] 
- 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 
- 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 


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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]); 
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.  
6.1. Primary Endpoints  
6.1.1. Progression-free survival per modified RECIST v1.1 
6.1.1.1. Primary analysis 
The following analyses will be based on the FAS using the strata assigned at randomization.  
PD below refers to PD by investigator assessment per modified RECIST v1.1.   Tumor-
related endpoints in this study will be based on RECIST v1.1 modified with respect to the 
definition of what constitutes PD as follows (Appendix 3 of the B9991016 protocol). Any of 
the following will constitute PD per modified RECIST v1.1: 
• Locoregional disease progression per RECIST v1.1 which is subsequently confirmed by 
pathology. Pathologic confirmation of progression will verify that radiographic changes 


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represent true tumor progression and not radiation effects or non-malignant contrast 
enhancement; 
• Locoregional clinically detectable progression that is confirmed by pathology; 
• Surgical removal (salvage) of primary tumor with tumor present on final pathology; 
• Salvage neck dissection >20 weeks (140 days) after completion of CRT with tumor 
present on final pathology; 
• Metastatic (distant metastases) disease progression per RECIST v1.1. Confirmation of 
pathology is recommended unless medically contraindicated or lesion location too high 
risk for biopsy. 
Local failure is defined as residual or recurrent viable tumor on pathologic evaluation from 
the site of original tumor location. Presence of tumor is required for declaration of a 
progression event which requires identification of viable tumor cells on final pathology. 
Tumor reappearing within the initial and immediately adjoining anatomical region of the 
primary will be considered local recurrence. 
Regional failure is defined as residual or recurrent viable tumor on pathologic evaluation 
from the regional lymph node basins (eg, neck nodes). Presence of tumor is required for 
declaration of a progression event which requires identification of viable tumor cells on final 
pathology. 
Distant metastatic disease is defined as new tumor identified at a site distant from the head 
and neck anatomic region or draining lymph nodes. Biopsy of any presumed distant 
metastatic disease is strongly recommended. A solitary, speculated lung mass/nodule is a 
second primary neoplasm and is not a disease progression event unless proven otherwise by 
biopsy in a patient with a smoking history. Multiple lung nodules/masses are considered 
distant metastases from the index cancer and constitutes a disease progression event unless 
proven otherwise by biopsy. 
Irradiation of the primary tumor and radiographically enlarged lymph nodes is considered 
part of the treatment under investigation in this clinical trial and therefore these target lesions 
remain evaluable lesions for response assessment. 
It is expected that the status of the primary tumor is assessed thoroughly at the beginning of 
the surgical procedure before undertaking nodal dissection. Presence of persistent disease at 
the primary site, confirmed by frozen section will be considered disease progression. 
Neck dissection parameters are described in Section 3.4 of the B9991016 protocol and will 
consist of a selective neck dissection unless a cytologic sampling of the nodes that appear 
enlarged is negative. Positive neck specimens removed within 140 days after completion of 
CRT will be considered part of the initial treatment plan and not considered as failures of 
initial management; positive specimens upon neck dissection beyond 140 days will be 
considered regional failures. 


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Progression-Free Survival (PFS) is defined as the time from the date of randomization to the 
date of the first documentation of PD or death due to any cause, whichever occurs first.  For 
example, the date of first documentation of PD when there is locoregional PD per RECIST 
v1.1 which is subsequently confirmed by pathology, will be the date of the locoregional PD 
per RECIST v1.1 rather than the date of pathology confirmation. 
PFS data will be censored on the date of the last adequate tumor assessment or clinical 
evaluation for patients who do not have an event (PD or death); the analysis will consider any 
PD or death as an event regardless of the number of prior missing tumor assessments or 
clinical evaluations or timing of the event with respect to 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 9.   
 
PFS (months) = [date of event or censoring– date of randomization +1]/30.4375 
Table 9. 
Outcome and Event Dates for PFS Analyses 
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment and no PD 
and no death  
Date of randomization 
Censored 
No adequate post-baseline tumor assessment or 
clinical evaluation and no death  
Date of randomization 
Censored 
PD or death 
Date of PD or death 
Event 
 
No PD and no death 
Date of last adequate tumor 
assessment or clinical evaluation 
documenting no PD 
Censored 
 
 
The primary efficacy analysis will compare the PFS time  between Arm A and Arm B, and 
will be performed using a 1-sided stratified log-rank test as described in Section 5.1.  
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by 
the randomization strata to calculate the hazard ratio. Each stratum will define a separate 
baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie for the i-
th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) defines 
the baseline hazard function for the i-th stratum and x defines the treatment arm (0=Arm B, 
1= Arm A) and β is the unknown regression parameter. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG). 
In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 200011), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of PFS. 


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In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the interim 
and the final analyses for PFS. 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median PFS time with 2-sided 95% CIs.  
In particular, the PFS rates at 12, 24, 36, 48 and 60 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)4 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 (2002)12 (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 arm.  
Reasons for censoring will be summarized according to the categories in Table 10 following 
the hierarchy shown. 
Table 10. PFS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment AND no PD AND no 
death 
No adequate baseline assessment  
2 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up]  
Withdrawal of consent 
3 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
4 
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 assessment  
No adequate post-baseline 
assessment 
5  
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
 
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
Frequency (number and percentage) of patients with each subtype of PD will be presented by 
treatment arm.  The subtype of PD is collected in the eCRF and includes the following: 
• Locoregional PD per RECIST v1.1 with pathologic confirmation 
• Locoregional clinically detectable progression with pathologic confirmation 
• Surgical removal (salvage) of primary tumor with tumor present on final pathology 
• Salvage neck dissection >20 weeks after completion of SOC CRT with tumor present on 
final pathology 


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• Metastatic (distant metastases) disease progression per RECIST v1.1. 
Time of Follow-Up for PFS 
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment arm. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment arms reversing the PFS censoring and event 
indicators. Kaplan-Meier estimates (product-limit estimates) will be presented by treatment 
arm together with a summary of associated statistics including the median time of follow-up 
for PFS with 2-sided 95% CIs.  In particular, the rates at 12, 24, 36, 48 and 60 months will be 
estimated with corresponding 2-sided 95% CIs. 
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 by treatment arm unless otherwise 
specified.   
Response endpoints (Best Overall Response [BOR], unconfirmed Objective Response 
[uOR], DR, TTR) will be analyzed separately based on  investigator assessment per modified 
RECIST v1.1 and based on investigator assessment per programmatically derived standard 
RECIST v1.1 (Appendix 3).   
6.2.2.1. Overall survival  
The following analyses will be based on the FAS using the strata assigned at randomization.   
Overall survival (OS) is defined as the time from the date of randomization 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– date of randomization +1]/30.4375 
The primary analysis of OS will compare the OS time between Arm A and Arm B, and will 
be performed using a 1-sided stratified log-rank test as described in Section 5.1.  
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by 
the randomization strata to calculate the hazard ratio. Each stratum will define a separate 
baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie for the i-
th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) defines 
the baseline hazard function for the i-th stratum and x defines the treatment arm (0=Arm B, 
1= Arm A) and β is the unknown regression parameter. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG). 


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In order to account for the group sequential design in this study, the repeated CI (RCI) 
method (Jennison and Turnbull, 200011), will be used to construct the 2-sided RCIs for the 
hazard ratio at the interim and the final analyses of OS. 
In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the interim 
and the final analyses for OS. 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median OS time with 2-sided 95% CIs.  
In particular, the OS rates at 12, 24, 36, 48, 60, 72, 84, and 96 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)4 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 (2002)12 (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 an event (death) and censoring reasons 
will be presented by treatment arm.  Reasons for censoring will be summarized according to 
the categories in Table 11 following the hierarchy shown. 
Table 11. OS Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient 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 > 18 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 arms reversing the OS censoring and event indicators.  Kaplan-Meier 
estimates (product-limit estimates) will be presented by treatment arm together with a 
summary of associated statistics including the median time of follow-up for OS with 2-sided 
95% CIs.  In particular, the rates at at 12, 24, 36, 48, 60, 72, 84, and 96 months will be 
estimated with corresponding 2-sided 95% CIs. 
6.2.2.2. Sensitivity analyses for progression-free survival 
The following sensitivity analyses will be performed to explore the robustness of the primary 
analysis results.  These analyses are regarded as purely exploratory. The sensitivity analyses 


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will repeat the primary analysis (p-value, HR and 95% CIs) described in Section 6.1.1.1 with 
the modifications below: 
• M1 - PFS per modified RECIST v1.1 following the censoring rules outlined in Table 12   
• M2 - PFS  per modified RECIST v1.1 on the PP analysis set using the censoring rules 
outlined in Table 9 
• M3- PFS  per modified RECIST v1.1 using an unstratified analysis using the censoring 
rules outlined in Table 9 
• M4 - PFS  per modified RECIST v1.1 using strata derived according to eCRF data 
instead of that entered in IRT using the censoring rules outlined in Table 9 
• S0 - PFS with PD programmatically derived based on investigator assessment per 
standard RECIST v1.1 with the censoring rules defined in Table 13 
• S1, S2, S3, S4 replicating the sensitivity analyses M1, M2, M3 and M4, respectively, for 
PFS with PD programmatically derived based on investigator assessment per standard 
RECIST v1.1.  The censoring rules associated with S1 are outlined in Table 14 
• S0_B - PFS with PD based on Blinded Independent Central Review (BICR) assessment 
per standard RECIST v1.1 with the censoring rules defined in Table 13 
• M1_B - PFS with PD based on BICR assessment per standard RECIST v1.1 with the 
censoring rules defined in Table 12. 
Table 12. Outcome and Event Date for PFS Sensitivity Analysis (M1)   
Scenario 
Date of Progression/Censoring 
Outcome 
No adequate baseline assessment 
Date of randomization a 
Censored a 
PD or death  
- 
following at most one missing or 
indeterminate post-baseline tumor 
assessment or clinical evaluation,  OR 
- 
≤ 36  weeks after the date of 
randomization 
Date of PD or death 
Event 
PD or death following two or more missing  or 
indeterminate post-baseline tumor assessments 
or clinical evaluations b  
Date of last adequate tumor 
assessment b or clinical evaluation 
documenting no PD prior to new 
anti-cancer therapy or missed 
assessments 
 
Censored 
 
No PD and no death 
New anti-cancer therapy given  
a If the patient dies ≤36 weeks after  date of randomization, the death is an event with date on death date. 
b If there are no adequate post-baseline tumor assessments or clinical evaluations prior to the PD or death, then 
the time without adequate assessment should be measured from the date of randomization; if the criteria were 
met the censoring will be on the date of randomization 
 


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Table 13. Outcome and Event Date for PFS Sensitivity Analysis (S0)  
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment and no PD 
and no death  
Date of randomization 
Censored 
No adequate post-baseline tumor assessment 
and no death  
Date of randomization 
Censored 
PD or death 
Date of PD or death 
Event 
No PD and no death 
Date of last adequate tumor 
assessment documenting no PD 
Censored 
 
Table 14. Outcome and Event Date for PFS Sensitivity Analysis (S1)  
Scenario 
Date of Progression/Censoring 
Outcome 
No adequate baseline assessment 
Date of randomization a 
Censored a 
PD or death  
- 
following at most one missing or 
indeterminate post-baseline tumor 
assessment,  OR   
- 
≤ 36  weeks after the date of 
randomization 
Date of PD or death 
Event 
PD or death following two or more missing  or 
indeterminate post-baseline tumor assessments b  Date of last adequate tumor 
assessment b documenting no PD 
prior to new anti-cancer therapy 
or missed assessments 
 
Censored 
 
No PD and no death 
New anti-cancer therapy given  
a If the patient dies ≤36 weeks after start date, the death is an event with date on death date. 
b If there are no adequate post-baseline tumor assessments prior to the PD or death, then the time without 
adequate assessment should be measured from the date of randomization; if the criteria were met the 
censoring will be on the date of randomization 
 
Methods for evaluating the validity of model assumptions 
The proportional hazards assumption will be checked visually by plotting log(-log(PFS)) 
versus log(time) within each randomization stratum. 
Schoenfeld residuals for the stratified Cox proportional regression model will be plotted to 
investigate graphically violations from the proportional hazards (PH) assumption; a non-zero 
slope is evidence of departure from PH.  The PH assumption will be formally tested using 
Schoenfeld’s residual test (Schoenfeld, 198018; Therneau & Grambsch, 200020).  Large 
departures from PH will be evidenced by a p-value <0.05. 
If these show large departures from proportional hazards, then PFS by modified RECIST 
v1.1 will also be analyzed based on restricted mean survival time (RMST) differences 
(Zhang, 201322).  


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Restricted Mean Survival Time (RMST) 
The hazard ratio estimate from the Cox proportional hazard model is routinely used to 
empirically quantify the between-arm difference under the assumption that the ratio of the 
two hazard functions is constant over time.  When this assumption is plausible, such a ratio 
estimate may capture the relative difference between two survival curves.  However, the 
clinical meaning of such a ratio estimate is difficult, if not impossible, to interpret when the 
underlying PH assumption is violated (ie, the hazard ratio is not constant over time).  
The RMST is a robust and clinically interpretable summary measure of the survival time 
distribution.  Unlike median survival time, it is estimable even under heavy censoring.  There 
is a considerable body of methodological research (eg, Royston and Parmar, 201116; 
Uno,Wei, et al., 201421; Zhang, 201322) about the use of RMST to estimate treatment effects 
as an alternative to the hazard ratio approach.   
The RMST methodology is applicable independently of the PH assumption and can be used, 
at a minimum, as a sensitivity analysis to explore the robustness of the primary analysis 
results.  However, when large departures from the PH assumption are observed, the log-rank 
test is underpowered to detect differences between the survival distributions for the treatment 
arms, and a test of the difference between the RMST for the experimental arm and the 
control arm may be more appropriate to determine superiority of the experimental arm 
compared to the control arm with respect to the time-to-event endpoint. 
In particular, as it pertains to the cut-off point (τ) to evaluate the RMST, it is noted that the 
cut-off point should not exceed the minimum of the largest observed time for both treatment 
arms so that the RMST of all treatment arms being evaluated can be adequately estimated 
and comparison between treatments is feasible; τ should be clinically meaningful and closer 
to the end of the study follow-up so that the majority of survival outcomes will be covered by 
the time interval.  The RMST up to time τ can then be interpreted as the expected survival 
time restricted to the common follow-up time τ among all patients.  The selection of τ should 
ensure that the RMST evaluation will not go beyond the maximum time point where the 
evaluation can be performed while also taking into account a large period of time that is 
expected to provide a meaningful assessment of treatment effect.  To avoid arbitrary 
selection of the common cut-off τ for both treatment arms, three sets of analyses will be 
performed: 
• τ1 = minimum of (largest observed PFS time for the experimental arm, largest observed 
PFS time for the control arm).   
• τ2 = minimum of (largest PFS event time for the experimental arm, largest PFS event 
time for the control arm). 
• τ3 = midpoint between τ1 and τ2. 
The treatment effect between the experimental arm and the control arm will be assessed 
based on the difference in RMST. The associated 95% CI for the difference in means and 1-
sided p-value will be generated.   


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Exploratory analyses to investigate the impact of potential prognostic or effect 
modifying (predictive) factors  
See subgroups as defined in Section 6.4. 
Multivariable Cox regression analysis will be carried out to assess and adjust the treatment 
effect for relevant baseline factors of potential prognostic impact. A stepwise selection 
procedure will serve to identify explanatory variables of potential prognostic values 
additional to the randomization strata which will be included in all models during the 
selection procedure. The Cox's Proportional Hazard model is defined as:  
h(t) = h(0;t) eXb 
where h(0;t) defines the baseline hazard function and X defines the vector of explanatory 
variables and b the unknown vector of regression parameters.  
In the stepwise selection procedure, variables are entered into and removed from the model 
in such a way that each forward selection step can be followed by one or more backward 
elimination steps. The stepwise selection process terminates if no further variable can be 
added to the model or if the variable just entered into the model is the only variable removed 
in the subsequent backward elimination. The level of significance for an explanatory variable 
to enter the model is set to 0.15 (p-value of Score test) and the significance level for 
removing it is set to 0.40 (p-value of Wald test). This analysis will be performed using the 
stepwise selection method in SAS (Proc PHREG). Once this procedure stops, the factor 
'treatment arm' will be added to the last selected model in order to evaluate the effect of 
treatment on PFS time when adjusted for the selected explanatory variables. The hazard 
ratios of all selected explanatory variables and of treatment effects will be reported including 
2-sided 95% CIs. No interactions will be considered. Post-baseline factors will not be 
considered for the model. 
PFS per modified RECIST v1.1 vs PFS per standard RECIST v1.1 
Summaries of PFS assessment per modified RECIST v1.1 versus standard RECIST v1.1 will 
be provided including numbers of concordant and discordant assessments as well as the 
number of cases where PFS is determined to occur at different timepoints based on the 
censoring rules described in Table 13 (S0 based on programmatically derived investigator 
assessment or S0_B based on BICR assessment). 
Table 15 outlines the possible outcomes per modified RECIST v1.1 and standard RECIST 
v1.1, a similar classification used for possible outcomes of assessment by investigator and 
BICR (Amit O, et al., 2011).1 


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Table 15. Possible Outcomes per Modified RECIST v1.1 vs Standard RECIST v1.1 
 
Standard  RECIST v1.1 
Modified 
RECIST v1.1 
Event  
No Event 
Event 
a = a1 + a2 + a3 
b 
No Event 
c 
d 
a1: number of agreements on timing and occurrence of event;  
a2: number of times agreement on event but modified RECIST v1.1 declares event later than RECIST v1.1;  
a3: number of times agreement on event but modified RECIST v1.1 declares event earlier than RECIST v1.1;  
N= a+b+c+d.  
The timing agreement of event is defined with a window of 28 days  
 
The following measure of discordance will be calculated for each treatment arm: 
• Total Event Discrepancy Rate: (b+c) / N 
• Early Discrepancy Rate (EDR): (a3+b) / (a+b) 
• Late Discrepancy Rate (LDR): (a2+c) / (a2+a3+b+c) 
• Overall Discrepancy Rate: (a2+a3+b+c) / N 
The EDR represents the positive predictive value of modified RECIST v1.1 assessment and 
quantifies the frequency with which modified RECIST v1.1 will declare PFS event earlier 
than standard RECIST v1.1 within each arm as a proportion of the total number of modified 
RECIST v1.1 assessed PFS events. 
The LDR quantifies the frequency with which modified RECIST v1.1 criteria assigns PFS 
event later than standard RECIST v1.1 criteria as a proportion of the total number of 
discrepancies within the treatment arm.  
Biopsy   
The following will be listed and summarized by treatment arm. 
Disease site, lesion number, clinical evaluation date and outcome, imaging evaluation date 
and outcome, whether biopsy was done, reason, date of biopsy sample and biopsy outcome, 
will be listed for each patient.  Lesions evaluated after PD per modified RECIST v1.1 will be 
flagged in the listing. 
In what follows, lesions evaluated from randomization until PD per modified RECIST v1.1 
will be considered. 
The number of times a lesion underwent clinical evaluation and/or underwent imaging 
evaluation will be summarized overall and by disease site.  


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For each clinical evaluation outcome and imaging evaluation outcome and for the 
combination of outcomes), the following will be summarized.  The denominator to calculate 
percentages is the total number of lesions evaluations; all lesion evaluations are counted if 
the same lesion is evaluated at multiple visits.   
• Number of lesion evaluations  
• Number and percentage of biopsies performed, reason and outcome  
• Number of and percentage of biopsies not performed and reason 
The following cross tabulations will be provided.  The denominator to calculate the 
percentages will be based on the total number of lesions evaluations; all lesion evaluations 
are counted if the same lesion is evaluated at multiple visits.  Biopsy status and outcome will 
include all combination of categories for biopsy performed (yes, no), reason to perform or 
not perform, and outcome if performed (positive, negative, inconclusive)  
• Clinical evaluation outcome vs. biopsy status and outcome  
• Imaging evaluation outcome vs. biopsy status and outcome  
• Combination of clinical and imaging outcome vs biopsy status and outcome 
• Clinical evaluation outcome vs. imaging evaluation outcome. 
6.2.2.3. Sensitivity analyses for overall survival 
The following sensitivity analyses will be performed to explore the robustness of the primary 
analysis results for OS.  These analyses are regarded as purely exploratory. The sensitivity 
analyses will repeat the primary analysis (p-value, HR and 95% CIs) described in Section 
6.2.2.1 with the modifications below: 
• PP analysis set; 
• unstratified; 
• using strata derived according to eCRF data instead of that entered in IRT. 
Methods for evaluating the validity of model assumptions 
The same methodology described in Section 6.2.2.2 for PFS will be used for OS. 
Exploratory analyses to investigate the impact of potential prognostic or effect 
modifying (predictive) factors  
The same methodology described in Section 6.2.2.2 for PFS will be used for OS. 
6.2.2.4. Locoregional failure 
Locoregional failure (LRF) is defined as locoregional PD per RECIST v1.1 with pathologic 
confirmation or locoregional clinically detectable progression with pathologic confirmation 
or salvage of primary tumor with tumor present on final pathology or salvage neck dissection 
>20 weeks after completion of CRT with tumor present on final pathology.     


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Time to LRF is defined as the time from the date of randomization to the date of the first 
documentation of locoregional PD per RECIST v1.1 with pathologic confirmation, 
locoregional clinically detectable progression with pathologic confirmation, salvage of 
primary tumor with tumor present on final pathology, salvage neck dissection >20 weeks 
after completion of CRT with tumor present on final pathology or death due to any cause, 
whichever occurs first.   
Time to LRF data will be censored on the date of the last adequate tumor assessment or 
clinical evaluation for patients who do not have an event (LRF or death); the analysis will 
consider any LRF or death as an event regardless of the number of prior missing tumor 
assessments or clinical evaluations or timing of the event with respect to initiation of anti-
cancer therapy.  
The censoring and LRF event date options to be considered are presented in Table 16.   
LRF (months) = [date of event or censoring– date of randomization +1]/30.4375 
Table 16.  Outcome and Event Dates for Time to LRF Analysis 
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment and no LRF 
and no death  
Date of randomization 
Censored 
No adequate post-baseline tumor assessment or 
clinical evaluation and no death  
Date of randomization  
Censored 
LRF or death 
Date of LRF or death 
Event 
No LRF and no death  
Date of last adequate tumor assessment 
or clinical evaluation documenting no 
LRF 
Censored 
 
The time to LRF in Arm A and Arm B will be compared based on the FAS using the strata 
assigned at randomization and using a 1-sided stratified log-rank test at 1-sided nominal 
alpha level of 0.025.   
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by 
the randomization strata to calculate the hazard ratio. Each stratum will define a separate 
baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie, for the 
i-th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 
(0=Arm B, 1= Arm A) and β is the unknown regression parameter. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG). 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median LRF time with 2-sided 95% 
CIs.  In particular, the LRF rates at 12, 24, 36, 48 and 60 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 


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Brookmeyer and Crowley (1982)4 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 (2002)12 (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 (LRF or death) and 
censoring reasons will be presented by treatment arm. 
Reasons for censoring will be summarized according to the categories in Table 17 following 
the hierarchy shown. 
Table 17.  Time to LRF Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment AND no LRF AND no 
death 
No adequate baseline 
assessment  
2 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up]  
Withdrawal of consent 
3 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
4 
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 assessment  
No adequate post-baseline 
assessment 
5 
No event (no LRF AND no Death) AND Distant Metastatic  
(DM) failure  
Distant Metastatic failure only 
6 
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
 
6.2.2.5. Distant metastatic failure 
Distant metastatic failure or distant metastasis (DM) is defined as new tumor identified at a 
site distant from the head and neck anatomic region or draining lymph nodes.   
Time to DM is defined as the time from the date of randomization to the date of the first 
documentation of metastatic disease progression per RECIST v1.1 or death due to any cause, 
whichever occurs first.  DM data will be censored on the date of the last adequate tumor 
assessment or clinical evaluation for patients who do not have an event (DM or death); the 
analysis will consider any DM or death as an event regardless of the number of prior missing 
tumor assessments or clinical evaluations or timing of the event with respect to initiation of 
anti-cancer therapy.  
The censoring and DM event date options to be considered are presented in Table 18.   
DM (months) = [date of event or censoring– date of randomization +1]/30.4375 


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Table 18. Outcome and Event Dates for Time to DM analysis 
Scenario 
Date of event/censoring 
Outcome 
No adequate baseline assessment and no 
DM and no  death  
Date of randomization 
Censored 
No adequate post-baseline tumor 
assessment or clinical evaluation and no 
death   
Date of randomization  
Censored 
DM or death 
Date of DM or death 
Event 
No DM and no  death  
Date of last adequate tumor assessment or 
clinical evaluation documenting no DM 
Censored 
 
The time to DM in Arm A and Arm B will be compared based on the FAS using the strata 
assigned at randomization and using a 1-sided stratified log-rank test at 1-sided nominal 
alpha level of 0.025.   
The treatment effect will be estimated using a Cox’s Proportional Hazard model stratified by 
the randomization strata to calculate the hazard ratio. Each stratum will define a separate 
baseline hazard function (using the 'STRATA' statement in SAS PROC PHREG), ie, for the 
i-th stratum the hazard function is expressed as: h(i;t) = h(i,0;t) exp(xβ), where h(i,0;t) 
defines the baseline hazard function for the i-th stratum and x defines the treatment arm 
(0=Arm B, 1= Arm A) and β is the unknown regression parameter. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG). 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median DM time with 2-sided 95% CIs.  
In particular, the DM rates at 12, 24, 36, 48 and 60 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)4 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 (2002)12 (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 (DM or death) and 
censoring reasons will be presented by treatment arm. 
Reasons for censoring will be summarized according to the categories in Table 19 following 
the hierarchy shown.   


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Table 19. Time to DM Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No adequate baseline assessment AND no DM AND no 
death 
No adequate baseline assessment  
2 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up]  
Withdrawal of consent 
3 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
4 
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 assessment  
No adequate post-baseline 
assessment 
5 
No event (no DM AND no Death) AND Locoregional 
(LRF) failure 
Locoregional failure only 
6  
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
 
6.2.2.6. Neck dissection 
A patient who had neck dissection can be identified by the “Surgery Details –Salvage 
Surgery Neck” eCRF. If the box “Yes” was checked for the question “Was neck dissection 
performed as expected per protocol?”, the patient had a neck dissection. 
The rate of neck dissection on each treatment arm will be estimated by dividing the number 
of patients with neck dissection recorded from randomization until PD per modified RECIST 
v1.1 or death due to any cause by the number of patients randomized to the respective 
treatment arm. The corresponding exact 2-sided 95% CIs will be provided by treatment arm.  
The rate of pathologically-positive neck dissection and rate of pathologically-negative neck 
dissection will be summarized using the same methodology as for the rate of neck dissection.   
The final pathology of neck dissection (positive or negative) can be identified from the 
“Outcome” field in the “Pathology Details” eCRF with “Lesion number” and “Date of 
sample” matching “Lesion number” and “Date of neck dissection” in the “Surgery Details –
Salvage Surgery Neck” eCRF.   
• Positive pathology includes the following outcomes from the “Pathology Details” eCRF: 
(1) live tumor cells present, or (2)10% or greater vital tumor tissues.   
• Negative pathology includes the remaining outcomes: (3) no live tumor cells present, (4) 
complete tumor regression, no evidence of vital tumor tissues, (5) less than 10% vital 
tumor tissue, or (6) not consistent with disease under study.   
The outcome of the pre-surgery biopsy sample (positive or negative) can be identified from 
the “Outcome of biopsy” field in the “Biopsy Sample Details” eCRF with “Lesion number” 
and “Date of biopsy sample” matching “Lesion number” and “Date of pre-surgery biopsy 
sample” in the “Surgery Details –Salvage Surgery Neck” eCRF. 


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The positive and negative predictive values (PPV and NPV respectively) of the biopsy to the 
final pathology will be calculated based on the subset of patients who had neck dissection 
and a pre-surgery biopsy sample (matching lesion number and date).   
• PPV = TP / (TP + FP) where TP is the number of lesions with true positive pre-surgery 
biopsy (pre-surgery biopsy positive and positive pathology) and FP is the number of 
lesions with false positive pre-surgery biopsy (pre-surgery biopsy positive and negative 
pathology).  
• NPV = TN / (TN + FN) where TN is the number of lesions with true negative pre-surgery 
biopsy (pre-surgery biopsy negative and negative pathology) and FN is the number of 
lesions with false negative pre-surgery biopsy (pre-surgery biopsy negative and positive 
pathology).   
6.2.2.7. Pathologic complete response 
Pathologic complete response (pCR) is defined as the absence of histologically identifiable 
residual cancer in any resected specimen and will be summarized separately for randomized 
patients who underwent salvage surgery at the primary site and for randomized patients who 
had neck dissection.  Further, a cross tabulation of pCR at the primary site (responder, not a 
responder, no salvage surgery) and in the neck (responder, not a responder, no salvage 
surgery) will be provided. 
Patients who underwent salvage surgery are identified in the “Surgery Details – Salvage 
Surgery Primary Site” or “Surgery Details – Salvage Surgery Neck” with answer “Yes” to 
“Was salvage surgery at primary site performed?” or “Was neck dissection performed as 
expected per protocol?”, respectively. 
Pathologic complete responders are patients who underwent, prior to PD per modified 
RECIST v1.1, salvage surgery/ neck dissectionwith a negative pathology, ie, with outcome in 
“Pathology Details eCRF” as  “no live tumor cells present”, “complete tumor regression”, 
“no evidence of vital tumor tissues”, “less than 10% vital tumor tissue”, or “not consistent 
with disease under study”.  Patients should be matched based on the lesion number and date 
of the sample if the “Pathology Details eCRF” and date of the surgery at the primary site/date 
of neck dissection.   
If more than one lesion was resected prior to PD per modified RECIST v1.1, a pathologic 
complete responder is a patient with 1) no resected lesion with a positive pathology AND 2) 
with at least one resected lesion with negative pathology.  
The pCR rate at primary site/neck in each treatment arm will be estimated by dividing the 
number of patients with pCR recorded at any visit from randomization until PD per modified 
RECIST v1.1 or death due to any cause by the number of randomized patients who had 
salvage surgery at the primary site/neck dissection, respectively, in each treatment arm. The 
corresponding exact 2-sided 95% CIs will be provided by treatment arm. 


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6.2.2.8. Objective response  
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the date of randomization until the first documentation 
of PD, according to the following rules. 
BOR Based on Unconfirmed Responses 
• uCR = one CR documented before first documentation of PD  
• uPR = one PR documented before first documentation of PD (and not qualifying for a 
CR)  
• SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after date of randomization and before first 
documentation of PD (and not qualifying for uCR or uPR). 
• Non-uCR/Non-PD (applicable only to patients with non-measurable disease at baseline) 
= at least one non-uCR/non-PD assessment (or better) ≥ 6 weeks after date of 
randomization and before first documentation of PD (and not qualifying for uCR or uPR). 
• PD = PD after date of randomization (and not qualifying for uCR, uPR or SD). 
• NE: all other cases.  
An objective status of uPR or SD cannot follow one of uCR.  SD can follow uPR only in the 
rare case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.   
Unconfirmed Objective Response (uOR) is defined as BOR of uCR or uPR. A patient will 
be considered to have achieved a uOR if the patient has a uCR or uPR which does not need 
to be confirmed at a subsequent assessment.   
Patients who do not have a post-baseline radiographic tumor assessment or clinical 
evaluation due to early progression, who die, progress, or drop out for any reason prior to 
reaching a uCR or uPR will be counted as non-responders in the assessment of uOR. Each 
patient will have an objective response status (0: no uOR; 1: uOR).  uOR rate (uORR) is the 
proportion of patients with uOR in the analysis set. 
uORR by treatment arm will be calculated along with the 2-sided 95% CI using the Clopper-
Pearson7 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 uBOR of uCR, uPR, SD, 
non-uCR/non-PD (applicable only to patients with non-measurable disease at baseline), PD 
and NE will be tabulated. Patients with uBOR of NE will be summarized by reason for 
having NE status. The following reasons will be used: 
• No baseline assessment  
• No post-baseline assessments due to death 


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• No post-baseline assessments due to other reasons  
• All post-baseline assessments have overall response NE 
• SD of insufficient duration (<6 weeks after date of randomization) 
The association of treatment effect and uOR will be tested by the General Association 
Statistic of the Cochran-Mantel-Haenszel test (CMH) with the randomization strata taken 
into account. The null hypothesis of no association in any of the randomization strata is 
tested against the alternative, which specifies that there is an association between treatment 
effect and tumor response at least in one randomization stratum. The CMH test will be 
performed at 1-sided nominal alpha level of 0.025.  
The stratified odds ratio in terms of uOR will also be estimated along with its 95% CI to 
compare study treatments. The odds ratio is defined as the odds of uOR with experimental 
treatment divided by the odds of uOR with control treatment. The Breslow-Day test will be 
used to check the homogeneity of the odds ratio across the randomization strata. It tests the 
null hypothesis that odds ratios in all strata are equal against the alternative hypothesis that at 
least in one stratum the odds ratio is different. 
In case the null hypothesis of homogeneity of odds ratios across strata is not rejected at the 2-
sided alpha level of 0.05, the common odds ratio will be determined using the Mantel-
Haenszel estimate (by the FREQ procedure using CMH option in SAS); if the null hypothesis 
of homogeneity of odds ratio across all strata is rejected, the odds ratio per stratum will be 
calculated with the corresponding exact CI. 
6.2.2.9. Duration of response 
Duration of Response (DR) is defined, for patients with uOR, as the time from first 
documentation of objective response (uCR or uPR) 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 or clinical assessment. The censoring rules for DR are 
described in Table 20. 
 
DR (months) = [date of event or censoring– first date of uOR +1]/30.4375 
Table 20. Outcome and Event Dates for DR Analyses 
Scenario 
Date of event/censoring 
Outcome 
PD or death 
Date of PD or death 
Event 
 
No PD and no death 
Date of last adequate tumor 
assessment or clinical evaluation 
documenting no PD 
Censored 
 
 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median DR time with 2-sided 95% CIs.  
In particular, the DR rates at 12, 24, 36, 48 and 60 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 


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Brookmeyer and Crowley (1982)4 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 (2002)12 (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 uOR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided. 
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to the categories in Table 21 following the hierarchy shown. 
Table 21.  DR Censoring Reasons and Hierarchy 
Hierarchy 
Condition 
Censoring Reason 
1 
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up]  
Withdrawal of consent 
2 
No event and lost to follow-up in any disposition page  
Lost to follow-up 
3 
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 assessment  
No adequate post-baseline 
assessment 
4  
No event and none of the conditions in the prior hierarchy 
are met  
Ongoing without an event 
 
The DR time or censoring time and the reasons for censoring will also be presented in a 
patient listing. 
6.2.2.10. Time to response 
Time to response (TTR) is defined, for patients with uOR, as the time from the date of 
randomization to the first documentation of objective response (uCR or uPR).  
 
TTR (in months) = [first date of uOR – date of randomization +1]/30.4375 
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3). 
6.2.3. PRO endpoints 
The NCCN FHNSI-22 was developed using methods consistent with the Food and Drug 
Administration (FDA) PRO guidance (FDA, 20099) and surveyed input from patients with 
advanced cancers and physician experts (Cella D, et al., 20116). The FHNSI-22 questionnaire 
is specifically designed to be a stand-alone instrument to measure disease symptoms, 
treatment side effects and overall quality of life in patients with head and neck cancer. 


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Responses on the FHNSI-22 questionnaire are used to calculate a total score and scores for 
four subscales: TSE, DRS-P, DRS-E, and FWB. The questionnaire contains 22 items with 5-
point Likert scales ranging from ‘not at all’ to ‘very much’. Higher scores mean better 
symptomatology, quality of life or functioning. The expected questionnaire completion time 
is about 5 minutes. 
The EuroQol EQ-5D-5L is a patient-completed questionnaire designed to assess health status 
in terms of a single index value or utility score (Herdman M, et al., 201110). There are 2 
components to the EuroQol EQ-5D-5L: a descriptive system in which individuals rate their 
level of problems (none, slight, moderate, severe, extreme/unable) in 5 areas (mobility, self- 
care, usual activities, pain/discomfort, and anxiety/depression) and a Visual Analogue Scale 
(VAS) in which patients rate their overall health status from 0 (worst imaginable) to 100 
(best imaginable).  Published weights are available that allow for the creation of a single 
summary score for the 5 Likert scale items. The expected questionnaire completion time is 
about 3 minutes or less. 
All PRO summaries/analyses will be based on the FAS, with two analysis periods: 
• Analysis including PRO data through EOT (including EOT)  
• Additional analysis including all PRO data (including data collected after EOT) 
6.2.3.1. Instrument completion rate 
For each treatment arm and at each time point, the number and percentage of patients who 
complete the FHNSI-22 and EQ-5D-5L will be summarized, as will the reasons for non-
completion of these measures.  
6.2.3.2. Descriptive summaries over time 
Only scheduled assessments will be included in the summaries that follow. 
For each treatment arm and at each assessment time point, summary statistics of the FHNSI-
22 total and  subscale scores, the EQ-5D-5L, and VAS at each time point will be reported as 
described in Section 5.2.3.   
For continuous endpoints (the total and subscale scores of the FHNSI-22, EQ-5D-5L, and 
VAS), change from baseline will be reported with N (number of non-missing values), mean, 
standard error, and 95% confidence intervals.  Only patients with both a baseline score and a 
post-baseline score will be included in the summary of change from baseline scores.  
Line charts depicting the means and mean changes of subscales together with standard error 
bars over time will be also provided.  
6.2.3.3. Time-to-event endpoints 
 There are three separate time-to-event endpoints based on time to deterioration (TTD) of  
1) HRQol;  
2) DRS-P;  


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3) ‘swallowing’.  
TTD is defined as the time from randomization to deterioration where deterioration is 
defined, respectively, as  
1) a 3 point decrease on the FWB scale for health-related quality of life (HRQoL);  
2) a 3 point decrease on the DRS-P for symptoms of disease;  
3) a 1 point decrease, in two consecutive assessments, on the ‘swallowing’ item of the 
FHNSI-22.  
The time to event for HRQoL and DRS-P will be calculated using the date of randomization 
and the date of the event, respectively.  The time to event for “swallowing” will be calculated 
using the date of randomization and the date of the first of the two consecutive assessments 
used to identify the event. Note that a decline in FWB subscale of the FHNSI-22 represents a 
worsening in HRQol. A decline in DRS-P score represents an increase in physical symptoms 
of disease. A decline in the ‘swallowing’ item score represents a decrease in the ability to 
swallow naturally and easily.   
Patients who do not have a TTD event will be censored on the date when they last completed 
a PRO assessment. 
TTD will be compared between treatment arms using a log-rank test stratified by 
randomization stratification factors.  The treatment effect will be estimated using a Cox 
Proportional Hazard model stratified by the randomization strata to calculate the hazard ratio. 
Each stratum will define a separate baseline hazard function (using the 'STRATA' statement 
in SAS PROC PHREG), ie, for the i-th stratum the hazard function is expressed as: h(i;t) = 
h(i,0;t) exp(xβ), where h(i,0;t) defines the baseline hazard function for the i-th stratum and x 
defines the treatment arm (0=Arm B, 1= Arm A) and β is the unknown regression parameter. 
Ties will be handled by replacing the proportional hazards model by the discrete logistic 
model (Ties=Discrete option in SAS PROC PHREG). 
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median TTD time with 2-sided 95% 
CIs.  In particular, the TTD rates at 12, 24, 36, 48, and 60 months will be estimated with 
corresponding 2-sided 95% CIs.  The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982)4 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 (2002)12 (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. 
6.2.3.4.  Binary and categorical endpoint  
Responder is a patient with improvement in swallowing, defined as a 1 point increase on the 
5-point Likert scale maintained for 2 consecutive assessments, in the single ‘swallowing’ 
item of the FHNSI-22, month 6 and 12 during the Maintenance Phase and also at EOT.  In 
accordance with published recommendations (Osoba D, et al., 200515; Brundage M, et al., 


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20075; Sloan JA, et al., 200719), proportions will be calculated including all patients with 
baseline questionnaires and counting those patients with missing questionnaires at a 
subsequent time point as not having improved. 
Responder on the swallowing item of the FHNSI-22 will be compared between treatment 
arms using the Cochran-Mantel-Haenszel test stratified by randomization stratification 
factors.  In this analysis, patients with missing questionnaires will be assigned as non-
responder. 
A sensitivity analysis will also be conducted.  Patients whose post baseline questionnaires 
were missing because of disease progression or death will be considered as non-responder, 
with other patients whose post baseline questionnaires were missing being excluded from the 
analysis.  
6.2.3.5. Continuous endpoints 
Longitudinal random intercept random slope mixed-effect model will be carried out for the 
total and subscale scores of the FHNSI-22, EQ-5D-5L, and VAS using PROC MIXED. 
Outcomes are PRO post-baseline scores and the predictors are the corresponding baseline 
PRO score, treatment, randomization stratification factor, time (treated as a continuous 
variable), and treatment-by-time interaction. Intercept and time are considered as random 
effects particular to each patient. All available data for each patient should be used in the 
analyses. All parameter estimates should be obtained using restricted maximum likelihood. 
The unstructured covariance structure should be used to define covariance between random 
effects (using option “Type=UN” as a part of the RANDOM statement in PROC MIXED). 
For the degrees-of-freedom calculations the Kenward and Roger algorithm should be used 
(using option “ddfm = kr” as a part of the MODEL statement in PROC MIXED). 
6.2.4. Pharmacokinetic endpoints 
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
arm.   
6.2.4.1. Avelumab 
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 phase, 
cycle (if applicable), and day in Arm A. Other standard parameters will be calculated, 
including but not limited to single and multiple dose Tmax, Tss,max, as data permit. 
Ctrough and Cmax for avelumab will be plotted for each dose using a box whisker plot by 
treatment phase, cycle (if applicable), and day within in order to assess the attainment of 
steady state in Arm A. 
Additionally, avelumab PK will be evaluated following cisplatin dosing by comparing the 
overall geometric mean ratios of Cmax and Ctrough in only Arm A on Day 8 of the CRT Phase 
to Day 1 of the Lead-in Phase. 
Pharmacokinetic parameters for avelumab will be taken from observed values or derived 
from plasma concentration-time data as described in Section 3.2.4. 


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6.2.4.2. Cisplatin (Total and Free) 
PK parameters for cisplatin (total and free) will be estimated using noncompartmental and/or 
compartment methods, if needed. Analyses will include Cmax, time to Tmax, AUCinf, t½, CL, 
and Vz as data permit.  Dose-normalized parameters [eg, Cmax (dn), AUCinf (dn)] will be 
reported as appropriate.  Descriptive statistics for the PK parameters for cisplatin will be 
provided in tabular form.  Cisplatin plasma concentrations will be summarized descriptively 
(n, mean, SD, CV, median, minimum, maximum, geometric mean, its associated CV, and 
95% CI) by nominal time. Individual patient and median profiles will be presented on both 
linear-linear and log-linear scales. 
Additionally, cisplatin PK (total and free) will be evaluated following avelumab or placebo 
dosing by comparing the overall geometric mean ratios of Cmax and AUCinf on Day 1 of the 
CRT Phase in Arm A to Day 1 of the CRT Phase in Arm B. 
Pharmacokinetic parameters for cisplatin (total and free) will be taken from observed values 
or derived from plasma concentration-time data as described in Section 3.2.4. 
6.2.5. 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. 
In addition, the relationship between exposure and efficacy and safety endpoints may be 
explored, as necessary, based on emerging efficacy and safety data. The analysis details will 
be provided in the Population Modeling Analysis Plan. The results of these modeling 
analyses may be reported separately from the clinical study report. The analyses will include 
patients in both the FAS and the safety analysis set. 
6.2.6. Biomarker endpoints 
There are two sets of biomarkers, those collected at screening (pre-treatment tumor sample), 
and the optional tumor sample after one dose of avelumab.  The optional tumor samples will 
be analyzed separately.   
Summary statistics for pre-treatment biomarkers will be presented by treatment arm and 
overall. Summary statistics for on-treatment biomarkers will additionally include the ratio to 
baseline for continuous biomarkers, and a contingency table for non-continuous biomarkers, 
as appropriate.  
Continuous biomarkers will be split at the median (< and ≥ median), and will be included as 
a covariate in an exploratory Kaplan-Meier analysis for PFS, as described in Section 6.1.1.1; 
no other covariates will be included.  Non-continuous biomarkers will either be split at an 
appropriate point in their distribution, and classified as above and below the split (0,1), or the 
actual categories will be included in the survival analysis. 


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6.2.7. Endpoints for immunogenicity data of avelumab  
All analyses described below are performed for the treatment arm containing avelumab (Arm 
A) unless otherwise specified.  
Blood samples for avelumab immunogenicity testing will be collected at pre-dose on Day 1 
of the Lead-in Phase, and Days 8, and 25 of the CRT Phase.  All samples should be drawn 
within 2 hours before the start of avelumab or placebo infusion. 
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.   
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 22.   
Table 22.  Patients Characterized Based on Anti-Drug Antibody Results (ADA Status) 
Category 
Definition 
Patients 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 post-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 23. 
For nAb, treatment-boosted is not applicable since no titer result is available. 


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Table 23.  Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) 
Category 
Definition 
Patients 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 post-
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.  
 
6.2.7.1. 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:  
• the last ADA assessment is positive AND patient is continuing treatment with avelumab, 
or 


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• the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (Day 25 of the CRT Phase) 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)4 and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)12 (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.  
6.2.7.2. 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.  
6.2.7.3. Analysis of PK and safety by immunogenicity status 
The following ADA and nAb status will be used for the analyses described below. 
ADA  
• ADA ever-positive versus ADA never-positive;  
• ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive. 


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nAb  
• nAb ever-positive versus nAb never-positive;  
• 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 pre-dose (within 2 hours before the start of 
avelumab/placebo infusion) and at the end of infusion (immediately before until 10 minutes 
after the end of avelumab/placebo infusion) on Days 1 of the Lead-in Phase and Days 8, and 
25 of the CRT Phase. 
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 8 of CRT Phase and the first positive ADA result is observed on Day 25 of 
CRT Phase, then the relative PK day for this Ctrough is -17. 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. 
• TEAEs, by SOC and PT;  
• TEAEs leading to dose reduction of avelumab, by SOC and PT; 


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• Age  
- Age < 65 years (Reference); 
- Age ≥ 65 years.  
• Gender 
- Male (Reference); 
- Female. 
• Race 
- White (Reference); 
- Asian; 
- Black or African American; 
- Other. 
• Ethnicity 
- Hispanic or Latino;  
- Not Hispanic or Latino (Reference). 
• Pooled Geographical Region  
- North America;  
- Western Europe (Reference); 
- Eastern Europe; 
- Asia; 
- Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional subgroups if including > 10% of the overall randomized population). 
• ECOG Performance Status at Baseline 
- 0 (Reference);  
- 1.   
• Subsite of Primary Diagnosis    
- Oral cavity (Reference);  
- Oropharynx; 
- Larynx; 
- Hypopharynx; 
- Other. 
Subset analyses for PFS, OS and DR will use the primary censoring rules described in 
Sections 6.1.1.1 and 6.2.2.1. All the subgroup analyses are exploratory. Treatment arms will 
be compared for PFS and OS using a 2-sided unstratified log-rank test for each subgroup 


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level and the unstratified HR and its corresponding 95% CI will be computed per subgroup 
level.  
All the subgroup analyses will be exploratory; no adjustment for multiplicity will be 
performed.  In the case of a low number of patients within a category (<5% of the 
randomized population), the categories will be pooled. 
To assess the heterogeneity of treatment effects for PFS and OS across the subgroup levels, 
two Cox regression model will be fitted with PFS or OS, respectively, as the dependent 
variable and  subgroup, treatment, and with and without the treatment-by-subgroup 
interaction as explanatory variables.  
• Model 1: factors + treatment + subgroup 
• Model 2: factors + treatment + subgroup + treatment×subgroup-variable  
A p-value for the interaction test (Wald’s test) will be provided together with the HR and 
corresponding 95% CI for the interaction model parameter.  
The HR for PFS and OS and corresponding 95% CIs for all subgroups will also be presented 
in a forest plot. 
The ORR odds ratio for each subgroup and corresponding 95% CIs will also be presented in 
a forest plot for each treatment arm. 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline summaries 
The following analyses will be based on the FAS overall and separately by treatment arm. 
6.5.1.1. Demographic characteristics 
Demographic characteristics and physical measurements will be summarized by treatment 
arm using the following information from the ‘Screening/Baseline Visit’ eCRF pages. 
• Demographic characteristics  
- Gender: Male, Female  
- Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, Other, Unknown 
- Ethnic origin:  
 Hispanic or Latino 
 Not Hispanic or Latino 
- Age (years): summary statistics  


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- Age categories:  
 < 65 years, ≥ 65 years; 
 < 65, 65-<75, 75-<85, ≥ 85 years. 
- Pooled Geographical Region (as applicable):  
 North America;  
 Western Europe; 
 Eastern 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 population). 
- Geographic Region (as applicable): 
 North America; 
 Latin America; 
 Western Europe; 
 Eastern Europe; 
 Middle East; 
 Australasia; 
 Asia; 
 Africa. 
- Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4  
• Physical measurements 
- Height (cm); 
- Weight (kg); 
- Body Mass Index (BMI) (kg/m2); 
- Body Surface Area (BSA) (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 arm, age, sex, race, ethnicity, height (cm), weight 
(kg), BMI (kg/m2), BSA (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 


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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. 
6.5.1.3. Disease characteristics 
Information on disease characteristics collected on ‘Primary Diagnosis’, ‘Substance Use’ and 
modified RECIST eCRF pages will be summarized overall and by treatment arm. Summary 
statistics will be presented for the following. 
From the ‘Primary Diagnosis’ eCRF page: 
• Site of primary tumor 
• Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page) 
• Time since initial diagnosis to date of randomization (months), defined as (date of 
randomization – date of initial diagnosis)/30.4375 
From the modified RECIST eCRF page: 
• Measurable disease (lesions) at baseline (Yes, No) 
• Involved tumor sites at baseline 
From the ‘Substance Use’ eCRF page: 
• Smoking history (never smoker, former smoker, current smoker) 
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. 
6.5.2. Study conduct and patient disposition 
The following analyses will be performed based on the FAS overall and separately by 
treatment arm. 
6.5.2.1. Patient disposition 
The percentages below will be calculated based on the number of patients in the FAS in each 
treatment arm. 
• Total number of patients screened overall; 
• Number of patients who discontinued from the study prior to randomization overall and by 
the main reason for discontinuation; 
• Number and percentage of randomized patients in each of the analysis sets defined in 
Section 4; 


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• Number and percentage of randomized patients with study drug ongoing  during the Lead-
in Phase;  
• Number and percentage of randomized patients who completed or discontinued study drug 
overall and by the main reason for discontinuation of study drug  during the Lead-in Phase;  
• Number and percentage of randomized patients who entered CRT Phase;  
• Number and percentage of randomized patients with study drug ongoing (separately for 
each study drug) during the CRT Phase;  
• Number and percentage of randomized patients who completed or discontinued study drug 
overall and by the main reason for discontinuation of study drug (separately for each study 
drug) during the CRT Phase;  
• Number and percentage of randomized patients with at least one study drug ongoing during 
the CRT Phase;  
• Number and percentage of randomized patients who completed or discontinued all study 
drugs, discontinued at least one study drug, and completed all study drugs during the CRT 
Phase;  
• Number and percentage of randomized patients who entered the Maintenance Phase;  
• Number and percentage of randomized patients with study drug ongoing during the 
Maintenance Phase;  
• Number and percentage of randomized patients who completed or discontinued study drug 
overall and by the main reason for discontinuation of study drug  during the Maintenance 
Phase;  
• Number and percentage of patients who entered follow-up; 
• Number and percentage of patients who completed or discontinued follow-up overall and 
by the main reason for discontinuation; 
• Number and percentage of patients who entered long-term follow-up; 
• 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: 
• Number and percentage of randomized patients overall, by region (Europe, EEA (required 
by EudraCT), North America, Latin America, Asia, Australasia, Middle East,  Africa), by 
country within region;  
• Number and percentage of randomized patients by center; 
• Number and percentage of randomized patients by randomization strata (IRT); 
• Number and percentage of randomized patients by randomization strata (eCRF); 
• Cross tabulation: stratum by IRT vs. stratum by eCRF; 


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• Cross tabulation: patients randomized (Arm A/Arm B/none) vs. patients treated  (Arm 
A/Arm B/none).  
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: 
• Patients who are dosed on the study despite not satisfying the inclusion criteria; 
• Patients who develop withdrawal criteria whilst on the study but are not withdrawn; 
• Patients who receive the wrong treatment or an incorrect dose;  
• Patients who receive an excluded concomitant medication; 
• 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 arm. 
The derivations below are provided for the following: 
• Avelumab or matching placebo administered as a 1-hour IV infusion at a dose of 10 mg/kg  
- on Day 1 of the Lead-in Phase (1 week prior to the start of the CRT Phase), and 
- on Days 8, 25, and 39 during the CRT Phase, and 
- once every 2 weeks in 4-week cycles for 12 months (52 weeks) during the Maintenance 
Phase.   
• Cisplatin 100 mg/m2 administered in 500 mL normal saline over a 60 – 120 minute infusion 
with an additional 1 to 1.5 L of fluid give post-hydration, on Days 1, 22, 43 during the CRT 
Phase 
• IMRT administered 70 Gy/35 fractions/7weeks, 1 fraction/day, 5 fractions/week)for 7 
weeks  during the CRT Phase. 
Analysis of exposure for avelumab (or matching placebo) and cisplatin will be based on the 
calculated actual dose levels: 
• Avelumab – total dose / weight  
• Cisplatin - total dose/m2 
Analysis of exposure for IMRT will be based on the total dose.  


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6.5.3.1. Exposure to avelumab or matching placebo  
Exposure to avelumab or matching placebo will be summarized by treatment phase (Lead-in, 
CRT, Maintenance).  In what follows, references to avelumab are meant to apply also to 
matching placebo. 
For Cycle X during the Maintenance Phase, actual cycle start date for each patient is 
• 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 (ie, avelumab dose>0 at that visit) 
• the first day of assessments in the Cycle X Day 1 visit, if the patient did not receive study 
treatment on that visit (ie, avelumab dose=0 at that visit).   
Actual cycle end date for each patient is,  
• for all cycles X except the last cycle, actual cycle end date =  actual cycle (X+1) start date 
– 1 day; 
• for the last cycle, actual cycle end date = actual cycle start date + 28 days – 1 day 
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7  
The dose level for avelumab is calculated as actual dose administered/weight (mg/kg). The 
last available weight of the patient on or prior to the day of dosing will be used. 
Lead-in Phase 
One dose of avelumab is planned to be administered in the Lead-in Phase, the number and 
percentage of patients who receive the dose will be summarized. 
CRT Phase 
During the CRT Phase, three doses of avelumab are planned to be administered (on Days 8, 
25, and 39 of CRT Phase) with a minimum of 14 days required to separate consecutive doses 
of avelumab or matching-placebo.  
Intended duration of avelumab treatment in CRT Phase (days) = ((39+14-1)-8+1) = 45  
Duration of exposure to avelumab in the CRT Phase (days) =  
(last dose date of avelumab – first dose date of avelumab + 14)   
Cumulative avelumab dose (mg/kg) is the sum of the actual doses of avelumab received in 
the CRT Phase.   
Actual Dose Intensity (DI) for avelumab in the CRT Phase = 
[cumulative dose in the CRT Phase (mg/kg)]/[intended duration of avelumab 
treatment in CRT Phase (days)/45] (mg/kg/45 days) 


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Relative Dose Intensity (RDI) for avelumab in the CRT Phase is calculated as follows: 
• Intended DI (mg/kg/45 days) = 30 (mg/kg/45 days) 
• RDI (%) = 100 × [actual DI] / [intended DI] = 100 × actual DI / 30.  
The summary of treatment exposure and compliance for avelumab in the CRT Phase will 
include the following information: 
• Duration of exposure to avelumab (days); 
• Total number of infusions received; 
• Cumulative dose (mg/kg); 
• Actual DI (mg/kg/45 days); 
• RDI (%). 
 
Maintenance Phase 
Each cycle for avelumab during the Maintenance Phase is defined by a 4-week period. The 
dose intensity (DI) and the relative dose intensity (RDI) for avelumab during the 
Maintenance Phase will be calculated for each patient across all cycles.  
Intended duration of avelumab treatment in the Maintenance Phase (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 + 28 – 1 
Duration of exposure to avelumab in the Maintenance Phase (weeks) =  
(last dose date of avelumab – first dose date of avelumab + 14)/7   
Cumulative dose (mg/kg) is the sum of the actual doses of avelumab received during the 
Maintenance Phase.   
Actual DI for avelumab in the Maintenance Phase 
• Overall actual DI (mg/kg/4-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/4].   
RDI for avelumab in the Maintenance Phase 
• Intended DI (mg/kg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [20 (mg/kg)] / [1 (4-week cycle)] = 20 (mg/kg/4-week 
cycle) 
• Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI] = 100 × [overall actual DI] / 
[20 (mg/kg/4-week cycle)]  


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The summary of treatment exposure and compliance for avelumab during the Maintenance 
Phase will include the following information: 
• Duration of exposure to avelumab (weeks); 
• Total number of infusions received; 
• Cumulative dose (mg/kg); 
• Actual DI (mg/kg/cycle); 
• RDI (%). 
Duration of exposure to avelumab across all treatment phases 
Duration of exposure to avelumab (weeks) = (last dose date of avelumab – first dose date 
of avelumab + 14) /7    
Total number of avelumab infusions received overall is the sum of the total number of 
infusions received in each treatment phase. 
 
6.5.3.2. Exposure to Cisplatin 
Cisplatin is to be administered only in the CRT Phase. Three doses of cisplatin (100 mg/m2) 
are planned to be administered on Days 1, 22, and 43 of the CRT Phase.   
Intended duration of cisplatin treatment in CRT Phase (weeks) = 63/7 = 9 weeks  
Duration of exposure to cisplatin in the CRT Phase (weeks) =  
(last dose date of cisplatin – first dose date of cisplatin + 21)/7   
Cumulative cisplatin dose (mg/m2) is the sum of the actual doses of cisplatin received in the 
CRT Phase.   
Actual Dose Intensity (DI) for cisplatin in the CRT Phase = 
[cumulative dose (mg/m2)]/[intended duration of cisplatin treatment (weeks) /9] (mg/ 
m2/9-weeks) 
Relative Dose Intensity (RDI) for cisplatin in the CRT Phase is calculated as follows: 
• Intended DI (mg/m2/9-weeks) = 300 (mg/m2/9-weeks) 
• RDI (%) = 100 × [actual DI] / [intended DI] = 100 × actual DI / 300.  
The summary of treatment exposure and compliance for cisplatin will include the following 
information: 
• Duration of exposure to cisplatin (weeks); 


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• Total number of doses a received; 
• Cumulative dose (mg/m2);  
• Actual DI (mg/m2/9-weeks); 
• RDI (%). 
a Per protocol, cisplatin dose can be split over a period of 2 to 4 consecutive days. 
Therefore, if cisplatin is given consecutively over 2-4 days, this will be viewed as a split 
dose.  Split doses will be summed up and categorized as a single dose.     
6.5.3.3. Exposure to IMRT  
IMRT is to be administered only in the CRT Phase.  The total dose and duration of IMRT 
administration will be calculated for each patient during the CRT Phase.  
Duration of IMRT (days) = number of days IMRT is administered.   
Total dose of IMRT (Gy) = duration of IMRT (days) × 2.  
The number of days IMRT is administered and compliance with IMRT administration 
(“Appropriate”, “Variation acceptable”, “Deviation unacceptable”) will be assessed by a 
central vendor for each patient during the CRT Phase.    
The summary of treatment exposure and compliance for IMRT will include the following 
information: 
• Duration of IMRT (days); 
• Total dose of IMRT (Gy);   
• Overall compliance (Appropriate, Variation acceptable, or Deviation unacceptable). 
6.5.3.4. Dose reductions 
Applicable to avelumab, matching placebo and cisplatin.   
For avelumab or matching placebo, 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 
overall and by treatment phase (Lead-in, CRT, Maintenance). 
For cisplatin, a dose reduction is defined as a reduction to dose level -1 (75 mg/m2) or dose 
level -2 (50 mg/m2). The number and percentage of patients with at least one one-dose level 
reduction, and with at least one two-dose level reduction as well as a breakdown of the 
number of dose reductions will be summarized. 


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6.5.3.5. Dose Delays  
Applicable to avelumab, matching placebo, and cisplatin. 
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) – Planned days between 
two consecutive doses. 
• Lead-in Phase:  not applicable 
• CRT Phase:   
- cisplatin:  the number of planned days between two consecutive doses is 21 days; 
- avelumab or matching placebo:  not applicable (note that the protocol mandates a 
minimum interval between doses but does not establish a fixed number of days between 
two consecutive doses); 
• Maintenance Phase (avelumab or matching placebo only):  the number of planned days 
between two consecutive doses is 14 days. 
Dose delays will be grouped into the following categories:  
• No delay;  
• CRT Phase: 1-2 days delay; 3-6 days delay; 
• Maintenance Phase: 1-3 days delay; 4-6 days delay; 
• 7 or more days delay. 
In the CRT Phase, no delay and 1-2 days delay will also be summarized together, and in the 
Maintenance Phase 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, ie, the worst case of delay if patients have multiple dose delays will be 
summarized  
• for avelumab or matching placebo: in the Maintenance Phase;  
• for cisplatin: in the CRT Phase. 
6.5.3.6. Infusion rate reductions  
Applicable to avelumab, matching placebo and cisplatin. 
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   
• for avelumab or matching placebo: overall and by treatment phase (Lead-in, CRT, 
Maintenance); 


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• for cisplatin: in the CRT Phase. 
6.5.3.7. Infusion interruptions 
Applicable to avelumab, matching placebo and cisplatin. 
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, 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  
• for avelumab or matching placebo: overall and by treatment phase (Lead-in, CRT, 
Maintenance); 
• for cisplatin: in the CRT Phase. 
6.5.4. Concomitant medications and non-drug treatments 
The following analyses will be based on the safety analysis set by treatment arm. 
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study drugs 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’.  


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A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page. 
6.5.5. Subsequent anti-cancer therapies 
The following analyses will be based on the FAS by treatment arm. 
Anti-cancer treatment will be provided in a data listing with data retrieved from ‘Follow-up 
Cancer 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 by treatment arm.  
6.6.1. Adverse events 
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period as defined in Section 3.5.1. 
All analyses described 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 with onset outside the on-treatment period will be flagged in the listings. 
• 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 (ie, no answer to the question ‘Relationship 
with study treatment’).  Related AEs are those related to any study drug (ie, at least one of 
the study drugs).  
• Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes). 
• 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). 
• 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 
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.  


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• 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). 
• 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). 
• 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 SRP and finalized for analysis of this study’s data prior to DB lock) 
• 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 
SRP and finalized for analysis of this study’s 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 arm, primary SOC 
and PT in decreasing frequency based on the frequencies observed for Arm A.  
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:  
• The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment arm: 
- TEAEs; 
- TEAEs, Grade ≥ 3; 
- Related TEAEs; 
- Related TEAEs, Grade ≥ 3; 
- TEAEs leading to dose reduction of avelumab;  
- TEAEs leading to dose reduction of cisplatin; 
- TEAEs leading to dose reduction of IMRT; 
- TEAEs leading to interruption of avelumab; 


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- TEAEs leading to interruption of cisplatin; 
- TEAEs leading to interruption of IMRT; 
- TEAEs leading to discontinuation of avelumab; 
- TEAEs leading to discontinuation of cisplatin; 
- TEAEs leading to discontinuation of IMRT; 
- TEAEs leading to discontinuation of any study drug (CRT Phase); 
- TEAEs leading to discontinuation of all study drugs (CRT Phase); 
- Related TEAEs leading to discontinuation of avelumab; 
- Related TEAEs leading to discontinuation of cisplatin; 
- Related TEAEs leading to discontinuation of IMRT; 
- Related TEAEs leading to discontinuation of any study drug (CRT Phase); 
- Related TEAEs leading to discontinuation of all study drugs (CRT Phase); 
- Serious TEAEs; 
- Related Serious TEAEs;  
- TEAEs leading to death; 
- Related TEAEs leading to death; 
- irAEs; 
- IRRs.  
• TEAEs by SOC and PT and worst grade 
• Related TEAEs by SOC and PT and worst grade  
• TEAEs leading to death by SOC and PT 
• Related TEAEs leading to death by SOC and PT 
In addition, the following tables will be created by treatment phase: 
• Overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment arm and treatment phase a :  
- TEAEs; 
- TEAEs, Grade ≥ 3; 
- TEAEs leading to discontinuation of avelumab; 
- Serious TEAEs; 
- irAEs; 
- IRRs. 
• TEAEs by SOC and PT and worst grade. 


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• TEAEs leading to death by SOC and PT. 
a AEs will be included in the summary for each treatment phase if the AE onset occurs 
anytime from first dose of study treatment in the treatment phase through minimum(first dose 
of study treatment in next treatment phase, end of on-treatment period). 
 
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 arm: 
• TEAEs leading to dose reduction of avelumab by SOC and PT; 
• TEAEs leading to dose reduction of cisplatin by SOC and PT; 
• TEAEs leading to dose reduction of IMRT 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).  
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:  
• 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 6.5.3.5). These IRRs will be considered as IRRs leading to 
interruption of infusion. 
• IRRs occurring on the day after infusion and subsequent dose administration had no delay 
(as defined in Section 6.5.3.5). 
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 arm: 
• TEAEs leading to interruption of avelumab by SOC and PT; 
• TEAEs leading to interruption of cisplatin by SOC and PT; 
• TEAEs leading to interruption of IMRT 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 arm: 


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• TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT; 
• TEAEs leading to both interruption and dose reduction of cisplatin by SOC and PT; 
• TEAEs leading to both interruption and dose reduction of IMRT by SOC and PT. 
This summary will take into account PTs with both actions as defined in Section 6.6.1, 
eventhough 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 each study drug and study 
treatment, by treatment arm: 
• TEAEs leading to discontinuation of avelumab by SOC and PT; 
• Related TEAEs leading to discontinuation of avelumab by SOC and PT; 
• TEAEs leading to discontinuation of cisplatin by SOC and PT;  
• Related TEAEs leading to discontinuation of cisplatin by SOC and PT;  
• TEAEs leading to discontinuation of IMRT by SOC and PT; 
• Related TEAEs leading to discontinuation of IMRT by SOC and PT; 
• TEAEs leading to discontinuation of any study drug by SOC and PT (CRT Phase); 
• Related TEAEs leading to discontinuation of any study drug by SOC and PT (CRT Phase); 
• TEAEs leading to discontinuation of all study drugs by SOC and PT (CRT Phase); 
• Related TEAEs leading to discontinuation of all study drugs by SOC and PT (CRT Phase). 
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information.  
In addition, the frequency (number and percentage) of patients with TEAEs leading to 
discontinuation of avelumab will be summarized by SOC and PT within each treatment arm 
and treatment phase.  
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 arm, and by treatment arm and treatment phase.   
• All deaths  
• Deaths within 30 days after last dose of study treatment 
• Reason for Death  
- Disease progression; 


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- 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: 
• AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5);  
• Flag for death within 30 days of last 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 arm: 
• SAEs by SOC and PT; 
• Related SAEs by SOC and PT. 
In addition, the frequency (number and percentage) of patients with SAEs will be 
summarized by SOC and PT within each treatment arm and treatment phase. 
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 arm: 
• irAEs leading to death, by Cluster and PT;  
• irAEs, by Cluster and PT; 
• irAEs, Grade ≥ 3, by Cluster and PT; 
• irAEs leading to discontinuation of avelumab, by Cluster and PT;  
• irAEs leading to discontinuation of cisplatin, by Cluster and PT;  
• irAEs leading to discontinuation of IMRT, by Cluster and PT;  
• irAEs leading to discontinuation of any study drug, by Cluster and PT (CRT Phase); 
• irAEs leading to discontinuation of all study drugs, by Cluster and PT (CRT Phase); 
• Serious irAEs, by Cluster and PT.  
In addition, the frequency (number and percentage) of patients with each of the following 
will be presented for irAEs by treatment arm and treatment phase:  


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• irAEs, by Cluster; 
• irAEs, Grade ≥ 3, by Cluster; 
• irAEs leading to death, by Cluster; 
• irAEs leading to discontinuation of avelumab, by Cluster;  
• Serious irAEs, by Cluster.  
 
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 arm: 
• IRRs leading to death, by PT (separately for IRRs associated with avelumab, associated 
with cisplatin, associated with either avelumab or cisplatin);  
• IRRs, by PT (separately for IRRs associated with avelumab, associated with cisplatin, 
associated with either avelumab or cisplatin); 
• IRRs, Grade ≥ 3, by PT (separately for IRRs associated with avelumab, associated with 
cisplatin, associated with either avelumab or cisplatin); 
• IRRs leading to discontinuation of avelumab, by PT;  
• IRRs leading to discontinuation of cisplatin, by PT;  
• IRRs leading to discontinuation of any study drug, by PT (CRT Phase);  
• IRRs leading to discontinuation of all study drugs, by PT (CRT Phase); 
• Serious IRRs, by PT (separately for IRRs associated with avelumab, associated with 
cisplatin, associated with either avelumab or cisplatin); 
• Time related to first onset of an IRR associated with avelumab (infusion 1, infusion 2, 
infusion 3, infusion 4 or later). 
In addition, the frequency (number and percentage) of patients with each of the following 
will be presented for IRRs by treatment arm and treatment phase 
• IRRs associated with avelumab, by PT  
• IRRs associated with avelumab, Grade ≥ 3, by PT  
• IRRs associated with avelumab leading to death, by PT  
• IRRs leading to discontinuation of avelumab, by PT;  
• Serious IRRs associated with avelumab, by PT; 
• Time related to first onset of an IRR associated with avelumab. 
 


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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. 
In addition, the following analyses will be presented for Tier-1 (irAEs and IRRs as defined in 
Appendix 1 and Appendix 2, respectively) and Tier-2 events separately.  CIs for risk 
difference will be calculated based on the unconditional exact method by Santner and Snell 
(1980)17.  No additional analyses will be presented for Tier-3 AEs.  
• Frequency (number and percentage) of patients with each of the following by treatment 
arm and PT or Clustered Term: 
- Tier-2 AEs 
- Tier-2 AEs Grade ≥ 3 
• Point estimate for risk difference and 95% CI for risk difference (experimental arm vs 
comparator arm) for each of the following by PT or Clustered Term: 
- irAEs 
- irAEs Grade ≥ 3 
- IRRs associated with avelumab 
- IRRs associated with avelumab, Grade ≥ 3 
- Tier-2 AEs 
- Tier-2 AEs Grade ≥ 3 
• The CIs reported are not adjusted for multiplicity and should be used for screening 
purposes only.  The 95% CIs are provided to help gauge the precision of the estimates for 
the risk difference and should be used for estimation purposes only. 
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 (eg, 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 (ie, 
Low, Normal, High).  


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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 (eg, hypokalemia) grades at baseline and post baseline will be set to 0 
when the variables are derived for summarizing high direction toxicity (eg, 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) 
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:  
• Lymphocyte count decreased:   
- derived absolute count does not meet Grade 2-4 criteria, and 
- % value < % LLN value, and 
- derived absolute count  ≥ 800/mm3 
• 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 arm: 
• ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN; 
•  AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN; 


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• (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN; 
• TBILI ≥ 2×ULN; 
• Concurrent  ALT ≥ 3×ULN and TBILI ≥ 2×ULN; 
• Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN; 
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN;  
• Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN; 
• 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, ie, 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 arms, by graphically displaying 
• peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at 
ALT=3×ULN and total bilirubin=2×ULN;  
• peak serum AST(/ULN) vs peak total bilirubin (/ULN) 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 concurrent 
(ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing)  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 (ie those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived). 
• 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. 
• 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 number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)). 


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The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie: 
• 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). 
•  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 
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)  
In addition, hematology and chemistry laboratory parameters by CTCAE grade (any grade 
and Grade ≥ 3) will also be summarized by treatment phase. Laboratory tests will be included 
in the summary for each treatment phase if the laboratory test date/time occurs anytime from 
first dose date/time of study treatment in the treatment phase through minimum(first dose 
date/time of study treatment in next treatment phase, end of on-treatment period). 
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:  
• shifts from baseline normal to at least one result above normal during on-treatment period  
• shifts from baseline normal to at least one result below normal during on-treatment period 
In this study, these apply to the following parameters:  
• Hematology: Absolute Monocytes, Absolute Eosinophils, Absolute Basophils 
• 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.  
• Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time (INR). 
• Urinalysis: protein, glucose, blood 
• Thyroid function tests: TSH, free T4 


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• Other parameters: adrenocorticotropic hormone (ACTH)  
• 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. 
6.6.6. Vital signs 
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 not be collected at End of Treatment. Height will 
be measured at screening only. 
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).  When 
triplicates are collected (for approximately 30 subjects in each treatment arm), 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, 


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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.   
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 arm, 
during the on-treatment period. The denominator to calculate percentages for each category 
is the number of patients evaluable for the category. 
• Pearson correlation between QT and HR, QTc (QTcB, QTcF) and HR using individual 
(non-averaged) baseline assessments  
• 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  
• 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. ECOG performance status 
The ECOG shift from baseline to highest score during the on-treatment period will be 
summarized by treatment arm. 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 
7.1. Introduction 
The goals of the interim analyses are to allow early stopping of the study for futility or to do 
an early determination of superiority of Arm A compared to Arm B based on PFS.  The 
interim analysis of PFS and OS will be performed as described in Sections 5.1.1 and 5.1.2 
using the methodology described in Section 6.1.1 for PFS and Section 6.2.2.1 for OS.   
At the time of the interim analysis for PFS, the interim analysis for OS will be performed by 
an independent statistician.  Unblinded results from the interim analysis for PFS and first 
interim analysis for OS will not be communicated to the Sponsor’s clinical team or to any 
party involved in the study conduct (apart from the independent statistician and E-DMC 
members) until the E-DMC has determined that either (i) PFS analysis has crossed the pre-
specified boundary for efficacy or (ii) the study needs to be terminated due to any cause, 
including futility or safety reasons.  Further details will be described in the E-DMC charter. 
At the time of final PFS analyses, both PFS and interim OS analysis will be performed by the 
Sponsor’s clinical team. All patients will continue to be followed for OS until the final OS 
analysis (or earlier if OS reaches statistical significance at an interim analysis). 
7.2. Interim Analyses and Summaries 
At each analysis time point, the critical boundaries for the group sequential test will be 
derived from the predefined spending function(s) as described in Section 5.1. The 
calculations of boundaries will be performed using EAST. 
7.2.1. Interim analysis for PFS 
Let u(t1) and u(tF) denote the upper critical boundaries based on the test statistics Z1 and ZF 
for efficacy at the interim and the final analysis, respectively, and let l(t1) and l(tF) denote the 
lower critical boundary for futility at the interim and final analysis, respectively.  For the 
final analysis, l(tF)=u(tF).  
The critical values u(t1) and l(t1) for the interim analysis of PFS are determined such as  
)
(
))
(
(
1
1
1
0
t
t
u
Z
P
α
=
≥
  and  
)
(
))
(
(
1
1
1
t
t
l
Z
Pa
β
=
≤
, 
where P0 and Pa denote the probabilities under the null hypothesis and the alternative 
hypothesis, respectively, and 
)
( 1t
α
 and
)
( 1t
β
 denote the α and β spent, respectively, based on 


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the predefined spending functions at information fraction t1 (t1 is calculated as the ratio of the 
number of PFS events observed at the time of the cut-off for the interim analysis and the total 
number of PFS events targeted for the final analysis).  
The boundary for the final efficacy analysis will be calculated such that 
025
.0
)
),
(
(
)
(
1
1
0
1
=
≥
<
+
F
F
u
Z
t
u
Z
P
t
α
 
As described in Section 5.1.2, if the number of PFS events in the final analysis deviates from 
the target number of PFS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analysis and the actual correlation between 
the two test statistics Z1 and ZF, so that the overall 1-sided significance level across all 
analyses and comparisons is preserved at 0.025.  
7.2.2. Interim analysis for OS  
No futility analysis will be performed for OS.  Let u(ti) and u(tF) denote the upper critical 
boundaries based on the test statistics Zi and ZF for efficacy at the ith interim and the final 
analysis, respectively, where i=1, 2, 3, 4.  
In what follows P0 denotes the probability under the null hypothesis, and 
)
( it
α
 denotes the α 
spent based on the predefined α-spending function at information fraction ti (ti is calculated 
as the ratio of the number of OS events observed at the time of the cut-off for the ith interim 
analysis and the total number of OS events targeted for the final analysis. 
For each comparison, the critical value u(t1) for the 1st interim analysis of OS is determined 
such as  
)
(
))
(
(
1
1
1
0
t
t
u
Z
P
α
=
≥
. 
Critical boundaries for the additional interim analyses and the final analysis of OS are 
calculated recursively as follows for each comparison  
u(t2) is derived such that 
)
(
))
(
),
(
(
)
(
2
2
2
1
1
0
1
t
t
u
Z
t
u
Z
P
t
α
α
=
≥
<
+
, 
u(t3) is derived such that 
)
(
))
(
),
(
),
(
(
)
(
3
3
3
2
2
1
1
0
2
t
t
u
Z
t
u
Z
t
u
Z
P
t
α
α
=
≥
<
<
+
, 
u(t4) is derived such that 
)
(
))
(
),
(
),
(
),
(
(
)
(
4
4
4
3
3
2
2
1
1
0
3
t
t
u
Z
t
u
Z
t
u
Z
t
u
Z
P
t
α
α
=
≥
<
<
<
+
. 
The boundary for the final efficacy analysis is derived such that 
.
025
.0
)
),
(
),
(
),
(
),
(
(
)
(
4
4
3
3
2
2
1
1
0
4
=
≥
<
<
<
<
+
F
F
u
Z
t
u
Z
t
u
Z
t
u
Z
t
u
Z
P
t
α
 
As described in Section 5.1.2, if the number of OS events in the final analysis deviates from 
the target number of OS events, the final analysis criteria will be determined as above taking 
into account the actual alpha spent at the interim analyses and the actual correlation between 
the four test statistics Zi (i=1, 2, 3, 4) and ZF, so that the overall 1-sided significance level 
across all analyses and comparisons is preserved at 0.025.  


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8. REFERENCES 
1. 
Amit O, et al.  Blinded independent central review of progression in cancer clinical 
trials: Results from a meta-analysis and recommendation from a PhRMA working 
group. European Journal of Cancer 47:1772-1778, 2011. 
2. 
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with 
oropharyngeal cancer. N Engl J Med 2010;363 (1);24-35. 
3. 
Ang KK, Zhang Q, Rosenthal, DI, et al. Randomized phase III trial of concurrent 
accelerated radiation plus cisplatin with or without cetuximab for stage III and IV head 
and neck carcinoma: RTOG 0522. J Clin Oncol 2014;32: 2940-2950. 
4. 
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982. 
5. 
Brundage M, Osoba D, Bezjak A, et al. Lessons learned in the assessment of health-
related quality of life: Selected examples from the National Cancer Institute of Canada 
Clinical Trials Group. J Clin Oncol 2007, 25:5078-5081. 
6. 
Cella D, Rosenbloom SK, Beaumont JL, et al. Development and validation of 11 
symptom indexes to evaluate response to chemotherapy. JNCCN 2011;9: 268-278. 
7. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika; 26, 404-413. 
8. 
EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-5L instrument.  
Version 2.1, April 2015. Available at: https://euroqol.org/wp-
content/uploads/2016/09/EQ-5D-5L_UserGuide_2015.pdf 
9. 
FDA. Guidance for Industry: Patient-reported outcomes measures; use in medical 
product development to support labeling claims. December 2009. Available at:  
https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf. 
10. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20: 1727-1736. 
11. Jennison C, Turnbull BW. In: Group Sequential Methods with Applications to Clinical 
Trials. Chapman & Hall/CRC, Boca Raton, 2000. 
12. Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience. 2002.   
13. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958. 
14. NCCN/FACT Head & Neck Symptom Index-22 (FHNSI-22) Scoring Guidelines 
(Version 2). Available at: http://www.facit.org/facitorg/questionnaires. 


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15. Osoba D, Bezjak A, Brundage M, et al. Analysis and interpretation of health-related 
quality-oflife data from clinical trials: Basic approach of The National Cancer Institute 
of Canada Clinical Trials Group. Eur J Cancer 2005, 41:280-287. 
16. Royston, P. and Parmar, M.K. The use of restricted mean survival time to estimate the 
treatment effect in randomized clinical trials when the proportional hazards assumption 
is in doubt. Statistics in medicine, 2011; 30(19), pp.2409-2421. 
17. Santner TJ, Snell MK. (1980). Small-sample confidence intervals for p1-p2 and p1/p2 
in 2 x 2 contingency tables. Journal of the American Statistical Association, 75:386–
394 
18. Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression 
model. Biometrika 1980; 67:145-53. 
19. Sloan JA, Dueck AC, Erickson PA, et al. Analysis and interpretation of results based on 
patient reported outcomes. Value Health 2007, 10:S106-S115 (suppl 2). 
20. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. 
Statistics for Biology and Health, 2000. 
21. Uno H, et al. Moving Beyond the Hazard Ratio in Quantifying the Between-Group 
Difference in Survival Analysis. J Clin Oncol 2014; 32. 
22. Zhang X. Comparison of restricted mean survival times between treatments based on a 
stratified Cox model. DOI 10.1515/bams-2013-0101 Bio-Algorithms and Med-Systems 
2013; 9(4): 183–9. 
 
 


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9. APPENDICES 
Appendix 1. Immune-Related Adverse Events 
The MedDRA PTs and clusters for irAEs are defined in the SRP for avelumab. 
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 24.  
This case definition is hierarchical, ie, each step is only checked for patients and events that 
have already met the prior step.   
Table 24. 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) OR C) 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: 
• Underlying malignancy / progressive disease. 
• Other medical conditions.  
• Prior or concomitant medications / 
procedures.   
• 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 (eg, 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.  
• 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.  
• 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 25 
or Table 26 and will be identified for IV drugs only.     
Table 25. Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs 
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 
• AE onset date = date of infusion of study drug AND  
• AE timing related to study drug (‘DURING’, ‘AFTER’) AND  
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND  
• AE  end date – AE onset date <=2  
3 
PT is included in the ‘IRRs CORE’ list  
4A 
• AE onset date = date of infusion of study drug AND  
• AE timing related to study drug in (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion 
 


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Table 26. Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets) 
Condition 
Selection criterion 
IRR can be associated with the first IV drug and/or subsequent IV drugs that are administered in 
combination.  Without loss of generality assume triplet IV with D1 administered first then D2 then D3.  
The IV study drug or drugs associated with the IRR need to be identified in the analysis data set to enable 
subsequent analysis. 
The following are not sequential and an AE can be classified as an IRR associated with multiple DJ  from 
one or more of  I, II, III, IV, V below: 
I - If the AE meets [1 AND 2A1] for a DJ then the AE is classified as an IRR associated with the DJ 
that meets the 2A1 criterion  
 II - If the AE meets [1 AND 2A2] for a DJ then the AE is classified as an IRR associated with the DJ  
and associated with DJ+1 that meets the 2A2 criterion  
III - If the AE meets [3 AND 4B] for any DJ then the AE is classified as an IRR associated with all 
DJ that meet the 4B criterion. 
IV- If the AE meets [3 AND 4A1] for a DJ then the AE is classified as an IRR associated with the DJ 
that meets the 4A1 criterion  
 V- If the AE meets [3 AND 4A2] for a DJ then the AE is classified as an IRR associated with the DJ  
and associated with DJ+1 that meets the 4A2 criterion  
1 
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list  
2A1 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of 
infusion of study drug DJ+1] AND 
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND  
• AE  end date – AE onset date <=2  
2A2 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) AND 
• AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’)  AND  
• AE  end date – AE onset date <=2  
3 
PT is included in the ‘IRRs CORE’ list  
4A1 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• [AE timing related to study drug DJ+1 (‘BEFORE’) OR AE onset date < date of 
infusion of study drug DJ+1] 
4A2 
• AE onset date = date of infusion of study drug DJ AND 
• AE timing related to study drug DJ (‘DURING’, ‘AFTER’) AND  
• AE timing related to study drug DJ+1 (‘DURING’, ‘AFTER’) 
4B 
AE onset on the day after infusion of study drug D J 
 


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Appendix 3. Programmatic Derivation of Tumor Response Using RECIST v1.1 
Methods of Tumor Assessment 
The following are considered “interchangeable” methods: Conventional CT, Spiral CT, 
Enhanced CT, MRI and Enhanced MRI.  
Period for Derivation of BOR and PFS 
The period is defined from randomization until PD per RECIST v1.1 (Appendix 4 of 
B9991016 protocol) or death due to any cause. 
Evaluation of Target Lesions at Each Visit 
• The sum of lesion dimensions (SLD) is only considered if the methods of assessments are 
consistent with baseline.  The “interchangeable” methods noted above are all considered 
consistent methods. 
• In the SLD, the longest diameter will be used for non-nodal lesions and the short axis 
dimension will be used for each lymph node included in the sum. 
• Complete Response (CR) is defined by the disappearance of all non-lymph node target 
lesions (where all target lesions are recorded with a length of 0 mm on the “Target 
Lesions” eCRF).  Any pathological lymph nodes (recorded as target lesion) must have 
reduction in short axis to <10 mm.  Note: the SLD may not be zero if lymph nodes are 
included as target lesions. 
• Partial Response (PR) is defined by a 30% or more decrease in SLD of target lesions, 
taking as reference the baseline SLD. 
• Progressive Disease (PD) is defined by a 20% or more increase in the SLD of target 
lesions relative to nadir (smallest SLD considering baseline and all assessments prior to 
the timepoint under evaluation), with a minimum absolute increase of 5 mm relative to 
nadir.   
- If only a subset of target lesions are assessed and the sum of the non-missing lesion 
diameters results in an increase above of at least 5 mm and at least 20% above the 
nadir, then the progression criteria will have been met. 
• Stable Disease (SD) is assigned when neither sufficient shrinkage to qualify for CR or 
PR, nor sufficient increase to qualify for PD is observed, taking as reference the nadir. 
• No Target Lesion at Baseline (NB) is assigned if “No Target Lesion” is checked, on the 
“Target Lesions” eCRF.   
• Not All Evaluated (NAE) is assigned if: 
- Any individual target lesion is evaluated as “Indeterminate” on the “Target Lesions” 
eCRF 
- Inconsistent methods are used for any target lesions after randomization 
- One or more target lesions are not assessed 


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- One or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Evaluation of Non-Target Lesions at Each Visit 
The lesions assessed are only considered for CR, Non-CR/Non-PD and PD if the methods of 
assessments are consistent with baseline.  The “interchangeable” methods noted above are all 
considered consistent methods. 
• CR is defined by the complete disappearance of all non-target lesions (where all 
non-target lesions are marked ‘Absent Lesion or Normal Lymph Node’ on the “Non-
Target Lesion” eCRF).   
• Non-CR/Non-PD is defined by persistence of one or more non-target lesions (ie, if all 
non-target lesions are marked ‘Present/Not Increased’ on the “Non-Target Lesion” 
eCRF). 
• PD is assigned if any non-target lesion is marked “Increased” or “Present (First 
Appearance” on the “Non-Target Lesion” eCRF.   
• No Non-Target Lesion at Baseline (NB) is assigned if “No Non-Target Lesions” is 
marked on the “Non-Target Lesions” eCRF. 
• Not All Evaluated (NAE) is assigned if: 
- Any individual non-target lesion is evaluated as “Indeterminate” (marked as 
“Indeterminate” on the “Non-Target Lesions” eCRF) 
- Inconsistent methods are used for any non-target lesions after randomization  
- One or more non-target lesions are not assessed. 
 
New Lesion: is defined by the appearance of 1 or more new lesions (where any lesion is 
marked ‘New’ on the “New Measurable Lesions” or “New Non-measurable Lesions” 
eCRFs).  In addition, any lesion that is recorded for the first time after the start date without 
being marked as “New” on the “New Lesions” eCRF must be queried.  In case the 
inconsistency is not resolved at time of data base snapshot/lock, the lesion will be considered 
as new and the patient in progression at that time point.  Note: the requirement for consistent 
methods of assessment with baseline, obviously, does not apply for new lesions. 
Objective Response Status At Each Assessment 
• Overall response is determined from the derived target and non-target lesion data using 
conventions in Table 27 under the assumption that there are no new lesions identified at 
the visit. If there are any new lesions at a time point, then the response is PD at that 
time point regardless of target or non-target lesion response. 
• Objective status after a change in modality that is not considered interchangeable is 
classified as NE. 


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• To group target and non-target lesion measurements to the corresponding actual post-
baseline tumor assessment visit, a clustering algorithm is applied.  Each cluster represents 
an actual visit.  For each patient, the number of clusters is equal to the maximum number 
of assessments available among all target and non-target lesions.  The SAS procedure, 
Proc Fastclus, is applied to a variable that represents the days from randomization to the 
date of the scan for lesion (date of scan – randomization +1).  Then the assessments of 
lesions (target, non-target, new) that occurred close to each other in time will be assigned 
to the same cluster. 
The rules for derived objective status for each visit are presented in Table 27. 
Table 27. Derivation of Objective Status Based on Target and Non-Target Lesion 
Response Assuming No New Lesions 
Target Lesion Response 
Non-Target Lesion Response 
Objective Status 
CR 
CR 
CR 
CR 
Non-CR/Non-PD 
PR 
CR 
PD  
PD 
CR 
NAE 
PR 
PR 
CR 
PR 
PR 
Non-CR/Non-PD 
PR 
PR 
PD 
PD 
PR 
NAE 
PR 
SD 
CR 
SD 
SD 
Non-CR/Non-PD 
SD 
SD 
PD 
PD 
SD 
NAE 
SD 
PD 
Any  
PD 
NAE 
PD 
PD 
NAE 
CR 
Non-CR/Non-PD 
NAE 
NE 
NB 
CR 
CR 
NB 
Non-CR/Non-PD 
 
Non-CR/Non-PD 
 
NB 
PD 
PD 
NB 
NAE 
NE 
CR 
NB 
CR 
PR 
NB 
PR 
SD 
NB 
SD 
PD 
NB 
PD 
NAE 
NB 
NE 


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CR=Complete Response, PR=Partial Response, SD=Stable Disease, PD=Progressive Disease, 
NAE=Not All Evaluated; NE= Not Evaluable 
Note: If non-target (or target) lesions are not collected at baseline, then the overall response is equivalent to 
the target (or non-target) lesions response, respectively. 
If there are any new lesions at a time point, then the response is PD at that time point regardless of target or 
non-target lesion response. 
 
Date of Response at Each Visit 
If there are multiple assessments within a cluster, then the earliest scan date associated with 
the evaluation will be used as the date of the assessment.  As such: 
• The date of progressive disease is derived as the earliest date that PD has been 
documented, ie, the earliest date of: (target lesion assessments when the target lesion 
response is PD, non-target lesion assessments where the lesion status is ‘increased’ and 
the non-target lesion response is ‘PD’, new lesion) 
• The date of CR, PR, non-CR/non-PR, SD, NE is derived as the date of the first 
radiographic evaluation included in the cluster. 
Best Overall Response Evaluation for Each Patient 
• Best overall response is derived from the sequence of objective responses reported during 
the “Period for Derivation of Best Overall Response”. 
• The best overall response is the best response: CR, PR, SD, Non-CR/Non-PD, PD or NE  
- For a patient to qualify for a best response of SD, the overall response evaluation 
must have met the stable disease criteria at least once ≥6 weeks (42 days) after 
randomization. 
- NE is assigned for all cases that do not qualify as CR, PR, SD, Non-CR/Non-PD or 
PD.   
- If a patient’s first overall response other than NE is PD then the patient’s best overall 
response is PD.  If the first response of SD before the minimum period for SD defined 
above is followed by a PD then the best overall response is PD.