Clinical trial NCT02951156
Conditions: Diffuse Large B-Cell Lymphoma
Sponsor: Pfizer
Start date: 2016-12-16; Completion date: 2019-12-02
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study B9991011 is a multi-center, international, randomized, open label, 2 component (Phase 1b followed by Phase 3), parallel-arm study of avelumab in combination with various agents for the treatment of Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL).

Detailed description:
The target study population of this Phase 1b/3 registrational study is patients with R/R DLBCL who have completed at least 2 (but not more than 4) lines of prior rituximab-containing multi-agent chemotherapy, and/or in whom autologous stem cell transplant (ASCT) has failed, or who are not candidates for ASCT or who are not eligible for intensive chemotherapy. Patients who are ineligible for intensive second line chemotherapy must have received at least one prior rituximab-containing combination chemotherapy regimen. The study will assess the safety, efficacy, pharmacokinetics (PK), immunogenicity of the 3 avelumab-based combination regimens tested, and collect patient reported outcome (PRO) data.

Arms: arm 1: avelumab/utomilumab/rituximab arm 2: avelumab/utomilumab/azacitidine arm 3: avelumab/rituximab/bendamustine arm 4: Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine arm 5: Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin
Interventions: intervention 1: Avelumab intervention 2: Utomilumab intervention 3: Rituximab intervention 4: Azacitidine intervention 5: Bendamustine intervention 6: Gemcitabine intervention 7: Oxaliplatin
Intervention descriptions: intervention 1: Investigational fully human anti-PD-L1 monoclonal antibody intervention 2: Investigational, fully human IgG2 CD 137/4-1BB agonist intervention 3: CD20-directed cytolytic antibody intervention 4: Antimetabolite antineoplastic agent and demethylation agent. intervention 5: Alkylating drug intervention 6: Nucleoside analogue intervention 7: Platinum-based drug

Protocol documents:
Prot_000.pdf: 
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PHASE 1B/PHASE 3 MULTICENTER STUDY OF AVELUMAB (MSB0010718C)IN 
COMBINATION REGIMENSTHAT INCLUDE AN IMMUNE AGONIST, 
EPIGENETIC MODULATOR, CD20 ANTAGONIST AND/OR CONVENTIONAL 
CHEMOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY 
DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)
JAVELIN DLBCL
Investigational Product Number:
MSB0010718C
PF-05082566
Investigational Name:
Avelumab (MSB0010718C)
Utomilumab (PF-05082566)
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2016-002904-15
Protocol Number:
B9991011
Javelin DLBCL
Phase:
1b/3
The document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, 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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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
LIST OF FIGURES.................................................................................................................14
APPENDICES.........................................................................................................................14
PROTOCOL SUMMARY.......................................................................................................15
SCHEDULE OF ACTIVITIES................................................................................................19
1. INTRODUCTION...............................................................................................................36
1.1. Indication.................................................................................................................39
1.2. Mechanism of Action..............................................................................................39
1.3. Background and Rationale......................................................................................39
1.3.1. Diffuse Large B-Cell Lymphoma...............................................................39
1.3.2. Pharmaceutical and Therapeutic Background............................................40
1.3.2.1. Avelumab (MSB0010718C).....................................................40
1.3.2.2. Avelumab Safety.......................................................................41
1.3.2.3. Avelumab Pharmacokinetics.....................................................43
1.3.2.4. Immunogenicity of Avelumab in Humans................................43
1.3.2.5. Rituximab..................................................................................44
1.3.2.6. Utomilumab (PF-05082566).....................................................44
1.3.2.7. Utomilumab Safety...................................................................45
1.3.2.8. Utomilumab Efficacy................................................................46
1.3.2.9. Utomilumab Pharmacokinetics.................................................46
1.3.2.10. Utomilumab Immunogenicity.................................................47
1.3.2.11. Combination of a 4-1BB Agonist Antibody 
(Utomilumab) with a PD-1 Antagonist.............................................47
1.3.2.12. Preliminary Safety Summary for Study B9991004 Phase 
1b Combination A (Avelumab/Utomilumab)....................................48
1.3.2.13. Azacitidine..............................................................................49
1.3.2.14. Bendamustine..........................................................................50
1.3.2.15. Gemcitabine............................................................................50
1.3.2.16. Oxaliplatin...............................................................................51
1.4. Study Rationale.......................................................................................................52
1.4.1. High Unmet Medical Need.........................................................................52
1.4.2. Avelumab in DLBCL.................................................................................52


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1.4.3. Rationale for Treatment Arm A (Avelumab, Rituximab, and 
Utomilumab)....................................................................................................54
1.4.4. Rationale for Treatment Arm B (Avelumab, Azacitidine, and 
Utomilumab)....................................................................................................57
1.4.5. Rationale for Treatment Arm C (Avelumab, Rituximab and 
Bendamustine).................................................................................................59
1.4.6. Rationale for Control Arm Combinations for Phase 3 
(Rituximab/Bendamustine or Rituximab/Gemcitabine/Oxaliplatin)...............60
1.4.6.1. Rituximab/Bendamustine Safety...............................................62
1.4.6.2. Rituximab/Gemcitabine/Oxaliplatin Safety..............................62
1.5.Summary of Benefit/Risk Assessment....................................................................63
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................64
2.1. Objectives................................................................................................................64
2.2. Endpoints.................................................................................................................66
3. STUDY DESIGN.................................................................................................................68
3.1. Study Overview.......................................................................................................68
3.1.1. Phase 1b......................................................................................................68
3.1.2. Dose-Limiting Toxicity Definition.............................................................72
3.1.3. Phase 3........................................................................................................73
4. PATIENT SELECTION......................................................................................................75
4.1. Inclusion Criteria.....................................................................................................75
4.2. Exclusion Criteria....................................................................................................77
4.3. Lifestyle Guidelines................................................................................................79
4.3.1. Contraception..............................................................................................79
4.4. Sponsor’s Qualified Medical Personnel..................................................................81
5. STUDY TREATMENTS.....................................................................................................82
5.1. Allocation to Treatment..........................................................................................82
5.2. Patient Treatment Compliance................................................................................83
5.3. Investigational Product Supplies.............................................................................83
5.3.1. Dosage Form(s) and Packaging..................................................................83
5.3.1.1. Avelumab..................................................................................83
5.3.1.2. Utomilumab...............................................................................83
5.3.1.3. Rituximab..................................................................................84


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5.3.1.4. Azacitidine................................................................................84
5.3.1.5. Bendamustine............................................................................84
5.3.1.6. Gemcitabine..............................................................................84
5.3.1.7. Oxaliplatin.................................................................................84
5.3.2. Preparation and Dispensing........................................................................85
5.3.2.1. Avelumab Preparation...............................................................85
5.3.2.2. Utomilumab Preparation...........................................................85
5.3.2.3. Rituximab Preparation...............................................................85
5.3.2.4. Azacitidine Preparation.............................................................85
5.3.2.5. Bendamustine Preparation.........................................................85
5.3.2.6. Gemcitabine Preparation...........................................................85
5.3.2.7. Oxaliplatin Preparation.............................................................86
5.4. Administration.........................................................................................................86
5.4.1. Avelumab....................................................................................................86
5.4.2. Utomilumab................................................................................................86
5.4.3. Rituximab...................................................................................................87
5.4.4. Azacitidine..................................................................................................87
5.4.5. Bendamustine.............................................................................................88
5.4.6. Gemcitabine................................................................................................88
5.4.7. Oxaliplatin..................................................................................................88
5.4.8. Treatment Following Evidence of Radiological Disease Progression.......88
5.4.9.Food Requirements.....................................................................................89
5.5. Recommended Dose Modifications........................................................................89
5.5.1. Special Precautions for Avelumab Administration....................................90
5.5.2. Management of Avelumab Infusion-Related Reactions.............................91
5.5.2.1. Tumor Lysis Syndrome.............................................................92
5.5.2.2. Immune-Related Adverse Events..............................................94
5.5.3. Recommended Treatment Modifications for Phase 1b Treatment 
Arm A............................................................................................................101
5.5.3.1. Treatment Delays....................................................................101
5.5.3.2. Dose Reductions for Avelumab, Utomilumab, and 
Rituximab........................................................................................101
5.5.3.3. Managementof Immune-Related Adverse Events..................101


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5.5.3.4. Management of Infusion-Related Reactions...........................102
5.5.3.5. Avelumab and Utomilumab....................................................102
5.5.3.6. Rituximab................................................................................102
5.5.3.7.Management of Tumor Lysis Syndrome.................................102
5.5.4. Recommended Treatment Modifications for Phase 1b Treatment 
Arm B.............................................................................................................108
5.5.4.1. Treatment Delays....................................................................108
5.5.4.2. Dose Reductions for Avelumab and Utomilumab..................108
5.5.4.3. Dose Interruptions for Azacitidine..........................................108
5.5.4.4. Management of Immune-RelatedAdverse Events..................108
5.5.4.5. Management of Infusion-Related Reactions...........................109
5.5.4.6. Avelumab and Utomilumab....................................................109
5.5.4.7. Management of Tumor Lysis Syndrome.................................109
5.5.5. Recommended Treatment Modifications for Phase 1b Treatment 
Arm C.............................................................................................................112
5.5.5.1. Dose Modifications for Avelumab, Bendamustine, and 
Rituximab........................................................................................112
5.5.5.2. Treatment Delays....................................................................112
5.5.5.3. Dose Reductions for Rituximab and Avelumab......................112
5.5.5.4. Dose Reductions for Bendamustine........................................112
5.5.5.5. Management of Immune-Related Adverse Events..................113
5.5.5.6. Management of Infusion-Related Reactions...........................113
5.5.5.7. Avelumab................................................................................113
5.5.5.8. Rituximab................................................................................113
5.5.5.9. Bendamustine..........................................................................113
5.5.5.10. Management of Tumor Lysis Syndrome...............................114
5.6. Recommended Treatment Modifications for Phase 3...........................................118
5.6.1. Experimental Treatment Arm D...............................................................118
5.6.2.Control Treatment Arm E (Rituximab/Bendamustine)............................118
5.6.3. Cycle Delays for Bendamustine and Rituximab Drug-Related 
Toxicities........................................................................................................118
5.6.4. Dose Reductions for Rituximab................................................................118
5.6.5. Dose Reductions for Bendamustine..........................................................118


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5.6.6. Management of Infusion-Related Reactions............................................119
5.6.7. Rituximab.................................................................................................119
5.6.8. Bendamustine...........................................................................................119
5.6.9.Management of Tumor Lysis Syndrome..................................................119
5.7. Investigator’s Choice Treatment Arm E 
(Rituximab/Gemcitabine/Oxaliplatin).....................................................................122
5.7.1. Cycle Delays.............................................................................................123
5.7.2. Dose Reductions for Oxaliplatin..............................................................123
5.7.3. Dose Reductions for Gemcitabine............................................................123
5.7.4. Dose Reductions for Rituximab................................................................124
5.7.5. Management of Infusion-Related Reactions............................................124
5.7.6. Rituximab.................................................................................................124
5.7.7. Oxaliplatin................................................................................................124
5.7.8.Tumor Lysis Syndrome............................................................................124
5.7.9. Treatment Modifications for Hematologic Toxicities..............................124
5.8. Investigational Product Storage............................................................................128
5.9. Investigational Product Accountability.................................................................129
5.9.1. Destruction of Investigational Product Supplies......................................130
5.10. Concomitant Treatments.....................................................................................130
5.10.1. Concomitant Radiotherapy.....................................................................130
5.10.2. Supportive Care Guidelines....................................................................130
5.10.3. Concomitant Surgery..............................................................................131
5.10.4. Other Prohibited Concomitant Medications and Treatments.................131
6. STUDY PROCEDURES...................................................................................................132
6.1. Screening...............................................................................................................132
6.2. Treatment Period...................................................................................................133
6.3. Follow-Up Visits...................................................................................................133
6.4. Patient Withdrawal................................................................................................133
7. ASSESSMENTS................................................................................................................134
7.1. Safety Assessment.................................................................................................134
7.1.1. Pregnancy Testing....................................................................................134
7.1.2. Laboratory Safety Assessments................................................................135


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7.1.3. Electrocardiograms...................................................................................136
7.1.4. Disease Response Assessment (Lugano Criteria).....................................137
7.1.4.1. Expedited Blinded Independent Central Review for 
Disease Progression.........................................................................138
7.2. Pharmacokinetics Assessments.............................................................................138
7.2.1. Blood for PK Analysis of Avelumab........................................................139
7.2.2. Blood for PK Analysis of Utomilumab....................................................139
7.2.3. Blood for PK Analysis of Rituximab........................................................139
7.2.4. Blood for PK Analysis of Azacitidine......................................................139
7.2.5. Blood for PK Analysis of Bendamustine and metabolite (M3)................139
7.3. Immunogenicity Assessments...............................................................................139
7.3.1. Blood for Analysis of Anti-Avelumab Antibodies (ADA) and 
Neutralizing Anti-Avelumab Antibodies (NAb)...........................................140
7.3.2. Blood for Analysis of Anti-Utomilumab Antibodies (ADA) and 
Neutralizing Anti-Utomilumab Antibodies (NAb).......................................140
7.3.3. Blood for Analysis of Anti-Rituximab Antibodies (ADA) and 
Neutralizing Anti-Rituximab Antibodies (NAb)...........................................140
7.4. Biomarkers............................................................................................................140
7.4.2.1. Additional Research................................................................144
7.5. Patient-Reported Outcomes...................................................................................144
8. ADVERSE EVENT REPORTING....................................................................................146
8.1. Requirements.........................................................................................................146
8.1.1. Additional Details on Recording Adverse Events on the CRFs...............147
8.1.2. Eliciting Adverse Event Information........................................................147
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal section)...........................................................................148
8.1.4. Time Period for Collecting AE/SAE Information....................................148
8.1.4.1. Reporting SAEs to Pfizer Safety.............................................148
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF...............148
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8.1.5. Causality Assessment...............................................................................148
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities................149
8.2. Definitions.............................................................................................................149
8.2.1. Adverse Events.........................................................................................149
8.2.2. Abnormal Test Findings...........................................................................150
8.2.3. Serious Adverse Events............................................................................150
8.2.4. Hospitalization..........................................................................................151
8.3. Severity Assessment..............................................................................................153
8.4. Special Situations..................................................................................................153
8.4.1. Protocol-Specified Serious Adverse Events.............................................153
8.4.2. Potential Cases of Drug-Induced Liver Injury..........................................153
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................155
8.4.3.1. Exposure During Pregnancy....................................................155
8.4.3.2. Exposure During Breastfeeding..............................................156
8.4.3.3. Occupational Exposure...........................................................156
8.4.4. Medication Errors.....................................................................................157
8.4.4.1. Medication Errors....................................................................157
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................157
9.1. Sample Size Determination...................................................................................158
9.2. Statistical Methods and Properties........................................................................159
9.3. Analysis Population...............................................................................................160
9.3.1. Full Analysis Sets.....................................................................................160
9.3.2. Per Protocol Analysis Set.........................................................................160
9.3.3. Evaluable for DLT Analysis Set...............................................................160
9.3.4. Safety Analysis Set...................................................................................160
9.3.5. PK Analysis Set........................................................................................160
9.3.6. Immunogenicity Analysis Set...................................................................160
9.3.7. Biomarker Analysis Set............................................................................161
9.3.8. Pharmacogenomic Analysis Set...............................................................161
9.3.9. PRO Analysis Set.....................................................................................161


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9.4. Efficacy Analysis..................................................................................................161
9.4.1. Analysis of the Primary Endpoint.............................................................161
9.4.2. Analysis of Secondary Endpoints.............................................................163
9.4.2.1. Overall Survival......................................................................163
9.4.2.2. Progression-Free Survival at 6 Months...................................163
9.4.2.3. Time to Tumor Response........................................................164
9.4.2.4. Duration of Response..............................................................164
9.4.2.5. Disease Control.......................................................................164
9.4.2.6. Analysis of PD-L1 andMRD..................................................164
9.5. Analysis of Pharmacokinetics and Pharmacodynamics........................................164
9.5.1. Analysis of the Pharmacokinetics of Study Drugs...................................165
9.5.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling..............................165
9.6. Analysis for Avelumab, Rituximab and Utomilumab Immunogenicity...............165
9.7. Analysis of Patient-Reported Outcomes...............................................................166
9.10. Analysis of Other Endpoints...............................................................................167
9.11. Safety Analysis....................................................................................................167
9.11.1. Adverse Events.......................................................................................167
9.12. Laboratory Abnormalities...................................................................................168
9.13. Electrocardiograms..............................................................................................168
9.14. Interim Analysis..................................................................................................169
9.15. Data Monitoring Committee...............................................................................170
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................170
11. DATA HANDLING AND RECORD KEEPING...........................................................171
11.1. Case Report Forms/Electronic Data Record.......................................................171
11.2. Record Retention.................................................................................................172
12. ETHICS............................................................................................................................172
12.1. Institutional Review Board/Ethics Committee....................................................172
12.2. Ethical Conduct of the Study..............................................................................172
12.3. Patient Information and Consent.........................................................................172


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12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP.........................................................................................................................173
13. DEFINITION OF END OF TRIAL.................................................................................174
13.1. End of Trial in All Other Participating Countries...............................................174
13.2. End of Trial in All Participating Countries.........................................................174
14. SPONSOR DISCONTINUATION CRITERIA..............................................................174
15. PUBLICATION OF STUDY RESULTS........................................................................174
15.1. Communication of Results by Pfizer..................................................................174
15.2. Publications by Investigators..............................................................................175
16. REFERENCES................................................................................................................177
LIST OF TABLES
Table1.
Phase 1b Schedule of Activities...........................................................................20
Table2.
Phase 3 Schedule of Activities.............................................................................27
Table3.
Required Contraception Timeframes After Last Dose of Individual Study 
Drugs.....................................................................................................................80
Table4.
Avelumab Treatment Modifications for Symptoms of Infusion Related 
Reactions...............................................................................................................91
Table5.
Management of Immune Related Adverse Events...............................................95
Table6.
Treatment Arm A (Avelumab, Rituximab, and Utomilumab) Treatment 
Modifications for Investigational Product Related Hematologic Toxicities......103
Table7. Treatment Arm A (Avelumab, Rituximab, and Utomilumab) Treatment 
Modifications for Investigational Product-Related Non-Hematologic 
Toxicities............................................................................................................104
Table8.
Treatment Arm B (Azacitidine, Avelumab, and Utomilumab) Treatment 
Modifications for Investigational Product-Related Hematologic Toxicities......109
Table9.
Treatment Arm B (Azacitidine, Avelumab, and Utomilumab) Treatment 
Modifications for Investigational Product-Related Non-Hematologic 
Toxicities............................................................................................................110
Table10. Bendamustine Dose Reduction...........................................................................113
Table11. Treatment Arm C (Bendamustine, Rituximab, and Avelumab) Treatment 
Modifications for Investigational Product-Related Hematologic Toxicities......115
Table12. Treatment Arm C (Bendamustine, Rituximab, and Avelumab) Treatment 
Modifications for Investigational Product-Related Non-Hematologic 
Toxicities............................................................................................................115
Table13. Bendamustine Dose Reduction Levels...............................................................119


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Table14. Treatment Arm E: (Bendamustine and Rituximab) Treatment 
Modifications for Drug-Related Hematologic Toxicities...................................120
Table15. Treatment Arm E:  Treatment Modifications for Treatment-Related 
Non-Hematologic Toxicities..............................................................................120
Table16. Oxaliplatin Dose Reduction Levels....................................................................123
Table17. Treatment Arm E (Gemcitabine, Oxaliplatin, and Rituximab).  Treatment 
Modifications for Drug-Related Hematologic Toxicities...................................125
Table18. Treatment Arm E (Gemcitabine, Oxaliplatin, and Rituximab).  Treatment 
Modifications for Drug-Related Non-Hematologic Toxicities...........................125
Table19. Required Laboratory Tests.................................................................................135
Table20. Probability of Confirming Safety in the First 6 or 12 DLT Evaluable 
Patients................................................................................................................159
Table21. Conditional Power for the Phase 1b Based on the Interim Analysis Results.....169
LIST OF FIGURES
Figure1. A20 Lymphoma Model Data Showing Synergy of Simultaneous PD-L1, 
Anti-4-1BB, and Rituximab Blockade.................................................................56
Figure2. Study Design.........................................................................................................74
Figure3.
Dosing Schema: Phase 1b and Phase 3.................................................................75
Figure4. Assessment and Initial Management of Tumor Lysis Syndrome.........................93
APPENDICES
Appendix1. Abbreviations....................................................................................................184
Appendix2. Response Criteria for Malignant Lymphoma....................................................188
Appendix3. Eastern Cooperative Oncology Group Performance Status (ECOG PS)..........190
Appendix4. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE)..................................................................................191
Appendix5. International Prognostic Index (IPI)..................................................................192


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PROTOCOL SUMMARY
Study B9991011 is a multi-center, international, randomized, open-label, 2-component 
(Phase1b followed by Phase3), parallel-arm study of avelumab in combination with various 
agents for the treatment of Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma 
(DLBCL).  Agents that will be tested include:
(i) Utomilumab, a novel fully human IgG2 monoclonal antibody agonist of 4-1BB (CD137, 
TNFRSF9),
(ii) Azacitidine, a deoxyribonucleic acid (DNA) methyltransferase inhibitor (DNMTi) and 
epigenetic agent which has been shown to have potential immune priming activity through 
various mechanisms that include the induction of Programmed Death 1 (PD-1) on tumor 
infiltrating lymphocytes (TILs) and PD-L1 on tumor cells as well as the induction of tumor 
neo-antigen expression,
(iii) Rituximab, a CD20 antagonist antibody, and
(iv) Bendamustine, an alkylating chemotherapy agent, which is one of the National 
Comprehensive Cancer Network (NCCN) recommended agents for the salvage therapy of 
patients with DLBCL who are ineligible for high dose chemotherapy and autologous stem 
cell transplant (ASCT).
1
The treatment regimens in the study include avelumab combined with:
(i) Rituximab plus utomilumab,
(ii) Azacitidine plus utomilumab, or
(iii) Rituximab plus bendamustine.
Avelumab will be administered as a 1 hour intravenous (IV) infusion once every 2weeks of 
each 28-day cycle.  In order to mitigate infusion related reactions, a premedication with an 
antihistamine and with paracetamol (acetaminophen) approximately 30 to 60minutes prior to 
each dose of avelumab is mandatory (for example, 25-50mg diphenhydramine and 
500-650mg paracetamol [acetaminophen] IV or oral equivalent).  This may be modified 
based on local treatment standards and guidelines, as appropriate. 
Premedication prior to rituximab is mandatory; if avelumab is administered more than 1hour 
after rituximab then the premedication must be repeated.  The line should be flushed, 
according to local practice, between infusions, and a new administration set should be used 
for avelumab.
Site staff should make every effort to target the timing of avelumab infusion to be as close to 
1hour as possible.  However, given the variability of infusion pumps from site to site, time 
windows of minus 10minutes and plus 20minutes is permitted (ie, infusion time is 
50-80minutes).  The exact duration of infusion should be recorded in both source documents 
and Case Report Forms (CRFs). 


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Utomilumab is administeredin this study as a 1hour IV infusion at 100mg fixed dose of 
each 28-day cycle.  Avelumab must be administered at least 1hour after the end of 
utomilumab administration until the patient is no longer achieving clinical benefit.  If Cycle1 
and 2dosing administration is well tolerated; Cycle3 and subsequent cycles may decrease 
administration of utomilumab and avelumab from at least 1hour apart to 30-60minutes 
apart. 
Utomilumab is administered for as long as the patient is benefitting.  Treatment through 
progression of disease is permitted if the Investigator and Sponsor agree and the patient has 
provided written consent. 
Azacitidine 40 mg/m2(SC) will be administered in the morning on Days 1 -5 of each 28-day 
cycle, until the patient is no longer achieving clinical benefit.
Rituximab is administered in this study at the dose of 375mg/m2up to 8cycles maximum as 
an IV infusion in the morning of each 28day cycle on Day1.  Rituximab infusion must be 
completed at least 1hour prior to utomilumab and bendamustine.
Rituximab should not be administered as an IV push or bolus.  Premedication with 
acetaminophen and an antihistamine should be administered 30minutes before each 
IVinfusion. 
Premedication prior to rituximab is mandatory; if avelumab is administered more than 1hour 
after rituximab, then the premedication must be repeated.  The first infusion should be 
initiated at a rate of 50mg/hr.  In the absence of infusion toxicity, the rate of infusion may be 
increased by 50mg/hr increments every 30minutes, to a maximum of 400mg/hr.
Subsequent infusions of rituximab should be initiated at a rate of 100mg/hr.  In the absence 
of infusion toxicity, the rate of infusion may be increased by 100mg/hr increments at 
30minute intervals, to a maximum of 400mg/hr.
Bendamustine is administered in the Phase1b (Treatment ArmC) and in the Phase3 
investigational arm (in the event that Treatment ArmC advances to the Phase3 component 
of the study) at 90mg/m2IVinfusion up to 6cycles maximum.  Intra-patient dose escalation 
is not permitted.  Note that in the Phase3 Investigator’s Choice option (ArmE), 
bendamustine is administered at a higher dose of 120mg/m2on Days1 and 2 of each 28-day 
cycle, for up to 6cycles. 
Gemcitabine is administered at 1000mg/m2IV infusion up to 6cycles maximum on Day2 
and Day17 of each 28day cycle as part of the Investigator’s Choice option (ArmE) in 
Phase3.  Gemcitabine must be administered at a fixed dose rate of 16.7mg/m2/minute over 
60minutes.  This prolonged administration schedule has been shown to achieve superior 
intracellular drug concentration as compared with the 30minute IV schedule.
Oxaliplatin is administered at 100mg/m2IV infusion up to 6 cycles maximum on Day2 and 
Day17 of each 28-day cycle as part of the Investigator’s Choice option (Arm E) in Phase3.


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Gastrointestinal toxicity related to oxaliplatin may manifest as nausea and vomiting, and may 
be managed with prophylactic and/or therapeutic anti-emetic therapy.  Oxaliplatin is 
administered over 2hours on Day2 following gemcitabine.
If a patient with documented progression of disease (PD) per Lugano criteria continues to 
experience clinical benefit, per Investigator’s clinical judgment and following discussion 
between the Investigator and the Sponsor, the patient may be eligible for continued treatment 
with avelumab and/or utomilumab.  The Investigator’s judgment should be based on the 
overall benefit-risk assessment and on the patient’s clinical condition, including: 
performance status, clinical symptoms, adverse events, and laboratory data.  Other agents in 
the regimen combination with avelumab and/or utomilumab may also be considered for 
continuation if in the Investigator’s clinical judgment the patient may achieve clinical 
benefit.  See Section 5.4for treatment duration limits for agents other than avelumab and 
utomilumab.
The criteria that must be met are as follows: (i) No decline in Eastern Cooperative Group 
Performance Status (ECOG PS), (ii) Absence of rapid progression of disease by radiographic 
imaging, (iii) Absence of progressive tumor at critical anatomical sites (eg, cord 
compression) requiring urgent alternative medical intervention, and (iv) Absence of clinical 
signs and symptoms (including worsening of laboratory values) of disease progression. 
Before continuation of treatment, the patient must be re-consented and informed that by 
continuing receiving the investigational products on study, they may be foregoing treatment 
with approved therapies with possible clinical benefits.
Based on the safety and efficacy observed in the Phase1b part of this study, one (1) regimen 
will potentially be selected for further investigation in the Phase3 component of this study.  
In the Phase3 component, patients will be randomized in a 1:1ratio to either the 
avelumab-based treatment regimen selected in the Phase1b component or the Investigator’s 
Choice treatment option to determine whether the selected avelumab-based treatment 
regimen is superior to the Investigator’s Choice treatment option in prolonging 
progression-free survival (PFS).
The target study population of this Phase1b/Phase3 registration study will comprise patients 
with R/R DLBCL who have completed at least 2 (but not more than 4) lines of prior 
rituximab/multi-agent chemotherapy, and/or in whom ASCT has failed, or who are not 
eligible for intensive chemotherapy or who are not candidates for ASCT.  The study will 
assess the safety, efficacy, pharmacokinetics (PK), immunogenicity, and patient-reported 
outcomes (PROs) of each avelumab-based combination regimen.
The primary objective of the Phase1b component of the study will be to make a preliminary 
assessment of safety and efficacy for each combination regimen.  Each treatment arm after 
safety is confirmed in the first 6and/or 12patients will be expanded to a total of 28patients 
per arm in order to potentially select a treatment regimen to be advanced to the Phase3 
component of the study.  This decision will be based upon the objective response rate (ORR), 


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6-month durable response rate (DRR), progression-free survival (PFS) rate at 6months, and 
the safety profile of each avelumab-based combination regimen.
In the Phase3 component, the primary objective will be to demonstrate superiority in PFS (as 
assessed by Blinded Independent Central Review [BICR]) of the avelumab-based 
combination regimen identified in Phase1b, over the control treatment, Investigator’s Choice 
treatment option chemotherapy (ie, rituximab/bendamustine or 
rituximab/gemcitabine/oxaliplatin) in 220patients (110patients per arm).


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SCHEDULE OF ACTIVITIES
The Schedule of Activities tables provide an overview of the protocol visits and procedures.  
Refer to Table1and Table2of the protocol for detailed information on each procedure and 
assessment required for compliance with the protocol. 
The Investigator may schedule visits (unplanned) in addition to those listed in the Schedule 
of Activities tables in order to conduct evaluations or assessments required to protect the 
well-being of the patient.


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Table1. Phase 1b Schedule of Activities 
Cycle Length: 28 Days Each
Cycle 1
Cycles 2,3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen (28
days prior 
to random
ization)
Day 1 Day 
2/3
Day 7 Day 8 Day 
15/16
Day 22 Day 1/2 Day 2/3
Day 15/
16
End of 
Treatment/
Withdrawal
Follow-Up 
Visits
Days: 30, 
60, and 90 
afterlast 
dose
Survival
Follow-Up27
Visit window days
0
0
1
1
1
1
0
0
2
3
7
3
7
Written informed consent
X
Medical oncology history 
(including prior treatment 
regimens)
X
 
General medical history
X
Full physical examination 
(PE)
1
Full PEduring Screening and first day of Cycles 3, 6, 9, 12, every 3 cycles thereafter, and at EOT
1
Contraception check2
X
X
X
X
X
Baseline signs and 
symptoms
3
X
ECOG PS and IPI Score4
X
X
X
X
Weight
X
X
X
X
X
X
Vital signs5
X
X
X
X
Disease stagingand 
response assessment 
(Lugano Classification)
6
18F-FDG PET-CT: Performed 6weeks prior torandomization, thenonce every 12weeks(1week)from randomization 
and at EOT (unless performed 6weeks before EOT)
After 12-monthsfrom randomization, 18F-FDG PET-CT is performed every 24weeks(1week)until PD.
X6
X6
Blood collection for 
Minimal residual disease 
(MRD) assessment
7
MRD assessment to align with time-points for tumor staging and response assessment (PET-CT):  Prior to randomization,
thenonce every 12weeks and at EOT (unless performed 6weeks before EOT).
After 12-months from randomization,performedevery 24weeks(1week)until PD.
12-Lead ECG8
ECGs will be performed in singlicate during screening or prior to the first day of study treatment, and in triplicate during the 
study, pre-and post-infusion/SC doseon the first dosing days (Day 1 and Day 2) of Cycles 1 and 2, on the second avelumab 
dose of Cycle 1 (Day16), at EOT/early withdrawal and as clinically indicated.
LVEF (by MUGA or 
ECHO) (time window 
5days)9
X
X
Laboratory tests10
X 
X
X
X
X
X
X
Hematology11
X 
X
X
X
X
X
X
Blood Chemistry12
X 
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
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Cycle Length: 28 Days Each
Cycle 1
Cycles 2,3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen (28
days prior 
to random
ization)
Day 1 Day 
2/3
Day 7 Day 8 Day 
15/16
Day 22 Day 1/2 Day 2/3
Day 15/
16
End of 
Treatment/
Withdrawal
Follow-Up 
Visits
Days: 30, 
60, and 90 
afterlast 
dose
Survival
Follow-Up27
Visit window days
0
0
1
1
1
1
0
0
2
3
7
3
7
ACTH, FT4, and 
TSH13
Measured at screening, every 8weeks from first dose of treatment for 2 additional measurements, and then 
every 12weeks thereafter while on treatment
X
X
HBV, HCV14
Measured at screening and then every 6months from first dose of treatment and as clinically indicated
X
Urinalysis15
X 
X
X
X
X
X
X
Pregnancy test
16
X 
X
X
X
X
X
X
X
Registration/
Randomization17
X
Premedication18
X 
X
X
X
X
X
Avelumab 
administration: All 
study Treatment 
Arms; A, -B and -C
19
X
X
X
X
X
Utomilumab 
administration –
Treatment Arms A 
and B
20
X
X
X
Rituximab administration 
Treatment ArmsA and 
C21
X
X
X
Azacitidine 
administration Treatment 
Arm B22
X
Days 
1-5
X
Days 1-5
X
Bendamustine 
administration Treatment 
Arm C23
X
X 
X
Adverse Events24
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
Concomitant 
Medications25
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
X
Subsequent 
anti-cancer 
treatments
26
X 
X
Survival update27
X


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Cycle Length: 28 Days Each
Cycle 1
Cycles 2,3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen (28
days prior 
to random
ization)
Day 1 Day 
2/3
Day 7 Day 8 Day 
15/16
Day 22 Day 1/2 Day 2/3
Day 15/
16
End of 
Treatment/
Withdrawal
Follow-Up 
Visits
Days: 30, 
60, and 90 
afterlast 
dose
Survival
Follow-Up27
Visit window days
0
0
1
1
1
1
0
0
2
3
7
3
7
Mandatory provision 
of FFPE tumor 
tissue
28
X
Optional provision of 
de novotumor 
biopsy29
X
X
Blood forAvelumab 
PK36
X
X 
X
After Cycle 1, blood for 
avelumab, rituximab, 
utomilumab, azacitidine, and 
bendamustine PKwill be 
collected prior to dosing and 
post dose at 0.5 hour for 
Blood for Rituximab
PK37
X
X
X 
X
Blood for 
Utomilumab  PK38
X
X
Blood for Azacitidine 
PK39
X
Day 1
and 
Day 5
Blood for 
Bendamustine PK40
X
Blood for Avelumab 
ADA 
(Immunogenicity) 
Testing41
X
X
30 (3) days 
after the end 
of therapy
CCI
CCI


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Cycle Length: 28 Days Each
Cycle 1
Cycles 2,3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen (28
days prior 
to random
ization)
Day 1 Day 
2/3
Day 7 Day 8 Day 
15/16
Day 22 Day 1/2 Day 2/3
Day 15/
16
End of 
Treatment/
Withdrawal
Follow-Up 
Visits
Days: 30, 
60, and 90 
afterlast 
dose
Survival
Follow-Up27
Visit window days
0
0
1
1
1
1
0
0
2
3
7
3
7
Blood for Rituximab 
ADA 
(Immunogenicity) 
Testing42
X
azacitidine and 1 hour for 
bendamustine on the first day of 
Cycles 4 and 6
and
ADA (Immunogenicity 
Testing) after Cycle1 will be 
collected prior to dosing on the 
first day of Cycles4 and 6.
See footnotes for details.
X
30 (3) days 
after the end 
of therapy
Blood for 
Utomilumab ADA 
(Immunogenicity) 
Testing43
X
X
30 (3) days 
after the end 
of therapy
Abbreviations: = ongoing/continuous event; ECG = electrocardiogram; HRQL = health-related quality of life; EC = ethics committee; IRB = institutional 
review board, 
1. Physical Examination (PE): Includesan examination of major body systems:general appearance, as well as head, eyes, ears, nose, and throat (HEENT), 
neck, cardiovascular, lungs, abdomen, lymph nodes, genitourinary, extremities, neurological, skin, musculoskeletal, and weight (height at screening only). 
2. Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need to affirm that they meet 
the criteria for the correct use of 2 of the selected methods of contraception.  The Investigator (or his or her designee) will discuss with the patient the need to 
use 2 highly effective contraception methods consistently and correctly and document the conversation in the patient’s medical chart.  In addition, the 
Investigator (or his or her designee) will instruct the patientto call immediately if one or both selected contraception methods are discontinued, or if 
pregnancy is known or suspected in the patient or in the patient’s partner. 
3. Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within the 14days prior to randomization. 
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) performed as part of screening (ECOG PS0 or 1) and at time points noted in 
schedule above andInternational Prognostic Index (IPI) Score(2 or 3) [assessed at Screening].
5. Vital Signs:Temperature, Blood pressure (BP) and heart rate (HR) to be recorded in the seated position after the patient has been sittingquietly for at least 
5minutes on the first day of each treatment cycle.
6. Staging and Response Assessment: Lugano Classification: 18F-FDG PET-CT performed 6weeks prior to randomization.  Then it should be performed
once every 12weeks (1week)from randomizationand at EOT (unless performed within the prior 6-weeks).  After 12-monthsfromrandomization, 
18F-FDG PET-CT is performed every 24weeks (
CCI
1week). If a patient discontinues treatment for reasons other than disease progression,Staging and 
Response Assessment will be performeduntil disease progressionregardless of initiation of subsequent anti cancer therapy.  See Study Manual for more 
details. All radiographic images must be collected.  


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7. Blood Collection for Minimal Residual Disease (MRD) Assessment: 6 mL whole blood draw for processing into plasma will be collected to align with 
time-points for tumor staging and response assessment by PET-CT,prior to randomizationthenonce every 12weeksand at EOT (unless performed 
6weeks before EOT).  After 12-months from randomization, performed every 24weeks (1week) until PD.  See 7.4and Laboratory Manual for additional 
details.
8. 12-Lead ECG:All patients require a single ECG measurement at screening or prior to the first day of the first treatment cycle in the study to confirm 
eligibility. On-treatment ECGs will be performed pre-and post-infusion/SC doseon the first dosing days (Day1 and Day2) of Cycles1 and 2, for the 
second dose of avelumab in Cycle1 (Day16) and EOT/early withdrawal.  At each time point, three(3) consecutive 12-lead ECGs (triplicates) will be 
performed approximately 2minutes apart to determine mean QTcF (average of triplicates).  When coinciding with blood sample draws for pharmacokinetics 
(PK), ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  If patient 
experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should be obtained at time of the event.  If the 
mean QTcF is prolonged (>500msec), the ECGs should be re-evaluated by a qualified person at the institution for confirmation and repeated as clinically 
indicated.  Additional triplicate ECGs may be performed as clinically indicated.  Clinically significant findings observed onany 12-lead ECGs should be 
recorded as adverse events. 
9. ECHO/MUGA for LVEF (multiple gated acquisition (MUGA) or echocardiogram (ECHO):An ECHO/MUGA must be performed for patients within 
60-days of randomization (and as clinically warranted thereafter) and EOT.  Same method throughout study for each individual patient, if possible. 
10.Laboratory Tests: Please refer to Laboratory Manual for detailed instructions and Table19. 
11.Hematology:No need to repeat for Cycle1 Day1 if Screening assessment performed within 3 days prior to the first day of the first cycle.
12.Blood Chemistry:Includes all tests indicated onthe Chemistry Panel.  No need to repeat for Cycle1 Day1 if screening assessment performed within 3days 
priorto the first day of the first cycle. 
13.ACTH, FT4, and TSH:ACTH, Free T4 and TSH will be measured at screening, every 8weeks from first dose of treatment for 2additional measurements, 
and then every 12weeks thereafter while on treatment, End of Treatment, at the 30-day post-treatment visit, and as clinically indicated.
14.HBV Serology and HCV Serology: measured at screening and then every 6monthsfrom first dose of treatment, End of Treatment,and as clinically 
indicated.
15.Urinalysis:Dipstick is acceptable.  Microscopic analyses should be performed if dipstick abnormal.  No need to repeat on for Cycle1 Day1 if Screening 
assessment performed within 3days prior to the first day of the first cycle.
16.Pregnancy Test (serum/urine):For female patients of childbearing potential, aserum pregnancy test, with sensitivity of at least 25mIU/mLand assayed in 
a certified laboratory, will be performed on two occasions prior to starting study therapy, once at the start of screening and once at the baseline visit 
immediately before investigational product administration.  Urine pregnancy tests with sensitivity of at least 25mIU/mL will also be routinely repeated at 
every treatment cycle during the active treatment period, at the end of study therapy,at 30, 60,and 90days during safety follow up period, and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Urine test kits with sensitivity of at least 25mIU/mL may be 
utilized at every treatment cycle during the study in accordance with instructions provided in its package insert.  Patients of childbearing potential who have 
missed a menstrual period or who show an indeterminate or positive result on the urine test may not further progress in the study until pregnancyis ruled out 
using further diagnostic testing (eg,anegative qualitative serum pregnancy test conducted at a certified laboratory).  Additional pregnancy tests may also be 
undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.


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17.Randomization:Allocation of patients to treatment groups will proceed through the use of an Interactive Response Technology (IRT) System.  Study 
treatment must start within 7days after patient randomization.
18.Premedications:In regimen with: avelumab 5.4.1; utomilumab5.4.2; rituximab5.4.3; azacitidine 5.4.4; bendamustine 5.4.5; gemcitabine 5.4.6; 
oxaliplatin 5.4.7.  See Sections3.1.1and 3.1.3for details regarding sequencing of treatment.
19.Avelumab Administration, please refer to Sections 3.1.1and 5.4.1.
20.Utomilumab Administrationplease refer to Sections 3.1.1and 5.4.2.
21.Rituximab Administration please refer to Sections 3.1.1and 5.4.3.
22.Azacitidine Administration please refer to Sections 3.1.1and 5.4.4.
23.Bendamustine Administration please refer to Sections 3.1.1and 5.4.5.
24.Adverse Events: The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each subject begins from the time the 
patient provides informed consent, which is obtained before the patient’s participation in the study (ie, before undergoing any study-related procedure and/or 
receiving patient’s participation in the study (ie, before undergoing any study-related procedure and/or receiving investigational product), during each patient 
clinic visit, through and including a minimum of 90days after the last administration of the investigational product.  For patients who are screen failures, the 
active collection period ends when screen failure status is determined.  If a patient begins a new anti-cancer therapy, the recording period for non-serious 
AEs ends at the time the new treatment is started; however, SAEs must continue to be recorded on the CRF during the above-indicated activecollection 
period.  
25.Concomitant Medications: Concomitant medications and treatments including herbal supplements will be recorded from 28days prior to the start of study 
treatment, during each patient clinic visit,and up to 90days after the last dose of study treatment (at Days30, 60, and 90 post-treatment 3days).  All 
concomitant medications should be recorded in the CRF, including supportive care drugs (eg, anti-emetic treatment and prophylaxis), the drugs used to treat 
adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
26.Subsequent Anti-Cancer Treatments:To be collected.
27.Survival Update:After discontinuation of study treatment, post-study survival status will be collected every 2months until deathor withdrawal of consent 
for survival follow-up.  This includes the collection of information on subsequent anti-cancertherapies.  Telephone communication is acceptable.
28.Mandatory provision of FFPE Tumor Tissue:A biopsy (archived or Screening) will be collected at Screening.  Archival samples can be provided as an 
FFPE block containing tumor tissue or as a minimum of 15 (preferably25) unstained FFPE tumor slides suitable for PD-L1 expression and other 
tissue/molecular profiling assessments (blocks are preferable, see Section 7.4and Laboratory Manual for details).  Note that a de novotumor biopsy must be 
obtained at Screening if an archival sample is not available (see #32below).
29.OptionalProvision ofde novoTumor Biopsy:An optional baseline de novo(ie, fresh) biopsy of an accessible tumor lesion may be obtained during 
screening and/or at EOT (note that a de novotumor biopsy must be obtained at Screening if an archival specimen is not available to satisfy the requirement 
for the mandatory FFPE tumor tissue).  The de novo
CCI
biopsy or biopsies should be processed as FFPE (see Central Lab Manual), and the resulting FFPE 
tissue block(s) [one per time point]should be submitted to the Central Laboratory.
 
 
CCI


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36.Blood for Avelumab PK: (All Phase 1b Treatment Arms A, B and C):Blood samples (3.5mL whole blood at each time point) will be collected from all 
patients in the study at pre-dose and 1hour (at the end of infusion) followingthe first dose on the Day2 of Cycle1, and additional samples will be collected 
on Day8 and 16 of Cycle1.  Pre-dose samples will also be collected on Day1 of Cycles4 and 6.
37.Blood for Rituximab PK: (Treatment Arms A and C):Blood samples (4mL whole blood at each time point) will be collected from all patients at 
pre-dose and at the end of infusion on Cycle1, and then on Days7, 15 and 22 of Cycle1.  Pre-dose samples will also be collected on Day1 of Cycles4 
and6.
38.Blood for Utomilumab PK (Treatment Arm A and Arm B):Blood samples (4.0mL whole blood at each time point) will be collected from all patients at 
pre-dose, and 1hour (at the end of infusion) following the first dose on Day 2 of the first cycle in the study, and then on Day16 of Cycle1.  Pre-dose 
samples will also be collected on Day1 of Cycles4 and 6. 
39.Blood for Azacitidine PK (Treatment Arm B):Blood samples (2mL whole blood at each time point) will be collected from all patients in the study at 
pre-dose, 0.5, 1, 2, and 4hours on Day1 and 5 of Cycle1.  Samples pre-dose and at 0.5hour will also be collected on Day1 of Cycles4 and 6.
40.Blood for Bendamustine (and M3 metabolite) PK (Treatment Arm C):Blood samples (2mL whole blood at each time point) will be collected from all 
patients at pre-dose and at 1hour (at the end of infusion), 2, and 4hours following the first dose in the first cycle.  Samples at pre-dose and 1hour will also 
be collected following the first dose of Cycles4 and 6.
41.Blood for Avelumab ADA (Immunogenicity) Testing (All Treatment Arms):All samples (3.5mL) should be drawn within 2hours prior to the start of 
dosing.  Blood samples (3.5mL whole blood at each time point) for avelumab immunogenicity testing will be collected pre-dose on Day2 of Cycle1 and 
pre-dose on Day1 of Cycles4 and 6.  Additional samples for ADAs will be collected at 30 (3)days after the end of therapy.  A sample for ADA analysis 
will be drawn at the time of early withdrawal.
42.Blood for Rituximab ADA (Immunogenicity) Testing (Treatment Arms A and C):All samples (4.0mL) should be drawn within 2hours prior to the 
start of dosing.  Blood samples (3.5mL whole blood at each time point) for rituximab immunogenicity testing will be collected pre-dose on Day1 of Cycle1 
and pre-dose on Day1 of Cycles4 and 6.  Additional samples for ADAs will be collected at 30 (3)days after the end of therapy.  A sample for ADA 
analysis will be drawn at the time of early withdrawal. 
43.Blood for Utomilumab ADA (Immunogenicity) Testing (Treatment Arm A and Arm B):All samples (4.0mL) should be drawn within 2hours before 
the start of treatment.  Blood samples (3.5mL whole blood at each time point) for utomilumab immunogenicity testing will be collected pre-dose on Day2 
of Cycle1 and pre-dose on Day1 of Cycles4 and 6.  Additional samples for ADAs will be collected at 30 (
CCI
3)days after the end of therapy.  A sample for 
ADA analysis will be drawn at the time of early withdrawal.
CCI
CCI


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Table2. Phase 3 Schedule of Activities
Cycle 1
Cycles 2, 3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen 
(28 
days 
prior to 
random
ization)
Day 1
Day 2
Day 15
Day 17
Day 1
Day 2
Day 15
Day 17
End of 
Treatment/
Withdrawal
Follow-
Up Visits 
Days: 30, 
60, and 
90 after 
last dose
Survival 
Follow-
Up27
Visit window days
0
0
2
2
0
0
2
2
3
7 
3
7
Written informed consent
X
Medical oncology history 
(including prior treatment 
regimens)
X
General medical history
X
Full physical examination 
(PE)
1
Full PEduring Screening and first day of Cycles 3, 6, 9, 12, every 3 cycles thereafter, and at EOT1
Contraception check2
X
X
X 
X 
X
Baseline signs and 
symptoms
3
X
ECOG PS and IPI Score4
X
X
X 
X
Weight
X
X
X
X 
X 
X
Vital signs5
X
X
X 
X
Disease staging and 
response assessment 
(Lugano Classification)
6
18F-FDG PET-CT: Performed 6weeks prior to randomization, thenevery 12weeks (1week)from randomization, 
and at 
EOT (unless performed 6weeks before EOT).
After 12-monthsfrom randomization, 18F-FDG PET-CT is performed every 24weeks (1week)until PD
X 
X
Blood collection for MRD 
assessment
7
MRD assessment to align with time-points for tumor staging and response assessment by PET-CTprior torandomizationthen 
once every 12weeksand at EOT (unless performed 6weeks before EOT).  
After 12months from randomization, performed every 24weeks (1week) until PD
12-Lead ECG8
ECGs will be performed in singlicate during screening or prior to the first day of study treatment, and in triplicate duringthe study, 
pre-and post-infusion/SC doseon the first dosing days (Day1 and Day2) of Cycles1 and 2 on the second avelumab dose of 
Cycle1 (Day16) at EOT/early withdrawal and as clinically indicated
LVEF (by MUGA or 
ECHO) (time window 
5days)9
X
X
Laboratory tests10
X 
X
X
X
X 
X 
X
Hematology11
X 
X
X
X
X 
X 
X
Blood Chemistry12
X 
X
X
X
X 
X 
X
Coagulation
X
X
X
X 
X 
X


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Cycle 1
Cycles 2, 3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen 
(28 
days 
prior to 
random
ization)
Day 1
Day 2
Day 15
Day 17
Day 1
Day 2
Day 15
Day 17
End of 
Treatment/
Withdrawal
Follow-
Up Visits 
Days: 30, 
60, and 
90 after 
last dose
Survival 
Follow-
Up27
Visit window days
0
0
2
2
0
0
2
2
3
7 
3
7
ACTH, FT4, and 
TSH13
Measured prior to study enrollment, every 8weeks from first dose of treatment for 2 additional measurements, and 
then every 12weeks thereafter while on treatment
X 
X
HBV, HCV14
Measured prior to study enrollmentand then every 6 months from first dose of treatment and as clinically indicated
X
Urinalysis15
X 
X
X
X
X 
X 
X
Pregnancy test16
X 
X
X
X 
X 
X
Randomization17
X
Premedication18
X 
X 
X
X
X 
X
Treatment Arm D:  
Selected Regimen 
from Phase 1b 
Advancing to 
Phase319
Follow Schedule for Selected Regimen from Phase 1b.
Treatment Arm E 
Investigator’s Choice 
Rituximab of the R/Benda 
and R/GemOx 
Investigator’s Choice 
Option20
X
X
X
Treatment Arm E 
Investigator’s Choice 
Bendamustine of the 
R/Benda Investigator’s 
Choice Option21
X 
X
X 
X
Treatment Arm E 
Investigator’s Choice 
Gemcitabine of the 
R/Gem/Ox Investigator’s 
Choice Option22
X
X
X
X
Treatment Arm E 
Investigator’s Choice 
Oxaliplatin of the 
R/Gem/Ox Investigator’s 
Choice Option23
X
X
X
X


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Cycle 1
Cycles 2, 3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen 
(28 
days 
prior to 
random
ization)
Day 1
Day 2
Day 15
Day 17
Day 1
Day 2
Day 15
Day 17
End of 
Treatment/
Withdrawal
Follow-
Up Visits 
Days: 30, 
60, and 
90 after 
last dose
Survival 
Follow-
Up27
Visit window days
0
0
2
2
0
0
2
2
3
7 
3
7
Adverse Events24
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Concomitant 
Medication25
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Subsequent  
anti-cancer 
treatments
26
X 
X
Survival update27
X
Mandatory provision 
of FFPE Tumor 
Tissue27
X
Optional provision of 
de novotumor 
biopsy29
X
X
Blood for Avelumab 
PK36
X 
X
Days 8 and 
16
After Cycle 1, blood for avelumab PK will be 
collected prior to dosing on the first day of Cycles 4 
and 6.
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Cycle 1
Cycles 2, 3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen 
(28 
days 
prior to 
random
ization)
Day 1
Day 2
Day 15
Day 17
Day 1
Day 2
Day 15
Day 17
End of 
Treatment/
Withdrawal
Follow-
Up Visits 
Days: 30, 
60, and 
90 after 
last dose
Survival 
Follow-
Up27
Visit window days
0
0
2
2
0
0
2
2
3
7 
3
7
Blood for Rituximab 
PK37
X
X
Days 7 15 
and  22
After Cycle 1, blood for rituximab PK will be 
collected prior to dosing on the first day of Cycles4 
and 6.
Blood for 
Utomilumab PK38
X 
X
Day 16
After Cycle 1, blood for utomilumab PK will be 
collected prior to dosing on the first day of  Cycles 4 
and 6
Blood for Azacitidine 
PK39
X
Days 1 
and 5
After Cycle 1, blood for azacitidine PK will be 
collected prior to dosing and at 0.5 hr on the first 
day of Cycles 4 and 6.
Blood for 
Bendamustine PK40
X
After Cycle 1, blood for bendamustine PK will be 
collected prior to dosing and at 1 hr on the first day 
of Cycles 4 and 6.
Blood for Avelumab 
ADA 
(Immunogenicity) 
Testing41
X
After Cycle 1, blood for ADA (immunogenicity 
testing) will be collected prior to dosing on the first 
day of Cycles 4 and 6. 
See footnotes for details.
X
30 (3) 
days 
after the 
end of 
therapy
Blood for Rituximab 
ADA 
(Immunogenicity) 
Testing42
X
X
30 (3) 
days 
after the 
end of 
therapy
Blood for 
Utomilumab ADA 
(Immunogenicity) 
Testing43
X
X
30 (3) 
days 
after the 
end of 
therapy
Patient Reported 
Outcomes:  BFI, and 
EQ-5D-5L) 
X44
ePRO device will be used to administer the questionnaires every 7 days
44
X44


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Cycle 1
Cycles 2, 3, 4, 5, and 6
Cycles >6
End of Treatment/Follow-Up
Visit Identifier
Screen 
(28 
days 
prior to 
random
ization)
Day 1
Day 2
Day 15
Day 17
Day 1
Day 2
Day 15
Day 17
End of 
Treatment/
Withdrawal
Follow-
Up Visits 
Days: 30, 
60, and 
90 after 
last dose
Survival 
Follow-
Up27
Visit window days
0
0
2
2
0
0
2
2
3
7 
3
7
Patient Reported 
Outcomes: NCCN-FACT 
FLymSI-18
X45
ePRO device will be used to administer the questionnaires every 28 days
45
X45
Abbreviations: = ongoing/continuous event; ECG = electrocardiogram; 
 
; EC = ethics committee; IRB = institutional review board, BFI = Brief Fatigue Inventory.
1. Physical Examination (PE): Includesan examination of major body systems: general appearance, as well as head, eyes, ears, nose, and throat (HEENT), 
neck, cardiovascular, lungs, abdomen, lymph nodes, genitourinary, extremities, neurological, skin, musculoskeletal, and weight (height at screening only).
2. Contraception Check: Male patients who are able to father children and female patients who are of childbearing potential will need toaffirm that they meet 
the criteria for the 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 2highly effective contraception methods consistently and correctly and document the conversation in the patient’s medical 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 knownor suspected in the patient or in the patient’s partner. 
3. Baseline Signs and Symptoms: Patients will be asked about any signs and symptoms experienced within the 14days prior to randomization.
4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) at screening (ECOG PS0 or 1) and time points noted in schedule aboveand 
International Prognostic Index (IPI) Score (2 or 3) assessed at Screening.
5. Vital Signs:Temperature, Blood pressure (BP) and heart rate (HR) to be recorded in the seated position after the patient has been sitting quietly for at least 
5minutes on the first day of each treatment cycle.
6. Staging and Response Assessment:18F-FDG PET-CT performed 6weeks prior to randomization,once every 12weeks (1week)from randomization
and atEOT (unless performed within the prior 4weeks).  After 12monthsfrom randomization, 18F-FDG PET-CT is performed every 24weeks (1week).  
If a patient discontinues treatmentfor reasons other than disease progression,Staging and Response Assessment will beperformed untildisease progression
regardless of initiationof subsequent anti cancer therapy.  See Study Manual for details.  All radiographic images must be collected.  
7. Blood Collection for Minimal Residual Disease (MRD) Assessment: 6mL whole blood draw for processing into plasma will be collected to align with 
time-points for tumor staging and response assessment by PET-CT prior to randomizationthenonce every 12weeks and at EOT (unless performed 
6weeks before EOT).  After 12-months from randomization, performed every 24weeks (1week)until PD.  See 7.4
CCI
and Laboratory Manual for additional 
details.
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8. 12-Lead ECG:All patients require a single ECG measurement at screening or prior to the first day of the first treatment cycle in the study to confirm 
eligibility.  On treatment ECGs will be performed pre-and post-infusion/SC doseon the first dosing days (Day1 and 2) of Cycles1 and 2 for the second 
dose of avelumab in Cycle1 (Day16) and EOT/early withdrawal.  At each time point, three(3) consecutive 12-lead ECGs (triplicates) will be performed 
approximately 2minutes apart to determine mean QTcF (average of triplicates).  When coinciding with blood sample draws for pharmacokinetics (PK), 
ECG assessment should be performed prior to blood sample collection, such that the blood sample is collected at the nominal time.  If patient experiences a 
cardiac or neurologic AE (specifically syncope, dizziness, seizures, or stroke) triplicate ECGs should be obtained at time of the event.  If the mean QTcF is 
prolonged (>500msec), the ECGs should be reevaluated by a qualified person at the institution for confirmation and repeated as clinically indicated.  
Additional triplicate ECGs may be performed as clinically indicated.  Clinically significant findings observed on any 12-lead ECGs should be recorded as 
adverse events.
9. ECHO/MUGA for LVEF (multiple gated acquisition (MUGA) or echocardiogram (ECHO):An ECHO/MUGA must be performed for patients within 
60-days of the first dose at Cycle1 (and as clinically warranted) and EOT.  Same methold throughout study for each individual patient, if possible.
10.Laboratory Tests: Please refer to Laboratory Manual for detailed instructions and Table19. 
11.Hematology:No need to repeat for Cycle1 if screening assessment performed within 3days prior to that date.
12.Blood Chemistry:Includes all tests indicated on the Chemistry Panel.  No need to repeat for Cycle1 if screening assessment performed within 3days prior 
to that date. 
13.ACTH, FT4, and TSH:ACTH, Free T4 and TSH will be measured prior to study enrollment, every 8weeks from first dose of treatment for 2additional 
measurements, then every 12weeks thereafter while on treatment, End of Treatment, at the 30-day post-treatment visits, and as clinically indicated.
14.HBV Serology and HCV Serology: measured prior to study enrollmentand then every 6monthsfrom first dose of treatment, End of Treatment,and as 
clinically indicated.
15.Urinalysis:Dipstick is acceptable.  Microscopic analyses should be performed if dipstick abnormal.  No need to repeat prior to Cycle1 if screening 
assessment performed within 3 days prior to Cycle1.
16.Pregnancy Test (serum/urine):For female patients of childbearing potential, aserum pregnancy test, with sensitivity of at least 25mIU/mLand assayed in 
a certified laboratory, will be performed on two occasions prior to starting study therapy, once at the start of screening and once at the baseline visit 
immediatelybefore investigational product administration.  Urine pregnancy tests with sensitivity of at least 25mIU/mLwill also be routinely repeated at 
every treatment cycle during the active treatment period, at the end of study therapy, at 30, 60 and 90days during safety follow up period, and additionally 
whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Urine test kits with sensitivity of at least 25mIU/mL may be 
utilized at every treatment cycle during the study in accordance with instructions provided in its package insert.  Patients of childbearing potential who have 
missed a menstrual period or who show an indeterminate or positive result on the urine test may not further progress in the study until pregnancy is ruled out 
using further diagnostic testing (eg,anegative qualitative serum pregnancy test conducted at a certified laboratory).  Additional pregnancy tests may also be 
undertaken if requested by institutional review board/ethics committee (IRB/ECs) or if required by local regulations.
17.Randomization:Allocation of patients to treatment groups will proceed through the use of an Interactive Response Technology (IRT) System.  Study 
treatment must start within 7days after patient randomization.
18.Premedications:In regimen with: avelumab 5.4.1; utomilumab5.4.2; rituximab5.4.3; azacitidine 5.4.4; bendamustine 5.4.5; gemcitabine 5.4.6; 
oxaliplatin 5.4.7. 
19.Selected Regimen from Phase 1b Treatment Arm D: Refer to Table1for dose/administration schedule of selected regimen advancing to Phase3.


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20.Rituximab Administration, Investigator’s Choice Option Treatment Arm E:Dosed at 375mg/m2every 28days on Day1.  Patientsmay continue 
treatment with rituximab for up to 8cycles maximum. 
21.Bendamustine Administration, Investigator’s Choice Option Arm E: dosed 120mg/m2Days1 and 2 every 28days for up to 6cycles maximum.  Refer 
to Sections 3.1.3and 5.4.5.
22.Investigators Choice Option Treatment Arm E Gemcitabine: Dosed at 1000mg/m2Day2 and -17 every 28days.  Up to 6cycles maximum.  Refer to 
Sections3.1.3and 5.4.6.
23.Investigators Choice Option Treatment Arm E Oxaliplatin: Dosed at 100mg/m
2Day2 and -17 every 28days.  Up to 6cycles maximum.  Refer to 
Sections3.1.3and 5.4.7.
24.Adverse Events: The time period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each subject begins from the time the 
patient provides informed consent, which is obtained before the patient’s participation in the study (ie, before undergoing any study-related procedure and/or 
receiving patient’s participation in the study (ie, before undergoing any study-related procedure and/or receiving investigational product), during each patient 
clinic visit, and including a minimum of 90daysafter the last administration of the investigational product.  For patients who are screen failures, the active 
collection period ends when screen failure status is determined.  If a patient begins a new anti-cancer therapy, the recording period for non-serious AEs ends 
at the time the new treatment is started; however, SAEs must continue to be recorded on the CRF during the above-indicated active collection period.
25.Concomitant Medications: Concomitant medications and treatments including herbal supplements will be recorded from 28days prior to the start of study 
treatment, during each patient clinic visit,and up to 90days after the last dose of study treatment (at Days30, 60, and 90 post-treatment 3days).  All 
concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic treatment and prophylaxis), the drugs used to treat 
adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions).
26.Subsequent anti-cancertreatments:To be collected.
27.Survival Update:After discontinuation of study treatment, post study survival status will be collected every 2months until deathor withdrawal of consent 
for survival follow-up.  This includes the collection of information on subsequent anti-cancer therapies.  Telephone communication is acceptable.
28.Mandatory Provision of FFPE Tumor Tissue: A biopsy (archived or Screening) will be collected at Screening.  Archival samples can be provided as an 
FFPE block containing tumor tissue or as a minimum of 15 (preferably 25) unstained FFPE tumor slides suitable for PD-L1 expression and other 
tissue/molecular profiling assessments (blocks are preferable; see Section 7.4and Laboratory Manual for details).  Note that a de novotumor biopsy must be 
obtained Screening if an archival sample is not available (see #30 below).
29.Optional Provision ofDe NovoTumor Biopsy:An optional baseline de novo(ie, fresh) biopsy of an accessible tumor lesion may be obtained during 
screening and/or at EOT (note that a de novotumor biopsy must be obtained at Screening if an archival specimen is not available to satisfy the requirement 
for the mandatory FFPE tumor tissue.  The de novo
CCI
biopsy or biopsies should be processed as FFPE (see Central Laboratory Manual), and the resulting 
FFPE tissue block(s) [one per time point] should be submitted to the Central Laboratory.
 
 
 
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36.Blood for Avelumab PK: (Treatment Arm D only):Blood samples (3.5mL whole blood at each time point) will be collected from all patients at pre-dose 
and 1hour (at the end of infusion) following the first dose on Day2 of Cycle1, and an additional sample will be collected on Day8 and 16 of Cycle1.  
Pre-dose samples will also be collected on Day1 of Cycles4 and 6. 
37.Blood for Rituximab PK (Treatment Arm D only):Blood samples (4mL whole blood at each time point) will be collected from all patients atpre-dose 
and at the end of infusion on Cycle1, and then on Days7, 15 and 22 of Cycle1.  Pre-dose samples will also be collected on Day1 of Cycles4 and 6.
38.Blood for Utomilumab Pharmacokinetics:  Blood samples (4mL whole blood at each time point) willbe collected from all patients at pre-dose, and 
1hour (at the end of infusion) following the first dose on Day2 of Cycle1 in the study, and then on Day16 of Cycle1.  Pre-dose samples will also be 
collected on Day1 of Cycles4 and 6. 
39.Blood for Azacitidine Pharmacokinetics:Blood samples (2mL whole blood at each time point) will be collected from all patients at pre-dose, 0.5, 1, 2, 
4hours on Day1 and 5 of Cycle1.  Samples pre-dose and at 0.5hour will also be collected on Day1 of Cycles4 and 6.
40.Blood for Bendamustine (and M3 metabolite) Pharmacokinetics (Treatment Arm D only):Blood samples (2mL whole blood at each time point) will 
be collected from all patients at pre-dose and 1hour (at the end of infusion),2, and 4hours following the first dose in the first cycle.  Samples at pre-dose and 
1hour will also be collected following the first dose of Cycles4 and 6.
41.Blood for Avelumab ADA (Immunogenicity) Testing:All samples (3.5mL) should be drawn within 2hours prior to the start of dosing.  Blood samples 
(3.5mL whole blood at each time point) for avelumab immunogenicity testing will be collected pre-dose on Day 2 of Cycle1 and pre-dose on Day1 of 
Cycles4 and 6.  Additional samples for ADAs will be collected at 30 (3)days after the end of therapy in Treatment ArmD only.  A sample for ADA 
analysis will be drawn at the time of early withdrawal.
42.Blood for Rituximab ADA (Immunogenicity) Testing (Treatment Arm D only):All samples (4mL) should be drawn within 2hours prior to the start of 
dosing.  Blood samples (3.5mL whole blood at each time point) for rituximab immunogenicity testing will be collected pre-dose on the first day of Cycle1 
and pre-dose on Day1 of Cycles4 and 6.  Additional samples for ADAs will be collected at 30 (3)daysafter EOT only if Treatment Arm D contains 
rituximab.  A sample for ADA analysis will be drawn at the time of early withdrawal. 
43.Blood for Utomilumab ADA (Immunogenicity) Testing:All samples (4mL) should be drawn within 2hours before the start of treatment.  Blood samples 
(3.5mL whole blood at each time point) for utomilumab immunogenicity testing will be collected pre-dose on Day2 of Cycle1 and pre-dose on Day1 of 
Cycles4 and 6.  Additional samples for ADAs will be collected at 30 (3) days after the end of therapy only if Treatment ArmD contains utomilumab.  A 
sample for ADA analysis will be drawn at the time of early withdrawal.
44.Patient Reported Outcomes (PRO):  The Brief Fatigue Inventory (BFI) and EQ-5D-5L questionnaires will be administered. An electronic PRO (ePRO) 
device will be given to each patient for first day of the first cycle.  The ePRO device will prompt the patient to complete the questionnaires on the first day of 
the first visit.  After completing the questionnaires on the first day of the first visit, the device will prompt the patient to complete the questionnaires every 
7
CCI
days.  If a patient does not complete the questionnaires on the day the patient is prompted, the device will prompt the patient to complete the questionnaires
each subsequent day of the week until the questionnaires are completed.  At the 90-day follow-up visit the device will be collected from the patient.
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45.Patient Reported Outcomes (PRO):  The NCCN-FACT FLymSI-18 questionnaire will be administered.  An electronic PRO (ePRO) device will be given 
to each patient for first day of the first cycle.  The ePRO device will prompt the patient to complete the questionnaire on the first day of the first visit.  After 
completing the questionnaire on the first day of the first visit, the device will prompt the patient to complete the questionnaire every 28
CCI
days.  If a patient 
does not complete the questionnaire on the day the patient is prompted, the device will prompt the patient to complete the questionnaire each subsequent day 
of the week until the questionnaire is completed.  At the 90-day follow-up visit the device will be collected from the patient. 
 
 
 
 
 
 
 
 


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1.INTRODUCTION
Study B9991011 is a multi-center, international, randomized, open-label, 2-component 
(Phase1b followed by Phase3), parallel-arm study of avelumab in various combinations for 
the treatment of Relapsed or Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL).  
Agents that will be tested in combination with avelumab include: 
(i) Utomilumab, a novel, fully human, IgG2 monoclonal antibody agonist of 4-1BB,
(ii) Azacitidine, a DNA methyltransferase inhibitor (DNMTi), which has been shown to have 
the potential to prime immune activity through various mechanisms that include: (a) the 
induction of Programmed Death 1 (PD-1) on tumor infiltrating lymphocytes (TILs) and 
(b)PD-L1 on tumor cells, (c) the induction of tumor neoantigen expression, and (d) the 
inhibition of myeloid derived suppressor cells (MDSCs),
(iii) Rituximab, a CD20 antagonist antibody, 
(iv) Bendamustine, an alkylating chemotherapy agent, which is one of the National 
Comprehensive Cancer Network1recommended agents for the salvage therapy of patients 
with DLBCL who are ineligible for high-dose chemotherapy and autologous stem cell 
transplant (ASCT).
The treatment regimens tested in the study include avelumab in combination with:
(i) Rituximab and utomilumab,
(ii) Azacitidine and utomilumab, 
(iii) Rituximab and bendamustine.
Based on the safety and efficacy observed in the Phase1b component of the study, a single 
avelumab-based combination regimen will potentially be selected to be further investigated 
in the randomized Phase3 component of the study.  In the Phase3 component, patients will 
be randomized (1:1) to the avelumab-based treatment regimen selected in the Phase1b 
component or to Investigator’s Choice treatment to determine whether the selected treatment 
regimen is superior to the Investigator’s Choice treatment in prolonging progression-free 
survival (PFS).
The target study population of this Phase1b/3 registrational study is patients with R/R 
DLBCL who have completed at least 2 (but not more than 4) lines of prior 
rituximab-containing multi-agent chemotherapy, and/or in whom ASCT has failed, or who 
are not candidates for ASCT or who are not eligible for intensive chemotherapy.  The study 
will assess the safety, efficacy, pharmacokinetics (PK), immunogenicity of the 
3avelumab-based combination regimens tested, and collect patient reported outcome (PRO) 
data.


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The primary objective of the Phase1b component of the study will be to make a preliminary 
assessment of safety and efficacy for each combination regimen.  In order to help select a 
treatment regimen suitable for testing in the Phase3 component of the study, each treatment 
arm withouta safety signal in the first 6 and/or 12patients tested will be expanded to a total 
of 28patients per arm.  The decision to advance a specific treatment arm into the Phase3 
part will be based upon a hierarchical assessment of (a) the investigator-observed objective 
response rate (ORR), (b) the 6month durable response rate (DRR) and (c) the PFS rate at 
6months.  The overall safety profile of each combination regimen will also be taken into 
consideration.  The treatment combination regimens that will beassessed in the Phase1b 
component of the study include:
Arm A: Avelumab/Utomilumab/Rituximab
(i) Rituximab 375mg/m2(IV) will be administered on the morning of Day1 of each 28-day 
cycle for a maximum of 8cycles.
(ii) Utomilumab 100mg fixed dose (IV) will be administered on the morning of Day2 of 
each 28-day cycle in Cycles1 and 2 (or if well-tolerated in Cycles1 and 2, then again on 
Day1 in Cycle3 and in all subsequent cycles) until the patient no longer receives clinical 
benefit. 
Utomilumab must have completed administration at least 1 hour prior to avelumab in 
Cycles1 and 2.  If well-tolerated in Cycles1 and 2, then in Cycle3 and in all subsequent 
cycles, the time window of dose administration between utomilumab and avelumab may be 
decreasedfrom 1hour to 30-60minutes apart.
(iii) Avelumab 10mg/kg (IV) will be administered every 2weeks on Day2 and Day16 of 
each 28-day cycle in Cycle1 and Cycle2 (or if well tolerated in Cycle1 and Cycle2, on 
Day1 and Day15 in Cycle3 and in all subsequent cycles) until the patient no longer receives 
clinical benefit.
Avelumab must be administered at least 1hour after the end of the utomilumab infusion in 
Cycle1 and Cycle2.  If well-tolerated in Cycle1 and Cycle2, then in all subsequent cycles,
the time window of dose administration between avelumab and utomilumab may be 
decreased from 1hour to 30-60minutes apart.
Arm B: Avelumab/Utomilumab/Azacitidine
(i) Azacitidine 40mg/m2(SC) will be administered in the morning on Days1 -5 of each 
28-day cycle, until the patient is no longer achieving clinical benefit.
Azacitidine must have completed administration at least 1hour prior to utomilumab when 
dosed on the same day.


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(ii) Utomilumab 100mg fixed dose (IV) will be administered on the morning of Day2 of 
each 28-day cycle in Cycles1 and 2 (or if well-tolerated in Cycles1 and 2, then again on 
Day1 in Cycle3 and in all subsequent cycles) until the patient no longer receives clinical 
benefit. 
Utomilumab must have completed administration at least 1hour prior to avelumab in Cycle1 
and Cycle2.  If well-tolerated in Cycle1 and Cycle2, then in Cycle3 and in all subsequent 
cycles, the time window of dose administration between utomilumab and avelumab may be 
decreased from 1hour to 30-60minutes apart.
(iii) Avelumab 10mg/kg (IV) will be administered every 2weeks on Day2 and Day16 of 
each 28-day cycle in Cycle1 and Cycle2 (or if well tolerated in Cycle1 and 2, then on 
Day1 and Day15 in Cycle3 and in all subsequent cycles) until the patient no longer receives 
clinical benefit.
Avelumab must be administered at least 1hour after the end of utomilumab infusion in 
Cycle1 and Cycle2.  If well-tolerated in Cycle1 and Cycle2, then in all subsequent cycles, 
the time window of dose administration between utomilumab and avelumab may be 
decreased from 1hour to 30-60minutes apart.
Arm C: Avelumab/Bendamustine/Rituximab
(i) Rituximab 375mg/m2(IV) will be administered on the morning of Day1 of each 28-day 
cycle for a maximum of 8cycles.
(ii) Bendamustine 90mg/m2(IV) will be administered on Days2 and 3 of each 28-day cycle 
in Cycle1 and Cycle2.  If bendamustine is well-tolerated in Cycle1 and 2, then 
bendamustine may be administered on Day1 and Day2 in Cycle3 (and all subsequent 
cycles).  Bendamustine is administered for a maximum of 6cycles.
(iii) Avelumab 10mg/kg (IV) will be administered every 2weeks on Day2 and Day16 of 
each 28-day cycle in Cycle1 and Cycle2 (or if well tolerated in Cycle1 and 2, then on 
Day1 and Day15 in Cycle3 and in all subsequent cycles) until the patient no longer receives 
clinical benefit.  Avelumab administration should be at least 1 hour after the end of the 
bendamustine infusion.
Continued Treatment with Avelumab and/or Utomilumab
Per Investigator clinical judgment and following discussion between the Investigator and the 
Sponsor, if a patient with documented progressive disease (PD) continues to receive clinical 
benefit, treatment with avelumab and/or utomilumab may be continued.  The Investigator’s 
judgment must be based on the overall benefit-risk assessment, and on the patient’s clinical 
condition, including performance status (PS), clinical symptoms, adverse events (AEs), and 
laboratory data.  Other agents in the regimen combination with avelumab and/or utomilumab 
may also be considered for continuation if in the Investigator’s clinical judgment the patient 
may achieve clinical benefit.  See Section 5.4for treatment duration limits for agents other 
than avelumab and utomilumab.


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1.1.Indication
Patients with R/R DLBCL who have completed at least 2 (but not more than 4) lines of prior 
rituximab-containing multi-agent chemotherapy, and/or in whom autologous SCT (ASCT) 
has failed or who are not candidates for ASCT, or who are not eligible for intensive 
chemotherapy.
1.2.Mechanism of Action
The investigational product common to each treatment arm in the Phase1b is avelumab 
(MSB0010718C), a fully-human monoclonal antibody of the immunoglobulin (Ig) G1 
isotype directed against the PD-L1 cell surface antigen that is expressed by tumor cells, as 
well as by various immune cells.  MSB0010718C has a calculated molecular weight of 
143,832Daltons.
PD-L1 (B7-H1 or CD274) and its receptor, PD-1, have an established role in the suppression 
of T cell responses.  The PD-1 receptor is expressed on activated CD4+and CD8
+Tcells.  
Through interaction with its ligands, PD-L1 and PD-L2, PD-1 delivers a series of strong 
inhibitory signals that inhibit Tcell function.
2,3,4
Avelumab selectively binds PD-L1 and competitively blocks its interaction with PD-1.  As 
compared with anti PD-1 antibodies that target Tcells, avelumab targets tumor cells and 
therefore is expected to have potentially fewer side effects, including a lower risk of 
autoimmune-related safety issues, as blockade of PD-L1 leaves the PD-L2/PD-1 pathway 
intact to promote peripheral self-tolerance.
5  For additional details on the relevant in vitro and 
nonclinical studies, see the avelumab Investigator’s Brochure.6
1.3.Background and Rationale
1.3.1.Diffuse Large B-Cell Lymphoma
Diffuse Large B-Cell Lymphoma (DLBCL) is a heterogeneous disease with subtypes 
distinguished by various clinical, pathologic, and molecular characteristics.
7
It is the most common type of lymphoma, accounting for 30-40% of all newly diagnosed 
cases of non-Hodgkin Lymphoma (NHL), and more than 80% of all aggressive lymphomas.  
The median age at the time of diagnosis is ~70years.8,9,10
The World Health Organization (WHO) classification of lymphoid malignancies 
acknowledges the heterogeneity of DLBCL by recognizing a broad category termed ‘DLBCL 
not otherwise specified’ (DLBCL-NOS) as well as a variety of DLBCL subtypes.11
Within the DLBCL-NOS category, gene expression profiling studies have identified two 
principal molecular subtypes: (i) germinal center B-cell (GCB) and (ii) activated B-cell 
(ABC).  These subtypes represent lymphomas arising from different stages of lymphoid 
differentiation.  The GCB subtype arises from centroblasts and expresses genes usually 
active in germinal center Bcells, whereas the ABC subtype arises from B-cells at a plasmatic 
stage, just prior to germinal center exit, and expresses genes frequently expressed in mature 
plasma cells.  This molecular distinction has prognostic implications in treatment-naïve


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DLBCL patients, with the GCB subtype being associated with a more favorable prognosis.8  
The prognostic significance of the cell of origin beyond first line has not, however, been 
established. A signiﬁcant advance in recent years has been the better understanding of MYC
alterations.  MYC is rearranged in 5% to 15% of DLBCL-NOS(DiffuseLarge B-cell 
Lymphoma, not otherwise specified), and is frequently associated with BCL2 or, to a lesser 
extent, BCL6 translocation, in the so-called “double-hit” or “triple-hit” lymphomas that are 
included in the updated 2016 WHO classiﬁcation in the new category of high-grade B-cell 
lymphoma (HGBCL), with rearrangements of MYC and BCL2 and/or BCL6.11
Approximately 75% of patients with DLBCL present with advanced stage disease.  The 
established frontline standard of care (SOC) is R-CHOP comprised of rituximab, 
cyclophosphamide, doxorubicin, vincristine, and prednisone (5-year OS 58%).  The majority 
(~60%) of patients with DLBCL may be cured with this regimen, but patients who have 
treatment failure with R-CHOP have a very poor outcome.  Ten to fifteen percent of patients 
have primary refractory disease (no response, or relapse within 3 months of therapy), and an 
additional 20-25% relapse following an initial response to therapy.  Most relapses occur 
within the first 2years following treatment.
7,8
Patients who are refractory to induction therapyor who relapse after achieving a complete 
response may be considered for salvage chemotherapy.  If their disease is chemosensitive, 
they may be considered for high-dose chemotherapy followed by autologous stem cell 
transplant (ASCT).
7
High-dose chemotherapy and ASCT have been shown to provide the best chance of cure for 
patients with chemotherapy-sensitive relapse.  However, due to advanced age and 
comorbidities, only approximately half of all patients are eligible for this intensive treatment 
approach, and, of the transplant-eligible patients, only half are chemosensitive to salvage 
therapy and proceed to transplant, of which less than half will be cured.8
The development of more effective salvage strategies consequently remains an area of 
significant clinical importance, and a very high unmet medical need, especially in patients 
who are not candidates for high-dose chemotherapy.  Patients with primary refractory disease 
following R-CHOP present the greatest clinical challenge, with less than 10% achieving 
durable remissions with salvage therapy.8
1.3.2.Pharmaceutical and Therapeutic Background
1.3.2.1.Avelumab (MSB0010718C)
Avelumab (MSB0010718C) is a fully human monoclonal antibody (mAb) of the 
immunoglobulin (Ig) G1 isotype.  
Avelumab selectively binds to programmed death ligand1 (PD-L1) and competitively blocks 
its interaction with programmed death protein1 (PD-1).  Compared with anti PD-1 
antibodies, that target Tcells, 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 ligand2 (PD-L2)/PD-1 pathway intact to 
promote peripheral self-tolerance.
1


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1.3.2.2.Avelumab Safety
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMDSerono, and is being 
studied in Phase1, 2 and 3 clinical protocols in avariety of cancers, including non-small cell 
lung cancer, gastric cancer, Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, 
urothelial cancer, head and neck cancer, and Hodgkin’s and non-Hodgkin’s Lymphomas, as 
single agent or in combination with chemotherapy, tyrosine kinase inhibitors, radiotherapy, 
or other immune modulating agents.
Thesafety profile of avelumab administered intravenously (IV) as single agentat a dose of 
10mg/kg every 2weeks (Q2W) has been characterized primarily in 1738adult patientsfrom 
studies EMR100070-001 in various solid tumors (N=1650)and EMR100070-003 PartAin 
Merkel cell carcinoma(N=88).Study EMR100070-001 consists of 2parts, a dose escalation 
phase and a dose expansion phase, which is performed in selected tumor types.  
As of 09 June 2016, a total of 53patients were treated in the dose escalation phase of the 
EMR100070-001study, with 4, 13, 15, and 21patients treated with avelumab doses of 1, 3, 
10, and 20mg/kgQ2W, respectively.  None of the patients treated with doses up to 10mg/kg 
experienced a dose limiting toxicity (DLT), and the 10mg/kg dose of avelumab was thus 
considered a safe and well tolerated dose for further investigation in the dose expansion 
cohorts.  One DLT (a Grade3 immune relatedadverse event characterized by increased 
creatine kinase, myositis, and myocarditis) was observed in 1patient at the dose of 20mg/kg.
The dose expansion phase of study EMR100070-001included patients with non-small cell 
lung cancer, gastric cancer, breast cancer, colorectal cancer, castrationresistant 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 PartAwasconducted in patients withMerkel cell carcinoma. 
A summary of pooled safety data from patients treated at 10mg/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%), infusionrelated reaction (17.1%), weight 
decreased (16.6%), vomiting (16.2%), anemia (14.9%), abdominal pain (14.4%), 
cough(13.8%), pyrexia (13.6%), dyspnea (13.2%), edema peripheral (11.9%), back pain 
(11.8%), and arthralgia (10.4%).
Treatment-related TEAEs were observed in 1164 (67.0%)patients, and the most frequent 
(5%) were fatigue (17.7%), infusionrelated 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 177patients (10.2%) experienced Grade3 treatment-related TEAEs, and the most 
frequent (0.5%)were fatigue (1.0%), lipase increased (1.0%),GGT increased (0.6%), 
infusionrelated reaction (0.6%), andAST increased (0.5%).


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A total of 777(44.7%)patients had at least 1serious 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 911deaths (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 4deaths (0.2%) attributed to a treatment-related TEAE by 
the investigatorand which occurred up to 30days after the last dose of avelumab: 
pneumonitis (1case), acute liver failure (1case), respiratory distress(in the context of sepsis)
(1case), and autoimmune hepatitis with hepatic failure (1case).In addition, 1patient died 
with acute respiratory failure (in the context of lung cancer progression) considered related to 
avelumab by the investigator 37days after the last dose of avelumab.  The cause of deathwas 
marked as “other” or “unknown” in 17(1.0%) and 83(4.8%) of cases, respectively.
A total of 244patients (14.0%) permanently discontinued avelumab treatment due to TEAEs, 
including 107patients (6.2%) discontinuing because of treatment-related TEAEs.  The most 
frequent treatment related TEAEs leading to treatment discontinuation were infusionrelated 
reaction (1.8%), GGT increased (0.4%), and diarrhea, fatigue, autoimmune disorder, ALT 
increased, blood 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 
247patients (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 11.7weeks. The most frequent 
irAEs were thyroiddisorders including hypothyroidism (5.2%), hyperthyroidism (0.4%) and 
thyroiditis (0.2%), immune-related rash (5.2%), immune-relatedcolitis (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: type1diabetes mellitus, immune-related nephritis/renal 
dysfunction, hypopituitarism, uveitis and Guillain-Barre Syndrome.The majority of irAEs 
were Grade1 or Grade2 in severity, with 39 (2.2%)being of Grade3 severity.Fatal 
outcome was reported in 1patient (0.1%) with immune-related pneumonitis, and 2patients 
(0.1%) with immune-related hepatitis. Other relevant irAEs reported with avelumab outside 
the pooled safety dataset included 1case of fatal immune-related myocarditis in 
StudyB9991002 (avelumab incombination with axitinib for renal cell carcinoma (RCC)), 
1case of non-fatal immune-related myocarditis in the 20mg/kg cohort of the dose escalation 
phase of Study EMR100070-001, and 2patients with non-fatalgraft versus host disease 
(GVHD) in Study B9991007 (avelumab in patients with classical Hodgkin’s lymphoma).
Infusion-related reactions (IRRs): a total of 439patients (25.3%) experienced at least 1IRR, 
defined as a TEAE coded under the PTs of infusion related reaction, drug hypersensitivity, 
hypersensitivity, anaphylactic reaction, typeI 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 


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related reaction (17.0%), chills (5.4%), and pyrexia (3.6%). Most of the events were of 
Grade1 or Grade2 severity.  Grade3 IRRsoccurred in 12patients (0.7%) including 
3patients (0.2%) who experienced Grade4 IRRs.  No Grade5 IRRs were reported.  In most 
cases, the first occurrence of an IRR was related to the first infusion, with only 6patients 
experiencing the first IRR at the fifth or later infusion. All Grade3IRRs occurred with the 
first (7patients) or second (5patients) infusion. Overall, 21.6% of patients had 1IRR, 
2.6%of patients had 2IRRs, 14patients (0.8%) had 3IRRs, and 3patients had >3IRRs. 
IRR recurrence after the fourth infusion was rare (15patients) and all recurrent IRRs wereof
Grade1 or 2severity.In 35patients (2.0%), treatment was permanently discontinued 
because of an IRR.
1.3.2.3.Avelumab Pharmacokinetics
Available PK data from EMR100070-001 show that the concentration at the end of the 
dosing interval (Ctrough) increased more than proportionally to dose between 1 to 10mg/kg 
and proportionally to dose for doses above 10mg/kg. The terminal half-life (t
1/2) also 
increased with dose; however, the geometric mean values for t
1/2were similar for the 
10mg/kg and 20mg/kg dose levels, at 94.6hours (3.96days) and 99.1hours (4.1days), 
respectively. This PK characteristic suggests that target mediated drug disposition is 
involved in the clearance of avelumab and that high PD-L1 target receptor occupancy (TO) is 
likely achieved throughout the dosing interval at doses of 10mg/kg and 20mg/kg given 
every 2weeks.
The 10mg/kg dose Q2W achieved high TO (mean TO >90%) of PD-L1 in peripheral blood 
mononuclear cells (PBMC) during the entire dosing interval, as determined from exvivo 
studies. Based on the invitro TOdata and the observed trough serum avelumab levels in the 
dose escalation cohorts of Study EMR100070-001, TO was predicted to reach or exceed 
95%throughout the entire dosing interval in more subjects in the 10mg/kg dose group than 
in the 3mg/kg dose group.
Avelumab is eliminated by intracellular lysosomal proteolytic degradation throughout the 
entire body and therefore is not expected to be affected by small molecule drugs that are 
cytochrome P450 (CYP) enzyme modulators or by transporter modulators.  Population PK 
analysis did not show any meaningful effects on clearance of avelumab from premedication 
with acetaminophen (paracetamol) or diphenhydramine, nor from concomitant medication 
with ibuprofen, acetylsalicylic acid, opioids, corticosteroids, and biological therapies 
evaluated to date.
1.3.2.4.Immunogenicity of Avelumab in Humans
Immunogenicity assessment included all subjects from Studies EMR100070-001 and 
EMR100070-003 treated with 10mg/kg of avelumab once every 2weeks (Q2W) who had at 
least one valid anti-drug antibody (ADA) result as of the data cut-off date of 09 June 2016.  
Of the 1738patients treated with avelumab, 1558 were evaluable for treatment-emergent 
ADAs and 64(4.1%) tested positive. Titers were generally low across ADA ever-positive 
subjects,with no clear relationship between the duration of immunogenicity response and the 


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maximum observed titer.  Current data suggest there is no clinically meaningful impact of 
ADA positivity on PK, efficacy, or safety.  
Additional information for avelumab may be found in the SRSD, which for this study is the 
avelumab Investigator’s Brochure.
6
1.3.2.5.Rituximab
Rituximab is a CD20-directed cytolytic monoclonal antibody that is approved in the 
following lymphoma indications: (i) as a single agent in relapsed or refractory, low-grade or 
follicular, CD20
+, B-cell NHL, (ii) in previously untreated follicular, CD20+, B-cell NHL in 
combination with cyclophosphamide/vincristine/ prednisone (CVP) chemotherapy, (iii) as a 
single agent in non-progressing (including stable disease), low-grade, CD20+, B-cell NHL, 
(iv) after first-line CVP chemotherapy, and (v) in previously untreated diffuse large B-cell, 
CD20+NHL in combinationwith cyclophosphamide, doxorubicin, vincristine, prednisone 
(CHOP) or other anthracycline-based chemotherapy regimens.  The other registered 
indications are CD20
+chronic lymphocytic leukemia (CLL) and rheumatoid arthritis (RA) in 
combination with methotrexate in adult patients with moderately-to severely-activeRA who 
have an inadequate response to one or more tumor necrosis factor(TNF) antagonist 
therapies. 
The CHOP chemotherapy regimen has remained the mainstay frontline therapy for DLBCL 
patients.  The addition of rituximab to this chemotherapy backbone dramatically improved 
outcomes, with a complete response rate of 76% vs. 63%, p=0.005, and a reduced risk of 
treatment failure and death (risk ratios, 0.58 [95 percent confidence interval, 0.44 to 0.77] 
and 0.64 [0.45 to 0.89], respectively), establishing R-CHOP as the standard of care in 
DLBCL, with approximately 60% of patients being cured.
1,7,8  The most common (25%) 
adverse reactions of rituximab observed inclinical trials of patients with NHL are infusion 
reactions, fever, lymphopenia, chills, infection, and asthenia.  Further information about 
rituximab may be found in the Rituxan
United States package insert (USPI).12
Rituximab and any concomitant therapy must be discontinued in patients who develop viral 
hepatitis, and appropriate treatment including anti-viral therapy must be instituted.
Additional information for rituximab may be found in the SRSD, which for this study is the 
RituxanUSPI.
12
1.3.2.6.Utomilumab(PF-05082566)
4-1BB (CD137, TNFRSF9), first identified as an inducible co-stimulatory receptor expressed 
on activated T cells,is a membrane-spanning glycoprotein of the Tumor Necrosis Factor 
receptor superfamily (TNFRSF).  4-1BB expression is generally activation dependent and 
encompasses a broad subset of immune cells including activated NK and natural killer 
T(NKT) cells, regulatory Tcells, dendritic cells (DC) including follicular DC, stimulated 
mast cells, differentiating myeloid cells, monocytes, neutrophils, and eosinophils.
13,14


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Following 4-1BB activation, TRAF -1 and -2, pro-survival members of the TNFR-associated 
factor (TRAF) family, are recruited to the 4-1BB cytoplasmic tail resulting in downstream 
activation of NFkB and the Mitogen Activated Protein (MAP) Kinase cascade including Erk, 
Jnk, and p38 MAP kinases.  NFkB activation leads to up-regulation of Bfl-1 and Bcl-XL, 
pro-survival members of the Bcl-2 family.  The pro-apoptotic protein Bim is down-regulated 
in a TRAF1 and Erk-dependent manner.15
Numerous studies of murine and human Tcells have indicated that 4-1BB promotes 
enhanced cellular proliferation, survival, and cytokine production.
16  Reports have shown that 
4-1BB agonist monoclonal antibodies (mAbs) increase co-stimulatory molecule expression 
and markedly enhance cytolytic Tlymphocyte responses, resulting in anti-tumor efficacy in 
various models.  4-1BB agonist mAbs have demonstrated efficacy in prophylactic and 
therapeutic settings in bothmonotherapy and combination therapy tumor models, and have 
established durable anti-tumor protective T-cell memory responses.
17 4-1BB agonists also 
inhibit autoimmune reactions in a variety of autoimmunity models.
18  The dual activity of 
4-1BB has the potential to convey anti-tumor activity while at the same time dampening 
autoimmune side effects that have been associated with immunotherapeutic agents that break 
immune tolerance.
1.3.2.7.Utomilumab Safety
In Study B1641001, utomilumab was given as a single agent in patients with solid tumors or 
R/R B-cell lymphoma (PortionA), and was given in combination with rituximab in patients 
with R/R CD20+NHL (PortionB). The administered dose levels were 0.006mg/kg to 
10mg/kg once every 4weeks (Q4W) for PortionA, and 0.03mg/kg to 10mg/kg Q4W for 
PortionB.  The maximum tolerated dose (MTD) for utomilumab was not reached as a single 
agent or in combination with rituximab.  Rituximab was administered only in Cycle1 at a 
fixed dose of 375mg/m2, once per week for a total of 4weeks.  The first dose of rituximab 
was administered on Cycle1 Day (-7) followed by the second dose a week later on Day(0) 
followed by utomilumab on C1D1.  No DLT or Grade4 or 5 treatment-related AEs were 
observed in either study portion. 
Based on a data cutoff date of 06-Jun-2016, 61patients in PortionA (54male, 32female, 
mean age of 61.8) and 47patients in PortionB (26male, 21female, mean age of 58) were 
treated.
The most frequently observed (10% of patients; all grades) treatment-relatedTEAEsin 
PortionA with 86patients was fatigue (11.6%). Treatment-related TEAEs were mostly 
Grade1 or Grade2 with only three treatment-related Grade3 TEAEsreported (fatigue, ALT 
elevation, and hyponatremia). Note: After the data cut-off date,causality of the Grade3 
ALT elevation was re-assessed as not related to utomilumabby the investigator. Only 
1patient permanently discontinued treatment withutomilumab for a Grade2 
treatment-related TEAE of enterocolitis. Only 3treatment-relatedserious AEs (SAEs) were 
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The most frequently observed (10% of patients; all grades)treatment-related TEAEs in 
PortionB with 47patients were fatigue (23.4%) and infusion-related reaction (21.3%). 
Treatment-related TEAEswere either Grade1 or Grade2 in severity. There were no 
reported TEAEs leading to permanent treatment discontinuation. There were no DLTs, study 
related deaths, clinically significant ECG, or vital sign changes reported in either PortionA 
or PortionB.
Additional information for utomilumab may be found in the SRSD, which for this study is 
the utomilumab Investigator’s Brochure(IB).
19
1.3.2.8.Utomilumab Efficacy
The anti-tumor activity of single agent utomilumab in patients with advanced malignancies 
and utomilumab in combination with rituximab in patients with CD20 positive NHL is being 
assessed in Study B1641001.  This study does not have a control arm, and tumor responses 
are reported by Investigators per Response Evaluation Criteria in Solid Tumors 
(RECIST1.1)20and irRECIST for patients enrolled in the expansion cohort of PortionA93 or 
International Working Group (IWG) criteria21for PortionB.  Forty-seven patients in 
PortionA and 40patients in PortionB (24male, 16female, mean age 60.8years) have been 
treated.
19
As of the data cut-off date 06 June 2016, inPortionA of the study, best objective responses 
observed have been 1confirmed CR(Complete Response)and 1confirmed PR(Partial 
Response)in MCC were reported in patients who were treated at 0.24mg/kg and 0.6mg/kg,
respectively.  In addition, 1patient with anti-PD-1 refractory melanoma treated at 0.24mg/kg 
had a PR that was not yetconfirmed at the time of data cut-off date; however, theresponse 
was confirmed at a subsequent assessment. In addition, 1patient with anti-PD-1 refractory 
melanoma treated at 0.24mg/kg had a greater than 30% reduction in the diameters of 
multiple target tumors but was considered to have stable disease (irSD) per Immune-related 
Response Criteria Derived from RECIST 1.1.
In PortionB, 8patients with follicular lymphoma (7patients were refractory to prior 
rituximab-containing regimen) achieved an objective response: 4patientsachieved a CR 
(2treated at1.2mg/kg, 1 at 0.12mg/kg, and 1 at 0.03mg/kg) and 4patients achieved PR 
(2treated at 0.18mg/kg, 1treated at 1.2mg/kg, and 1treated at 5.0mg/kg).  One(1)patient 
with CD20+Hodgkin’s lymphoma treated at 1.2mg/kg achieved a PRand 1patient with 
Mantle Cell Lymphoma (MCL) treated at a utomilumab dose of 2.4mg/kg achieved a PR.  
1.3.2.9.Utomilumab Pharmacokinetics
Preliminary PK data following single dose of treatments are available for 81patients (46 in 
PortionA (utomilumab monotherapy) and 35 in PortionB (utomilumab + rituximab) in 
StudyB1641001.  Following the attainment of Cmax, utomilumab serum concentrations 
showed a bi-exponential decline with a mean terminal elimination half-life of 208-349hrs, a 
low systemic clearance (CL = 0.265 to 0.389mL/hr/kg) and a small volume of distribution 
(Vss = 83.3-231mL/kg) in Cycle1 of PortionA.  In PortionB, utomilumab also showed a 
bi-exponential decline with a mean terminal elimination half-life of 274-550 hrs, a low 


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systemic clearance (CL = 0.175-0.335mL/hr/kg) and a small volume of distribution 
(Vss=88.4-164mL/kg).  A dose proportional increase in exposure was observed.
Simulations were performed at various dosing schedules which indicated that theexposure at 
dose levels higher than 0.12mg/kg was above the assumed efficacious concentration with 
both once every 3weeks (Q3W) and once Q4W schedule.  Although body weight was 
identified as a significant covariate on CL, it accounted for only a small percentage 
(~<7%)of the inter-individual variability in serum utomilumab exposure.  In addition, 
simulations indicated that utomilumab exposure is similar between body weight based and 
fixed dosing regimens.  Therefore, this supports a fixed dosing regimenin utomilumab 
clinical studies.
19
1.3.2.10.Utomilumab Immunogenicity
ADA to utomilumab in human serum were determined using a validated, quasi-quantitative 
bridging electro chemi-luminescence method.  Preliminary analyses based on 
quality-controlled, non-quality-assured data are presented.  In PortionA, 9out of 61 (14.8%) 
patients exhibited positive ADA prior to treatment with utomilumab.  Thirty-five out of 
61patients (57.4%) were positive for ADA for at least one time point regardless of baseline 
ADA status.  Among 35ADA-positive patients, 7 (20%) exhibited positive neutralizing 
antibody (Nab) against utomilumab.
In PortionB, 2 out of 41(4.9%) patients exhibited positive ADA against utomilumab prior to 
treatment with utomilumab plus rituximab.  Three out of 41patients (7.3%) were positive for 
ADA for at least 1time point regardless of baseline ADA status when administered in 
combination with rituximab.  Among 3ADA-positive patients, 1(33.3%) exhibited positive
Nab against utomilumab.19
The impact of ADA on PK of utomilumab was characterized.  ADA negative patients were 
defined as those with negative antibody status for all samples collected during the study 
including baseline (pre-treatment).  ADA positive patients were defined as those with at least 
positive ADA sample anytime during the study including baseline (pre-treatment).  The CL 
was similar in ADA negative and ADA positive patients suggesting that ADA statushad 
minimal impact on the PK of utomilumab.19
1.3.2.11.Combination of a 4-1BB Agonist Antibody (Utomilumab) with a PD-1 
Antagonist
Tumor expression of PD-L1 may limit the ability of cytotoxic Tcells to directly kill tumor 
cells.
22  Therefore, if a 4-1BB agonist is used to stimulate tumor-specific cytotoxic Tcells, 
PD-L1 expressed at the tumor cell surface may down-modulate Tcell activity.  A 4-1BB 
agonist antibody resistant mouse MC38 colon cancer tumor model expressing PD-L1 was 
used to examine anti-tumor activity using the combination of a 4-1BB agonist antibody with 
PD-1 antagonist antibody compared with either agent alone.  Consistent with the proposed 
mechanism for thecombination, significant increases in CD8
+effector memory cells and 
tumor responsive IFN-producing cells were found in the spleens of mice treated with the 


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combination.  In addition, preliminary toxicology data in mice suggest that the toxicity of an 
anti-4-1BB agonist is not increased by the addition of an anti-PD-1 antagonist.
The combination of a 4-1BB agonist antibody with a PD-1 antagonist antibody shows 
significant inhibition tumor growth in a colon carcinoma model.  C57BL6 mice were 
subcutaneously implanted with 1x106MC38 murine colon carcinoma cells.  Tumor growth 
was monitored and animals randomized to four groups of 8 when the tumors reached an 
average size of 150mm3and intraperitoneally dosed with vehicle (phosphate-buffered saline; 
PBS), 1mg/kg anti-mouse 4-1BB agonist (MAB9371), 10mg/kg anti-mouse PD-1 
antagonist (RMP1-14), or the simultaneous combination of the two once every 5days for a 
total of two doses.  The study was terminated when tumor sizes of the controls reached 
1000mm3.  Combination treatment of animals with 4-1BB agonist in combination with a 
PD-1 antagonist resulted in 63.2% reduction in tumor growth as compared with vehicle 
controls (unpaired t test *p = 0.0125).  Significant tumor growth inhibition by either agent 
dosedindividually was not observed.
1.3.2.12.Preliminary Safety Summary for Study B9991004 Phase 1b Combination A 
(Avelumab/Utomilumab)
B9991004 is an ongoing Phase1b/2 open-label, multi-center, multiple-dose study to evaluate 
the safety, pharmacokinetic (PK), pharmacodynamics, and preliminary antitumor activity of 
avelumab (anti-PD-L1) at 10mg/kg Q2W in combination with other cancer immunotherapies 
in patients with locally advanced or metastatic solid tumors.  The objective of this study is to 
assess the safety and early signs of efficacy of avelumab in combinations with various other 
cancer immunotherapies, optimizing dosing regimens as appropriate in a limited series of 
indications.  Initially, this study is evaluating the safety and antitumor activity of avelumab in 
combination with utomilumab (PF-05082566, anti 4-1BB agonist); CombinationA.  
Combinations of avelumab with other immune modulators will be added to the study via 
protocol amendments based on emerging preclinical and clinical data. 
In the Phase1b lead-in for combinationA, 18patients with NSCLC were randomized in a 
1:1:1 across 3cohorts to receive utomilumab at 500mg (CohortA1), 100mg (CohortA2), or 
20mg (CohortA3) in combination with 10mg/kg of avelumab.  The DLT observation period 
was 2cycles (1cycle = 28days).  If a DLT was observed in 2 or more of 6patients, the 
cohort would be stopped.  Each utomilumab dose level determined as tolerable in 
combination with 10mg/kg of avelumab (ie, not meeting the DLT criteria) in the Phase1b 
lead-in of the study will continue enrollment in Phase2 for up to 22additional patients with 
NSCLC in each cohort. Once the Phase1b lead-in for NSCLC is completed and safety of the 
utomilumab dose levels in combination with 10mg/kg of avelumab is determined, Phase2 
cohorts, designated as A4: melanoma (N=28), A5: squamous cell carcinoma head and neck 
(SCCHN) (N=35) and A6: triple negative breast cancer (TNBC) (N=40) will be enrolled 
initially at the 100mg dose.  The dose may be modified based on emerging efficacy and 
safety data from NSCLC expansion cohorts.
Study B9991004 is currently ongoing; therefore, the following safety summary of 
combination A is considered preliminary and may be subject to change.


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As of the 16 May 2016cutoff date, the study has enrolled 18patients, 6patients each in 
CohortsA1, A2 and A3.  Patients received 10mg/kg avelumab Q2W in combination with 
utomilumab at 500mg, 100mg, or 20mg Q4W.  The DLT observation period has been 
completed for CombinationA. The median duration of treatment with avelumab was 
12weeks (range 4 to 17.9weeks), and the median duration of treatment with utomilumab 
was 12weeks (range 4 to 19.9weeks).  All patients received treatment at assigned doses.  No 
treatment discontinuation due to adverse event wasreported.
The most common treatment emergent, all causality Grade 3, 4 TEAEs were 
dyspnea(16.7%), hypoxia(16.7%) andnausea (5.6%).  There were notreatment-emergent, 
treatment-relatedGrade3, 4 or 5AEsreported.  All three dose levels were well tolerated.  
There were3cases of fatal outcome (Grade5) attributed to disease progression.
A total of 12serious adverse events (SAEs) were reported in 5patients (3patients in the 
20mg dose cohort and 1patient each at 100 and 500mg dose cohorts), including 3patients 
with Grade5 events of disease progression.  All SAEs were assessed as not related to study 
treatments (avelumab and utomilumab). 
Additional information for utomilumab may be found in the SRSD, which for this study is 
the utomilumab IB.19
1.3.2.13.Azacitidine
Azacitidine is a cytosine analog and a potent DNA methyl-transferase inhibitor, which 
induces DNA demethylation.  Azacitidine is used for the treatment of patients with 
higher-risk myelodysplastic syndrome (MDS), and for a subgroup of acute myeloid leukemia 
(AML) and chronic myelomonocytic leukemia (CMML) patients.
It is indicated for the treatment of patients with the following French-American-British 
(FAB) MDS subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts 
(if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory 
anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation 
(RAEB-T), and CMML.
Compared to conventional care regimens, treatment with azacitidine has resulted in improved 
outcomes in MDS, including delayed leukemic transformation, increased survival in patients 
with higher-risk MDS, and prolonged overall survival in patients with oligoblastic AML 
(20-30% bone marrow blasts).23,24
The most common adverse reactions (>30%) by subcutaneous route are: nausea, anemia, 
thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, 
constipation, neutropenia and ecchymosis.  The most common adverse reactions by 
intravenous route include: petechiae, rigors, weakness and hypokalemia.
Azacitidine and its metabolites are primarily excreted by the kidneys.  The risk of toxic 
reactions may be greater in patients with impaired renal function.  Azacitidine is potentially 
hepatotoxic in patients with severe pre existing hepatic impairment.  Caution is required in 


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patients with known liver disease.  Azacitidine is administered by the subcutaneous route in 
this protocol. 
Additionalinformation for azacitidine may be found in the SRSD, which for this study is the 
VidazaUSPI.
25
1.3.2.14.Bendamustine
Bendamustine is analkylating agent indicated for the treatment of patients with chronic 
lymphocytic leukemia (CLL) and indolent B-cell non-Hodgkin’s lymphoma (NHL) that have 
progressed during or within 6months of treatment with rituximab (or with a 
rituximab-containing regimen).
The most common non-hematologic adverse reactions (30%) are: nausea (75%), fatigue 
(57%), vomiting (40%), diarrhea (37%) and pyrexia (34%).  The most common 
non-hematologic Grade3 or 4 adverse reactions (5%) are fatigue (11%), febrile neutropenia 
(6%), and pneumonia, hypokalemia and dehydration, each reported in5% of patients.
The most common serious adverse reactions occurring in 5% of patients are: febrile 
neutropenia and pneumonia.  Other important serious adverse reactions reported in clinical 
trials and/or postmarketing experience are: acute renal failure, cardiac failure, 
hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.  Serious 
drug-related adverse reactions reported in clinical trials included myelosuppression, 
infection, pneumonia, tumor lysis syndrome and infusion reaction. 
Patients with myelosuppression following treatment with bendamustine are more susceptible 
to infections.  Opportunistic infection prophylaxis is recommended per local guidelines.  
Prophylactic use of G-CSF in all cycles for patients 60years old randomized to armC is 
mandatory (and armD in Phase3, if armC is selected to advance to the Phase3 component).
High-dose therapy with stem cell support is the reference treatment for relapsed lymphoma, 
but is not appropriate for all patients, due to advanced age and comorbidities.  Conventional 
salvage chemotherapies have been used with limited efficacy and significant toxicity. 
Bendamustine is active in indolent B-cell NHL and CLL.  Clinical activity in combination 
with rituximab in patients with relapsed and refractory DLBCL has been evaluated with 
ORRs ranging from45.8% to 62.7%.7,27,28
Additional information for bendamustine may be found in the SRSD, which for this study is 
the Treanda
USPI.
26
1.3.2.15.Gemcitabine
Gemcitabine is a nucleoside analogue that exhibits antitumor activity.  Gemcitabine exhibits 
cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also 
blocking the progression of cells through the G1/S-phase boundary.  The registered 
indications of gemcitabine are as follows:


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Breast Cancer -Gemcitabine in combination with paclitaxel is indicated for the first-line 
treatment of patients with metastatic breast cancer after failure of prior 
anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically 
contraindicated.
Non-Small Cell Lung Cancer -Gemcitabine is indicated in combination with cisplatin for the 
first-line treatment of patients with inoperable, locally advanced (StageIIIA or IIIB), or 
metastatic (StageIV) non-small cell lung cancer.
Pancreatic Cancer -Gemcitabine is indicated as first-line treatment for patients with locally 
advanced (nonresectable StageII or StageIII) or metastatic (StageIV) adenocarcinoma of 
the pancreas.  Gemcitabine is indicated for patients previously treated with 5-FU.
Myelosuppression is the principal DLT with gemcitabine therapy.  Dosage adjustments for 
hematologic toxicity are frequently needed.
Gemcitabine is associated with transient elevations of one or both serum transaminases in 
approximately 70% of patients.
Additional information for gemcitabine may be found in the SRSD, which for this study is 
the Gemzar
USPI.
29
1.3.2.16.Oxaliplatin
Oxaliplatin is indicated in combination with 5-fluorouracil and folinic acid in the adjuvant 
treatment of StageIII colon cancer after complete resection of primary tumor, and in 
metastatic colorectal cancer.
The most frequent adverse events of oxaliplatin in combination with 5-fluorouracil/folonic 
acid are: gastrointestinal (diarrhea, nausea, vomiting and mucositis), haematological 
(neutropenia, thrombocytopenia), and neurological (acute and dose cumulative peripheral 
sensory neuropathy). 
High dose therapy with stem-cell support is the reference treatment for relapsed lymphoma, 
but is not appropriate for all patients, due to advanced age and comorbidities.  Conventional 
salvage chemotherapies have been used with limited efficacy and significant toxicity. 
Rituximab, gemcitabine and oxaliplatin has been evaluated as a salvage regimen in relapsed 
orrefractory lymphoma patients who are not eligible for high dose therapy, with 
demonstrated overall response rates ranging from 46% to 83%.29,30,31
Additional information for oxaliplatin may be found in the SRSD, which for this study is the 
EloxatinUSPI.
32


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1.4.Study Rationale
1.4.1.High Unmet Medical Need
The current NCCN Guidelines1for DLBCL recommend treatment with R-CHOP or an 
attenuated dose of R-CHOP (mini-CHOP in patients >80years with comorbidities) in 
patients with newly diagnosed DLBCL with all stages of disease.  Approximately60% of 
patients will be cured following R-CHOP; however, 30% to 50% of those with advanced 
disease will be either primary refractory (~15%) or resistant (~25%) to R-CHOP.1,7,8
DLBCL patients who are refractory to induction therapy or who relapse following achieving 
a complete response may be considered for salvage chemotherapy.  If their disease is 
chemosensitive, they may be considered for high-dose chemotherapy and ASCT.7
High-dose chemotherapy followed by ASCT provides the best chance of a cure in relapsed or 
refractory patients in the second-line treatment setting; however, due to advanced age or 
co-morbidities, only ~50% of patients that fail first-line R-CHOP are fit for high dose 
chemotherapy, and of these, only ~50% are chemosensitive in second-line and suitable for 
ASCT.8  Even if eligible for high-dose chemotherapy, patients may refuse ASCT, or be 
ineligible for other reasons.  Even in patients who are eligible for treatment with high-dose 
chemotherapy followed by ASCT, only a minority are cured. 
Overall, >30% of DLBCL patients ultimately relapse.  According to the European Society of 
Medical Oncology (ESMO) guidelines, relapsed and refractory DLBCL patients who are not 
suitable for high-dose chemotherapy should be enrolled in clinical trials testing the activity of 
novel drugs.33
The following rituximab-containing chemotherapy regimens are currently recommended by 
the NCCN Guidelines (version 1.0 2016) for 2L salvage therapy and beyond in patients that 
are not eligible for high dose chemotherapy and ASCT: Bendamustine 
rituximab, 
brentuximab, CEPP, CEOP, DA-EPOCH rituximab, GDP rituximab, 
Gem/Ox rituximab, lenalidomide rituximab, and rituximab.
1
In spite of these salvage therapies, the outcome of patients that fail treatment with R-CHOP, 
and who are not eligible for high-dose chemotherapy or ASCT is dismal, with a median PFS 
of only 3.6months.7  The treatment options for these patients remain very limited, and there 
is consequently a high unmet medical need in R/R DLBCL patients that meet the study 
eligibility criteria, with the development of more effective salvage strategies able to prolong 
PFS and OS being of significant interest.
1.4.2.Avelumab in DLBCL
Programmed death-ligand 1 (PD-L1) and its receptor, PD-1, have a known role in the 
suppression of T-cell responses.  The PD-1 receptor is expressed on activated CD4+and 
CD8+Tcells.  By interaction with its ligands, PD-L1 and PD-L2, PD-1 delivers a series of 
strong inhibitory signals to inhibit T-cell function.
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In lymphoma, blocking the PD-1/PD-L1 interaction is a novel immunotherapeutic approach.  
Preliminary data indicate that PD-1 blockade is clinically active in specific hematologic 
cancers, including lymphoma.34,35,36
The tumor microenvironment in lymphoma is highly immunosuppressive, and inhibits the 
anti-tumor immune response.  Tumor-infiltrating lymphocytes (TILs) within the 
microenvironment of DLBCL express PD-L1 tovarying extents, and tumor cells themselves 
may express PD-L1 at the cell surface with varying intensities.
37  PD-L1 expression is 
associated with a poor prognosis: patients with PD-L1-positive DLBCL have an inferior 
overall survival (OS) as comparedwith PD-L1-negative DLBCL.38
Kiyasu, et al. studied PD-L1 expression on DLBCL tumor cells and TILs in 1,253 newly 
diagnosed/untreated DLBCL formalin-fixed, and paraffin embedded samples from Kurume 
University, Japan.
38  Samples were double-stained with antibodies against PD-L1 and the 
B-cell surface marker Pax5.  PD-L1 positivity was defined arbitrarily as 30% of cells with 
membrane/cytoplasmic staining and Pax5
+.  By this criterion, ~11% of DLBCL B-cells were 
found to be PD-L1+.  Additionally, 15.3% of non-B-cells in the microenvironment (mPD-L1) 
were PD-L1+DLBCL.  PD-L1+B-cells and non-B cells were found to be associated with the 
ABC subtype as well as Epstein-Barr Virus (EBV) positivity.  The frequency of PD-1
+TILs 
was, furthermore, found to be greater in the GCB subtype.  Patients with PD-L1+DLBCL 
had an inferior OS as compared with PD-L1-(p=0.0009).  No OS difference was observed 
between mPD-L1 positive and negative (p=0.31), indicating that it is B-cell surface 
expression of PD-L1 that impacts the disease natural history most significantly. 
These results indicate that inhibition of the PD-1/PD-L1 checkpoint axis may be of 
therapeutic relevance to this disease, at the minimum, in those patients with B-cell PD-L1 
positivity.  The threshold of 30% cell surface expression has not, however, been clinically 
validated, and it is possible that patients with a lower percentage (<30%) of PD-L1 positive 
B-cells may benefit from anti-PD-L1 blockade.  This issue will need to be determined 
empirically.
Further data relating to levels of soluble PD-L1 also suggest a prognostic role for the 
PD-1/PD-L1 axis in DLBCL, and the potential therapeutic relevance of PD-1/PD-L1 
blockade.  The clinical impact of soluble programmed cell death ligand 1 (sPD-L1), 
detectable in plasma, was evaluated in 288 newly diagnosed DLBCL patients.  Patients with 
elevated sPD-L1 had a poorer prognosis than those with low levels of sPD-L1, with a 3-year 
OS of 76% versus 89% (p <0.001).39  This further supports the potential use of PD-1/PD-L1 
axis blockade in DLBCL, and the investigation of therapeutic strategies using PD-1/PD-L1 
axis inhibitors.
Finally, it has been showed that TILs in DLBCL can be re-activated by the blockade of 
PD-L1 which can restore the autologous anti-tumor T-cell response.
40
A study investigating PD-1/PD-L1 axis blockade using the PD-1 inhibitor nivolumab as 
monotherapy in DLBCL, has shown a distinct, but lackluster response, with an ORR of 36% 
(CR 9%, PR 27% and SD 27%).  The 6-month PFS was, furthermore, 24%.
41


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The sample size in this study was, however, small with 4responders out of a total of 
11patients. 
However, the expression of PD-L1 at the cell surface of DLBCL blasts as well as tumor 
infiltrating Tcells (TILs), and other data linking the PD-1/PD-L1 checkpoint axis to survival 
outcomes, suggests that it may be possible to augment the observed monotherapy signal 
through rational combination with other agents.
The response rate of anti-PD-1 monotherapy in DLBCL was significantly lower than that 
observed in classic Hodgkin’s lymphoma (cHL), which gave a response rate of 87%, and a 
6month PFS of 86%.  The difference in ORR and PFS between cHL and DLBCL, may be 
attributed to the presence of a distinct targetable molecular lesion in cHL, namely the9p24.1
amplicon which contains both PD-1 and PD-L1 and leads to their overexpression and which 
is found in cHL at high frequency, but is not present in DLBCL.  There are two potential 
ways in which to further explore the use of PD-1/PD-L1 checkpoint blockade in DLBCL.  
The first is to attempt to define and target a sub-population of patients based upon PD-L1 cell 
surface expression.  This approach would, however, limit the relevance of checkpoint 
blockade to a small subset of patients with DLBCL.  The alternativeapproach, explored in 
the current study, is to attempt to define a basis for increasing the immunogenicity
 of 
DLBCL through the rational combination of PD-1/PD-L1 checkpoint blockade with other 
agents.
The target population in the current study has been defined to broadly align with the 
nivolumab DLBCL study population, with a view to augmenting the checkpoint inhibitor 
signal seen in the nivolumab monotherapy study, through various triplet chemotherapy-free 
and chemotherapy combinations.  Rather than using the anti-PD-1 monoclonal antibody 
nivolumab, the current study will test the anti-PD-L1 monoclonal antibody avelumab. 
Agents that will be tested in combination with avelumab include: (i) utomilumab a novel 
fully humanized IgG2 mAb agonist of 4-1BB, (ii)the epigenetic agent azacitidine, which has 
been shown to have potential immune priming activity through various mechanisms 
including the induction of PD-1 on TILs and PD-L1 on tumor cells, as well as the induction 
of tumor neo-antigen expression, (iii) the CD20 antagonist mAb rituximab, and (iv) the 
chemotherapy agent bendamustine, which is one of the NCCN recommended agents for the 
salvage therapy of DLBCL patients that are ineligible for high-dose chemotherapy and 
ASCT.
The aim of the Phase 1b componentof the study is to determine whether any of these three 
experimental triplet combinations can augment the efficacy signal previously observed in an 
R/R DLBCL target population following PD-1/PD-L1 checkpoint axis inhibition using the 
PD-1 inhibitor nivolumab. 
1.4.3.Rationale for Treatment Arm A (Avelumab, Rituximab, and Utomilumab)
CD137 (4-1BB) is a co-stimulatory receptor belonging to the TNF receptor superfamily.  It 
regulates the activity of a broad range of immune cells, including CD4
+and CD8
+T-cells, 
regulatory cells (Tregs), dendritic cells, and natural killer (NK) cells.  Agonistic anti-CD137 


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mAbs have been shown to increase T-cell proliferation, differentiation to memory cells, and 
resistance to apoptosis in CD8
+Tcells.  CD137 agonism can also inhibit Treg function.
42  
These immunostimulatory effects of CD137 agonism provide an independent rationale for 
the combination of the 4-1BB agonist utomilumab with the PD-L1 inhibitor avelumab. 
CD137 expression has, furthermore, been observed on T cells and TILs in DLBCL, with 
higher CD137 expression conferring an improved OS, independently suggesting thatCD137 
agonism with utomilumab may impact DLBCL natural history.
43
CD137 is expressed at the cell surface of a variety of immune cells following activation, 
including NK cells.  Antibody-dependent cell-mediated cytotoxicity (ADCC), largely 
mediated by NK cells, is thought to be an importantmode of action for rituximab. NK cells 
mediate ADCC by binding the Cregion of antibodies through their Fc receptor. 
CD137 agonism has been shown to enhance the ADCC activity of NK cells.  R/R DLBCL 
patients treated with rituximab continue to express CD137, and consequently bind 
utomilumab.  Treatment with rituximab increases cell surface CD137 expression.
44
Anti-CD137 agonist mAbs have been shown to enhance the anti-lymphoma activity of 
rituximab by enhancing ADCC.
44   It is consequently possible that by enhancing NK cell 
activity with CD137 agonism the ADCC activity of rituximab may be restored in patients 
that are relapsed or refractory to rituximab.  This hypothesis was first tested in vitro using 
lymphoma cell lines.  It was shown that recognition of rituximab-coated tumor Bcells 
induces CD137 up-regulation on human NK cells, a phenomenon that is time dependent and 
peaks at 24hours.  Subsequent stimulation of these NK cells with anti-CD137 mAb enhances 
rituximab-dependent cytotoxicity against the lymphoma cells (cytotoxic granules 
mobilization).44
These results were confirmed in vivousing a syngeneic immunocompetent mouse model, and 
a human xenotransplant model of lymphoma.  This data suggests an innovative approach to 
enhance the efficacy of rituximab based on sequential targeting of both the tumor and 
immune system.  Rituximab will induce up-regulation of CD-137 on NK cells involved in 
ADCC, and the agonistic anti-CD137 mAb can then subsequently be administered to 
enhance the NK-cell mediated killing of rituximab-coated tumor cells.
44  CD137 agonism 
may in this way potentially re-activate rituximab activity in patients that are relapsed or 
refractory to rituximab in the context of R-CHOP.  Combination therapy of an anti-PD-1 
mAb with rituximab achieved a 66% ORR in patients with relapsed follicular lymphoma 
previously treated with rituximab.
45
Data suggests that the combination of PD-L1 antagonism and anti-4-1BB agonism may be 
synergistic.  In both a colon carcinoma and melanoma model, pronounced tumor inhibition 
was observed in animals receiving anti-PD-1 and anti-4-1BB concomitantly.  They had a 
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Other pre-clinical studies indicated that PD-L1 expression confers resistance to therapeutic 
anti-CD137 antibody in mice with established tumors.  The resistance is accompanied by 
failure of antigen specific CD8
+cytotoxic TLs to destroy tumor cells without impairment of 
cytotoxic TL function.  Blockade of PD-L1 or PD-1 using mAbs could reverse this resistance 
and enhance therapeutic efficacy.
46
A mastocytoma cell line negative for PD-L1, was either mock transfected or transfected with 
a PD-L1 construct.  The cells were then injected into the strain of mouse where the tumor 
cells were derived (DBA/2).  Anti-PD-L1 mAbs were shown to abrogate the response to 
anti-4-1BB mAbs, suggesting that PD-L1 blockade might enhance the response to 
anti-4-1BB.
The hypothesis that a triplet comprising avelumab, rituximab and utomilumab might provide 
enhanced clinical activity in DLBCL has been tested in an A20 lymphoma model 
(Unpublished Pfizer data on file).  In this model the triplet combination of avelumab, 
anti-4-1BB, and rituximab resulted in a higher frequency of tumor-free mice than either of 
the corresponding doublets or monotherapy (Figure1).
Figure1. A20 Lymphoma Model Data Showing Synergy of Simultaneous PD-L1, 
Anti-4-1BB, and Rituximab Blockade
4-1BB/PD-L1/CD20 Triplet Regress Large A20 Lymphomas
Treatments
# Tumor-Free Mice
Isotypes
0 / 8
Anti-CD20
0 / 8
Avelumab
0 / 8
Avelumab/ Anti-CD20
0 / 8
Anti-4-1BB
3 / 8
Anti-4-1BB/ Avelumab
4 / 8
Anti-4-1BB/ Anti-CD20
4 / 8
Anti-4-1BB/ Avelumab/ Anti-CD20
7 / 8
Together this data provides a compelling rationale for evaluating safety and efficacy of 
PD-L1 checkpoint blockade in combination with anti-4-1BB agonism and CD137 inhibition.


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1.4.4.Rationale for Treatment Arm B (Avelumab, Azacitidine, and Utomilumab)
Following the observation that NSCLC patients previously treated with a combination of two 
epigenetic agents (entinostat and azacitidine) had a higher frequency of response to 
monotherapy with the anti-PD-1 inhibitor nivolumab, it was hypothesized that epigenetic 
priming might sensitize cancer cells to PD-1/PD-L1 axis blockade.  This resulted in multiple 
investigations to explore potential mechanisms of action of epigenetic agents in this context.  
In one study, treatment with azacitidine increased the cell surface expression of PD-L1 on 
NSCLC cell lines.
47
Further studies have provided evidence implicating multiple other mechanisms that support a 
potential immune priming role for azacitidine, and potentially also other epigenetic agents in 
the contextof checkpoint blockade.  Preclinical data demonstrated that the addition of 
azacitidine and entinostat to anti-PD-1 and anti-CTLA-4 mAbs, resulted in a significant 
decrease in tumor-infiltrating FoxP3
+Tregs compared with either untreated tumors or tumors
treated with anti-PD-1 and anti-CTLA-4 antibodies.48
PTPL1encodes a cytoplasmic tyrosine phosphatase with roles in numerous physiological and 
pathological processes.  Among the potential roles in carcinogenesis, the PTPL1 gene 
product can impact cancer development through its capacity to counteract the activity of 
oncogenic tyrosine kinases or its inhibitory interaction with the death receptor Fas.
The frequency of PTPL1 methylation I patients with DLBCL is significantly higher as 
compared with non-malignant lymphoid controls (59.6% of DLBCL versus6.3% in reactive 
lymph node proliferation).  It has been suggested that azacitidine has therapeutic potential in 
NHL as it may re-induce the expression of PTPL1.  This suggests a tumor-suppressor role for 
PTPL1 in lymphoma, and suggests that azacitidine may induce growth inhibition in NHL 
through the demethylation of PTPL1.
49
A Phase 1/2 study (N=45) of patients with advanced NSCLC examined the epigenetic effects 
of azacitidine administered at 40mg/m2in combination with entinostat.  In the Phase1 
component of the study, azacitidine was administered at a starting dose of 30mg/m2, and 
escalated to 40mg/m2in an attempt to define an epigenetically targeted dose rather than a 
cytotoxic one.  No significant dose-limiting toxicities (DLTs) were observed, and 40mg/m2
was selected for the Phase2 study.  Promoter methylation status in circulating DNA from 
patient plasma collected prior to therapy, and following 1cycle of treatment, was assessed in 
26patients.  Ten of these patients had at least 2methylated target genes on Day0, and were 
shown to have a decreased level of methylation of 2 or more of these genes by Day29.  It 
was notable that 80% of ‘methylation signature’ positive patients achieved either stable 
disease or objective responses (ORs).50  A Phase2 study combining the anti-PD-1 
monoclonal antibody nivolumab, azacitidine (40mg/m2), and entinostat in NSCLC patients 
is currently ongoing (NCT01928576).
Furthermore, it was observed that chemo-resistance is associated with aberrant DNA 
methylation in DLBCL.  Prolonged exposure to low-dose DNMTIs (decitabine or 
azacitidine) reprograms chemo-resistant-cells to become doxorubicin sensitive, without any 
major toxicity in vivo.  A Phase1 study of azacitidine followed by R-CHOP in the 


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treatment-naïve patients with DLBCL explored doses of azacitidine ranging from 25mg/m2
to 75mg/m2.  Two of ten patients treated at 75mg/m2experienced a DLT,
51suggesting that 
the 75mg/m2used routinely in MDS may not be well-tolerated in treatment-naïve DLBCL, 
and may consequently be even less well tolerated in later lines of therapy.  It is notable in this 
context, that pre-and post-azacitidine treatment biopsies obtained from six patients 
confirmed SMAD1 demethylation and chemosensitization in all patients, even those treated 
at 25mg/m2and 50mg/m
2.
51  This raises the possibility of testing a dose less than 75mg/m2.  
Azacitidine has been shown to induce the expression of immune-related genes at doses which 
are lower than those necessary for the induction of cytotoxicity in vitro.  This phenomenon is 
also observed clinically in patients with DLBCL at doses as low as 25mg/m2. 
In light of: (i) the hematologic and non-hematologic toxicities observed at the standard 
cytotoxic azacitidine 75mg/m2dose, (ii) the fact that DLTs have been observed in patients 
with DLBCL at this dose, and (iii) the fact that the cytotoxic effects of azacitidine are still 
observed at doses of 50mg/m2, the 50mg/m2 dose appears to define the upper limit of the 
azacitidine pharmacodynamic window encompassing both hypomethylation (at the lower 
dose end) and cytotoxicity (at the higher dose end).  The 40mg/m2 azacitidine dose has, 
furthermore, been shown to be a clinically safe dose in patients with NSCLC, making this a 
reasonablecandidate dose for testing in the epigenetic priming context.  This dose is 
expected to minimize the cytotoxic effects of azacitidine, while at the same time preserving 
its hypomethylating effects.  The 40mg/m2 dose is higher than 25mg/m2, a dose which has 
been shown to exert the full hypomethylating effects on key target genes such as SMAD1.  
Consequently, it is likely that 40mg/m2 will prove to provide an optimal combination of 
hypomethylation and mild and tolerable cytotoxicity.
Immunomodulatory effects of hypomethylating agents through demethylation of the tumor 
genome results in the increased expression of tumor antigens and neo-antigens.  It has been 
shown that decitabine can induce specific autologous cytotoxic Tlymphocytes against some 
mouse cancer testis antigens (CTAs) in leukemia cells both in vitro and in vivo, therefore 
inducing autologous immune response, and that this response may contribute to disease 
control.
52  It was also demonstrated that treatment with azacitidine or decitabine re-induces 
the expression of cancer germline (CG) antigens in myeloid cell lines, in AML and in MDS 
patients (in combination with decitabine).  This is the result of CpG island promoter 
hypomethylation of CG genes following hypomethylating agent (HMA) therapy.53
Azacitidine sensitizes tumor cells to T-cell mediated cytotoxicity and modulates NK cell 
activity.  It has been shown that azacitidine treatment leads to recognition of tumor cells by 
host T-cells and enhances direct ex vivo cytotoxicity.  Cancer testis antigens are established 
targets for immune recognition in cancer.  Azacitidine upregulates cancer testis antigens 
expression in tumor cells following demethylation.  It is hypothesized that the combination of 
azacitidine with checkpoint inhibition may preferentially boost T-cell responses against 
cancer-testis antigens.
53


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It has been shown that azacitidine treatment increases the expression of several killer-cell 
immunoglobulin-like receptors (KIRs) in proliferating NK cells both in vitroand in MDS 
patients undergoing azacitidine treatment, and that azacitidine-exposed proliferating NK cells 
have a higher functionality.
54
Proliferating NK cells exposed to azacitidine in vitro have considerably higher responses 
against K562cells, suggesting that NK cells with an active uptake of azacitidine may mount 
improved responses againsttumor targets. 
When combined with avelumab, azacitidine may consequently lead to an enhanced 
anti-tumor response by increasing the expression of tumor antigens and tumor neo-antigens, 
by sensitizing malignant cells to cytotoxic Tcells, by inhibiting Tregs and suppressing 
MDSCs, and by inducing tumor cell PD-L1 expression.  Azacitidine may also have a 
synergistic effect when combined with a 4-1BB agonist by increasing NK cell activity. 
The data showing the potential for synergy between anti-PD-L1 and a 4-1BB agonist, as well 
as the potential for azacitidine to prime the responses to anti-PD-L1, supports the testing of 
the azacitidine, anti-PD-L1 and the 4-1BB agonist triplet.
1.4.5.Rationale for Treatment Arm C (Avelumab, Rituximab and Bendamustine)
Emerging data support the rationale for combining immune checkpoint inhibitors with 
chemotherapy.56,57  Chemotherapy has been shown to have immune-stimulatory properties 
throughthe release of neoantigens and adjuvants by dying cells, increasing susceptibility to 
immune attack, and preferentially reducing immunosuppressive cells such as T regulatory 
cells.
58,5959  Most conventional chemotherapy agents, such as platinum-based agents, are 
mutagenic.
60  Therefore, treatment with chemotherapy may result in the expression of 
neoepitopes, which may enhance checkpoint inhibitor activity.  In preclinical studies, the 
combination of avelumab with chemotherapy (gemcitabine, oxaliplatin, and 5FU) showed 
improved anti-tumor activity over single-agent chemotherapy.6
Several checkpoint inhibitors have been combined with chemotherapy agents.  The addition 
of ipilimumab to dacarbazine resulted in an improvement in OS in previously untreated 
melanoma compared with dacarbazine alone.
61  Ipilimumab was combined with 
platinum-doublet chemotherapy in SCLC as well as NSCLC with encouraging results.63  
Combinations of the PD-1 inhibitors (pembrolizumab, nivolumab) as well as a PD-L1 
inhibitor (atezolizumab) with platinum-doublet chemotherapy showed acceptable safety 
profiles with early evidence of clinical activity that appeared to be higher than expected for 
platinum-doublet therapy alone, particularly for atezolizumab.64,65,66,67
Chemotherapy is important for reducing tumor load and shedding antigens, as well as having 
an inhibitory effect on regulatory cells and myeloid suppressive cells.  Chemotherapy agents 
may also have suppressive effects on Tregs and myeloid/macrophage cells, thus allowing 
immunotherapy to be moreeffective.  Shed tumor antigens are taken up by monocytes and 
dendritic cells and may help initiate anti-tumor Tcell responses.  Immunotherapy has the 
capacity to greatly enhance the response to chemotherapy by bolstering and activating the 
immune response prior to antigen release, thereby enabling the immune system to mount an 


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antigen specific response when tumor cells are killed.
68  In preclinical studies, the 
combination of avelumab with chemotherapies demonstrated improved anti-tumor activity.
6
In a rapidly progressive disease like DLBCL, chemotherapy is expected to help gain rapid 
control over the disease, giving the immunotherapy time to work.  The lack of suchearly 
disease control is a potential risk of chemotherapy-free drug regimens, and the incorporation 
of chemotherapy as an avelumab combination partner in addition to its potential immune 
priming role through antigen shedding and tumor debulking, should provide an adequate 
window of time in which the immunotherapy can demonstrate its effects.  R/Benda has been 
chosen as the chemotherapy of choice in the Phase1b component of the study based upon the 
fact that: (i) it has less hepatoxicity than R/Gem/Ox (perlabel), (ii) it has a well-documented 
safety and efficacy profile, and (iii) it is listed as one of the recommended therapies for R/R 
DLBCL in the NCCN guidelines. 
1.4.6.Rationale for Control Arm Combinations for Phase 3 (Rituximab/Bendamustine 
or Rituximab/Gemcitabine/Oxaliplatin)
High-dose chemotherapy followed by autologous stem-cell transplant is the treatment of 
choice for relapsed lymphoma, but is not appropriate for all patients, due to age and 
accompanying comorbidities.  Conventional salvage chemotherapy has been used, but it has 
limited efficacy and is associated with significant toxicity. 
No standardized chemotherapy regimen is available for elderly or frail patients with relapsed 
or refractory DLBCL.  Cardiotoxicity associated with anthracyclines limits the utility of 
CHOP, and there is a significant need for effective and well-tolerated chemotherapeutic 
approaches for patients with aggressive NHL who have limited therapeutic options following 
chemotherapy and ASCT failure, as well as patients with impaired cardiac function who 
cannot receive anthracycline-based therapy.27
The following rituximab-containing chemotherapy regimens are currently recommended 
(NCCN Guidelines version 2.2015) for 2L salvage therapy and beyond in patients that are 
not eligible for high dose chemotherapy followed by ASCT: bendamustine 
rituximab, 
brentuximab, CEPP, CEOP, DA-EPOCH rituximab, GDP rituximab, 
Gem/Ox rituximab, lenalidomide rituximab, and rituximab.  These regimens are also 
used in third line salvage and beyond in younger ‘fit’ patients who fail high dose 
chemotherapy and ASCT, or for whom ASCT is not appropriate.
1
None of the options listed above have become a formal standard of care in R/R DLBCL.  
Both R/Benda and R/Gem/Ox are used in the US and European Union (EU), and both have 
been extensively studied in the R/R DLBCL setting.  Different EU countries and different 
sites within the US and EU have specific preferences for using R/Benda or R/Gem/Ox.  For 
example, although widely used across the US and Germany, R/Benda is not frequently used 
in other EU regions.  There are also specific preferences for R/Benda or R/Gem/Ox in 
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In the Phase 1component of study B9991011, R/Benda was chosen as the preferred 
chemotherapy backbone over R/Gem/Ox, as the use of R/Gem/Ox is associated with 
transient elevations of aspartate aminotransferase/ alanine aminotransferase(AST/ALT) in 
~70% of patients.29  Note that the ESMO guidelines differ from the NCCN guidelines, in that 
they do not recommend the use of R/Benda in first relapse, preferring instead either a clinical 
trial or the use of platinum and/or gemcitabine based regimens for R/R DLBCL patients who 
are not eligible for transplant.  Beyond first relapse, the ESMO guidelines recommend a 
clinical trial as the preferred therapeutic option.
33
Bendamustine is activein indolent B cell lymphomas and chronic lymphocytic leukemia.  It 
demonstrated clinical activity in combination with rituximab in patients with relapsed and 
refractory DLBCL with an overall response ranging from 45.8% to 62.7%.
7,27,28
An ORR of 45.8% with a complete response rate of 15.3% and a partial response rate of 
30.5% was demonstrated with a rituximab/bendamustine combination in 61patients with 
relapsed or refractory DLBCL who were determined by their physicians not to be good 
candidates for ASCT or aggressive salvage regimen.  The median duration of response was 
17.3months and the median PFS 3.6months.  Grade3 or 4 hematological toxicities included: 
neutropenia (36%), leukopenia (29%), thrombocytopenia (22%) and anemia (12%).  The 
majority of patients received bendamustine at 120mg/m2on Days1 and 2 and rituximab at 
375mg/m2on Day1 every 28days for up to 6cycles.
7
A multicenter Phase2 study assessed the efficacy and safety of bendamustine combined with 
rituximab in relapsed or refractory DLBCL patients who were not eligible for ASCT or had 
undergone ASCT, previously treated with one to three prior chemotherapy regimens.
27
Rituximab 375mg/m2IV infusion was administered on Day1 and bendamustine 120mg/m2
by IV infusion on Days2 and 3 of each 21-day cycle for up tosix cycles. 
Sixty-three patients were enrolled.  The ORR was 62.7% (95% CI, 49.1% to 75.0%), with a 
CR rate of 37.3% (95% CI, 25.0% to 50.9%).  The median PFS was 6.7months (95%CI, 
3.6to 13.7months).  The most frequently observed Grade3 or 4 adverseevents were 
hematologic: lymphopenia (78.0%), neutropenia (76.3%), leukopenia (72.9%), CD4 
lymphopenia (66.1%), and thrombocytopenia (22.0%).
27
Rituximab, gemcitabine, and oxaliplatin are active as a salvage regimen in relapsed or 
refractory lymphoma patients who are not eligible for high dose therapy, with demonstrated 
overall response rates ranging from 46% to 83%.29,30
A series of 46patients with relapsed or refractory B-cell lymphoma (72% had Diffuse Large 
B-cell Lymphoma) was conducted in 2007.  Patients received up to eight cycles of 
R/Gem/Ox (rituximab 375mg/m2 on Day1, gemcitabine 1000mg/m2and oxaliplatin 
100mg/m2on Day2).  After 4cycles of R/Gem/Ox, the overall response rate was 83%[50% 
complete response (CR)/unconfirmed CR (CRu)].  In patients who had previously received 
rituximab, the CR/CRu rate after eight cycles was 65%.  The 2-year event-free and overall 
survival rates (median follow-up of 28months) were 43% and 66%,respectively.  The 
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R/Gem/Ox showed promising activity with acceptable toxicity in patients with 
relapsed/refractory B-cell lymphoma who are not eligible for high dose therapy.30  These 
results compared favorably with data for conventional chemotherapy regimens, which show 
low response rates and few durable responses.  Each component of the R/Gem/Ox regimen 
may contribute to the efficacy, and the results of this study support a synergistic or 
supra-additive action for rituximab when combined with gemcitabine and oxaliplatin.
30
A multicenter Phase2 study was conducted in 49patients with refractory or relapsed 
DLBCL, with prior rituximab treatment in 63% of patients.  Rituximab 375mg/m2was 
administered on Day1 and gemcitabine and oxaliplatin at doses of 1000mg/m2 and 
100mg/m2 respectively on Day2.  Cycles were repeated every 15days.  After 4cycles, the 
complete remission rate was 44% and the partial remission rate 17%, with an overall 
response rate of 61%.  These multicenter study results confirmed that the R/Gem/Ox regimen 
provides a consistent response rate in patients with relapsed-refractory DLBCL.
69
A patient in first relapse that received R/Benda would not generally be re-treated with 
R/Benda in later lines of therapy.  The same is true for R/Gem/Ox.  Consequently, by 
allowing Investigator’s Choice of either R/Gem/Ox or R/Benda, the study accommodates 
patients previously treated with one or the other combination in an earlier line of therapy. 
A review of the R/Gem/Ox and R/Benda literature does not allow fora direct comparison of 
the efficacy of one versus the other as the studies are small, the target populations different, 
and the observed ORR and PFS values variable.  Although overall the literature suggests that 
the ORR is higher for R/Gem/Ox than for R/Benda, the apparently higher ORR does not 
translate into an increased PFS.  Furthermore, the R/Gem/Ox studies are in an earlier line of 
therapy, making it hard to compare data across studies. 
From the perspective of safety, both R/Benda (90mg/m2and 120mg/m2doses) and 
R/Gem/Ox have an acceptable safety profile, with neutropenia and thrombocytopenia being 
the most frequent toxicities for both combinations.
7,27,28,30,70
1.4.6.1.Rituximab/Bendamustine Safety
The commonest reasons for bendamustine dose reduction are neutropenia and 
thrombocytopenia.  Neutropenia, thrombocytopenia, and anemia, each occur in about 
45%of patients (all grades; around 30%, 16% and 15% of Grade3, respectively). 
Other common adverse events (all grades, mainly Grade1 or 2 in severity) include nausea 
(41%), constipation (25 to 50%), anorexia (14 to 34%), dehydration (10%), fatigue(21%), 
diarrhea (18%), and fever (17).  Severe (Grade3) infections can be observed.7,27,28
1.4.6.2.Rituximab/Gemcitabine/Oxaliplatin Safety
The most common toxicities are hematologic, with 98% of patients developing neutropenia, 
(including 43% to 73% of patients developing a Grade3 neutropenia on at least 1 occasion).  
About 90% of patients experience thrombocytopenia, including about 44% with at least one 
Grade3 episode.  Neurotoxicity is reported in 35% to 45% of patients, mostly
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Grade2 (approximately 7% of Grade3/4).  Nausea and vomiting occur in the majority of 
patients, but at Grade2 or lower.30,70
1.5.Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article3(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. 
Approximately 75% of patients with DLBCL present with advanced stagedisease, and the 
majority (~60%) of patients may be cured with R-CHOP.  However, patients with refractory 
or relapsing disease have a poor prognosis.  High-dose chemotherapy and ASCT represent 
the best second-line treatment option, but eligibility for such intensive treatments is often 
limited by advanced age and comorbidities, and in addition only a fraction of patients is 
eventually cured by this approach.  The development of novel, safe and more effective 
salvage strategies remains a high clinical priority. 
Avelumab has demonstrated clinical activity in patients with a variety of advanced solid 
tumors in the expansion cohorts of the ongoing Phase1 Trial EMR 100070-001.  The clinical 
safety data with single-agent avelumab in patients with advanced solidtumors available to 
date, suggest an acceptable safety profile of the compound.  Most of the observed events 
were either in line with those expected in patients with advanced solid tumors or with those 
observed with other monoclonal antibodies blocking the PD-1/PD-L1axis (Section1.3.2).  
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 H1receptor (H1) blocker and 
acetaminophen.
The anti-4-1BB agonist mAb, utomilumab, has also demonstrated clinical activity as 
monotherapy in patients with advanced solid tumors and in combination with rituximab in 
patients with NHL in an ongoing Phase1 Trial B1641001.  The clinical safety profile of 
utomilumabsupports its use as both a single agent and in combination with rituximab 
(Section1.3.2.6).  Pyrexia, fatigue, decreased appetite, dizziness, and skin rashes represent 
the most common utomilumab related AEs when given as a single agent, and they were 
generally mild to moderate in intensity.  While clinically significant irAEs have not been 
observed with utomilumab, risk mitigation measures have been implemented in ongoing 
clinical studies with utomilumab, including this clinical trial protocol.  These include 
guidelines for treatment interruption and discontinuation in case of treatment-related irAEs.
The combination of avelumab with utomilumab is being evaluated in patients with advanced 
solid malignancies in the ongoing Phase1b/2 Trial B9991004 in which avelumab 10mg/kg 
every 2weeks is administered with utomilumab at doses of 20mg, 100mg, or 500mg every 
4weeks.  As of 16March 2016, preliminary safety data were available for 5patients in each 
utomilumab dose level cohort.  Thirty-three treatment-emergent AEs were reported overall, 


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with 6(18%) being drug related.  All drug-related AEs(nausea, vomiting, fatigue, diarrhea, 
infusion reaction) were either Grade1 or Grade2 and were in line with the previously 
reported safety profiles for the two drugs when dosed separately.  The events of infusion 
reaction (n=2) were reported as related to avelumab in 2patients in the avelumab plus 
500mg utomilumabcohort (utomilumab is dosed first; followed 30minutes later by 
avelumab).  No drug-related AEs were reported in the avelumab plus 100mg 
utomilumabcohort.  In addition, 4SAEs (all unrelated) have been noted: Grade5 pneumonia 
(prior to study entry), Grade3 nausea (100mg utomilumab cohort), Grade2 constipation 
(100mg utomilumab cohort), Grade3 lung infection (20mg utomilumab cohort). 
With exception for fatigue, pyrexia and decreased appetite, which are usually low-grade 
events observed with both avelumab and utomilumab single agents, there are no additional 
expected overlapping toxicities between the two agents.  Given their distinct mechanisms of 
action and toxicity profiles, additional safety concerns are not expected from this 
combination.  Of note, the utomilumabdose to be administered in this trial (100mg 
[approximately 1.2mg/kg] once every 4weeks) is considerably lower than the highest dose 
tested (10mg/kg every 4weeks) as asingle agent and in combination with rituximab in 
Study B1641001 and is thereby expected to provide an adequate safety margin for evaluation 
in combination with avelumab.  In the current study, patients will be monitored closely for 
toxicity and in the event of significant toxicity or if unexpected safety concerns arise from 
the B9991004trial, this study protocol will be amended to include additional guidance and/or 
a modified dosing regimen, if applicable. 
The preclinical rationale for the three tripletcombination regimens are outlined in 
Section1.4.  A safety analysis of the three combinations did not predict any significant 
potential for overlapping toxicities.
Based on the above, the projected benefit/risk of the three combinations to be tested in this 
study is anticipated to be favorable, and supports their investigation in patients with 
relapsed/refractory DLBCL.
2.STUDY OBJECTIVES ANDENDPOINTS
2.1.Objectives
Phase 1b PrimaryObjective:
To asses safety, efficacy, and potentially select the most active treatment regimen 
among 3treatment arms to advance to the Phase3 component of the study.
Phase 1b Secondary Objectives:
To evaluate the pharmacokinetics (PK) of each treatment arm.
To assess the immunogenicity of each treatment arm.


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To evaluate PD-L1 expression levels in tumor cells and cells of the tumor 
microenvironment (for example, infiltrating lymphocytes) as candidate predictive 
biomarkers with their relationship to selected clinical response parameters.
To evaluate the relationship between minimal residual disease burden as assessed 
using serial blood samples with selected clinical response parameters.
 
 
 
Phase 3 Primary Objective:  
To demonstrate superiority in PFS as assessed by the Blinded Independent Central
Review (BICR) of the selected Phase1b avelumab-based combination regimen over 
Investigator’s Choice chemotherapy.
Phase 3 Secondary Objectives: 
To compare overall survival (OS) between the selected Phase1b avelumab-based 
combination regimen to Investigator’s Choice chemotherapy.
To further evaluate the efficacy of each treatment arm.
To evaluate the overall safety profile of each treatment arm.
To evaluate the PK of the selected Phase1b avelumab-based combination regimen.
To assess the immunogenicity of the selected Phase1b avelumab-based combination 
regimen.
To evaluate patient-reported outcomes (PROs) in the selected Phase1b 
avelumab-based combination regimen versus Investigator’s Choice chemotherapy.
To evaluate PD-L1 expression levels in tumor cells and cells of the tumor 
microenvironment (for example, infiltrating lymphocytes) as candidate predictive 
biomarkers with their relation to selected clinical response parameters.

CCI
To evaluate the relationship between minimal residual disease burden as assessed 
using serial blood samples with selected clinical response parameters.


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2.2.Endpoints
Phase 1b Primary Endpoint:
Dose Limiting Toxicity (DLT).
Objective Response (OR) as assessed by the Investigator per Lugano Response 
Classification Criteria.71
Phase 1b Secondary Endpoints:
Safety: AEs and laboratory abnormalities as graded by National Cancer Institute 
(NCI) Common Terminology Critera for Adverse Events (CTCAE) v.4.03; vital signs 
(blood pressure, heart rate); electrocardiograms (ECGs).
Duration of Response (DR), Time to Tumor Response (TTR),Disease Control (DC), 
Progression-Free Survival (PFS), as assessed by the Investigator per Lugano 
Response Classification Criteria and Overall Survival (OS).
Pharmacokinetics: PK parameters of avelumab, rituximab, utomilumab, azacitidine 
and bendamustine as data permit: maximum plasma concentration (C
max), time to 
maximum plasma concentration (Tmax), area under the plasma concentration time 
curve from time 0 to hours post dose (AUC0-, where is dependent on the analyte) 
apparent plasma clearance (CL/F), and apparent volume of distribution (V/F) of each 
analyte following single and multiple dosing.
Immunogenicity: Anti-drug antibodies (ADA); neutralizing antibodies (Nab) against 
avelumab, rituximab, and utomilumab.
PD-L1 expression levels in tumor cells and cells of the tumor microenvironment at 
baseline.

CCI
Minimal residual disease burden (MRD) as assessed using serial blood samples.
 
 
CCI


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Phase 3 -Primary Endpoint:
Progression-Free Survival (PFS) as determined by Blinded Independent Central 
Review (BICR) per Lugano Response Classification Criteria. 
Phase 3 -Secondary Endpoints: 
Overall Survival (OS).
PFS by Investigator assessment.
Objective Response (OR), Time toTumor Response (TTR), Duration of Response 
(DR), and Disease Control (DC) by BICR and Investigator assessment.
Safety: AEs and laboratory abnormalities as graded by National Cancer Institute 
(NCI) Common Terminology Critera for Adverse Events (CTCAE) v.4.03; vital signs 
(blood pressure, heart rate); electrocardiogram (ECG).
Pharmacokinetics: PK parameters of avelumab, rituximab, utomilumab, azacitidine, 
and bendamustine (depending on the treatment being tested in Phase3) will be 
determined as data permit:maximum plasma concentration (Cmax), time to maximum 
plasma concentration (Tmax), area under the plasma concentration time curve from 
time 0 to hours post dose (AUC0-, where is dependent on the analyte) apparent 
plasma clearance (CL/F), and apparent volume of distribution (V/F) of each analyte 
following single and multiple dosing.
Immunogenicity: anti-drug antibodies (ADA) and neutralizing antibodies (Nab) 
against avelumab, rituximab, and utomilumab.
Patient-Reported Outcomes: Fatigue measured via Brief Fatigue Inventory (BFI) 
questionnaire, disease symptoms and quality of life (QoL) measured via the NCCN-
FACT FLymSI-18 questionnaire, and QoL measured via the EQ-5D-5L 
questionnaire.
PD-L1 expression levels in tumor cells and cells of the tumor microenvironment at 
baseline.

CCI
Minimal residual disease burden as assessed using serial blood samples.


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3.STUDY DESIGN
3.1.Study Overview
Study B9991011 is a multicenter, international, randomized, open-label, 2-component (Phase 
1b followed by Phase 3), parallel-arm study of avelumab in combination with: 
(i) rituximab (CD20 antagonist) and utomilumab (4-1BB agonist);
(ii) azacitidine (DNA methyltransferase inhibitor [DNMTi]) and utomilumab (4-1BB 
agonist); or 
(iii) rituximab (CD20 antagonist) and bendamustine (chemotherapy). 
Crossover between treatment arms will not be permitted.
The target study population of this Phase 1b/Phase 3 registrational study will comprise 
patients with R/R DLBCL following at least 2 (but not more than 4) lines of prior 
rituximab/multi-agent chemotherapy, and/or failed ASCT, or who are not eligible for 
intensive chemotherapy or candidates for ASCT.  The study will assess safety, efficacy, PK, 
and immunogenicity, and patient reported outcomes (see Figure2).
Patients for whom first-line therapy failed may be categorized into two distinct groups: 
(i)any response, with progression occurring after 3months of therapy (relapsed disease), 
(ii)no response, or progression within 3months of therapy (refractory disease).
3.1.1.Phase 1b
CCI
The primary objective of the Phase1b component is to make a preliminary assessment of 
dose-limiting toxicities in each treatment arm (N=6 each), and then to potentially select a 
treatment regimen to be advanced to the Phase3 component based on efficacy including the 
observed ORR (as assessed by the Investigator) and safety profile in each expanded 
treatment arm (N꞊28 each).
Crossover between treatment arms will not be permitted.


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The following treatment regimens will be assessed in the Phase1b component of the study, 
with all treatments being administered in 28-day cycles:  See Figure3for dosing schematic. 
Treatment Arm A: Avelumab/Rituximab/Utomilumab 
(i) Rituximab 375mg/m2(IV) will be administered on the morning of Day1 of each 28-day 
cycle for a maximum of 8cycles.
(ii) Utomilumab 100mg fixed dose (IV) will be administered on the morning of Day2 of 
each 28-day cycle in Cycles1 and 2 (or if well-tolerated in Cycles1 and 2, then on Day1 in 
Cycle3 and in all subsequent cycles) at least 1hour after the rituximab infusion is complete, 
until the patient no longer receives clinical benefit. 
Utomilumab must have completed administration at least 1hour prior to avelumab in 
Cycles1 and 2.  If well-tolerated in Cycles1 and 2, then in Cycle3 and in all subsequent 
cycles, the time window of dose administration between utomilumab and avelumab may be 
decreased from 1hour to 30-60minutes apart.
(iii) Avelumab 10mg/kg (IV) will be administered every 2weeks on Day2 and Day16 of 
each 28-day cycle in Cycle1 and Cycle2 (or if well tolerated in Cycle1 and 2, then on 
Day1 and Day15 in Cycle3 and in all subsequent cycles) until the patient no longer receives 
clinical benefit.
Avelumab must be administered at least 1hour after the end of the utomilumab infusion in 
Cycle1 and Cycle2.  If well-tolerated in Cycle1 and Cycle2, then in all subsequent cycles, 
the time window of dose administration between avelumab and utomilumab may be 
decreased from 1hour to 30-60minutes apart.
Treatment Arm B: Avelumab/Azacitidine/Utomilumab 
(i) Azacitidine 40mg/m2(SC) will be administered at the site in the morning on Days1-5 of 
each 28-day cycle until the patient is no longer receiving clinical benefit.
Azacitidine must have completed administration at least 1hour prior to utomilumab when 
dosed on the same day.
(ii) Utomilumab 100mg fixed dose (IV) will be administered on the morning of Day2 of 
each 28-day cycle in Cycles1 and 2 (or if well-tolerated in Cycles1 and 2, then on Day1 in 
Cycle3 and in all subsequent cycles) until the patient no longer receives clinical benefit. 
Utomilumab must have completed administration at least 1hour prior to avelumab in Cycle1 
and Cycle2.  If well-tolerated in Cycle1 and Cycle2, then in Cycle3 and in all subsequent 
cycles, the time window of dose administration between utomilumab and avelumab may be 
decreased from 1hour to 30-60minutes apart.


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(iii) Avelumab 10mg/kg (IV) will be administered every 2weeks on Day2 and Day16 of 
each 28-day cycle in Cycle1 and Cycle2 (or if well tolerated in Cycle1 and 2, then on 
Day1 and Day15 in Cycle3 and in all subsequent cycles) until the patient no longer receives 
clinical benefit.
Avelumab must be administered at least 1hour after the end of utomilumab infusion in 
Cycle1 and Cycle2.  If well-tolerated in Cycle1 and Cycle2, then in all subsequent cycles, 
the time window of dose administration between utomilumab and avelumab may be 
decreased from 1hour to 30-60minutes apart.
Treatment Arm C: Avelumab/Bendamustine/Rituximab
(i) Rituximab 375mg/m2(IV) will be administered on the morning of Day1 of each 28-day 
cycle for a maximum of 8cycles.
(ii) Bendamustine 90mg/m2(IV) will be administered on Days2 and 3 of each 28-day cycle 
in Cycle1 and Cycle2.  If bendamustine is well-tolerated in Cycle1 and 2, bendamustine 
may be administered on Day1 and Day2 in Cycle3 (and all subsequent cycles).  
Bendamustine is administered for a maximum of 6cycles.
(iii) Avelumab 10mg/kg (IV) will be administered every 2weeks on Day2 and Day16 of 
each 28-day cycle in Cycle1 and Cycle2 (or if well tolerated in Cycle1 and 2, then on 
Day1 and Day15 in Cycle3 and in all subsequent cycles) until the patient no longer receives 
clinical benefit.  Avelumab administration should be at least 1hour after the end of the 
bendamustine infusion.
A dose level -1 (3mg/kg) to be tested only in the event of excessive toxicity attributable to 
avelumab at 10mg/kg is permitted.
Continued Treatment with Avelumab and/or Utomilumab
Per Investigator clinical judgment and following discussion between the Investigator and the 
Sponsor, if a patient with documented progressive disease (PD) continues to receive clinical 
benefit, treatment with avelumab and/or utomilumab may be continued.  The Investigator’s 
judgment must be based on the overall benefit-risk assessment, and on the patient’s clinical 
condition, including performance status (PS), clinical symptoms, adverse events (AEs), and 
laboratory data.  Other agents in the regimen combination with avelumab and/or utomilumab 
may also be considered for continuation if in the Investigator’s clinical judgment the patient 
may achieve clinical benefit.  See Section 5.4for treatment duration limits for agents other 
than avelumab and utomilumab.
In the Phase 1b component of the study, pre-specified Go/No-Go criteria are configured to 
identify with95% confidence a treatment regimen that is superior to rituximab/ 
bendamustine benchmark data (ie, historical reference control) with respect to one or more of 
the following (in a hierarchical manner):  


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1. ORR (ie, proportion of patients achieving CR or PR).
2. Six-month DRR (ie, proportion of patients with CR or PR persisting for at least 
6months).
3. PFS rate at 6months.
In the final analysis of the Phase 1b the decision-making process will include the following 
steps:
1. In each treatment arm, the null hypothesis that the ORR does not exceed 46% 
(H0:ORR 46%) will be tested against the alternative hypothesis (H1: ORR >46%) 
at a one-sided level of significance =0.025 using the binomial distribution.
2. If the null hypothesis for ORR is not rejected for any of the three treatment arms, the 
study will not proceed to Phase3.
3. If only 1treatment arm meets the ORR criterion, then that arm will be evaluated in 
Phase3.
4. If 2treatment arms meet the ORR criterion, then the Phase3 investigational arm 
may be selected based on Criterion1, 6-month DRR.  In each treatment arm, the null 
hypothesis that the 6-month DRR does not exceed 23% (H0:6 Mo DRR 23%) will 
be tested against the alternative (H1: 6 Mo DRR >23%) at a one-sided level of 
significance =0.025 using the binomial distribution. 
5. If only 1treatment arm meets the 6-month DRR criterion, then that arm will be 
evaluated in Phase3.  If none, or >1treatment arm meets the 6-month DRR criterion, 
then the Phase3 investigational arm may be selected based upon PFS rate at
6months.  In each treatment arm, the null hypothesis that the proportion of paitents 
who are progression-free at 6months does not exceed 31% (H0: PFS rate at 6months 
31%), will be tested against the alternative (H1: PFS rate at 6months >31%) at a 
one-sided level of significance =0.025 using the using the binomial distribution. 
6. If only 1 treatment arm meets the PFS rate at 6months criterion, then that arm will be 
evaluated in Phase3.  If none or >1treatment arm meets the PFS rate at 6months 
criterion, then the totality of safety and efficacy data will be taken into consideration 
when determining which arm to take forward into the Phase3.
In addition, there will be aformal interim analysis (IA) in the Phase1b component of the
study, performed 13weeks after 8patients in each treatment arm have been randomized 
(Section9.14). The purpose of the IA is to allowfor the early stopping of any treatment arm
for futility based on ORR.


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3.1.2.Dose-Limiting Toxicity Definition
The severity of adverse events will be graded according to CTCAE version 4.03 (see 
Appendix4).
Up to 12DLT-evaluable(see Section 9.3.3) patientswill be randomized into each treatment 
armin the Phase 1b and evaluated for DLT during the first cycle of treatment as follows:
Randomize and treat up to 6DLT-evaluable patients in each treatment arm:
If 1of 6patients experience DLT, the treatment armwill be expanded to 
randomize up to 28patients;
If 3of up to 6patients experience DLT, randomization in the specific treatment 
armwill be discontinued;
If 2of 6patients experience DLT, the treatment armwill be expanded to 
randomize to 6additional DLT-evaluable patients;
If 3of 12patients experience DLT, the treatment armwill be expanded to 
randomize up to 28patients;
If 4of up to 12patients experience DLT, randomization in the specific 
treatment armwill be discontinued.
A Pfizer Internal Review Committee (IRC) evaluation of the first 6and/or 12 DLT-evaluable 
patients in each treatment arm will occur after the last patient has completed one cycle 
(4weeks) of treatment.  Enrollment will be halted while the first 6DLT-evaluable patients in 
each treatment arm are evaluated for safety.
For the purpose of selecting the regimen to advance into Phase3, any of the adverse events 
listed below occurring during the DLT observation period (4weeks from the time of thefirst 
study treatment administration (Cycle1, Day1) that are attributable to an agent in the 
combination (and not incontrovertibly related to underlying disease or intercurrent illness)), 
will be classified as DLTs:
Hematologic
Grade4 neutropenia (absolute neutrophil count [ANC] <500cells/mm
3) not 
recovering to Grade3 lasting >7days (despite the use of G-CSF–see 
Section5.5.5.2).
Grade3 febrile neutropenia (ANC <1000/mm3) with a single temperature of 
>38.3degrees Celsius (>101.0degrees Fahrenheit) or a sustained temperature of
38.0degrees Celsius (100.4degrees Fahrenheit) for more than 1hour, with or 
without associated sepsis or that leads to a delay in the next cycle of therapy(despite 
the use of G-CSF –see Section 5.5.5.2).


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Grade3 neutropenic infection(despite the use of G-CSF –see Section 5.5.5.2).
Grade4 thrombocytopenia, or Grade3 thrombocytopenia associated with clinically 
significant bleeding (requiring red cell transfusion).
Grade4 anemia (despite red blood cell transfusion).
Non-Hematologic:  
Any Grade3 toxicity, exceptfor the following:
Transient (6hours) Grade3 flu-like symptoms or fever controlled with standard 
medical management.
Transient (24hours) Grade3 fatigue, localized skin reactions, or headache that 
resolves to Grade1.
Grade3 nausea or vomiting resolved to Grade1 in ˂72hours following the 
initiation of adequate medical management.
Grade3 diarrhea that resolved to Grade1 in <72hours following the initiation of 
adequate medical management.
Grade3 skin toxicity resolved to Grade1 in ˂7days. 
Tumor flare.
Single laboratory values that are out of the normal range, that do not have any clinical 
correlate, and resolve to Grade1 within 7days with adequate medical management.
Abnormal laboratory tests should be repeated.  While the rules for adjudicating DLTsin the 
context of selecting the regimen to advance to Phase3 clinical trial are specified above, AEs 
not listed above, or any AE meeting the DLT criteria above but occurring outside of the DLT 
observation period may be defined as a DLT following consultation between the Sponsor and 
the Investigator, based upon the overall emerging safety profile.
3.1.3.Phase 3
In Phase3 (N=220) the primary objective is to demonstrate superiority in PFS (as assessed 
by Blinded Independent Central Review (BICR) of the treatment combination identified in 
Phase 1b, over the control treatment, namely Investigator’s Choice chemotherapy comprised 
of rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin.
Crossover between treatment arms will not be permitted.
The following combination treatment regimens will be assessed in the Phase3 part of the 
study, with all treatments being administered in 28-day cycles:  


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Treatment Arm D:Combination regimen selected from the Phase1b part of the study (from 
Treatment ArmA, B, or C).  See Figure3for dosing schematic.
Treatment Arm E:Investigator’s Choice options:
Rituximab/bendamustine; 
Rituximab (375mg/m2Day1 of each 28-day each cycle);
Bendamustine (120mg/m2Day1 and Day2 of each 28-day cycle).
Rituximab/gemcitabine/oxaliplatin;
Rituximab (375mg/m2Day1 of each 28-day cycle);
Gemcitabine (1000mg/m2on Day2 and Day17 of each 28-day cycle);
Oxaliplatin (100mg/m2on Day2 and Day17 of each 28-day cycle).
Note that the Investigator mustpre-specify which chemotherapy regimen (R/Benda or 
R/Gem/Ox) each patient will receive in the event that they are randomized to the 
Investigator’s Choice arm, prior to randomization.
Figure2. Study Design


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Figure3. Dosing Schema: Phase 1b and Phase 3
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.
Patient eligibility should be reviewed and documented by an appropriate member of the 
Investigator’s study team before patients are enrolled into the study. 
4.1.Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Any of the following as defined by the WHO, 2016 lymphoid neoplasm 
classificationsand histologically confirmed:
Diffuse large B-cell lymphoma (DLBCL), Not Otherwise Specified (NOS);
Germinal center B-cell type (GCB);
Activated B-cell type (ABC).


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High-grade B-cell lymphoma (HGBCL)-NOS.
HGBCL with MYC and BCL2 and/or BCL6 rearrangements.
T-cell histocyte-rich large B-cell lymphoma.
EBV+ DLBCL, NOS.
HHV8+ DLBCL, NOS.
2. Documentation that the disease is relapsed or refractory following at least 2lines (and 
a maximum of 4lines) of prior rituximab containingmulti-agent chemotherapy which 
may include an autologous stem cell transplantation unless patients are not considered 
suitable for intensive second-line chemotherapy or autologous stem cell 
transplantation.  Patients who are ineligible for intensive second line chemotherapy, 
must have received at least one prior rituximab-containing combination 
chemotherapy regimen.
3. Patients previously treated with bendamustine must have experienced a response 
duration 6months. 
4. Documentation of baseline measurable disease with at least 1 bi-dimensional lesion
with longest diameter (LDi)>1.5cm on CT scan which is fluorodeoxyglucose (FDG) 
avid on PET scan.
5. A biopsy (archived or Screening/recent) will be collected at Screening. 
6. Estimated life expectancy 3months.
7. At least 18years of age (or 20years in Japan).
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
9. All adverse events must have resolved to NCI CTCAE v.4.03 Grade1 (with the 
exception of alopecia and other Grade2 AEs not considered medically relevant in 
the judgment of the Investigator).
10.Patients must have an adequate bone marrow function, including:
a. Absolute neutrophil count (ANC) 1.5 x 109/L;
b. Platelet count 100 x 109/L;
c. Hemoglobin 8g/dL.
11.Patients must have adequate liver function, including:


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a. Total bilirubin level 1.5 × upper limit of normal (ULN); 
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
2.5xULN.
12.Patients must have an adequate renal function as evidenced by a creatinine clearance 
40mL/min as calculated using the Cockcroft-Gault equation.
13.Serum or urine pregnancy test (for females of childbearing potential) must be 
negative.
14.Female patients of non-childbearing potential must meet at least 1 of the following 
criteria:
Achieved postmenopausal status,defined as follows: cessation of regular menses 
for at least 12consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the post-menopausal state;
Have undergone a documented hysterectomy and/or bilateral oophorectomy;
Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are 
considered to be of childbearing potential.
15.Evidence of a personally signed and dated informed consent document indicating that 
the patient has been informed of all pertinent aspects of the study.
16.Patients must be willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
17.Must be willing to receiveprophylactic granulocyte colony stimulating factor 
(G-CSF) in all cycles,for patients 60years old randomizedto armC(andarmDin 
Phase3,if armC is selected to advance to the Phase3 component).
4.2.Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Active central nervous system (CNS) lymphoma.
2. Prior organ transplantation including prior allogeneic SCT.
3. Prior therapy with an anti PD-1, anti PD-L1, anti PD-L2, anti CD137, or 
anti-cytotoxic Tlymphocyte associated antigen 4 (CTLA-4) antibody (including 
ipilimumab, tremelimumab or any other antibody, or drug specifically targeting T-cell 
co-stimulatory or immune checkpoint pathways).


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4. Use of any standard or experimental anti-cancer therapy within 2weeks prior to first 
dose of study treatment, including cytoreductive therapy and radiotherapy, 
immunotherapy, or cytokine therapy (except for erythropoietin).
5. Use of any non-drug anti-cancer therapy including chimeric antigen receptor (CAR) 
T-Cell (CAR-T-Cell) therapy.
6. Major surgery within 28days prior to first dose of study treatment. 
7. Diagnosis of any other malignancy 3years prior to first dose of study treatment, 
with the exception of: (i) adequately treated basal cell or squamous cell skin cancer, 
(ii) carcinoma in situ of the breast or cervix, or (iii) low-grade (Gleason 6) prostate 
cancer on surveillance without any plans for treatment intervention (eg, surgery, 
radiation, or castration).
8. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome.
9. HepatitisB virus (HBV) or hepatitisC virus (HCV) infection at screening (positive 
HBV surface antigen, positive HBV core antibody or HCV ribonucleic acid (RNA) if 
anti-HCV antibody screening test positive).
10.Active infection requiring systemic therapy.
11.Vaccination within 4 weeks prior to randomization and while on trial is prohibited 
except for administration of inactivated vaccines.
12.Peripheral neuropathy with functional impairment (for the Phase3 component only 
due to oxaliplatin).
13.Current use of immunosuppressive medication, EXCEPT for the following: 
a.)intranasal, inhaled, eye drops, topical steroids, or local steroid injection 
(eg,intra-articular injection); b.) Systemic corticosteroids at physiologic doses 
10mg/day of prednisone or equivalent; c.) Steroids as premedication for 
hypersensitivity reactions (eg, CT scan premedication).
14.Active autoimmune disease that might deteriorate when receiving an 
immuno-stimulatory agent.  Patients with diabetes typeI, vitiligo, psoriasis, or hypo-
or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
15.Known anaphylaxis or severe hypersensitivity to rituximab or other monoclonal 
antibodies, mannitol, or any of the compounds used in this study or to compounds 
with a similar chemical or biological composition.72


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16.Clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke/transient ischemic attack [TIA]/symptomatic pulmonary embolism 
(<6months prior to enrollment), myocardial infarction (<6months prior to 
enrollment), unstable angina, congestive heart failure (New York Heart Association 
Classification ClassII), orserious cardiac arrhythmia requiring medication, other 
severe acute or chronic medical (including colitis, inflammatory bowel disease, 
pneumonitis, uncontrolled asthma, or psychiatric conditions 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 investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the Investigator, would make the patient inappropriate for entry into this 
study.
17.Known alcohol or drug abuse.
18.Pregnant female patients; breastfeeding female patients; fertile male patients and 
female patients of childbearing potential who are unwilling or unable to use 2highly 
effective methods of contraception for a defined timeframe dependent on study 
treatment assignedper protocol and, where applicable, in agreement with local 
prescribing informationfor individual drugs(SeeSection 4.3.1).
19.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, including their family members, 
directly involved in the conduct of the study.
20.Participation in other studies involving investigational drugs within 4weeks prior to 
Cycle1 Day1 and/or during study participation.
21.Current use or anticipated need for treatment with drugs that are known strong 
CYP1A2 inhibitors, including their administration within 10days prior to patient 
randomization (ie,ciprofloxacin, fluvoxamine, clinafloxacin, exoxacin, oltipraz, 
propranolol, rofecoxib, thiabendole and zafirlukast).
22.Current use or anticipated need for treatment with drugs that are known CYP1A2 
inducers, including their administration within 10days prior to patient randomization 
(ie, omeprazole, phenytoin). 
4.3.Lifestyle Guidelines
4.3.1.Contraception
In this study, fertile male patients and female patients who are of childbearing potential will 
receive avelumab, which the teratogenic risk is currently unknown.  Avelumab will be 
combined with rituximab, utomilumab, azacitidine, bendamustine, gemcitabine and/or 
oxaliplatin. 


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Patients who are, in the opinion of the Investigator, sexually active and at risk for pregnancy 
with their partner(s) must agree to use 2methods of highly effective contraception 
throughout the study.  Contraception must also be continued after the last dose of study 
treatment is received as mandated by the relevant IBfor experimental study drugs or by local 
prescribing information for marketed study drugs.
Table3. Required Contraception Timeframes After Last Dose ofIndividual Study 
Drugs
Study Drug
Contraception Timeframeper Individual SRSD
IB
Avelumab
60 days
Utomilumab
90 daysa
SPC
USPI
Rituximab
12months
12 months
Azacitidine
90 days
Women of childbearing potential 
should be advised toavoid pregnancy 
during treatment
Bendamustine
Women of childbearing potentialuse 
effective methods of contraception 
both before and during treatment.
Men are advised not to father a child 
during and for up to 6 months 
following cessation oftreatment
b
90days
Gemcitabine
Women should not become pregnant
during treatment
Do not become pregnant
Oxaliplatin
Women should not become pregnant 
during treatment
Women of childbearing potential 
should be advised to avoid 
becoming pregnant while receiving 
treatment
a. In France, the required timeframe for contraception followingutomilumabtreatmentis 120days.
b. In France, the required timeframe for contraception followingbendamustine treatment is 180days.
SPC= Summary of Product Characteristics;USPI= United States Package Insert
The Investigator or his or her designee, in consultation with the patient, will confirm that the 
subject has selected 2appropriate methods of contraception for the individual patient [and 
his/her partner(s)] from the list of permitted contraception methods (see below) and will 
confirm that the patient has been instructed in their consistent and correct use.  At time points 
indicated in the Schedule of Activities, the investigator or designee will inform the patient of 
the need to use 2highly effective methods of contraception consistently and correctly and 
document the conversation, and the patient’s affirmation, in the patient’s chart.  In addition, 
the Investigator or designee will instruct the patient to call immediately if 1 or both of the 
selected contraception methods is discontinued or if pregnancy is known or suspected in the 
patient or partner. 


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Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or 
male subject’s female partner plans to remain on the same treatment throughout the 
entire study and has been using that hormonal contraceptive for an adequate period of 
time to ensure effectiveness. 
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a separate spermicidal product 
(ie,foam, gel, film, cream, or suppository).  For countries where spermicide is not 
available or condom plus spermicide is not accepted as highly effective contraception, 
this option is not appropriate.  Note: The German Regulatory Authority 
(Paul-Ehrlich-Institut) does not recognize condoms asa highly effective 
contraception method even if used in conjunction with spermicide.
4. Male sterilization with absence of sperm in the post vasectomy ejaculate.
5. Bilateral tubal ligation or bilateral salpingectomy or bilateral tubal occlusive 
procedure (provided that occlusion has been confirmed in accordance with the 
device’s label).
4.4.Sponsor’s Qualified Medical Personnel
To facilitate access to appropriately qualified medical personnel regarding on study-related 
medical questions or problems, patients are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product 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 the 
Investigator 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 Investigator 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 Investigator site.


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5.STUDY TREATMENTS 
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator 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 approveduse (ICH E61.33).  
All supplies will be provided centrally by the Sponsor or locally by the trial site, subsidiary 
or designee, depending on local country operational or regulatory requirements.
5.1.Allocation to Treatment
The Investigator’s knowledge of thetreatment should not influence the decision to enroll a 
particular patient or affect the order in which patients are enrolled.
Once the patient has provided a signed Informed Consent Form (ICF) and has met inclusion 
and exclusion criteria, the Investigator or delegate will request the study treatment 
assignment using the Interactive Response Technology (IRT) system (interactive web-based 
response [IWR]/interactive voice response [IVR] system).  Study treatment must start within 
7days after patient randomization.
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number.  The site personnel will then be provided with a treatment assignment and 
dispensable unit (DU) or container number when drug is being supplied via the IRT system.  
The IRT system will provide a confirmation report containing the patient number and DU or 
container number assigned.  The confirmation report must be stored in the site’s files.
There is a 24-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 IRTsystem.
Note: The IRT is the source of the patient number.  The IRT system will provide the patient 
number at the end of the first IRT patient transaction.
Qualified patients in the Phase1b component of the study will be randomized (1:1:1) to 
receive either avelumab in combination with (i) rituximab (CD20 antagonist)/utomilumab 
(4-1BB agonist) in Treatment ArmA, or (ii) azacitidine (DNMTi)/ utomilumab (4-1BB 
agonist) in Treatment ArmB, or (iii) rituximab (CD20 antagonist)/bendamustine 
(chemotherapy) in Treatment ArmC. 
Qualified patients in the Phase3 component of the study will be randomized (1:1) to the 
selected regimen from Phase1b or Investigator’s Choice chemotherapy comprised of either 
rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin.
In Phase1b, randomization will not be stratified.


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In Phase3, randomization will be stratified according to: (i) International Prognostic Score 
(IPI) 2(low/low intermediate risk) or 3(high intermediate/high risk) and (ii) Relapsed 
vs.Refractory status.  The stratification will be centrally allocated across all centers via the 
IRT system.  At the time of randomization, Investigators will be asked to provide the 
Investigator’s Choice chemotherapy if a patient is randomized to ArmE (a prioriselection of 
rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin).
In Phase3, the selection of the best control treatment for each patient must be decided by the 
Investigator and documented prior to randomization.
5.2.Patient Treatment Compliance
The site will complete the required dosage Preparation Record located in the Investigational 
Product Manual.  The use of the Preparation Record is preferred, but does not preclude the 
use of an existing appropriate clinical site documentation system.  The existing clinical site
's 
documentation system should capture all pertinent/required information on the preparation 
and administration of the dose.  This may be used in place of the Preparation Record 
following approval from the Pfizer designated study monitor.
5.3.Investigational Product Supplies
All supplies will be provided centrally by the Sponsor or locally by the trial site, subsidiary 
or designee, depending on local country operational or regulatory requirements.
5.3.1.Dosage Form(s) and Packaging
5.3.1.1.Avelumab
Avelumab is a sterile, clear, and colorless solution intended for IV administration.  Avelumab 
is formulated as a 20mg/mL solution and will be supplied by the Sponsor in single-use glass 
vials, stoppered with a rubber septum and sealed with an aluminum polypropylene flip-off 
seal.
Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines.  Avelumab will be packed in 
cartons each containing one vial.  The information on the labels will be in accordance with 
approved submission documents. 
Avelumab will be shipped in transport cool containers (2C to 8C) that are monitored with 
temperature monitoring devices.
5.3.1.2.Utomilumab
Utomilumab is a sterile, colorless solution intended for IV administration.  For Phase1b, 
utomilumab will be presented at a concentration of 10mg/mL in single-use glass vials closed 
with a rubber stopper and sealed with an aluminum overseal.  For Phase3, utomilumab will 
be presented at a concentration of 25mg/mL in single-use glass vials closed with a rubber 
stopped and sealed with an aluminum overseal.


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Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines.  Utomilumab will be packed 
in cartons each containing one vial.  The information on the labels will be in accordance with 
approved submission documents. 
Utomilumab will be shipped in transport cool containers (2C to 8C) that are monitored 
with temperature monitoring devices.
5.3.1.3.Rituximab
Rituximab is commercially available in multiple presentations.  All supplies will be provided 
centrally by the Sponsor or locally by the trial site, subsidiary or designee, depending on 
local country operational or regulatory requirements.  Detailed information regarding 
rituximab formulation can be found in the Package Insert (PI) or Summary of Product 
Characteristics (SPC).
5.3.1.4.Azacitidine
Azacitadine is commercially available in multiple presentations.  All supplies will be 
provided centrally by the Sponsor or locally by the trial site, subsidiary or designee, 
depending on local country operational or regulatory requirements.  Detailed information 
regarding azacitidine formulation can be found in the PI or SPC.
5.3.1.5.Bendamustine
Bendamustine is commercially available in multiple presentations.  All supplies will be 
provided centrally by the Sponsor or locally by the trial site, subsidiary or designee, 
depending on local country operational or regulatory requirements.  Detailed information 
regarding bendamustine formulation can be found in the PI or SPC.
5.3.1.6.Gemcitabine
Gemcitabine is commercially available in multiple presentations.  All supplies will be 
provided centrally by the Sponsor or locally by the trial site, subsidiary or designee, 
depending on local country operational or regulatory requirements.  Detailed information 
regarding gemcitabine formulation can be found in the PI or SPC.
5.3.1.7.Oxaliplatin
Oxaliplatin is commercially available in multiple presentations.  All supplies will be 
provided centrally by the Sponsor or locally by the trial site, subsidiary or designee, 
depending on local country operational or regulatory requirements.  Detailed information 
regarding oxaliplatin formulation can be found in the PI or SPC.


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5.3.2.Preparation and Dispensing
5.3.2.1.Avelumab Preparation
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard cleanup procedures for biologic products.
For administration in this trial, avelumab must be diluted with 0.9% sodium chloride (normal 
saline solution).  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 (IP Manual).  Tubing with in line, low protein binding 
0.2micron filter made of polyether sulfone (PES) must be used during administration of 
avelumab.
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kgs).  All patients should be weighed within 3days prior to 
dosing for every cycle to ensure they did not experience either a weight loss or gain 
>10%from the weight used for the last dose calculation.  For weight change less than 
10%the decision to recalculate the avelumab dose can be in accordance with institutional 
practice.  If the patient experienced either a weight loss or gain >10% compared to the weight 
used for the last dose calculation, the amount of study drug must be recalculated.
Avelumab must not be used for any purpose other than for the trial.  The administration of 
trial drug to patients who have not been enrolled into the trial is prohibited.  Vials are for 
single use only.  Any unused portion of the solution must be discarded in a biohazard waste 
disposal container with final disposal according to accepted local and national standards of 
incineration.
5.3.2.2.Utomilumab Preparation
Preparation instructions for utomilumab are identical to those for avelumab (Section5.3.2.1).  
Specific preparation and dispensing instructions are provided in the IP Manual.
5.3.2.3.Rituximab Preparation
Refer to specific preparation and dispensing instructions provided in the IP Manual.
5.3.2.4.Azacitidine Preparation
Refer to specific preparation and dispensing instructions provided in the IP Manual.
5.3.2.5.Bendamustine Preparation
Refer to specific preparation and dispensing instructions provided in theIP Manual.
5.3.2.6.Gemcitabine Preparation
Refer to specific preparation and dispensing instructions provided in the IP Manual.


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5.3.2.7.Oxaliplatin Preparation
Refer to specific preparation and dispensing instructions provided in the IP Manual.
5.4.Administration
Administration of investigational products should be performed by an appropriately 
qualified, Good Clinical Practice (GCP) trained, and experienced member of the study staff 
(eg,physician, nurse, physician’s assistant, practitioner, pharmacist, or medical assistant)as 
allowed by local, state, and institutional guidance.  All trial treatments will be administered at 
the Investigational site.
A Complete Blood Count (CBC) and Chemistry panel(core chemistry required as noted by 
“*” in Table19)are to be reviewed and signed off by medically qualified study personnel 
prior to dosing at each visit.  This safety precaution is to ensure that protocol toxicity
 
thresholds are not exceeded prior to treatment commencement at each dosing visit.
Investigational product administration details will be recorded on the CRF.
5.4.1.Avelumab
All study treatments will be administered at the investigational site on an outpatient basis as 
described in the IP Manual.
Avelumab will be administered as a 1hour IV infusion, -10/+20minutes (50-80minutes),
once every 2weeks of each 28-day cycle.  In order to mitigate infusion related reactions, a 
premedication with an antihistamine and with paracetamol (acetaminophen) approximately 
30 to 60minutes prior to each dose of avelumab is mandatory (for example, 25-50mg 
diphenhydramine and 500-650mg paracetamol [acetaminophen] IV or oral equivalent).  This 
may be modified based on local treatment standards and guidelines, as appropriate. 
Premedication prior to rituximab is mandatory; if the avelumab is administered more than 
1hour after the rituximab infusion then the premedication must be repeated.  The line should 
be flushed, according to local practice, between infusions, and a new administration set 
should be used for avelumab.
Site staff should make every effort to target the timing of avelumab infusion to be as close to 
1hour as possible.  However, given the variability of infusion pumps from site to site, time 
windows of minus 10minutes and plus 20minutes is permitted (ie, infusion time is 
50-80minutes).  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 5.6.6.
5.4.2.Utomilumab
Utomilumab is administered in this study as a 1hour IV infusion, -10/+20minutes 
(50-80minutes),at 100mg fixed dose of each 28-day cycle and must have completed 
administration at least 1hour before avelumab administration until the patient is no longer 
achieving clinical benefit.  If Cycle1 and Cycle2 dosing administration was well tolerated, 


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Cycle3 and subsequent cycles may decrease administration of utomilumab and avelumab 
from at least 1hour apart to 30-60minutes apart.  Utomilumab is administered for as long as 
the patient is continuing to achieve clinical benefit.
5.4.3.Rituximab
Rituximab is administered in this study at the dose of 375mg/m2up to 8cycles maximum as
an IV infusion in the morning of each 28day cycle on Day1.  Rituximab infusion must have 
completed at least 1hour prior to utomilumab and bendamustine.
Rituximab should not be administered as an IV push or bolus.  Premedication with 
acetaminophen and an antihistamine should be administered 30minutes before each 
IVinfusion. 
Premedication prior to rituximab is mandatory; if the avelumab is administered more than 
1hour after the rituximab then the premedication must be repeated.  The line should be 
flushed, according to local practice, between infusions, and a new administration set should 
be used for avelumab.
The first infusion should be initiated at a rate of 50mg/hr.  In the absence of infusion 
toxicity, the rate of infusion may be increased by 50mg/hr increments every 30minutes, to a 
maximum of 400mg/hr.
Subsequent infusions should be initiated at a rate of 100mg/hr.  In the absence of infusion 
toxicity, the rate of infusion may be increased by 100mg/hr increments at 30minute 
intervals, to a maximum of 400mg/hr.
The infusion should be interrupted or slowed for infusion reactions.  Upon improvement of 
symptoms, continue the infusion at one-half the previous rate.  Medical management should 
be instituted (glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions 
as needed.  Depending on the severity of the infusion reaction and the required interventions, 
temporarily or permanently discontinue rituximab.
In the event that dosing with rituximab in Cycle1 is interrupted andthe full dose of 
rituximab cannot be administered within 24hours, repeat dosing for a maximum of one 
repeated rituximab infusion may in some instances be acceptable following discussion with 
the Sponsor stating that in the opinion of the Investigator thepatient is suitable for 
re-treatment.  This will only be allowed if the patient received less than half of the planned 
rituximab doses, and if the reason for dose interruption does not include a Grade3 toxicity 
attributed to rituximab.  Any patient requiring two dose interruptions, each of which prevent 
administration of the full rituximab dose within 24hours will be withdrawn from the study.
5.4.4.Azacitidine
Azacitidine is administered at a dose of 40mg/m2until the patient is no longer receiving 
clinical benefit as a SC injectionat the site(not IV infusion), on Day1 to Day5 in the 
morning of each 28-day cycle.  Intra-patient dose escalation is not permitted.  Azacitidine 
must have completed administration at least 1hour prior to utomilumab. 


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Patients should be premedicated for nausea and vomiting (as per local practice).  The site 
should be rotated for each injection (thigh, abdomen, or upper arm).  New injections should 
be administered at least one inch from an old site, and never to areas where the site is tender, 
bruised, red, or hard.
5.4.5.Bendamustine
Bendamustine is administered in the Phase1b (Treatment ArmC) and in the Phase3 
investigational arm (in the event that Treatment ArmC advances to the Phase3 part of the 
study) at 90mg/m2IVinfusion up to 6cycles maximum.  Intra-patient dose escalation is not 
permitted. 
Note that in the Phase3 Investigator’s Choice option (ArmE), bendamustine is administered 
at a higher dose of 120mg/m2on Days1 and 2 of each 28-day cycle, for up to 6cycles. 
Measures to prevent infusion reactions and anaphylaxis including antihistamines, 
antipyretics, and corticosteroids should be considered in subsequent cycles in patients who 
have previously experienced Grade1 or Grade2 infusion reactions.  Bendamustine is infused 
intravenously over 60minutes.  Patients with myelosuppression following treatment with 
bendamustine are more susceptible to infections.  Opportunistic infection prophylaxis is 
consequently recommended per local guidelines.Prophylactic use of G-CSF in all cycles for 
patients 60years old randomized to armC is mandatory (and armD in Phase3, if armC is 
selected to advance to the Phase3 component).
5.4.6.Gemcitabine
Gemcitabine is administered at 1000mg/m2IV infusion up to 6cycles maximum on Day2 
and Day17 of each 28day cycle as part of the Investigator’s Choice option (ArmE) in 
Phase3.
Gemcitabine must be administered at a fixed dose rate of 16.7mg/m2/minute over 
60minutes.  This prolonged administration schedule has been shown to achieve superior 
intracellular drug concentration as compared with the 30minute IV schedule.29
5.4.7.Oxaliplatin
Oxaliplatin is administered at 100mg/m2IV infusion up to 6cycles maximum on Day2 and 
Day17 of each 28-day cycle as part of the Investigator’s Choice option (ArmE) in Phase3.
Gastro-intestinal toxicity related to oxaliplatin may manifest as nausea and vomiting, and 
may be managed with prophylactic and/or therapeutic anti-emetic therapy.  Oxaliplatin is 
administered over 2hours on Day2 following gemcitabine.
5.4.8.Treatment Following Evidence of Radiological Disease Progression
If a patient with documented PD continues to experience clinical benefit, per Investigator’s 
clinical judgment and following discussion between the Investigator and the Sponsor, the 
patient may be eligible for continued treatment with avelumab and/or utomilumab.  The 
Investigator’s judgment should be based on the overall benefit-risk assessment and on the 


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patient’s clinical condition, including: performance status, clinical symptoms, adverse events, 
and laboratory data.  Other agents in the regimen combination with avelumab and/or 
utomilumab may also be considered for continuation if in the Investigator’s clinical judgment 
the patient may achieve clinical benefit.  See Section 5.4for treatment duration limits for 
agents other than avelumab and utomilumab.
The criteria that must be met are as follows: (i) No decline inECOG performance status, 
(ii)Absence of rapid progression of disease by radiographic imaging, (iii) Absence of 
progressive tumor at critical anatomical sites (eg, cord compression) requiring urgent 
alternative medical intervention, and (iv) Absence of clinical signs and symptoms (including 
worsening of laboratory values) of disease progression. 
Before continuation of treatment, the patient must be re-consented and informed that by 
continuing receiving the investigational products on study, they may be foregoing treatment 
with approved therapies with possible clinical benefits.
5.4.9.Food Requirements
All investigational products may be administered without regard for food.
5.5.Recommended Dose Modifications
Every effort should be made to administer investigational products using the planned dose 
and schedule. 
Dose modifications may occur in one of three ways during study conduct:
Within a cycle, dosing may be interrupted until adequate recovery from toxicities; 
Next cycle administration may be delayed due to persisting toxicity when a new cycle 
is due to commence;
Dose reduction may be required in a subsequent cycle based on toxicity experienced 
in the previous cycle. 
Patients whose treatment is delayed due to adverse events should be evaluated at intervals of 
oneweek or less until adequate recovery has been documented.  Dose reductions are only 
allowed for bendamustine and oxaliplatin.  No dose reductions are allowed for avelumab, 
utomilumab, rituximab, or gemcitabine.  Intra-patient dose escalation is not allowed for any 
of the study drugs at any time. 
Any suspected immune-related adverse event should be managed according to the 
Management of Immune Related Adverse Events (irAEs) guidance (see Table5).
In Treatment ArmsA and B, the same irAEs management guidelines will apply to both 
avelumab and utomilumab.  In addition, in the event of an irAE, dosing with rituximab 
(ArmsA and C), azacitidine (ArmB), and/or bendamustine (ArmC) should continue per 


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protocol, but may be interrupted for the same duration as avelumab or utomilumab, or for 
longer at the discretion of the Investigator, following prior discussion with the Sponsor.
In the event that it is necessary to permanently discontinue treatment with avelumab, all other
study drugs must also be discontinued.  In the event that it becomes necessary to stop dosing 
with one or more of the other drugs in the combination, avelumab dosing may continue per 
protocol.
In the event of significant toxicity; dosing may be delayed and/or reduced as outlined below.  
In the event of multiple toxicities, dose modifications should be based on the worst observed 
toxicity.  Patients must be instructed to notify Investigators at the first occurrence of any 
adverse symptom/s.
Additional Recommended Treatment Modifications relevant to each of the three treatment 
arms in the Phase1b component of the study may also be found in Section 5.5.3, and for the 
Investigator’sChoice options in the control treatment arm of the randomized Phase 3 
component are inSection 5.6.2. 
All treatment modification recommendations must be followed unless previously discussed 
with and agreed by the Sponsor.  All dose modifications/adjustments must be clearly 
documented in the patient
's notes and in the CRF.
5.5.1.Special Precautions for Avelumab Administration
As with all monoclonal antibody therapies, there is a risk of allergic reaction including 
anaphylactic shock.
In order to mitigate the risk of avelumab related infusion-related reactions, a pre-medication 
regimen comprising 25 to 50mg IV (or oral equivalent) diphenhydramine, and 650mg IV 
(or oral equivalent) acetaminophen/paracetamol (per local practice) is mandatory, and should 
be administered approximately 30 to 60minutes prior to each dose of avelumab.  This may 
be modified, as appropriate, according to local treatment practice and guidelines.
Premedication prior to rituximab is mandatory; if the avelumab is administered more than 
1hour after the rituximab infusion then the premedication must be repeated.  The line should 
be flushed, according to local practice, between infusions, and a new administration set
should be used for avelumab.
Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment and administration of therapy for anaphylaxis, 
such as the ability to implement immediate resuscitation measures.  Steroids (dexamethasone 
10mg), epinephrine (1:1,000dilution), allergy medications (IV antihistamines), 
bronchodilators or equivalents and oxygen should be available for immediate access.  
Infusion of avelumab will be stopped in case ofGrade2 infusion-related, allergic, or 
anaphylactic reactions.  Following avelumab infusion, patients must be observed for 2hours 
for potential infusion-related reactions.  If an allergic reaction occurs, the patient should be 


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treated according to the best available medical practice.  Patients should be instructed to 
report any delayed reactions to the Investigator immediately. 
Investigators should additionally monitor patients closely for potential irAEs, which may
become manifest at any time after thefirst dose of treatmentof treatment.  Immune-related 
adverse events described with this class of drugs include pneumonitis, colitis, hepatitis, 
endocrinopathies including thyroid disorders (hyperthyroidism, hypothyroidism, thyroiditis), 
adrenal insufficiency, hypophysitis, and diabetes mellitus, renal dysfunction, encephalitis, 
eye disorders (uveitis, iritis), myositis and myocarditis.  However, potential irAEs can occur 
in any organ or tissue.Treatment recommendations for the management of irAEs are 
outlined in Section 5.5.2andTable5.
5.5.2.Management of Avelumab Infusion-Related Reactions
Symptoms may include one or more of the following: fever, chills, rigors, diaphoresis, and 
headache. 
Once the avelumab infusion rate has been decreased by 50% due to an infusion-related 
reaction, the same decreased infusion rate must be used for all subsequent infusions. 
Table4.
Avelumab Treatment Modifications for Symptoms of Infusion Related 
Reactions
NCI-CTCAE Grade 
Treatment Modifications
Grade 1 -Mild
Mild and transient reaction;infusion interruption not 
indicated;interventionsnot indicated.

Decrease avelumab infusion rate by 50% and 
monitor closely for any worsening.
Grade 2 -Moderate
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (for example, 
antihistamines, NSAIDs, narcotics,IVfluids); 
prophylactic medications indicated for 24 hours.

Temporarily discontinue avelumab infusion.

Resume infusion at 50% of the previous rate 
once the infusion-related reaction has resolved 
or decreased to at least Grade1 in severity, and 
monitor closely for any worsening.
Grade 3 or Grade 4 -Severe or Life-threatening
(a) Grade 3: Prolonged (for example, not rapidly 
responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms 
following initial improvement; hospitalization indicated 
for clinical sequelae.
(b) Grade 4:Life-threatening consequences;urgent 
intervention indicated.

Stop the avelumab infusion immediately and 
disconnect infusion tubing from the subject.  

Subject have to bewithdrawn immediately from 
avelumab treatment, and must not receive any 
further avelumab treatment.
IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse 
Events, NSAIDs=nonsteroidal anti-inflammatory drugs.
In the event of a Grade2 infusion-related reaction that does not improve or that worsens 
following implementation of the modifications indicated in Table4(including reducing the 
infusion rate by 50%), the Investigator may consider treatment with corticosteroids, and the 
infusion should not be resumed.  At the next dose, the Investigator may consider the addition 


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of H2-blocker antihistamines (eg, famotidine or ranitidine), meperidine, or ibuprofento the 
mandatory premedication.  Prophylactic steroids are NOT permitted. 
5.5.2.1.Tumor Lysis Syndrome
Since avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), there is 
a potential risk of syndrome, especially when used in combination with other 
ADCC-inducing agents.  In the event that this occurs, patients should be treated per local 
guidelines, and the management algorithm (see Figure4) published by Howard et al. should 
be followed.


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Figure4. Assessment and Initial Management of Tumor Lysis Syndrome


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5.5.2.2.Immune-Related Adverse Events
NOTE:for Treatment ArmsA and B, the same immune-related adverse events (irAEs)
management guidelines apply to both avelumab and utomilumab.
As inhibition of PD-L1 by avelumab stimulates the immune system, irAEs may occur.  
Treatment of irAEs is dependent upon their severity (NCI-CTCAE grade):
Grade1 to 2: treat symptomatically or with moderate dose steroids, and more 
frequent monitoring;
Grade1 to 2 (persistent): manage as per high-grade (ie, Grade3 to 4) AEs;
Grade3 to 4: treat with high-dose corticosteroids.
Any event suspected to be immune-related should be managed according to the guidance for 
management of immune-related adverse events in this section and in Table5.
In the event of an irAE, the dose of avelumab shouldbe modified in accordance withTable5
(see below).
Immune-related adverse events described with this class of drugs include:  pneumonitis, 
colitis, hepatitis, endocrinopathies including thyroid disorders (hyperthyroidism, 
hypothyroidism, thyroiditis), adrenal insufficiency, hypophysitis, and diabetes mellitus or 
hyperglycemia, rash, nephritis and renal dysfunction, encephalitis, eye disorders (including 
uveitis, iritis), and other immune-mediated reactions including myositis and myocarditis.
Any adverse event which may have an underlying immune-mediated mechanism including 
those described above, and without other confirmed etiologies, should be considered 
immune-related and managed according to guidelines describedin this section.


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Table5. Management of Immune Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4.03)
Initial Management
Follow-upManagement
Grade 1
Diarrhea: <4 stools/day over Baseline
Colitis: Asymptomatic 
Continue avelumab therapy.
Symptomatic treatment (eg,loperamide)
Close monitoring for worsening 
symptoms.
Educate subject to report worsening 
immediately
If worsens:
Treat as per Grade2,3, or4
Grade 2
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated 
<24hours; not interfering with ADL
Colitis:Abdominal pain; blood in 
stool 
Withhold avelumab therapy.
Symptomatic treatment
If improves to Grade1: 
Resume avelumab therapy.
If persists >5 to 7 days or recurs:
Treat as per Grade3 to 4.
Grade 3 to 4
Diarrhea (Grade3): 7 stools per day 
over Baseline; incontinence; IV 
fluids 24hrs; interfering with ADL
Colitis (Grade3): Severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade4: life-threatening, perforation
Withhold avelumab for Grade 3.
Permanently discontinue avelumab for 
Grade 4 or recurrent Grade 3.
1.0 to 2.0mg/kg/day 
methlyprednisolone IV or equivalent.
Add prophylactic antibiotics for 
opportunistic infections 
Consider lower endoscopy. 
If improves: 
Continue steroids until Grade1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids 
taper (for initial Grade 3).
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5mg/kg (if no 
contraindication).
Note: Infliximab should not be used in 
cases of perforation or sepsis.
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4.03)
Initial Management
Follow-upManagement
Grade 1 to 2 
Covering 30% body surface area 
Continue avelumab therapy.
Symptomatic therapy (for example, 
antihistamines, topical steroids). 
If persists >1 to 2 weeks or recurs: 
Withold avelumab therapy
Consider skin biopsy 
Consider 0.5 to 1.0mg/kg/day 
prednisone orequivalent.  Once 
improving, taper steroids over at least 
1month, consider prophylactic 
antibiotics for opportunistic infections, 
and resume avelumab therapy
If worsens: 
Treat as Grade3 to 4. 


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Grade 3 to 4
Grade 3: Covering >30% body 
surface area; 
Grade 4: Life threatening 
consequences
Withhold avelumab for Grade 3.
Permanently discontinue forGrade 4 or 
recurrent Grade 3.
Consider skin biopsy
Dermatology consult
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibioticsfor 
opportunistic infections.
If improves to Grade≤1: 
Taper steroids over at least 1 month; 
resumeavelumab therapy following 
steroids taper (forinitial Grade 3).
Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4.03)
Initial Management
Follow-upManagement
Grade 1
Radiographic changes only 
Consider withholdingavelumab therapy 
Monitor for symptoms every 2 to 3 days 
Consider Pulmonary and Infectious 
Disease consults 
Re-assess at least every 3 weeks
If worsens: 
Treat as per Grade2 or Grade3 to 4. 
Grade 2
Mild to moderate new symptoms 
Withhold avelumab therapy
Pulmonary and Infectious Disease 
consults
Monitor symptoms daily, consider 
hospitalization. 
1.0-2.0 mg/kg/day prednisone or
equivalent. 
Add prophylactic antibioticsfor 
opportunistic infections.
Consider bronchoscopy, and lung 
biopsy. 
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade≤1, 
taper steroids over at least 1 month and 
then resume avelumab therapy 
following steroids taper
If not improving after 2 weeks or 
worsening: 
Treat as per Grade3 to 4. 
Grade 3 to 4
Grade 3: Severe new symptoms; New 
/ worsening hypoxia; 
Grade 4: Life-threatening 
Permanently discontinue avelumab 
therapy
Hospitalize. 
Pulmonary and Infectious Disease 
consults.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent. 
Add prophylactic antibiotics for 
opportunistic infections 
Consider bronchoscopy, and lung 
biopsy. 
If improves to Grade≤1: 
Taper steroids over at least 1 month. 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression 
(for example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or mycophenolate 
mofetil). 
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4.03)
Initial Management
Follow-upManagement
Grade 1
Grade 1 AST or ALT > ULN to 3.0 x 
ULN and / or total bilirubin > ULN 
to 1.5 x ULN 
Continue avelumab therapy.
Continue liver function monitoring 
If worsens: 
Treat as Grade2 or 3 to 4 
Grade 2
AST or ALT >3.0 to 5 x ULN and / 
or total bilirubin >1.5 to 3 x ULN 
Withhold avelumab therapy
Increase frequency of monitoring to 
every 3 days. 
If returns to Grade1: 
Resume routine monitoring, resume 
avelumab therapy.
If elevations persist >5 to 7 days or 
worsens: Treat as Grade 3 to 4.


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Grade 3 to 4
AST or ALT >5 x ULN and / or total 
bilirubin >3 x ULN 
Permanently discontinue avelumab 
therapy 
Increase frequency of monitoring to 
every 1 to 2days 
1.0 to 2.0 mg/kg/day of prednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections 
Consult gastroenterologist
Consider obtaining MRI/CT scan of 
liver and liver biopsy if clinically 
indicated.
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 
1.5xULN
Continue avelumab therapy
Continue renal function monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased >1.5 and 
6xULN
Withhold avelumab therapy
Increase frequency of monitoring to
every 3 days
1.0 to 2.0 mg/kg/day prednisone or
equivalent.
Add prophylactic antibiotics for
opportunistic infections
Consider renal biopsy
If returns to Grade 1:
Taper steroids over at least 1 month,and 
resume avelumab therapyfollowing 
steroids taper.
If worsens:
Treat as Grade 4.
Grade 3 to 4
AST or ALT >5 x ULN and/or total
bilirubin >3 x ULN
Permanently discontinueavelumab 
therapy
Increase frequency ofmonitoring to 
every 1 to2 days
1.0 to 2.0 mg/kg/dayprednisone or 
equivalent
Add prophylactic antibioticsfor 
opportunistic infections
Consult gastroenterologist/hepatologist
Consider obtaining MRI/CTscan of liver 
and liver biopsyif clinically warranted
If returns to Grade 1:
Taper steroids over at least 1 month
If does not improve in >3 to 5 days, 
worsensor rebounds:
Add mycophenolate mofetil 1 gram (g) 
twicedaily
If no response within an additional 3 to 5
days, consider other 
immunosuppressants
per local guidelines.


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Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 endocrinopathies 
(hypothyroidism, hyperthyroidism, 
adrenal insufficiency, type I 
diabetesmellitus)
Continue avelumab therapy. 
Endocrinology consult if needed
Start thyroid hormone replacement
therapy (for hypothyroidism),anti-
thyroid treatment (for
hyperthyroidism), corticosteroids (for
adrenalinsufficiency) or insulin (for
Type I diabetes mellitus) as
appropriate.
Rule-out secondary endocrinopathies
(ie,hypopituitarism / hypophysitis)
Continue hormone
replacement/suppression andmonitoring 
of endocrine function asappropriate.
Grade 3 or Grade 4 
endocrinopathies (hypothyroidism,
hyperthyroidism, adrenal 
insufficiency, type I diabetes
mellitus)
Withhold avelumab therapy
Consider hospitalization
Endocrinology consult
Start thyroid hormone replacement
therapy (for hypothyroidism),anti-
thyroid treatment (for
hyperthyroidism), corticosteroids (for
adrenal insufficiency) or insulin (for
type I diabetes mellitus) asappropriate.
Rule-out secondary endocrinopathies
(ie,hypopituitarism / hypophysitis)
Resume avelumab once symptoms
and/or laboratory tests improve to
Grade 1 (with or without hormone
replacement/suppression).
Continue hormone
replacement/suppression and
monitoring of endocrine function as
appropriate.


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Hypopituitarism/Hypophysitis
(secondary endocrinopathies)
If secondary thyroid and/or adrenal
insufficiency is confirmed 
(ie,subnormal serum FT4 with
inappropriately low TSH and/or low
serum cortisol with inappropriately low
ACTH):

Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in
women)

Hormone 
replacement/suppressive therapy
as appropriate

Perform pituitary MRI and visual
field examination as indicated
If hypophysitis confirmed:

Continue avelumab if mild 
symptoms with normal MRI.
Repeat the MRI in 1 month

Withhold avelumab if moderate, 
severe 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 atleast 1 month.

Add prophylactic antibiotics for
opportunisticinfections.
Resume avelumab once symptomsand 
hormone tests improve toGrade 1 (with 
or without hormonereplacement).
In addition, for hypophysitis with
abnormal MRI, resume avelumabonly 
once shrinkage of the pituitarygland on 
MRI/CT scan isdocumented.
Continue hormone
replacement/suppression therapyas 
appropriate.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and/or new laboratory 
cardiac biomarker elevations 
(eg,BNP, troponin, CK-MB) or 
cardiac imaging abnormalities 
suggestive of myocarditis.
Withhold avelumab therapy.
Hospitalize.  
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management. 
   
Cardiologyconsult to establish etiology 
and rule-out immune-mediated 
myocarditis.
If symptoms improve and 
immune-mediated etiology is ruled out, 
re-start avelumab therapy.
If symptoms do not improve/worsen, 
viral myocarditis is excluded, and 
immune-mediated etiology is suspected 
or confirmed following cardiology 
consult, manage as immune-mediated 
myocarditis.


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Guideline based supportive treatment as 
appropriate per cardiology consult.*
Consider myocardial biopsy if 
recommended per cardiology consult.
Immune-mediated myocarditis
Permanently discontinue avelumab.
Guideline based supportive treatment as 
appropriate per cardiology consult.*
1.0 to 2.0 mg/kg/dayprednisone or 
equivalent
Add prophylactic antibiotics for 
opportunistic infections.
Once improving, taper steroids over at 
least 1 month.
If no improvement or worsening, 
consider additional immunosuppressions 
(eg, azathioprine, cyclosporine A).
*Local guidelines, or eg,ESC guidelines (https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines) 
orAHA guidelines 
(http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001)
Other irAEs (not described above)
Other irAEs (not described above) 
(NCI-CTCAE v4.03)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signsor 
symptoms suggestive of apotential 
irAE
Withhold avelumab therapy pending
clinical investigation
If irAE is ruled out, manage as
appropriate according to thediagnosis 
and consider re-startingavelumab 
therapy
If irAE is confirmed, treat as 
Grade2 or 3 irAE.
Grade 2 irAE or first occurrenceof 
Grade 3 irAE
Withhold avelumab therapy
1.0 to 2.0 mg/kg/day prednisone or
equivalent
Add prophylactic antibiotics for
opportunistic infections
Specialty consult as appropriate
If improves to Grade 1:
Taper steroids over at least 1 month
and resume avelumab therapyfollowing 
steroids taper.
Recurrence of same Grade 3irAEs
Permanently discontinue avelumab
therapy
1.0 to 2.0 mg/kg/dayprednisone or 
equivalent
Add prophylactic antibiotics for
opportunistic infections
Specialty consult as appropriate
If improves to Grade 1:
Taper steroids over at least 1month.
Grade 4
Permanently discontinue avelumab
therapy
1.0 to 2.0 mg/kg/day
prednisone or equivalent and/or other
immunosuppressant as needed
Add prophylactic antibiotics for
opportunistic infections
Specialtyconsult.
If improves to Grade 1:
Taper steroids over at least 1 month


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Requirement for 10 mg per dayor 
greater prednisone orequivalent for 
more than 12weeks for reasons other 
thanhormonal replacement foradrenal 
insufficiency
Persistent Grade 2 or 3 irAE
lasting 12 weeks or longer
Permanently discontinue avelumab
therapy
Specialty consult
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine aminotransferase;
AST=aspartate aminotransferase;BNP=B-type natriuretic peptide; CK-MB=creatine kinase MB; CT= computed
tomography; FSH=follicle-stimulating hormone; GH=growth hormone; IGF-1=insulin-like growth factor 1;
irAE=immune-related adverse event; IV=intravenous; LH=luteinizing hormone; MRI=magnetic resonance imaging;
NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for Adverse Events;
PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal.
5.5.3.Recommended Treatment Modifications for Phase 1b Treatment Arm A
Dose modifications for drug-related toxicities related to avelumab, utomilumab, and 
rituximab are detailed in Table6and Table7.  If atoxicity can be attributed just to one of the 
drugs in the combination, dose modifications can be implemented independently for each 
drug.  In instances where it is not possible to attribute the toxicity to only one of the three 
drugs, the avelumab treatment modifications detailed in Table6and Table7should be 
followed for all 3drugs.
5.5.3.1.Treatment Delays
A new treatment cannot start unless the ANC is 1.0 x109/L, the platelet count is 75x109/L, 
and non -hematologic toxicities have returned to baseline or Grade1 severity.
A new treatment may be delayed for a maximum duration of 4weeks to allow for ANC and 
platelet count recovery.  In the event that recovery does not occur within 4weeks, all study 
drugs must be permanently discontinued.  The 4weeks recovery window commences on the 
day of the planned treatment.
If avelumab treatment is delayed due to toxicities attributable to avelumab and/or 
utomilumab (eg, pneumonitis or hypothyroidism), rituximab administration does not need to 
be delayed.  If the start of rituximab administration is delayed dueto toxicities attributable to 
rituximab, administration of utomilumab and avelumab does not need to be delayed delayed. 
5.5.3.2.Dose Reductions for Avelumab, Utomilumab, and Rituximab
No dose reductionsare permitted for avelumab, utomilumab, or rituximab.
5.5.3.3. Management of Immune-Related Adverse Events 
The irAE management guidelines outlined in Section 5.5.2.2apply to both avelumab and 
utomilumab.  Any event suspected to be immune related should be managed according to the 
guidance for management of immune related adverse event in Table5.


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In case of a potential irAE, besides the management related to avelumab and utomilumab 
therapy, rituximab doses may also be modified or interrupted based on the guidance provided 
for avelumab-utomilumab-rituximab combination toxicity management Table6and Table7, 
product labeling and institutional guidelines according to Investigator’s best medical 
judgment.
5.5.3.4.Management of Infusion-Related Reactions
5.5.3.5.Avelumab and Utomilumab
Guidelines for the management of avelumab infusion-related reactions are outlined in 
Section5.5.2.2.  The same management guidelines are applicable to utomilumab 
infusion-related reactions.
5.5.3.6.Rituximab
Rituximab may cause severe, including fatal, infusion reactions.  Severe reactions typically 
occur during the first infusion, with time to onset typically being 30-120minutes. 
Patients with pre-existing cardiac or pulmonary conditions, those who have experienced prior 
cardio-pulmonary adverse reactions, and those with high numbers of circulating malignant 
cells (25,000/mm3) should be closely monitored.  In order to mitigate infusion related 
reactions, a premedication with an antihistamineand with paracetamol (acetaminophen) 
approximately 30 to 60minutes prior to each dose of avelumab is mandatory (for example, 
25-50mg diphenhydramine and 500-650mg paracetamol [acetaminophen] IV or oral 
equivalent.  This may be modified based on local treatment standards and guidelines, as 
appropriate. 
5.5.3.7.Management of Tumor Lysis Syndrome
Avelumab, utomilumab, and rituximab are associated with a potential risk of tumor lysis 
syndrome.  Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or 
hyperphosphatemia resulting from tumor lysis, which may be fatal, can occur within 
12-24hours after the first infusion of rituximab.  A high number of circulating malignant 
cells (25,000/mm3) or high tumor burden confers a greater risk of Tumor Lysis Syndrome 
(TLS). 
In the event that tumor lysis syndrome occurs, patients should be treated per local guidelines, 
and the recommended management algorithm published by Howard et al. followed 
(seeFigure4).


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Table6.
Treatment Arm A (Avelumab, Rituximab, and Utomilumab) Treatment 
Modifications for Investigational Product Related Hematologic Toxicities
Hematologic Toxicity
(NCI CTCAE 
version4.03)
Avelumab
Rituximab
Utomilumab
Grade 1
Continue per schedule
Continue per schedule Continue per schedule
Grade 2
Continue per schedule Continue per schedule Continue per schedule
Grade 3
Hold treatment up to 
4weeks until 
Grade1, or baseline, 
then rechallenge.
Permanent 
discontinuation if 
recurrence to Grade3.
(Unless resolve to 
Grade 1 or baseline 
within 7 days 
following appropriate 
medical management).
Hold treatment up to 
4weeks until 
Grade1, or baseline 
then rechallenge.
Permanent 
discontinuation if 
recurrence to Grade3.
(Unless resolve to 
Grade 1 or baseline 
within 7 days 
following appropriate 
medical management).
Hold treatment up to 
4weeks until Grade1, or 
baseline then rechallenge.
Permanent discontinuation 
if recurrence to Grade3 
(Unless resolve to 
Grade1 or baseline 
within 7 days following 
appropriate medical 
management).
Grade 4
Permanent 
discontinuation 
(Unless resolve to 
Grade 1, or baseline 
within 7 days 
following appropriate 
medical management).
Permanent 
discontinuation 
(Unless resolve to 
Grade 1 or baseline 
within 7 days 
following appropriate 
medical management).
Permanent discontinuation.
(Unless resolved to 
Grade1 or baseline 
within7 days following 
appropriate medical 
management).


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Table7. Treatment Arm A (Avelumab, Rituximab, and Utomilumab) Treatment Modifications for Investigational 
Product-Related Non-Hematologic Toxicities
Non-Hematologic Toxicity
(NCI CTCAE v. 4.03)
Avelumab
Rituximab
Utomilumab
Progressive multi-focal 
leuco-encephalopathy (PML) -
any grade
Permanently discontinue
Permanently discontinue
Permanently discontinue
Viral Hepatitis B –any grade
Permanently discontinue
Permanently discontinue
Permanently discontinue. 
Grade 3 infection
Permanently discontinue
Permanently discontinue
Permanently discontinue. 
Grade 3 cardiac arrhythmia
Permanently discontinue
Permanently discontinue
Permanently discontinue
Grade 3 renal toxicity 
(eg,acute kidney injury, urine 
output decreased)
Permanently discontinue
Permanently discontinue
Permanently discontinue
Grade 3 muco-cutaneous 
reactionsincluding 
paraneoplastic pemphigus, 
Steven-Johnson syndrome, 
lichenoid dermatitis, 
vesciculobullous dermatitis, 
and toxic epidermal necrolysis
Permanently discontinue
Permanently discontinue
Permanently discontinue
See irAEs management guidelines for dermatologic toxicity (Table5), which are applicable to both avelumab and Utomilumab
Any Grade 3 liver function 
test abnormality
Permanently discontinue 
Permanently discontinue 
Permanently discontinue
See irAEs management guidelines for hepatic toxicity (Table5), which are applicable to both avelumab and Utomilumab
Other -Grade 1
Continue per schedule.
Continue per schedule.
Continue per schedule.


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Non-Hematologic Toxicity
(NCI CTCAE v. 4.03)
Avelumab
Rituximab
Utomilumab
Other Grade 2
Hold treatment until the toxicity resolves to 
Grade 1 up to 4 weeks.
Exceptions:

Transient flu-like symptoms or fever, 
which are controlled by medical 
management.

Transient fatigue, local reactions, or 
headache, that resolve to Grade1.

Nausea or vomiting controlled by 
medical management.

Amylase or lipase abnormalities not 
associated with symptoms or clinical 
manifestations of pancreatitis.

Tumor flare.

Single non-hematologic laboratory 
values that do not have any clinical 
correlates, and resolve to Gr1 within 
7days following appropriate medical 
management.

Endocrine deficiencies that are 
manageable by hormone replacement 
therapy.
As per as avelumab. 
As per avelumab.
Other -Grade 3
Hold treatment up to 4 weeks until the 
toxicity resolves to Grade 1 
If Grade 3 recurs: permanently discontinue
Exceptions:

Transient flu-like symptoms or 
fever,which are controlled by 
medical management.
As per avelumab.
As per avelumab.


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Non-Hematologic Toxicity
(NCI CTCAE v. 4.03)
Avelumab
Rituximab
Utomilumab

Transient fatigue, local reactions, or 
headache, that resolve to Grade 1.

Nausea or vomiting resolved to 
Grade1 in ˂72 hours following the 
initiation of adequate medical 
management.

Tumor flare.

Single non-hematologic laboratory 
values that are out of the normal 
range, that do not have any clinical 
correlates, and resolve to Grade1 
within 7 days following appropriate 
medical management.

Endocrine deficiencies that are 
manageable by hormone 
replacement therapy.

Other -Grade 4
Permanent discontinuation.
Exceptions:

Single non-hematological 
laboratory valuesthat do not have 
clinical correlates, and resolve 
within 7days following appropriate 
medical management.
As per avelumab.
As per avelumab.


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Non-Hematologic Toxicity
(NCI CTCAE v. 4.03)
Avelumab
Rituximab
Utomilumab
irAEs
See Table5.
Continue dosing if Grade 2, however, dosing 
maybe withheld until irAE resolution and the 
time of avelumab and utomilumab dosing 
recommence according to Investigator 
judgment. 
For Grade 3irAEs, permanently discontinue. 
See Table5.
Infusion-related reactions
See Section 5.5.4.5.
Medical management (eg, glucocorticoids, 
epinephrine, bronchodilators, and oxygen) for 
infusion reactions as clinically indicated. 
Depending on the severity of the infusion 
reaction and the required interventions, 
rituximab should be temporarily or permanently 
discontinued. 
The infusion must re-commenced at a minimum 
of a 50%reduction in rate following symptoms 
resolution.
See Section5.5.4.5.


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5.5.4.Recommended Treatment Modifications for Phase 1b Treatment Arm B
The recommended utomilumab, and avelumab dose modifications for drug-related toxicities 
are detailed in Section 5.5.3.2.  If a toxicity can be attributed to just one of the drugs in the 
combination, dose modifications may be implemented independently for each drug.  In 
instances where it is not possible toattribute a specific toxicity to just one of the three drugs, 
the guidelines for avelumab should be followed for all 3drugs. 
5.5.4.1.Treatment Delays
A new treatment cannot start unless ANC 1.0 x 109/L, platelets 75x 109/L, and 
non-hematologic toxicities have returned to baseline or Grade1 severity. 
The start of a new treatment may be delayed for 4weeks to allow for ANC and platelet count 
recovery.  In the event that recovery does not occur within 4 weeks, all study drugs should be 
permanently discontinued.  The 4-week recovery time window commences on the day of the 
planned treatment (see Table8and Table9).
If avelumab treatment is delayed due to toxicities potentially attributable to avelumab and/or 
utomilumab (eg, pneumonitis or hypothyroidism), azacitidine administration does not need to 
be delayed.  If azacitidine treatment is delayed due to toxicities potentially attributable to 
azacitidine, administration of avelumab and utomilumab does not need to be delayed.
5.5.4.2.Dose Reductions for Avelumab and Utomilumab 
Dose reductions are not permitted for avelumab and utomilumab.
5.5.4.3.Dose Interruptions for Azacitidine
Azacitidine dosing interruption is not allowed within a cycle unless an unacceptable or 
unexpected azacitidine related toxicity occurs (eg, renal failure).  In this case, azacitidine 
dosing may be resumed following the implementation of the dose interruption guidelines 
detailed in this section. 
If, for unforeseen circumstances, (for reasons other than toxicity, eg, emergency surgery) the 
patient omits a dose of azacitidine within a cycle, the dose may be given in the same cycle if 
no more than a 2-day delay has occurred, and the patient remains likely to obtain clinical 
benefit.
The recommended azacitidine, utomilumab, and avelumab treatment modifications for 
treatment-related hematologic toxicities are described in Table8.
5.5.4.4. Management of Immune-Related Adverse Events
The same irAEs management guidelines outlined in Section 5.5.3.3and Table5apply to 
avelumab and utomilumab.
Any adverse event suspected to be immune-related should be managed according to the 
guidance for management of irAEs (seeTable5).


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In the case of potential irAEs, in addition to the management related to avelumab and 
utomilumab therapy, azacitidine doses may also be modified or interrupted based on the 
guidance provided for avelumab/utomilumab/azacitidine combination toxicity management, 
product labeling, and institutional guidelines according to the Investigator’s best medical 
judgment.
5.5.4.5.Management of Infusion-Related Reactions
5.5.4.6.Avelumab and Utomilumab
Guidelines for the management of avelumab infusion-related reactions are outlined in 
Section5.5.2.  The same management guidelines for avelumab infusion-related reactions are 
also applicable to utomilumab.
5.5.4.7.Management of Tumor Lysis Syndrome
Avelumab and utomilumab are both associated with a potential risk of tumor lysis syndrome.  
In the event that this occurs patients should be treated per local guidelines, referencing the 
recommended management algorithm published by Howard et al. (seeFigure4).
Table8.
Treatment Arm B (Azacitidine, Avelumab, and Utomilumab) Treatment 
Modifications for Investigational Product-Related Hematologic Toxicities
Hematologic Toxicity
(Platelets and Neutrophils 
only)
(NCI CTCAE v. 4.03)
Azacitidine 
Avelumab 
Utomilumab 
Grade 1 
Continue per schedule. 
Continue per schedule.
Continueper schedule.
Grade 2 
Continue per schedule. 
Continue per schedule. 
Continue per schedule.
Grade 3 
Hold treatment up to 
4weeks until Grade 1, 
or baseline then 
rechallenge.
Permanent 
discontinuation if 
recurrence of Grade3 
(Unless recovers to 
Grade1, or baseline 
within 7 daysfollowing 
appropriate medical 
management).
Hold treatment up to 
4weeks until Grade 1, 
or baseline then 
rechallenge.
Permanent 
discontinuation if 
recurrence of Grade3 
(Unless recovers to 
Grade1, or baseline 
within 7 daysfollowing 
appropriate medical 
management).
Hold treatment up to 
4weeks until Grade 1 
or baseline, then 
rechallenge.
Permanent 
discontinuation if 
recurrence of Grade3 
(Unless recovers to 
Grade1 or baseline 
within 7 daysfollowing 
appropriate medical 
management).
Grade 4
Permanent 
discontinuation.
(Unless resolve to 
Grade1 or baseline 
within 7 days following 
appropriate medical 
management).
Permanent 
discontinuation.
(Unless resolve to 
Grade1, or baseline 
within 7 days following 
appropriate medical 
management).
Permanent 
discontinuation.
(Unless resolved to 
Grade1 or baseline 
within7 days following 
appropriate medical 
management).


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Table9.
Treatment Arm B (Azacitidine, Avelumab, and Utomilumab) Treatment 
Modifications for Investigational Product-Related Non-Hematologic 
Toxicities
Non-Hematologic 
Toxicity
(NCI CTCAE v. 4.03) 
Azacitidine
Avelumab
Utomilumab
Renal Toxicity -Serum 
creatinine or BUN 2x 
baseline valueor serum 
bicarbonate level 
<20mmol/L.
Grade 2: Hold dosing up to 
4weeks.
If laboratory tests return to 
baseline or to Grade 1, 
resume treatment
If Grade 2 recurs or worsen 
to Grade 3 or Grade 4, 
permanently discontinue
If Grade 3 or Grade 4, 
permanently discontinue
See “Other -Grade 2” in this 
table.
See “Other -Grade 2” 
in this table.
Other -Grade 1
Continue per schedule. 
Continue per schedule. 
Continue per schedule.
Other -Grade 2
As per avelumab.
Hold treatment up to 4 weeks 
until the toxicity resolves to 
Grade 1 
Exceptions:

Transient flu-like 
symptoms or fever, which 
are controlled by medical 
management.

Transient fatigue, local 
reactions, or headache, 
that resolve to Grade1.

Nausea or vomiting 
controlled by adequate 
medical management.
Amylase or lipase 
abnormalities not 
associated with symptoms 
or clinical manifestations 
of pancreatitis.

Tumor flare.

Single non-hematologic 
laboratory values that do 
not have any clinical 
correlates, and resolve to 
Gr1 within 7 days 
following appropriate 
medical management.

Endocrine deficiencies 
that are manageable by 
hormone replacement 
therapy.
As per avelumab.
Other -Grade 3
As per avelumab.
Hold treatment up to 4 weeks 
until the toxicity resolves to 
Grade 1.
As per avelumab.


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Non-Hematologic 
Toxicity
(NCI CTCAE v. 4.03) 
Azacitidine
Avelumab
Utomilumab
If Grade 3 recurs: permanently 
discontinue.
Exceptions:

Transient flu-like 
symptoms or fever, which 
are controlled by adequate 
medical management.

Transient fatigue, local 
reactions, or headache, 
that resolve to Grade1.

Nausea or vomiting 
resolve to Grade 1 in 
˂72hours following the 
initiation of adequate 
medical management.

Tumor flare.

Single non-hematologic 
laboratory values that are 
out of the normal range 
that do not have any 
clinical correlates, and 
resolve to Grade1 
within 7 days following 
appropriate medical 
management.

Endocrine deficiencies 
that are manageable by 
hormone replacement 
therapy.
Other -Grade 4
As per avelumab.
Permanent discontinuation.
Exceptions:
Single non-hematological 
laboratory values that do 
not have clinical correlates, 
and resolve within 7 days 
following appropriate 
medical management.
As per avelumab.
irAEs
Continue dosing if 
Grade2, however, dosing 
may be withheld until irAE 
resolution, and the time of 
avelumab and utomilumab 
dosing recommence 
according to the 
Investigator’s judgment. 
For Grade 3 permanently 
discontinue.
See Section 5.5.2.2.
See Section 5.5.2.2.


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5.5.5.Recommended Treatment Modifications for Phase 1b Treatment Arm C
5.5.5.1.Dose Modifications for Avelumab, Bendamustine, and Rituximab 
Dose modifications for avelumab, bendamustine, and rituximab in the case of drug-related 
toxicities are detailed in Table11and Table12.  If a toxicity can be attributed to just one of 
the drugs in the combination, dose modifications may be performed independently for each 
drug.  In instances where it is not possible to attribute a toxicity to just one of the three drugs, 
the avelumab treatment modifications detailed in Table11and Table12(see below) must be 
followed for all 3drugs.
5.5.5.2.Treatment Delays 
Treatment cannot be administered until ANC 1.0 x109/L, platelets 75x109/L, and 
non-hematologic toxicities have returned to baseline or Grade1 severity.
The administration of the study drug treatments at the beginning of each cycle may be 
delayed for a maximum duration of 4weeks to allow for ANC and platelet count recovery.  
In the event that recovery does not occur within two weeks, all study drugs must be 
permanently discontinued.  The 4weeks recovery window commences on the day of the 
planned treatment 
Myelosuppression is a known side effect of bendamustine therapy. Prophylactic use of 
G-CSF in all cycles for patients 60years old randomized to armC is mandatory (and armD 
in Phase3, if armC is selected to advance to the Phase3 component).  The use of colony
stimulating factor for the treatment of neutropenia is allowed in any cycle, according to 
NCCN guidelines.1  In addition,patients may receive erythropoietin, iron supplements, 
and/or transfusions as clinically indicated for the management of anemia. 
If avelumab treatment in the next cycle is delayed due to toxicities potentially attributable to 
avelumab (eg, pneumonitis orthyroid disease), bendamustine administration and rituximab 
administration does not need to be delayed.  If the start of rituximab administration in the 
next cycle is delayed due to toxicities attributable to rituximab, administration of 
bendamustine and avelumab does not need to be delayed.  If the start of bendamustine 
administration in the next cycle is delayed due to toxicities attributable to bendamustine, 
avelumab and rituximab administration does not need to be delayed.
5.5.5.3.Dose Reductions for Rituximaband Avelumab
No dose reductions are permitted for rituximab or avelumab.
5.5.5.4.Dose Reductions for Bendamustine
Following dose interruption or cycle delay due to toxicity, the bendamustine dose may need 
to be reduced when treatment is resumed according to the grade of the toxicity.
Dose reduction of bendamustine by 1 dose level is allowed depending on the nature and 
grade of the toxicity (see Table10).


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Once the bendamustine dose has been reduced, it should be administered at the same reduced 
dose level in all subsequent cycles.  No dose re-escalation of bendamustine is allowed 
following dose reduction.
Table10. Bendamustine Dose Reduction
Bendamustine (mg/m2)
90
60
Patients requiring more than1dose reduction of bendamustine should permanently 
discontinue treatment, but may continue treatment with avelumab and rituximab.
5.5.5.5. Management of Immune-Related Adverse Events
The irAE management guidelines in Table5apply to both avelumab and utomilumab.
Any event suspected to be immune-related should be managed according to the guidance for 
management of irAEs (see Table5).  In the case of a potential irAE, in addition to the 
management related to avelumab and utomilumab therapy, rituximab doses may also be 
modified or interrupted based on the guidance for the avelumab/utomilumab/rituximab 
combination toxicity management section, product labeling, and institutional guidelines 
according to Investigator’s clinical judgment. 
5.5.5.6.Management of Infusion-Related Reactions
5.5.5.7.Avelumab
Guidelines for the management of avelumab infusion-related reactions are detailed in 
Section5.5.2. 
5.5.5.8.Rituximab
Rituximab can cause severe, including fatal, infusion reactions.  Severe reactions typically 
occur during the first infusion, with a time of onset of 30-120minutes. 
Patients with pre-existing cardiac or pulmonary conditions, those who have experienced prior 
cardio-pulmonary adverse reactions, and those with high numbers of circulating malignant 
cells (25,000/mm3), should be closely monitored.
5.5.5.9.Bendamustine
Infusion reactions to bendamustine are common.  Symptoms include: fever, chills, pruritus 
and rash.  In rare instances severe anaphylactic and anaphylactoid reactions have occurred, 
especially in the second and subsequent cycles of therapy.  Patients should be asked about 
symptoms suggestive of infusion reactions following their first cycle of therapy.  As per the 
bendamustine label, in order to mitigate bendamustine infusion-related reactions a 
pre-medication regimen including antihistamines, antipyretics and corticosteroids should be 
considered in subsequent cycles in patients who have previously experienced Gr1 or Gr2 


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infusion reactions.  Discontinuation should be considered in patients with Gr3 infusion 
reactions.
5.5.5.10.Management of Tumor Lysis Syndrome
Avelumab and rituximab are associated with a potential risk of tumor lysis syndrome.  See 
Figure4. 
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, some fatal, can occur within 12-24hours after the first infusion of rituximab.  A 
high number of circulating malignant cells (25,000/mm3) or high tumor burden confers a 
greater risk of TLS. 
Tumor lysis syndrome associated with bendamustine treatment has occurred in patients in 
clinical trials and in post-marketing reports.  The onset tends to be within the first treatment 
cycle of bendamustine and, without intervention, may lead to acute renal failure and death.  
Preventive measures include vigorous hydration and close monitoring of blood chemistry, 
particularly potassium and uric acid levels.  Allopurinol has also been used during the 
beginning of bendamustine therapy.  However, there may be an increased risk of severe skin 
toxicity when bendamustine and allopurinol are administered concomitantly.
In the event of Tumor Lysis Syndrome, patients should be treated per local guidelines, 
referencing the recommended management algorithm published by Howard et al. 
(seeFigure4).


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Table11. Treatment Arm C (Bendamustine,Rituximab, and Avelumab) Treatment 
Modifications for Investigational Product-Related Hematologic Toxicities
Hematologic Toxicity
(Platelets and Neutrophils 
only)
(NCI CTCAE v. 4.03)
Bendamustine 
Rituximab 
Avelumab
Grade 1
Continue per schedule.
Continue per schedule.
Continue per schedule.
Grade 2
If ANC Grade 2
(1.0x109/L), continue 
per schedule, if platelets 
Grade2hold until 
Grade 1 (75x109/L).
If ANC Grade2 
(1.0x109/L), continue 
per schedule, if platelets 
Grade2 hold until 
Grade 1 (75x109/L).
If ANC Grade2 
(1.0x109/L), continue 
per schedule, if platelets 
Grade 2 hold until 
Grade 1 (75x109/L).
Grade 3 
Hold treatment until 
Grade 2 following 
appropriate medical 
management then 
rechallenge at the same 
dose level
Hold treatment until 
Grade 2 following 
appropriate medical 
management then 
rechallenge 
Hold treatment until 
Grade 2 following 
appropriate medical 
management then 
rechallenge 
Grade 4
Hold treatment until 
Grade 2 following 
appropriate medical 
management then 
rechallenge at the next 
lower dose level
Hold treatment until 
Grade 2 following 
appropriate medical 
management then 
rechallenge 
Hold treatment until 
Grade 2 following 
appropriate medical 
management then 
rechallenge 
Table12. Treatment Arm C (Bendamustine, Rituximab, and Avelumab) Treatment 
Modifications for Investigational Product-Related Non-Hematologic 
Toxicities
Non-Hematologic Toxicity 
(NCI CTCAE v. 4.03)
Bendamustine 
Rituximab
Avelumab 
Progressive multi-focal 
leuco-encephalopathy (PML) 
-any Grade
Permanently discontinue Permanently discontinue 
Permanently discontinue
Viral Hepatitis -any Grade
Permanently discontinue  Permanently discontinue  Permanently discontinue 
Grade 3 infection
Permanently discontinue
Permanently discontinue 
Permanently discontinue
Grade 3 muco-cutaneous 
reactions including 
paraneoplastic pemphigus, 
Steven-Johnson syndrome, 
lichenoid dermatitis, 
vesiculobullous dermatitis, 
and toxic epidermal 
necrolysis
Permanently discontinue
Permanentlydiscontinue
Permanently discontinue
For dermatologic toxicity see 
irAEs management guidelines 
(Table5).
Any Grade 3 liver function 
test abnormality
Permanently discontinue Permanently discontinue
Permanentlydiscontinue. 
See irAEs management guidelines 
(Table5).
Grade 3 cardiac arythmia
Permanently discontinue Permanently discontinue 
Permanently discontinue
Grade 3 renal toxicity 
(eg,acute kidney injury, 
Permanently discontinue Permanently discontinue 
Permanently discontinue


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Non-Hematologic Toxicity 
(NCI CTCAE v. 4.03)
Bendamustine 
Rituximab
Avelumab 
urineoutput decreased)
Other -Grade 1
Continue per schedule 
Continue per schedule 
Continue per schedule
Other -Grade 2
Hold treatment until the 
toxicity resolves to 
Grade1 then rechallenge 
at the same dose level.
If skin reactions occur and 
are progressive, 
bendamustine should be 
discontinued.
As per avelumab. 
Hold treatment until the toxicity 
resolves to Grade 1.
Exceptions:

Transient flu-like symptoms 
or fever, which are controlled 
by medical management.

Transient fatigue, local 
reactions, or headache, that 
resolve to Gr1

Nausea or vomiting 
controlled by medical 
management.

Amylase or lipase 
abnormalities not associated 
with symptoms or clinical 
manifestations of 
pancreatitis.

Tumor flare.

Single non-hematologic 
laboratory values that do not 
have any clinical correlates, 
and resolve to Gr1 within 
7days following appropriate 
medical management.

Endocrine deficiencies that 
are manageable by hormone 
replacement therapy.
Other -Grade 3
Hold treatment up to 
4weeks until the toxicity 
resolves to Grade1 then 
rechallenge.
Rechallenge after the First 
episode:
same dose level.
Rechallenge after the 
Second episode: 
decrease bendamustine by 
1dose level.
Third episode: 
permanently discontinue.
If skin reaction occur and 
are progressive, 
bendamustine should be 
discontinued.
As per avelumab.
Hold treatment up to 4 weeks until 
the toxicity resolves to Grade1.
If Grade3 recurs, permanently 
discontinue.
Exceptions:

Transient flu-like symptoms 
or fever, which are controlled 
by medical management.

Transient fatigue, local 
reactions, or headache, that 
resolve to Grade1.

Nausea or vomiting resolved 
to Grade 1 in ˂72hours 
following the initiation of 
adequate medical
management.

Tumor flare.

Single non-hematologic 
laboratory values that are out 
of the normal range, that do 
not have any clinical 


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Non-Hematologic Toxicity 
(NCI CTCAE v. 4.03)
Bendamustine 
Rituximab
Avelumab 
correlate, and resolve to 
Grade1 within 7days 
following appropriate 
medical management.

Endocrine deficiencies that 
are manageable by hormone 
replacement therapy.
Other -Grade 4
Permanently discontinue 
for skin reaction
For other toxicities:
Hold treatment up to 4 
weeks until the toxicity 
resolves to Grade 1 then 
rechallenge.
Rechallenge after the First 
episode: 
decrease bendamustine by 
1dose level.
Second episode: 
permanently discontinue.
As per Avelumab.
Permanent discontinuation.
Exceptions:
Single non-hematological 
laboratory values that do not 
have clinical correlates, and 
resolve within 7 days 
followingappropriate 
medical management.
irAEs
Continue dosing if 
Grade2, however, 
dosing may be withheld 
until irAE resolution and 
the time of avelumab 
dosing recommence 
according to Investigator 
judgment. 
For Grade3 permanently 
discontinue.
See Section 5.5.2.2.
See Section 5.5.2.2.
Infusion-related reactions
See Section 5.5.5.6.
Medical management 
(eg,glucocorticoids, 
epinephrine, 
bronchodilators, and 
oxygen) for infusion 
reactions may be given as 
clinically indicated. 
Depending on the severity 
of the infusion reaction 
and the required 
interventions, rituximab 
should be temporarily or 
permanently discontinued. 
The infusion must be 
continued at a minimum of 
50% reduction in rate 
following symptoms 
resolution.
See Section 5.5.5.6.


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5.6.Recommended Treatment Modifications for Phase 3
5.6.1.Experimental Treatment Arm D
The experimental treatment arm to be tested in the Phase3 will be selected at the end of the 
Phase1b.  The same treatment modification guidelines will apply to the experimental 
treatment arms in both the Phase1b and 3.  For therelevant treatment modification 
guidelines see Section5.5.
5.6.2.Control Treatment Arm E(Rituximab/Bendamustine)
Dose modifications for bendamustine and rituximab for drug-related toxicities are detailed in 
Table14and Table15.  If a toxicity may be attributed to just one of the drugs in the 
combination, dose modifications can be performed independently for each drug.
5.6.3.Cycle Delays for Bendamustine and Rituximab Drug-Related Toxicities
A new treatment cycle cannot start until ANC 1.0 x109/L, platelets 75 x109/L, and 
non-hematologic toxicities have returned to baseline or Grade1 severity.
The administration of the study drug treatments at the beginning of each cycle may be 
delayed for a maximum duration of 4weeks to allow for ANC and platelet count recovery.  
In the event that recovery does not occur within 4weeks, all study drugs will be permanently 
discontinued.  The 4weeks recovery window commences on Day1 of the planned cycle.
Myelosuppression is a known side effect of bendamustine therapy.  Prophylactic use of 
G-CSF in all cycles for patients 60years old randomized to armC is mandatory (and armD 
in Phase3, if armC is selected to advance to the Phase3 component).  Theuse of 
colony-stimulating factor for the treatment of neutropenia is allowed in any cycle, per NCCN 
guidelines.1  Additionally, patients may receive erythropoietin, iron supplements, and/or 
transfusions (as clinically indicated) for the management of anemia. 
If the start of rituximab administration in the next cycle is delayed due to toxicities 
attributable to rituximab, administration of bendamustine should not be delayed.  If the start 
of bendamustine administration in the next cycle is delayed due to toxicities attributable to 
bendamustine, rituximab administration should not be delayed.
5.6.4.Dose Reductions for Rituximab 
Dose reductions are not permitted for rituximab.
5.6.5.Dose Reductions for Bendamustine 
Following dose interruption or cycle delay due to toxicity, the bendamustine dose may need 
to be reduced when treatment is resumed, depending on the grade of the toxicity.
Once the bendamustine dose has been reduced, it should be administered at the reduced dose 
level in all subsequent cycles.  No dose re-escalation of bendamustine is allowed. 


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Table13. Bendamustine Dose Reduction Levels
Bendamustine (mg/m2)
120
90
60
Patients requiring more than 2dose reductions of bendamustine should permanently 
discontinue treatment with bendamustine, and rituximab.
5.6.6.Management of Infusion-Related Reactions
5.6.7.Rituximab
Rituximab can cause severe, including fatal, infusion reactions. 
Severe reactions typically occur during the first infusion, with a time of onset of 
30-120mins. 
Patients with pre-existing cardiac or pulmonary conditions, those who have experienced prior 
cardio-pulmonary adverse reactions, and those with high numbers of circulating malignant 
cells (25,000/mm3) should be closely monitored.
5.6.8.Bendamustine
Infusion reactions to bendamustine are common.  Symptoms include: fever, chills, pruritus 
and rash.  In rare instances severe anaphylactic and anaphylactoid reactions have occurred, 
especially in the second and subsequent cycles of therapy.  Patients should be asked about 
symptoms suggestive of infusion reactions following their first cycle of therapy.  As per the 
bendamustine label, in order to mitigate bendamustine infusion-related reactions a 
pre-medication regimen including antihistamines, antipyretics and corticosteroidsshould be 
considered in subsequent cycles in patients who have previously experienced Gr1 or -2 
infusion reactions.  Discontinuation should be considered in patients with Gr3 infusion 
reactions.
5.6.9.Management of Tumor Lysis Syndrome
Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from 
tumor lysis, some fatal, can occur within 12-24hours after the first infusion of rituximab.  A 
high number of circulating malignant cells (25,000/mm3) or high tumor burden confers a 
greater risk of TLS.  A high number of circulating malignant cells (25,000/mm3) or high 
tumor burden confers a greater risk of TLS.  Tumor lysis syndrome associated with 
bendamustine treatment has occurred in patients in clinical trials, and in post-marketing 
reports.  The onset tends to be within thefirst treatment cycle of bendamustine and, without 
intervention, may lead to acute renal failure and death.  Preventive measures include: 
vigorous hydration and close monitoring of blood chemistry (particularly potassium and uric 
acid levels).  Allopurinol has also been used during the initiation of bendamustine therapy.  
However, there may be an increased risk of severe skin toxicity when bendamustine and 
allopurinol are administered concomitantly.


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In the event that Tumor Lysis Syndrome occurs, patients should be treated per local 
guidelines, and the recommended management algorithm published by Howard et al. (see 
Section5.5.2.1and Figure4).
Table14. Treatment Arm E: (Bendamustine and Rituximab) Treatment Modifications 
for Drug-Related Hematologic Toxicities
Toxicity
(Platelets and 
Neutrophils only)
Bendamustine Dosing at Start of the Next 
Cycle 
Rituximab Dosing at Start of 
the Next Cycle
Grade 1
Continue per schedule.
Continue per schedule.
Grade 2
If ANC Grade2 (1.0 x109/L), continue per 
schedule, if platelets Grade 2hold until 
Grade 1(75x109/L).
If ANC Grade2 (1.0 x109/L), 
continue per schedule, if 
platelets Grade2hold until 
Grade 1(75x109/L).
Grade 3 
Delay dosing until ANC 1.0 x 109/L and 
platelets 75 x 109/L.
Delay dosing until ANC 
1.0x109/L and platelets 
75x109/L.
Grade 4
Delay dosing until ANC 1.0 x 109/L and 
platelets 75 x 109/L.
Once blood counts have improved, 
bendamustine can be reinitiated at the 
discretion of the treating physician.  In 
addition, dose reduction may be warranted.
First episode: decrease by 1 dose level.
Second episode: decrease by 1 additional dose 
level.
Delay dosing until ANC 
1.0x109/L and platelets 
75x109/L.
Once blood counts have 
improved, Rituximab can be 
reinitiated at the discretion of 
the treating physician.
Table15. Treatment Arm E:  Treatment Modifications for Treatment-Related 
Non-Hematologic Toxicities
Non-HematologicToxicity 
(NCI CTCAE v. 4.03)
Bendamustine 
Rituximab
Progressive multi-focal 
leuco-encephalopathy (PML) -any 
grade
Permanently discontinue.
Permanently discontinue.
Viral Hepatitis –any Grade
Permanently discontinue. 
Permanently discontinue. 
Grade 3 infection
Permanently discontinue.
Permanently discontinue. 
Grade 3 muco-cutaneous reactions 
including paraneoplastic pemphigus, 
Steven-Johnson Syndrome, lichenoid 
dermatitis, vesciculobullous 
dermatitis, and toxic epidermal 
necrolysis
Permanently discontinue.
Permanently discontinue.
Grade 3 renal toxicity (rising serum 
creatinine acute kidney injury, urine 
output decreased (oliguria)
Permanently discontinue.
Permanently discontinue.
Any Grade 3 liver function test 
abnormality
Withold bendamustine.
Once toxicity has recovered to 
Rituximab dosing must be 
withheld for any liver function 
test AEs Grade 3 (even if 


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Non-HematologicToxicity 
(NCI CTCAE v. 4.03)
Bendamustine 
Rituximab
Gr 1, bendamustine can be 
re-initiated at the lower dose 
level. 
If Gr 3 toxicity recurs, once 
toxicity has recovered to 
Gr1 bendamustine should be
decreased by 1 dose level. 
Bendamustine should be 
discontinued at the third 
recurrence.
asymptomatic) until the values 
return to baseline or to Gr1.  
In cases of potential liver 
injury, a consultation with a 
hepatologist is mandatory in the 
event that a decision be made to 
initiate treatment with 
anti-inflammatory medications.
Other -Grade 1
Continue per schedule.
Continue per schedule.
Other -Grade 2
Withold bendamustine. 
Once toxicity has recovered to 
Gr1, bendamustine can be 
re-initiated at the same dose 
level.
If skin reactions occur and are 
progressive, bendamustine 
should be discontinued.
If the toxicity resolves to Gr1 
by the time of the next 
administration, treatment may 
continue. 
If the toxicity does not resolve 
to Gr1 by the time of the next 
administration despite 
appropriate medical 
management, the next infusion 
should be omitted. 
Once the toxicity has recovered 
to Gr1, rituximab can be 
re-initiated.
If skin reactions occur and are 
progressive, both bendamustine 
and rituximab should be 
discontinued.
Other -Grade 3
Withold bendamustine.
Once the toxicity has recovered 
to Gr1, bendamustine can be 
reinitiated at a lower dose level. 
If Gr 3toxicity recurs, once 
non-hematological toxicity has 
recovered to Gr1, 
bendamustine should be 
decreased by 1 dose level. 
Bendamustine should be 
discontinued at third recurrence.
If skin reactions occur and are 
progressive, bendamustine 
should be discontinued.
If the toxicity resolves to 
Grade1 by the time of the 
next administration, treatment 
may continue. 
If the toxicity does not resolve 
to Grade1 by the time of the 
next administration (despite 
appropriate medical 
management), the next infusion 
should be omitted. 
Once the toxicity has recovered 
to Grade1, rituximab can be 
re-commenced.
Rituximab should be 
discontinued at the third 
recurrence.


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Non-HematologicToxicity 
(NCI CTCAE v. 4.03)
Bendamustine 
Rituximab
Other -Grade 4
Permanently discontinue for skin 
reactions.
For other non-hematologic 
toxicities,withold bendamustine.
Once toxicity has recovered to 
Gr1, bendamustine can be 
reinitiated at a lower dose level. 
If Gr 4 toxicity recurs, once 
toxicity has recovered to Gr1, 
bendamustine should be 
decreased by 1 dose level. 
Bendamustine should be 
discontinued following a third 
recurrence.
If the toxicity resolves to Gr1 
by the time of the next 
administration, treatment may 
continue. 
If the toxicity does not resolve 
to Gr1 by the time of the next 
administration (despite 
appropriate medical 
management), the next infusion 
should be omitted. 
Once it has recovered to Gr1, 
rituximab may be re-initiated.
Rituximab should be 
discontinued following a third 
recurrence.
Rituximab dosing must be 
withheld for any liver function 
test AEs Gr3, even if 
asymptomatic, until the values 
return to baseline or to Gr1.  
In cases of potential liver 
injury, a consultation with a 
hepatologist is mandatory 
should a decision be made to 
initiate treatment with 
anti-inflammatory medications.
Infusion-related reactions
SeeSection 5.6.6.
Medical management 
(eg,administration of 
glucocorticoids, epinephrine, 
bronchodilators, and oxygen) 
for infusion reactions may be 
given as clinically indicated. 
Depending on the severity of 
the infusion reaction and the 
required interventions, 
rituximab should be 
temporarily or permanently 
discontinued. 
The infusion must be continued 
at a minimum of 50% reduction 
in rate following symptoms 
resolution.
5.7.Investigator’s Choice Treatment Arm E (Rituximab/Gemcitabine/Oxaliplatin)
The recommended dose modifications for gemcitabine, oxaliplatin and rituximab in the event 
of drug-related toxicities are detailed in Table17and Table18.


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5.7.1.Cycle Delays 
A new cycle cannot start until ANC 1.0 x109/L, platelets 100 x109/L, and non-hematologic 
toxicities have returned to baseline or Grade1 severity.
The administration of the study drug treatments may be delayed for a maximum duration of 
4weeks to allow for ANC and platelet count recovery.  In the event that count recovery does 
not occur within two weeks, all three study drugs will be permanently discontinued.  The 
4weeks recovery window commences on Day1 of the planned cycle.
If the start of rituximab administration in the next cycle is delayed due to toxicities 
attributable to rituximab, the administration of gemcitabine and oxaliplatin should not be 
delayed.
If the start of gemcitabine administration in the next cycle is delayed due to toxicities 
attributable to gemcitabine, administration of rituximab and oxaliplatin should not be 
delayed.
If the start of oxaliplatin administration in the next cycle is delayed due to toxicities 
attributable to oxaliplatin, administration of rituximab and gemcitabine should not be 
delayed.
5.7.2.Dose Reductions for Oxaliplatin 
Following dose interruption or cycle delay due to non-hematological toxicities, the 
oxaliplatin dose may need to be reduced when treatment is resumed.
Dose reduction of oxaliplatin by 1dose level will be allowed depending on the nature and 
grade of the toxicity encountered (seeTable16).
Once the oxaliplatin dose has been reduced for a given patient, all subsequent cycles should 
be administered at that dose level.  No dose re-escalation of oxaliplatin is allowed following 
a dose reduction.
Patients requiring more than 2dose reductions of oxaliplatin should permanently discontinue
treatment with oxaliplatin, but may continue treatment with rituximab and gemcitabine.
Table16. Oxaliplatin Dose Reduction Levels
Oxaliplatin (mg/m2)
100
75
5.7.3.Dose Reductions for Gemcitabine
No dose reductions for gemcitabine are permitted, however delays are permitted as indicated 
inSection5.7.9.


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5.7.4.Dose Reductions for Rituximab
No dose reductions for rituximab are permitted.
5.7.5.Management of Infusion-Related Reactions
5.7.6.Rituximab
Rituximab can cause severe, including fatal, infusion reactions. 
Severe reactions typically occur during the first infusion with a time of onset of 
30-120minutes. 
Patients with pre-existing cardiac or pulmonary conditions, those who have experienced prior 
cardio-pulmonary adverse reactions, and those with high numbers of circulating malignant 
cells (25,000/mm3) should be closely monitored.
5.7.7.Oxaliplatin
Special surveillance should be ensured for patients with a history of allergic manifestations to 
other platinum-containing products.  In case of anaphylactic manifestations, the infusion 
should be interrupted immediately, and appropriate symptomatic treatment commenced.  
Re-administration of oxaliplatin in such patients is contra-indicated.  Cross-reactions, which 
may be fatal, have been reported with all platinum compounds.  In case of oxaliplatin 
extravasation, the infusion must be stopped immediately, and the usual institutional 
guidelines for symptomatic treatment initiated.
5.7.8.Tumor Lysis Syndrome
See Section 5.6.9.
5.7.9.Treatment Modifications for Hematologic Toxicities
Dose reduction is not anticipated in the event of hematologic toxicity, however, dosing of the 
3drugs should be delayed until neutrophil and platelet counts have fully recovered (as 
indicated above). 


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Table17. Treatment Arm E (Gemcitabine, Oxaliplatin, and Rituximab).  Treatment 
Modifications for Drug-Related Hematologic Toxicities
HematologicToxicity
(Platelets and Neutrophils 
only)
(NCI CTCAE v.4.03)
Gemcitabine 
Oxaliplatin 
Rituximab 
Grade 1
Continue per schedule. 
Continue per schedule. 
Continue per schedule.
Grade 2 Neutrophils
Continue per schedule.
Continue per schedule.
Continue per schedule.
Grade 2 (platelets only)
Delay administration until 
the platelet counts have 
recovered to 
100x109/L.
Delay administration 
until the platelet counts 
have recovered to 100x 
109/L.
Delay administration 
until the plateletcounts 
have recovered to 100x 
109/L.
Grade 3 or Grade 4 
Delay administration until 
counts have recovered to 
ANC 1000x 109/L and 
platelet counts have 
recovered 100 x 109/L. 
First episode: 
Resume at same dose 
level.
Second episode: 
Resume at same dose 
level.
Third episode: 
Permanently discontinue.
Delay administration 
until counts have 
recovered to ANC 1000 
x 109/L and platelet 
counts have recovered 
100 x 109/L. 
First episode: 
Resume at same dose 
level.
Second episode: 
Resume at same dose 
level.
Third episode: 
Permanently discontinue.
Delay administration 
until counts have 
recovered to ANC 1000 
x 109/L and platelet 
counts have recovered 
100 x 109/L. 
First episode: 
Resume at same dose 
level.
Second episode: 
Resume at same dose 
level.
Third episode: 
Permanently 
discontinue.
Table18. Treatment Arm E (Gemcitabine, Oxaliplatin, and Rituximab).  Treatment 
Modifications for Drug-Related Non-Hematologic Toxicities
Non-HematologicToxicity
(NCI CTCAE v. 4.03)
Gemcitabine
Oxaliplatin
Rituximab
Progressive multi-focal 
leuco-encephalopathy 
(PML) -any Grade
Permanently discontinue. Permanently discontinue.
Permanently 
discontinue.
Hemolytic uremic syndrome 
(HUS) -any grade 
Permanently discontinue. Permanently discontinue. Permanently 
discontinue.
Viral hepatitis -any grade
Permanently discontinue. Permanently discontinue.
Permanently 
discontinue.
Grade3 infection
See below 
recommendations for 
‘Other -Grade3, 
Grade4’
See below 
recommendations for 
‘Other -Grade3, 
Grade4’
Permanently 
discontinue.
Mucositis/stomatitis (with 
or without neutropenia)
See below 
recommendations for 
‘Other’ according to 
Delay next oxaliplatin 
treatment until recovery 
to Grade 1 or less and/or 
See below 
recommendations 
for ‘Other’ 


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Non-HematologicToxicity
(NCI CTCAE v. 4.03)
Gemcitabine
Oxaliplatin
Rituximab
grade
the neutrophil count is 
1.5 x 109/L.  Then 
oxaliplatin dosing may be 
resumed at the same 
dose.
according to grade.
Grade3 renal toxicity 
(eg,acute kidney injury, 
urine output decreased )
See below 
recommendations for 
‘Other -Grade 3, 
Grade4’
See below 
recommendations for 
‘Other -Grade 3, 
Grade4’
Permanently 
discontinue.
Any Grade 3 liver function 
test abnormality
See below 
recommendations for 
‘Other -Grade 3, 
Grade4’
See below 
recommendations for 
‘Other -Grade 3, 
Grade4’
Rituximab dosing 
must be withheld, 
even if the patient is 
asymptomatic, until 
the values return to 
baseline or to Gr1, 
then rituximab 
dosing may be 
resumed at the same 
dose.  In cases of 
potential liver 
injury, a 
consultation with a 
hepatologist is 
mandatory should a 
decision be made to 
initiate treatment 
with 
anti-inflammatory 
medications.  
Grade 3 muco-cutaneous 
reactions including 
paraneoplastic pemphigus, 
Steven-Johnson syndrome, 
lichenoid dermatitis, 
vesciculobullous dermatitis, 
and toxic epidermal 
necrolysis
See below 
recommendations for 
“Other -Grade 3, 
Grade4”
See below 
recommendations for 
“Other -Grade 3, 
Grade4”
Permanently 
discontinue
Respiratory symptoms 
In case of severe 
dyspnea, permanently 
discontinue
In case of unexplained 
respiratory symptom,any 
grade, such as 
non-productive cough, 
dyspnea, crepitations or 
pulmonary infiltrates, 
oxaliplatin should be 
discontinued until further 
pulmonary investigations 
exclude interstitial lung 
disease.  If it is excluded, 
oxaliplatin dosing may be 
resumed at the same 
dose.  If it is confirmed, 
See below 
recommendations 
for “Other” 
according to grade


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Non-HematologicToxicity
(NCI CTCAE v. 4.03)
Gemcitabine
Oxaliplatin
Rituximab
oxaliplatin must be 
permanently 
discontinued.
Grade 3 cardiac arrhythmia See below 
recommendations for 
“Other -Grade3, 
Grade4”
See below 
recommendations for 
“Other -Grade3, 
Grade4”
Permanently 
discontinue
Significant paresthesia 
lasting between 7 and 13 
days after each 
administration of oxaliplatin 
See below 
recommendations for 
“Other” according to 
grade
Dose must be reduced to 
75mg/m2.
See below 
recommendations 
for “Other” 
according to grade
Abnormal neurological 
examination, or significant 
paresthesia lasting for 
14days 
See below 
recommendations for 
“Other” according to 
grade
Oxaliplatin must be 
stopped until the 
symptoms improve and 
then restarted at a dose of 
75mg/m2.
See below 
recommendations 
for “Other” 
according to grade
Pharyngeal dysesthesia 
See below 
recommendations for 
“Other” according to 
grade
Increase duration of the 
oxaliplatin infusion from 
2hours to 6hours.
See below 
recommendations 
for “Other” 
according to grade
Other -Grade 1
Continue per schedule. 
Continue per schedule.
Continue per 
schedule.
Other -Grade 2
Delay administration in 
case of a clinically 
significant Grade2 
non-hematological 
toxicity. 
Once it has recovered to 
Grade1, gemcitabine 
can be re-initiated at 
same dose level.
Delay administration in 
case of a clinically 
significant Grade2 
non-hematological 
toxicity. 
Once it has recovered to 
Grade 1, oxaliplatin can 
be re-initiated at same 
dose level.
If the toxicity 
resolves toGrade1 
by the time of the 
next administration, 
treatment may 
continue. 
If the toxicity does 
not resolve to 
Grade1 by the 
time of the next 
administration 
despite appropriate 
medical treatment, 
the next infusion 
should be omitted. 
Once it has 
recovered to 
Grade1, rituximab 
can be re-initiated.
Other -Grade 3, Grade 4
Delay administration in 
case of a clinically 
significant Grade2 
non-hematological 
toxicity. 
Once the toxicity has 
recovered to Grade1, 
gemcitabine may be
Delay administration in 
case of a clinically 
significant Grade2 
non-hematological 
toxicity. 
Once the toxicity has 
recovered to Grade1, 
oxaliplatin may be 
If the toxicity 
resolves to Grade1 
by the time of the 
next administration, 
treatment may 
continue. 
If the toxicity does 
not resolve to 


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Non-HematologicToxicity
(NCI CTCAE v. 4.03)
Gemcitabine
Oxaliplatin
Rituximab
reinitiated at the same 
dose level. 
If toxicity recurs, once 
the toxicity has 
recovered to Grade1 
gemcitabine may be 
reinitiated at the same 
dose level. 
Gemcitabine should be 
discontinued following a 
third recurrence.
reinitiated at the same 
dose level. 
If toxicity recurs, once 
the toxicity has recovered 
to Grade1 oxaliplatin 
may be reinitiated at the 
same dose level. 
Oxaliplatin should be 
discontinued following a 
third recurrence.
Grade1 by the 
time of the next 
administration 
despite appropriate 
medical treatment, 
the next infusion 
should be omitted. 
Once it has 
recovered to 
Grade1, rituximab 
can be 
re-commenced.
Rituximab should be 
discontinued 
following a third 
recurrence.
Infusion-related reactions 
As per institutional 
guidelines
See Section 5.7.5.
Medical 
management 
(eg,glucocorticoids, 
epinephrine, 
bronchodilators, and 
oxygen) for infusion 
reactions may be 
given as clinically 
indicated. 
Depending on the 
severity of the 
infusion reaction and 
the required 
interventions, 
rituximab should be 
temporarily or 
permanently 
discontinued. 
The infusion must 
be continued at a 
minimum of 
50%reduction in 
rate following 
symptoms 
resolution.
5.8.Investigational Product Storage 
The Investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparators and/or marketed products, are stored in a 
secured area with controlled access under required storage conditions and in accordance with 
applicable regulatory requirements.


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Investigational product should be stored in its original container and in accordance with the 
label.  See the IP Manual, package insert, or equivalent for storage conditions of the product 
once reconstituted and/or diluted.
Storage conditions stated in the SRSD (eg, investigator’s brochure [IB], core data sheet 
[CDS], United States package insert [USPI], summary of product characteristics [SPC], or 
local product document [LPD]) 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 thatensures active daily evaluation 
for excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site withthe capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularlyinspected to ensure it is maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer 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 Pfizer.  Once 
an excursion is identified, the investigational product must be quarantined and not useduntil 
Pfizer provides documentation of permission to use the investigational product.  It will not be 
considered a protocol deviation if Pfizer approves the use of the investigational product after 
the temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions.  Specific details regarding information the site should report for each 
excursion will be provided to the site. 
Site staff will instruct patients on the proper storage requirements for take home 
investigational products. 
5.9.Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 


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5.9.1.Destruction of Investigational Product Supplies 
The Sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the Investigator site, the 
Investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.10.Concomitant Treatments
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, inactivated influenza vaccine).  If there is a clinical indication for one of these 
or other medications or vaccinations specifically prohibited during the trial, permanent 
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. 
Prior/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 berecorded 
from 28days prior to the start of study treatment and up to 90days after the last dose of 
study treatment (at Days30, 60, and 90 post-treatment +3days).  All concomitant 
medications and Non Drug Supportive Interventions should be recorded in the CRF including 
supportive care drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat 
adverse events or chronic diseases, and non drug supportive interventions (eg, transfusions).
Medications intended solely for supportive care (ie, antiemetics, analgesics, megestrol 
acetate for anorexia) are allowed.
5.10.1.Concomitant Radiotherapy
Local radiotherapy of isolated lesions with palliative intent (eg, bleeding, pain, compression) 
is acceptable; however, all attempts should be made to rule inor out disease progression.  
Palliative radiotherapy is permitted if considered medically necessary by the treating 
physician.  If palliative radiotherapy is needed to control pain, the site(s) of disease causing 
pain should also be present at baseline; otherwise, painful lesions requiring radiotherapy will 
be considered as a sign of disease progression.
5.10.2.Supportive Care Guidelines
Palliative and supportive care for disease related symptoms may be administered at the 
investigator’s discretion and according to any available American Society of Clinical 
Oncology (ASCO) guidelines.


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Patients should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator including but not limited to the items outlined below: 
Diarrhea: All patients who experience diarrhea should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion;
Nausea/Vomiting: Nausea and vomiting should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic antiemetic therapy according to standard institutional practice.  Patients 
should be strongly encouraged to maintain liberal oral fluid intake. 
Anti infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in: Table5Avelumab Management of Immune related Adverse Events;
Anti inflammatory or narcotic analgesics may be offered asneeded. 
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 coumadin derivatives or other anticoagulants (including direct 
Xainhibitors) may be allowed; however, appropriate monitoring of prothrombin 
time/international normalized ratio (PT/INR) should be performed.
5.10.3.Concomitant Surgery
In case of surgical procedure, study treatment should be delayed.  All attempts should be 
made to rule in or out disease progression.  Re initiation should be discussed with the 
Sponsor.
5.10.4.Other Prohibited Concomitant Medications and Treatments
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 
Anti-cancer systemic chemotherapy or biological therapy.
Immunotherapy not specified in this protocol. 
Investigational agents other than avelumab and utomilumab. 
Radiation therapy (with the exception noted above in Section 5.10.1).
Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs (see 
Table5above and Clarification about Steroid Use below).


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Medications or vaccinations specifically prohibited in the exclusion criteria are also 
not allowed during the active treatment period; however, the administration of 
inactivated vaccines (eg, influenza vaccine) is allowed during the study.
Herbal remedies or vitamins used as anti-cancer treatments.
Herbal remedies with immunostimulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin).
Daily intake over 2grams acetaminophen/paracetamol.
Clarifications About Steroid Use with Avelumab: Data have indicated that corticosteroids 
have an adverse effect on T-cell function and that they inhibit and damage lymphocytes.
86,87  
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-CTLA-4 compounds 
have indicated that short-term use of steroids may be employed without compromising 
clinical outcomes.
88  Therefore, the use of steroids during this trial is restricted as follows:
Premedication: steroid inclusion in the premedication regimen for bendamustine is 
allowed as described in the Schedule of Activities.
Therapeutic use: for the treatment of infusion related reactions and irAEs, steroids are 
permitted according to the modalities indicated in Table5: Avelumab Management of 
Immune-Related Adverse Events.
Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
10mg prednisone daily is acceptable.
Prophylactic use prior to CT(Computerized Tomography)or MRI(Medical 
ResonanceImaging).
Intranasal, inhaled topical steroids, eye drops, or local steroid injection (eg,
intra-articular injection) are allowed.
6.STUDY PROCEDURES 
6.1.Screening
For screening procedures in the Phase1b and Phase3 components of the study, see Table1
and Table2.  All patients must sign an informed consent document prior to undergoing any 
study-specific procedures.
To allow for additional flexibility in scheduling patient visits and procedures, Screening and 
first day of the first study cycle procedures may be completed on the same day.  See the 
Schedule of Activities.  However, screening assessments for eligibilityMUST have already 
been completed before the patient is randomized.


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6.2.Treatment Period
For treatment period procedures, see Schedule of Activities.
Treatment schedules are comprised of 28-day cycles.  To allow for patient and Investigator 
schedules, holidays, and weather or other emergencies requiring clinical facilities to be 
closed, all patient visits may be performed as noted in Schedule of Activities.  For details of 
on-treatment procedures and visit time window schedules, see Phase1b (Table1) and 
Phase3 (Table2) Schedule of Activities.
6.3.Follow-Up Visits
For follow-up procedures, see Schedule of Activities.
6.4.Patient Withdrawal
Patients may withdraw from the study at anytime at their own request, or they may be 
withdrawn at any time 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:
1. Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to 
continue study treatment, provided that the treating physician, after discussion with 
the Sponsor, has determined that the benefit/risk for doing so is favorable (See 
Section5.4.8for details and exceptions);
2. Global deterioration of health status requiring discontinuation;
3. Unacceptable toxicity.  If the unacceptable toxicity is attributed to one of the two 
study treatments, the investigator (in discussion with the Sponsor) may continue 
treatment with the other study treatment;
4. Pregnancy;
5. Significant protocol violation;
6. Lost to follow-up;
7. Patient refused further treatment;
8. Study terminated by Sponsor;
9. Death.


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Reasons for withdrawal from study follow-up may include:
1. Study terminated by Sponsor;
2. Lost to follow-up;
3. Refused further follow-up;
4. 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.  If 
the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further 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.  Patients in the Phase3 
component of the study who have disease progression per Investigator’s assessment, should 
remain on treatment until PD is confirmed by BICR.  For details, refer to Table1and 
Table2. 
7.1.Safety Assessment
Safety assessment will include collection of AEs, Serious Adverse Events (SAEs), vital 
signs, and physical examinations, ECG (12-Lead), echocardiogram (ECHO) or multiple 
gated acquisition(MUGA) scans, laboratory assessments, including pregnancy tests and 
verification of concurrent medications.
7.1.1.Pregnancy Testing
For female patients of childbearing potential, a serum pregnancy test with sensitivity of at 
least 25mIU/mL, will be performed on 2occasions prior to starting administration of study 


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treatment, once at the start of screening and once at the baseline visit immediately before 
starting the investigational product.  Following a negative pregnancy result at screening, 
appropriate contraception must be commenced and a second negative pregnancy test result 
will then be required at the baselinevisit before the patient may receive the investigational 
product.  Urine pregnancy tests with sensitivity of at least 25mIU/mL,will also be routinely 
repeated at every treatment cycle during the active treatment period, at the end of study 
treatment,at30, 60 and 90days during safety follow up period,and additionally whenever 
1menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Urine test 
kits with sensitivity of at least 25mIU/mL may be utilized at every treatment cycle during 
the study in accordance with instructions provided in its package insert.  Patients of 
childbearing potential who have missed a menstrual period or who show an indeterminate or 
positive result on the urine test may not further progress in the study until pregnancy is ruled 
out using further diagnostic testing (eg,A negative qualitative serum pregnancy test 
conducted at a certified laboratory).  Additional pregnancy tests may also be undertaken if 
requested by institutional review boards (IRBs)/ethicscommittees (ECs) or if required by 
local regulations.  In the case of a positive confirmed pregnancy, the subject will be 
withdrawn from administration of investigational product but may remain in the study. 
7.1.2.Laboratory Safety Assessments
Hematology, blood chemistry, and urinalysis will be collected at time points described in the 
Schedule of Activitiesand analyzed at local laboratories.  They may also be performed when 
clinically indicated.  The required laboratory tests are listed in Table19.
Table19.Required Laboratory Tests
Hematology
Chemistry Panel
(* denotes core 
chemistry test)
Urinalysis
Coagulation 
Tests
Pregnancy 
Tests
Hemoglobin
ALT*
Urine dipstick for 
protein, glucose, and 
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
Calcium*
Total Bilirubin* 
BUN or Urea*
Creatinine*
Glucose (non-fasted)*
Phosphorus or Phosphate*
Albumin
Total Protein
Uric Acid
Amylase*


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Gamma glutamyl 
transferase (GGT)
Cholesterol
Creatine kinase
C-reactive protein (CRP) 
Lactate dehydrogenase 
(LDH)
Lipase*
Triglycerides
Hepatitis Tests:HBV, 
HCV testing
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, gamma glutamyl transferase, 
prothrombin time (PT)/INR, alkaline phosphatase, and acetaminophen levels.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPTT=activated partial thromboplastin 
time, AST=aspartate aminotransferase, BUN=blood urea nitrogen, CRP=C-reactive protein, 
GGT=gamma-glutamyltransferase, HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international 
normalized ratio, LDH=lactate dehydrogenase,TSH=thyroid-stimulating hormone, WBC=white blood cell
7.1.3.Electrocardiograms
A standard 12-lead (with a 10second rhythm strip) tracing will be used for all ECGs. 
All patients require a single ECG measurement at screening.  On treatment ECGs will be 
performed pre-and post-infusion/SC doseon Day1 of Cycles1 and 2 and also on Day16 of 
Cycle1 (See Schedule of Activities).  Triplicate 12-lead (with a 10-second rhythm strip) 
tracing will be used for all other ECGs.  It is preferable that the machine used has a capacity 
to calculate the standard intervals automatically.  For triplicate ECGs, 3consecutive 12-lead 
ECGs will be performed approximately 2minutes apart to determine mean QTcF interval.  If 
the mean QTcF interval is prolonged (>500msec, ie, CTCAE Grade3), then the ECGs 
should be re evaluated by a qualified person at the site for confirmation as soon as the finding 
is made, including verification that the machine reading is accurate.  If manual reading 
verifies a QTc of >500msec, immediate correction for reversible causes (including 
electrolyte abnormalities, hypoxia and concomitant medications for drugs with the potential 
to prolong the QTcF interval) should be performed.  In addition, repeat ECGs should be 
immediately performed hourly for at least 3hours until the QTcF interval falls below 
500msec.  If the QTcF interval reverts to less than 500msec, 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 QTcF intervals rise above 500msec the investigational product will be 
held until the QTcF interval decreases to 500msec.  Patients will then restart the 
investigational product at the next lowest dose level or dose delayed as appropriate for 
specificinvestigational product.  If the QTcF interval has still not decreased to <500msec 
after 2weeks, or if at any time a patient has a QTcF interval >515msec or becomes 


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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.
If a patient experiences any cardiac or neurologic AEs (especially syncope, dizziness, 
seizures, or stroke), an ECG in triplicate should be obtainedat 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).
7.1.4.Disease Response Assessment (Lugano Criteria)
18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography (PET) imaging will be 
used in conjunction with Computerized Tomography (CT) imaging.  It will beperformed 
6weeks prior torandomizationthenonce every 12weeks (1week)from randomization 
and at EOT (unless performed 6weeks before EOT). After 12-monthsfrom randomization, 
18F-FDG PET-CT is performed every 24weeks(1week) until PD.  If a patient 
discontinues treatment for reasons other than disease progression, Staging and Response 
Assessment will be performed until disease progression regardless of initiation of subsequent 
anti cancer therapy.  See Study Manual for more details.
The baseline18F-FDG PET-CT imaging will be used to determine evaluable target lesions 
for each patient.  For 18F-FDG PET-CT, tumor background ratios and development of new 
sites of abnormality will be recorded.
Results of the 18F-FDG PET studies will be scored according to methods developed by the 
American Collegeof Radiology Imaging Network.  All centers participating in the study will 
use the same 18F-FDG PET methodologies and measures, to the extent possible, and for 
Phase3, one center will be designated as the central vendor for response evaluation to be 
usedfor final interpretation of 18F-FDG PET data.
Anti-cancer activity will be assessed at baseline, during treatment as specified in the 
Schedule of Activities, whenever disease progression is suspected (eg, symptomatic 
deterioration), at the time of withdrawal from treatment (if not performed in the previous 
4weeks) and at follow-up visits until disease progression regardless of initiation of 
subsequent anti-cancer therapy.
Assessment of response will be made usingthe Response Criteria for Malignant Lymphoma 
(Appendix2).  
All patients’ files and radiologic images and pathology samples must be available for source 
verification and for potential peer review.


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7.1.4.1.Expedited Blinded Independent Central Review for Disease Progression
Tumor assessments must continue until confirmation of disease progression by BICR, 
regardless of the Investigator’s assessment of PD. 
To mitigate the potential for bias in determining disease progression, expedited BICR will be 
performed for Investigator-assessed disease progression.  Upon investigator-assessed disease 
progression, all radiographic images collected for a patient from screening onwards will be 
submitted to the BICR for expedited review.  See Study Manual for process details. 
Every effort should be made to keep the patient on study treatment until the BI
CR has 
completed the radiographic image review, unless contraindicated by the Investigator.
7.2.Pharmacokinetics Assessments
Blood sampleswill be collected for PK analysis collected into an appropriately labeled tubes 
as outlined in the Schedule of Activities.  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. 
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 time 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.

C
C
I
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.
 
 
  
 


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7.2.1.Blood for PK Analysis of Avelumab
Blood samples (3.5mL whole blood) for PK analysis of avelumab will be collected into 
appropriately labeled tubes as outlined in the Schedule of Activities.  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.
7.2.2.Blood for PK Analysis of Utomilumab
Blood samples (4mL whole blood at each time point) will be collected into appropriately 
labeled tubes for PK analysis of utomilumab as outlined in the Schedule of Activities.  Blood 
for PK samples will be drawn from the contralateral arm of the drug infusion.
7.2.3.Blood for PK Analysis of Rituximab
Blood samples (4mL whole blood at each time point) will be collected into appropriately 
labeled tubes for PK analysis of rituximab as outlined in the Schedule of Activities.  Blood 
for PK samples will be drawn from the contralateral arm of the drug infusion.
7.2.4.Blood for PK Analysis of Azacitidine
Blood samples (2mL whole blood at each time point) will be collected into appropriately 
labeled tubes for PK analysis of azacitidine as outlined in the Schedule of Activities.  Blood 
for PK samples will be drawn from the contralateral arm of the drug infusion.
7.2.5.Blood for PK Analysis of Bendamustine and metabolite (M3)
Blood for PK samples will be drawn from the contralateral arm of the drug infusion.  Blood 
samples (2mL whole blood at each time point) will be collected into appropriately labeled 
tubes for PK analysis of bendamustine and M3 as outlined in the Schedule of Activities.  
Blood for PK samples will be drawn from the contralateral arm of the drug infusion.
7.3.Immunogenicity Assessments
Blood samples will be collected for development of Anti-Drug Antibodies (ADAs) and 
Neutralizing Antibodies (NAbs) intoappropriately labeled tubes.  This monitoring will take 
place at regular intervals during the treatment and follow up periods as described in the 
Schedule of Activities.
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 validated analytical methods in compliance with 
Pfizer standard operating procedures.  Samples determined to be positive for ADA 
may be further characterized for NAb.
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 


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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. 
7.3.1.Blood for Analysis of Anti-Avelumab Antibodies (ADA) and Neutralizing 
Anti-Avelumab Antibodies (NAb)
Blood samples (approximately 3.5mL of whole blood) will be collected for determination 
of Anti-Avelumab Antibodies (ADA) and Neutralizing Anti-Avelumab Antibodies (NAb) 
into appropriately labeled tubes at visits specified in the Schedule of Activities.  Blood for 
ADA/NAB samples will be drawn from the contralateral arm of the drug infusion.
7.3.2.Blood for Analysisof Anti-Utomilumab Antibodies (ADA) and Neutralizing Anti-
Utomilumab Antibodies (NAb)
Blood samples (approximately 4mL of whole blood) will be collected for determination of 
Anti-Utomilumab Antibodies (ADA) and Neutralizing Anti-Utomilumab Antibodies (NAb) 
into appropriately labeled tubes at visits specified in the Schedule of Activities.  Blood for 
ADA/NAB samples will be drawn from the contralateral arm of the drug infusion.
7.3.3.Blood for Analysis of Anti-Rituximab Antibodies (ADA) and Neutralizing 
Anti-Rituximab Antibodies (NAb)
Blood samples (approximately 4mL of whole blood) will be collected for determination of 
Anti-Rituximab Antibodies (ADA) and Neutralizing Anti-Rituximab Antibodies (NAb) into 
appropriately labeled tubes at visits specified in the Schedule of Activities.  Blood for 
ADA/NAB samples will be drawn from the contralateral arm of the drug infusion.
7.4.Biomarkers 
CCI
 
 
.
PD-L1 expression in tumor cells will be retrospectively assessed and may be used to 
determine PD-L1 positivity (as determined witha validated PD-L1 central lab IHC test)
using analgorithm and cut-offwhich will be specified prior to analysis).
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PD-L1 expression in cells of the tumor microenvironment (for example, immune 
cells/infiltrating lymphocytes) may also be determined to explore possible correlations with 
outcome to treatment and other biomarker assessments.
Monitoring of minimal residual disease (MRD) will be performed using next-generation 
sequencing.  This will entail analysis of archival/fresh baseline tumor tissue for 
immunoglobulin gene rearrangement signature(s), with MRD then monitored in serial blood 
draws collected at baseline and at time-points which align with tumor staging and response 
assessment by PET-CT or CT alone through EOT (see Laboratory Manual for details).
 
 
 
 
 
 
 
 
 
 
 
Details of time points and sampling are provided in the Schedules of ActivitiesTable1and 
Table2
CCI
.
In order to complete all the assessments on tumor materials and blood and fecal samples, the 
Sponsor or the designated Contract Research Organization (CRO) will provide instructions 
and necessary supplies to the site, including shipping materials and prepaid mailers.  Please 
refer to the Central Laboratory Manual for detailedinformation.
Collection and storage of samples will be detailed in the Central Laboratory Manual.  The 
panel of biomarkers might be adjusted based on results from ongoing research related to 
anti-PD-1/PD-L1 therapies and/or safety; therefore, each patientwill also be asked whether 
any remaining tumor tissue and/or blood-derived samples can be stored at a central 
repository (until such time as these samples cannot support any further analysis) and can be 
used for future exploratory research on the drug(s) and / or disease-related aspects.  A 
patient’s consent to the use of any remaining samples for such future exploratory research 
shall be optional and shall not affect the patient’s participation in the current trial.  Biomarker 
C
C
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C
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I
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analyses may be conducted after the conclusion of this study and may be based on samples 
derived from multiple studies.
Tissue collection: A biopsy (archived or Screening) will be collected at Screening.  Archived 
tissue samples can be provided as either blocks or slides (see “provision of samples” 
paragraph immediately below).  Endoscopic biopsies, core needle biopsies, excisional 
biopsies, punch biopsies, and surgical specimens are suitable.  Fine needle aspiration biopsies 
are not suitable.  Biopsies are only to be obtained from safely accessible tumor tissue sites.
Provision of archival samples: 1) Priority: tumor containing formalin-fixed, 
paraffin-embedded (FFPE) tissue block; 2) Priority: if the tumor containing FFPE tissue 
block cannot be provided in total, sections fromthis block should be provided that are freshly 
cut and mounted on positively-charged glass slides (SuperFrost Plus are recommended).  
Preferably, 25slides should be provided; if not possible, a minimum of 15slides is required 
for PD-L1 expression analysis and other tissue/molecular profiling assessments.
Tissue processing: The cancer tissues should be fixed in 10% neutral buffered formalin, 
paraffin embedded, and routinely processed for histological evaluation.  Formalin substitutes 
are not suitable as fixatives.  See Laboratory Manual for additional details on sample 
provisioning and tissue processing.  Sample and tissue repository: Biomarker samples may 
be stored beyond the end of the trial and utilized at a later time jointly with samples from 
other studies in order to investigate actions of the investigational drug(s) or aspects of the 
disease under study and/or to support the development of an IHC-based investigational 
PD-L1 assay.
Optional De NovoTumor Biopsy: An optional baseline de novo(ie, fresh) biopsy of an 
accessible tumor lesion may be obtained during screening and/or at EOT (note that a denovo
tumor biopsy must be obtained at Screening if an archival specimen is not available to satisfy 
the requirement for the mandatory FFPE tumor tissue).  All denovobiopsy or biopsies 
should be processed as FFPE (see Central Lab Manual), and the resulting FFPE tissue 
block(s) [one per time-point] should be submitted to the Central Laboratory.
 
 
 
 
 
 
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CCI
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
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7.4.2.1.Additional Research
Unless prohibited by local regulations or IRB/EC decision, subjects will be asked to indicate 
on the consent form whether they will allow banked biospecimens to also be used to design 
and conduct research in order to gain a further understanding of other diseases and to 
advance science, including development of other medicines for patients. 
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimens specified in the Banked Biospecimens section will be used.  Subjects may still 
participate in the study if they elect not to allow their banked biospecimens to be used for the 
additional purposes described in this section.
7.5.Patient-Reported Outcomes
 
During the Phase3 component of the study, the NCCN-FACT FLymSI-18 (FlymSI-18), 
Brief BFI and EQ-5D-5L questionnaires will be administered via a hand-held electronic 
device designed to administer patient reported outcome questionnaires (ePRO).  Each patient 
will be given the ePRO device at the first day of the first cycle.  The ePRO device will 
prompt the patient to complete the questionnaires at on the first day of the first visit.  After 
completing the questionnaires on the first day of the first visit, the device will prompt the 
patient to complete the BFI and EQ-5D-5L every 7days and the FlymSI-18 every 28days.  If 
a patient does not complete the questionnaires on the day the patient is prompted, the device 
will prompt the patient to complete the questionnaires each subsequent day of the week until 
the questionnaires are completed.  At the 90-day follow-up visit the device will be collected 
from the patient (seeTable2).
NCCN-FACT FLymSI-18:
The FlymSI18, which is a revised, more symptom focused version of the FACT-Lym, was 
developed to be part of the Functional Assessment of Chronic Illness Therapy (FACIT) 
system.  Unlike the FACT-Lym, the FlymSI-18 was developed following the 2009 Food and 
Drug Administration (FDA) guidance on patient reported outcomes measures with the input 
from the Food and Drug Administration (FDA).
74  The FlymSI-18 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 advanced lymphoma.74
The FlymSI-18 questionnaire was validated using a sample of patients with advanced 
lymphoma (stageIII or IV).
74
CCI
Responses on the 18items of the FlymSI-18 questionnaire are used to calculate a total score 
and scores for four subscales; Treatment Side Effect (TSE), Disease Related Symptoms 
Physical subscale (FLymSI DRS P), Disease Related Symptoms Emotional subscale 
(FlymSIDRS E), and Function/Well-being subscale.  The FlymSI DRS-P and 
FlymSI-DRS-E can be used to calculate an overall disease related symptom score, the 


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FlymSI-DRS.  The questionnaire contains 18Likert items.  The expected completion time for 
a patient is 4 to 6minutes.75
Brief Fatigue Inventory (BFI):
The BFI contains 9items and it was developed to be MD Anderson to assess fatigue and the 
impact of fatigue on the patient.  The BFI was validation work was based on a sample of 
305patients with cancer, some of whom were under in-patients care and some were under 
out-patient care at the time.  The questionnaire contains 3items related to the severity of 
fatigue and 6items assessing the degree to which fatigue interferes with different aspects of 
quality of life.  Response on each item will be based on a 0-10Likert scale.  Although the 
developers of the BFI suggest using the using all three fatigue severity items when estimating 
the level of fatigue, as per precedence found in FDA label claims, only item3, (the “worst 
level of fatigue in the last 24-hours” item) will be used for estimating fatigue intensity.  The 
level of fatigue interference will be based on all interferes items a per the user manual forthe 
questionnaire.  The expected completion time for a patient is 3 to 5minutes.
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.
82  There are two components to the EuroQol 
EQ-5D-5L: a Likert scale system in which individuals rate their level of problems (none, 
slight, moderate, severe, extreme/unable) in 5areas (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. 
The responses to the 5Likert scale items are used to calculate a utility score.  The response 
on the visual analogue scale item is used as a self-reported health status score.  The expected 
questionnaire completion time for a patient is estimated to be about 12minutes.75
CCI
 
  
 
 
 
 


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8.ADVERSE EVENT REPORTING
8.1.Requirements
The table below summarizesthe requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2)non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
CCI
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported asdescribed in the following 
paragraphs.
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Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24hours of awareness of the event by the investigatorare to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event
within 24hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Eventssection below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 
subject death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLYupon request.
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.
8.1.1.Additional Details on Recording Adverse Events on the CRFs
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2.Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.


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8.1.3.Withdrawal From the Study Due to Adverse Events (see also the Patient 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the
Requirementssection above.
8.1.4.Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 90days after the last administration of the investigational product.  For patients 
who are screen failures, the active collection period ends when screen failure status is 
determined.
8.1.4.1.Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at leasta reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.  Follow up by the investigator continues 
throughout and after the active collection period and until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.  If 
a patient begins a new anticancer therapy, SAEs occurring during the above-indicated active 
collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2.Recording Non-Serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.  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.  If 
a patient begins a new anti-cancer therapy, the recording period for non-serious AEs ends at 
the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
8.1.5.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 on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 


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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.  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, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6.Sponsor’s Reporting Requirementsto Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2.Definitions
8.2.1.Adverse Events
An AE is any untoward medical occurrence in a study subject 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 signs and symptoms;
Changes in physical examination findings;
Hypersensitivity;
Drug abuse;
Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:
Drug overdose;
Drug withdrawal;
Drug misuse;
Drug interactions;
Extravasation;


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Exposure during pregnancy (EDP);
Exposure via breastfeeding;
Medication error;
Occupational exposure.
Worsening of signs and symptoms of the malignancy under study should be recorded 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.
8.2.2.Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditionsare met: 
Test result is associated with accompanying symptoms; and/or
Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or
Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) 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 
recording as an AE.
8.2.3.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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Or that is considered to be:
An important medical event.
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 subject 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.
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 active collection 
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 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteriafor Adverse Events (CTCAE) 
Grade5 (see the Severity Assessment Section 8.3).
A serious injury that can cause a serious deterioration in state of health can include:
A life-threatening illness, even if temporary in nature;
A permanent impairment of a body function or permanent damage to a body 
structure; 
A condition necessitating medical or surgical intervention to prevent the above 
2bulleted items;
Examples: clinically relevant increase in the duration of a surgical procedure; a 
condition that requires hospitalization or significant prolongation of existing 
hospitalization;
Any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;
Fetal distress, fetal death, or any congenital abnormality or birth defects.
8.2.4.Hospitalization
Hospitalization is defined as any initial admission (even less than 24hours) 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 


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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is assessed for medical importance.
Hospitalization does not include the following:
Rehabilitation facilities;
Hospice facilities;
Respite care (eg, caregiver relief);
Skilled nursing facilities;
Nursing homes;
Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE.  Examples include:
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);
Social admission (eg, subject 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 forthe individual subject;
Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.


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8.3.Severity Assessment
GRADE Clinical Description of Severity
0  
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject
's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4.Special Situations
8.4.1.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 Section 8.1.4.1, Serious Adverse Event Reporting Requirements. 
8.4.2.Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liverinjury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3times the upper limit of 
normal (×ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 ×ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 ×ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.


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The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:
Subjects with AST/ALT and TBilibaseline values within the normal range who 
subsequently present with AST OR ALT values >3 ×ULN AND a TBili value 
>2×ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2×ULN or not available;
For subjects with baseline AST OR ALT ORTBili values above the ULN, the 
following threshold values areused in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
Preexisting AST or ALT baseline values above the normal range:AST or ALT values 
>2times the baseline values AND >3 ×ULN; or >8×ULN (whichever is smaller).
Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN orif the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or proteinadduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitisA, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 


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All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3.Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24hours of investigator 
awareness.
8.4.3.1.Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:
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).
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 subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT 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 subject 
reports that she is pregnant and has been exposed to a cytotoxic product by inhalation or 
spillage) to Pfizer Safety using the EDP supplemental form.  This must be done irrespective 
of whether an AE has occurred and within 24hours of awareness of the exposure.  The
information submitted should include the anticipated date of delivery (see below for 
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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 Safety 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 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported toPfizer Safety 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 1month should bereported 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 sponsor.  Further 
follow-up of birth outcomes willbe 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 subject with the Pregnant Partner Release of Information Form 
to deliver to his partner.  The investigator must document in the source documents that the 
subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.3.2.Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported,irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3.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.


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An occupational exposure is reported to Pfizer Safety within 24hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4.Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1.Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength.
Medication errors include:
Medication errors involving subject 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 subject.
Such medication errors occurring to a study participant are to be capturedon the medication 
error pageof the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24hours on a CT SAE Report 
Form only when associated with an SAE.
9.DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 


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modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment.
9.1.Sample Size Determination
Phase 1b
It is expected that up to ~84 patients will be randomized among 3treatment arms (28patients 
each) in Phase1b.  The null hypothesis that the ORR for one arm does not exceed 46% 
(H
0:ORR46%) will be tested against the alternative hypothesis (H1: ORR>46%) at a 
one-sided level of significance =0.025 using the binomial distribution.  28patients in each 
treatment arm will provide at least 79.7% power to reject the null hypothesis if the true ORR 
is at least 73% (ORR 73%).
If there are 18objective responders out of 28patients treated in a given treatment arm, then 
it will be declared that for that treatment arm the null hypothesis cannot be rejected.  If there 
are 19objective responders out of 28patients treated in a given treatment arm, the null 
hypothesis will be rejected for that treatment arm and clinically meaningful activity has been 
demonstrated.
Phase 3
The primary objective of this component of the study is to demonstrate that the selected 
Phase1b avelumab-based combination regimen is superior to Investigator’s Choice 
chemotherapy in prolonging PFS (as assessed by BICR).
The Phase3 component of the study is designed to test the null hypothesis that the true PFS 
hazard rate for the selected Phase1b combination regimen is greater than or equal to the one 
for Investigator’s choice chemotherapy (hazard ratio [HR] 1) versus the alternative 
hypothesis that the true hazard rate is smaller in the selected Phase1b combination regimen 
(HR<1).
The study will randomize (1:1) a total of approximately 220patients stratified by IPI score 
(2 vs. 3) and primary disease (refractory vs. relapsed).  The sample size for the study is 
based on the assumptions that the median PFS for patients receiving Investigator’s choice 
chemotherapy is 3.6months1and that treatment with the selected Phase1b combination 
regimen is expected to increase the median to PFS 6months, corresponding to a HR of 
0.60under the exponential model assumption.
If the true HR is 0.6 under the alternative hypothesis, a total of 164PFS events will be 
required to have 90% power to demonstrate superiority using a stratified one-sided log-rank 
test at a one-sided 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 spending function (= -10) to determine the non-binding futility boundary.


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Assuming a 15% drop-out rate for PFS within each treatment arm, a non-uniform accrual 
accomplished over a 9-month period and a minimum follow-up of approximately 12months 
after the last patient is randomized, a total of approximately 220patients will need to be 
randomized in a 1:1ratio to the selected Phase1b combination regimen or Investigator’s 
Choice chemotherapy.  The data cutoff for the primary PFS analysis will occur after the 
target number of events has been reached in both comparisons and the last patient 
randomized in the study has been followed for at least 12months after randomization.
The key secondary efficacy objective for this component of the study is to compare the 
selected Phase1b combination to Investigator’s Choice and demonstrate that the selected 
Phase1b combination regimen is superior to Investigator’s choice chemotherapy in 
prolonging OS.  The sample size of 220patients will also allow the assessment of the effect 
on OS of the selected Phase1b combination regimen versus Investigator’s Choice 
chemotherapy.  OS will be tested if superiority with respect to PFS has been demonstrated.  
This hierarchical testing approach will allow control of the overall probability of Type1 error 
at 0.025(1-sided).  The median OS for patients receiving Investigator’s Choice 
chemotherapy is assumed to be 8months,69and treatment with the selected Phase1b 
avelumab-based combination regimen is expected to increase median OS to 12.3months, 
corresponding to an HR of 0.65under the exponential model assumption.  If the true HR is 
0.65 under the alternative hypothesis, a total of 174deaths will be required to have 
80%power to detect a HR of 0.65 for OS at the one-sided significance level of 0.025 using a 
stratified log-rank test and a 3-look group sequential design with Lan-DeMets 
(O’Brien-Fleming) -spending function to determine the efficacy boundary.  These 
calculations further assume a 5% drop-out rate for OS within each treatment arm and a 
follow-up of approximately 20months after the last patient is randomized.  The data cutoff 
for the final OS analysis will occur after the target number of events has been reached.
9.2.Statistical Methods and Properties
An IRC evaluation of the first 6and/or 12DLT evaluable patients in each treatment arm will 
occur after the last patient has completed one cycle of treatment.  Enrollment will be halted 
while the first 6DLT evaluable patients in each treatment arm are being evaluated for safety.
Table20shows the probability of confirming the safety in the first 6or 12DLT evaluable 
patients for a range of true DLT rates.  For example, for a DLT that occurs in 10% of 
patients, there is 97.3%probability of confirming safety and expanding the corresponding 
treatment arm.  Conversely, for a DLT that occurs with a rate of 70%, the probability of 
treatment arm expansion is 1.2%.
Table20. Probability of Confirming Safety in the First 6 or 12 DLT Evaluable 
Patients
True 
underlying 
DLT rate
5% 
10% 
20% 
30% 
40% 
50% 
60% 
70%
Probability of 
expanding 
dose
0.997 
0.973 
0.816 
0.556 
0.306
0.135
0.047 
0.012


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9.3.Analysis Population
9.3.1.Full Analysis Sets
The Full Analysis Set will include all randomized patients.  Patients will be classified 
according to the treatment assigned at randomization.  The Full Analysis Set will be the 
primary analysis set for evaluating all efficacy endpoints and patient characteristics.
9.3.2.Per Protocol Analysis Set
The Per-Protocol Analysis Set is a subset of the Full Analysis Set and will include patients 
who receive at least 1dose of study treatment and do not meet specific criteria expected to 
impact the primary objective of the study.  The criteria used to exclude patients from the 
per-protocol analysis set will be pre-specified in the SAP.  The Per-Protocol Analysis Set 
will be used for sensitivity analyses for the primary efficacy endpoint.
9.3.3.Evaluable for DLT Analysis Set
The DLT Analysis Set is the analysis set for the safety confirmation and includesrandomized 
patients in each armwho are eligible for the study, receive at least 1dose of studytreatment, 
and either experience DLT during the first cycle, or complete the primary DLT observation 
period for 4weeks. Patients without DLTs who withdraw from study before completing the 
4week DLT observation period for reasons other than dose limiting toxicity (eg, missed 
appointments or development of rapidly progressing disease) are not evaluable for DLT. 
9.3.4.Safety Analysis Set
The Safety Analysis Set will include all patients who receive at least 1dose of investigational 
drug.  Patients will be classified according to the treatment assigned at randomization unless 
the incorrect treatment(s) are received throughout the dosing 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.
9.3.5.PK Analysis Set
The PK Concentration Analysis Set is a subset of the safety analysis set and will include 
patients who have at least 1concentration above the lower limit of quantitation (LLQ) for 
avelumab, utomilumab, rituximab, bendamustine, or azacitidine.
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, utomilumab, rituximab, 
bendamustine, or azacitidine.
9.3.6.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 either avelumab, utomilumab 
or rituximab.


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9.3.7.Biomarker Analysis Set
The Biomarker Analysis Set is a subset of the Safety Analysis Set and will include all 
patients who have at least 1baseline biomarker assessment.  Analysis sets will be defined 
separately for blood-based and tumor tissue-based biomarkers.
 
 
9.3.9.PRO Analysis Set
The PRO analysis set is a subset of the efficacy set and will include patients with at least one 
baseline (Day1 of Cycle1 data) assessment and one post-baseline assessement from either 
the BFI, the NCCN-FACT-FLymSI-18, or the EQ-5D-5L questionnaire. 
 
 
 
9.4.Efficacy Analysis
All efficacy analyses will be performed on the Full Analysis Set unless otherwise specified.
All analyses will be performed by using SAS
Version9.1.3 or higher.
All primary and secondary endpoints based on radiological assessments of tumor burden 
(ie,PFS, OR, TTR, DR, DC) will be derived using the local radiologist’s/investigator’s 
assessment.  In addition, radiographic images and clinical information collected on Phase3 
component of the study will also be reviewed by BICR to verify investigator reported tumor 
assessments.  Review by BICR will be used for the primary analyses.
In the Phase3 component, the primary analyses of PFS by BICR assessment will be repeated 
on the Per-Protocol Analysis Set as sensitivity analyses.  All planned sensitivity analyses will 
be described in the Statistical Analysis Plan (SAP).
9.4.1.Analysis of the Primary Endpoint
Phase 1b
CCI
DLTs will be graded according to NCI-CTCAE version 4.03 and coded 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.
DLTs will be summarized by number and percentage of patients with DLTs, by treatment 
group, primary SOC and PT.
CCI


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OR is defined as a CR or PR per Lugano response classification criteria from randomization 
until disease progression or death due to any cause.  A patient will be considered to have 
achieved an OR if the patient has a sustained CR or PR as per Lugano response classification 
criteria definitions.  Otherwise, the patient will be considered as a non-responder in the OR 
rate (ORR) analysis.  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.
Phase 3
PFS is defined as the time from randomization to the date of the first documentation of 
objective PD or death due to any cause, whichever occurs first.
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start new anti-cancer treatment prior to 
an event, or for patients with an event following two or more missing tumor assessments.  
Patients who do not have a baseline tumor assessment or who do not have anypost baseline 
tumor assessments will be censored on the day of randomization, with a duration of 1 day, 
unless death occurred on or before the time of the second planned tumor assessment in which 
case the death will be considered as an event.
A stratifiedlog-rank test (one sided) will be used within each comparison at the interim 
and/or final analyses with the overall significance level preserved at 0.025 (one 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 75
thpercentiles will be reported.  The Cox proportional hazards model will be fitted 
to compute the treatment hazard ratios and the corresponding 95% CIs.
PFS by BICR assessment will also be evaluated based on the Per-Protocol Analysis Set as a 
sensitivity analyses, using the stratified log-rank test (one sided, =0.025).
A sensitivity analysis for PFS by BICR assessment will also be performed counting all PD 
and deaths as events regardless of missing assessments or timing of the event.
Proportional Hazards Assumption Evaluation
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 proportional hazards (PH).  The PH assumption will be 
formally tested using Schoenfeld’s residual test.
91  Large departures from PH will be 
evidenced by a p-value <0.05. 


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In addition, the PH assumption will be checked visually by plotting 
log(-log(S(t)) versus log(t), 
where S(t) is the estimated survival function (for PFS) at time t.
If these show large departures from proportional hazards, then PFS by BICR assessment will 
also be analyzed based on restricted mean survival time (RMST) differences.
92
The RMST up to time t* can then be interpreted as the expected survival time restricted to 
the common follow-up time t* among all patients.  Here t* = min of (largest observed 
survival time for the experimental arm, largest observed survival time for control arm) in 
months.  RMST can be estimated consistently by the area under the Kaplan-Meier curve over 
[0, t*]. 
The associated 95% CI for the difference in means and one-sided p-value will be generated.  
RMST as a function of t* and the associated treatment effect between the selected Phase 1b 
combination regimen and Investigator’s Choice chemotherapy will be plotted against time t*.
9.4.2.Analysis of Secondary Endpoints
9.4.2.1.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.
In the Phase3 component of the study, OS will be hierarchically tested for significance at the 
time of PFS analysis, provided the primary PFS endpoint is statistically significant at the 
interim or final analyses of PFS.  A stratified log-rank test (onesided) will be used at the 
interim and/or final analyses with the overall significance level preserved at 0.025 (one 
sided). 
In both components, OS time associated with each treatment arm will be summarized using 
the Kaplan Meier method and displayed graphically where appropriate.  Confidence intervals 
(CIs) for the 25
th, 50
th, and 75
thpercentiles will be reported.  In the Phase3 component, the 
Cox proportional hazards model will be fitted to compute the treatment hazard ratios and the 
corresponding 95%CIs.  
9.4.2.2.Progression-Free Survival at 6 Months
A patient will be considered to be progression-free at 6months if the patient has disease 
assessment demonstrating non-progression for at least 6months after randomization.  The 
PFS rate at 6months for each treatment arm will be estimated by dividing the number of 
patients who are progression-free at 6months by the total number of patients randomized to 
the respective treatment arm.  The corresponding exact 2-sided 95% CIs will be provided by 
treatment arm. Kaplan-Meier estimates of the PFS rate at 6months and the corresponding 
exact 2-sided 95% CIs will also be provided by treatment arm.


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9.4.2.3.Time to Tumor Response 
TTR is defined, for patients with an OR per the Lugano Disease Assessment Response, 
Lugano response classification criteria, as the time from randomization to first 
documentation of objective tumor response (CR or PR).
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max, 
Q1, Q3).
9.4.2.4.Duration of Response
DR is defined, for patients with an OR per Lugano response classification criteria, as the time 
from first documentation of OR (CR or PR)to the first documentation of objective tumor 
progression or death due to any cause, whichever occurs first.  Censoring rules for DR will 
follow those described 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.
The 6-month DRR for each treatment arm will be estimated by dividing the number of 
patients who achieve and maintain an OR for at least 6months by the total number of 
patients randomized to the respective treatment arm.  The corresponding exact 2-sided 95% 
CIs will be provided by treatment arm.
9.4.2.5.Disease Control
DC is defined as Best Overall Response of CR, PR, or SD.  DC rate (DCR) is the proportion 
of patients with DC.
DCR will be summarized by frequency counts and percentages.
9.4.2.6.Analysis of PD-L1 and MRD
The relationship between different PD-L1 expression levels in tumor cells and cells of the 
tumor microenvironment (eg, infiltrating lymphocytes) and selected clinical response 
parameters will be assessed.  The relationship between minimal residual disease burden and 
selected clinicalresponse parameters will be assessed.  Detailed methodology for statistical 
analysis of these endpoints will be documented in the SAP.
9.5.Analysis of Pharmacokinetics and Pharmacodynamics
The Central Laboratory, analytical laboratories (eg, PK, ADA, NAb), and Pfizer clinical 
assay group (CAG) colleagues will be unblinded.  If early analysis of the PK data is 
necessary (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.  Blinded analysis of PK/PD 
samples will only be for Phase3 component of the study. 


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9.5.1.Analysis of the Pharmacokinetics of Study Drugs
If data permit or if considered appropriate, plasma pharmacokinetic parameters including the 
maximum plasma concentration (Cmax), time to maximum plasma concentration (T
max), 
trough plasma concentrations (C
trough) and area under the plasma concentration versus time 
curve (AUC
last, AUC) for avelumab, rituximab, utomilumab, azacitidine and bendamustine 
will be estimated using non compartmental analysis.  Area under the plasma concentration 
versus time curve to infinity (AUC
inf), terminal elimination half life (t
1/2), oral plasma 
clearance (CL/F)[CL for IV dosing], apparent volume of distribution (V
ss/F or V
z/F)[V
ssfor 
IV dosing], accumulation ratio (R
ac) will be also estimated.  The single-dose and steady state 
PK parameters will be summarized descriptively by treatment arm, cycle and day. 
Select PK parameters (ie,Cmax, C
trough, and other parameters, as appropriate) for each analyte 
in the three avelumab-based combination regimenswill be compared to historical data for 
that analyteas monotherapyto assessany drug-drug interactionpotentialamong the drugs 
coadministered within each combination regimen.
For all study drugs, concentrations will be summarized descriptively (n, mean, SD, 
coefficient of variation (CV), median, minimum, maximum, geometric mean and its 
associated CV) bytreatment arm, cycle, day and nominal time.  Individual patient and 
median profiles of the concentration time data will be plotted by treatment arm, cycle and 
day (single dose and steady state) using nominal times.  Individual and median profiles will 
be presented on both linear linear and log linear scales.
The observed trough concentrations for each study drug will be plotted using a box whisker 
plot by cycle and day in order to assess the attainment of steady state.  The observed 
accumulation ratio willbe summarized descriptively.  
9.5.2.Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/PD) Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data fromother studies to investigate any 
association between study drug exposure and biomarkers or significant safety endpoints.  The 
results of these analyses, if performed, may be reported separately.
9.6.Analysis for Avelumab, Rituximab and Utomilumab Immunogenicity
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be summarized by treatment for each dosing interval for avelumab, 
rituximab and utomilumab.  For patients with positive ADA, the magnitude (titer), time of 
onset, and duration of ADA response will also be described, if data permit.  The effect of 
ADA on avelumab, rituximab and utomilumab concentrations will be evaluated.
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 
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9.7.Analysis of Patient-Reported Outcomes
NCCN-FACT FLymSI-18, Brief Fatigue Inventory (BFI), and EQ-5D-5L will be scored 
according to their respective validation papers and user’s guides.
The FlymSI DRS P will be used to determine the Time to Deterioration (TTD) in physical 
symptoms of disease.  TTD is defined as the time from first dose (baseline) to the first time 
the patient’s score shows a 3point or greater decrease in the FlymSI DRS P (note: lower 
scores represent lower quality of life and high symptoms burden on the FLymSI-18 scores).  
If a patient has not deteriorated prior to the FlymSI DRS P assessment, the patient will be 
censored at the last time assessment time point.  Kaplan Meier plots will be used to display 
deterioration over time and a log-rank test will be used tocompare the TTD between the two 
treatment arms.  The median time and 2-sided 95% CI for the median will be provided based 
on the Brookmeyer Crowley method.
83
Yost and Eton (2005) established that a3-point or greater change from baseline as the 
minimally important difference (MID) change from baseline on the FACT scales because a 
change that large or greater would correlate with change in disease symptoms and status.84  
For the BFI scores, a 3-point or greater change assumed to meet or surpass the threshold of a 
minimally important change. 
Similarly, the BFI will be used to determine the Time to Deterioration (TTD) in terms of 
fatigue.  TTD is defined as the time fromfirst dose (baseline) to the first time the patient’s 
score shows a 3point or greater increase in the worst fatigue in the past 24hours item 
(ie,item 3) (with higher scores representing higher levels of fatigue on the BFI).  If a patient 
has not experienced deterioration in terms of fatigue (ie, higher fatigue) prior to the last 
assessment with the BFI questionnaire, the patient will be censored at the assessment time 
point.  Kaplan-Meier plots will be used to display deterioration over time and a log-rank test 
will be used to compare the TTD between the 2treatment arms.  The median time and 
2-sided 95% CI for the median will be provided based on the Brookmeyer-Crowley 
method.83
Additionally, symptom subscale improvement in physical symptoms of disease will be 
defined as an increase of at least 3points in the FlymSI–DRS-P subscale score of the 
FlymSI-18.  In terms of fatigue, improvement will be defined as a decrease of at least 
3points from baseline on theworst fatigue question of the BFI.  A chi-square test will be 
used to compare treatment arms.  To minimize bias due to differential follow-up, the 
improvement analysis will be limited to scores observed during the first 4months of 
treatment.  Within-group and between-group comparisons to baseline in order to assess 
symptom improvement among treatment arms will also be performed.  To test the robustness 
of the MID of 3points, sensitivity analyses using 2 and 4points will be explored.
Patient reported disease-/treatment-related symptoms of lymphoma, function/well-being, and 
general health status will also be assessed.  Summary statistics [mean, standard deviation, 
median, range and 95% CI] of absolute scores will be reported for all of the subscales of the
FlymSI-18, the BFI subscales, utility score and self-reported health status score from the 
EQ5D5L.  The mean change of absolute scores from baseline (and 95%CI) will also be 


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assessed.  Line charts depicting the means and mean changes of items and subscales over 
time will be provided for each treatment arm.  Additional exploratory analyses may be 
performed, such as repeated measures mixed effects modeling and analyses of patients who 
experienced a complete response.
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.10.Analysis of Other Endpoints
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, and safety parameters.  Data will also be displayed graphically, 
where appropriate.
9.11.Safety Analysis
The Safety Analysis Set will be the primary population for safety evaluation. 
9.11.1.Adverse Events
CCI
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 
CCI
CCI


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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 cycle and 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.
9.12.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.
9.13.Electrocardiograms
The analysis of ECG results will be based on patients in the safety analysis set with baseline 
and on treatment ECG data. 
ECG measurements (an average of the triplicate measurements, if applicable) will be used for 
the statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors [ie, 
Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, QTc and by 
study arm.  Individual QT (all evaluated corrections) intervals will be listed by treatment arm 
and time.  The most appropriate correction factor will be selected and used for the following 
analyses of central tendency and outliers and used for the study conclusions. 
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 by study arm and time point.  For each patient and by treatment, the 
maximum change from baseline will be calculated as well as the maximum post baseline 


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interval across time points.  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 (one or more 
correction method will be used).  Shift tables will also be provided for ECG abnormality at 
baseline vs. on treatment (yes, no, not done: (n,%)).  Patients experiencing clinically relevant 
morphological ECG changes will be summarized (including frequency and percentage).
The effect of drug concentrations on corrected QT change from baseline will be explored 
graphically.  Additional concentration corrected QT analyses may be performed.  Data may 
be pooled with other study results and/or explored further with PK/PD models.
9.14.Interim Analysis
Phase 1b
The purpose of the IA in the Phase1b component of thestudy is to allow for early stopping 
of any treatment armfor futility based on ORR. Thecutoff for the IA is13weeks after 
8patients in each treatment arm have been randomized. If 2responses are observed for 
8patients in a treatment arm, further enrollment in the treatment arm maybe stopped.
Table21provides the conditional power of the Phase1b when the futility boundary is 
crossedat the time of the IA based on the test of hypothesisdescribedin Section9.1.
Table21. Conditional Power for the Phase 1b Based on the Interim Analysis Results
Responders/Number of 
patients
True ORR=50% 
True ORR=60% 
True ORR=73%
0/8
<0.001
0.001
0.016
1/8
<0.001
0.004
0.064
2/8
0.001
0.016
0.170
Phase 3
The purpose of the IAin the Phase3 component of this study is to allow for early stopping of 
the study for efficacy or futility (based on PFS) and to further assess the safety of the selected 
Phase1b avelumab-based combination regimen.  The IA will be performed after all of the 
patients have been randomized in the study.
The Phase3 component of the study is designed to have 1IA and the final analysis, both 
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 Type1 error rate, a 
fraction of alpha (0.006) for efficacy will be spent at the IA and accounted for in the overall 
Type1 error rate if the IA 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 


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boundary.  The overall significance level for the efficacy analysis of PFS will be preserved at 
0.025(1-sided test).
The IA will be performed following approximately 109 PFS events (67% of the 164PFS 
events planned at the end of the study).  If the value of the test statistic exceeds the efficacy 
boundary (z <-2.514, p <0.006), then the superiority of the selected Phase1b regimen 
compared to Investigator’s Choice chemotherapy in prolonging PFS may be demonstrated.  
If the value of the test statistic exceeds the futility boundary (z>0.037, p>0.515) the study 
may be stopped for futility.  If the results of the IA indicate serious safety concerns, the 
Sponsor will communicate with the Health Authorities regarding stopping the relevant 
investigational arms of the clinical trial.
The key secondary OS endpoint will be analyzed using a hierarchical testing procedure, 
provided the primary endpoint is statistically significant favoring the selected Phase1b 
combination regimen.  Up to 3analyses are planned for OS: at the time of the interim PFS 
analysis, at the time of the final analysis for PFS, and at 100% (final OS analysis) of the 
174OS events required for each comparison.  An -spending function according to 
Lan-DeMets (O’Brien-Fleming) independent of the one used for the primary efficacy 
analysis will be used to determine the efficacy boundary.  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 the selected Phase1b combination regimen.
9.15.Data Monitoring Committee
This study will use an IRC in the Phase1b component of the study and an E-DMCfor the 
Phase3 component of the study. 
TheIRCwill review the safety data from the Phase1b according to the IRC charter in order 
to support the selection of an adequately safe experimental arm for the Phase3 componentof 
the study.
The E-DMC will be responsible for ongoing monitoring of the efficacy and safety of patients 
in thePhase3 component of thestudyaccording to the E-DMC charter.  The 
recommendations made by the EDMC 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. 
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.


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During study conduct and/or after study completion, the Investigator site may be patient to 
review bythe institutional review board (IRB)/ethics committee (EC), and/or to quality 
assurance audits performed by Pfizer, or companies working with or on behalf of Pfizer, 
and/or to inspection by appropriate regulatory authorities.
The Investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the Investigator will cooperate with Pfizer 
or its agents to prepare the Investigator site for the Inspection and will allow Pfizer or its
agent, whenever feasible, to be present during the inspection.  The Investigator 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 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 isimportant 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/ElectronicData Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The Investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the Investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital or the physician patient chart.  In these
cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those datathat 
will be recorded on the CRF, and for which the CRF will stand as the source document.


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11.2.Record Retention
To enable evaluations and/or inspections 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/assent 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 15years after completion or 
discontinuationof 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/assent 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 toeliminate apparent immediate hazards to the patients.  In 
that event, the Investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2.Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, 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 Guidelines for Good Clinical Practice (ICH 1996), 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. 


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When study data are compiled for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by numerical code based on a 
numbering system provided by Pfizer in order to de-identify study patients. The Investigator 
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/assent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent/assent documents used during the informed consent process and any 
subject recruitment materials must be reviewed and approved by Pfizer, 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 thatthe 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 mustbe documented in the source documents.
The Investigator, or a person designated by the Investigator, will obtain written informed 
consent from each patient or the patient’s legallyacceptable representative, and the patient’s 
assent, when applicable, before any study-specific activity is performed, unless a waiver of 
informed consent has been granted by an IRB/EC.  The Investigator will retain the original of 
each patient
's signed consent/assent document.
12.4.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 
regulatory authority in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation ofthe benefits and risks of the investigational 
product, Pfizer should be informed immediately. 


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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 OFTRIAL
13.1.End of Trial in All Other Participating Countries
End of trial in a Member State of the European Union is definedas 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 Participating Countries
End of trial in all other participating countries is defined as last patient last visit (LPLV).
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 at any time.
If a study is prematurely terminated, Pfizer will promptly notify the Investigator.  After 
notification, the Investigator must contact all participating patients and the hospital pharmacy 
(if applicable) within 1month.  As directed by Pfizer, all study materials must be collected 
and all CRFs completed to the greatest extent possible.
15.PUBLICATION OF STUDYRESULTS
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 studyor 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 1year of the primary completion date (PCD) for 


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studies in adult populations or within 6months of the PCD for studies in pediatric 
populations.
PCDdate is defined as the date that the final patient was examined or received an 
intervention for the purposes of final collection of data for the primary outcome, whether the 
clinical study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts 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 1year of the PCD for studies in adult populations or within 6 months of 
the PCD 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 the 
principal Investigator (PI) of the results of the study based on information collected or 
generated by the PI, whether or not the results are favorable to the Pfizer product.  However, 
to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the Investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “publication”) 
before it is submitted or otherwise disclosed.
The Investigator will provide any publication to Pfizer at least 30days before it is submitted 
for publication or otherwise disclosed.  If any patent action is required to protect intellectual 
property rights, the investigator agrees todelay the disclosure for a period not to exceed an 
additional 60days.
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 Investigator’s sites, and that any subsequent publications 
by the PI will reference that primary publication.  However, if a joint manuscript has not 
been submitted for publication within 12months 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.


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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 andany 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 issueregarding treatment of study patients, and the CSA will control as to all other 
issues.


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the Functional Assessment of Cancer Therapy (FACT) Anemia and Fatigue Scales. 
Journal of Pain and Symptom Management, 24(6), 547-561.
86. Schleimer RP, Jacques A, Shin HS, et al. Inhibition of T cell-mediated cytotoxicity by 
anti-inflammatory steroids. J Immunol. 1984; 132:266-71.
87. Khan MM, Immunosuppressive Agents. In: Immunopharmacology. New York:
Springer; 2008.
88. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events 
and kinetics of response with ipilimumab. J Clin Oncol. 2012 Jul 20; 30(21):2691.
89. A predictive model for aggressive non-Hodgkin’s lymphoma. The International 
Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 
1993;329:987-994.
90. Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression 
model. Biometrika 1980; 67:145-53.
91. Therneau TM, Grambsch PM. Modeling Survival Data: Extending the Cox Model. 
Statistics for Biology and Health 2000.
92. 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.
93. Wolchok JD, Hoos A, O’Day S et a., Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res.  
09;12:7412-7420.


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Appendix1.Abbreviations
Abbreviation
Term
5FU
5-Fluorouracil
ABC
Activated B-cell
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
alanine aminotransferase
AML
Acute Myeloid Leukemia
ANC
Absolute Neutrophil Count
Anti–CTLA-4
Anti-cytotoxic T-lymphocyte-associated antigen-4
ASCT
Autologous stem cell transplant
AUC
Area Under the Curve
AUC0
Area under the plasma concentration time curve from time0 
to hours post dose
AST
aspartate aminotransferase
BFI
Brief Fatigue Inventory
BICR
Blinded Independent Central Review
BOR
Best Overall Response
CAR-T
Chimeric Antigen Receptor T-Cell
CBC
Complete blood count
CDS
core data sheet
CG
Cancer germline
CLL
Chronic Lymphocytic Leukemia
Cmax
Maximum Plasma Concentration
CMML
chronic myelomonocytic leukemia
CNS
Central nervous system
CR
Complete response
CRF
case report form
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
Clinical Study Report
CT
Computerized Tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CVP
Cyclophosphamide/Vincristine/Prednisone
CYP
Cytochrome P450
DC
Disease Control
DCR
Disease Control Rate
DLBCL
Diffuse Large B-cell Lymphoma
DLT
Dose-Limiting Toxicity
DMC
data monitoring committee


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Abbreviation
Term
DNA
deoxyribonucleic acid
DNMTi
DNAmethyltransferase inhibitor
DR
Duration of Response
DRR
Durable Response Rate
DLBCL-NOS
Diffuse Large B-Cell Lymphoma-nototherwise specified
EBV+
Epstein-Barr Virus positive
EC
ethics committee
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
E-DMC
External Data Monitoring Committee 
EDP
Exposure during pregnancy
ePRO
Electronically captured patient reported outcome
EQ-5D-5L
EuroQol 5-dimension 5-level questionnaire
ESMO
European Society of Medical Oncology
EudraCT
European Clinical Trials Database
FAB
French-American-British
FACIT
Functional Assessment of Chronic Illness Therapy
FACT
Functional Assessment of CancerTherapy
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United 
States)
FDG
Fluorodeoxyglucose
FFPE
Formalin-Fixed, Paraffin-Embedded
FL
Follicular Lymphoma
FlymSI-18
Follicular Lymphoma Symptom Index –18 item 
questionnaire
FSH
Follicle-stimulating hormone
GCB
Germinal Center B-cell
GCP
Good Clinical Practice
G-CSF
Granulocyte-Colony Stimulating Factors
GGT
Gamma glutamyl transferase
HBV
Hepatitis B Virus
HCV
hepatitis C Virus
HGBCL
High-Grade B-cell Lymphoma
HHV8
Human herpesvirus 8
HIV
Human immunodeficiency virus
HMA
Hypomethylating agent
HRQL
Health-Related Quality of Life
IA
Interim analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
IHC
Immunohistochemistry
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Abbreviation
Term
ICH
International Conference on Harmonisation
ID
Identification
Ig
Immunoglobulin
IND
Investigational New Drug Application
INR
International Normalized Ratio
IP
Investigational Product
IPI
International Prognostic Index
irAE
immune-Related Adverse Event
IRB
Institutional Review Board
IRC
Internal Review Committee
IRR
Infusion related reaction
IRT
Interactive Response Technology
IUD
Intrauterine device
IV
Intravenous
IVR
Interactive Voice Response
IWG
International Working Group
IWR
Interactive Web Response
KIRs
Killer-cell immunoglobulin-like receptors
LDi
Longest diameter
LFT
Liver Function Test
LPD
Local Product Document
LPLV
Last Patient Last Visit 
MAP
Mitogen Activated Protein
MCC
Merkel Cell Carcinoma
MDS
Myelodysplastic Syndrome
MDSCs
Myeloid derived suppressor cells
MID
Minimally important difference
MRD
Minimal residual disease
MRI
Medical resonance imaging
MTD
Maximum Tolerated Dose
N/A
Not applicable
Nab
Neutralizing antibodies
NCCN
National Comprehensive Cancer Network
NCCN-FACT FLymSI-18
FACT/NCCN-Lymphoma Symptom Index 18 item 
questionnaire
NCI
National Cancer Institute
NHL
Non-Hodgkin’s lymphoma
NOS
Not Otherwise Specified
NSAIDs
Nonsteroidal anti-inflammatory drugs
ORR
Overall Response Rate
OS
Overall Survival
PET
Positron Emission Tomography
PBMC
Peripheral blood mononuclear cells


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Abbreviation
Term
PBS
Phosphate-Buffered Saline
PCD
Primary Completion Date
PD
Progression of Disease
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PES
Polyether sulfone
PFS
Progression-Free Survival
PI
Principal Investigator
PK
Pharmacokinetic
PR
Partial Response
PRO
Patient Reported Outcome
 
PT
Prothrombin Time
Q2W
Every 2 weeks
RAEB
Refractory Anemia with Excess Blasts
RAEB-T
Refractory Anemia with Excess Blasts-T
RCC
Renal cell carcinoma
RNA
Ribonucleic acid
R/R
Relapsed/Refractory
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SCCHN
Squamous Cell Carcinoma Head and Neck
SCL
Supply Chain Lead
SIB
Suicidal ideation and behavior
SOC
Standard Of Care
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SRSD
Single Reference Safety Document
TEAE
Treatment Emergent Adverse Event
TILs
Tumor Infiltrating Lymphocytes
TO
Target receptor occupancy
TSE
Treatment Side Effect
TSH
Thyroid Stimulating Hormone
TTD
Time to Deterioration
TNFRSF
Tumor Necrosis Factor Receptor Superfamily
ULN
Upper Limit of Normal
US
United States
USPI
United States Package Insert
VAS
Visual Analogue Scale
WHO
World Health Organization
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Appendix2.Response Criteria for Malignant Lymphoma
From the International Workshop to Standardize Response Criteria for Lymphomas


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Appendix3.Eastern Cooperative Oncology Group Performance Status (ECOG PS)
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 selfcare 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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Appendix4.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 thisprotocol.  Alternatively, the NCI CTCAE may be reviewed online at the 
following NCI website:  http://ctep.cancer.gov/reporting/ctc.html.


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Appendix5.International Prognostic Index (IPI)
International Prognostic Index
89
ALLPATIENTS
INTERNATIONAL INDEX, ALL PATIENTS
Age >60 years
Low
0 or 1
Serum LDH > normal
Low-intermediate
2
Performance status 2-4
High-intermediate
3
Ann Arbor Stage III or IV
High 
4 or 5
Extranodal involvement >1 site 

SAP_001.pdf: 
Avelumab
B9991011 (MSB0010718C, PF-05082566) Statistical Analysis Plan – Phase 1b   
PFIZER CONFIDENTIAL
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B9991011 – PHASE 1B
PHASE 1B/PHASE 3 MULTICENTER STUDY OF AVELUMAB (MSB0010718C) IN 
COMBINATION REGIMENS THAT INCLUDE AN IMMUNE AGONIST, 
EPIGENETIC MODULATOR, CD20 ANTAGONIST AND/OR CONVENTIONAL 
CHEMOTHERAPY IN PATIENTS WITH RELAPSED OR REFRACTORY 
DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)
JAVELIN DLBCL
STATISTICAL ANALYSIS PLAN
Compounds:
MSB0010718C
PF-05082566
Compound Name:
Avelumab
Utomilumab
Version:
2.0
Date:
12-Feb-2018
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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B9991011 (MSB0010718C, PF-05082566) Statistical Analysis Plan – Phase 1b   
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
APPENDICES ...........................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................8
2.1. Study Objectives .......................................................................................................8
2.2. Study Design .............................................................................................................9
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoints...................................................................................................10
3.2. Secondary Endpoints...............................................................................................12
3.2.1. Safety Endpoints.........................................................................................12
3.2.2. Efficacy Endpoints......................................................................................12
3.2.3. Pharmacokinetic Endpoints ........................................................................12
3.2.4. Immunogenicity Endpoints.........................................................................13
3.2.5. Biomarker Endpoints..................................................................................13
3.4. Baseline Variables...................................................................................................14
3.4.1. Study Drug, Study Treatment and Baseline Definitions ............................14
3.4.2. Baseline Characteristics..............................................................................15
3.5. Safety Endpoints .....................................................................................................15
3.5.1. Adverse Events...........................................................................................15
4. ANALYSIS SETS ...............................................................................................................16
4.1. Full Analysis Set .....................................................................................................16
4.2. Safety Analysis Set..................................................................................................16
4.3. Other Analysis Sets .................................................................................................16
4.3.1. DLT-evaluable Analysis Set.......................................................................16
4.3.2. PK Analysis Sets.........................................................................................16
4.3.3. Biomarker Analysis Set..............................................................................17
4.3.4. Immunogenicity Analysis Set.....................................................................17
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................17
5.1. Hypotheses and Decision Rules ..............................................................................17
5.1.1. Hypotheses and Sample Size Determination..............................................17
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5.1.2. Decision Rules............................................................................................17
5.2. General Methods .....................................................................................................19
5.2.1. Data Handling After the Cut-off Date ........................................................19
5.2.2. Pooling of Centers ......................................................................................19
5.2.3. Presentation of Continuous and Qualitative Variables...............................20
5.2.4. Definition of Study Day..............................................................................20
5.2.5. Definition of Start of New Anti-cancer Drug Therapy...............................20
5.2.6. Definition of Start of New Anti-cancer Therapy........................................20
5.2.7. Definition of On-treatment Period..............................................................21
5.2.8. Standard Derivations and Reporting Conventions .....................................21
5.2.9. Unscheduled Visits.....................................................................................22
5.2.10. Adequate Baseline Tumor Assessment ....................................................22
5.2.11. Adequate Post-baseline Tumor Assessment.............................................22
5.3. Methods to Manage Missing Data ..........................................................................22
5.3.1. Missing Data...............................................................................................22
5.3.1.1. Pharmacokinetic Concentrations...............................................23
5.3.1.2. Pharmacokinetic Parameters .....................................................23
5.3.2. Handling of incomplete Dates ....................................................................23
5.3.2.1. Disease History .........................................................................23
5.3.2.2. Adverse Events..........................................................................24
5.3.2.3. Prior and Concomitant Medications..........................................24
5.3.2.4. Exposure....................................................................................25
5.3.3. Imputation Rules for Date of Last Contact and Efficacy Assessments......25
5.3.3.1. Date of Last Contact..................................................................25
5.3.3.2. Death Date.................................................................................26
5.3.3.3. Tumor Assessments...................................................................26
5.3.3.4. Date of Start of New Anti-cancer Therapy ...............................27
6. ANALYSES AND SUMMARIES ......................................................................................29
6.1. Primary Endpoints...................................................................................................29
6.1.1. DLTs...........................................................................................................29
6.1.1.1. Primary Analysis.......................................................................29
6.1.2. Objective Response as Assessed by the Investigator per Response 
Criteria for Malignant Lymphoma...................................................................29


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6.1.2.1. Primary Analysis.......................................................................29
6.2. Secondary Endpoint(s) ............................................................................................30
6.2.1. Safety Endpoints.........................................................................................30
6.2.2. Efficacy Endpoints......................................................................................30
6.2.2.1. Tumor Shrinkage from Baseline ...............................................30
6.2.2.2. Disease Control .........................................................................31
6.2.2.3. Duration of Response................................................................31
6.2.2.4. 6-month Durable Response .......................................................31
6.2.2.5. Time to Response......................................................................32
6.2.2.6. Progression-free Survival..........................................................32
6.2.2.7. Progression-free Survival at 6 Months......................................34
6.2.2.8. Overall Survival ........................................................................35
6.2.3. Pharmacokinetic Endpoints ........................................................................35
6.2.4. Population Pharmacokinetic Endpoints......................................................37
6.2.5. Endpoints for Immunogenicity Data of Avelumab, Rituximab and 
Utomilumab .....................................................................................................37
6.2.5.1. Time to and Duration of ADA and nAb Response ...................39
6.2.5.2. ADA Titer .................................................................................40
6.2.5.3. Analysis of PK, Safety and Efficacy by Immunogenicity 
Status .................................................................................................40
6.2.6. Analysis of PD-L1 and MRD .....................................................................42
6.4. Subset Analyses.......................................................................................................43
6.5. Baseline and Other Summaries and Analyses.........................................................44
6.5.1. Baseline Summaries....................................................................................44
6.5.1.1. Demographic Characteristics ....................................................44
6.5.1.2. Medical History.........................................................................45
6.5.1.3. Disease Characteristics..............................................................45
6.5.1.4. Prior Anti-Cancer Therapies .....................................................47
6.5.2. Study Conduct and Patient Disposition......................................................48
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6.5.2.1. Patient Disposition ....................................................................48
6.5.2.2. Protocol Deviations...................................................................49
6.5.3. Study Treatment Compliance and Exposure ..............................................49
6.5.3.1. Exposure to Avelumab..............................................................50
6.5.3.2. Exposure to Utomilumab ..........................................................51
6.5.3.3. Exposure to Rituximab..............................................................52
6.5.3.4. Exposure to Bendamustine........................................................53
6.5.3.5. Exposure to Azacitidine ............................................................54
6.5.3.6. Dose Reductions........................................................................54
6.5.3.7. Dose Interruptions.....................................................................55
6.5.3.8. Dose Delays...............................................................................55
6.5.3.9. Infusion Rate Reductions ..........................................................57
6.5.3.10. Infusion Interruptions..............................................................57
6.5.4. Concomitant Medications and Non-drug Treatments.................................58
6.5.5. Subsequent Anti-cancer Therapies .............................................................58
6.6. Safety Summaries and Analyses .............................................................................59
6.6.1. Adverse Events...........................................................................................59
6.6.1.1. All Adverse Events....................................................................60
6.6.1.2. Adverse Events Leading to Dose Reduction.............................62
6.6.1.3. Adverse Events Leading to Interruption of Study 
Treatment...........................................................................................62
6.6.1.4. Adverse Events Leading to Discontinuation of Study 
Treatment...........................................................................................63
6.6.2. Deaths .........................................................................................................64
6.6.3. Serious Adverse Events ..............................................................................65
6.6.4. Other Significant Adverse Events ..............................................................65
6.6.5. Laboratory Data..........................................................................................66
6.6.5.1. Hematology and Chemistry Parameters....................................66
6.6.5.2. Other Laboratory Parameters ....................................................70
6.6.6. Vital Signs ..................................................................................................70
6.6.7. Electrocardiogram.......................................................................................71
6.6.8. MUGA/ECHO............................................................................................72
6.6.9. Physical Examination .................................................................................73


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6.6.10. ECOG Performance Status .......................................................................73
7. INTERIM ANALYSES.......................................................................................................73
8. REFERENCES ....................................................................................................................74
9. APPENDICES .....................................................................................................................75
LIST OF TABLES
Table 2.
PK Parameters to be Determined for Avelumab, Rituximab, Utomilumab, 
Azacitidine, Bendamustine and its M3 Metabolite...............................................13
Table 3.
Conditional Power for the Phase 1b Based on the Interim Analysis Results .......19
Table 4.
Outcome and Event Dates for PFS and DR Analyses ..........................................33
Table 5.
PFS Censoring Reasons and Hierarchy................................................................34
Table 6.
OS Censoring Reasons and Hierarchy..................................................................35
Table 7.
Patients Characterized Based on Anti-Drug Antibody Results (ADA 
Status) ...................................................................................................................37
Table 8.
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status) ...................................................................................................................38
Table 9.
Case Definition for irAEs.....................................................................................75
Table 10.
Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs..............................................................77
Table 11.
Case Definition for IRRs – IV Study Drugs Administered in Combination 
(eg, Doublets or Triplets)......................................................................................78
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................75
Appendix 2. Infusion Related Reactions .................................................................................77
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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991011 is based on the protocol amendment 
3 dated 11DEC2017.  
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991011 – Phase 1b.  This document may modify the plans outlined in 
the protocol; however, any major modifications of the primary endpoint definition or its 
analysis will also be reflected in a protocol amendment.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie,
pharmacokinetic (PK) concentrations and parameters, immunogenicity parameters, minimal 
residual disease (MRD), biomarkers). The primary analysis will include all data up to a cut-
off date corresponding to 12 months (52 weeks) after the last patient is randomized.  The 
final analysis of the data will be performed after last patient last visit (LPLV) in the study. 
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes.
2.1. Study Objectives
Primary Objectives
•
To assess safety, efficacy, and potentially select the most active treatment regimen 
among 3 treatment arms to advance to the Phase 3 component of the study. 
Secondary Objectives
•
To evaluate the PK of each treatment arm;
•
To assess the immunogenicity of each treatment arm;
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•
To evaluate PD-L1 expression levels in tumor cells and cells of the tumor 
microenvironment (for example, infiltrating lymphocytes) as candidate predictive 
biomarkers with their relationship to selected clinical response parameters;
•
To evaluate the relationship between minimal residual disease burden as assessed 
using serial blood samples with selected clinical response parameters.
 
 
 
2.2. Study Design
Study B9991011 is a multicenter, international, parallel-arm, randomized, open-label, 
2-component (Phase 1b followed by Phase 3) study of avelumab in combination with: 
(i) rituximab (CD20 antagonist) and utomilumab (4-1BB agonist);
(ii) azacitidine (DNA methyltransferase inhibitor [DNMTi]) and utomilumab (4-1BB 
agonist), and 
(iii) rituximab (CD20 antagonist) and bendamustine (chemotherapy). 
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The target study population of this Phase 1b/Phase 3 registrational study will comprise 
patients with relapsed/refractory (R/R) DLBCL following at least 2 (but not more than 
4) lines of prior rituximab/multi-agent chemotherapy, and/or failed ASCT, or who are not
eligible for intensive chemotherapy or candidates for ASCT.  
The primary objective of Phase 1b is to make a preliminary assessment of dose-limiting 
toxicities in each treatment arm (N=6 each), and then potentially select a treatment regimen 
to be advanced to Phase 3 based on efficacy including the observed ORR (as assessed by the 
Investigator) and safety profile in each expanded treatment arm (N ꞊28 each).
It is expected that up to 84 patients will be randomized among three treatment arms 
(28 patients each) in Phase 1b.
In order to determine which treatment arm should be evaluated in Phase 3, pre-specified 
Go/No Go criteria are configured to identify with ≥95% confidence a treatment regimen that 
is superior to rituximab /bendamustine benchmark data (ie, historical reference control) with 
respect to one or more of the following (in a hierarchical manner):  
1. Objective Response Rate (ORR) (ie, proportion of patients achieving CR or PR).
2. 6-month Durable Response Rate (DRR) (ie, proportion of patients with CR or PR 
persisting for at least 6 months).
3. Progression-free survival (PFS) rate at 6 months.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints

Dose Limiting Toxicity (DLT):
Severity of adverse events (AEs) will be graded according to National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. For the 
purpose of selecting the regimen to advance into Phase 3, any of the AEs listed below 
occurring during the DLT observation period (4 weeks from the time of the first study 
treatment administration (Cycle 1, Day 1) until the planned administration of the second 
cycle that are attributable to an agent in the combination (and not incontrovertibly related 
to underlying disease or intercurrent illness), will be classified as DLTs.
Hematologic:

Grade 4 neutropenia (absolute neutrophil count [ANC] <500 cells/mm3) not 
recovering to ≤Grade 3 lasting >7 days (despite the use of G-CSF).

Grade ≥ 3 febrile neutropenia (ANC <1000/mm3) with a single temperature of 
>38.3 degrees Celsius (>101.0 degrees Fahrenheit) or a sustained temperature of 
≥38.0 degrees Celsius (100.4 degrees Fahrenheit) for more than 1 hour, with or 
without associated sepsis or that leads to a delay in the next cycle of therapy (despite 
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
Grade ≥3 neutropenic infection (despite the use of G-CSF).

Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with clinically 
significant bleeding (requiring red cell transfusion).

Grade 4 anemia (despite red blood cell transfusion).
Non-Hematologic:
Any Grade ≥3 toxicity, except for the following:

Transient (≤6 hours) Grade 3 flu-like symptoms or fever controlled with standard
medical management.

Transient (≤24 hours) Grade 3 fatigue, localized skin reactions, or headache that 
resolves to Grade ≤1.

Grade 3 nausea, or vomiting resolved to Grade <1 in ˂72 hours following the 
initiation of adequate medical management.

Grade 3 diarrhea that resolved to Grade ≤1 in <72 hours following the initiation of 
adequate medical management.

Grade 3 skin toxicity resolved to Grade 1 in ˂7 days.

Tumor flare.

Single laboratory values that are out of the normal range, that do not have any clinical
correlate, and resolve to Grade <1 within 7 days with adequate medical management.
Abnormal laboratory tests should be repeated. While the rules for adjudicating DLTs in 
the context of selecting the regimen to advance to Phase 3 clinical trial are specified 
above, AEs not listed above, or any AE meeting the DLT criteria above but occurring 
outside of the DLT observation period may be defined as a DLT following consultation 
between the Sponsor and the Investigator, based upon the overall emerging safety profile.

Objective Response (OR) as assessed by the Investigator per Lugano Response 
Classification Criteria.
OR is defined as complete response (CR) or partial response (PR) according to Response 
Criteria for Malignant Lymphoma from the date of randomization until the date of the 
first documentation of progressive disease (PD).


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3.2. Secondary Endpoints
3.2.1. Safety Endpoints

AEs as graded by NCICTCAE v4.03;
AEs will be graded by the investigator according to CTCAE v4.03 and coded using the 
Medical Dictionary for Regulatory Activities (MedDRA).

Laboratory abnormalities as graded by NCI CTCAE v4.03;

Vital signs (blood pressure, heart rate);

Electrocardiogram (ECG).
3.2.2. Efficacy Endpoints

Duration of Response (DR), Time to Tumor Response (TTR), Disease Control (DC), 
Progression-free survival (PFS), as assessed by the Investigator per Lugano Response 
Classification Criteria and Overall Survival (OS).
DR is defined, for patients with an objective response (OR), as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of 
objective progression of disease (PD) or death due to any cause.  
DC is defined as CR, PR, or SD.  Criterion for SD must have been met at least 6 weeks 
after the date of randomization.
TTR is defined, for patients with an OR, as the time from the date of randomization to the 
first documentation of objective response (CR or PR). 
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.
OS is defined as the time from the date of randomization to the date of death due to any 
cause.
3.2.3. Pharmacokinetic Endpoints

Pharmacokinetics: PK parameters of avelumab, rituximab, utomilumab, azacitidine and 
bendamustine, as data permit: maximum plasma concentration (Cmax), time to maximum 
plasma concentration (Tmax), area under the plasma concentration time curve from time 0 
to hours post dose (AUC0-, where is dependent on the analyte) apparent plasma 
clearance (CL/F), and apparent volume of distribution (V/F) each analyte following 
single and multiple dosing.


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Avelumab
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•
MRD burden as assessed using serial blood samples.
 
 
 
3.4. Baseline Variables
3.4.1. Study Drug, Study Treatment and Baseline Definitions
In Phase 1b, ‘study drug’ refers to avelumab, utomilumab, azacitidine, rituximab or 
bendamustine, and ‘study treatment’ (or ‘treatment arm’) refers to one of the following:
•
Arm A: avelumab/rituximab/utomilumab;
•
Arm B: avelumab/azacitidine/utomilumab;
•
Arm C: avelumab/bendamustine/rituximab.
Start and end dates of study treatment
•
The date/time of first dose of study treatment in a combination arm is the earliest 
date/time of the first non-zero dose date/time for the study drugs in the combination. 
•
The date/time of last dose of study treatment in a combination arm is the latest date/time 
of the last non-zero dose date/time for the study drugs in the combination.
Definition of baseline: 
Definition of baseline for efficacy 
 analyses 
The last measurement prior to randomization will serve as the baseline measurement for 
efficacy 
 analyses. If such a value is missing, the last measurement prior to the first 
dose of study treatment will be used as the baseline measurement except for analyses of
tumor assessments data where the baseline assessment would be considered as missing. 
Definition of baseline for immunogenicity analyses:
The last available assessment prior to the start of treatment with the given biologic (ie,
rituximab, utomilumab, avelumab) is defined as ‘baseline’ result or ‘baseline’ assessment.  If 
per protocol an assessment is planned to be performed prior to the first dose of the given 
biologic and the assessment is performed on the same day as the first dose of that biologic
but the assessment time point is not collected or is missing, it will be assumed that the 
assessment was performed prior to the biologic’s administration.
CCI
CCI
CCI


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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 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Baseline for RR and QT/QTc interval assessments will be derived from the visit where both 
RR and QT are not missing. Triplicate ECGs are collected in the study and the baseline for 
each ECG measurement is the average of the pre-dose replicate measurements on the 
baseline day. Unscheduled assessments will not be included in the calculation of the average. 
QTcB and QTcF will be derived based on RR and QT.  The average of the replicate 
measurements will be determined after the derivation of the individual parameter at each 
time point.
3.4.2. Baseline Characteristics
Baseline characteristics (including demographics, physical measurements, disease history 
and prior anti-cancer therapies) are described in Section 6.5.1.  These baseline characteristics 
are not planned to be included as stratification variables or covariates in statistical models 
unless otherwise specified in Section 6. 
3.5. Safety Endpoints
3.5.1. Adverse Events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period for the first time, or if the worsening of an event is during the 
on-treatment period. 
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.


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Adverse Events of Special Interest (AESIs)
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendices 1 and 2, 
respectively.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
The full analysis set (FAS) will include all randomized patients.  Patients will be classified 
according to the study treatment assigned at randomization. 
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug. 
Patients will be classified according to the study treatment assigned at randomization unless 
the incorrect treatment(s) was/were received throughout the dosing period in which case 
patients will be classified according to the first study treatment received. 
4.3. Other Analysis Sets
4.3.1. DLT-evaluable Analysis Set 
The DLT-evaluable Analysis Set is a subset of the safety analysis set and includes 
randomized patients in each arm who are eligible for the study, receive at least 1 dose of
study treatment, and either experience DLT during the first cycle, or complete the primary 
DLT observation period of 4 weeks.
Patients without DLTs who withdraw from study before completing the 4-week DLT 
observation period for reasons other than toxicity (eg, missed appointments or development 
of rapidly progressing disease) are not evaluable for DLT.
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, utomilumab, rituximab, bendamustine or its M3 
metabolite, or azacitidine. 
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, utomilumab, rituximab, 
bendamustine or its M3 metabolite, or azacitidine.


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4.3.3. Biomarker Analysis Set 
The Biomarker Analysis Set is a subset of the safety analysis set and will include all patients 
who have at least one baseline biomarker assessment.  Analysis sets will be defined 
separately for blood-based, fecal stool-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, utomilumab or 
rituximab.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and Sample Size Determination
Approximately 84 patients will be randomized 1:1:1 among three treatment arms 
(28 patients/arm) in Phase 1b. 
There is no formal hypothesis testing for safety.  However before expanding randomization 
past the first 6 and/or 12 DLT-evaluable patients in each treatment arm, safety must be 
confirmed in the first 6 and/or 12 patients evaluable for DLT in each treatment arm.    
For efficacy, within each treatment arm, the following hypothesis will be tested 
H0: ORR ≤46%, versus H1: ORR > 46%
at 1-sided significance level of 0.025.  With 28 patients per treatment arm, there is 79.7% 
power to reject H0 if the true ORR under H1 is ≥73%. 
5.1.2. Decision Rules
A Pfizer Internal Review Committee (IRC) evaluation of the first 6 and/or 12 DLT-evaluable 
patients in each treatment arm will occur after the last patient has completed one cycle of 
treatment. Enrollment will be halted while the first 6 DLT-evaluable patients in each 
treatment arm are evaluated for safety.
Up to 12 DLT-evaluable patients will be randomized into each treatment arm in the Phase 1b 
and evaluated for DLT during the first cycle of treatment as follows:

Randomize and treat up to 6 DLT-evaluable patients in each treatment arm:

If 1 of 6 patients experience DLT, the treatment arm will be expanded to 
randomize up to 28 patients;

If 3 of up to 6 patients experience DLT, randomization in the specific treatment 
arm will be discontinued;

If 2 of 6 patients experience DLT, the treatment arm will be expanded to 
randomize to 6 additional DLT-evaluable patients;


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
If 3 of 12 patients experience DLT, the treatment arm will be expanded to 
randomize up to 28 patients;

If 4 of up to 12 patients experience DLT, randomization in the specific 
treatment arm will be discontinued.
The efficacy of each treatment combination will be evaluated using pre-specified Go/No-Go 
criteria configured to identify with ≥95% confidence a treatment regimen that is superior to 
rituximab/bendamustine benchmark data (historical reference control) with respect to one or 
more of the following in a hierarchical manner: ORR, 6-month DRR and PFS rate at 
6 months.  In the final analysis of the phase 1b the decision-making process will include the 
following steps:
1. In each treatment arm, H0: ORR ≤46 vs H1: ORR >46%) will be tested at 1-sided 
α=0.025 using the binomial distribution;
2. If H0 for ORR is not rejected for any of the three treatment arms, the study will not 
proceed to Phase 3;
3. If only one treatment arm meets the ORR criterion, then that treatment arm will be 
evaluated in Phase 3;
4. If ≥2 treatment arms meet the ORR criterion, then the selection of the treatment arm will 
be based on the 6-month DRR criterion. In each treatment arm, H0: 6-month DRR ≤23% 
vs H1: 6-month DRR >23% will be tested at 1-sided α=0.025 using the binomial 
distribution;
5. If only one treatment arm meets the 6-month DRR criterion, then that treatment arm will 
be evaluated in Phase 3;  
6. If none or >1 treatment arm meets the 6-month DRR criterion, then the selection of the 
treatment arm will be based on the PFS rate at 6 months. In each treatment arm, H0: PFS 
rate at 6 months ≤31% vs H1: PFS rate at 6 months >31% will be tested at a 1-sided 
α=0.025 using the binomial distribution;
7. If only one treatment arm meets the PFS rate at 6 months criterion, then that treatment 
arm will be evaluated in Phase 3;  
8. If none, or >1 treatment arm meets the PFS rate at 6 months criterion, then the totality of 
safety and efficacy data will be taken into consideration when determining which arm to 
take forward into the Phase 3.
In addition, there will be a formal interim analysis (IA), performed 13 weeks after 8 patients 
in each treatment arm have been randomized. The purpose of the IA in the Phase 1b 
component of the study is to allow for early stopping of any treatment arm for futility based 
on ORR.  The cutoff for the IA is 13 weeks after 8 patients in each treatment arm have been 
randomized.  If 2 responses are observed for 8 patients in a treatment arm, further 
enrollment in the treatment arm may be stopped.


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Table 3 provides the conditional power of the Phase 1b when the futility boundary is crossed 
at the time of the IA based on the test of hypothesis described in Section 5.1.1.
Table 3.
Conditional Power for the Phase 1b Based on the Interim Analysis Results
Responders/Number of 
patients
True ORR=50%
True ORR=60%
True ORR=73%
0/8
<0.001
0.001
0.016
1/8
<0.001
0.004
0.064
2/8
0.001
0.016
0.170
5.2. General Methods
As described in Section 3.4.1, in Phase 1b ‘treatment arm’ refers to one of the following:

Arm A: avelumab/rituximab/utomilumab;

Arm B: avelumab/azacitidine/utomilumab;

Arm C: avelumab/bendamustine/rituximab.
Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment arm.
DLTs will be summarized based on the DLT-evaluable Analysis Set by treatment arm.
Other safety data, exposure data, concomitant medications and non-drug treatments will be 
summarized based on the Safety Analysis Set by treatment arm. 
PK data will be summarized based on the PK Analysis Set by treatment arm.
Biomarker data will be summarized based on the Biomarker Analysis Set by treatment arm.
Immunogenicity data will be summarized based on the Immunogenicity Analysis Set by 
treatment arm.
PRO data will be summarized based on the FAS Analysis Set by treatment arm.
5.2.1. Data Handling After the Cut-off Date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of Centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients randomized/treated at each center.


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5.2.3. Presentation of Continuous and Qualitative Variables
Continuous variables will be summarized using descriptive statistics 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.
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.
5.2.6. Definition of Start of New Anti-cancer Therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.2 and Section 6.2.2).


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The start date of new anti-cancer therapy is the earliest date after the date of 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 ‘Concomitant Radiation Therapy’, and 
‘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’, 
‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, ‘Concomitant Surgery’, 
and ‘Follow-up Surgery’ eCRF pages.
5.2.7. Definition of On-treatment Period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard Derivations and Reporting Conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

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. 


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
BMI (kg/m2) = weight (kg)/[height (m)]2.

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 42 days prior to and including the date of 
randomization.

All documented lesions must have non-missing PET scores.
5.2.11. Adequate Post-baseline Tumor Assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, or PD can be determined (see Section 6.1.2.1).  Time points where the response is 
not evaluable (NE) or no assessment was performed will not be used for determining the 
censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing Data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, 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
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.  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. 


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
If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014.

In all other cases the missing medication day or missing medication month will be 
replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete medication stop date will not be imputed. 
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.


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
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.

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 


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following assessment. If both a previous and following assessments are not available, this 
assessment will not be used for any calculations.
5.3.3.4. Date of Start of New Anti-cancer Therapy
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy 
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment.

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.


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IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy].
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY ;
ELSE IF
YYYY = Year of min [max(PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM = Month of min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy].
THEN 
imputed start date = min [max(PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]);
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.


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6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology. 
All analysis described in what follows apply to patients enrolled in Phase 1b.
6.1. Primary Endpoints
6.1.1. DLTs
6.1.1.1. Primary Analysis
DLTs will be graded according to NCI-CTCAE version 4.03 and coded 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.
For the first 6 and/or 12 DLT-evaluable patients in each treatment arm, the number and 
percentage of patients with DLTs will be listed and summarized by treatment arm, primary 
SOC and PT in decreasing frequency based on the frequencies observed for treatment arm A.
6.1.2. Objective Response as Assessed by the Investigator per Response Criteria for 
Malignant Lymphoma
6.1.2.1. Primary Analysis
The following analyses will be based on the FAS by treatment arm. Assessment of response 
will be made using Response Criteria for Malignant Lymphoma. Assessments below refer to 
investigator assessment. 
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. Only tumor assessments performed on or before the 
start date of any further anti-cancer therapies will be considered in the assessment of BOR.  
Clinical deterioration will not be considered as documentation of disease progression.

CR = CR documented before first documentation of PD.

PR = PR documented before first documentation of PD (and not qualifying for a CR).

SD = at least one SD assessment (or better) ≥6 weeks after the date of randomization and 
before first documentation of PD (and not qualifying for CR or PR).

PD = first documentation of PD after the date of randomization (and not qualifying for 
CR, PR, SD).

NE:  all other cases.
An objective status of PR or SD cannot follow one of CR.
Objective Response (OR) is defined as BOR of CR or PR according to Response Criteria 
for Malignant Lymphoma.


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Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set.
ORR by treatment arm will be calculated along with the 2-sided 95% CI using the Clopper-
Pearson method (exact CI for a binomial proportion as computed by default by the FREQ 
procedure using the EXACT option). 
In addition, the frequency (number and percentage) of patients with a BOR of CR, PR, SD, 
PD, and NE will be tabulated. Patients with BOR of NE will be summarized by reason for 
having NE status. The following reasons will be used:

No baseline assessment.

No post-baseline assessments due to death.

No post-baseline assessments due to other reasons.

All post-baseline assessments have overall response NE.

New anti-cancer therapy started before first post-baseline assessment.

SD of insufficient duration (<6 weeks after the date of randomization).
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.  Assessment of response 
will be made using Response Criteria for Malignant Lymphoma. Tumor-related endpoints 
will be analyzed based on investigator assessment.
6.2.2.1. Tumor Shrinkage from Baseline
Tumor shrinkage will be summarized as the percent change from baseline in lymph nodes 
and extranodal sites (sum of the product of the diameters (SPD)) per time point. It will be 
derived as:

((SPD at week XX – SPD at baseline)/SPD at baseline) × 100.
The maximum reduction in lymph nodes and extranodal sites from baseline will be derived 
across all the post-baseline assessments until documented disease progression, excluding 
assessments after start of subsequent anti-cancer therapy, as:


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
Minimum of ((SPD at week XX – SPD at baseline)/SPD at baseline) × 100.
A waterfall plot of maximum percent reduction in the SPD will be created by treatment arm. 
These plots will display the best percentage change from baseline in the SPD of lymph nodes 
and extranodal sites for each patient with at least one adequate baseline and one post-baseline 
assessment.
6.2.2.2. Disease Control
Disease Control (DC) is defined as BOR of CR, PR, or SD.  DC rate (DCR) is the proportion 
of patients with DC.   
DCR will be summarized by frequency counts and percentages.
6.2.2.3. Duration of Response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are as described for PFS 
in Table 3.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment arm together 
with a summary of associated statistics including the median DR time with 2-sided 95% CIs.  
In particular, the DR rate at 3, 6, 9, 12 and 18 months will be estimated with corresponding 
2-sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley and the CIs for the survival function estimates at the time points defined above will 
be derived using the log-log transformation according to Kalbfleisch and Prentice
(conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI 
on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.
6.2.2.4. 6-month Durable Response 
The 6-month DRR for each treatment arm will be estimated by dividing the number of 
patients who achieve and maintain an objective response for at least 6 months by the total 
number of patients randomized to the respective treatment arm.  
The corresponding exact 2-sided 95% CIs will be provided by treatment arm using the 
Clopper-Pearson method (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option).


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6.2.2.5. Time to Response
Time to response (TTR) is defined, for patients with OR, as the time from the date of 
randomization to the first documentation of objective response (CR or PR). 
TTR (in months) = [first date of OR – date of randomization +1]/30.4375.
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.6. Progression-free Survival
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.   
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing or 
inadequate post-baseline tumor assessments.  Patients who do not have an adequate baseline 
tumor assessment or who do not have an adequate post-baseline tumor assessment will be 
censored on the date of randomization unless death occurred on or before the time of the 
second planned tumor assessment (ie, ≤24 weeks after the date of randomization) in which 
case the death will be considered an event.
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every 12 (±1) weeks until PD regardless of initiation of 
subsequent anti-cancer therapy.  After 12 months from date of randomization, tumor 
assessments will be conducted less frequently, ie, at 26-week (6-month) intervals.
The censoring and event date options to be considered for the PFS and DR analysis are 
presented in Table 4.  
PFS (months) = [date of event or censoring– date of randomization +1]/30.4375.


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Table 4.
Outcome and Event Dates for PFS and DR Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of randomizationa
Censoreda
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤24 weeks after the date of randomization.
Date of PD or death
Event
PD or death 
-
after 2 or more missing or inadequate post-
baseline tumor assessments.
Date of last adequate tumor
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor 
assessments.
Censored
No PD and no death.
Date of last adequate tumor
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor
assessments.
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression.
Not applicable
Information is ignored. 
Outcome is derived 
based on documented 
progression only.
New anti-cancer therapy given.
Date of last adequate tumor 
assessmentb documenting no PD 
before new anti-cancer therapy is 
given or missed tumor
assessments.
Censored
a However if the patient dies ≤24 weeks after the date of randomization the death is an event with date on death 
date.
b If there are no adequate post-baseline assessments prior to the PD or death, then the time without adequate 
assessment should be measured from the date of randomization; if the criteria were met the censoring will be on 
the date of randomization.
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 rate at 3, 6, 9, 12 and 18 months will be estimated with corresponding 
2-sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley and the CIs for the survival function estimates at the time points defined above will 
be derived using the log-log transformation according to Kalbfleisch and Prentice
(conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI 
on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.  
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment arm. Reasons for censoring will be 
summarized according to the categories in Table 5 following the hierarchy shown.


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Table 5.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy. 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Subject refused 
further follow-up] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment 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 rate at 3, 6, 9, 12 and 18 months will be 
estimated with corresponding 2-sided 95% CI.
6.2.2.7. Progression-free Survival at 6 Months
A patient will be considered to be progression-free at 6 months, if the patient has a disease 
assessment demonstrating non-progression for at least 6 months after randomization.  
The PFS rate at 6 months for each treatment arm will be estimated by dividing the number of 
patients who are alive and progression-free at 6 months by the total number of patients 
randomized to the respective treatment arm.  The corresponding exact 2-sided 95% CIs will 
be provided by treatment arm using the Clopper-Pearson method (exact CI for a binomial 
proportion as computed by default by the FREQ procedure using the EXACT option).


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6.2.2.8. Overall Survival
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.
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 rate at 6, 12, 18, 24 and 30 months will be estimated with corresponding 
2-sided 95% CIs.  The CIs for the median will be calculated according to Brookmeyer and 
Crowley and the CIs for the survival function estimates at the time points defined above will 
be derived using the log-log transformation according to Kalbfleisch and Prentice
(conftype=loglog default option in SAS Proc LIFETEST) with back transformation to a CI 
on the untransformed scale. The estimate of the standard error will be computed using 
Greenwood’s formula.  
Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment arm. Reasons for censoring will be summarized according to 
the categories in Table 6 following the hierarchy shown.
Table 6.
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) = Subject refused 
further follow-up] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date >10 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 rate at 6, 12, 18, 24 and 30 months will be estimated with 
corresponding 2-sided 95% CI.
6.2.3. Pharmacokinetic Endpoints
The following pharmacokinetic analyses will be presented by analyte and treatment arm
based on the PK analyses set.  


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Ctrough and Cmax for avelumab, rituximab, utomilumab, azacitidine, bendamustine and its M3 
metabolite will be summarized descriptively (n, mean, SD, CV, median, minimum,
maximum, geometric mean, its associated CV, and 95% CI) by treatment arm, cycle, and 
day. Additional parameters may also be calculated as appropriate and as data permit,
including, but not limited to:

Following Single Dose (SD): Tmax, AUClast, Tlast, AUC sd,, AUC sd,inf, t1/2, CL or CL/F,
and Vz or Vz/F.

Following Multiple Dose (MD): Tss,max, AUClast, Tlast, AUCss,, Css,max, t1/2, Css,av, CL or 
CL/F, Vz or Vz/F, and Rac (AUCss,/AUCsd,).
Pharmacokinetic parameters for avelumab, rituximab, utomilumab, azacitidine,
bendamustine and its M3 metabolite will be taken from observed values or derived from 
serum or plasma concentration-time data as described in Section 3.2.3.
Presentation of pharmacokinetic data will include:

Descriptive statistics (n, mean, SD, %CV, median, minimum, maximum) of serum or 
plasma concentrations will be presented in tabular form by treatment arm, cycle, day and 
nominal time. 

Linear-linear and log-linear plots of mean and median serum or plasma concentrations by 
nominal time for avelumab, rituximab, utomilumab, azacitidine, bendamustine and its M3 
metabolite will be presented for PK sampling days by treatment arm, cycle, and study 
day. Similar plots will be presented for each individual patient’s concentrations. Patients 
who have undergone intrapatient dose reduction or escalation will be excluded from the 
median serum or plasma concentration-time plots.

Pharmacokinetic parameters for avelumab, rituximab, utomilumab, azacitidine,
bendamustine and its M3 metabolite will be listed and summarized by treatment arm, 
cycle and study day using descriptive statistics (n, mean, SD, %CV, median, minimum, 
maximum, geometric mean and its associated %CV, and 95% CI). Tmax will only be
summarized with n, median, minimum, and maximum. PK parameters with zero values 
will be excluded from the calculation of geometric means and its associated %CV. If an 
intrapatient dose escalation or reduction occurs, data from this patient will only be 
included in descriptive statistics and summary plots up to the time of the dose change. 

Box plots for AUC and Cmax in Cycle 1 for avelumab, rituximab, utomilumab, 
azacitidine, bendamustine and its M3 metabolite will be generated. Individual data 
points, the geometric mean and the median of the parameter in each treatment will be 
overlaid on the box plots. If a treatment arm has limited evaluable PK data (n<4), 
matchstick plots showing changes in AUC and Cmax for each drug in individual patients 
will then be generated. The geometric mean of the parameter in each treatment will be 
overlaid in the plots. For the analytes administered in 2 (rituximab, utomilumab) or 
3 (avelumab) treatment arms and for analytes with more than 1 dosing day in a Cycle
(azacitidine, bendamustine), data will be plotted for each treatment arm on the same 


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figure by cycle and dosing day. Ctrough and Cmax / Css, max (if applicable) for avelumab,
rituximab, utomilumab, azacitidine, bendamustine and its M3 metabolite will be plotted 
for each treatment arm using a box-whisker plot by cycle and day within cycle in order to 
assess the attainment of steady-state.
6.2.4. Population Pharmacokinetic Endpoints
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab, rituximab, utomilumab, azacitidine, bendamustine and its M3 
metabolite exposure and biomarkers or significant safety/efficacy endpoints. The results of 
these analyses, if performed, may be reported separately.
6.2.5. Endpoints for Immunogenicity Data of Avelumab, Rituximab and Utomilumab
All analyses described below will be performed by treatment arm for each study drug.
All samples for ADA and nAb analyses for avelumab (3.5 mL), rituximab (4.0 mL) and 
utomilumab (4.0 mL) will be collected within 2 hours prior to the start of dosing on Day 1 in 
Cycle 1 (rituximab), Day 2 in Cycle 1 (avelumab and utomilumab) and Day 1 in Cycles 4 
and 6 (rituximab, avelumab and utomilumab). Additional samples for immunogenicity 
analysis will be collected at 30 (3) days after the end of therapy.  A sample for ADA 
analysis will be drawn at the time of early withdrawal/treatment discontinuation.
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb. 
As of the finalization of this SAP, the nAb assay for avelumab is not yet available, therefore 
the analyses of avelumab nAb data described in the following sections will only be 
conducted contingent upon assay and data availability at the time of reporting.
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 7.  
Table 7.
Patients Characterized Based on Anti-Drug Antibody Results (ADA Status)
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
ADA never-positive 
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint).
Number of patients with at least one 
valid ADA result at any time point.
ADA ever-positive 
At least one positive ADA result at any 
timepoint, 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 
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 


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Category
Definition
Subjects at Risk (Denominator for 
Incidence)
patient has at least one positive past-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 8. 
For nAb, treatment-boosted is not applicable since no titer result is available.
Table 8.
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Subjects at Risk (Denominator for 
Incidence)
nAb never-positive 
No positive nAb results at any time point
Number of patients with at least one 
valid ADA result at any time point.
nAb ever-positive 
At least one positive nAb result at any time 
point
Number of patients with at least one 
valid ADA result at any time point.
Baseline nAb 
positive
A positive nAb result at baseline
Number of patients with valid baseline 
ADA result.
Treatment-induced 
nAb
Patient is not nAb positive at baseline and  has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive past-
baseline ADA result.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR).
Transient nAb 
response
If patients with treatment-induced nAb have (a
single positive nAb result or duration between 
first and last positive result <16 weeks) and 
nAb result at the last assessment is not 
positive.
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR).
Persistent nAb 
response
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR).
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result.
The number and percentage of patients in each ADA and nAb category will be summarized.


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6.2.5.1. 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 study drug + 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 ongoing treatment with study drug, 
or

The last ADA assessment is positive AND patient discontinued treatment with study 
drug, AND the last planned ADA assessment (day 30 follow-up visit) is after the cut-off 
date.
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result. 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley
(1982) and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2011) (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided.
As data permit, the analyses described above will be repeated for patients with treatment-
induced nAb. 


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6.2.5.2. 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. 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. 
6.2.5.3. Analysis of PK, Safety and Efficacy by Immunogenicity Status
The following ADA and nAb status will be used for the analyses described below.
ADA 

ADA ever-positive versus ADA never-positive.

ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive
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 effect of ADA on avelumab, utomilumab and rituximab concentrations will be 
evaluated. The following analyses will include patients in both the immunogenicity analysis 
set and in the PK parameter analysis set.  The PK endpoint pertinent to the immunogenicity 
analyses is Ctrough.
Ctrough 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 over nominal time and by ADA 
status will be presented. 
As data permit, the analyses described above will be repeated for nAb. This analysis will 
only be performed if nAb assays are available for all 3 biologics, including avelumab.
Safety and immunogenicity status
The following analyses will include patients in the immunogenicity analysis set.


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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.

TEAEs leading to dose reduction of rituximab, by SOC and PT.

TEAEs leading to dose reduction of utomilumab, by SOC and PT.

TEAEs leading to discontinuation of avelumab, by SOC and PT.

TEAEs leading to discontinuation of rituximab, by SOC and PT.

TEAEs leading to discontinuation of utomilumab, by SOC and PT.

TEAEs leading to discontinuation of study treatment by SOC and PT.

Grade ≥3 TEAEs, by SOC and PT.

SAEs, by SOC and PT.

IRRs, by PT.
For patients who had at least one IRR and have treatment-induced ADA, time related to first 
onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later) will be summarized 
taking into account whether the  IRR occurred on or after the first ADA positive assessment 
or whether the IRR occurred before the first ADA positive assessment.  
As data permit, the analyses described above will be repeated for nAb. This analysis will 
only be performed if nAb assays are available for all 3 biologics, including avelumab.
Efficacy and immunogenicity status
For the ADA ever-positive patients, a listing will be prepared with patient ID, start and stop 
of avelumab treatment, date of first positive ADA result, time to ADA response, duration of 
ADA response, date of last ADA positive result, BOR, DR, PFS time or censoring time and 
reason for censoring, and OS time or censoring time and reason for censoring.  If applicable, 
date of first positive nAb result, time to nAb response, duration of nAb response, date of last 
nAb positive result will also be presented.  Tumor-related endpoints will be presented based 
on Investigator assessment. 
For the ADA ever-positive patients, the percent change from baseline in target lesions as well 
as the first occurrence of a new lesion and patient off avelumab treatment will be displayed 
against time point (weeks) in a line plot. Additional symbols will indicate the first and last 
ADA positive result and, if applicable, the first and last nAb positive result.  Plot will be 
presented based on Investigator assessment.


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6.2.6. Analysis of PD-L1 and MRD
The following biomarker analyses will be based on the biomarker analysis set by treatment 
arm:
•
PD-L1 expression will be reported by intensity score (0, +1, +2, +3) and percent of 
neoplastic cells expressing PD-L1 at each intensity score.  The sum of percents of 
neoplastic cells presenting at +1 or greater scores will be reported as the percent of 
PD-L1 positive neoplastic cells.  PD-L1 expression by inflammatory cells will be 
reported by intensity score (0, +1, +2, +3) and location (cytoplasmic, membrane, or both).
•
CD8 expression (positive/negative) as determined by pathologist review will be reported 
as percent of cells or as cells per mm2 scored as CD8-positive in the region of interest. 
Regions of interest are defined by the tumor mass as determined by pathologist review: 
ALL, all tumor areas within the tumor mass; invasive margin (IM), tumor mass and 
adjacent tissues measured from the edge of the tumor at approximately 500 μm into the 
tumor mass and adjacent tissues; PD-L1-positive center of tumor (CT+), PD-L1 positive 
regions of the tumor mass excluding IM; PD-L1-negative center of tumor (CT-),
PD-L1-negative regions of the tumor mass excluding IM.
PD-L1 and CD8 expression values will be summarized descriptively as appropriate (n, mean, 
SD, CV, median, minimum, maximum, geometric mean, associated CV, and 95% CI) by 
treatment arm, and time-point, including baseline assessments.  Values will be plotted for 
each treatment arm and time-point using a box-whisker plot in order to assess changes from
baseline.
Correlations between PD-L1 and CD8 expression values (at baseline and on-treatment) and 
selected efficacy endpoints will be assessed retrospectively.  
MRD status will be summarized descriptively as appropriate (n, positive/negative status, 
mean, SD, CV, median, minimum, maximum, geometric mean, associated CV, and 95% CI) 
by treatment arm, and time-point, including baseline assessments. Correlations between 
MRD assessed qualitatively (positive/negative) and/or quantitatively (at baseline and on-
treatment) and selected efficacy endpoints will be assessed retrospectively.
 
 
 
 
 
CCI


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6.4. Subset Analyses
Subset analyses are not planned.
CCI
CCI
CCI


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6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline Summaries
The following analyses will be based on the FAS 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/Latino (Yes/No).

Age (years): summary statistics.

Age categories: 

<65 years, ≥65 years.

< 65, 65-<75, 75-<85, ≥85 years.

Pooled Geographical Region (as applicable): 

North America.

Europe.

Asia.

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including >10% of the 
overall randomized population).

Geographic Region (as applicable):

North America.

Latin America.

Western Europe.

Eastern Europe.


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
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 
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 Abuse’
and Tumor Assessment 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.


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
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.

Initial histopathological classification (including sub-category).

Classification based on molecular profiling.

Stage and substage at initial diagnosis.

Time since most recent recurrence/progression (months), defined as (date of 
randomization – date of most recent recurrence/progression)/30.4375.

Primary disease type (Refractory vs Relapsed).

Stage and substage at current diagnosis.
From the Tumor Assessment eCRF pages:

Involved tumor sites at baseline
From the ‘Substance Use’ eCRF page:

Smoking history.

Never smoker vs current vs former smoker.

Smoking exposure (pack-years): 0, <20, 20-<40, ≥40 and summary statistics.

Years since quitting: never smoker, current smoker, <5, 5-<10, ≥10 and summary 
statistics.
Specifications for computation:

Cigarette equivalents are calculated as follows: one cigar is regarded equivalent to 
5 cigarettes and 1 pipe is regarded equivalent to 3 cigarettes.

Duration of nicotine consumption [years]:
(end of nicotine consumption – start of nicotine consumption + 1) / 365.25.

Pack-years:

Calculate cigarette equivalents per day using the conversion factors given above.

Convert to packs per day where 20 cigarettes are regarded as 1 pack.


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


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
Listing of anti-cancer surgeries.
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.

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.

Number and percentage of randomized patients with study drug ongoing (separately for 
each study drug administered in combination).

Number and percentage of randomized patients who discontinued study drug overall and 
by the main reason for discontinuation of study drug (separately for each study drug
administered in combination).

Number and percentage of patients who entered follow-up.

Number and percentage of patients who 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, Middle East, Asia, Australasia, 
Africa), by country within region.

Number and percentage of randomized patients by center.

Cross tabulation: patients randomized (Arm A/Arm B/Arm C/none) vs. patients treated 
(Arm A/Arm B/Arm C/none).


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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 or 
satisfying exclusion 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.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  
For Cycle X, 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, any study drug with 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, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 

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 (in days) – 1 day.
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7.


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When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included. 
Exposure may be summarized (per cycle and/or overall) as dose received (cumulative dose, 
actual dose intensity) and as dose received relative to intended dose (relative dose intensity 
[RDI]).  
The information that will be summarized depends on how the study drug is dosed (eg, 
infusion cyclical).
The derivations below are provided for the following with 1 cycle = 4 weeks.

Avelumab administered as a 1-hour IV infusion at a dose of 10 mg/kg once every 
2 weeks in 4-week cycles.     
Avelumab is administered on Day 2 and Day 16 in Cycle 1 and Cycle 2.  If avelumab is
well tolerated in Cycle 1 and Cycle 2, then it will be administered on Day 1 and Day 15 
of Cycle 3 and all subsequent cycles until the patient no longer receives clinical benefit.

Utomilumab administered as an IV infusion at a fixed dose of 100 mg once every 
4 weeks in 4-week cycles.
Utomilumab is administered on the morning of Day 2 in Cycles 1 and 2.  If utomilumab 
is well-tolerated in Cycles 1 and 2, then it will be administered on Day 1 in Cycle 3 and 
all subsequent cycles until the patient no longer receives clinical benefit.

Rituximab administered as in IV infusion at a dose of 375 mg/m2 once (on Day 1) every 
4 weeks in 4-week cycles for up to 8 cycles.

Bendamustine administered as in IV infusion at a dose of 90 mg/m2 on Days 1 and 2 or 
Days 2 and 3 of each 4-week cycle for up to 6 cycles.
Bendamustine is administered on Days 2 and 3 in Cycle 1 and Cycle 2. If bendamustine 
is well-tolerated in Cycle 1 and 2, then bendamustine may be administered on Days 1 and 
2 in Cycle 3 and all subsequent cycles for up to 6 cycles.

Azacitidine administered as a SC injection at a dose of 40 mg/m2 from Day 1 to Day 5 of 
each 4-week cycle.
6.5.3.1. Exposure to Avelumab 
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.
Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of avelumab +1)/7, 


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where end date = start date of last cycle with non-zero dose of  avelumab + 28.
Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab – first dose date of avelumab + 14)/7.  
Cumulative dose in a cycle or overall is the sum of the actual doses of avelumab received in 
a cycle or overall, respectively.  
Actual Dose Intensity (DI)

By cycle actual DI (mg/kg/4-week cycle) = [cumulative dose in the cycle (mg/kg)]/[cycle 
duration (weeks)/4].

Overall actual DI (mg/kg/4-week cycle) = [overall cumulative dose (mg/kg)] / [intended 
duration of treatment with avelumab (weeks)/4].  
Relative Dose Intensity (RDI)  

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).

By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [20 (mg/kg/4-week cycle)].  

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [20 (mg/kg/4-week cycle)].
6.5.3.2. Exposure to Utomilumab 
The dose level for utomilumab is fixed (mg). 
Intended duration of treatment with utomilumab (weeks) = 
(end date–date of first dose of utomilumab +1)/7.
where end date = start date of last cycle with non-zero dose of  utomilumab + 28.
Duration of exposure to utomilumab (weeks) = 
(last dose date of utomilumab – first dose date of utomilumab + 28)/7.  
Cumulative dose in a cycle or overall is the sum of the actual doses of utomilumab received 
in a cycle or overall, respectively.  


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Actual Dose Intensity (DI)

By cycle actual DI (mg/4-week cycle) = [cumulative dose in the cycle (mg)]/[cycle 
duration (weeks)/4].

Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with utomilumab (weeks)/4].  
Relative Dose Intensity (RDI)  

Intended DI (mg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [100 (mg)] / [1 (4-week cycle)]  = 100 (mg/4-week 
cycle).

By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [100 (mg/4-week cycle)].  

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [100 (mg/4-week cycle)].
6.5.3.3. Exposure to Rituximab 
The dose level for rituximab is calculated as actual dose administered/BSA (mg/m2). The last 
available BSA of the patient on or prior to the day of dosing will be used.
Intended duration of treatment with rituximab (weeks) = 
(end date–date of first dose of rituximab +1)/7, 
where end date = start date of last cycle with non-zero dose of rituximab + 28 – 1.
Duration of exposure to rituximab (weeks) = 
(last dose date of rituximab – first dose date of rituximab + 28)/7.
Cumulative dose in a cycle or overall is the sum of the actual doses of rituximab received in 
a cycle or overall, respectively.  
Actual Dose Intensity (DI)

By cycle actual DI (mg/m2/4-week cycle) = [cumulative dose in the cycle 
(mg/m2)]/[cycle duration (weeks)/4].

Overall actual DI (mg/m2/4-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with rituximab (weeks)/4].  


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Relative Dose Intensity (RDI)  

Intended DI (mg/m2/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [375 (mg/m2)] / [1 (4-week cycle)] = 375 (mg/m2/4-
week cycle).

By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [375 (mg/m2/4-week cycle)].  

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [375 (mg/m2/4-week cycle)].
6.5.3.4. Exposure to Bendamustine 
The dose level for bendamustine is calculated as actual dose administered/BSA (mg/m2). 
The last available BSA of the patient on or prior to the day of dosing will be used.
Intended duration of treatment with bendamustine (weeks) = 
(end date–date of first dose of bendamustine +1)/7, 
where end date = start date of last cycle with non-zero dose of  bendamustine + 28.
Duration of exposure to bendamustine (weeks) = 
(last dose date of bendamustine – first dose date of bendamustine + d)/7,
where d=1 if the patient discontinues bendamustine prior to the 2 days of planned dosing in 
the last cycle or d=27 otherwise.  
Cumulative dose in a cycle or overall is the sum of the actual doses of bendamustine
received in a cycle or overall, respectively.  
Actual Dose Intensity (DI)

By cycle actual DI (mg/m2/4-week cycle) = [cumulative dose in the cycle 
(mg/m2)]/[cycle duration (weeks)/4].

Overall actual DI (mg/m2/4-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with bendamustine (weeks)/4].  
Relative Dose Intensity (RDI)  

Intended DI (mg/m2/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [180 (mg/m2)] / [1 (4-week cycle)] = 180 (mg/m2/4-
week cycle).

By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [180 (mg/m2/4-week cycle)].  


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
Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [180 (mg/m2/4-week cycle)].
6.5.3.5. Exposure to Azacitidine 
The dose level for azacitidine is calculated as actual dose administered/BSA (mg/m2). The 
last available BSA of the patient on or prior to the day of dosing will be used.
Intended duration of treatment with azacitidine (weeks) = 
(end date–date of first dose of azacitidine +1)/7, 
where end date = start date of last cycle with non-zero dose of azacitidine + 28 – 1.
Duration of exposure to azacitidine (weeks) = 
(last dose date of azacitidine – first dose date of azacitidine + d)/7,
where d=1 if the patient discontinues azacitidine prior to the 5 days of planned dosing in the 
last cycle or d=24 otherwise.  
Cumulative dose in a cycle or overall is the sum of the actual doses of azacitidine received 
in a cycle or overall, respectively.  
Actual Dose Intensity (DI)

By cycle actual DI (mg/m2/4-week cycle) = [cumulative dose in the cycle 
(mg/m2)]/[cycle duration (weeks)/4].

Overall actual DI (mg/m2/4-week cycle) = [overall cumulative dose (mg/m2)] / [intended 
duration of treatment with azacitidine (weeks)/4].  
Relative Dose Intensity (RDI)  

Intended DI (mg/m2/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [200 (mg/m2)] / [1 (4-week cycle)]  = 200 (mg/m2/4-
week cycle).

By cycle RDI (%) = 100 × [by cycle actual DI] / [intended DI]                                                            
= 100 × [by cycle actual DI] / [200 (mg/m2/4-week cycle)].  

Overall RDI (%) = 100 ×  [overall actual DI] / [intended DI]                                                                
= 100 ×  [overall actual DI] / [200 (mg/m2/4-week cycle)].
6.5.3.6. Dose Reductions 
Applicable to avelumab, utomilumab, azacitidine, bendamustine and rituximab. Dose 
reduction is defined as actual non-zero dose <90% of the planned dose. 


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The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized. 
6.5.3.7. Dose Interruptions
Applicable to azacitidine and bendamustine.  
An interruption is defined as a 0 mg/m2 dose administered on one or more days. What 
follows defines how dose interruptions will be counted in the case of multiple dose 
interruptions.

If an interruption occurs consecutively for at least two days due to the same reason, then 
it will be counted only once (example: If the actual dose for azacitidine on days 1-3 is 
40 mg/m2 and actual dose on days 4-5 is 0 mg/m2, and dose is administered again on days 
6 and 7, and dose interruption on days 4-5 is due to AE, then the total number of dose 
interruptions is 1).

If an interruption occurs consecutively for at least two days due to different reasons, then 
it will be counted for each reason (example: If the actual dose for azacitidine on
days 1-3 is 40 mg/m2 and actual dose on days 4-5 is 0 mg/m2, and dose is administered 
again on days 6 and 7, and dose interruption on day 4 is due to AE and dose interruption 
on day 5 is due to dosing error, then the total number of dose interruptions is 2). 

If an interruption occurs for more than one day due to the same reason, but the days are 
not consecutive, ie, there is at least one dosing day in between, then each dose 
interruption will be counted as a different occurrence (example: If the actual dose on days 
1, 3 and 5, is 40 mg/m2 and actual dose on days 2 and 4 is 0 mg/m2, and dose 
interruptions on day 2 and 4 are both due to dosing error, the total number of dose 
interruptions is 2). 
A dose interruption is not considered a dose reduction.
The number and percentage of patients with dose interruptions and the corresponding reasons 
will be summarized.
6.5.3.8. Dose Delays 
Avelumab 
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. 
For the first dose of Cycle 1 
Dose Delay (days) = day of first dose of avelumab – 2. 
After the first dose of Cycle 1
Dose Delay (days) = Date of dose x – Date of dose (x-1) – d, where d = 13 for the first 
dose of Cycle 3 and d = 14 for all others.


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Utomilumab
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.
In Cycle 1, 
Dose Delay (days) = day of first dose of utomilumab – 2. 
In Cycle >1
Dose Delay (days) = Date of first dose of utomilumab in Cycle x – Date of first dose of 
utomilumab in Cycle (x-1) – d, where d = 27 if x = 3 and d=28 if x = 2 or x ≥4.
Rituximab
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.
In Cycle 1, 
Dose Delay for Dose 1 (days) = day of first dose of rituximab in Cycle 1 – 1. 
In Cycle >1
Dose Delay for Dose x (days) = Date of first dose of rituximab in Cycle x – Date of first 
dose of rituximab in Cycle (x-1) – 28.
Bendamustine
Dose delay is the difference between the actual time between the last non-zero dose of a 
cycle and the actual first non-zero dose of the next cycle and the planned time between the 
same two doses. Dose delay is only calculated for the first dose of bendamustine 
administered in each cycle.
In Cycle 1, 
Dose Delay for Dose 1 (days) = day of first dose of bendamustine – 2. 
In Cycle >1
Dose Delay (days) = Date of first dose of bendamustine in Cycle x – Date of first dose of 
bendamustine in Cycle (x-1) – d, where d = 27 if x = 3 and d=28 if x = 2 or x ≥4.
Azacitidine
Dose delay is the difference between the actual time between the last non-zero dose of a 
cycle and the actual first non-zero dose of the next cycle and the planned time between the 
same two doses. Dose delay is only calculated for the first dose of azacitidine administered 
in each cycle.


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In Cycle 1, 
Dose Delay for Dose 1 (days) = day of first dose of azacitidine – 1. 
In Cycle >1
Dose Delay for Dose x (days) = Date of first dose of azacitidine in Cycle x – Date of first 
dose of azacitidine in Cycle (x-1) – 28.
Dose delays will be grouped into the following categories: 

No delay.

1-2 days delay.

3-6 days delay.

7 or more days delay.
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Cycle 1 Day 2, then the next avelumab administration date will be on Cycle 1 
Day 16; however, if the patient receives avelumab at Cycle 1 Day 17 or 18, this is considered 
as 1-2 days delay.  
No delay and 1-2 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.
6.5.3.9. Infusion Rate Reductions
Applicable to avelumab, utomilumab, rituximab, bendamustine.
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.
Infusion rate reductions are not applicable to azacitidine.
6.5.3.10. Infusion Interruptions
Applicable to avelumab, utomilumab, rituximab, bendamustine.
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.
Infusion interruptions are not applicable to azacitidine.


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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 medications, which started 
prior to first dose date of study treatment and continued on on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study medications and pre-medications for study drug, which are started before the first dose 
of study treatment. 
Prior and concomitant medications will be summarized from the ‘General Concomitant 
Medications’ eCRF page. Pre-medications for study drug will also be summarized separately
from the ‘Pre-Medication Treatment’ eCRF page.
Summary of prior medications, summary of concomitant medications and summary of pre-
medications will include the number and percentage of patients by Anatomical Therapeutic 
Chemical (ATC) Classification level 2 and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. If any prior or concomitant medication is classified into 
multiple ATC classes, the medication will be summarized separately under each of these 
ATC classes. The summary tables will be sorted on decreasing frequency of drug class and 
decreasing frequency of drug name in a given drug class. In case of equal frequency 
regarding drug class (respectively drug name), alphabetical order will be used. In case any 
specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category. 
A listing of prior medications and a listing of concomitant medications will be created with 
the relevant information collected on the ‘General Concomitant Medications’ eCRF page. A 
listing of pre-medications will be created with the relevant information collected on the ‘Pre-
Medication Treatment’ eCRF page.
All concurrent procedures, which were undertaken any time during the on-treatment period, 
will be listed according to the eCRF page ‘General Non-drug Treatments’. 
A listing of concurrent procedures will be created with the relevant information collected on 
the ‘General Non-drug Treatments’ eCRF page.
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’, ‘Concomitant Radiation Therapy’, ‘Follow-up Radiation Therapy’, 
‘Concomitant Surgery’, and ‘Follow-up Surgery’ eCRF pages. 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Therapy’ and ‘Follow-up Surgery’ eCRF pages.


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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 for the first time, or if the worsening of an event is during the 
on-treatment period as defined in Section 3.5.1.
All analyses described will be based on TEAEs (started during the on-treatment period) if not 
otherwise specified. The AE listings will include all AEs (whether treatment-emergent or 
not). AEs outside the on-treatment period will be flagged in the listings.

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.

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 Safety Review Plan and finalized for analysis of the current studies 
data prior to DB lock).


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
Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs, documented in 
the Safety Review Plan and finalized for analysis of the current studies data prior to DB 
lock).
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment 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 utomilumab.

TEAEs leading to dose reduction of rituximab.

TEAEs leading to dose reduction of bendamustine.

TEAEs leading to dose reduction of azacitidine.

TEAEs leading to interruption of avelumab.


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
TEAEs leading to interruption of utomilumab.

TEAEs leading to interruption of rituximab.

TEAEs leading to interruption of bendamustine.

TEAEs leading to interruption of azacitidine.

TEAEs leading to discontinuation of avelumab.

TEAEs leading to discontinuation of utomilumab.

TEAEs leading to discontinuation of rituximab.

TEAEs leading to discontinuation of bendamustine.

TEAEs leading to discontinuation of azacitidine.

TEAEs leading to discontinuation of any study drug.

TEAEs leading to discontinuation of all study drugs.

Related TEAEs leading to discontinuation of avelumab.

Related TEAEs leading to discontinuation of utomilumab.

Related TEAEs leading to discontinuation of rituximab.

Related TEAEs leading to discontinuation of bendamustine.

Related TEAEs leading to discontinuation of azacitidine.

Related TEAEs leading to discontinuation of any study drug.

Related TEAEs leading to discontinuation of all study drugs.

Serious TEAEs.

Related Serious TEAEs.

TEAEs leading to death.

Related TEAEs leading to death.

irAEs.

IRRs.


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
TEAEs by SOC and PT and worst grade.

Related TEAEs by SOC and PT and worst grade.

TEAEs related to avelumab by SOC and PT and worst grade.

TEAEs related to utomilumab by SOC and PT and worst grade.

TEAEs related to rituximab by SOC and PT and worst grade.

TEAEs related to bendamustine by SOC and PT and worst grade.

TEAEs related to azacitidine by SOC and PT and worst grade.

TEAEs related to any study drug by SOC and PT and worst grade.

TEAEs leading to death by SOC and PT.

Related TEAEs leading to death by SOC and PT.

TEAEs Excluding SAEs, with frequency ≥5% in any treatment arm by SOC and PT.
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 utomilumab by SOC and PT.

TEAEs leading to dose reduction of rituximab by SOC and PT.

TEAEs leading to dose reduction of bendamustine by SOC and PT.

TEAEs leading to dose reduction of azacitidine 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 


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
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 6.5.3.6). 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 6.5.3.6).
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 utomilumab by SOC and PT.

TEAEs leading to interruption of rituximab by SOC and PT.

TEAEs leading to interruption of bendamustine by SOC and PT.

TEAEs leading to interruption of azacitidine 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:

TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT.

TEAEs leading to both interruption and dose reduction of utomilumab by SOC and PT.

TEAEs leading to both interruption and dose reduction of rituximab by SOC and PT.

TEAEs leading to both interruption and dose reduction of bendamustine by SOC and PT.

TEAEs leading to both interruption and dose reduction of azacitidine 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.


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
Related TEAEs leading to discontinuation of avelumab by SOC and PT.

TEAEs leading to discontinuation of utomilumab by SOC and PT.

TEAEs leading to discontinuation of rituximab by SOC and PT.

TEAEs leading to discontinuation of bendamustine by SOC and PT.

TEAEs leading to discontinuation of azacitidine by SOC and PT.

Related TEAEs leading to discontinuation of utomilumab by SOC and PT.

Related TEAEs leading to discontinuation of rituximab by SOC and PT.

Related TEAEs leading to discontinuation of bendamustine by SOC and PT.

Related TEAEs leading to discontinuation of azacitidine by SOC and PT.

TEAEs leading to discontinuation of any study drug by SOC and PT.

Related TEAEs leading to discontinuation of any study drug by SOC and PT.

TEAEs leading to discontinuation of all study drugs by SOC and PT.

Related TEAEs leading to discontinuation of all study drugs by SOC and PT.
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’
eCRFs, by treatment arm.  

All deaths.

Deaths within 30 days after last dose of study treatment.

Reason for Death.

Disease progression.

Study treatment toxicity.

AE not related to study treatment.

Unknown.


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
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.
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 utomilumab, by Cluster and PT.

irAEs leading to discontinuation of rituximab, by Cluster and PT.

irAEs leading to discontinuation of bendamustine, by Cluster and PT.

irAEs leading to discontinuation of azacitidine, by Cluster and PT.

irAEs leading to discontinuation of any study drug, by Cluster and PT.

irAEs leading to discontinuation of all study drugs, by Cluster and PT.

Serious irAEs, by Cluster and PT.


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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.

IRRs, by PT.

IRRs, Grade ≥3, by PT.

IRRs leading to discontinuation of avelumab, by PT.

IRRs leading to discontinuation of utomilumab, by PT.

IRRs leading to discontinuation of rituximab, by PT.

IRRs leading to discontinuation of bendamustine, by PT.

IRRs leading to discontinuation of azacitidine, by PT.

IRRs leading to discontinuation of any study drug, by PT.

IRRs leading to discontinuation of all study drugs, by PT.

Serious IRRs, by PT.

Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later).  For IV study drugs administered in combination the infusion numbers are those 
associated with the regimen, rather than the individual study drugs.
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
6.6.5. Laboratory Data
6.6.5.1. Hematology and Chemistry Parameters
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03.
Non-numerical qualifiers (with the exception of fasting flags) will not be taken into 
consideration in the derivation of CTCAE criteria (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 


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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). 
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 


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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.

(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 a post-
baseline TBILI ≥2×ULN, ALT ≥3×ULN or AST ≥3×ULN will be provided.


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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 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).
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.


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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: all urinalysis parameters.

Other parameters: hormone, viral serology and immunology parameters.

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 on Day 1 and Day 15 of each 
cycle for the first 6 cycles, and on Day 1 only for cycles >6. Weight will also 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. 


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6.6.7. Electrocardiogram
ECG summaries will include all ECG assessments from the on-treatment period.  All ECG 
assessments will be listed, and those collected outside the on-treatment period will be flagged 
in the listing. QTcB and QTcF will be derived based on RR and QT (see below). The 
average of the replicate measurements should be determined after the derivation of the 
individual parameter at each time point.
Selecting Primary QT Correction for Heart Rate
The analysis of QT data is complicated by the fact that the QT interval is highly correlated 
with heart rate.  Because of this correlation, formulas are routinely used to obtain a corrected 
value, denoted QTc, which is independent of heart rate. This QTc interval is intended to 
represent the QT interval at a standardized heart rate. Several correction formulas have been 
proposed in the literature. For this analysis we will use some of those methods of correction, 
as described below. The QT interval corrected for heart rate by the Bazett’s formula, QTcB, 
is defined as 
RR
QT
QTcB 
,
the QT interval corrected for heart rate by the Fridericia’s formula, QTcF, is defined as 
3 RR
QT
QTcF 
,
where RR represents the RR interval of the ECG, in seconds, and can be estimated as 
60/Heart Rate.  
Although Bazett’s correction is the historical standard, it does not perform well when heart 
rate fluctuates. Fridericia’s formula may perform better under these conditions. If QTcB and 
QTcF methods do not adequately correct for HR and there are a sufficient number of patients 
(eg, >30) with baseline ECGs, an alternate correction to achieve the goal of getting 
uncorrelated QTc and RR is based on a linear regression methods which yields, theoretically, 
uncorrelated QTc and RR.
Linear regression method:

Fit a model QT = a + b × RR to baseline data.

Use the estimated slope,  
^
b , to correct QT.

Corrected QT for heart rate will be computed as follows:
QTcP = QT + 
^
b × (1- RR)


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Data will be summarized using QTcF and QTcB. However, if these are not appropriate for 
the data set due to an observed large correlation between corrected QT and HR using the 
baseline assessments, the results will also be summarized using QTcP.  
ECG Summaries
The following analyses will be performed for each applicable ECG parameters (RR, PR, 
QRS, QT, ventricular rate -denoted as HR in what follows-, and QTc) by treatment 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, if applicable, QTcP) 
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.
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. MUGA/ECHO
LVEF% 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.  In addition, LVEF% will be summarized as frequency (number and percentage) 
of patients with: 


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
a shift from baseline normal to at least one result below the institutional lower limit of 
normal during the on-treatment period.

≥10-point decrease from baseline in LVEF% during the on-treatment period.

≥10-point decrease from baseline in LVEF% to a post-baseline value < LLN during the 
on-treatment period.

≥15-point decrease from baseline in LVEF%.

≥15-point decrease from baseline in LVEF% to a post-baseline value < LLN during the 
on-treatment period.
Clinically significant findings will be listed.
6.6.9. Physical Examination
Number and percentage of patients with abnormal findings in physical examination will be 
summarized by body system.
6.6.10. 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
See Section 5.1.2.


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8. REFERENCES
1.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.
2.
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika; 26, 404-413.
3.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
4.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience  
5.
Cheson B, Fisher RI, Barrington SF, et al. Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification. J Clin Oncol 2014; 32:3059-68.


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9. APPENDICES
Appendix 1. Immune-Related Adverse Events
The MedDRA PTs and clusters for irAEs are defined in the Safety Review Plan (SRP) for 
avelumab.
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 9.  This 
case definition is hierarchical, ie, each step is only checked for patients and events that have 
already met the prior step.  
Table 9.
Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’.
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement.
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs if 
A) OR B) below are met then the AE is in for the 
next step.
A) conmed ATC code is in (H02A, H02B, H02C, 
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 10
or Table 11 and will be identified for IV drugs only.     
Table 10.
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 11.
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].


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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.