Conditions: Renal Cell Cancer
Keywords: Cancer renal cell cancer kidney disease kidney neoplasms axitinib, sunitinib
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 886
Healthy volunteers: no

Brief summary:
This is a phase 3 randomized trial evaluating the anti-tumor activity and safety of avelumab in combination with axitinib and of sunitinib monotherapy, administered as first-line treatment, in patients with advanced renal cell carcinoma

Detailed description:

Arms:
arm 1: Avelumab administered at 10 mg/kg IV every two weeks in combination with axitinib, 5 mg PO BID. arm 2: Sunitinib given at 50 mg PO QD on schedule 4/2

Interventions: intervention 1: Avelumab (MSB0010718C) intervention 2: Axitinib (AG-013736) intervention 3: Sunitinib
Intervention descriptions: intervention 1: IV treatment Avelumab administered at 10 mg/kg IV every two weeks intervention 2: Oral treatment Axitinib given 5 mg PO BID intervention 3: Oral treatment Sunitinib given at 50 mg PO QD on schedule 4/2

Protocol document:
Prot_000.pdf: 
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CLINICAL PROTOCOL 
Renal Cell Carcinoma − Javelin Renal 101 
A PHASE 3, MULTINATIONAL, RANDOMIZED, OPEN-LABEL, 
PARALLEL-ARM STUDY OF AVELUMAB (MSB0010718C) IN COMBINATION 
WITH AXITINIB (INLYTA®) VERSUS SUNITINIB (SUTENT®) MONOTHERAPY 
IN THE FIRST-LINE TREATMENT OF PATIENTS WITH ADVANCED RENAL 
CELL CARCINOMA 
Compounds: 
MSB0010718C, AG-013736, SU011248  
Compound Names: 
Avelumab, Axitinib, Sunitinib  
US IND Number: 
 
 
European Clinical Trials Database 
(EudraCT) Number: 
2015-002429-20 
Protocol Number: 
B9991003 
Phase: 
3 
 
 
 
 
 
 
  
  
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
LIST OF TABLES .............................................................................................................. 26 
LIST OF FIGURES ............................................................................................................. 27 
APPENDICES .................................................................................................................... 27 
PROTOCOL SUMMARY................................................................................................... 28 
SCHEDULE OF ACTIVITIES ............................................................................................ 40 
1. INTRODUCTION ........................................................................................................... 56 
1.1. Mechanism of Action/Indication.......................................................................... 56 
1.2. Background and Rationale ................................................................................... 56 
1.2.1. Renal Cell Carcinoma ............................................................................. 56 
1.2.2. Pharmaceutical and Therapeutic Background .......................................... 57 
1.2.2.1. Avelumab (MSB0010718C) ................................................... 57 
1.2.2.2. Axitinib (INLYTA, AG-013736) .......................................... 59 
1.2.2.3. Sunitinib Malate (SUTENT®, SU011248)............................... 61 
1.2.3. Rationale for Studying Avelumab in Combination with Axitinib in 
Patients with Advanced Renal Cell Carcinoma ............................................. 62 
1.2.4. Rationale for Avelumab, Axitinib, and Sunitinib Starting Dosing 
Regimens ..................................................................................................... 68 
1.2.4.1. Avelumab and Axitinib Starting Dosing Regimens ................. 68 
1.2.4.2. Sunitinib Starting Dosing Regimen ......................................... 68 
1.3. Summary of Benefit/Risk Assessment ................................................................. 68 
2. STUDY OBJECTIVES AND ENDPOINTS .................................................................... 70 
2.1. Objectives ........................................................................................................... 70 
2.2. Endpoints ............................................................................................................ 71 
3. STUDY DESIGN ............................................................................................................ 72 
3.1. Study Overview ................................................................................................... 72 
3.1.1. Study Treatment ...................................................................................... 73 
3.1.2. Tumor Assessments................................................................................. 74 
3.1.3. Safety Assessments ................................................................................. 76 
3.1.4. Patient Outcomes .................................................................................... 76 
3.1.5. Pharmacokinetic/Immunogenicity Assessments ....................................... 76 
3.1.6. Biomarker Assessments........................................................................... 76 
4. PATIENT SELECTION .................................................................................................. 76 


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4.1. Inclusion Criteria ................................................................................................. 76 
4.2. Exclusion Criteria ................................................................................................ 78 
4.3. Lifestyle Guidelines ............................................................................................ 81 
4.3.1. Contraception .......................................................................................... 81 
4.3.1.1. Male Participant Contraception ............................................... 82 
4.3.1.2. Female Participant Reproductive Status .................................. 82 
4.3.1.3. Woman of Childbearing Potential (WOCBP) .......................... 82 
4.3.1.4. Contraception Methods ........................................................... 83 
4.4. Sponsor Qualified Medical Personnel .................................................................. 84 
5. STUDY TREATMENTS ................................................................................................. 85 
5.1. Allocation to Treatment ....................................................................................... 85 
5.2. Patient Compliance.............................................................................................. 86 
5.3. Investigational Product Supplies .......................................................................... 86 
5.3.1. Dosage Form(s) and Packaging ............................................................... 86 
5.3.1.1. Avelumab ............................................................................... 86 
5.3.1.2. Axitinib .................................................................................. 87 
5.3.1.3. Sunitinib ................................................................................. 87 
5.3.2. Preparation and Dispensing ..................................................................... 87 
5.3.2.1. Avelumab ............................................................................... 87 
5.3.2.2. Axitinib .................................................................................. 88 
5.3.2.3. Sunitinib ................................................................................. 88 
5.4. Administration .................................................................................................... 88 
5.4.1. Avelumab ................................................................................................ 88 
5.4.2. Axitinib ................................................................................................... 89 
5.4.3. Sunitinib.................................................................................................. 90 
5.4.4. Treatment After Initial Evidence of Radiologic Disease Progression 
in Both Arms ................................................................................................ 90 
5.4.5. Food Requirements ................................................................................. 91 
5.4.6. Recommended Dose Modifications ......................................................... 92 
5.4.6.1. Intrapatient Axitinib Dose Escalation and Dose Reduction ..... 92 
5.4.6.2. Sunitinib Dose Modifications ................................................. 93 
5.4.6.3. Management of Axitinib- or Sunitinib-Related 
Hypertension .................................................................................. 93 


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5.4.6.4. Axitinib Dose Modifications, Avelumab Infusion 
Omissions, and Sunitinib Dose Modifications for 
Treatment-Related Toxicity ............................................................ 94 
5.4.6.5. Special Precautions for Avelumab Administration ................ 101 
5.4.6.6. Management of Avelumab Infusion-Related Reactions ......... 101 
5.4.6.7. Management of Avelumab-related Severe 
Hypersensitivity Reactions and Flu-like Symptoms ...................... 102 
5.4.6.8. Management of Avelumab-Related Tumor Lysis 
Syndrome ..................................................................................... 103 
5.4.6.9. Management of Avelumab Immune-Related Adverse 
Events .......................................................................................... 105 
5.5. Investigational Product Storage ......................................................................... 112 
5.6. Investigational Product Accountability .............................................................. 113 
5.7. Destruction of Investigational Product Supplies ................................................. 114 
5.8. Concomitant Treatments .................................................................................... 114 
5.8.1. Inhibitors and Inducers of CYP Enzymes .............................................. 114 
5.8.2. Hematopoietic Growth Factors .............................................................. 115 
5.8.3. Concomitant Surgery ............................................................................. 115 
5.8.4. Concomitant Radiotherapy .................................................................... 116 
5.8.5. Other Prohibited Concomitant Medications and Therapies .................... 116 
5.9. Rescue Medications and Supportive Care .......................................................... 117 
5.9.1. Supportive Care Guidelines ................................................................... 117 
6. STUDY PROCEDURES ............................................................................................... 118 
6.1. Screening .......................................................................................................... 118 
6.1.1. Tumor Biospecimens ............................................................................. 118 
6.2. Treatment Period ............................................................................................... 119 
6.3. End of Treatment/Withdrawal and Follow-up Visits .......................................... 119 
6.4. End of the Study ................................................................................................ 119 
6.5. Patient Withdrawal ............................................................................................ 120 
7. ASSESSMENTS ........................................................................................................... 121 
7.1. Safety Assessment ............................................................................................. 121 
7.1.1. Pregnancy Testing ................................................................................. 122 
7.1.2. Adverse Events ..................................................................................... 122 


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7.1.3. Laboratory Safety Assessments ............................................................. 122 
7.1.4. Physical Examinations and Vital Signs .................................................. 124 
7.1.5. (12-Lead) Electrocardiogram Measurements ......................................... 124 
7.2. Patient-Reported Outcome Assessments ............................................................ 125 
7.2.1. FKSI-19 ................................................................................................ 125 
7.2.2. EuroQoL EQ-5D ................................................................................... 126 
7.3. Pharmacokinetics Assessments (Arm A only) .................................................... 126 
7.3.1. Blood Sample Collection for Pharmacokinetic Analysis ........................ 126 
7.3.2. Collection of Axitinib Pharmacokinetic Samples ................................... 127 
7.3.3. Collection of Avelumab Pharmacokinetic Samples ................................ 127 
7.4. Immunogenicity Assessment ............................................................................. 127 
7.5. Translational and Pharmacodynamic Assessments ............................................. 127 
7.5.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies .............. 128 
7.5.2. Peripheral Blood ................................................................................... 128 
7.6. Banked Biospecimens ....................................................................................... 128 
7.6.1. Markers of Drug Response .................................................................... 128 
7.6.2. Additional Research .............................................................................. 130 
7.7. Tumor Assessments ........................................................................................... 130 
7.8. Expedited Blinded Independent Central Review for Disease Progression ........... 132 
8. ADVERSE EVENT REPORTING ................................................................................ 132 
8.1. Adverse Events ................................................................................................. 132 
8.2. Reporting Period ............................................................................................... 132 
8.3. Definition of an Adverse Event ......................................................................... 133 
8.3.1. Avelumab Adverse Event of Special Interest ......................................... 134 
8.4. Medication Errors .............................................................................................. 134 
8.5. Abnormal Test Findings .................................................................................... 135 
8.6. Serious Adverse Events ..................................................................................... 135 
8.6.1. Protocol-Specified Serious Adverse Events ........................................... 136 
8.6.2. Potential Cases of Drug-Induced Liver Injury ........................................ 136 
8.7. Hospitalization .................................................................................................. 137 
8.8. Severity Assessment .......................................................................................... 138 
8.9. Causality Assessment ........................................................................................ 139 


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8.10. Exposure During Pregnancy ............................................................................ 139 
8.11. Occupational Exposure .................................................................................... 140 
8.12. Withdrawal Due to Adverse Events (also see Section 6.5 Patient 
Withdrawal) ........................................................................................................ 141 
8.13. Eliciting Adverse Event Information................................................................ 141 
8.14. Reporting Requirements .................................................................................. 141 
8.14.1. Serious Adverse Event Reporting Requirements .................................. 141 
8.14.2. Non-Serious Adverse Event Reporting Requirements .......................... 142 
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ............. 142 
9. DATA ANALYSIS/STATISTICAL METHODS .......................................................... 142 
9.1. Sample Size Determination ............................................................................... 142 
9.2. Analysis Populations ......................................................................................... 145 
9.2.1. Full Analysis Set ................................................................................... 145 
9.2.2. Per Protocol Analysis Set ...................................................................... 145 
9.2.3. Safety Analysis Set ............................................................................... 145 
9.2.4. Pharmacokinetic Analysis Set ............................................................... 145 
9.2.5. Biomarker Analysis Set ......................................................................... 146 
9.2.6. Immunogenicity Analysis Set ................................................................ 146 
9.3. Efficacy Analysis .............................................................................................. 146 
9.3.1. Analysis of Primary Endpoints .............................................................. 146 
9.3.2. Analysis of Secondary Endpoints .......................................................... 147 
9.4. Analysis of Other Endpoints .............................................................................. 151 
9.4.1. Statistical Analysis of Biomarker Endpoints .......................................... 151 
 
 
 
 
 
9.5. Safety Analysis ................................................................................................. 151 
9.6. Interim Analysis ................................................................................................ 153 
9.7. Data Monitoring Committee .............................................................................. 155 
9.8. Cardiac Events Adjudication Committee ........................................................... 156 
10. QUALITY CONTROL AND QUALITY ASSURANCE............................................. 156 
11. DATA HANDLING AND RECORD KEEPING ......................................................... 157 
11.1. Case Report Forms/Electronic Data Record ..................................................... 157 
11.2. Record Retention ............................................................................................. 158 


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12. ETHICS ...................................................................................................................... 158 
12.1. Institutional Review Board/Ethics Committee ................................................. 158 
12.2. Ethical Conduct of the Study ........................................................................... 158 
12.3. Patient Information and Consent ...................................................................... 159 
12.4. Patient Recruitment ......................................................................................... 160 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .................................................................................................................... 160 
13. DEFINITION OF END OF TRIAL ............................................................................. 160 
13.1. End of Trial in a Member State ........................................................................ 160 
13.2. End of Trial in All Other Participating Countries ............................................. 160 
14. SPONSOR DISCONTINUATION CRITERIA ........................................................... 160 
15. PUBLICATION OF STUDY RESULTS ..................................................................... 161 
15.1. Communication of Results by Pfizer ................................................................ 161 
15.2. Publications by Investigators ........................................................................... 161 
16. REFERENCES ............................................................................................................ 163 
 
LIST OF TABLES 
Table 1. 
Axitinib Dose Levels ............................................................................. 93 
Table 2. 
Sunitinib Dose Levels............................................................................ 93 
Table 3. 
Axitinib Dose Modifications and Avelumab Infusion Omissions for 
Investigational Product-Related Toxicity ............................................... 95 
Table 4. 
Sunitinib Dose Modifications for Investigational Product Related 
Toxicity ............................................................................................... 100 
Table 5. 
Treatment Modification for Symptoms of Infusion-Related 
Reactions Caused by Avelumab .......................................................... 102 
Table 6. 
Management of Avelumab Immune-Related Adverse Events .............. 106 
Table 7. 
Required Laboratory Tests .................................................................. 123 
Table 8. 
Required Laboratory Tests Post IA3 Cut Off Date (28-Apr-2020) ....... 124 
Table 9. 
PFS and OS in the PD-L1+ population – Efficacy and Futility 
Boundaries .......................................................................................... 154 
Table 10. 
PFS and OS in the ‘All Comers’ Population – Efficacy Boundaries ..... 155 
Table 11. 
Objective Response Status at Each Assessment for Patients with 
Measurable Disease at Baseline ........................................................... 173 
Table 12. 
Overall Responses Derived from Changes in Target, Non-target, 
and New Lesions ................................................................................. 175 
 


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LIST OF FIGURES 
Figure 1. 
Assessment and Initial Management of Tumor Lysis Syndrome 
(TLS) .................................................................................................. 104 
Figure 2. 
Testing Strategy .................................................................................. 143 
 
APPENDICES 
Appendix 1. ECOG Performance Status ........................................................................ 168 
Appendix 2. Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Guidelines .......................................................................................... 169 
Appendix 3. Immune related Response Criteria Derived from RECIST 1.1 
(irRECIST) ........................................................................................ 174 
Appendix 4. FACT-Kidney Symptom Index (FKSI)-19 ................................................ 176 
Appendix 5. Euro Qol 5-Dimension (EQ-5D) ................................................................. 177 
Appendix 6. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ................................................................. 179 
Appendix 7. Abbreviations and Definitions of Terms .................................................... 180 
Appendix 8. Treatment Recommendations for Symptoms of Infusion-Related 
Reactions Caused by Avelumab ........................................................ 183 


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PROTOCOL SUMMARY 
Background and Rationale: 
Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes about 3% of 
all malignant tumors in adults.1  RCC is often first detected at an advanced stage, with 
25-30% of patients with metastatic disease at diagnosis.  Until 2005, interferon-alpha 
(IFN-α) and high-dose interleukin (IL)-2 therapies were the standards of care for patients 
with advanced RCC (aRCC), albeit with modest efficacy.  Since then, development and 
approval of multiple Vascular Endothelial Growth Factor (VEGF) pathway and Mammalian 
Target of Rapamycin (mTOR) inhibitors have significantly improved the outcomes of aRCC 
patients.  These agents include the VEGF receptor (VEGFR) Tyrosine Kinase Inhibitors 
(TKIs) sunitinib, pazopanib, axitinib and sorafenib; the anti-VEGF monoclonal antibody 
bevacizumab; and the mTOR inhibitors temsirolimus and everolimus.  However, durable and 
complete responses in aRCC patients are uncommon; the majority of patients will eventually 
develop resistance, exhibit disease progression while on therapy, and succumb to death due 
to metastatic disease.  Response rates for previously treated aRCC patients are in the 
15-25% range, and median survival after diagnosis is under 1 year.1   
There is a strong rationale for considering immunotherapy in aRCC patients.  Cytokine-based 
immunotherapy, especially high-dose IL-2, exhibited durable responses in some aRCC 
patients.  There are anecdotal reports of spontaneous remissions in aRCC patients with 
evidence of antigen-specific lymphocyte infiltration in tumor tissues.2  These reports have 
generated considerable interest in immunotherapeutic approaches in the treatment of aRCC 
patients, especially with advent of immune checkpoint inhibitors such as anti- Programmed 
cell Death protein-1 (PD-1) and anti- Programmed Death-Ligand 1 (PD-L1) monoclonal 
antibodies in recent years.  Upregulation of PD-1 receptor on tumor-infiltrating lymphocytes 
(TILs), and its ligand PD-L1 on tumors, are associated with more aggressive disease and 
poor prognosis.3,4   
Monoclonal antibodies (mAb) that block the PD-1/PD-L1 interaction are novel 
immunotherapeutic approaches for aRCC, which have shown single-agent efficacy in 
patients whose disease has progressed following VEGF pathway inhibitor therapy.5,6  
Nivolumab, a high-affinity, fully human anti-PD-1 mAb has shown durable tumor responses 
with an objective response rate (ORR) of about 20% and median progression-free survival 
(PFS) of about 16 weeks in heavily pretreated aRCC patients.30,31  When nivolumab was 
combined with a VEGF TKI (sunitinib or pazopanib), it demonstrated more pronounced 
anti-tumor response.  Amin et al reported the data from combinations of sunitinib or 
pazopanib with nivolumab at the American Society of Clinical Oncology (ASCO) 2014 
annual meeting.37  The pazopanib plus nivolumab arm was discontinued due to safety issues; 
however, sunitinib (50 mg; 4 weeks on, 2 weeks off) was successfully combined with 
nivolumab 5 mg/kg every 3 weeks (Q3W), and dose expansion was subsequently completed 
in previously untreated aRCC patients.  ORR was 52% (17/33) for nivolumab in combination 
with sunitinib, and 45% (9/20) for nivolumab in combination with pazopanib.  Median 
duration of response (DR) was 37.1 weeks (95% CI: 18.1-80.0+), and median PFS was 
48.9 weeks (95% CI: 41.6-66.0) with sunitinib plus nivolumab.  MPDL3280A, another 


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human mAb that targets PD-L1, has shown ORR of 13% and a stable disease ≥24 weeks rate 
of 32% in patients with previously treated RCC when administered as a single agent.  Results 
from the combination of bevacizumab 15 mg/kg Q3W with MPDL3280A (20 mg/kg) were 
presented by McDermott et al at the European Society for Medical Oncology (ESMO) 
2014 annual meeting.32  Data were limited, but in previously untreated aRCC patients, there 
were 4 of 10 (40%) patients who had partial responses (PRs).  Five additional patients had a 
best response of stable disease (SD), and all these patients (9 out of 10) were still on 
treatment at the time of analysis.  These data, although preliminary, demonstrate the benefit 
of combining an anti-PD-1 or PD-L1 antibody with an anti-VEGF pathway agent in aRCC 
patients. 
The combination of nivolumab with ipilimumab, a fully human monoclonal antibody to 
CTLA-4, showed acceptable safety and encouraging antitumor activity in metastatic RCC.  
Patients were randomized to receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg 
(arm N3 + I1) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm N1 + I3) IV Q3W for 
4 doses then nivolumab 3 mg/kg IV Q2W until progression/toxicity.  Confirmed ORR was 
observed in 9/21 patients in arm N3 + I1 and in 11/23 patients in arm N1 + I3.  The median 
PFS was 36.6 weeks and 38.3 weeks in arm N3 + I1 and in arm N1 + I3, respectively.7 
In 2016, nivolumab single agent was approved as 2nd line therapy for aRCC based on the OS 
benefit reported in the Phase 3 CheckMate 025 trial.65  In patients with previously treated 
aRCC, median OS was 25.0 months with nivolumab (95% CI: 21.8 to not estimable) vs 
19.6 months (95% CI: 17.6, 23.1) with everolimus (HR= 0.73; 98.5% CI, 0.57 to 0.93; 
P=0.002) and fewer Grade 3 or 4 AEs occurred with nivolumab than with everolimus.  
More recently, data presented at ASCO GU 2017 on the Phase 2 randomized IMmotion 
150 trial testing atezolizumab (MPDL3280A) with or without bevacizumab vs sunitinib 
monotherapy in aRCC, demonstrated a PFS benefit in the PD-L1 positive subpopulation, 
with a median PFS of 14.7 months (95% CI: 8.2, 25.1) for the combination compared to 
7.8 month (95% CI: 3.8, 10.8) for sunitinib monotherapy (HR= 0.64; 95%CI: 0.38, 1.08; 
P=0.095).66 
Avelumab (MSB0010718C) is a fully human mAb of the immunoglobulin (Ig) G1 isotype 
that specifically targets and blocks PD-L1.  Avelumab is the proposed International 
Nonproprietary Name (INN) for the anti-PD-L1 monoclonal antibody MSB0010718C.  
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial cancer, and 
Hodgkin’s Lymphoma, as a single agent or in combination with chemotherapy, tyrosine 
kinase inhibitors, or other immune-modulating agents.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  


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Axitinib is an oral, potent and selective inhibitor of VEGFRs 1, 2, and 3, approved 
multinationally for the treatment of aRCC after failure of one prior systemic therapy (actual 
indication varies according to region/country).20  The anti-tumor activity of single-agent 
axitinib 5 mg twice daily (BID) in previously untreated patients with clear cell aRCC was 
assessed against sorafenib in a randomized, open-label, Phase 3 trial.  Although the study did 
not demonstrate a statistically significant difference in PFS, axitinib was associated with a 
longer median PFS (mPFS) time (mPFS of 10.1 months [95% CI: 7.2, 12.1] with axitinib vs. 
6.5 months [95% CI 4.7, 8.3] with sorafenib, stratified hazard ratio 0.77 [95% CI: 0.56, 
1.05]).  The mPFS observed with axitinib in this study was similar to those demonstrated 
earlier in Phase 3 clinical trials of other approved VEGFR TKIs in the first-line treatment of 
aRCC patients.8  Toxicities were generally tolerable and manageable, and similar to those 
observed in clinical trials of axitinib in pre-treated aRCC patients.9 
The most common adverse events (>20% of patients) reported among 1445 cancer patients 
receiving single-agent axitinib (regardless of causality) include diarrhea, hypertension, 
decreased appetite, nausea, weight decreased, dysphonia, palmar plantar erythrodysaesthesia 
syndrome, hypothyroidism, and proteinuria.  The most frequent Grade ≥3 adverse events 
were hypertension, fatigue, and diarrhea.18 
The risk of hepatotoxicity is low in patients with aRCC with axitinib, with an overall rate of 
Grade 3/4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increased 
<0.6% for each.26  The incidence of hematological toxicity was also low with axitinib in this 
patient population (eg, Grade 3/4 platelet count decreased and neutrophil count decreased 
0.3% for each).26 


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Sunitinib malate (SUTENT®) is an oral multitargeted TKI of stem cell receptor factor (KIT), 
platelet-derived growth factor-receptors (PDGFRs), VEGFRs, glial cell-line neurotrophic 
factor receptor (RET), FMS-like tyrosine kinase 3 (FLT3), and colony stimulating factor 
receptor Type 1 (CSR-1R) that has approved multinationally for the treatment of aRCC.  
Results from an international randomized Phase 3 trial comparing sunitinib to IFN-α in 
750 treatment-naïve metastatic RCC patients demonstrated a statistically significant 
improvement in PFS and ORR for sunitinib over IFN-α.23  Median PFS assessed by 
third-party blinded independent central review (BICR) was significantly longer (11 months) 
for sunitinib than for IFN-α (5 months) with a hazard ratio of 0.42 (95% CI: 0.32, 0.54) 
(p<0.001).  Sunitinib was also associated with a higher ORR than IFN-α by third-party BICR 
(31% vs. 6% for IFN, p<0.001).  Median overall survival (OS) was 26.4 months for sunitinib 
arm and 21.8 months for IFN-α with a hazard ratio of 0.821 (95% CI: 0.673 – 1.001),  
p = 0.051 (log-rank).  
Hepatotoxicity is a known risk associated with sunitinib therapy, with Grade 3/4 AST and 
ALT increased reported in 2% and 3% of treatment-naïve patients with aRCC, respectively.28  
In addition, liver failure and treatment related deaths have been reported in clinical trials 
(7/2281 [0.3%]) and post-marketing experience with sunitinib.28  Sunitinib has also been 
shown to have hematologic toxicity, with Grade 3/4 platelet count decreased 9% and 
neutrophil count decreased 17% in treatment-naïve patients with aRCC, leading to treatment 
interruptions, dose reductions and potentially decrease in therapeutic benefit for patients.28  
In addition rapid-onset of acute renal failure was observed in patients with metastatic renal 
cell carcinoma when sunitinib was given in combination with tremelimumab.53 
Since axitinib causes less hepatic and hematologic toxicity than sunitinib, it is considered to 
be a better partner for pairing with other anti-cancer agents such as avelumab. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
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Preliminary Safety Data of Avelumab in Combination with Axitinib 
The combination of avelumab with axitinib is being tested in study B9991002, a Phase 1b 
open-label, dose-finding study aiming to evaluate the safety, pharmacokinetics and 
pharmacodynamics of avelumab in combination with axitinib in patients with previously 
untreated aRCC.  This study was designed to establish the dosing regimen of avelumab and 
axitinib to be used for any further study with this combination.  Study B9991002 is 
comprised of a dose-finding phase and a dose-expansion phase.  The initial doses to be tested 
(Dose Level 1, [DL1]) were avelumab 10 mg/kg IV Q2W in combination with axitinib 5 mg 
orally (PO) twice a day (BID) continuously, with 2 lower dose levels to be explored only if 
the Maximum Tolerated Dose (MTD) was exceeded in DL1.  
The dose-finding phase was completed on 12 February 2016.  The 6 patients enrolled in this 
phase of the study completed the 4-week DLT follow-up period as per protocol 
(corresponding to 2 cycles of 2 weeks each).  There was 1 DLT reported: Grade 3 
proteinuria, related to axitinib per investigator assessment, which resolved after reducing the 
dose of axitinib to 3 mg BID.  As of 12 February 2016, the AEs recorded in the dose-finding 
phase were mostly low grade and manageable, with no new unexpected safety signals for the 
combination when compared to the safety profile of each drug as monotherapy.  No patients 
discontinued the combination due to AEs.  Based on these findings, the MTD\RP2D for the 
combination is avelumab 10 mg/kg IV Q2W and axitinib 5 mg PO BID continuously.  
Enrollment in the dose-expansion began on 15 February 2016, with a target enrollment of 
approximately 48 patients.  As of 15 August 2016, 46 patients were enrolled and started 
treatment in this part of the study, and 52 patients were treated overall (6 patients in the 
dose-finding part and 46 patients in the dose-expansion part). 
As of 15 August 2016, the B9991002 study clinical database included data from 47 treated 
patients (6 patients in the dose-finding part and 41 patients in the dose-expansion part).  
Overall, the reported TEAEs were mostly low grade and manageable.  The most frequent 
TEAEs (any cause, any grade, experienced by ≥10% patients) were dysphonia (17 patients, 
36.2%), fatigue (16 patients, 34.0%), hypertension (14 patients, 29.8%), diarrhea 
(13 patients, 27.7%), constipation (11 patients, 23.4%), nausea (9 patients, 19.1%), 
arthralgia, dyspnea, palmar-plantar erythrodysesthesia syndrome, rash (8 patients each, 
17.0%), decreased appetite, headache, hypothyroidism, infusion-related reactions (IRR), 
vomiting (7 patients each, 14.9%), alanine aminotransferase (ALT) increased (6 patients, 
12.8%), dizziness, lipase increased, mucosal inflammation and proteinuria (5 patients each, 
10.6%).  Fifteen (15) patients (31.9%) experienced a Grade 3 TEAE of any cause, including 
hypertension (5 patients, 10.6%), lipase increased, amylase increased and ALT increased 
(2 patients each, 4.3%), aspartate aminotransferase (AST) increased, dehydration, fatigue, 
gamma-glutamyltransferase increased, hyponatremia, hypophosphatemia, IRR, spinal cord 
compression, mucosal inflammation, pain in extremity, palmar-plantar erythrodysesthesia 
syndrome, proteinuria, pulmonary embolism, rash, venous thrombosis and urticaria (1 patient 
each, 2.1%).  Three (3) patients (6.4%) experienced a Grade 4 TEAEs of any cause: lipase 
increased (2 patients, 4.3%) and blood creatine phosphokinase increased (1 patient, 2.1%).  
One (1) case of Grade 5 TEAE myocarditis (see below for details) was recorded.  All 
Grades 3-5 TEAEs were assessed as related to study treatment by the investigator with the 


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exception of gamma-glutamyltransferase increased, hyponatremia, spinal cord compression, 
and pulmonary embolism. 
With respect to the potential immune-related AEs, 7 patients (14.9%) developed Grade 1-2 
hypothyroidism, 3 patients (6.4%) Grade 1 hyperthyroidism, and 1 patient (2.1%) Grade 1 
autoimmune hypothyroidism.  In addition, diarrhea (27.7 %, all of Grade 1-2 severity), rash 
(17% all grades, 2.1% Grade 3), ALT increased (12.8% all grades, 4.3% Grade 3), and AST 
increased (8.5% all grades, 2.1% Grade 3) were reported.  Both hyperthyroidism and 
hypothyroidism are expected AEs for both avelumab and axitinib.  Rash, diarrhea and 
increased liver enzymes have also been reported with axitinib monotherapy.  Medical review 
of these cases to confirm their immune-related nature is ongoing.  In addition, there was one 
case of fatal myocarditis which was assessed as related to both avelumab and axitinib by the 
investigator and in which pathology confirmed an immune-mediated cause. 
Seven (7) out of 47 treated patients included in the study database discontinued study 
treatment: 4 patients due to disease progression, 2 patients due to adverse event (fatal 
myocarditis and Grade 3 creatinine phosphokinase increased, 1 patient each), and 1 due to 
consent withdrawal. 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 f 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
In conclusion, as of 15 August 2016, the safety profile of the combination appears consistent 
with that of each study drug as monotherapy.  Safety continues to be closely monitored by 
the B9991002 study team and discussed in regular teleconferences between the study team 
and the investigators.  
In addition, as of 15 August 2016, 36 out of 47 patients in the clinical database were treated 
for at least 12 weeks prior to the analysis cut-off date and were included in the analysis of 
best overall response (BOR).  The BOR included 1 patient with confirmed CR (2.8%), 
15 patients with confirmed PR and 4 patients with unconfirmed PR (52.8%), 9 patients with 
SD (25.0%), 5 patients with PD (13.9%) and 2 patients not evaluable for response (5.6%; one 
patient died before the first oncologic assessment due to myocarditis, and another one who 
never started the combination treatment, discontinued axitinib treatment due to Grade 3 
creatinine phosphokinase increased).  The objective response rate (including confirmed and 
unconfirmed responses) is 55.6% (95% CI: 38.1-72.1). 


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Based on the safety and efficacy data described above, further investigation of avelumab in 
combination with axitinib in the patient population chosen for this study appears feasible. 
Study Objectives: 
Primary Objective 
• To demonstrate that avelumab in combination with axitinib is superior to sunitinib 
monotherapy in prolonging PFS or OS in the first-line treatment of PD-L1 positive 
patients (patient population prospectively defined as noted in Section 7.5.1) with 
aRCC. 
Secondary Objectives 
• To demonstrate that avelumab in combination with axitinib is superior to sunitinib 
monotherapy in prolonging PFS in the first-line treatment of patients with aRCC 
unselected for PD-L1 expression. 
• To demonstrate that avelumab in combination with axitinib is superior to sunitinib 
monotherapy in prolonging OS in the first-line treatment of patients with aRCC 
unselected for PD-L1 expression. 
• To evaluate other measures of efficacy of avelumab in combination with axitinib and 
sunitinib monotherapy in the first-line treatment of aRCC patients. 
• To evaluate progression-free survival on next-line of therapy (PFS2). 
• To evaluate the overall safety profile of avelumab in combination with axitinib and 
sunitinib monotherapy in the first-line treatment of aRCC patients.  
• To evaluate the time to treatment discontinuation/failure due to toxicity. 
• To evaluate the proportion of patients who discontinued treatment due to toxicity. 
• To evaluate the population pharmacokinetics of avelumab and axitinib when 
administered in combination. 
• To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may 
aid in the identification of a patient subpopulation most likely to benefit from 
treatment with avelumab in combination with axitinib and sunitinib monotherapy. 
• To assess the immunogenicity of avelumab when combined with axitinib. 
• To evaluate the effects of avelumab in combination with axitinib and sunitinib 
monotherapy on patient-reported outcomes. 


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 f 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
Study Endpoints: 
Primary Endpoints 
• Progression-Free Survival (PFS) based on Blinded Independent Central Review 
(BICR) assessment per RECIST v.1.1 for PD-L1 positive patients (patient population 
prospectively defined as noted in Section 7.5.1). 
• Overall Survival (OS) for PD-L1 positive patients (patient population prospectively 
defined as noted in Section 7.5.1). 
Secondary Endpoints 
• PFS by BICR assessment per RECIST v.1.1 for patients unselected for PD-L1 
expression. 
• OS for patients unselected for PD-L1 expression. 
• Objective Response (OR), Disease Control (DC), Time to Tumor Response (TTR) 
and Duration of Response (DR) based on BICR assessment and based on Investigator 
assessment, per RECIST v.1.1. 
• Progression-Free Survival (PFS) based on Investigator assessment per RECIST v.1.1. 
• Progression-Free Survival on next-line therapy (PFS2).  
• Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03 
(Appendix 6); vital signs (blood pressure, pulse rate). 
• Time to treatment discontinuation/failure due to toxicity. 
• Treatment discontinuation due to toxicity. 


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• PK parameters including trough concentrations (Ctrough) of avelumab and trough 
concentrations (Ctrough) and maximum concentrations (Cmax) of axitinib.  
• Tumor tissue biomarker status (ie, positive or negative; based on, for example, PD-L1 
expression and/or quantitation of tumor infiltrating CD8+ T lymphocytes as assessed 
by immunohistochemistry [IHC]). 
• Measures of clinical outcome (PFS, OS, OR, DC, TTR, and DR) in 
biomarker-positive and biomarker-negative subgroups. 
• Anti-drug antibodies (ADAs; nAbs) of avelumab when in combination with axitinib. 
• Patient-Reported Outcomes (PRO): FACT-Kidney Symptom Index (FKSI-19), 
EuroQol 5-Dimension (EQ 5D). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Design: 
This is a Phase 3, multinational, multicenter, randomized, open-label, parallel 2-arm study in 
which approximately 830 patients, including a minimum of 580 PD-L1 positive patients 
(patient population prospectively defined as noted in Section 7.5.1) are planned to be 
randomized in a 1:1 ratio to receive either avelumab in combination with axitinib or sunitinib 
monotherapy.  
Arm A: avelumab 10 mg/kg IV Q2W in a 6-week cycle + axitinib 5 mg PO BID. 
Arm B: sunitinib 50 mg PO QD on Schedule 4/2. 
Patients will be stratified according to Eastern Cooperative Oncology Group Performance 
Status (ECOG PS) (0 vs. 1) and region (United States vs Canada/Western Europe vs the rest 
of the world). 
Crossover between treatment arms will not be permitted. 


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Study Treatment: 
In Arm A, patients will receive: 
• Avelumab as a 1-hour IV infusion Q2W in a 6-week cycle.  
• Axitinib PO BID, with or without food, on a continuous dosing schedule.  
Treatment with study drugs may continue until confirmed disease progression assessed by 
BICR (see Section 5.4.4 for further details on treatment continuation after initial evidence of 
disease progression [PD]), patient refusal, patient lost to follow up, unacceptable toxicity, or 
the study is terminated by the sponsor, whichever comes first (see Section 6.5 Study 
Withdrawal). 
Axitinib treatment may be adjusted by dosing interruption with or without dose reduction 
(Section 5.4.6).  Avelumab treatment modification for drug-related toxicities, including 
irAEs and infusion-related AEs is described in Section 5.4.6. 
Axitinib intrapatient dose escalation may occur if relevant criteria are met (see 
Section 5.4.6.1). 
Patients in Arm A who stop one of the two study drugs (avelumab or axitinib) for reasons 
other than confirmed disease progression may continue on single agent treatment with the 
other drug until confirmed disease progression per BICR assessment (RECIST v.1.1), patient 
refusal, patient lost to follow up, unacceptable toxicity, or the study is prematurely 
terminated by the sponsor, whichever comes first.  At the end of study, Arm A patients who 
are still deriving clinical benefit from study treatment will be provided with an option for 
continued study treatment (eg, rollover study). 
Patients who stop avelumab after initial clinical benefit while on treatment and then 
experience radiologic disease progression by BICR assessment thereafter will be eligible for 
re-treatment with avelumab at the discretion of the investigator and after discussion with the 
sponsor’s medical monitor if 1) no cancer treatment was administered other than axitinib 
since the last dose of avelumab, 2) the patient does not meet the safety withdrawal criteria, 
and 3) the trial is still open.  
Patients who develop disease progression per BICR assessment on study treatment but are 
otherwise continuing to derive clinical benefit from study treatment (see Section 5.4.4) will 
be eligible to continue with avelumab combined with axitinib, or single-agent avelumab, or 
single-agent axitinib provided that the treating physician has determined that the benefit/risk 
for doing so is favorable.  
In Arm B, patients will receive: 
• Sunitinib PO 50 mg QD on a schedule of 4 weeks on treatment followed by 2 weeks 
off treatment (Schedule 4/2 in 6-week cycles).  


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Treatment with sunitinib may continue until confirmed disease progression assessed by 
BICR (see Section 5.4.4 for further details on treatment continuation after initial evidence of 
PD), patient refusal, patient lost to follow up, unacceptable toxicity, or the study is 
terminated by the sponsor, whichever comes first (see Section 6.5 Study Withdrawal). 
Patients who develop disease progression assessed by BICR on study treatment but are 
otherwise continuing to derive clinical benefit from study treatment (see Section 5.4.4) will 
be eligible to continue with sunitinib provided that the treating physician has determined that 
the benefit/risk for doing so is favorable. 
Sunitinib treatment may be adjusted by dosing interruption with or without dose reduction 
(see Section 5.4.6).  
After review of images by BICR is stopped following the final analyses for PFS performed 
as specified in the protocol (Section 9.6), permanent discontinuation of treatment will be 
performed as per investigator-assessed disease progression (see Section 7.7).  
Statistical Methods: 
For some endpoints, analyses will also be performed on the subset of PD-L1+ patients.  The 
associated analyses sets will be a subset of the analyses sets defined below restricted to the 
PD-L1+ population. 
Full Analysis Set 
The full analysis set will include all patients who are randomized.  Patients will be classified 
according to the treatment and stratum assigned at randomization.  The full analysis set will 
be the primary population for evaluating all efficacy endpoints and patient characteristics. 
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 1 dose of study treatment and do not have major protocol deviations 
expected to impact the primary objective of the study.  Major protocol deviations will be 
pre-specified in the Statistical Analysis Plan (SAP).  The Per-Protocol Analysis Set will be 
used for sensitivity analyses of the primary efficacy endpoints. 
Sample Size Determination and Testing Strategy: 
The following statistical hypotheses will be tested to address the primary objective: 
H01: HRPFS+ ≥1 vs. H11: HRPFS+ <1  
H02: HROS+ ≥1 vs. H12: HROS+ <1 
where HRPFS+ and HROS+ are the hazard ratios (Arm A vs. Arm B) of PFS and OS, 
respectively, in the PD-L1+ population. 


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In addition the following statistical hypotheses will be tested to address the secondary 
objectives: 
H03: HRPFS ≥1 vs. H13: HRPFS <1 
H04: HROS ≥1 vs. H14: HROS <1 
where HRPFS and HROS are the hazard ratios (Arm A vs. Arm B) of PFS and OS, respectively, 
in the ‘all comers’ population (patients unselected for PD-L1 expression). 
Overall type I-error will be maintained at or below 1-sided 0.025 by allocating α=0.004 to the 
PFS comparison in PD-L1+ patients and by allocating α=0.021 to the OS comparison in the 
PD-L1+ population.  A gatekeeping procedure will be used to allow further testing of PFS 
and OS in the PD-L1 ‘all comers’ population as described in Figure 2 (Section 9.1).  The 
significance levels for each test will also take into account the group sequential nature of the 
design (see Section 9.6).  
For the primary PFS comparison, 336 PFS events by BICR assessment in the PD-L1+ 
population will provide 90% power to detect a HR of 0.65 using a 1-sided log rank test at a 
significance level of 0.004, and a 2-look group sequential design with Lan-DeMets 
(O’Brien-Fleming) α-spending function to determine the efficacy boundary and a Gamma 
Family (-15) β-spending function to determine the non-binding futility boundary. 
For the primary OS comparison, 368 OS events in the PD-L1+ population will provide 
90% power to detect a hazard ratio of 0.70 using a 1-sided log-rank test at a significance 
level of 0.021, and a 4-look group-sequential design with Lan-DeMets (O’Brien-Fleming) 
α-spending function to determine the efficacy boundary and a Gamma Family 
(-3) β-spending function to determine the non-binding futility boundary. 
The study will randomize a total of approximately 830 patients, including a minimum 
580 PD-L1 positive patients, using a 1:1 randomization, stratified by ECOG PS (0 versus 1) 
and region (United States vs Canada/Western Europe vs the rest of the world).  
The sample size for this study is determined based on the following: 
1. The median PFS for patients receiving sunitinib is 11 months27 and the median PFS 
for patients receiving avelumab in combination with axitinib is 16.9 months for 
PD-L1 positive patients and 15.7 months for patients unselected for PD-L1 
expression; this corresponds to a hazard ratio (HR) of 0.65 and 0.7, respectively under 
the exponential model assumption;  
2. The median OS for patients receiving sunitinib is 26.4 months27 and the median OS 
for patients receiving avelumab in combination with axitinib is 37.7 months for 
PD-L1 positive patients and 35.2 months for patients unselected for PD-L1 
expression; this corresponds to a hazard ratio (HR) of 0.7 and 0.75, respectively under 
the exponential model assumption; 
3. PFS drop-out rate of approximately 15% and OS drop-out rate of approximately 5%; 


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4. 70% of the randomized patients are PD-L1 positive; 
5. Non-uniform patient accrual accomplished over a 21 month period. 
The sample size of approximately 830 patients will also allow an assessment of PFS and OS 
in the ‘all comers’ population.  
If H01 is rejected then PFS in the ‘all comers’ population can be tested and 490 PFS event by 
BICR assessment will provide 90% power to detect a HR of 0.70 using a 1-sided log rank 
test at a significance level of 0.004, and a 2-look group sequential design with Lan-DeMets 
(O’Brien-Fleming) α-spending function to determine the efficacy boundary.  
If either H02 or H03 are rejected, then OS in the ‘all comers’ population can be tested at the 
sum of the significance levels associated with the significant H02 and H03 tests (see Figure 2, 
Section 9.1).  With 534 OS events, the power is 91% (if both H02 and H03 are rejected), 90% 
(if H02 is rejected and H03 is not rejected) or 74% (if H02 is not rejected and H03 is rejected) to 
detect a HR of 0.75 using a 1-sided log rank test at a significance level of 0.025, 0.021 or 
0.004, respectively, and a 4-look group sequential design with Lan-DeMets 
(O’Brien-Fleming) α-spending function to determine the efficacy boundary.  
The data cutoff for the primary PFS analysis will occur after the target number of PFS events 
by BICR assessment in the PD-L1+ population has been reached and the last patient 
randomized in the study has been followed for at least 12 months after randomization.  
The data cutoff for the primary OS analysis will occur after the target number of deaths in the 
PD-L1+ population has been reached. 
The study will be considered positive if the stratified log-rank test for either PFS or OS in the 
PD-L1+ population is significant at the respective α levels.  
SCHEDULE OF ACTIVITIES 
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to the Study Procedures and Assessments sections of the protocol for detailed 
information on each procedure and assessment required for compliance with the protocol.  
The investigator may schedule visits (unplanned visits) in addition to those listed in the 
Schedule of Activities table in order to conduct evaluations or assessments required to 
protect the well-being of the patient. 






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Visit Identifiers1 
Screening 
Study Treatment 
(1 cycle = 6 weeks = 42 days) 
 
Cycle 1 
Cycles ≥2 
≤28 Days Prior to 
Randomization 
Day 1 
 
Day 15 
(±3 days) 
Day 29 
(±3 days) 
Day 1 
(±3 days) 
Day 15 
(±3 days) 
Day 29 
(±3 days) 
Mandatory Archival FFPE Tumor 
Tissue26 
X 
 
 
 
 
 
 
Mandatory Recent FFPE Tumor 
Tissue Block27 
X 
 
 
 
 
 
 
Anti-Avelumab Antibodies and 
Neutralizing Antibodies28 
(Arm A only) 
 
X 
X 
X 
X (Cycles 2, 3, 4, 6 
then every 2 Cycles 
thereafter up to 
Cycle 16) 
 
X (Cycles 2, 3, 
4 only) 
 
Footnotes for Schedule of Activities for SCREENING and STUDY TREATMENT periods  
1. Visit Identifiers: All assessments should be performed prior to dosing with study treatments unless otherwise indicated.  Acceptable time windows for 
performing each assessment are described in the column headers.    
2. Informed Consent: Must be obtained prior to undergoing any study-specific procedure. 
3. Medical/Oncological History: To include information on prior systemic adjuvant or neoadjuvant therapy regimens, surgery, and radiation therapy. 
4. Baseline Signs/Symptoms: To be recorded pre-dose on Cycle 1 Day 1.  Patients will be asked about any signs and symptoms experienced within the 
14 days prior to randomization. 
5. Physical Examination: Includes an examination of major body systems and weight (height included at screening only).  Weight will be collected before 
each avelumab infusion.  From Cycle 2 onward PE will be performed on Day 1 on each cycle.  Additional PE may be performed if clinically indicated.  
ECOG PS: Arm B (Sunitinib Arm): From Cycle 2 onward, Days 15 and 28 ECOG PS will be performed by telephone call (eg, nurse) in a standardized 
form, unless the patient is visiting the site for other reasons.  Arm A (this option is applicable only to patients on treatment with single agent axitinib, after 
they have visited the site every 2 weeks for additional 2 full cycles following avelumab permanent discontinuation): Days 15 and 29 ECOG PS will be 
performed by telephone call (eg, nurse) in a standardized form, unless the patient is visiting the site for other reasons. 
6. Contraception Check: Male patients with female partner of childbearing potential and female patients who are of childbearing potential will need to 
affirm that they meet the criteria for correct use of 1 of the selected methods of contraception (see Section 4.3.1 for details on methods allowed).  The 
investigator or his or her designee will discuss with the patient the need to use 1 highly effective contraception methods consistently and correctly and 
document such conversation in the patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if the 
selected contraception method is discontinued, or if pregnancy is known or suspected in the patient or the patient’s partner. 


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7. Vital Signs: Vital signs to include, blood pressure, pulse rate.  Vital signs will be monitored at screening and on Days 1, 15, and 29 of each cycle during 
the study.  Blood pressure and pulse rate should be taken with the patient in the seated position after the patient has been sitting quietly for at least 5 
minutes.  Two blood pressure/pulse readings will be taken at least 1 hour apart at each clinic visit.  Arm B (Sunitinib Arm): From Cycle 2 onward Days 15 
and 29 vital signs will be performed and collected at home by the patient and communicated to the site study team during the telephone call (eg, nurse) in a 
standardized form, unless the patient is visiting the site for other reasons.  Arm A (this option is applicable only to patients on treatment with single agent 
axitinib, after they have visited the site every 2 weeks for additional 2 full cycles following avelumab permanent discontinuation): Days 15 and 29 vital 
signs will be performed and collected at home by the patient and communicated to the site study team during the telephone call (eg, nurse) in a 
standardized form, unless the patient is visiting the site for other reasons.  
8. Home Blood Pressure Monitoring: All patients will receive home blood pressure monitoring devices and blood pressure will be monitored at home.  
Patients will monitor their blood pressure at least once daily (in Arm A before taking the morning dose of axitinib, and in Arm B before taking the daily 
dose of sunitinib during the 4 weeks of treatment and any time during the day in the 2 weeks off treatment), and blood pressure should be recorded in a 
patient diary.  Patients should be instructed to contact the site immediately for guidance if their systolic blood pressure rises above 150 mm Hg, diastolic 
blood pressure rises above 100 mm Hg, or if they develop symptoms perceived to be related to elevated blood pressure (eg, headache, visual disturbances), 
although a different blood pressure threshold for contacting the site may be used according to the investigator’s clinical judgment (see Section 5.4.6.3).   
9. Hematology, Blood Chemistry (full panel), and Coagulation: Required tests are listed in Table 7.  Full chemistry panel (required tests are listed in 
Table 7) is required at screening, on Day 1 of each cycle.  May also be performed when clinically indicated.  Arm B (Sunitinib Arm): From Cycle 2 
onward, Days 15 and 29 laboratory assessments will be performed by local laboratories unless the patient is visiting the site for other reasons.  The patient 
will be instructed to email/fax the results of the laboratories assessments to the site and bring them in at the next visit.  Arm A (this option is applicable 
only to patients on treatment with single agent axitinib, after they have visited the site every 2 weeks for additional 2 full cycles following avelumab 
permanent discontinuation): Days 15 and 29 laboratory assessments will be performed by local laboratories unless the patient is visiting the site for other 
reasons.  The patient will be instructed to email/fax the results of the laboratories assessments to the site and bring them in at the next visit.  
10. Blood Chemistry (core panel): Core chemistry panel (required tests are listed in Table 7) is required on Days 15 and 29 of each cycle.   
11. Thyroid Function Tests: Free T4, TSH, tests will be performed at screening, Cycle 2 Day 1, Cycle 3 Day 1, then every 2 cycles thereafter.  Additional 
tests should be performed when clinically indicated.  Hypothyroidism should be treated per standard medical practice to maintain euthyroid state.  See 
Table 7. 
12. ACTH: ACTH tests will be performed at screening, Cycle 3 Day 1, then every 2 cycles thereafter.  Additional tests should be performed when clinically 
indicated.  See Table 7.  
13. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at least 25 mIU/mL, will be 
performed on two occasions prior to starting study treatment: once at the start of screening and once at the baseline visit immediately before investigational 
product administration.  During treatment, pregnancy tests (serum or urine test) will also be routinely repeated on Days 1, 15, and 29 of each treatment 
cycle during the active treatment period and additionally whenever one menstrual cycle is missed or when potential pregnancy is otherwise suspected.  
Additional pregnancy tests may also be undertaken if requested by IRB/ECs or if required by local regulations.  Results of the pregnancy test should be 
evaluable prior to each dosing.  (see Section 7.1.1). 
14. Urinalysis (Table 7): Required only at Screening.  If protein ≥2+ by semiquantitative method (eg, urine dipstick), protein will have to be quantified by 
24 hour urine collection.  To be performed as clinically indicated at other timepoints. 


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15. 12-Lead ECG: See Section 7.1.5 for details.  All patients require a triplicate ECG measurement at screening.  On-treatment ECGs will be performed on 
Days 1, 15, and 29 of Cycle 1 before avelumab infusion and at the end of infusion in Arm A and before sunitinib drug intake in Arm B.  At each time point, 
3 consecutive 12-lead ECGs (triplicates) will be performed approximately 2 minutes apart to determine mean QTc (average of triplicates).  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 QTc is prolonged (>500 msec), 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.  At that time, creatinine kinase (CK) and troponin should be performed in 
association with clinically indicated ECG assessments.  When coinciding with blood sample draws for pharmacokinetics (PK), ECG assessment (as well as 
CK and troponin, if clinically indicated) should be performed prior to PK blood sample collection, such that the PK blood sample is collected at the 
nominal time. 
16. Tumor Assessments: CT or MRI will include chest, abdomen and pelvis (CAP) at all time points.  The CT and MRI scans should be performed with 
contrast agents unless contraindicated for medical reasons.  Premedication prior contrast media administration as per local guidelines is allowed (see 
Section 5.8.5).  Bone scintigraphy/bone scans and brain scans/head CT/MRI are also required at screening.  Bone lesion(s) identified at screening by bone 
scan can be further assessed by CT or MRI as per local practice and subsequently re-assessed by CT or MRI as per tumor assessment schedule.  If bone 
scintigraphy/bone scan is the preferred assessment method for bone lesion(s) as per local practice, re-assessment during study should occur every 12 weeks 
after randomization.  Bone scan will also be repeated during study as clinically indicated (eg, patient describes new or worsening bone pain, or has 
increasing alkaline phosphatase level, or other signs and symptoms of new/progressing bone metastases) or at the time of complete response (CR) 
confirmation.  Brain must be included in subsequent tumor assessments if a patient has brain metastases at screening, otherwise brain will only be 
evaluated when clinically indicated.  The same imaging technique used to characterize each identified and reported lesion at screening will be employed in 
the following tumor assessments.  Anti-tumor activity will be assessed through radiological tumor assessments conducted at screening, at 6 weeks after 
randomization then every 6 weeks from randomization up to 18 months after randomization and every 12 weeks thereafter until confirmed disease 
progression by BICR assessment (see Section 5.4.4 for further details on treatment continuation after initial evidence of PD) regardless of initiation of 
subsequent anti-cancer therapy.  Further imaging assessments may be performed at any time if clinically indicated (eg, suspected PD, symptomatic 
deterioration, etc.).  The schedule of assessments should be fixed according to the calendar, regardless of treatment schedule, treatment delays or 
interruptions.  Imaging assessments are to be scheduled using the randomization date as the reference date for all time points and are NOT to be scheduled 
based on the date of the previous imaging time point.  CR and PR must be confirmed with repeated imaging performed at least 4 weeks after initial 
documentation of response.  If radiologic imaging shows progressive disease (PD), then tumor assessment should be repeated after at least 4 weeks to 
confirm PD.  Assessment of response will be made using RECIST v.1.1 and immune-related response criteria (irRECIST) (Nishino 2014, Appendix 3).  
All radiographic images will be collected and objectively verified by an independent third-party core imaging laboratory (blinded independent central 
review [BICR]) as described in the Study Manual.  After review of images by BICR is stopped following the final analyses for PFS performed as specified 
in the protocol (Section 9.6), permanent discontinuation of treatment will be performed as per investigator-assessed disease progression.  After review of 
images by BICR is stopped, confirmation of disease progression ≥4 weeks after the PD was first noticed will no longer be required.  irRECIST-defined 
antitumor activity will no longer be collected as per PACL dated 02 September 2019.  See Section 7.7 for additional information. 
17. Follow-up for Axitinib/Sunitinib Dosing Compliance: Follow-up by telephone will be done on Day 5 of the first cycle to confirm patient understanding 
and compliance with dosing instructions.  Axitinib dosing compliance will also be assessed following any dose modification.  If needed, patient will be 
retrained. 


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18. Adverse Events: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  For SAEs, the active reporting period 
to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 90 calendar 
days after the last administration of the investigational product.  SAEs occurring to a patient after the active reporting period has ended should be reported 
to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of 
being related to investigational product are to be reported to the sponsor.  AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) 
from the time the patient has taken at least 1 dose of study treatment through and including 90 calendar days after the last administration of the study drug.  
If a patient begins a new anticancer therapy, the AE reporting period for nonserious AEs ends at the time the new treatment is started.  Death must be 
reported if it occurs during the SAE reporting period after the last dose of investigational product, irrespective of any intervening treatment.  Arm B 
(Sunitinib Arm): From Cycle 2 onward, Days 15 and 29 AEs collection will be performed by telephone call (eg, nurse) in a standardized form, unless the 
patient is visiting the site for other reasons.  Arm A (this option is applicable only to patients on treatment with single agent axitinib, after they have visited 
the site every 2 weeks for additional 2 full cycles following avelumab permanent discontinuation): Days 15 and 29 AEs collection will be performed by 
telephone call (eg, nurse) in a standardized form, unless the patient is visiting the site for other reasons.  Based on the observed (laboratory tests) and 
reported findings during the telephone call, the patient might be required to visit the site.  The investigator must document in writing the results of the 
phone call in a specific form and data are to be reported in the CRF. 
19. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and 
up to 90 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non drug supportive interventions 
(eg, transfusions).  Arm B (Sunitinib Arm): From Cycle 2 onward, Days 15 and 29 concomitant medications collection may be performed by telephone call 
(eg, nurse) in a standardized form, unless the patient is visiting the site for other reasons.  Arm A (this option is applicable only to patients on treatment 
with single agent axitinib, after they have visited the site every 2 weeks for additional 2 full cycles following avelumab permanent discontinuation): Days 
15 and 29 concomitant medications collection may be performed by telephone call (eg, nurse) in a standardized form, unless the patient is visiting the site 
for other reasons.  
20. Patient-Reported Outcome Questionnaire: FKSI-19 and EUROQoL 5-Dimension (EQ-5D) are to be administered on Day 1 (on randomization) of 
Cycle 1, and at Day 1 of each Cycle.  PROs are to be administered always prior to any other test/procedure is performed. 
21. Randomization: An interactive voice and web response system will be used for randomization to a treatment arm.  Required information: site and patient 
identifiers and demographic information.  Study treatment should begin within 3 days after randomization.   
22. Study Treatment: Avelumab will be given as a 1-hour intravenous infusion every 2 weeks in a 6-week cycle.  Axitinib will be given orally twice daily PO 
on a continuous daily dosing schedule.  Sunitinib will be given orally 50 mg taken once daily, on a schedule 4 weeks on treatment followed by 2 weeks off 
(Schedule 4/2). 
23. Pharmacokinetics for axitinib: In Arm A only, PK samples for axitinib (3 mL) will be collected at 2 hours post-dose on Day 1 of Cycle 1 and then at 
pre-dose and 2 hours post-dose for axitinib on Day 15 and 29 of Cycle 1.  Details are outlined in Section 7.3. 


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24. Pharmacokinetics for avelumab: In Arm A only, pre-dose PK samples for avelumab (3.5 mL) will be taken on Day 1, Day 15 and Day 29 of Cycle 1, on 
Day 1 and Day 29 of Cycles 2-4, Day 1 of Cycle 6 and then every 2 cycles thereafter up to Cycle 16.  Pre-dose samples can be taken up to 2 hours prior to 
the start of avelumab infusion.  Details are outlined in Section 7.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
f
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
26. Mandatory Archival FFPE Tumor Tissue: An archival formalin fixed, paraffin embedded (FFPE) tumor tissue block from primary diagnosis specimen 
must be provided for all patients enrolled in the study and submitted to the Central Laboratory prior to randomization.   
 
 
 
 
 
 
p
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  Cytology samples 
(eg, FFPE cell pellet from Fine Needle Aspiration biopsy) are not acceptable.  See Section 6.1.1 and Section 7.5.1. 
27. Mandatory Recent FFPE Tumor Tissue Block: A baseline de novo tumor biopsy (biopsied tumor lesion should not be a RECIST target lesion) must be 
obtained for all patients enrolled.  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  For baseline de novo biopsy, tumor 
tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted.  The de novo 
biopsy(ies) should be formalin-fixed and paraffin-embedded as per routine (see Study Manual), and the resulting FFPE tissue block(s) should be submitted 
to the Central Laboratory.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  See Section 6.1.1 and Section 7.5.1.  
28. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab).  In Arm A one blood sample (3.5 mL) for 
anti-avelumab antibodies will be collected pre-dose at Day 1, Day 15 and Day 29 of Cycle 1, at Day 1 and Day 29 of Cycles 2-4 at Day 1 of Cycle 6, and 
then every 2 cycles thereafter up to Cycle 16.  All samples should be drawn within 2 hours before start of avelumab infusion.  All the samples that are 
positive for ADA may also undergo characterization for Nab.  See Section 7.4. 
29. MUGA Scan or ECHO.  For the evaluation of the left ventricular ejection fraction, the technique used at screening will be consistently used throughout 
the study, in the following assessments.  
30. Cardiac Enzymes: B-type natriuretic peptide (BNP), troponin, creatine kinase-MB (CK-MB) will be performed at screening and on Cycles 1 2 and 3 on 
Days 1, 15 and 29.  Cardiac enzymes may be also performed when clinically indicated (see also footnote 15).  The 99th percentile should be used to define 
a positive troponin value, and every positive test should be repeated.  Arm A: troponin test results must be reviewed by the treating physician before each 
avelumab administration. 






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9. Thyroid Function Tests: Free T4 and TSH tests will be performed at End of Treatment/Withdrawal visit and Follow-up visits at 30 ±3, 60 ±3, and  
90 ±3 days after the last dose.  Additional tests should be performed when clinically indicated.  See Table 7. 
10. ACTH Test: ACTH tests will be performed at End of Treatment/Withdrawal visit and Follow-up visit at 30 ±3, 60 ±3, 90 ±3 days after the last dose.  
Additional tests should be performed when clinically indicated.  See Table 7. 
11. Serum/Urine Pregnancy Test: For female patients of childbearing potential, a serum or urine pregnancy test, with sensitivity of at least 25 mIU/mL, 
will be performed at the End of Treatment/Withdrawal visit and at 30 ±3, 60 ±3 (Arm B only).  Days Follow-up visit and additionally whenever one 
menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by 
IRB/ECs or if required by local regulations.  
12. Urinalysis: Required only at the End of Treatment.  To be performed as clinically indicated at other timepoints. 
13. 12-Lead ECG: See Section 7.1.5 for details.  Triplicate ECG measurements should be performed at end of treatment, and when clinically indicated.  
Creatinine kinase (CK) and troponin should be performed in association with clinically indicated ECG assessements.  Clinically significant findings seen 
on follow-up ECGs should be recorded as adverse events. 
14. Tumor Assessments: CT or MRI will include chest, abdomen and pelvis (CAP) at all time points.  The CT and MRI scans should be performed with 
contrast agents unless contraindicated for medical reasons.  Premedication prior contrast media administration as per local guidelines is allowed (see 
Section 5.8.5).  Bone scintigraphy/bone scans and brain scans/head CT/MRI are also required at screening.  Bone lesion(s) identified at screening by bone 
scan can be further assessed by CT or MRI as per local practice and subsequently re-assessed by CT or MRI as per tumor assessment schedule.  If bone 
scintigraphy/bone scan is the preferred assessment method for bone lesion(s) as per local practice, re-assessment during study should occur every 
12 weeks after randomization.  Bone scan will also be repeated during study as clinically indicated (eg, patient describes new or worsening bone pain, or 
has increasing alkaline phosphatase level, or other signs and symptoms of new/progressing bone metastases) or at the time of complete response (CR) 
confirmation.  Brain must be included in subsequent tumor assessments if a patient has brain metastases at screening, otherwise brain will only be 
evaluated when clinically indicated. 
The same imaging technique used to characterize each identified and reported lesion at screening will be employed in the following tumor assessments.  
Anti-tumor activity will be assessed through radiological tumor assessments conducted at screening, at 6 weeks from randomization, then every 6 weeks 
up to 18 months after randomization and every 12 weeks thereafter until confirmed disease progression by BICR assessment regardless of initiation of 
subsequent anti-cancer therapy.  The schedule of assessments should be fixed according to the calendar, regardless of treatment schedule, treatment 
delays or interruptions.  Imaging assessments are to be scheduled using the randomization date as the reference date for all time points and are NOT to be 
scheduled based on the date of the previous imaging time point.  Further imaging assessments may be performed at any time if clinically indicated (eg, 
suspected PD, symptomatic deterioration, etc.).  CR and PR must be confirmed with repeated imaging performed at least 4 weeks after initial 
documentation of response.  If radiologic imaging shows progressive disease (PD), then tumor assessment should be repeated after at least 4 weeks to 
confirm PD.  Assessment of response will be made using RECIST v.1.1 
 
 
 
 
 
 
 
 
.  
All radiographic images will be collected and objectively verified by an independent third-party core imaging laboratory (blinded independent central 
review [BICR]) as described in the Study Manual.  After review of images by BICR is stopped following the final analyses for PFS performed as 
specified in the protocol (Section 9.6), permanent discontinuation of treatment will be performed as per investigator-assessed disease progression.  After 
review of images by BICR is stopped, confirmation of disease progression ≥4 weeks after the PD was first noticed will no longer be required.     
irRECIST-defined antitumor activity will no longer be collected as per PACL dated 02 September 2019.  See Section 7.7 for additional information. 


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15. Adverse Events: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  For SAEs, the active reporting 
period to Pfizer or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 90 calendar 
days after the last administration of the investigational product.  SAEs occurring to a patient after the active reporting period has ended should be 
reported to the sponsor if the investigator becomes aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable 
possibility of being related to investigational product are to be reported to the sponsor. 
AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of study treatment 
through and including 90 calendar days after the last administration of the study drug.  If a patient begins a new anticancer therapy, the AE reporting 
period for nonserious AEs ends at the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last 
dose of investigational product, irrespective of any intervening treatment. 
16. Concomitant Medications/Treatments: Concomitant medications and treatments will be recorded from 28 days prior to the start of study treatment and 
up to 90 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs 
(eg, anti-emetic treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions 
(eg, transfusions).  
17. Survival Assessment: All patients will be followed for survival and subsequent anticancer therapies every 3 months (±14 days) until death, end of the 
study or patient withdrawal of consent, whichever comes first.  Information will be collected by telephone call unless the patient is visiting the site for 
other reasons.  The Sponsor will request an “ad hoc” survival update prior to each protocol-specified interim analysis and final analysis.  The investigator 
or designee must make every effort to collect the patient’s status through contacting the patient or a relative or their usual health care provider by 
telephone or other allowed methods.  These contact attempts should be documented in the patient’s medical record.  
18. Patient-Reported Outcome Questionnaire: FKSI-19 and EUROQoL 5-Dimension (EQ-5D) are to be administered at the End of Treatment/Withdrawal 
visit.  PROs should be administered prior to other End of Treatment/Withdrawal measures.  Beyond End of Treatment (ie, follow-up period), PRO 
assessments will be collected at the same time a tumor assessment is performed.  
19. Pharmacokinetics: In Arm A, PK blood samples for avelumab (3.5 mL) will be taken 1 month after end of avelumab treatment.  Details are outlined in 
Section 7.3.   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
p
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
21. De Novo Tumor Biopsy: A de novo (ie, fresh biopsy) tumor sample should also be collected at End of Treatment/Withdrawal visit, unless clinically 
contraindicated.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be 
submitted.  The de novo biopsy(ies) should be formalin-fixed and paraffin-embedded as per routine (see Study Manual), 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 should be submitted to the Central Laboratory.  See Section 7.5.1. 
22. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (Nab): In Arm A, one blood sample (3.5 mL) for 
anti-avelumab antibodies (and simultaneous pharmacokinetic draws for measurement of avelumab) will be collected at 30 days after the end of avelumab 
treatment.  All the samples that are positive for ADA may also undergo characterization for Nab.  See Section 7.4.  
23. MUGA Scan or ECHO.  For the evaluation of the left ventricular ejection fraction, the technique used at screening will be consistently used throughout 
the study, in the following assessments. 






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Footnotes for Schedule of Activities for STUDY TREATMENT, END OF TREATMENT and FOLLOW-UP periods POST IA3  
1. 
Visit Identifiers: During treatment, all assessments should be performed prior to dosing with study treatment/s unless otherwise indicated.  Acceptable time 
windows for performing each assessment are described in the column headers.    
2. 
End of Treatment/Withdrawal: Obtain these assessments if not completed in the prior week, except for tumor assessments, which need not be repeated if 
performed within the prior 6 weeks. 
3. 
Short- and Long-Term Follow-up: All patients will be followed for safety every 30 days through 90 days after the last dose of investigational product or until the 
time of initiation of new anticancer treatment whichever comes first.  During the Long-Term Follow-Up until the end of the study, all patients will be followed 
every 3 months for survival and new systemic anticancer treatment will be collected. 
4. 
Informed Consent: Re-consent must be obtained as applicable. 
5. 
Weight: To be collected before each avelumab infusion.  See Section 5.4.1 for details on avelumab dose calculation. 
6. 
ECOG PS: During treatment, ECOG PS should be performed in parallel to any tumor assessment by imaging. 
7. 
Contraception Check: Male patients with female partner of childbearing potential and female patients who are of childbearing potential will need to affirm that 
they meet the criteria for correct use of 1 of the selected methods of contraception (see Section 4.3.1 for details on methods allowed).  The investigator or his or her 
designee will discuss with the patient the need to use 1 highly effective contraception methods consistently and correctly and document such conversation in the 
patient’s chart.  In addition, the investigator or his or her designee will instruct the patient to call immediately if the selected contraception method is discontinued, 
or if pregnancy is known or suspected in the patient or the patient’s partner.  For female patients of childbearing potential, Day 29 contraception check will be 
collected by telephone call.  Arm B: contraception requirements/checks should be maintained for at least 49 days after the last sunitinib dose. 
8. 
Vital Signs: Vital signs include blood pressure and pulse rate.  Blood pressure and pulse rate should be taken with the patient in the seated position after the patient 
has been sitting quietly for at least 5 minutes.  Two blood pressure/pulse readings will be taken at least 1 hour apart at each clinic visit. 
9. 
Hematology, Blood Chemistry: (see Table 8): Additional assessments to be performed when clinically indicated.   
10. Thyroid Function Tests: (see Table 8): Additional tests to be performed when clinically indicated.  Hypothyroidism should be treated per standard medical 
practice to maintain euthyroid state. 
11. ACTH: Additional tests to be performed when clinically indicated. 
12. Serum/Urine Pregnancy Test: For female patients of childbearing potential, during treatment, pregnancy tests (serum or urine test) will be routinely repeated on 
Days 1 and 29 of each treatment cycle or whenever 1 menstrual cycle is missed or when potential pregnancy is otherwise suspected.  Day 29 pregnacy test result 
will be collected by telephone call.  Additional pregnancy tests may also be undertaken if requested by IRB/ECs or if required by local regulations (for details see 
Section 7.1.1).  
13. MUGA Scan or ECHO: On treatment to be performed as per institutional practice.  For the evaluation of the left ventricular ejection fraction (LVEF), the 
technique used at screening should be consistently used throughout the study, in the following assessments.  
14. Tumor Assessments: CT or MRI will include chest, abdomen and pelvis (CAP) at all time points.  The CT and MRI scans should be performed with contrast 
agents unless contraindicated for medical reasons.  Premedication prior contrast media administration as per local guidelines is allowed (see Section 5.8.5).  Bone 
scintigraphy/bone scans and brain scans/head CT/MRI are required on treatment if bone and/or brain lesions are identified at screening.  Bone lesion(s) identified at 
screening by bone scan can be further assessed by CT or MRI as per local practice and subsequently re-assessed by CT or MRI as per tumor assessment schedule.  
If bone scintigraphy/bone scan is the preferred assessment method for bone lesion(s) identified at screening, re-assessment during study should occur every 12 
weeks after randomization.  Bone scan will also be repeated during study as clinically indicated (eg, patient describes new or worsening bone pain, or has 
increasing alkaline phosphatase level, or other signs and symptoms of new/progressing bone metastases) or at the time of complete response (CR) confirmation.  
Brain must be included in subsequent tumor assessments if a patient has brain metastases at screening, otherwise brain will only be evaluated when clinically 
indicated.  The same imaging technique used to characterize each identified and reported lesion at screening will be employed in the following tumor assessments.  
During treatment, anti-tumor activity will be assessed through radiological tumor assessments conducted every 6 weeks from randomization up to 18 months after 


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randomization and every 12 weeks thereafter until disease progression by investigator assessment or initiation of subsequent anti-cancer therapy, whichever is 
earlier (see Section 5.4.4 for further details on treatment continuation after initial evidence of PD).  Further imaging assessments may be performed at any time if 
clinically indicated (eg, suspected PD, symptomatic deterioration, etc.).  The schedule of assessments should be fixed according to the calendar, regardless of 
treatment schedule, treatment delays or interruptions.  Imaging assessments are to be scheduled using the randomization date as the reference date for all time 
points and are NOT to be scheduled based on the date of the previous imaging time point.  CR and PR must be confirmed with repeated imaging performed at least 
4 weeks after initial documentation of response.  Assessment of response will be made using RECIST v.1.1.  See Section 7.7 for additional information. 
15. Adverse Events: Adverse events should be documented and recorded at each visit using NCI CTCAE version 4.03.  For SAEs, the active reporting period to Pfizer 
or its designated representative begins from the time that the patient provides informed consent, which is obtained prior to the patient’s participation in the study, 
ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 90 calendar days after the last administration of 
the investigational product.  SAEs occurring to a patient after the active reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a reasonable possibility of being related to investigational product are to be 
reported to the sponsor.  AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) from the time the patient has taken at least 1 dose of 
study treatment through and including 90 calendar days after the last administration of the study drug.  If a patient begins a new anticancer therapy, the AE 
reporting period for nonserious AEs ends at the time the new treatment is started.  Death must be reported if it occurs during the SAE reporting period after the last 
dose of investigational product, irrespective of any intervening treatment.   
16. Concomitant Medications/Treatments: Concomitant medications and treatments should be recorded from 28 days prior to the start of study treatment and up to 
90 days after the last dose of study treatment.  All concomitant medications should be recorded in the CRF including supportive care drugs (eg, anti-emetic 
treatment and prophylaxis), the drugs used to treat adverse events or chronic diseases, and non drug supportive interventions (eg, transfusions).   
17. Patient-Reported Outcome Questionnaire: FKSI-19 and EUROQoL 5-Dimension (EQ-5D).  PROs are to be administered always prior to any other 
test/procedure is performed. 
18. Study Treatment: Avelumab will be given as a 1-hour intravenous infusion every 2 weeks in a 6-week cycle.  Axitinib will be given orally twice daily PO on a 
continuous daily dosing schedule.  Sunitinib will be given orally 50 mg taken once daily, on a schedule 4 weeks on treatment followed by 2 weeks off (Schedule 
4/2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
p
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
20. De Novo Tumor Biopsy: A de novo (ie, fresh biopsy) tumor sample should be collected unless clinically contraindicated.  Tumor tissue from cytologic sampling 
(eg, fine needle aspiration, including FFPE cell pellet material), is not adequate and should not be submitted.  The de novo biopsy(ies) should be formalin-fixed and 
paraffin-embedded as per routine (see Study Manual), 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
should be submitted to the Central Laboratory.  See Section 7.5.1. 
21. New Anticancer Treatments/Survival Assessment: All patients will be followed for survival and subsequent anticancer therapies every 3 months (±14 days) until 
death, end of the study or patient withdrawal of consent, whichever comes first.  Information will be collected by telephone call unless the patient is visiting the site 
for other reasons.  The Sponsor will request an “ad hoc” survival update prior to each protocol-specified interim analysis and final analysis.  The investigator or 
designee must make every effort to collect patient’s status through contacting the patient or a relative or their usual health care provider by telephone or other 
allowed methods.  These contact attempts should be documented in the patient’s medical record. 


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1. INTRODUCTION 
1.1. Mechanism of Action/Indication 
Previously Untreated Advanced Renal Cell Carcinoma (aRCC). 
The mechanisms of action of each investigational product are described in Sections 1.2.2.1 
and Section 1.2.2.2. 
1.2. Background and Rationale 
1.2.1. Renal Cell Carcinoma 
Renal cell carcinoma (RCC) is the most common kidney cancer and constitutes about 3% of 
all malignant tumors in adults.1  RCC is often first detected at an advanced stage, with 
25-30% of patients with metastatic disease at diagnosis. 
RCC arises from the renal epithelium and 5 major subtypes are currently recognized.  
Approximately 70-80% of these are clear cell RCC tumors while other less common cell 
types include papillary (Type I and II), chromophobe, collecting duct, and unclassified 
RCC.12  Four RCC predisposing genes have been identified – MET protooncogene, von 
Hippel-Lindau (VHL) tumor suppressor gene, fumarate hydratase (FH) tumor suppressor 
gene, and Birt-Hogg-Dubé tumor suppressor gene (BHD). 
Patients with von Hippel-Lindau disease have a >70% risk of developing clear cell RCC.  
This hereditary form of RCC is caused by germline mutations in the VHL tumor suppressor 
gene on chromosome 3p.  More than 90% of sporadic clear cell RCC involves somatic VHL 
gene mutations or methylation.  VHL gene mutations lead to loss of function of the VHL 
protein, accumulation of hypoxia-inducible transcription factors (eg, HIF-1alpha and HIF-2 
alpha) which translocate to the nucleus and increase transcription of angiogenesis factors 
(such as vascular endothelial growth factor [VEGF] and platelet derived growth factor 
[PDGF]) which induce tumorigenesis.  Clear cell RCC is a highly vascular tumor with high 
expression of VEGF, VEGF receptor (VEGFR), and PDGF receptor (PDGFR).13   
About one-third of patients with clear cell RCC present with Stage IV disease.  Systemic 
therapy is given to patients with advanced disease (relapsed or Stage IV) that is not amenable 
to complete resection.  However, it is recommended that these patients undergo a 
cytoreductive nephrectomy where possible, prior to beginning systemic therapy, as per 
treatment guidelines.14   
There are 7 molecularly targeted agents approved in the United States (US) as systemic 
therapy for advanced RCC that is predominantly clear cell.  First-line systemic therapy is 
usually one of the VEGFR tyrosine kinase inhibitors (TKIs) (sunitinib, pazopanib, or 
sorafenib), the monoclonal anti-VEGF antibody bevacizumab (given in combination with 
IFN α) or the mammalian target of rapamycin (mTOR) inhibitor, temsirolimus.  These drugs 
are used sequentially as single agents in subsequent lines of therapy for advanced clear cell 
RCC.14-17 


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1.2.2. Pharmaceutical and Therapeutic Background  
1.2.2.1. Avelumab (MSB0010718C) 
One of the investigational products in the present clinical trial is avelumab (MSB0010718C), 
a fully human monoclonal antibody (mAb) of the immunoglobulin (Ig) G1 isotype.  
Avelumab is the proposed International Nonproprietary Name (INN) for the anti-PD-L1 
monoclonal antibody MSB0010718C.  
Avelumab selectively binds to programmed death-ligand 1 (PD-L1) and competitively blocks 
its interaction with programmed death protein 1 (PD-1).  Compared with anti-PD-1 
antibodies, that target T-cells, avelumab targets tumor cells, and therefore, is expected to 
have fewer side effects, including a lower risk of autoimmune-related safety issues, as 
blockade of PD-L1 leaves the programmed death ligand 2 (PD-L2)/PD-1 pathway intact to 
promote peripheral self-tolerance.36  For complete details of the in vitro and nonclinical 
studies, refer to avelumab investigator’s brochure (IB).19 
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial cancer, and 
Hodgkin’s Lymphoma, as single agent or in combination with chemotherapy, tyrosine kinase 
inhibitors, or other immune-modulating agents.  
As of 05 November 2015, more than 1400 patients have been treated with avelumab.  The 
largest trial is study EMR100070-001, a Phase 1, open-label, multiple-ascending dose 
clinical study aimed to investigate the safety, tolerability, pharmacokinetics (PK), biological 
activity, and clinical activity of avelumab in patients with metastatic or locally advanced 
solid tumors.  Study EMR100070 001 consists of 2 parts, a dose-escalation phase and a 
dose-expansion phase, which is performed in selected tumor indications.  Avelumab is 
administered intravenously (IV) at the assigned dose level as a 1-hour infusion once every 
2 weeks (Q2W).  
 
 
 
 
  
 
 
 
 
 
  
 
 
 f 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
  


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Complete information for avelumab may be found in the single reference safety document 
(SRSD), which for this study is the avelumab IB.  The reference safety information (RSI) can 
be found in tabular format in Section 6.2 of the avelumab IB.19 
1.2.2.2. Axitinib (INLYTA, AG-013736) 
One of the investigational products in the present clinical trial is axitinib (INLYTA, 
AG-013736), an oral, small molecule, TKI selective for VEGFRs 1, 2, and 3, approved 
multinationally for the treatment of advanced RCC after failure of one prior systemic therapy 
(actual indication varies according to region/country).20  
Axitinib is an adenosine triphosphate (ATP)-competitive inhibitor that binds to the 
unphosphorylated (non-activated) “DFG-out” conformation of the catalytic domain of a 
receptor tyrosine kinase.  In enzymatic assays, axitinib was found to be highly potent 
(Ki = 28 picomolar) against the kinase activity of juxta-membrane (JM) domain containing 
human VEGFR 2 recombinant protein.18  In additional kinase assays, axitinib showed potent 


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and ATP-competitive inhibition of the VEGFRs 1, 2, and 3 and PDGFR-β, but not other 
closely-related family kinases.  Receptor binding studies and cell-based assays confirmed 
that axitinib is a potent and selective inhibitor of VEGFRs 1, 2, and 3.  Axitinib was shown 
to have antiangiogenic activity in a number of models including spontaneous pancreatic 
islet-cell tumors of RIP-TAG-2 transgenic mice model and demonstrated anti-tumor efficacy 
including marked cytoreductive anti-tumor activity in multiple tumor models implanted in 
athymic mice.  
The safety and efficacy of axitinib were evaluated in a randomized, open-label, multicenter 
Phase 3 study.  Patients with advanced RCC (99% clear cell) whose disease had progressed 
on or after treatment with 1 prior systemic therapy, including sunitinib-, bevacizumab-, 
temsirolimus-, or cytokine-containing regimens were randomized to receive axitinib (N=361) 
or sorafenib (N=362).  There was a statistically significant advantage for axitinib over 
sorafenib for the primary PFS endpoint, 6.7 months (95% CI: 6.3, 8.6) vs 4.7 months (95% 
CI: 4.6, 5.6), respectively (p <0.0001).  There was no statistically significant difference 
between the treatment arms in the secondary overall survival (OS) endpoint, 20.1 months 
(95% CI: 16.7, 23.4) vs 19.2 months (95% CI: 17.5, 22.3) for axitinib and sorafenib, 
respectively.  The ORR was 19.4% (95% CI: 15.4, 23.9) for axitinib and 9.4% (95% CI: 
6.6, 12.9) for sorafenib.  The most common (≥20%) adverse reactions observed in this study 
following treatment with axitinib were diarrhea, hypertension, fatigue, decreased appetite, 
nausea, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight 
decreased, vomiting, asthenia, and constipation.9 
In another randomized, open-label, Phase 3 trial, treatment-naïve clear cell RCC patients 
were randomized (2:1) to receive axitinib (N=192) or sorafenib (N=96).  There was no 
significant difference in median PFS between patients treated with axitinib or sorafenib, 
10.1 months (95% CI: 7.2, 12.1) vs 6.5 months (95% CI 4.7, 8.3), respectively, with stratified 
hazard ratio 0.77 (95% CI: 0.56, 1.05).  The axitinib ORR assessed by an Independent 
Radiology Review Committee was 32%, risk ratio 2.21, (95% CI: 1.31, 3.75, stratified 
one-sided p=0.0006).  Adverse events more common (≥10%) with axitinib versus sorafenib 
were diarrhoea, hypertension, weight decrease, decreased appetite, dysphonia, 
hypothyroidism, and upper abdominal pain; those more common with sorafenib versus 
axitinib included palmar-plantar erythrodysesthesia (hand-foot) syndrome and rash, alopecia 
and erythema.8  Toxicities in this clinical trial were generally tolerable and manageable and 
similar to those observed in clinical trials with axitinib in pre-treated aRCC patients.8 
Overall, the adverse events reported for axitinib in clinical studies were considered generally 
tolerable and manageable.  For single-agent axitinib, the most common adverse events 
(>20% of patients) reported from 1445 cancer patients regardless of causality included 
diarrhea, hypertension, decrease appetite, nausea, weight decreased, dysphonia, 
palmar-plantar erythrodysaesthesia syndrome, hypothyroidism, and proteinuria.  Grade ≥3 
events that occurred most frequently were hypertension, fatigue, and diarrhea. 


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Following oral administration, axitinib is rapidly absorbed (median Tmax 2.5-4.1 hours).  
The plasma half life of axitinib ranges from 2.5 to 6.1 hours and steady-state is expected 
within 2 to 3 days of dosing.  Dosing of axitinib at 5 mg twice daily resulted in 
approximately 1.4-fold accumulation compared to administration of a single dose.  At steady 
state, axitinib exhibits approximately linear pharmacokinetics within the 1-mg to 20-mg dose 
range.  The mean absolute bioavailability of axitinib after an oral 5 mg dose is 58%.  Axitinib 
can be administered with or without food.  Axitinib is metabolized primarily in the liver by 
CYP3A4/5 and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1.  The predominant 
sulfoxide and N-glucuronide metabolites in human plasma show approximately ≥400-fold 
less in vitro potency against VEGFR-2 compared to axitinib. 
Complete information for axitinib may be found in the single reference safety document 
(SRSD), which for this study is the axitinib IB.  The RSI can be found in tabular format in 
Section 7.8 of the axitinib IB.18  
1.2.2.3. Sunitinib Malate (SUTENT®, SU011248) 
One of the investigational products in the present clinical trial is sunitinib malate 
(SUTENT®), which is an oral, multitargeted TKI of KIT, PDGFRs, VEGFRs, RET, and 
FLT3, approved multinationally for the treatment of aRCC. 
The safety and efficacy of sunitinib were evaluated in an international, randomized Phase 3 
trial comparing sunitinib to IFN-α in 750 treatment-naïve patients with clear-cell mRCC.23 
Patients were randomized 1:1 to receive sunitinib 50 mg BID schedule 4/2 (ie, 4 weeks on 
treatment followed by 2 weeks off treatment) in 6-week cycles or IFN-α 9MU via 
subcutaneous (SC) injection 3 times a week in 6-week cycles.  The primary endpoint was 
PFS.  Secondary endpoints included ORR, OS, and adverse events.  Baseline characteristics 
were well balanced and included pooled median age of 60 years and prior nephrectomy in 
90% of patients.  Median PFS assessed by third-party BICR was significantly longer 
(11 months) for sunitinib than for IFN-α (5 months) with a hazard ratio of 0.42 (95% CI 
0.32, 0.54) (p<0.001).  The results were similar in the analysis using the investigator’s 
assessment: 11 months vs. 4 months, with a hazard ratio of 0.42 (95% CI, 0.33 to 0.52; 
p<0.001).  Sunitinib was also associated with a higher ORR than IFN-α by BICR (31% vs. 
6% for IFN-α, p<0.001).  Median OS was 26.4 months for the sunitinib arm, and 21.8 for 
IFN-α (hazard ratio for death, 0.821, 95% CI. 0.673 1.001, p = 0.051 (log-rank).  These 
results demonstrated a statistically significant improvement in PFS and ORR for sunitinib 
over IFN-α in the first-line treatment of mRCC patients.  Eight percent of patients withdrew 
from the study due to adverse event on the sunitinib arm vs. 13% on the IFN-α arm.  The 
most common (≥20%) adverse reactions observed in this study following treatment with 
sunitinib were diarrhea, fatigue, nausea, stomatitis, vomiting, hypertension, hand-foot 
syndrome, and mucosal inflammation.23 
Overall, the adverse events reported for sunitinib in clinical studies have been considered 
tolerable and manageable.  The most common adverse events, regardless of causality, 
reported from 9955 patients with solid malignant tumors treated with single-agent sunitinib 
in a variety of clinical trials included diarrhea (51.5%), fatigue (47.8%), nausea (42.3%), 


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decreased appetite (38.3%), vomiting (33.6%), palmar-plantar erythrodysaesthesia syndrome 
(28.5%), hypertension (27.3%), stomatitis (25.0%), dysgeusia (25.8%), and mucosal 
inflammation (25.1%).  
In adults, repeated dosing studies over a range of 25-100 mg daily doses followed by 
off-treatment periods have identified a 50 mg dose on the Schedule 4/2 (4 weeks of therapy 
followed by a 2-week off period) as a tolerable, dose dense regimen.21,22  Steady state levels 
of sunitinib and its active metabolite SU012662 are reached 7-10 days after repeated daily 
dosing.  Drug accumulation with repeated 4- or 6-week cycles has not been observed.  No 
dose-dependent changes in Tmax or t1/2 have been observed.  Sunitinib is metabolized 
primarily by the cytochrome P450 enzyme, 3A4 (CYP3A4).  The terminal elimination 
half-lives of sunitinib and SU012662 are approximately 40 hours and 80 hours, respectively.  
Complete information for sunitinib may be found in the single reference safety document 
(SRSD), which for this study is the sunitinib IB.  The reference safety information (RSI) can 
be found in tabular format in Section 7.8 of the sunitinib IB.29 
1.2.3. Rationale for Studying Avelumab in Combination with Axitinib in Patients with 
Advanced Renal Cell Carcinoma 
Tumor angiogenesis is a complex dynamic process necessary for the continued growth of 
solid tumors.  VEGF is one of the most important angiogenic factors secreted by the tumor 
and other cells.  Its production is enhanced by several stimuli, including hypoxia.  VEGF and 
VEGFRs are critical components of the processes leading to the branching, extension, and 
survival of endothelial cells which form new blood vessels during angiogenesis, and which is 
an absolute necessity for tumor growth beyond microscopic size.  Inhibitors of angiogenesis 
are now widely used in the treatment of cancer, and most of these agents inhibit the VEGF 
pathway.  VEGF pathway inhibitors include the VEGFR TKIs axitinib, sunitinib, pazopanib, 
and sorafenib, and the monoclonal anti-VEGF antibody bevacizumab.  VEGF pathway 
inhibitors have been approved in a number of indications, including the treatment of 
aRCC.10,11 
Until 2005, IFN-α and high-dose IL-2 therapies were the standards of care for patients with 
aRCC, albeit with modest efficacy.  Since then, the increasing knowledge of the tumor 
biology, namely of the role of tumor angiogenesis and its mediators, led to the development 
and approval of multiple VEGF-pathway and mTOR-inhibitors have significantly improved 
the outcomes of aRCC patients.  These agents include the VEGFR TKIs sunitinib, pazopanib, 
axitinib and sorafenib; the anti-VEGF monoclonal antibody bevacizumab; and the mTOR 
inhibitors temsirolimus and everolimus.  However, durable and complete responses in aRCC 
patients are uncommon; the majority of patients will eventually develop resistance, exhibit 
disease progression while on therapy, and succumb to death due to metastatic disease.  
Response rates for previously treated aRCC patients are in the 15-25% range, and median 
survival after diagnosis is under 1 year.1  
There is a strong rationale for considering immunotherapy in aRCC patients.  Cytokine-based 
immunotherapy, especially high-dose IL-2, exhibited durable responses in some aRCC 
patients.  There are anecdotal reports of spontaneous remissions in aRCC patients with 
evidence of antigen-specific lymphocyte infiltration in tumor tissues.2  These reports have 


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generated considerable interest in immunotherapeutic approaches in the treatment of aRCC 
patients, especially with advent of immune checkpoint inhibitors such as anti-PD1 and 
anti-PD-L1 antibodies in recent years.  Upregulation of PD-1 receptor on TILs, and its ligand 
PD-L1 on tumors, are associated with more aggressive disease and poor prognosis.3,4   
Monoclonal antibodies (mAb) that block the PD-1/PD-L1 interaction are novel 
immunotherapeutic approaches for aRCC, which have shown single-agent efficacy in 
patients whose disease has progressed following VEGF pathway inhibitor therapy.5,6  
Nivolumab, a high-affinity, fully human anti-PD-1 monoclonal antibody (mAb) has shown 
durable tumor response with ORR of about 20% and median PFS of about 16 weeks in 
heavily pretreated aRCC patients.30,31  When nivolumab was combined with a VEGF TKI 
(sunitinib or pazopanib), it demonstrated more pronounced anti-tumor response.  Amin et al 
reported the data from combinations of sunitinib or pazopanib with nivolumab at the ASCO 
2014 annual meeting.37  
 
 
 
 
 
 
 
  
 
 
 sunitinib (50 mg, 4 wks on, 2 wks off) was successfully combined with 
nivolumab 5 mg/kg every 3 weeks (Q3W), and dose expansion was subsequently completed 
in previously untreated aRCC patients.  ORR was 52% (17/33) for nivolumab in combination 
with sunitinib, and 45% (9/20) for nivolumab in combination with pazopanib.  Median 
duration of response was 37.1 weeks (95% CI: 18.1-80.0+), and median PFS was 48.9 weeks 
(95% CI: 41.6-66.0) with sunitinib plus nivolumab.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  Results from the combination 
of bevacizumab 15 mg/kg Q3W with MPDL3280A were also presented by McDermott et al 
at the ESMO 2014 annual meeting.32  Data were limited, but in previously untreated aRCC 
patients, there were 4/10 (40%) partial responses (PRs).  Five additional patients had a best 
response of stable disease, and all responding patients (9 out of 10) were still on treatment at 
the time of analysis.  These data, although preliminary, demonstrate the benefit of combining 
a PD-1 or PD-L1 antibody with an anti-VEGF pathway agent in aRCC patients. 
The combination of nivolumab with ipilimumab, a fully human monoclonal antibody to 
CTLA-4, showed acceptable safety and encouraging antitumor activity in metastatic RCC.  
Patients were randomized to receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg (arm N3 + 
I1) or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm N1 + I3) IV Q3W for 4 doses then 
nivolumab 3 mg/kg IV Q2W until progression/toxicity.  Confirmed ORR was observed in 
9/21 patients in arm N3 + I1 and in 11/23 patients in arm N1 + I3.  The median PFS was 
36.6 weeks and 38.3 weeks in arm N3 + I1 and in arm N1 + I3, respectively.7 
In 2016, nivolumab single agent was approved as 2nd line therapy for aRCC based on the OS 
benefit reported in the Phase 3 CheckMate 025 trial.65  In patients with previously treated 
aRCC, median OS was 25.0 months with nivolumab (95% CI: 21.8 to not estimable) vs 
19.6 months (95% CI: 17.6, 23.1) with everolimus (HR= 0.73; 98.5% CI, 0.57 to 0.93; 
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More recently, data presented at ASCO GU 2017 on the Phase 2 randomized IMmotion 
150 trial testing atezolizumab (MPDL3280A) with or without bevacizumab vs sunitinib 
monotherapy in aRCC, demonstrated a PFS benefit in the PD-L1 positive subpopulation, 
with a median PFS of 14.7 months (95% CI: 8.2, 25.1) for the combination compared to 
7.8 month (95% CI: 3.8, 10.8) for sunitinib monotherapy (HR= 0.64; 95% CI: 0.38, 1.08; 
P=0.095).66 
Avelumab is a fully human mAb of the IgG1 isotype that specifically targets and blocks 
PD-L1.33  Avelumab is the proposed International Nonproprietary Name (INN) for the 
anti-PD-L1 monoclonal antibody MSB0010718C.  
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in a wide variety of adult cancers, such as non-small cell lung cancer, gastric cancer, 
Merkel cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial cancer, and 
Hodgkin’s Lymphoma, as single agent or in combination with chemotherapy, tyrosine kinase 
inhibitors, or other immune-modulating agents.  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
  
 
 
  
  
 
 
  
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
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Axitinib is an oral, potent and selective inhibitor of VEGFRs 1, 2, and 3, approved 
multinationally for the treatment of aRCC after failure of one prior systemic therapy (actual 
indication varies according to region/country).20  Anti-tumor activity of single-agent axitinib 
5 mg BID in previously untreated patients with clear cell aRCC was assessed against 
sorafenib in a randomized, open-label, Phase 3 trial.  Although the study did not demonstrate 


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a statistically significant difference in PFS between patients treated with axitinib or 
sorafenib, axitinib was associated with a longer median PFS time {mPFS of 10.1 months 
(95% CI: 7.2,12.1) with axitinib vs. 6.5 months (95% CI: 4.7, 8.3) with sorafenib, stratified 
hazard ratio 0.77 (95% CI: 0.56, 1.05)}.  The mPFS observed with axitinib in this study was 
similar to those demonstrated earlier in Phase 3 clinical trials of other approved VEGFR 
TKIs in the first-line treatment of aRCC patients.8  Toxicities in this clinical trial were 
generally tolerable and manageable, and similar to those observed in clinical trials with 
axitinib in pre-treated aRCC patients.9 
The most common adverse events (>20% of patients) reported among 1445 cancer patients 
receiving single-agent axitinib (regardless of causality) include diarrhea, hypertension, 
decreased appetite, nausea, weight decreased, dysphonia, palmar plantar erythrodysaesthesia 
syndrome, hypothyroidism, and proteinuria.  The most frequent Grade ≥3 adverse events 
were hypertension, fatigue, and diarrhea.18 
Hepatotoxicity is a known risk associated with sunitinib therapy, with Grade 3/4 AST and 
ALT increased reported in 2% and 3% of treatment-naïve patients with aRCC, respectively.28  
In addition, liver failure and treatment related deaths have been reported in clinical trials 
(7/2281 [0.3%]) and post-marketing experience with sunitinib.28  Sunitinib has also been 
shown to have hematologic toxicity, with Grade 3/4 platelet count decreased 9% and 
neutrophil count decreased 17% in treatment-naïve patients with aRCC, leading to treatment 
interruptions, dose reductions and potentially decrease in therapeutic benefit for patients.28  
In addition rapid-onset of acute renal failure was observed in patients with metastatic renal 
cell carcinoma when sunitinib was given in combination with tremelimumab.53 
The risk of hepatotoxicity is low in patients with aRCC with axitinib, with an overall rate of 
Grade 3/4 ALT or AST increased <0.6% for each.26  The incidence of hematological toxicity 
was also low with axitinib in this patient population (eg, Grade 3/4 platelet count decreased 
and neutrophil count decreased 0.3% for each.26  
Since axitinib causes less hepatic and hematologic toxicity than sunitinib, it is considered to 
be a better partner for pairing with other anti-cancer agents such as avelumab. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
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Preliminary Safety Data of Avelumab in Combination with Axitinib 
The combination of avelumab with axitinib is being tested in study B9991002, a Phase 1b 
open-label, dose-finding study aiming to evaluate the safety, pharmacokinetics and 
pharmacodynamics of avelumab in combination with axitinib in patients with previously 
untreated aRCC.  This study was designed to establish the dosing regimen of avelumab and 
axitinib to be used for any further study with this combination.  Study B9991002 is 
comprised of a dose-finding phase and a dose-expansion phase.  The initial doses to be tested 
(Dose Level 1, [DL1]) were avelumab 10 mg/kg IV Q2W in combination with axitinib 5 mg 
orally (PO) twice a day (BID) continuously, with 2 lower dose levels to be explored only if 
the Maximum Tolerated Dose (MTD) was exceeded in DL1.  
The dose-finding phase was completed on 12 February 2016.  The 6 patients enrolled in this 
phase of the study completed the 4-week DLT follow-up period as per protocol 
(corresponding to 2 cycles of 2 weeks each).  There was 1 DLT reported: Grade 3 
proteinuria, related to axitinib per investigator assessment, which resolved after reducing the 
dose of axitinib to 3 mg BID.  As of 12 February 2016, the AEs recorded in the dose-finding 
phase were mostly low grade and manageable, with no new unexpected safety signals for the 
combination when compared to the safety profile of each drug as monotherapy.  No patients 
discontinued the combination due to AEs.  Based on these findings, the MTD\RP2D for the 
combination is avelumab 10 mg/kg IV Q2W and axitinib 5 mg PO BID continuously.  
Enrollment in the dose-expansion began on 15 February 2016, with a target enrollment of 
approximately 48 patients.  As of 15 August 2016, 46 patients were enrolled and started 
treatment in this part of the study, and 52 patients were treated overall (6 patients in the 
dose-finding part and 46 patients in the dose-expansion part). 
As of 15 August 2016, the B9991002 study clinical database included data from 47 treated 
patients (6 patients in the dose-finding part and 41 patients in the dose-expansion part).  
Overall, the reported TEAEs were mostly low grade and manageable.  The most frequent 
TEAEs (any cause, any grade, experienced by ≥10% patients) were dysphonia (17 patients, 
36.2%), fatigue (16 patients, 34.0%), hypertension (14 patients, 29.8%), diarrhea 
(13 patients, 27.7%), constipation (11 patients, 23.4%), nausea (9 patients, 19.1%), 
arthralgia, dyspnea, palmar-plantar erythrodysesthesia syndrome, rash (8 patients each, 
17.0%), decreased appetite, headache, hypothyroidism, infusion-related reactions (IRR), 
vomiting (7 patients each, 14.9%), alanine aminotransferase (ALT) increased (6 patients, 
12.8%), dizziness, lipase increased, mucosal inflammation and proteinuria (5 patients each, 
10.6%).  Fifteen (15) patients (31.9%) experienced a Grade 3 TEAE of any cause, including 
hypertension (5 patients, 10.6%), lipase increased, amylase increased and ALT increased 
(2 patients each, 4.3%), aspartate aminotransferase (AST) increased, dehydration, fatigue, 
gamma-glutamyltransferase increased, hyponatremia, hypophosphatemia, IRR, spinal cord 
compression, mucosal inflammation, pain in extremity, palmar-plantar erythrodysesthesia 
syndrome, proteinuria, pulmonary embolism, rash, venous thrombosis and urticaria (1 patient 
each, 2.1%).  Three (3) patients (6.4%) experienced a Grade 4 TEAEs of any cause: lipase 


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increased (2 patients, 4.3%) and blood creatine phosphokinase increased (1 patient, 2.1%).  
One (1) case of Grade 5 TEAE myocarditis (see below for details) was recorded.  All 
Grades 3-5 TEAEs were assessed as related to study treatment by the investigator with the 
exception of gamma-glutamyltransferase increased, hyponatremia, spinal cord compression, 
and pulmonary embolism. 
With respect to the potential immune-related AEs, 7 patients (14.9%) developed Grade 1-2 
hypothyroidism, 3 patients (6.4%) Grade 1 hyperthyroidism, and 1 patient (2.1%) Grade 1 
autoimmune hypothyroidism.  In addition, diarrhea (27.7 %, all of Grade 1-2 severity), rash 
(17% all grades, 2.1% Grade 3), ALT increased (12.8% all grades, 4.3% Grade 3), and AST 
increased (8.5% all grades, 2.1% Grade 3) were reported.  Both hyperthyroidism and 
hypothyroidism are expected AEs for both avelumab and axitinib.  Rash, diarrhea and 
increased liver enzymes have also been reported with axitinib monotherapy.  Medical review 
of these cases to confirm their immune-related nature is ongoing.  In addition, there was one 
case of fatal myocarditis which was assessed as related to both avelumab and axitinib by the 
investigator and in which pathology confirmed an immune-mediated cause. 
Seven (7) out of 47 treated patients included in the study database discontinued study 
treatment: 4 patients due to disease progression, 2 patients due to adverse event (fatal 
myocarditis and Grade 3 creatinine phosphokinase increased, 1 patient each), and 1 due to 
consent withdrawal. 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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In conclusion, as of 15 August 2016, the safety profile of the combination appears consistent 
with that of each study drug as monotherapy.  Safety continues to be closely monitored by 
the B9991002 study team and discussed in regular teleconferences between the study team 
and the investigators.  
In addition, as of 15 August 2016, 36 out of 47 patients in the clinical database were treated 
for at least 12 weeks prior to the analysis cut-off date and were included in the analysis of 
best overall response (BOR).  The BOR included 1 patient with confirmed CR (2.8%), 
15 patients with confirmed PR and 4 patients with unconfirmed PR (52.8%), 9 patients with 
SD (25.0%), 5 patients with PD (13.9%) and 2 patients not evaluable for response (5.6%; one 
patient died before the first oncologic assessment due to myocarditis, and another one who 


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never started the combination treatment, discontinued axitinib treatment due to Grade 3 
creatinine phosphokinase increased).  The objective response rate (including confirmed and 
unconfirmed responses) is 55.6% (95% CI: 38.1-72.1). 
Based on the safety and efficacy data described above, further investigation of avelumab in 
combination with axitinib in the patient population chosen for this study appears feasible. 
1.2.4. Rationale for Avelumab, Axitinib, and Sunitinib Starting Dosing Regimens 
1.2.4.1. Avelumab and Axitinib Starting Dosing Regimens 
In Arm A, avelumab will be given in combination with axitinib.  The avelumab dosing 
regimen will be 10 mg/kg administered as a 1-hour intravenous (IV) infusion every 2 weeks 
(Q2W, 3 doses in a 6-week cycle).  
The axitinib starting dosing regimen will be 5 mg administrated orally (PO) twice daily 
(BID) with or without food.  
These dosing regimens have been proven to be safe and tolerable in study B9991002 (see 
Section 1.2.3). 
1.2.4.2. Sunitinib Starting Dosing Regimen 
In Arm B, the sunitinib dose will be 50 mg PO once daily (QD) continuously for 
4 consecutive weeks followed by a 2-week off-treatment period (Schedule 4/2 in 6-week 
cycles) with or without food.  This dose schedule has proven to be safe and efficacious in 
patients with aRCC and has been approved by regulatory authorities worldwide. 
1.3. Summary of Benefit/Risk Assessment 
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted. 
Blocking the PD-1/PD-L1 pathway by agents binding either PD-1 or PD-L1 (anti-PD1 mAB 
or anti-PDL1 mAB) is a novel immunotherapeutic approach for aRCC, and anti-PD1 and 
anti-PDL1 agents have shown single-agent efficacy in patients whose disease has progressed 
following VEGF pathway inhibitor therapy.  Furthermore, anti-PD1/PD-L1 antibodies have 
shown to produce objective response rates of 13% to 52% as single agents or in combination 
with a VEGF pathway inhibitor in patients with aRCC.5,32,37  Recent studies suggested that 
TKI administration induces PD-L1 expression which might lead to immune tolerance and 
acquired resistance to VEGF targeted agents such as axitinib.51,52  Therefore, the addition of 
axitinib, which is a standard therapy for patients with RCC, might lead to synergistic activity 
with avelumab in treating patients with aRCC. 
Thus far, avelumab has demonstrated a manageable safety profile and significant anti-tumor 
activity in various tumor types, including aRCC (see Section 1.2.2.1).19 


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Axitinib is approved multinationally for the treatment of aRCC after failure of one prior 
systemic therapy.  Furthermore, axitinib has been studied as first line treatment in a Phase 3 
trial and in this setting the safety profile is comparable to the ones experienced by second line 
patients.8,9  Overall, the adverse events reported for axitinib in clinical studies is considered 
tolerable and manageable, and are well characterized (see Section 1.2.2.2).  Moreover, since 
axitinib causes less hepatic and hematologic toxicity than sunitinib, it is considered to be a 
better partner for pairing with other anti-cancer agents such as avelumab. 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
  
 
  Given the occurrence in the early phases of treatment of the 2 cases 
described above, the study plans to monitor patients at regular intervals as described in the 
Schedule of Activities, including MUGA/Echocardiogram, ECG, BNP, troponin and CK-MB 
monitoring.  Moreover guidelines about the management of suspect or confirmed cases of 
myocarditis and relevant avelumab management instructions have been added to Table 6.  
As to the anti-tumor activity of the combination, preliminary data with the combination are 
encouraging as 1 confirmed CR (2.6%), 19 PRs overall (15 confirmed PRs) (52.8%), 9 SDs 
(25%) have been reported for a objective response rate (confirmed and unconfirmed) of 
55.6% (95% CI: 38.1-72.1). 
As for the control arm of the study B9991003, sunitinib is approved multinationally for the 
first line treatment of aRCC patients.  Overall, the adverse events reported for sunitinib in 
clinical studies are well characterized and considered tolerable and manageable.  The choice 
of sunitinib as control treatment for the study appears therefore justified. 
In conclusion, the proposed scientific rationale and the preliminary benefit-risk profile of 
avelumab plus axitinib observed in study B9991002 support the further investigation of the 
combination in the patient population chosen for this study. 


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2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
Primary Objective 
• To demonstrate that avelumab in combination with axitinib is superior to sunitinib 
monotherapy in prolonging PFS or OS in the first-line treatment of PD-L1 positive 
patients (patient population prospectively defined as noted in Section 7.5.1) with 
aRCC. 
Secondary Objectives 
• To demonstrate that avelumab in combination with axitinib is superior to sunitinib 
monotherapy in prolonging PFS in the first-line treatment of patients with aRCC 
unselected for PD-L1 expression. 
• To demonstrate that avelumab in combination with axitinib is superior to sunitinib 
monotherapy in prolonging OS in the first-line treatment of patients with aRCC 
unselected for PD-L1 expression. 
• To evaluate other measures of efficacy of avelumab in combination with axitinib and 
sunitinib monotherapy in the first-line treatment of aRCC patients. 
• To evaluate progression-free survival on next-line of therapy (PFS2). 
• To evaluate the overall safety profile of avelumab in combination with axitinib and 
sunitinib monotherapy in the first-line treatment of aRCC patients. 
• To evaluate the population pharmacokinetics of avelumab and axitinib when 
administered in combination. 
• To evaluate the time to treatment discontinuation/failure due to toxicity. 
• To evaluate the proportion of patients who discontinued treatment due to toxicity. 
• To evaluate candidate predictive biomarkers in pre-treatment tumor tissue that may 
aid in the identification of a patient subpopulation most likely to benefit from 
treatment with avelumab in combination with axitinib and sunitinib monotherapy. 
• To assess the immunogenicity of avelumab when combined with axitinib. 
• To evaluate the effects of avelumab in combination with axitinib and sunitinib 
monotherapy on patient-reported outcomes. 


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2.2. Endpoints 
Primary Endpoints 
• Progression-Free Survival (PFS) based on Blinded Independent Central Review 
(BICR) assessment per RECIST v.1.134 for PD-L1 positive patients (patient 
population prospectively defined as noted in Section 7.5.1).  
• Overall Survival (OS) for PD-L1 positive patients (patient population prospectively 
defined as noted in Section 7.5.1). 
Secondary Endpoints 
• PFS by BICR assessment per RECIST v.1.1 for patients unselected for PD-L1 
expression 
• OS for patients unselected for PD-L1 expression. 
• Objective Response (OR), Disease Control (DC), Time to Tumor Response (TTR) 
and Duration of Response (DR) based on BICR assessment and based on Investigator 
assessment, per RECIST v.1.1.34 
• Progression-Free Survival (PFS) based on Investigator assessment per RECIST 
v.1.1.34 
• Progression-Free Survival on next-line therapy (PFS2).  
• Adverse events (AEs) and laboratory abnormalities as graded by National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
v4.03 (Appendix 6); vital signs (blood pressure, pulse rate). 
• Time to treatment discontinuation/failure due to toxicity). 
• Treatment discontinuation due to toxicity. 


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• PK parameters including trough concentrations (Ctrough) of avelumab and trough 
concentrations (Ctrough) and maximum concentrations (Cmax) of axitinib.  
• Tumor tissue biomarker status (ie, positive or negative; based on, for example, PD-L1 
expression and/or quantitation of tumor infiltrating CD8+ T lymphocytes as assessed 
by immunohistochemistry [IHC]). 
• Measures of clinical outcome (PFS, OS, OR, DC, TTR, and DR) in 
biomarker-positive and biomarker-negative subgroups. 
• Anti-drug antibodies (ADAs; nAbs) of avelumab when in combination with axitinib. 
• Patient-Reported Outcomes (PRO): FACT-Kidney Symptom Index (FKSI-19), 
EuroQol 5-Dimension (EQ 5D). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
3. STUDY DESIGN 
3.1. Study Overview 
This is a Phase 3, multinational, multicenter, randomized (1:1), open-label, parallel 2-arm 
study in which approximately 830 patients including a minimum of 580 PD-L1 positive 
patients (patient population prospectively defined as noted in Section 7.5.1) are planned to be 
randomized to receive either avelumab in combination with axitinib or sunitinib 
monotherapy.  
Arm A: avelumab 10 mg/kg IV Q2W in a 6-week cycle + axitinib 5 mg PO BID. 
Arm B: sunitinib 50 mg PO QD on Schedule 4/2. 
Patients will be stratified according to ECOG PS (0 vs. 1) and region (United States vs 
Canada/Western Europe vs the rest of the world). 
Crossover between treatment arms will not be permitted. 


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3.1.1. Study Treatment  
In Arm A, patients will receive: 
• Avelumab as a 1-hour IV infusion Q2W in a 6-week cycle.  
• Axitinib PO BID, with or without food, on a continuous dosing schedule.  
Treatment with study drugs may continue until confirmed disease progression assessed by 
BICR (see Section 5.4.4 for further details on treatment continuation after initial evidence of 
PD), patient refusal, patient lost to follow up, unacceptable toxicity, or the study is 
terminated by the sponsor, whichever comes first (see Section 6.5 Study Withdrawal).  
Axitinib treatment may be adjusted by dosing interruption with or without dose reduction 
(Section 5.4.6).  Avelumab treatment modification for drug-related toxicities, including 
irAEs and infusion-related AEs is described in Section 5.4.6.  Axitinib intrapatient dose 
escalation may occur if relevant criteria are met (see Section 5.4.6.1). 
Patients in Arm A who stop one of the two study drugs (avelumab or axitinib) for reasons 
other than confirmed disease progression as assessed by BICR may continue on single-agent 
treatment with the other drug until disease progression by BICR assessment (RECIST v.1.1), 
patient refusal, patient lost to follow up, unacceptable toxicity, or the study is prematurely 
terminated by the sponsor, whichever comes first.  At the end of study, Arm A patients who 
are still deriving clinical benefit from study treatment will be provided with an option for 
continued study treatment (eg, rollover study). 
Patients who stop avelumab after initial clinical benefit while on treatment and then 
experience radiologic disease progression by BICR assessment thereafter will be eligible for 
re-treatment with avelumab at the discretion of the investigator and after discussion with the 
sponsor’s medical monitor if 1) no cancer treatment was administered other than axitinib 
since the last dose of avelumab, 2) the patient does not meet the safety withdrawal criteria, 
and 3) the trial is still open.  
Patients who develop confirmed radiological disease progression by BICR assessment on 
study treatment but are otherwise continuing to derive clinical benefit from study treatment 
(see Section 5.4.4) will be eligible to continue with avelumab combined with axitinib, or 
single-agent avelumab, or single-agent axitinib provided that the treating physician has 
determined that the benefit/risk for doing so is favorable.  
In Arm B, patients will receive: 
• Sunitinib PO 50 mg QD on a schedule of 4 weeks on treatment followed by 2 weeks 
off treatment (Schedule 4/2 in 6-week cycles).  
Treatment with sunitinib may continue until confirmed disease progression assessed by 
BICR (see Section 5.4.4 for further details on treatment continuation after initial evidence of 
PD), patient refusal, patient lost to follow up, unacceptable toxicity, or the study is 
terminated by the sponsor, whichever comes first (see Section 6.5 Study Withdrawal). 


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Patients who develop radiological disease progression assessed by BICR on sunitinib 
treatment but are otherwise continuing to derive clinical benefit (see Section 5.4.4) will be 
eligible to continue with sunitinib provided that the treating physician has determined that the 
benefit/risk for doing so is favorable. 
Sunitinib treatment may be adjusted by dosing interruption with or without dose reduction 
(see Section 5.4.6).  
After review of images by BICR is stopped following the final analyses for PFS performed 
as specified in the protocol (Section 9.6), permanent discontinuation of treatment will be 
performed as per investigator-assessed disease progression (see Section 7.7). 
3.1.2. Tumor Assessments 
Anti-tumor activity will be assessed by radiological tumor assessments and will be based on 
RECIST guidelines v. 1.134 for primary and secondary endpoints.  
 
 
 
 
 
 
 
  Computerized tomography (CT) or magnetic 
resonance imaging (MRI) will include chest, abdomen and pelvis (CAP) at all time points.  
The CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons.  Premedication prior contrast media administration as per local guidelines is 
allowed (see Section 5.8.5).  Bone scintigraphy/bone scans and brain scans/head CT/MRI are 
also required at screening.  Bone lesion(s) identified at screening by bone scan can be further 
assessed by CT or MRI as per local practice and subsequently re-assessed by CT or MRI as 
per tumor assessment schedule.  If bone scintigraphy/bone scan is the preferred assessment 
method for bone lesion(s) as per local practice, re-assessment during study should occur 
every 12 weeks after randomization.  Bone scan will also be repeated during study as 
clinically indicated (eg, patient describes new or worsening bone pain, or has increasing 
alkaline phosphatase level, or other signs and symptoms of new/progressing bone metastases) 
or at the time of complete response (CR) confirmation.  Brain must be included in subsequent 
tumor assessments if a patient has brain metastases at screening, otherwise brain will only be 
evaluated when clinically indicated. 
The same imaging technique used to characterize each identified and reported lesion at 
screening will be employed in the following tumor assessments. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
screening, at 6 weeks from randomization, then every 6 weeks up to 18 months after 
randomization and every 12 weeks thereafter until documented confirmed disease 
progression by BICR assessment (see Section 5.4.4 for further details on treatment 
continuation after initial evidence of PD) regardless of initiation of subsequent anti-cancer 
therapy.  In addition, radiological tumor assessments will also be conducted whenever 
disease progression is suspected (eg, symptomatic deterioration).  
The schedule of assessments should be fixed according to the calendar, regardless of 
treatment schedule, treatment delays or interruptions.  Imaging assessments are to be 
scheduled using the randomization date as the reference date for all time points and are NOT 
to be scheduled based on the date of the previous imaging time point.  


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CR and PR must be confirmed with repeated imaging performed at least 4 weeks after initial 
documentation of response.  If radiologic imaging shows progressive disease (PD), then 
tumor assessment should be repeated after at least 4 weeks to confirm PD.  Further details are 
provided in Section 5.4.4. 
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions unless increase in size has been observed following completion of radiation 
therapy. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Blinded Independent Central Review (BICR) will review all radiological images.  All 
radiographic images will be collected and objectively verified by an independent third-party 
core imaging laboratory as described in the Study Manual.  After review of images by BICR 
is stopped following the final analyses for PFS performed as specified in the protocol 
(Section 9.6), permanent discontinuation of treatment will be performed as per 
investigator-assessed disease progression (see Section 7.7).  After review of images by BICR 
is stopped, confirmation of disease progression ≥4 weeks after the PD was first noticed will 
no longer be required.  
Post IA3, during treatment, tumor assessments will be conducted every 6 weeks from 
randomization up to 18 months after randomization and every 12 weeks thereafter until 
disease progression by investigator assessment or initiation of subsequent anti-cancer 
therapy, whichever is earlier (see Section 5.4.4 for details on treatment continuation after 
initial evidence of PD). 
irRECIST-defined antitumor activity will no longer be collected as per PACL dated 
02 September 2019. 
All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 


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3.1.3. Safety Assessments 
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the Schedule of Activities.  However, after the first 
9 months of treatment for each patient, the Sponsor in conjunction with E-DMC might 
consider to reduce the assessment frequency (eg, once every 1 cycle) according to the 
emerging safety profile of the avelumab plus axitinib combination.  
3.1.4. Patient Outcomes  
PROs will be assessed using 2 published and validated instruments: FACT-Kidney Symptom 
Index (FKSI)-19 and EUROQol 5-Dimension (EQ-5D).  
3.1.5. Pharmacokinetic/Immunogenicity Assessments 
Sparse plasma/serum PK/Immunogenicity sampling will be collected for axitinib, avelumab, 
and anti-drug antibodies (ADA).  Sampling will only be done in patients randomized to 
Arm A.  Refer to the SOA and Section 7.3 for additional details of the PK collections.  
Samples should be obtained from the opposite arm to the one being used for avelumab IV 
infusion.  
3.1.6. Biomarker Assessments  
Mandatory archival and baseline (recent) tumor tissue will be collected from all patients to 
support investigation and, as appropriate, clinical validation of biomarkers that may predict 
response to treatment.  End of treatment tumor tissue from a de novo biopsy may also be 
obtained unless clinically contraindicated to support investigation of mechanisms of 
resistance.  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Biomarker assessments are described in the Schedule of Activities and 
in Sections 7.5 
 
 
 
4. PATIENT SELECTION 
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular patient is suitable for this protocol. 
4.1. Inclusion Criteria 
Patient eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before patients are included in the study.  


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Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study: 
1. Diagnosis: 
• Histologically or cytologically confirmed advanced or metastatic renal cell 
carcinoma with a clear cell component.  Advanced RCC patients are patients 
affected by unresectable disease either unresectable locally advanced or 
metastatic disease; 
• A formalin-fixed, paraffin-embedded (FFPE) tumor tissue block from a de novo 
tumor biopsy obtained during screening will be required (biopsied tumor lesion 
should not be a RECIST target lesion).  Alternatively, a recently obtained archival 
FFPE tumor tissue block (not cut slides from a primary or metastatic tumor 
resection or biopsy can be provided if the following criteria are met: 1) the biopsy 
or resection was performed within 1 year of randomization AND 2) the patient 
has not received any intervening systemic anti-cancer treatment from the time the 
tissue was obtained and randomization onto the current study.  If an FFPE tissue 
block cannot be provided as per documented regulations then 15 unstained slides 
(10 minimum) will be acceptable (see Section 6.1.1); 
• Availability of an archival FFPE tumor tissue block from primary diagnosis 
specimen (if available and not provided per above).  If an FFPE tissue block 
cannot be provided as per documented regulations,then 15 unstained slides 
(10 minimum) will be acceptable (see Section 6.1.1); 
• At least one measureable lesion as defined by RECIST version 1.1 that has not 
been previously irradiated. 
2. Evidence of a personally signed and dated informed consent document indicating that 
the patient (or a legally acceptable representative, as allowed by local 
guideline/practice) has been informed of all pertinent aspects of the study.  
3. Patients who are willing and able to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures. 
4. Age ≥18 years (≥20 years in Japan).  
5. Estimated life expectancy of at least 3 months. 
6. ECOG PS 0 or 1. 
7. No evidence of uncontrolled hypertension as documented by 2 baseline blood 
pressure (BP) readings taken at least 1 hour apart.  The baseline systolic BP readings 
must be ≤140 mm Hg, and the baseline diastolic BP readings must be ≤90 mm Hg.  
Use of antihypertensive medications to control BP is allowed.  


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8. Adequate bone marrow function, including: 
• Absolute Neutrophil Count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L; 
• Platelets ≥100,000/mm3 or ≥100 x 109/L; 
• Hemoglobin ≥9 g/dL (may have been transfused). 
9. Adequate renal function, including: 
• Estimated creatinine clearance ≥30 mL/min as calculated using the 
Cockcroft-Gault (CG) equation; 
• Urinary protein <2+ by urine dipstick.  If dipstick is ≥2+, then 24-hour urinary 
protein <2 g per 24 hours. 
10. Adequate liver function, including: 
• Total serum bilirubin ≤1.5 x ULN;  
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
≤2.5 x ULN.  
11. Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) as assessed 
by either multigated acquisition (MUGA) scan or echocardiogram (ECHO). 
12. Serum pregnancy test (for females of childbearing potential) negative at screening. 
13. Male patients able to father children and female patients of childbearing potential and 
at risk for pregnancy must agree to use 2 highly effective methods of contraception 
(see Section 4.3.1) throughout the study and for at least 90 days after the last dose of 
assigned treatment. 
4.2. Exclusion Criteria 
Patients with any of the following characteristics/conditions will not be included in the study: 
1. The following prior therapies are excluded:  
• Prior systemic therapy directed at advanced or metastatic RCC. 
• Prior adjuvant or neoadjuvant therapy for RCC if disease progression or relapse 
has occurred during or within 12 months after the last dose of treatment. 
• Prior immunotherapy with IL-2, IFN-α, or anti-PD-1, anti-PD-L1, anti-PD-L2, 
anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) 
antibody (including ipilimumab), or any other antibody or drug specifically 
targeting T-cell co-stimulation or immune checkpoint pathways. 


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• Prior therapy with axitinib and/or sunitinib as well as any prior therapies with 
other VEGF pathway inhibitors.  
2. Participation in other therapeutic studies within 4 weeks prior to randomization. 
3. Patients with newly diagnosed brain metastases or patients with known symptomatic 
brain metastases requiring steroids.  Patients with previously diagnosed brain 
metastases are eligible if they have completed their treatment and have recovered 
from the acute effects of radiation therapy or surgery prior to randomization, have 
discontinued corticosteroid treatment for these metastases for at least 4 weeks and are 
neurologically stable.  
4. Major surgery ≤4 weeks or major radiation therapy ≤2 weeks prior to randomization.  
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been 
completed at least 48 hours prior to patient randomization.  
5. Persisting toxicity related to prior therapy NCI CTCAE v4.0 Grade >1; however, 
sensory neuropathy Grade ≤2 is acceptable. 
6. Current or prior use of immunosuppressive medication within 7 days prior to 
randomization, except the following: 
• Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection); 
• Systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone or 
equivalent; 
• Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).  
7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥3), any 
history of anaphylaxis.  
8. Known prior or suspected hypersensitivity to study drugs or any component in their 
formulations. 
9. Diagnosis of any other malignancy within 5 years prior to randomization, except for 
adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on 
surveillance with no plans for treatment intervention (eg, surgery, radiation, or 
castration). 
10. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agents.  Patients with diabetes type I, vitiligo, psoriasis, hypo- or 
hyperthyroid disease not requiring immunosuppressive treatment are eligible. 


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11. Gastrointestinal abnormalities including: 
• Inability to take oral medication; 
• Requirement for intravenous alimentation; 
• Prior surgical procedures affecting absorption including total gastric resection; 
• Treatment for active peptic ulcer disease in the past 6 months; 
• Active gastrointestinal bleeding, unrelated to cancer, as evidenced by clinically 
significant hematemesis, hematochezia or melena in the past 3 months without 
evidence of resolution documented by endoscopy or colonoscopy; 
• Malabsorption syndromes. 
12. Active infection requiring systemic therapy. 
13. Diagnosis of prior immunodeficiency or organ transplant requiring 
immunosuppressive therapy or known human immunodeficiency virus (HIV) or 
acquired immunodeficiency syndrome (AIDS)-related illness. 
14. Any test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating acute or 
chronic infection.  
15. Vaccination within 4 weeks of the first dose of avelumab and while on trial is 
prohibited except for administration of inactivated vaccines (for example, inactivated 
influenza vaccines). 
16. Requirement of anticoagulant therapy with oral vitamin K antagonists.  Low-dose 
anticoagulants for maintenance of patency of central venous access device or 
prevention of deep venous thrombosis is allowed.  Therapeutic use of low molecular 
weight heparin is allowed. 
17. Evidence of inadequate wound healing. 
18. Grade ≥3 hemorrhage within 4 weeks of patient randomization.  
19. Any of the following in the previous 12 months: myocardial infarction, 
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic 
congestive heart failure, LVEF less than LLN, clinically significant pericardial 
effusion, cerebrovascular accident, transient ischemic attack. 
20. Any of the following in the previous 6 months: deep vein thrombosis or symptomatic 
pulmonary embolism. 


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21. Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus 
extending to the heart. 
22. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2 or prolongation of the QTc 
interval to >500 msec.  
23. Current use or anticipated need for treatment with drugs or foods that are known 
strong CYP3A4/5 inhibitors, including their administration within 10 days prior to 
patient randomization (eg, grapefruit juice or grapefruit/grapefruit-related citrus fruits 
[eg, Seville oranges, pomelos], ketoconazole, miconazole, itraconazole, voriconazole, 
posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, 
nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, 
mibefradil, and conivaptan).  The topical use of these medications (if applicable), 
such as 2% ketoconazole cream, is allowed. 
24. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, 
including their administration within 10 days prior to patient randomization, 
eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, 
clevidipine, St John’s wort. 
25. Patients who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
investigator, or patients who are Pfizer employees directly involved in the conduct of 
the study.  
26. Pregnant female patients; breastfeeding female patients.  
27. Other severe acute or chronic medical conditions including colitis, inflammatory 
bowel disease, uncontrolled asthma and pneumonitis or psychiatric condition 
including recent (within the past year) or active suicidal ideation or behavior or 
laboratory abnormality that may increase the risk associated with study participation 
or 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. 
4.3. Lifestyle Guidelines 
4.3.1. Contraception 
In this study, patients will receive avelumab (for which the teratogenic risk is currently 
unknown) in combination with axitinib, which has been associated with teratogenic risk or 
sunitinib monotherapy which has been associated with teratogenic risk. 
The investigator or his or her designee, in consultation with the patient, will confirm that the 
patient has selected an appropriate method of contraception for the individual patient or her 
partner from the permitted list of contraception methods (see Section 4.3.1.4) and will 
confirm that the patient has been instructed in its consistent and correct use.  At time points 
indicated in the Schedule of Activities (SoA), the investigator or designee will inform the 


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patient of the need to use highly effective contraception consistently and correctly and 
document the conversation and the participant’s affirmation in the patient’s chart 
(participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception).  
Patients must agree to use at least 1 of the selected methods of contraception throughout the 
study and continue to do so for at least 30 days after the last dose of study treatment for 
patients in Arm A, and for at least 49 days after the last dose of study treatment for patients 
in Arm B.  In addition, the investigator or designee will instruct the patient to call 
immediately if the selected contraception method is discontinued or if pregnancy is known or 
suspected in the participant or partner. 
4.3.1.1. Male Participant Contraception 
Male patients with female partner of childbearing potential must agree to use a male condom 
during the intervention period and for at least 30 days after the last dose of study treatment 
for patients in Arm A, and for at least 49 days after the last dose of study treatment for 
patients in Arm B. 
4.3.1.2. Female Participant Reproductive Status 
A female patient is eligible to participate if she is not pregnant or breastfeeding and at least 
1 of the following conditions applies: 
• Is not a Women of Childbearing Potential (WOCBP) (see definitions in 
Section 4.3.1.2); 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), preferably with low user dependency, as described below 
during the intervention period and for at least 30 days after the last dose of study 
treatment for patients in Arm A, and for at least 49 days after the last dose of study 
treatment patients in Arm B.  The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.  
4.3.1.3. Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 


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Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview.  The method of documentation should be recorded in the participant’s medical 
record for the study. 
2. Postmenopausal female: 
• A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause.  
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT).  
• Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
4.3.1.4. Contraception Methods 
Highly Effective Methods
 That Have Low User Dependency  
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device (IUD). 
3. Intrauterine hormone-releasing system (IUS). 
4. Bilateral tubal occlusion. 
5. Vasectomized partner. 


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• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed.  If not, an additional highly effective method of contraception 
should be used.  The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods
 That Are User Dependent  
1. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
• oral; 
• intravaginal; 
• transdermal; 
• injectable. 
2. Progestogen-only hormone contraception associated with inhibition of ovulation: 
• oral; 
• injectable. 
3. Sexual abstinence: 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant. 
If exposure during pregnancy will occur, please refer to Section 8.10 Exposure During 
Pregnancy. 
4.4. Sponsor Qualified Medical Personnel 
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, patient study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patients participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems, however it should be used 


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only in the event that the established communication pathways between the investigational 
site and the study team are not available.  It is therefore intended to augment, but not replace 
the established communication pathways between the investigational site and study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigational site. 
5. STUDY TREATMENTS 
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).  For the purpose of this study, the 
investigational products are avelumab (MSB0010718C), axitinib (AG-013736), and 
sunitinib. 
5.1. Allocation to Treatment 
The investigator’s knowledge of the treatment 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 
3 days 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 patient number, and the date of birth of the patient.  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 IRT system.  
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 will be randomized in a 1:1 ratio to receive either avelumab in 
combination with axitinib (Arm A) or sunitinib monotherapy (Arm B).  


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Allocation of patients will be stratified according to ECOG PS 0 vs 1 and region (United 
States vs Canada/Western Europe vs the rest of the world).  This stratified randomization will 
be centrally allocated across all centers via the IRT system. 
5.2. Patient Compliance 
A patient diary will be provided to the patients to aid in axitinib (Arm A) and sunitinib 
(Arm B) compliance.  The diary will be maintained by the patient to include, unchanged, 
missed or changed axitinib doses (Arm A) or sunitinib doses (Arm B). 
In Arm A, patients will be required to return to the investigational site all bottles of axitinib 
every 6 weeks (at the end of each cycle) during the planned visit at the site.  The number of 
remaining axitinib tablets will be documented and recorded at each clinic visit.  The patient 
diary may also be used to support this part of the axitinib accountability process. 
In Arm B, patients will be required to return to the investigational site all bottles of sunitinib 
every 6 weeks (at the end of the cycle) during the planned visit at the site.  The number of 
sunitinib capsules remaining will be documented and recorded at clinic visit.  The patient 
diary may also be used to support this part of the sunitinib accountability process. 
The study site must follow up (for example, via a telephone call) with each patient on 
Cycle 1 Day 5 (±3 days) to confirm that the patient understands and is in compliance with 
axitinib or sunitinib dosing instructions.  If needed, the patient will be re-trained.  The same 
follow-up process will be applied in case the dose of axitinib or sunitinib is modified during 
the treatment period. 
5.3. Investigational Product Supplies 
Avelumab (MSB0010718C), axitinib (AG-013736), and sunitinib (SU011248) will be 
supplied for the study by Pfizer Global Clinical Supply, Worldwide Research and 
Development.  Drug supplies will be shipped to the study sites with a Drug Shipment and 
Proof of Receipt form.  This form will be completed, filed, and the shipment confirmed as 
directed on the bottom of the Drug Shipment and Proof of Receipt form.  The investigator 
shall take responsibility for and shall take all steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution, and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
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 20.0 mg/mL solution and will be supplied by the sponsor in single-use 
glass vials, stoppered with a rubber septum and sealed with an aluminum polypropylene 
flip-off seal. 


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Packaging and labeling will be in accordance with applicable local regulatory requirements 
and applicable Good Manufacturing Practice (GMP) guidelines.  Avelumab will be packed in 
boxes each containing one vial.  The information on the study treatment 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. Axitinib 
Axitinib will be supplied as 1 mg and 5 mg film-coated tablets for oral administration in 
light -resistant high-density polyethylene (HDPE) bottles with desiccant. 
5.3.1.3. Sunitinib 
Sunitinib will be supplied as hard gelatin oral capsules containing 12.5-mg or 
25-mg equivalents of sunitinib free base in light-resistant HDPE bottles. 
5.3.2. Preparation and Dispensing 
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
them and to the environment should undertake the preparation, handling, and safe disposal of 
chemotherapeutic agents. 
5.3.2.1. Avelumab 
Avelumab will be dosed at the investigational site. 
The contents of the avelumab vials are sterile and nonpyrogenic, and do not contain 
bacteriostatic preservatives.  Any spills that occur should be cleaned up using the facility’s 
standard cleanup procedures for biologic products. 
For application in this trial, avelumab drug product must be diluted with 0.9% saline solution 
(sodium chloride injection).  Detailed information on infusion bags and medical devices to be 
used for the preparation of the dilutions and subsequent administration will be provided in 
the Dosage and Administration Instruction contained in the Investigational Product Manual 
(IP Manual).  
Avelumab must not be used for any purpose other than the trial.  The administration of trial 
investigational product to patients who have not been enrolled into the trial is not covered by 
the trial insurance. 
Any unused portion of the solution should be discarded in biohazard waste disposal with 
final disposal by accepted local and national standards of incineration. 
See the Dosage and Administration Instruction in the IP Manual for instructions on how to 
prepare the investigational product for administration.  Investigational product should be 
prepared and dispensed by an appropriately qualified and experienced member of the study 
staff (eg, physician, nurse, physician’s assistant, practitioner, or pharmacist) as allowed by 
local, state, and institutional guidance. 


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5.3.2.2. Axitinib 
Axitinib is a hazardous drug (due to possible reproductive toxicity), and should be handled 
according to the recommended procedures described in the current edition of the American 
Society of Hospital Pharmacists (ASHP), Technical Assistance Bulletin on Handling 
Cytotoxic and Hazardous Drugs, American Hospital Formulary Service (AHFS) Drug 
Information (1999) and its references.  Procedures described in each institution’s pharmacy 
or hospital standard operating procedure manual should be followed when handling 
hazardous drugs. 
Axitinib will be provided in quantities appropriate for the study visit schedule.  A qualified 
staff member will provide the study treatment via a unique container number using the IRT 
system.  
Axitinib will be dispensed on Day 1 of each cycle or as otherwise indicated.  Patients should 
be instructed to keep their study treatment in the bottles provided and not transfer it to any 
other container.  In the event of dose modification, a request should be made of the patient to 
return all previously dispensed study treatment to the clinic. 
5.3.2.3. Sunitinib 
Sunitinib will be dispensed in opaque plastic bottles to protect the compounds from light.  
Sunitinib is a hazardous drug (due to possible reproductive toxicity) and should be handled 
according to the recommended procedures described in the current edition of the American 
Society of Hospital Pharmacists (ASHP), Technical Assistance Bulletin on Handling 
Cytotoxic and Hazardous Drugs, American Hospital Formulary Service (AHFS) Drug 
Information (1999) and its references.  Procedures described in each institution’s pharmacy 
or hospital standard operating procedure manual should be followed when handling 
hazardous drugs. 
Sunitinib will be provided in quantities appropriate for the study visit schedule.  A qualified 
staff member will provide the study treatment via a unique container number using the drug 
management system.  
Sunitinib will be dispensed on Day 1 of each cycle for the arm B or as otherwise indicated.  
Patients should be instructed to keep their study treatment in the bottles provided and not 
transfer it to any other container.  In the event of dose modification, a request should be made 
of the patient to return all previously dispensed study treatment to the clinic. 
5.4. Administration 
All investigational products will be administered on an outpatient basis. 
5.4.1. Avelumab 
The Drug Administration Instructions within the IP Manual contains specific instructions for 
avelumab dose calculation, reconstitution, preparation of the infusion fluid, and 
administration. 


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Avelumab will be administered on Days 1, 15 and 29 of each cycle after all 
procedures/assessments have been completed as described in the Schedule of Activities table.  
Avelumab may be administered up to 3 days before or after the scheduled Day 1 of each 
dose.  
Avelumab will be administered as a 1-hour IV infusion once every 2 weeks.  In order to 
mitigate infusion-related reactions, a premedication with an antihistamine and with 
paracetamol (acetaminophen) to be administered approximately 30 to 60 minutes prior to 
each dose of avelumab is mandatory (for example, 25-50 mg diphenhydramine and 
500-650 mg paracetamol [acet aminophen] IV or oral equivalent).  This may be modified 
based on local treatment standards and guidelines, as appropriate.  As per Amendment 8, 
premedication is no longer required unless clinically indicated by the presence/severity of 
prior infusion reactions.  Sites should make every effort to target infusion timing to be as 
close to 1 hour as possible.  However, given the variability of infusion pumps from site to 
site, time windows of -10 minutes and +20 minutes is permitted (ie, infusion time is 
60 minutes: -10 min/+20 min).  The exact duration of infusion should be recorded in both 
source documents and Case Report Form (CRF).  Possible modifications of the infusion rate 
for the management of infusion-related reactions are described in Section 5.4.6.6.  
The dose amount required to prepare the avelumab infusion solution will be based on the 
patient’s weight in kilograms (kg).  All patients should be weighed within 3 days prior to 
dosing for every infusion.  If the patient experienced either a weight loss or gain 
>10% compared to the weight used to calculate the prior dose, the amount of study drug 
required for preparation and administration for the current treatment must be recalculated 
using this most recent weight obtained.  For weight changes <10% compared to the weight 
used to calculate the prior dose, the decision on whether to recalculate the avelumab dose 
will be made in accordance with local practices.  Avelumab dose reduction for toxicity 
management is not permitted, however next administration may be omitted due to persisting 
toxicity as described in Table 3 and Section 5.4.6. 
Patients experiencing toxicity may require treatment adjustment or discontinuation according 
to the guidelines specified in Table 3. 
5.4.2. Axitinib 
Axitinib will be administered orally BID at approximately the same time in the morning and 
evening on a continuous dosing schedule, ie, without a break in dosing in the absence of 
drug-related toxicity (see Section 5.4.6).  Axitinib tablets are to be taken approximately 
12 hours apart and may be administered without regard to meals.  Tablets must not be 
crushed, split, or dissolved, and patients should be instructed to swallow the study medication 
whole without manipulation or chewing of the medication prior to swallowing.  
A dosing card will be provided to the patients to provide guidance for the correct use of 
axitinib.  
Patients must be instructed that if they miss a dose or vomit anytime after taking a dose, they 
must not “make it up” with an extra dose, but instead resume subsequent doses as prescribed.  


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Any missed dose may be taken late, up to 3 hours before the next scheduled dose of that day, 
otherwise, it should be skipped and dosing resumed with subsequent doses as prescribed.  
Patient must be instructed to record all doses (missed or vomited doses or extra doses) in a 
dosing diary supplied by the site.  If doses are missed or vomited or if an extra dose is taken, 
this must be indicated in the source documents and CRFs. 
Patients experiencing toxicity may require treatment adjustment or discontinuation according 
to the guidelines specified in Table 1 and Table 3. 
5.4.3. Sunitinib 
Sunitinib will be administered orally QD at approximately the same time daily continuously 
for 4 consecutive weeks followed by a 2-week off-treatment period (Schedule 4/2 in 6-week 
cycles), Sunitinib capsules are to be taken daily and may be administered without regard to 
meals.  Capsules must not be opened, split, or dissolved, and patients should be instructed to 
swallow the study medication whole without manipulation or chewing of the medication 
prior to swallowing.  
A dosing card will be provided to the patients to provide guidance for the correct use of 
sunitinib.  
Patients must be instructed that if they miss a dose or vomit anytime after taking a dose, they 
must not “make it up” with an extra dose, but instead resume subsequent doses as prescribed.  
Any missed dose may be taken late in the same day, otherwise, it should be skipped and 
dosing resumed with subsequent doses as prescribed.  Patient must be instructed to record all 
doses (missed or vomited doses or extra doses) in a dosing diary supplied by the site.  If 
doses are missed or vomited or if an extra dose is taken, this must be indicated in the source 
documents and CRFs. 
Patients experiencing toxicity may require treatment adjustment or discontinuation according 
to the guidelines specified in Table 2 and Table 4. 
5.4.4. Treatment After Initial Evidence of Radiologic Disease Progression in Both Arms 
Immunotherapeutic agents such as avelumab may produce anti-tumor effects by potentiating 
endogenous cancer-specific immune responses.  The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions.  
If radiologic imaging shows disease progression as assessed by BICR, tumor assessment 
should be repeated at least ≥4 weeks later in absence of clinical deterioration in order to 
confirm disease progression.  This confirmation of disease progression assessed by BICR 
will not affect the primary and secondary endpoints defined according to RECIST v.1.1. 
Patients will receive study treatment while waiting for confirmation of PD in absence of 
clinical deterioration, as defined by the following criteria:  


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• Absence of clinical signs and symptoms (including worsening of laboratory values) 
of disease progression.  
• No decline in ECOG performance status.  
• Absence of rapid progression of disease by radiographic imaging.  
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 
If repeat imaging no longer shows PD but rather CR, PR, or SD compared to the initial scan, 
treatment may be continued/resumed.  In determining whether or not the tumor burden has 
increased or decreased, investigators should consider all target as well as non target lesions 
(refer to the Study Manual).  
If the repeat imaging confirms PD by BICR assessment, patients should be discontinued from 
study treatment.  However, according to the investigator’s clinical judgment and after 
discussion between the investigator and the sponsor’s medical monitor, if a patient with 
evidence of PD is still experiencing clinical benefit, the patient may be eligible for continued 
treatment with single-agent avelumab, single-agent axitinib, or avelumab in combination 
with axitinib in Arm A, or sunitinib monotherapy in Arm B (crossover between treatment 
arms is not permitted).  The investigator’s judgment should be based on the overall 
benefit-risk assessment and the patient’s clinical condition, including performance status, 
clinical symptoms, adverse events and laboratory data.  
In patients who continue treatment beyond progression by BICR assessment, the oncologic 
assessments should continue to be performed as per SoA and be recorded in the CRF until 
the study treatment is permanently discontinued.  
Patients who stop avelumab after initial clinical benefit while on treatment and then 
experience radiologic disease progression confirmed by BICR thereafter will be eligible for 
re-treatment with avelumab at the discretion of the investigator and after discussion with the 
sponsor’s medical monitor if 1) no cancer treatment was administered other than axitinib 
since the last dose of avelumab, 2) the patient does not meet the safety withdrawal criteria, 
and 3) the trial is still open.  
After review of images by BICR is stopped following the final analyses for PFS performed 
as specified in the protocol (Section 9.6), permanent discontinuation of treatment will be 
performed as per investigator-assessed disease progression (see Section 7.7).  After review of 
images by BICR is stopped, confirmation of disease progression ≥4 weeks after the PD was 
first noticed will no longer be required. 
5.4.5. Food Requirements 
All investigational products may be administered without regard to food but patients must 
avoid foods that are known strong CYP3A4/5 inhibitors (eg, grapefruit juice or 
grapefruit/grapefruit-related citrus fruits [eg, Seville oranges, pomelos]). 


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5.4.6. Recommended Dose Modifications 
Every effort should be made to administer investigational product on the planned dose and 
schedule. 
In the event of significant toxicity, dosing may be delayed and/or reduced as described 
below.  In the event of multiple toxicities, dose modification should be based on the worst 
toxicity observed.  Patients are to be instructed to notify investigators at the first occurrence 
of any adverse symptom.  In addition to dose modifications, investigators are encouraged to 
employ best supportive care according to local institutional clinical practices and according 
to the guidance for selected adverse events provided below. 
For axitinib and sunitinib, dose modifications may occur in 2 ways: 
• Within a cycle: dosing interruption until adequate recovery and dose reduction, if 
required, during a given treatment cycle; 
• In the next cycle: dose reduction may be required in a subsequent cycle based on 
toxicity experienced in the previous cycle. 
For avelumab, no dose modifications are permitted in this study, but next infusion may be 
omitted based on persisting toxicity, as outlined in Table 3.  Dose modifications of axitinib 
and infusion omissions of avelumab may occur independently for the two drugs and will be 
reported in the CRF. 
Available axitinib and sunitinib dose levels for intrapatient dose modification are listed in 
Table 1 and in Table 2, respectively. 
5.4.6.1. Intrapatient Axitinib Dose Escalation and Dose Reduction 
Axitinib intrapatient dose increase to 7 and/or 10 mg in combination with avelumab is 
prohibited in France, as per Agence nationale de sécurité du médicaments et de produits de 
santé (ANSM) request.  
In other countries, intrapatient axitinib dose escalation is permitted up to 10 mg BID and may 
occur according to the criteria described below.  
Patients who tolerate the current axitinib dose without Grade >2 axitinib-related adverse 
events for 2 consecutive weeks have the option to have their axitinib dose increased (one 
dose level increase at a time) as indicated in Table 1 (unless the patient’s BP is 
>150/90 mm Hg or the patient is receiving antihypertensive medication).  Particular attention 
should be provided to a patient’s overall safety profile prior to implementing intrapatient 
axitinib dose escalation.  


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Table 1. 
Axitinib Dose Levels 
Dose Level 
Dose 
+2 
10 mg BID 
+1 
7 mg BID 
Potential Starting Dose 
5 mg BID 
-1 
3 mg BID 
-2 
2 mg BID 
Patients will be monitored closely for toxicity, and axitinib treatment may be adjusted by 
dosing interruption with or without dose reduction as indicated in Table 3.  Dosing 
interruption and/or dose reduction by 1, and if needed, 2 dose levels (one dose level decrease 
at a time) as indicated in Table 1 will be allowed depending on the type and severity of 
toxicity encountered.  Management of patients requiring more than 2 dose reductions of 
axitinib (one dose level decrease at a time) should be discussed with the sponsor’s medical 
monitor. 
Patients who have undergone dose reduction may also undergo dose re-escalation back to the 
previous dose level at the discretion of the Investigator in the absence of Grade ≥2 
non- hematologic treatment-related toxicity for at least 28 days. 
5.4.6.2. Sunitinib Dose Modifications 
Sunitinib dose interruptions and/or dose reduction by 1, and if needed 2 (one dose level 
decrease at a time), dose level(s) as indicated in Table 2 will be allowed depending on the 
type and severity of toxicity encountered provided that criteria for patient withdrawal in 
Section 6.5 have not been met.  If recovery to Grade ≤1 toxicity does not occur within 
6 weeks, investigator should discuss with the medical monitor about any dose modification 
and or treatment continuation.  Consult with the medical monitor before discontinuing the 
patient.  No more than 2 dose reductions are permitted in any patient.  If more than 2 dose 
reductions of sunitinib are required, further reductions should be discussed with the sponsor’s 
medical monitor. 
Table 2. 
Sunitinib Dose Levels 
Dose Level 
Dose 
Starting Dose 
50 mg QD 
-1 
37.5 mg QD 
-2 
25 mg QD 
Sunitinib dose re-escalation back to the previous dose level is permitted in the absence of 
Grade ≥3 hematologic or Grade ≥2 non-hematologic treatment-related toxicity during the 
previous treatment cycle. 
5.4.6.3. Management of Axitinib- or Sunitinib-Related Hypertension 
Patients will be issued BP cuffs (provided by the sponsor) for home monitoring and 
instructed to measure their BP at least once daily (in Arm A before taking the morning dose 
of axitinib, and in Arm B before taking the daily dose of sunitinib during the 4 weeks of 


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treatment and any time during the day in the 2 weeks off treatment).  All BP measurements 
will be recorded in a diary and brought to the nurse or study coordinator at each clinic visit.  
Patients should be instructed to contact the site immediately for guidance if their systolic 
blood pressure rises above 150 mm Hg, diastolic blood pressure rises above 100 mm Hg, or 
if they develop symptoms perceived to be related to elevated blood pressure (eg, headache, 
visual disturbances), although a different blood pressure threshold for contacting the site may 
be used according to the investigator’s clinical judgment. 
Blood pressure should be well-controlled prior to initiating therapy and patients should be 
monitored for hypertension.38,39  To treat an increase in BP, standard antihypertensives may 
be used (eg, thiazide or thiazide-like diuretics, angiotensin II receptor blockers, angiotensin 
converting-enzyme inhibitors, and calcium channel blockers, [except diltiazem since it is a 
strong CYP3A4 inhibitor],etc.).38,39 
For patients on sunitinib therapy, hypertension should be monitored and treated as needed 
with standard anti-hypertensive therapy.  
Dose modifications for axitinib and sunitinib in case of hypertension are described in 
Table 3. 
Post IA3, BP home monitoring will no longer be required. 
5.4.6.4. Axitinib Dose Modifications, Avelumab Infusion Omissions, and Sunitinib Dose 
Modifications for Treatment-Related Toxicity 
In Arm A, recommended axitinib dose modifications and avelumab infusion omissions in 
case of drug related toxicity are shown in Table 3.  The aforementioned guidelines might be 
further modified at the discretion of the sponsor based on the emerging safety profile of the 
combination.  The investigator can consider consulting with the sponsor’s medical monitor in 
case of persistent toxicity that would lead to dose modification or treatment discontinuation 
per toxicity treatment guidelines.  
In Arm B, recommended sunitinib dose modifications in case of drug-related toxicity are 
shown in Table 4.  
The 4-week sunitinib dosing period may not be extended to compensate for interruptions in 
sunitinib treatment due to any cause.  If recovery to Grade ≤1 toxicity does not occur within 
6 weeks, investigator should consider consulting with the medical monitor about any dose 
modification or treatment discontinuation.  


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Table 3. 
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
Hematologic 
Abnormalities 
Grade 1 
• 
Continue at the same dose level. 
• 
Continue as per schedule. 
Grade 2 
• 
Continue at the same dose level. 
• 
Continue as per schedule. 
 
Grade 3 
• 
Continue at the same dose level. 
• 
Withhold avelumab. 
• 
Re-initiate avelumab once toxicity is Grade 
≤1 or baseline. 
• 
Permanently discontinue avelumab if 
toxicities does not resolve to Grade ≤1 or 
baseline within 12 weeks (consider consult 
with the medical monitor before 
permanently discontinuing the treatment). 
Exceptions are: 
Laboratory values that do not have any 
clinical correlate. 
 
Grade 4 
• 
Withhold until recovery to Grade ≤2. 
• 
Then, reduce by 1 dose level and resume 
treatment. 
• 
For Grade 4 lymphopenia not associated with 
clinical events (eg, opportunistic infection) 
axitinib treatment may continue without 
interruption. 
• 
Permanently discontinue avelumab 
(consider consult with medical monitor 
before permanently discontinuing the 
treatment). 
Exceptions are: 
Laboratory values that do not have any 
clinical correlate.   
Proteinuria 
Dipstick negative or 
shows 1+ (Grade 1) 
• 
Continue at the same dose level. 
• 
Continue as per schedule. 
 
If dipstick shows >1+, perform 24 hour urine collection.  Dosing may continue 
while waiting for test results 
 
<2 g proteinuria/ 
24 hour 
• 
Continue at the same dose level. 


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Table 3. 
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
 
≥2 g proteinuria/ 
24 hours 
• 
Withhold until proteinuria is <2 g/24 hours. 
• 
Repeat 24-hour urine collection for 
proteinuria and creatinine clearance (interval 
at investigator discretion) until proteinuria is 
<2 g/24 hours.  
• 
Then, resume at the same dose level or reduce 
by 1 dose level as per investigator judgment. 
Hypertension 
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure ≤150 mm Hg 
(one or both readings)  
And 
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
≤100 mm Hg (one or 
both readings) 
• 
Continue at the same dose level. 
• 
See Section 5.4.6.3 for 
monitoring/management of axitinib-related 
hypertension. 
• 
Continue as per schedule. 
 
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >150 mm Hg 
OR 
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
>100 mm Hg 
• 
If not on maximal antihypertensive treatment, 
institute new or additional antihypertensive 
medication and continue at the same dose 
level.  
• 
If on maximal antihypertensive treatment, 
reduce by 1 dose level. 
• 
See Section 5.4.6.3 for 
monitoring/management of axitinib-related 
hypertension. 
• 
Continue as per schedule. 


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Table 3. 
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
 
2 systolic BP readings 
separated by at least 
1 hour show systolic 
pressure >160 mm Hg  
OR 
2 diastolic BP 
readings separated by 
at least 1 hour show 
diastolic pressure 
>105 mm Hg 
• 
Withhold until BP is less than 150/100 mm 
Hg1 and adjust antihypertensive medication. 
• 
Then, reduce by 1 dose level and resume 
treatment.  
• 
1 If axitinib dosing is temporarily 
discontinued, patients receiving 
antihypertensive medications should monitor 
closely for hypotension.  The plasma half-life 
of axitinib is 2-4 hours and BP usually 
decreases within 1-2 days following dosing 
interruption. 
• 
See Section 5.4.6.3 for 
monitoring/management of axitinib-related 
hypertension. 
• 
Continue as per schedule. 
 
Recurrent 
hypertension 
following previous 
dose reduction 
(2 systolic BP 
readings separated by 
at least 1 hour show 
systolic pressure 
>150 mm Hg) 
OR 
Recurrent diastolic BP 
>100 mm Hg (2 BP 
readings separated by 
at least 1 hour) 
following previous 
dose reduction 
• 
Repeat dose reduction by one lower dose 
level. 
• 
See Section 5.4.6.3 for 
monitoring/management of axitinib-related 
hypertension. 
• 
Continue as per schedule. 


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Table 3. 
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
Infusion-related 
Reaction  
Grade 1-4 
• 
Continue at the same dose level. 
• 
See Section 5.4.6.6 and Table 5. 
 
Hypersensitivity 
reactions 
Grade 3-4 
• 
Continue at the same dose level. 
• 
See Section 5.4.6.7 and Table 5. 
Tumor lysis syndrome 
Grade 1-4 
• 
See Other Non-Hematologic 
Toxicities and/or Laboratory Abnormalities. 
• 
See Section 5.4.6.8 and Figure 1. 
Immune-related AE 
(irAE) 
Grade 1-4 
• 
Grade 1: continue at the same dose level. 
• 
Grade 2-4: hold treatment until recovery to 
Grade ≤1 and restart axitinib at the same dose 
level for Grade 2 and at reduced dose level for 
Grade 3-4.  
• 
See Section 5.4.6.9 and Table 6.  
Stevens-Johnson 
syndrome 
Grade 3-4 
• 
Permanent discontinuation. 
• 
Permanent discontinuation. 
Other Non-hematologic 
Toxicities and 
Laboratory 
Abnormalities 
Grade 1  
• 
Continue at the same dose level. 
• 
Continue as per schedule.  
Grade 2 
• 
Continue at the same dose level. 
• 
Continue as per schedule. 


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Table 3. 
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
Toxicity 
NCI CTCAE 
Severity Grade 
Axitinib 
Avelumab 
Dose Modification 
Treatment Modification 
 
  
Grade 3 
• 
Reduce by 1 dose level. 
• 
Grade 3 toxicities controlled with 
symptomatic medications, or Grade 3 
asymptomatic biochemistry laboratory 
abnormalities: continue at the same dose 
or reduce by 1 dose level as per 
investigator judgment. 
• 
Withhold avelumab. 
• 
Re-initiate avelumab once toxicity is 
Grade ≤1 or baseline.  
• 
Permanently discontinue avelumab if 
toxicity does not resolve to Grade ≤1 or 
baseline value within 12 weeks (consider 
consult with medical monitor before 
permanently discontinuing the treatment). 
Exceptions are: 
• 
Laboratory values that do not have any 
clinical correlate (eg, amylase or lipase 
abnormality that is not associated with 
symptoms or clinical manifestations of 
pancreatitis). 
• 
Nausea and vomiting controlled by 
medical therapy. 
• 
Tumor flare phenomenon defined as 
local pain, irritation, or rash localized 
at sites of known or suspected tumor. 
 
Grade 4 
• 
Hold treatment until recovery to Grade ≤2.  
• 
Then, reduce by 1 dose level and resume 
treatment. 
• 
Grade 4 asymptomatic biochemistry 
laboratory abnormality: study treatment may 
continue without interruption.  
• 
Permanently discontinue avelumab 
(consider consult with the medical monitor 
before permanently discontinuing the 
treatment). 
Exceptions are: 
Laboratory values that do not have any 
clinical correlate. 
 
In case of LVEF decline in patients treated with the axitinib plus avelumab combination, Investigators are encouraged to consult with 
the Sponsor to discuss the management of axitinib therapy independently of any actions implemented for avelumab and the 
Investigator’s causality assessment of the event.


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Table 4. 
Sunitinib Dose Modifications for Investigational Product Related Toxicity 
Toxicity 
Grade 1/2 
Grade 3 or intolerable Grade 2 
Grade 4 
Non-Hematologic 
(exceptions: CHF, pancreatitis, 
necrotizing fasciitis, nephrotic 
syndrome and thrombotic 
microangiopathy).*** 
Continue at the same dose level 
Withhold dose until toxicity is 
Grade ≤1 or has returned to 
baseline, then resume treatment at 
the same dose level.* 
If the toxicity recurs with Grade 3 
severity (or intolerable Grade 2) at 
the discretion of the investigator, 
reduce the dose by 1 level.  
Withhold dose until toxicity is 
Grade ≤1 or has returned to baseline, 
then reduce the dose by 1 level and 
resume treatment, or discontinue at 
the discretion of the investigator.* 
 
Hematologic 
Continue at the same dose level 
Withhold dose until toxicity is 
Grade ≤2 or has returned to 
baseline, then resume treatment at 
the same dose level.** 
If the toxicity recurs with Grade 3 
severity, at the discretion of the 
investigator, reduce the dose by 
1 level. 
Withhold dose until toxicity is 
Grade ≤2 or has returned to baseline, 
then reduce the dose by 1 level and 
resume treatment.** 
 
Left Ventricular Ejection Fraction 
Reduction. 
Continue at the same dose level 
The dose should be interrupted 
and/or reduced if without clinical 
evidence of CHF but with an 
ejection fraction <50% and >20% 
below baseline. 
The dose should be interrupted and/or 
reduced if without clinical evidence 
of CHF but with an ejection fraction 
<50% and >20% below baseline. 
*Patients who develop Grade 4 hyperuricemia or Grade 3 hypophosphatemia without clinical symptoms may continue study treatment without interruption 
at the discretion of the Investigator.  Nausea, vomiting, or diarrhea persist at Grade 3 or 4 despite maximal medical therapy.  
**Patients who develop Grade 3 or 4 lymphopenia may continue study treatment without interruption.  Complicated neutropenia includes duration of 
Grade 4 longer than 7 days or concurrent fever or infection. 
***If occurs sunitinib should be discontinued. 
 


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5.4.6.5. Special Precautions for Avelumab Administration 
In order to mitigate avelumab infusion-related reactions, a premedication with an 
antihistamine and with paracetamol (acetaminophen) to be administered approximately 30 to 
60 minutes prior to each dose of avelumab is mandatory (for example, 25-50 mg 
diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent).  This 
may be modified based on local treatment standards and guidelines, as appropriate.  
As with all monoclonal antibody therapies, there is a risk of allergic reactions including 
anaphylactic shock.  Avelumab should be administered in a setting that allows for immediate 
access to an intensive care unit or equivalent environment and administration of therapy for 
anaphylaxis, such as the ability to implement immediate resuscitation measures.  Steroids 
(dexamethasone 10 mg), epinephrine (1:1,000 dilution), allergy medications 
(IV antihistamines), bronchodilators, or equivalents, and oxygen should be available for 
immediate access. 
Infusion of avelumab will be stopped in case of Grade ≥2 infusion-related, allergic, or 
anaphylactic reactions.  Following avelumab infusions, patients must be observed for 2 hours 
post-infusion for potential infusion-related reactions.  As per Amendment 8, the 2 hours 
observation post-infusion are no longer required unless clinically indicated.  If an allergic 
reaction occurs, the patient must be treated according to the best available medical practice.  
Guidelines for the emergency treatment of anaphylactic reactions are available at 
www.resus.org.uk/pages/reaction.pdf (Working Group of the Resuscitation Council [United 
Kingdom], www.erc.edu (European Resuscitation Council [European Union]), 
www.heart.org (American Heart Association [United States]), and www.american cpr.com 
(American Cardio-Pulmonary Resuscitation [CPR] Training™ [United States]).  Patients 
should be instructed to report any delayed reactions to the investigator immediately. 
Treatment recommendations for the management of infusion-related reactions, severe 
hypersensitivity reactions, and tumor lysis syndrome are outlined in Sections 5.4.6.6, 
Section 5.4.6.7 and Section 5.4.6.8, respectively. 
Investigators should also monitor patients closely for potential irAEs, which may become 
manifest at any time after the first dose of treatment.  Such events may consist of persistent 
rash, diarrhea and colitis, autoimmune hepatitis, arthritis, glomerulonephritis, 
cardiomyopathy, or uveitis and other inflammatory eye conditions.  However potential irAEs 
can occur in any organ or tissue.Treatment recommendations for the management of irAEs 
are outlined in Section 5.4.6.9. 
5.4.6.6. Management of Avelumab Infusion-Related Reactions  
Since avelumab is administered IV, infusion-related reactions may occur (with symptoms 
such as fever, chills, rigors, diaphoresis, and headache).  Treatment of the infusion-related 
reaction and modifications of avelumab infusion are mainly dependent upon severity, as 
indicated in Table 5.  


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Table 5. 
Treatment Modification for Symptoms of Infusion-Related Reactions 
Caused by Avelumab 
NCI CTCAE Grade  
Treatment Modification for Avelumab 
Grade 1 – mild 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated. 
Decrease the avelumab infusion rate by 50% and 
monitor closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hours. 
Temporarily discontinue avelumab infusion. 
Resume infusion at 50% of previous rate once 
infusion-related reaction has resolved or decreased 
to at least Grade 1 in severity, and monitor closely 
for any worsening. 
Grade 3 or Grade 4 – severe or life-threatening 
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
Stop the avelumab infusion immediately and 
disconnect infusion tubing from the patient. 
Patients have to be withdrawn immediately from 
avelumab treatment and must not receive any 
further avelumab treatment. 
IV=intravenous, NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events, 
NSAIDs=nonsteroidal anti-inflammatory drugs. 
Once the avelumab infusion rate has been decreased by 50% due to an infusion-related 
reaction, it must remain so for all subsequent infusions.  
Additional Modifications for Patients with Grade 2 Infusion-Related Reactions:  
In the event of a Grade 2 infusion-related reaction that does not improve or worsens after 
implementation of the modifications indicated in Table 5 (including reducing the infusion 
rate by 50%), the investigator may consider treatment with corticosteroids, and the infusion 
should not be resumed for that avelumab dose.  At the next avelumab dose, the investigator 
may consider the addition of H2-blocker antihistamines (eg, famotidine or ranitidine), 
meperidine, or ibuprofen to the mandatory premedication as clinically indicated.  
Prophylactic steroids are NOT permitted. 
5.4.6.7. Management of Avelumab-related Severe Hypersensitivity Reactions and 
Flu-like Symptoms  
As with all monoclonal antibody therapies, avelumab can induce flu-like symptoms and 
hypersensitivity reactions; including impaired airway, decreased oxygen saturation 
(<92%), confusion, lethargy, hypotension, pale/clammy skin, and cyanosis. 
If hypersensitivity reaction occurs, the patient must be treated according to the best available 
medical practice.  Guidelines for the emergency treatment of anaphylactic reactions are 
available at www.resus.org.uk/pages/reaction.pdf (Working Group of the Resuscitation 
Council [United Kingdom], www.erc.edu (European Resuscitation Council [European 
Union]), www.heart.org (American Heart Association [United States]), and www.american 
cpr.com (American Cardio-Pulmonary Resuscitation [CPR] Training™ [United States]).  
Patients should be instructed to report any delayed reactions to the investigator immediately. 


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Avelumab should be administered in a setting that allows for immediate access to an 
intensive care unit or equivalent environment if required.  Patients should be placed on 
monitor immediately, and epinephrine injection and dexamethasone infusion should be 
available for immediate access. 
For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable Nonsteroidal 
Anti-Inflammatory Drug (NSAID) dose (eg, ibuprofen 600 mg, naproxen sodium 500 mg) 
may be administered at investigator discretion 2 hours before and 8 hours after the start of 
each dose of avelumab IV infusion.  Alternative treatments for fever (eg, paracetamol or 
ibuprofen) and rigors (eg, meperidine) may be given to patients at the discretion of the 
investigator. 
Additional treatment recommendations for symptoms of avelumab infusion-related reactions 
are provided in Appendix 8 and may be modified based on local treatment standards and 
guidelines, as appropriate. 
5.4.6.8. Management of Avelumab-Related Tumor Lysis Syndrome 
Avelumab can induce antibody-dependent cell-mediated cytotoxicity (ADCC), so there is a 
potential risk of tumor lysis syndrome.  Should this occur, patients should be treated as per 
local guidelines and the management algorithm (Figure 1) published by Howard et al.48  


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Figure 1. Assessment and Initial Management of Tumor Lysis Syndrome (TLS) 
 
Measure serum potassium, phosphorus, calcium, creatinine, uric acid, and urine output
No TLS at diagnosis
Assess cancer mass
Laboratory TLS
≥2 abnormal laboratory
test values
No symptoms
Small or resected
localized tumor
Medium-size 
cancer mass
Large cancer mass
Bulky tumor or organ 
infiltration
Bone marrow replaced
with cancer
Assess cell-lysis potential
Assess cell-lysis potential
Low
High
Medium or
unknown
Low
High
Medium or
unknown
Negligible Risk
of Clinical TLS
No prophylaxis
No monitoring
Low Risk or
of Clinical TLS
Intravenous fluids
Allopurinol
Daily laboratory tests
High Risk of
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Laboratory tests every
6-8 hr 
Established
Clinical TLS
Intravenous fluids
Rasburicase
Cardiac monitoring
Intensive care unit
Laboratory tests every
4-6 hr 
High Risk of
Clinical TLS
Intravenous fluids
Allopurinol or ras-
buricase
Inpatient monitoring
Laboratory tests every
8-12 hr 
Assess patient
presentation
Preexisting nephropathy
Dehydration
Hypotension
Nephrotoxin exposure
No
Yes
Clinical TLS
Acute kidney injury
Symptomatic hypo-
calcemia
Dysrhythmia


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5.4.6.9. Management of Avelumab Immune-Related Adverse Events 
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur.  Treatment of 
irAEs is mainly dependent upon severity as reported in Table 6: 
• Grade 1 to 2: treat symptomatically or with moderate-dose steroids, more frequent 
monitoring; 
• Grade 1 to 2 (persistent): manage similar to Grade 3 to 4 AE; 
• Grade 3 to 4: treat with high-dose corticosteroids. 
For any irAE of any grade, the investigator may consider consulting with the sponsor’s 
medical monitor if deemed necessary. 
Treatment of irAEs should follow guidelines set forth in Table 6.  
Some potential immune-related adverse events described with anti-PD-L1 monoclonal 
antibodies such as avelumab may overlap with axitinib toxicities (eg, diarrhea, liver function 
tests increase).  Any adverse event suspected to be immune-related should be managed 
according to the guidance for management of immune-related adverse events in this 
Section 5.4.6.9. 
For overlapping potential immune-related toxicities Grade 2, hold both drugs used in the 
combination (avelumab and axitinib) and follow the specific management recommendations 
described in Table 6.  When the event resolves to Grade ≤1, restart therapy with axitinib.  If 
the Grade ≥2 event does not recur, restart avelumab at the next treatment dose.  If the 
Grade ≥2 event does not resolve to Grade ≤1 after holding avelumab for 2 treatment doses 
(up to 28 days) or if the Grade ≥2 event recurs after re-introduction of avelumab, 
permanently discontinue avelumab therapy.  
For Grade ≥3 overlapping potential immune-related toxicities follow the specific guidance on 
Table 6 for avelumab and hold axitinib.  When event resolved to Grade ≤1, restart therapy 
with axitinib at reduced dose level.  Avelumab should be permanently discontinued. 














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Table 6. 
Management of Avelumab Immune-Related Adverse Events 
Recurrence of same Grade 3 
irAEs 
Permanently discontinue 
avelumab therapy. 
1.0 to to 2.0 mg/kg/day 
prednisone or equivalent. 
Add prophylactic antibiotics 
for opportunistic infections.  
Specialty consult as 
appropriate. 
If improves to Grade ≤1:  
Taper steroids over at least 1 month. 
Grade 4  
 
Permanently discontinue 
avelumab therapy. 
1.0 to to 2.0 mg/kg/day 
prednisone or equivalent 
and/or other 
immunosuppressant as 
needed. 
Add prophylactic antibiotics 
for opportunistic infections.  
Specialty consult. 
If improves to Grade ≤1:  
Taper steroids over at least 1 month. 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Permanently discontinue 
avelumab therapy. 
Specialty consult. 
 
Abbreviations: ACTH=adrenocorticotropic hormone; ADL=activities of daily living; ALT=alanine 
aminotransferase; AST=aspartate aminotransferase; BNP=B-type natriuretic peptide; CK-MB=creatine kinase 
MB; CT= computed tomography; FSH=follicle-stimulating hormone; GH=growth hormone; 
IGF-1=insulin-like growth factor 1; irAE=immune-related adverse event; IV=intravenous; LH=luteinizing 
hormone; MRI=magnetic resonance imaging; NCI-CTCAE=National Cancer Institute-Common Terminology 
Criteria for Adverse Events; PRL=prolactin;T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper 
limit of normal. 
5.5. Investigational Product Storage  
The investigator, or an approved representative (eg, pharmacist), will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.  
Investigational product should be stored in its original container and in accordance with the 
label.  See the dosage and administration instructions (DAI), package insert, or equivalent for 
storage conditions of the products and once reconstituted and/or diluted (for avelumab only). 
• Avelumab must be stored in the refrigerator (between 2-8°C) or as specified in the 
product label.  
• Axitinib must be stored at controlled room temperature (between 15-30°C) or as 
specified in the product label. 


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• Sunitinib must be stored at controlled room temperature (between 15-30°C) or as 
specified in the product label. 
Storage conditions stated in the SRSD (ie, IB) will be superseded by the storage conditions 
stated on the label.  
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that ensures active daily evaluation 
for excursions should be available.  The operation of the temperature monitoring device and 
storage unit (for example, refrigerator), as applicable, should be regularly inspected to ensure 
it is maintained in working order.  
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation. 
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions.  
Site staff will instruct patients on the proper storage requirements for take-home 
investigational products. 
5.6. Investigational Product Accountability  
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All bottles of study drug must be 
returned to the investigator by the patient at the end of each cycle and at the end of the trial, 
the sponsor will provide instructions as to disposition of any unused investigational product 
if the investigative site is unable to destroy at site per local procedures.  


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5.7. Destruction of Investigational Product Supplies  
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented. 
5.8. Concomitant Treatments 
Medications or vaccinations specifically prohibited in the Exclusion Criteria are also not 
allowed during the active treatment period, except for administration of the 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, discontinuation from study therapy or 
medication/vaccination may be required.  The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the patient’s primary physician.  However, the 
decision to continue the patient on study therapy or medication/vaccination schedule requires 
the mutual agreement of the investigator, the sponsor, and the patient.  
Concomitant treatment considered necessary for the patient’s well being may be given at the 
discretion of the treating physician. 
All concomitant treatments, blood products, as well as non-drug interventions received by 
patients from screening until the end of study visit will be recorded on the CRF.  
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatment and up to 90 days after the last dose of 
study treatment.  All concomitant medications should be recorded in the CRF including 
supportive care drugs (eg, antiemetic treatment and prophylaxis), and the drugs used to treat 
adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions). 
Concurrent anticancer therapy with agents other than avelumab and axitinib in Arm A or 
sunitinib in Arm B is not allowed.  Medications intended solely for supportive care (ie, 
antiemetics, analgesics, megestrol acetate for anorexia) are allowed. 
Recommended medications to treat infusion-related reactions, hypersensitivity reactions, 
flu-like symptoms, tumor lysis syndrome and immune-related events are reported in 
Sections 5.4.6.5, Section 5.4.6.6, Section 5.4.6.7, Section 5.4.6.8, and Section 5.4.6.9, 
respectively.  
5.8.1. Inhibitors and Inducers of CYP Enzymes 
In vitro studies with human liver microsomes and recombinant CYP enzymes indicate that 
axitinib metabolism is primarily mediated by the CYP3A4/5, and to a lesser extent by 
CYP1A2, CYP2C19, and UGT1A1.  


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Sunitinib is primarily metabolized by liver enzymes, in particular CYP3A4.  There was a 
mean 1.8-fold increase in exposure of sunitinib when co-administered with ketoconazole, a 
potent inhibitor of CYP3A4 and a mean 4-fold decreased in exposure of sunitinib when 
co-administered with rifampin, a potent inducer of CYP3A4. 
The concomitant use of strong CYP3A4/5 inhibitors (eg, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, diltiazem, 
telithromycin, and voriconazole) should be avoided.  Selection of an alternate concomitant 
medication with no or minimal CYP3A4/5 inhibition potential is recommended.  Although 
axitinib and sunitinib dose adjustments have not been studied in patients receiving strong 
CYP3A4/5 inhibitors, consider a dose reduction if axitinib or sunitinib must be dosed with a 
CYP3A4/5 inhibitor.  
If coadministration of the strong CYP3A4/5 inhibitor is discontinued, the axitinib or sunitinib 
dose should be re-escalated (after 10 days) to that used prior to initiation of the strong 
CYP3A4/5 inhibitor.  
Coadministration of axitinib or sunitinib with strong CYP3A4/5 inducers (eg, rifampin, 
dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, and 
St. John’s wort) should be avoided.  Selection of concomitant medication with no or minimal 
CYP3A4/5 induction potential is recommended.  Moderate CYP3A4/5 inducers 
(eg, bosentan, efavirenz, etravirine, modafinil, and nafcillin) may also reduce the plasma 
exposure of axitinib or sunitinib and should be avoided if possible.  Consider a dose increase 
if axitinib or sunitinib must be dosed with a CYP3A4/5 inducer. 
If coadministration of the strong CYP3A4/5 inducer is discontinued, the axitinib or sunitinib 
dose should be de-escalated (after 10 days) to that used prior to initiation of the strong 
CYP3A4/5 inducer. 
A listing of CYP3A4 inhibitors and inducers will be provided to the sites and updated as 
needed. 
5.8.2. Hematopoietic Growth Factors 
Granulocyte colony stimulating factor may be used in agreement with American Society of 
Clinical Oncology (ASCO) guidelines.58 
Patients who enter the study on stable doses of erythropoietin or darbepoietin may continue 
this treatment, and patients may start either drug during the study at the discretion of the 
treating physician if clinically indicated. 
5.8.3. Concomitant Surgery  
No formal studies of the effect of axitinib on wound healing have been conducted; however, 
caution is advised based on the mechanism of action.  If a major surgery or an interventional 
procedure (eg, endoscopy) is required, treatment with axitinib must be interrupted at least 
24 hours before the procedure, and the patient BP should be monitored closely for 
hypotension.  Patients may resume axitinib 7 days after minor surgery and 2-3 weeks after 


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major surgery, assuming the wound has completely healed and there are no wound healing 
complications (eg, delayed healing, wound infection or fistula). 
In case of surgical procedure, avelumab treatment should be delayed.  Reinitiation should be 
discussed with the sponsor’s medical monitor. 
The appropriate interval of time between surgery and sunitinib treatment required to 
minimize the risk of impaired wound healing and bleeding has not been determined.  Based 
upon pharmacokinetic and clinical considerations of sunitinib, stopping sunitinib treatment is 
recommended at least 14 to 21 days prior to major elective surgery and at least 5-7 days 
before minor surgery.  Postoperatively, the decision to reinitiate sunitinib treatment should be 
based upon a clinical assessment of satisfactory wound healing and recovery from surgery. 
5.8.4. Concomitant Radiotherapy 
Local radiotherapy (limited field) of isolated lesions with palliative intent is acceptable and 
allowed throughout the study (ie, starting from screening trough end of treatment) if 
considered medically necessary by the treating physician.  All attempts should be made to 
rule out disease progression in the event of increased localized pain.  If palliative 
radiotherapy is needed to control pain, the site(s) of disease causing pain should also be 
present at baseline; otherwise, painful lesion(s) requiring radiotherapy will be considered as a 
sign of disease progression.  Consult the sponsor’s medical monitor prior to starting 
radiotherapy or prior to restarting study treatment after the end of radiotherapy. 
5.8.5. Other Prohibited Concomitant Medications and Therapies  
Patients enrolled on both arms are prohibited from receiving the following therapies while 
receiving study treatment:  
• Immunotherapy, immunosuppressive drugs (ie, chemotherapy or systemic 
corticosteroids except for short-term treatment of allergic reactions or for the 
treatment of irAEs).  Short-term administration of systemic steroids (eg, for allergic 
reactions or the management of irAEs) is allowed.  Topical and inhalation steroids are 
allowed. 
• Any vaccine therapies for the prevention of infectious disease within 4 weeks after 
the start of study treatment, except administration of the inactived vaccines (for 
example, inactivated influenza vaccine).  
• Bisphosphonate or denosumab treatment is not allowed unless it has been initiated 
more than 14 days prior to receiving the first administration of study treatment.  The 
need to initiate while on study treatment or increase the dose of these therapies during 
the study for patients who started >14 days before study treatment start, will be 
considered as indicative of disease progression leading to the discontinuation of 
patient from the study treatment unless disease progression can be completely ruled 
out and the exact reason for the use of these therapies must clearly be documented. 


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• Anti-cancer systemic chemotherapy or biological therapy or investigational agents 
other than avelumab and axitinib or sunitinib.  
• Other experimental pharmaceutical products. 
• Herbal remedies with immunomodulating properties (eg, mistle toe extract) or known 
to potentially interfere with major organ function (eg, hypericin). 
Clarifications about Steroid Use: Data indicate that corticosteroids have an adverse effect 
on T-cell function and that they inhibit and damage lymphocytes.40,41  Furthermore, as with 
all immunotherapies intended to augment cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit of the 
proposed study treatment.  However, studies with anti-CTLA4 compounds indicate that 
short-term use of steroids may be employed without compromising clinical outcomes.42  
Therefore, the use of steroids during this trial is restricted as follows: 
• Therapeutic use: for the treatment of infusion-related reactions and short-term 
treatment of irAEs, steroids are permitted according to the modalities indicated in 
Table 6. 
• Physiologic use: steroid replacement for adrenal insufficiency at doses equivalent to 
≤10 mg prednisone daily is acceptable. 
• Prophylactic use, eg, for the prevention of acute infusion-related reactions, is 
prohibited, except prior to CT or MRI. 
5.9. Rescue Medications and Supportive Care  
5.9.1. Supportive Care Guidelines  
Patients should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below:  
• 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 Table 6. 


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• Anti-inflammatory or narcotic analgesics may be offered as needed.  
Acetaminophen/paracetamol to a maximum total daily dose of 2 g is permitted.  Daily 
intake over 2 g is prohibited. 
• Patients who need to be on anticoagulant therapy during treatment should be treated 
with low molecular weight heparin.  If low molecular weight heparin cannot be 
administered, coumadin or other coumarin derivatives or other anti-coagulants 
(including direct Xa inhibitors) may be allowed; however, appropriate monitoring of 
prothrombin time/international normalized ratio (PT/INR) should be performed.  
6. STUDY PROCEDURES  
6.1. Screening 
For screening procedures, see Schedule of Activities (SOA) and Assessments section 
(Section 7).  
6.1.1. Tumor Biospecimens 
Provision of tumor biospecimen will be required for enrollment onto the study as follows: 
• Recent tumor biospecimen: a mandatory formalin-fixed, paraffin-embedded (FFPE) 
tumor tissue block from a de novo tumor biopsy must be obtained from all patients 
during screening.  The biopsied tumor lesion should not be a RECIST target lesion.  
Alternatively a recent archival formalin-fixed, paraffin-embedded (FFPE) tumor 
tissue block 
 
 
 
  
 
 
 
 
 
 
 can 
be provided  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• Archival tumor biospecimen: a mandatory archival FFPE tumor tissue block from 
the primary diagnosis specimen must be provided from all patients prior to 
randomization.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
• End of Treatment Tumor Biopspecimen: A de novo tumor sample (ie, fresh biopsy) 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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For all tumor biospecimen, tumor tissue from cytologic sampling (eg, fine needle aspiration, 
including FFPE cell pellet material) is not adequate and should not be submitted.  The 
de novo biopsy(ies) should be formalin-fixed and paraffin-embedded as per routine (see 
Study Manual), and the resulting FFPE tissue block(s) or slides should be submitted to the 
Central Laboratory.  Additional information on tumor biospecimen collection procedures is 
included in the Study Manual. 
6.2. Treatment Period 
For treatment period procedures, see Schedule of Activities (SOA) and Assessments 
(Section 7).  Of Note: From Cycle 2 onward, patients randomized to Arm B (Sunitinib Arm), 
are allowed to visit the site once per cycle as per clinical standard practice.  Patients in Arm 
A who have permanently discontinued avelumab and continue on treatment with single agent 
axitinib, will be required to visit the site every 2 weeks for additional 2 full cycles following 
avelumab discontinuation and then allowed to visit the study site only once per cycle as per 
standard clinical practice, unless clinically contraindicated.  Days 15 and 29 safety data as 
specified in the Schedule of Activities footnotes will be collected by email/fax and telephone 
call unless the patient is visiting the site for other reasons.  Based on observed (laboratory 
tests) and reported findings during the call, the patient might be required to visit the site.  The 
Investigator must document in writing the results of the phone call in a specific form and data 
are to be reported in the CRF.  
Post IA3, Days 15 and 29 safety assessments other than pregnancy tests will no longer be 
required unless clinically indicated.  Note: pregnancy test will be required on Days 1 and 29 
only. 
6.3. End of Treatment/Withdrawal and Follow-up Visits 
For follow-up procedures, see Schedule of Activities (SOA) and Assessments (Section 7).  
All patients will be followed for survival every 3 months (±14 days) until death, end of the 
study or patient withdrawal of consent, whichever comes first.  Information will be collected 
by telephone unless the patient is visiting the site for other reasons.  The investigator or 
designee must make every effort to collect the patient’s status through contacting the patient 
or a relative or their usual health care provider by telephone or other allowed methods.  
These contact attempts should be documented in the patient’s medical records.  See Schedule 
of Activities (SOA) for further details. 
6.4. End of the Study 
The study will end when at least 368 OS events in the PD-L1+ population (patient population 
prospectively defined as noted in Section 7.5.1) have occurred. 


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At the end of study, Arm A patients who are still deriving clinical benefit from study 
treatment will be provided with an option for continued study treatment (eg, rollover study). 
6.5. Patient Withdrawal 
Patients may withdraw from treatment at any time 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: 
• Objective confirmed disease progression assessed by BICR  (see Section 5.4.4 for 
further details on treatment continuation after initial evidence of PD).  However, 
patients with confirmed disease progression assessed by BICR who are continuing to 
derive clinical benefit from the study treatment will be eligible to continue with 
single-agent avelumab or axitinib, or with avelumab in combination with axitinib, or 
with sunitinib provided that the treating physician has determined that the benefit/risk 
for doing so is favorable.  After review of images by BICR is stopped following the 
planned final analyses for PFS specified in the protocol (Section 9.6), permanent 
discontinuation of treatment will be performed as per investigator-assessed disease 
progression. 
• Global deterioration of health status requiring discontinuation; 
• Unacceptable toxicity.  If the unacceptable toxicity in Arm A is attributed to one of 
the two study treatments, the investigator (in discussion with the sponsor’s medical 
monitor) may continue treatment with the other study treatment; 
• Pregnancy; 
• Significant protocol violation; 
• Lost to follow-up; 
• Patient refused further treatment (follow-up permitted by patient); 
• Study terminated by sponsor; 
• Death. 
Reasons for withdrawal from study follow-up may include: 
• Study terminated by sponsor; 
• Lost to follow-up; 


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• Refused further follow-up; 
• Death. 
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The investigator should inquire 
about the reason for withdrawal, request the patient to return all unused investigational 
product(s), request that the patient return for a final visit, if applicable, and follow up with 
the patient regarding any unresolved AEs. 
If the patient 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 
which he or she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team will be informed of these incidents in a timely fashion. 
7.1. Safety Assessment 
Safety assessments will include collection of AEs, Serious Adverse Events (SAEs), vital 
signs and physical examination, Electrocardiogram (ECG, 12-lead), laboratory assessments, 
including pregnancy tests and verification of concomitant medications. 
Safety will be monitored at regular intervals throughout the study by means of laboratory 
tests and clinical visits as described in the Schedule of Activities.  Of Note: From Cycle 2 
onward, patients randomized to Arm B (sunitinib Arm) are allowed to visit the site once per 
cycle as per clinical standard practice.  Patients in Arm A who have permanently 
discontinued avelumab and continue on treatment with single agent axitinib, will be required 
to visit the site every 2 weeks for additional 2 full cycles following avelumab discontinuation 
and then allowed to visit the study site only once per cycle as per standard clinical practice, 
unless clinically contraindicated.  Days 15 and 29 safety data as specified in the Schedule of 
Activities footnotes will be collected by email/fax and telephone call unless the patient is 
visiting the site for other reasons.  Based on observed (laboratory tests) and reported findings 
during the call, the patient might be required to visit the site.  The Investigator must 
document in writing the results of the phone call in a specific form and data are to be 
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However, after the first 9 months of treatment of each patient, the Sponsor in conjunction 
with E-DMC might consider to reduce the assessment frequency (eg, once every 1 cycle) 
according to the emerging safety profile of the avelumab in combination with axitinib.  
Post IA3, Days 15 and 29 safety assessments other than pregnancy test will no longer be 
required unless clinically indicated.  Note: pregnancy test will be required on Days 1 and 29 
only. 
7.1.1. Pregnancy Testing 
For female patients of childbearing potential, a serum pregnancy test, with sensitivity of at 
least 25 mIU/mL, will be performed on 2 occasions prior to starting study treatment - once at 
the start of screening, and once at the baseline visit immediately before the administration of 
avelumab in combination with axitinib or of sunitinib.  Following a negative pregnancy test 
result at screening, appropriate contraception must be commenced and another negative 
pregnancy test result will then be required at the baseline visit before the patient may receive 
the investigational product.  Serum or urine pregnancy tests will also be routinely repeated on 
Days 1, 15, and 29 of every cycle (on Days 1 and 29 only post IA3) during the active 
treatment period, at the end of study treatment, at 30 ±3, 60 ±3 (Arm B only) Days Follow-up 
and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is 
otherwise suspected.  In the case of a positive hCG test, the patient will be withdrawn from 
treatment but may remain in the study.   
Post IA3, Day 29 pregnacy test result will be collected by telephone call. 
Additional pregnancy tests may also be undertaken if requested by Institutional Review 
Board/Ethics Committees (IRB/ECs) or if required by local regulations.  
7.1.2. Adverse Events 
Assessment of adverse events will include the type, incidence, severity (graded by NCI 
CTCAE version 4.03), timing, seriousness, and relatedness. 
7.1.3. Laboratory Safety Assessments 
Hematology, blood chemistry, coagulation and urinalysis will be collected at the time points 
described in the Schedule of Activities (SOA) and analyzed at local laboratories.  They may 
also be performed when clinically indicated.  Clinically significant abnormal laboratory 
results should be repeated as soon as possible (preferably within 24-48 hours) and followed 
up as per standard clinical practice unless differently specified in the study protocol. 
The required laboratory tests are listed in Table 7. 


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Table 7. 
Required Laboratory Tests 
Hematology 
Chemistry Panel 
(* denotes core chemistry test) 
Urinalysis 
Coagulation 
Tests 
Pregnancy  
Tests 
Hemoglobin 
ALT* 
Protein, 
glucose, blood  
Urine 
dipstick/other 
semiquantitativ
e method, for 
urine protein: if 
≥2+, collect 
24-hour 
 
PT, INR 
For female 
patients of 
childbearing 
potential, serum 
or urine  
Platelets 
AST* 
PTT or aPTT 
WBC 
Alkaline Phosphatase* 
 
Absolute Neutrophils 
Sodium* 
 
Absolute Lymphocytes Potassium* 
 
Absolute Monocytes 
Magnesium* 
 
Absolute Eosinophils 
Chloride* 
 
Absolute Basophils 
Total Calcium* 
 
 
Corrected Calcium  
(at screening only)§ 
 
 
Total Bilirubin* ° 
 
 
BUN or Urea* 
 
 
Creatinine* 
 
 
 
Glucose (non-fasted)* 
 
 
 
 
Phosphorus or Phosphate* 
 
 
 
 
Albumin 
 
 
 
 
Total Protein 
 
 
 
Uric Acid 
 
 
 
Amylase 
 
 
 
 
Gamma glutamyl transferase 
(GGT) 
 
 
 
 
Cholesterol 
 
 
 
 
Creatine kinase 
 
 
 
 
C-reactive protein (CRP)  
 
 
 
 
Lactate dehydrogenase (LDH) 
 
 
 
 
Lipase 
 
 
 
 
Triglycerides 
 
 
 
 
HBV, HCV testing 
 
 
 
 
Thyroid Function Tests: TSH, 
free T4 
 
 
 
 
Other Tests:  
ACTH  
 
 
 
 
Cardiac Enzymes: 
B-type natriuretic peptide 
(BNP), troponin, and CK-MB 
(as per SoA).  
 
 
 
°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 or aPT)/INR, alkaline phosphatase.  
§Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]. 
 
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, aPT=activated prothrombin time, 
aPTT=activated partial thromboplastin time, AST=aspartate aminotransferase, BNP=B-type natriuretic 
peptide, BUN=blood urea nitrogen, CK-MB=Creatine kinase-MB, GGT=gamma-glutamyltransferase, 
HBV=hepatitis B virus, HCV=hepatitis C virus, INR=international normalized ratio,  
TSH=thyroid-stimulating hormone, WBC=white blood cell. 
 


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Table 8. 
Required Laboratory Tests Post IA3 Cut Off Date (28-Apr-2020) 
Hematology 
Chemistry Panel 
Pregnancy Tests 
Hemoglobin 
ALT 
For female patients of childbearing 
potential, serum or urine 
Platelets 
AST 
WBC 
ALP 
Absolute Neutrophils 
Total Bilirubin° 
 
Absolute Lymphocytes 
GGT 
 
 
Amylase 
 
 
Lipase 
 
 
Potassium 
 
 
Sodium 
 
 
Total Calcium 
 
 
Creatinine 
 
 
Creatine kinase 
 
 
Glucose (non-fasted) 
 
 
Cholesterol 
 
 
Triglycerides 
 
 
Thyroid Function Tests: Free T4, TSH 
 
 
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 or aPT)/INR, alkaline phosphatase. 
 
Abbreviations: ACTH=adrenocorticotropic hormone; ALP= alkaline phosphatase; ALT=alanine 
aminotransferase, AST=aspartate aminotransferase, GGT=gamma-glutamyl transferase, T4=thyroxine, 
TSH=thyroid-stimulating hormone, WBC=white blood cell. 
 
7.1.4. Physical Examinations and Vital Signs  
Physical examinations will be performed according to institutional guidelines on study days 
as described in the Schedule of Activities (SOA).  
The physical examination will include major body systems, weight, height (height will be 
measured at screening only), assessment of ECOG performance status. 
Vital signs (blood pressure, pulse rate) will be measured on study days as described in the 
Schedule of Activities (SOA).  Blood pressure and pulse rate should be taken with the patient 
in the seated position after the patient has been sitting quietly for at least 5 minutes.  Two 
blood pressure/pulse readings will be taken at least 1 hour apart at each clinic visit.  In 
addition, all patients will be monitoring BP at home as described in Section 5.4.6.3.  
Post IA3, physical examination in the clinic and BP home monitoring will no longer be 
required. 
7.1.5. (12-Lead) Electrocardiogram Measurements 
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECG 
assessments. 


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All patients require a triplicate ECG measurement at screening.  On-treatment ECGs will be 
performed as outlined in the SOA table.  At each time point, 3 consecutive 12-lead ECGs 
(triplicates) will be performed approximately 2 minutes apart to determine mean QTc 
(average of triplicates).  When coinciding with blood sample draws for PK, ECG 
assessment (as well as CK and troponin, if clinically indicated) should be performed 
prior to blood sample collection, such that the blood sample is collected at the nominal 
time.  
Clinically significant findings seen on subsequent ECGs should be recorded as adverse 
events.  In case of QTc >500 msec (ie, CTCAE Grade >2), ECG must be reviewed by 
qualified personnel at the site as soon as the finding is made, including verifying that the 
machine reading is accurate and that the Fridericia correction formula is applied.  If the 
manual reading verifies a rate corrected QTc of >500 msec, repeat ECG should be 
immediately performed at least two times approximately 2 to 4 minutes apart.  
An electronic reading of prolonged QTc must be confirmed by manual reading.  Prior to 
conclusion that an episode of prolongation of the QTc interval is due to study drug, thorough 
consideration should be given to potential precipitating factors (eg, change in patient clinical 
condition, effect of concurrent medication, electrolyte disturbance) and possible evaluation 
by specialist.  If QTc interval reverts to less than 500 msec, and in the judgment of 
investigator and sponsor is determined to be due to a cause other than study drug, treatment 
may be continued with regular ECG monitoring. 
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 QTc is 
prolonged (>500 msec), then 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.  At that time, CK and troponin should be 
performed in association with clinically indicated ECG assessements.  When coinciding with 
blood sample draws for PK, ECG assessment (as well as CK and troponin, if clinically 
indicated) should be performed prior to PK blood sample collection, such that the PK blood 
sample is collected at the nominal time.  
7.2. Patient-Reported Outcome Assessments 
In this trial, PROs will be assessed using 2 published and validated instruments: 
FACT-Kidney Symptom Index (FKSI)-19 (Appendix 4) and EuroQol 5-Dimension (EQ-5D) 
(Appendix 5).  
7.2.1. FKSI-19 
The FKSI-19 was developed to be part of the Functional Assessment of Chronic Illness 
Therapy (FACIT) system.  It is an instrument specifically designed to be a stand-alone 
instrument to measure symptoms and quality of life in patients with advanced kidney cancer.  
It contains 19 questions, some of which overlap with the FACT-G questions.43  The FKSI-19 
was developed in order to more comprehensively cover the items of interest in the quality of 
life measurement for aRCC patients.  A 9-item subscale of the FKSI known as the 
FKSI-Disease Related Symptoms subscale (FKSI-DRS) measuring advanced kidney cancer 


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disease related symptoms was created using inputs from oncologists and patients.44  This 
subscale includes the following 9 items: lack of energy, pain, losing weight, bone pain, 
fatigue, shortness of breath, coughing, bothered by fevers, and hematuria.  A parallel analysis 
from the FKSI validation study has been carried out to confirm the validity of this FKSI-DRS 
subscale.  The FKSI-DRS has been a subscale of both the FSKI-15 and the FSKI-19.  In 
validation studies, a change of 2-3 points has been established as the Minimally Important 
Difference (MID) for the FKSI-DRS.45 
The FKSI-19 questionnaire will be administered on the Cycle 1 Day 1, then at the beginning 
of the each treatment cycle as well as upon End of Treatment/Withdrawal.  Beyond End of 
Treatment (ie, follow-up period), PRO assessments will be collected at the same time a tumor 
assessment is performed.  The amount of time for a patient to complete the FKSI-19 
questionnaire is estimated to be about 3-5 minutes.  
7.2.2. EuroQoL EQ-5D 
The EuroQol EQ-5D is a 5-item patient-completed questionnaire designed to assess health 
status in terms of a single index value or utility score.46  There are two components to the 
EQ-5D; a Health State Profile which has individuals rate their level of problems (none, 
slight, moderate, severe, extreme/unable) in 5 areas (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression), and a Visual Analogue Scale (VAS) in which 
patients rate their overall health status from 0 (worst imaginable) to 100 (best imaginable).  
Published weights are available that allow for the creation of a single summary score.47  
Overall scores range from 0 to 1, with low scores representing a higher level of dysfunction.  
The EQ-5D questionnaire will be administered on Cycle 1 Day 1, then at the beginning of 
each treatment cycle, as well as upon End of Treatment/Study Withdrawal.  Beyond End of 
Treatment (ie, follow-up period), PRO assessments will be collected at the same time a tumor 
assessment is performed. The amount of time for a patient to complete the EQ-5D 
questionnaire is estimated to be about 2 minutes.  
7.3. Pharmacokinetics Assessments (Arm A only) 
PK blood samples will be collected from patients in Arm A only.  
7.3.1. Blood Sample Collection for Pharmacokinetic Analysis  
PK samples will be collected from patients in Arm A only.  Blood samples for axitinib PK 
and avelumab PK will be collected as outlined in SOA table.  Where noted in the SOA table, 
PK blood samples will be collected at approximately the same time as other assessments 
wherever possible. 
For all PK blood sample collections, the actual time of avelumab and axitinib dosing, as well 
as actual times of PK collections, will be recorded in the source documents and CRF.  On the 
days of axitinib PK sample collection, patients should be instructed to hold morning axitinib 
dosing until the pre-dose sample has been drawn.  On axitinib PK sampling days, the axitinib 
doses should be taken in the clinic under the supervision of the study site personnel.  


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In addition to PK blood samples collected at the scheduled times, additional PK blood 
samples for axitinib and avelumab should be collected from patients experiencing 
unexpected and/or serious AEs and the date and time of blood sample collection and of the 
last dosing prior to PK collection documented in the CRF. 
All efforts will be made to obtain the PK blood samples at the scheduled nominal time 
relative to dosing.  However, samples obtained within 10% of the nominal time (eg, within 
6 minutes of a 60-minute sample) will be considered protocol compliant, and the exact time 
of the sample collection noted on the CRF.  If a scheduled PK blood sample collection 
cannot be completed for any reason, the missed sample collection may be rescheduled with 
agreement of the investigator and sponsor. 
Patients who discontinue treatment with axitinib or avelumab do not need to continue the 
collection of the PK samples for the discontinued drug.  
PK blood samples will be assayed for avelumab and axitinib using validated analytical 
methods.  Additional details regarding the collection, processing, storage, and shipping of the 
blood samples will be provided in the study manual.  As part of the understanding of the PK 
of the study drug, samples may be used for potential qualitative and/or quantitative 
metabolite analyses and/or evaluation of the bioanalytical methods for avelumab and axitinib.  
The results of such analyses may be included in the clinical report. 
7.3.2. Collection of Axitinib Pharmacokinetic Samples 
At each time point for axitinib, a 3 mL whole blood sample will be collected into an 
appropriately labeled K3 EDTA tube to provide a minimum of 1 mL plasma for axitinib PK 
analysis. 
7.3.3. Collection of Avelumab Pharmacokinetic Samples 
A total of 3.5 mL of whole blood will be collected into a Serum Separator Tube (SST) at the 
designated times to provide serum for avelumab PK analysis. 
7.4. Immunogenicity Assessment 
A total of 3.5 mL of whole blood will be collected into a SST at the designated times to 
provide serum for evaluation of avelumab immunogenicity.  Immunogenicity blood samples 
will be assayed for anti-avelumab antibodies using a validated analytical method.  All of the 
samples that are positive for ADA may also undergo characterization for neutralizing 
antibodies.  Additional details regarding the collection, processing, storage, and shipping of 
the blood samples will be provided in the Study Manual. 
7.5. Translational and Pharmacodynamic Assessments 
A key objective of the biomarker analyses that will be performed in this study is to 
investigate candidate biomarkers that may have predictive value in identifying those patients 
who may benefit from treatment with the combination of avelumab and axitinib.  In addition, 
analyses of blood biomarkers obtained before, during and after treatment will provide an 
opportunity to investigate pharmacodynamic effects.  Samples collected at the End of 


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Treatment/Withdrawal visit enable investigation of potential mechanisms of resistance to the 
drug combination. 
7.5.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies 
Tumor biospecimens from archived tissue samples and metastatic lesions (see Section 6.1.1) 
will be used to analyze candidate DNA, RNA, or protein markers, or relevant signature of 
markers for their ability to identify those patients who are most likely to benefit from 
treatment with the study drugs.  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Tumor biopsies obtained at the End of Treatment will be used to investigate acquired 
mechanisms of resistance.  Only core needle or excisional biopsies, or resection specimen are 
suitable.  Cytologic preparations, such as fine needle aspirate biopsies  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
  
  
 
  
 
 
 
 
 
 
 
 
  
 
 


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Computerized tomography (CT) or magnetic resonance imaging (MRI) will include chest, 
abdomen and pelvis (CAP) at all time points.  The CT and MRI scans should be performed 
with contrast agents unless contraindicated for medical reasons.  Premedication prior contrast 
media administration as per local guidelines is allowed (see Section 5.8.5).  Bone 
scintigraphy/bone scans and brain scans/head CT/MRI are also required at screening.  Bone 
lesion(s) identified at screening by bone scan can be further assessed by CT or MRI as per 
local practice and subsequently re-assessed by CT or MRI as per tumor assessment schedule.  
If bone scintigraphy/bone scan is the preferred assessment method for bone lesion(s) as per 
local practice, re-assessment during study should occur every 12 weeks after randomization.  
Bone scan will also be repeated during study as clinically indicated (eg, patient describes 
new or worsening bone pain, or has increasing alkaline phosphatase level, or other signs and 
symptoms of new/progressing bone metastases) or at the time of complete response (CR) 
confirmation.  Brain must be included in subsequent tumor assessments if a patient has brain 
metastases at screening, otherwise brain will only be evaluated when clinically indicated. 


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The same imaging technique used to characterize each identified and reported lesion at 
screening will be employed in the following tumor assessments. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
screening, at 6 weeks from randomization, then every 6 weeks up to 18 months after 
randomization and every 12 weeks thereafter until documented confirmed disease 
progression by BICR assessment (see Section 5.4.4 for further details on treatment 
continuation after initial evidence of PD) regardless of initiation of subsequent anti-cancer 
therapy.  In addition, radiological tumor assessments will also be conducted whenever 
disease progression is suspected (eg, symptomatic deterioration). 
The schedule of assessments should be fixed according to the calendar, regardless of 
treatment schedule, treatment delays or interruptions.  Imaging assessments are to be 
scheduled using the randomization date as the reference date for all time points and are NOT 
to be scheduled based on the date of the previous imaging time point. 
CR and PR must be confirmed with repeated imaging performed at least 4 weeks after initial 
documentation of response.  If radiologic imaging shows progressive disease (PD), then 
tumor assessment should be repeated after at least 4 weeks to confirm PD.  See Schedule of 
Activities (SOA) and Section 5.4.4 for treatment after initial evidence of disease progression. 
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions unless increase in size has been observed following completion of radiation 
therapy. 
Assessment of response will be made using RECIST v. 1.134 (Appendix 2) 
 
 
 
 
 
 
 
 
 
Blinded Independent Central Review (BICR) will review all radiological images.  All 
radiographic images will be collected and objectively verified by an independent third-party 
core imaging laboratory as described in the Study Manual.  
After review of images by BICR is stopped following the final analyses for PFS performed 
as specified in the protocol (Section 9.6), permanent discontinuation of treatment will be 
performed as per investigator-assessed disease progression.  After review of images by BICR 
is stopped, confirmation of disease progression ≥4 weeks after the PD was first noticed will 
no longer be required.  
Post IA3, during treatment, tumor assessments will be conducted every 6 weeks from 
randomization up to 18 months after randomization and every 12 weeks thereafter until 
disease progression by investigator assessment or initiation of subsequent anti-cancer 
therapy, whichever is earlier (see Section 5.4.4 for further details on treatment continuation 
after initial evidence of PD). 
irRECIST-defined antitumor activity will no longer be collected as per PACL dated 
02 September 2019. 


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All patients’ files and radiologic images must be available for source verification and for 
potential peer review. 
7.8. Expedited Blinded Independent Central Review for Disease Progression 
To mitigate the potential for bias in determining disease progression, expedited BICR review 
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 the Study Manual for process 
details.  Every effort should be made to keep the patient on study treatment until the BICR 
has completed the radiographic image review, unless contraindicated by the investigator.  
The expedited BICR review performed for the investigator-assessed disease progression will 
end in parallel with the end of the BICR review. 
8. ADVERSE EVENT REPORTING 
8.1. Adverse Events 
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections.  
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as an SAE 
requiring immediate notification to Pfizer or its designated representative.  For all AEs, 
sufficient information should be obtained by the investigator to determine the causality of the 
AE.  The investigator is required to assess causality.  Follow-up by the investigator may be 
required until the event or its sequelae resolve or stabilize at a level acceptable to the 
investigator, and Pfizer concurs with that assessment. 
As part of ongoing safety reviews conducted by the sponsor, any non-serious adverse event 
that is determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To 
assist in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.  
8.2. Reporting Period 
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the patient provides informed consent, which is obtained prior to the patient’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 90 calendar days after the last 
administration of the investigational product.  SAEs occurring to patients after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.  


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AEs (serious and nonserious) should be recorded on the Case Report Form (CRF) from the 
time the patient has taken at least 1 dose of investigational product through and including 
90 calendar days after the last administration of study treatment.  
• If a patient begins a new anticancer therapy, the AE reporting period for nonserious 
AEs ends at the time the new treatment is started.  Death must be reported if it occurs 
during the SAE reporting period after the last dose of investigational product, 
irrespective of any intervening treatment. 
8.3. Definition of an Adverse Event 
An AE is any untoward medical occurrence in a clinical investigation patient administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  
• Abnormal test findings; 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Drug abuse; 
• Drug dependency. 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug misuse;  
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy (EDP); 
• Exposure via breastfeeding; 
• Medication error; 
• Occupational exposure; 


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• Worsening of signs and symptoms of the malignancy under study should be reported 
as AEs in the appropriate section of the CRF.  Disease progression assessed by 
measurement of malignant lesions on radiographs or other methods should not be 
reported as AEs. 
8.3.1. Avelumab Adverse Event of Special Interest  
Any AE that is suspected to be a potential irAE is considered an AE of special interest 
(AESI).  Specific guidance for the management of irAEs is provided in Section 5.4.6.9.  
AESIs are reported according to the general AE reporting rules specified in Sections 8.1 and 
Section 8.2. 
8.4. Medication Errors 
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong patient, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately. 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including: 
• Medication errors involving patient exposure to the investigational product; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating patient. 
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AEs are captured on an AE CRF page.  
The guidance on reporting of medication errors also applies to the reporting of overdose. 
For purposes of this study, an overdose of avelumab is defined as an increase ≥5% than the 
planned avelumab dose for that particular administration.  
As for axitinib and sunitinib, an overdose is defined as a dose greater than 10 mg BID and 
50 mg daily, respectively. 
• There is no specific treatment for avelumab, axitinib, or sunitinib overdose.  In the 
event of overdose with any of these study drugs, the patient should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided as 
clinically indicated. 


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For the purpose of this study, an underdose of avelumab, axitinib or sunitinib is defined as 
the administration of <80% of the planned dose for reasons other than treatment-related 
toxicities. 
8.5. Abnormal Test Findings 
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows:  
• Test result is associated with accompanying symptoms; and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or 
• Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
8.6. Serious Adverse Events 
A serious adverse event is any untoward medical occurrence at any dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect; 
• Progression of the malignancy under study (including signs and symptoms of 
progression) should not be reported as an SAE unless the outcome is fatal within the 
safety reporting period.  Hospitalization due to signs and symptoms of disease 
progression should not be reported as an SAE.  If the malignancy has a fatal outcome 
during the study or within the safety reporting period, then the event leading to death 
must be recorded as an AE and as an SAE with CTCAE (version 4.03) Grade 5 (see 
the section on Severity Assessment). 


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Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse. 
8.6.1. Protocol-Specified Serious Adverse Events  
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see section on Serious Adverse Event Reporting Requirements).  
8.6.2. Potential Cases of Drug-Induced Liver Injury  
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin that meet the criteria outlined 
below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events.  
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the patient’s individual baseline values and underlying conditions.  Patients who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values: 
• Patients with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values ≥3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value ≥2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value ≤2 × ULN or not available. 
• For patients with preexisting ALT OR AST OR total bilirubin values above the ULN, 
the following threshold values should be used in the definition mentioned above: 
• For patients with preexisting AST or ALT baseline values above the normal 
range, AST or ALT value ≥2 times the baseline values and ≥3 × ULN, or 
≥8 × ULN (whichever is smaller). 
• Concurrent with: 
• For patients with preexisting values of total bilirubin above the normal range: 
Total bilirubin increased from baseline by an amount of at least 1 × ULN or if the 
value reaches ≥3 × ULN (whichever is smaller). 


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The patient should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.  The possibility of hepatic 
neoplasia (primary or secondary) should be considered.  In addition to repeating 
measurements of AST and ALT, laboratory tests should include albumin, creatine kinase, 
total bilirubin, direct and indirect bilirubin, gamma-glutamyl transferase, prothrombin time 
(PT)/international normalized ratio (INR), and alkaline phosphatase.  A detailed history, 
including relevant information, such as review of ethanol, acetaminophen, recreational drug, 
and supplement consumption, family history, occupational exposure, sexual history, travel 
history, history of contact with a jaundiced person, surgery, blood transfusion, history of liver 
or allergic disease, and work exposure, should be collected.  Further testing for acute 
hepatitis A, B, or C infection and liver imaging (eg, biliary tract) may be warranted.  All 
cases confirmed on repeat testing as meeting the laboratory criteria defined above, with no 
other cause for Liver Function Test (LFT) abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs. 
8.7. Hospitalization 
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance. 
• Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (eg, caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• 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:  


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• Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality); 
• Social admission (eg, patient has no place to sleep); 
• Administrative admission (eg, for yearly physical examination); 
• Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol); 
• Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery); 
• Hospitalization for observation without a medical AE; 
• Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient; 
• Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE. 
8.8. Severity Assessment 
GRADE Clinical Description of Severity 
0 
No Change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances). 
1 
MILD Adverse Event 
2 
MODERATE Adverse Event 
3 
SEVERE Adverse Event 
4 
LIFE-THREATENING consequences; urgent intervention indicated 
5 
DEATH RELATED TO Adverse Event 


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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 
patient's usual function) but would not be classified as serious unless it met one of the criteria 
for SAEs listed above. 
8.9. Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is “unknown but not related to investigational product”, 
this should be clearly documented on study records.  
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable. 
For combination treatments, causality assessment will be performed for each of the 
individual drugs included in the combination.  
8.10. Exposure During Pregnancy 
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant women (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 


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If a study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
patient reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
• Spontaneous abortion includes miscarriage and missed abortion. 
• Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.  
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study patient with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the patient was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
8.11. Occupational Exposure 
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE. 


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An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a patient enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file. 
8.12. Withdrawal Due to Adverse Events (also see Section 6.5 Patient Withdrawal) 
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.  
When a patient withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below. 
8.13. Eliciting Adverse Event Information 
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study patient/parent(s)/legal guardian/legally acceptable representative.  In addition, each 
study patient/parent(s)/legal guardian/legally acceptable representative will be questioned 
about AEs. 
8.14. Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
8.14.1. Serious Adverse Event Reporting Requirements 
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.  In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be 
made immediately, irrespective of the extent of available AE information.  This timeframe 
also applies to additional new information (follow-up) on previously forwarded SAE reports 
as well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study patient initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE. 
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines and/or illnesses must be provided.  In the case of a patient death, a 


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summary of available autopsy escalations must be submitted as soon as possible to Pfizer or 
its designated representative.  
8.14.2. Non-Serious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information. 
Japan only: After the combination of avelumab with axitinib is approved for the treatment of 
aRCC by the Japanese Ministry of Health, Labour and Welfare (MHLW), investigators may 
be requested by Pfizer to obtain specific additional follow-up information if a reported 
treatment-related non-serious AE is found to be unexpected according to the Japanese 
Package Insert.  If this occurs, the investigator will be required to pursue and provide the 
additional information to Pfizer; as this information may be more detailed than the 
information captured on the adverse event case report form.  In general, the information will 
include enough detail regarding the description of the adverse event to allow for a complete 
medical assessment of the case and independent determination of possible causality.  
Information regarding other possible causes of the adverse event, such as concomitant 
medications and illnesses, must also be provided. 
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities 
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations. 
9. DATA ANALYSIS/STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment. 
9.1. Sample Size Determination 
The primary objective of this study is to demonstrate that avelumab in combination with 
axitinib is superior to sunitinib in prolonging PFS or OS in previously untreated PD-L1+ 
patients with aRCC.  
Secondary objectives of this study are to demonstrate that avelumab in combination with 
axitinib is superior to sunitinib in prolonging PFS and in prolonging OS in previously 
untreated patients with aRCC and that are unselected for PD-L1 expression (referred to as 
‘all comers’ in what follows). 


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The following statistical hypotheses will be tested to address the primary objective: 
H01: HRPFS+ ≥1 vs. H11: HRPFS+ <1  
H02: HROS+ ≥1 vs. H12: HROS+ <1 
where HRPFS+ and HROS+ are the hazard ratios (Arm A vs. Arm B) of PFS and OS, 
respectively, in the PD-L1+ population. 
In addition the following statistical hypotheses will be tested to address the secondary 
objectives: 
 
H03: HRPFS ≥1 vs. H13: HRPFS <1 
H04: HROS ≥1 vs. H14: HROS <1 
where HRPFS and HROS are the hazard ratios (Arm A vs. Arm B) of PFS and OS, respectively, 
in the ‘all comers’ population.Overall type I-error will be maintained at or below 1-sided 
0.025 by allocating α=0.004 to the PFS comparison in PD-L1+ patients and by allocating 
α=0.021 to the OS comparison in the PD-L1+ population.  A gatekeeping procedure will be 
used to allow further testing of PFS and OS in the PD-L1 ‘all comers’ population as 
described in Figure 2.  The significance levels for each test will also take into account the 
group sequential nature of the design (see Section 9.6).  
Figure 2. Testing Strategy 
 
For the primary PFS comparison, 336 PFS events by BICR assessment in the PD-L1+ 
population will provide 90% power to detect a HR of 0.65 using a 1-sided log rank test at a 
significance level of 0.004, and a 2-look group sequential design with Lan-DeMets 
(O’Brien-Fleming) α-spending function to determine the efficacy boundary and a Gamma 
Family (-15) β-spending function to determine the non-binding futility boundary. 


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For the primary OS comparison, 368 OS events in the PD-L1+ population will provide 
90% power to detect a hazard ratio of 0.70 using a 1-sided log-rank test at a significance 
level of 0.021, and a 4-look group-sequential design with Lan-DeMets (O’Brien-Fleming) 
α-spending function to determine the efficacy boundary and a Gamma Family (-3) 
β-spending function to determine the non-binding futility boundary. 
The study will randomize a total of approximately 830 patients, including a minimum 
580 PD-L1 positive patients, using a 1:1 randomization, stratified by ECOG PS (0 versus 1) 
and region (United States vs Canada/Western Europe vs the rest of the world).  
1. The sample size for this study is determined based on the following: the median PFS 
for patients receiving sunitinib is 11 months27 and the median PFS for patients 
receiving avelumab in combination with axitinib is 16.9 months for PD-L1 positive 
patients and 15.7 months for patients unselected for PD-L1 expression; this 
corresponds to a hazard ratio (HR) of 0.65 and 0.7, respectively under the exponential 
model assumption.  
2. The median OS for patients receiving sunitinib is 26.4 months27 and the median OS 
for patients receiving avelumab in combination with axitinib is 37.7 months for 
PD-L1 positive patients and 35.2 months for patients unselected for PD-L1 
expression; this corresponds to a hazard ratio (HR) of 0.7 and 0.75, respectively under 
the exponential model assumption; 
3. PFS drop-out rate of approximately 15% and OS drop-out rate of approximately 5%; 
4. 70% of the randomized patients are PD-L1 positive; 
5. non-uniform patient accrual accomplished over a 21 month period. 
The sample size of approximately 830 patients will also allow an assessment of PFS and OS 
in the ‘all comers’ population.  
If H01 is rejected then PFS in the ‘all comers’ population can be tested and 490 PFS event by 
BICR assessment will provide 90% power to detect a HR of 0.70 using a 1-sided log rank 
test at a significance level of 0.004, and a 2-look group sequential design with Lan-DeMets 
(O’Brien-Fleming) α-spending function to determine the efficacy boundary.  
If either H02 or H03 are rejected, then OS in the ‘all comers’ population can be tested at the 
sum of the significance levels associated with the significant H02 and H03 tests (see Figure 2).  
With 534 OS events, the power is 91% (if both H02 and H03 are rejected), 90% (if H02 is 
rejected and H03 is not rejected) or 74% (if H02 is not rejected and H03 is rejected) to detect a 
HR of 0.75 using a 1-sided log rank test at a significance level of 0.025, 0.021 or 0.004, 
respectively, and a 4-look group sequential design with Lan-DeMets (O’Brien-Fleming) 
α-spending function to determine the efficacy boundary.  


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The data cutoff for the primary PFS analysis will occur after the target number of PFS events 
by BICR assessment in the PD-L1+ population has been reached and the last patient 
randomized in the study has been followed for at least 12 months after randomization.  
The data cutoff for the primary OS analysis will occur after the target number of deaths in the 
PD-L1+ population has been reached. 
The study will be considered positive if the stratified log-rank test for either PFS or OS in the 
PD-L1+ population is significant at the respective α levels.  
9.2. Analysis Populations 
For some endpoints, analyses will also be performed on the subset of PD-L1+ patients.  The 
associated analyses sets will be a subset of the analysis sets defined below restricted to the 
PD-L1+ population. 
9.2.1. Full Analysis Set 
The full analysis set will include all patients who are randomized.  Patients will be classified 
according to the treatment and stratum assigned at randomization.  The full analysis set will 
be the primary population for evaluating all efficacy endpoints and patient characteristics. 
9.2.2. 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 1 dose of study treatment (avelumab in combination with axitinib or 
sunitinib) and do not have major protocol deviations expected to impact the primary 
objective of the study.  Major protocol deviations will be pre-specified in the SAP.  The 
Per-Protocol Analysis Set will be used for sensitivity analyses for the primary efficacy 
endpoints. 
9.2.3. Safety Analysis Set 
The safety analysis set will include all patients who receive at least 1 dose of study drug 
(avelumab, axitinib or sunitinib).  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. 
9.2.4. Pharmacokinetic Analysis Set 
The PK concentration analysis set will include all treated patients who have at least 
1 concentration above the below limit of quantitation (BLQ) of either of the study drugs in 
Arm A only.  
The PK parameter analysis set will include all treated patients who have at least 1 of the PK 
parameters of interest of either of the study drugs in Arm A only. 


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9.2.5. Biomarker Analysis Set 
The biomarker analysis set will include all patients who have received at least one dose of the 
study treatment and who have at least one baseline biomarker assessment. 
9.2.6. Immunogenicity Analysis Set 
The immunogenicity analysis set will include all treated patients in the avelumab in 
combination with axitinib arm only, who have at least 1 ADA sample collected. 
9.3. Efficacy Analysis 
All efficacy analyses will be performed on the Full Analysis Set unless otherwise specified.  
All analyses will be performed by using SAS Version 9.1.3 or higher.  
All primary and secondary endpoints based on radiological assessments of tumor burden 
(ie, PFS, OR, DR, DC, TTR) will be derived using the local radiologist’s/investigator’s 
assessment.  Radiographic images and clinical information collected on-study will also be 
reviewed by a BICR to verify investigator reported tumor assessments; this information will 
be used for the primary analysis. 
The primary analyses will be repeated on the per-protocol analysis set as a sensitivity 
analysis.  Further details and other sensitivity analyses will be described in the SAP. 
9.3.1. Analysis of Primary Endpoints 
PFS by BICR assessment in the PD-L1+ population. 
In what follows, progressive disease (PD) is based on BICR assessment.  
PFS is defined as the time from randomization to the date of the first documentation of 
objective progression of disease (PD) or death due to any cause, whichever occurs first. 
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start new anti-cancer treatment prior to 
an event, or for patients with an event after two or more missing tumor assessments.  Patients 
who do not have a baseline tumor assessment or who do not have any post-baseline tumor 
assessments will be censored on the 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 an event. 
A stratified log-rank test (one-sided) stratified by randomization stratification factors will be 
used at the interim and/or final analyses at the significance level associated with the testing 
strategy outlined in Section 9.1 for the testing of H01.  
PFS time associated with each treatment arm will be summarized using the Kaplan-Meier 
method and displayed graphically where appropriate.  Confidence intervals (CIs) for the 25th, 
50th and 75th percentiles will be reported.  The Cox proportional hazards model will be fitted 
to compute the treatment hazard ratio and the corresponding CI.  In order to account for the 


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group sequential design in this study, the repeated CI (RCI) method,67 will be used to 
construct the 2-sided RCIs for the hazard ratio at the interim and the final analyses of PFS.  
In addition, the unadjusted 95% CIs for the hazard ratio will also be reported at the interim 
and the final analyses for PFS. 
OS in the PD-L1+ population 
OS is defined as the time from date of randomization to date of death due to any cause.  
Patients last known to be alive will be censored at date of last contact.  
A stratified log-rank test (one-sided) stratified by randomization stratification factors will be 
used at the interim and/or final analyses at the significance level associated with the testing 
strategy outlined in Section 9.1 for the testing of H02.  OS time associated with each 
treatment arm will be summarized using the Kaplan-Meier method and displayed graphically 
where appropriate.  CIs for the 25th, 50th and 75th percentiles will be reported.  The Cox 
proportional hazards model will be fitted to compute the treatment hazard ratio and the 
corresponding CI.  In order to account for the group sequential design in this study, the RCI 
method,67 will be used to construct the 2-sided RCIs for the hazard ratio at the interim and 
the final analyses of OS.  In addition, the unadjusted 95% CIs for the hazard ratio will also be 
reported at the interim and the final analyses for OS. 
9.3.2. Analysis of Secondary Endpoints 
OS in the ‘all comers’ population 
The methodology described in Section 9.3.1 for OS in the PD-L1+ population will be 
followed for the assessment of OS in the ‘all comers’ population.  A stratified log-rank test 
(one-sided) stratified by randomization stratification factors will be used at the interim and/or 
final analyses at the significance level associated with the testing strategy outlined in 
Section 9.1 for the testing of H04.  
PFS by BICR assessment in the ‘all comers’ population 
The methodology described in Section 9.3.1 for PFS by BICR assessment in the PD-L1+ 
population will be followed for PFS by BICR assessment in the ‘all comers’ population.  A 
stratified log-rank test (one-sided) stratified by randomization stratification factors will be 
used at the interim and/or final analyses at the significance level associated with the testing 
strategy outlined in Section 9.1 for the testing of H03.  
The analyses of PFS outlined based on BICR assessment will be repeated based on the 
Investigator’s assessment.  No adjustement for multiplicity will be performed for these 
secondary analyses based on Investigator assessment. 
The analyses of other tumor-related endpoints will be based on the investigator’s assessment, 
as well as on the review of the BICR.  


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Objective Response (OR) 
Objective response is defined as a complete response (CR) or partial response (PR) according 
to (RECIST v.1.1; Appendix 2) recorded from randomization until disease progression 
assessed by BICR or death due to any cause.  Both CR and PR must be confirmed by repeat 
assessments performed no less than 4 weeks after the criteria for response are first met.  A 
patient will be considered to have achieved an OR if the patient has a sustained complete 
response (CR) or partial response (PR) according to RECIST v.1.1 definitions.  Otherwise, 
the patient will be considered as a non-responder in the OR rate 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 OR rate analysis.  
The OR rate (ORR) on each randomized treatment arm will be estimated by dividing the 
number of patients with objective response (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.  
In addition, the best overall response for each patient will be summarized by treatment arm. 
Disease Control (DC) 
Disease control (DC) is defined as complete response (CR), partial response (PR), or stable 
disease (SD) according to the RECIST v.1.1 (Appendix 2) recorded from randomization until 
disease progression assessed by BICR or death due to any cause.  DC at 24 weeks is defined 
as CR, PR or SD ≥24 weeks after randomization and prior to disease progression assessed by 
BICR or death due to any cause. 
The DC rate (DCR) and DCR at 24 weeks on each randomized treatment arm will be 
estimated by dividing the number of patients with CR, PR, or SD overall or ≥24 weeks by the 
number of patients randomized to the treatment arm.  The corresponding exact 2-sided 
95% CIs for DCR and DCR at 24 weeks will be provided by treatment arm.  
Time to Tumor Response (TTR) 
Time to tumor response (TTR) is defined, for patients with an objective response per 
RECIST v1.1 (Appendix 2), as the time from randomization to first documentation of 
objective tumor response (CR or PR).  
TTR will be summarized by treatment arm using descriptive statistics (n, mean, median, 
standard deviation, minimum, and maximum). 
Duration of Response (DR) 
Duration of response (DR) is defined, for patients with an objective response per 
RECIST v. 1.1 (Appendix 2), as the time from the first documentation of objective tumor 
response (CR or PR) to the first documentation of objective tumor progression assessed by 


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BICR or death due to any cause, whichever occurs first.  Censoring rules for DR will follow 
those described above for PFS.  
DR will be summarized by treatment arm using Kaplan-Meier method and displayed 
graphically, where appropriate.  The median DR and 95% CI for the median will be provided 
for each treatment arm. 
PFS on next-line therapy (PFS2) 
PFS2 is defined as the time from randomization to discontinuation of next-line treatment, 
second objective disease progression, or death from any cause, whichever occurs first.  PFS2 
will be summarized by treatment arm using Kaplan-Meier methodology and displayed 
graphically, where appropriate.  The median PFS2 and 95% CI for the median will be 
provided for each treatment arm. 
Patient-Reported Outcomes (PRO) 
The FKSI and EuroQol 5-Dimension (EQ-5D) will be scored according to their respective 
validation papers and user’s guides. 
For the FKSI-19, in addition to assessing median change over time between the two 
treatment groups, a time to deterioration analysis is planned, for the FKSI-DRS.  A 3 point 
change (within group) and a 2 point difference (between groups) has been established as 
clinically meaningful for this 9-item subscale.  Time to 3 point deterioration of FKSI-DRS 
will be analyzed by a log-rank test stratified by randomization stratification factors.  The time 
to deterioration associated with each treatment arm will be summarized using the 
Kaplan-Meier method and displayed graphically where appropriate.  Confidence intervals 
(CIs) for the 25th, 50th and 75th percentiles will be reported.  The Cox proportional hazards 
model will be fitted to compute the treatment hazard ratios and the corresponding 95% CI.  
The EuroQoL EQ-5D consists of 2 parts, the EQ-5D index (or simply EQ-5D) and EQ-VAS.  
The EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities, pain or 
discomfort, and anxiety or depression).  A unique EQ-5D health state is defined by 
combining one level from each of the 5 dimensions and is converted to a single summary 
index or health utility value.  The EQ-VAS is a visual analog scale where the patient 
indicates how good or bad his health is today by marking an appropriate point on a line 
between 0 to 100, which correspond to the worst and best imaginable health states. 
Missing values in the PRO instruments FKSI and EQ-5D will be handled following the 
guidance from their respective User Manuals.  For the FKSI multi-item scales, the score may 
be imputed as the mean of the non-missing questions if at least half the questions in that scale 
are answered.  For EQ-5D, the entire score for that cycle is deemed missing if the answer to 
any one of the 5 dimensions is missing.  EQ-5D will be analyzed by using repeated measures 
model.  


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Pharmacokinetic Analysis of Avelumab and Axitinib (Arm A Only) 
Standard plasma PK parameters for axitinib will be estimated using non-compartmental 
analysis.  For axitinib, standard PK parameters will include Cmax and Ctrough.  Descriptive 
statistics for the PK parameters for axitinib will be provided by dose, cycle and day of 
assessment in tabular form. 
Axitinib Ctrough and Cmax plasma concentrations will be summarized descriptively (n, mean, 
SD, CV, median, minimum, maximum, geometric mean, its associated CV, and 
95% confidence interval) by dose, cycle, and day.  The trough concentrations for axitinib will 
be plotted for each dose using a box-whisker plot by cycle and day in order to assess the 
attainment of steady state.  
Avelumab Ctrough plasma concentrations will be summarized descriptively (n, mean, SD, CV, 
median, minimum, maximum, geometric mean, its associated CV, and 95% confidence 
interval) by dose, cycle, and day.  The trough concentrations for avelumab will be plotted for 
each dose using a box-whisker plot by cycle and day in order to assess the attainment of 
steady state. 
The central laboratory, analytical laboratory, and Pfizer clinical assay group colleagues will 
be unblinded; avelumab and axitinib PK samples collected from Arm A (investigational arm) 
will be sent to the analytical lab for analysis.  If the need arises for an early analysis of the 
PK data (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. 
Immunogenicity Assessment (Arm A Only) 
For the immunogenicity data, the percentage of patients with positive ADA and neutralizing 
antibodies each will be reported.  For patients with positive ADA, the magnitude (titer), time 
of onset, and duration of ADA response will also be described, if data permit.  
Because the observed incidence of ADA is highly dependent on multiple factors including 
the assays used for ADA detection, timing of sample collection and immune status of the 
patients, the incidence of ADA observed in the planned study may differ from the incidence 
reported in historical clinical trials.  
Population Pharmacokinetic and Exposure Response Analysis 
Avelumab disposition will be evaluated using a population PK model for the drug and the 
relationship between exposure and efficacy and safety endpoints will be explored, as 
necessary, based on emerging efficacy and safety data.  The results of these modeling 
analyses may be reported separately from the clinical study report.  


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Analysis of Biomarker Endpoints  
Biomarker status (ie, positive or negative) may be determined by a predictive biomarker test 
with an established scoring algorithm defining positive and negative that is developed by the 
Sponsor.  Analysis of primary and secondary efficacy endpoints in sub-groups defined by 
biomarker status will be performed and reported as described above.  Comparisons will be 
made between biomarker sub-groups (positive and negative) within treatment arms and 
between treatment arms within biomarker sub-groups. 
9.4. Analysis of Other Endpoints 
Descriptive statistics will be used to summarize all patient characteristics, treatment 
administration/compliance, safety parameters, and biomarkers.  Data will also be displayed 
graphically, where appropriate. 
9.4.1. Statistical Analysis of Biomarker Endpoints 
Biomarkers will be assessed separately for whole blood, serum, plasma, archival tumor 
tissue, and de novo tumor biopsies.  In each case, summaries of baseline levels, changes from 
baseline (where appropriate), gene alteration or biomarker signature status, will be reported.  
For continuous variables summary statistics may include the mean, ratio to baseline, standard 
deviation, median, 25th and 75th quartile, %CV and minimum/maximum levels of biomarker 
measures; for categorical variables, summary may include number and percentage, odds ratio 
as appropriate. 
Data from biomarker assays will be analyzed using graphical methods and descriptive 
statistics such as linear regression, t-test, and analysis of variance (ANOVA).  The statistical 
approach may examine correlations of biomarker results with pharmacokinetic parameters 
and measures of anti-tumor efficacy. 
 
 
 
 
 
 
 
 
 
 
 
 f 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
9.5. Safety Analysis 
The Safety Analysis Set will be the primary population for safety evaluation.  Summaries of 
AEs and other safety parameters will be provided, by treatment arm, as appropriate.  


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Adverse Events 
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  The severity of the toxicities will be graded according to 
the NCI CTCAE v4.03 whenever possible (http://ctep.info.nih.gov/reporting/ctc.html).  The 
frequency of patients experiencing treatment emergent adverse events corresponding to body 
systems and MedDRA preferred term will be reported.  Adverse events will be graded by 
worst NCI CTCAE v4.03 Grade.  Adverse events 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 or higher, 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. 
Time to treatment discontinuation/failure due to toxicity  
Time to treatment discontinuation/failure due to toxicity is defined as the time from first dose 
of study treatment to discontinuation of study treatment due to an adverse event or death due 
to study treatment toxicity.  Time to treatment discontinuation/failure due to toxicity will be 
summarized by treatment arm using Kaplan-Meier methodology and displayed graphically, 
where appropriate.  The median time to treatment discontinuation/failure due to toxicity and 
95% CI for the median will be provided for each treatment arm. 
Treatment discontinuation due to toxicity 
Treatment discontinuation due to toxicity is defined as the discontinuation of study treatment 
due to an adverse event or death due to study treatment toxicity.  The rate of treatment 
discontinuation due to toxicity in each treatment arm will be estimated by dividing the 
number of patients who meet the above criteria by the number of patients in the safety set.  
The corresponding exact 2-sided 95% CIs will be provided for each treatment arm. 
Laboratory Abnormalities 
The laboratory 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.  


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MUGA or ECHO 
Reports and assessments of cardiac function will be recorded.  MUGA or ECHO scan results 
will be summarized using NCI CTCAE version 4.03 by treatment group. 
Electrocardiograms  
ECG measurements (an average of the triplicate measurements) will be used for the 
statistical analysis and all data presentations.  Any data obtained from ECGs repeated for 
safety reasons after the nominal time-points will not be averaged along with the preceding 
triplicates.  Interval measurements from repeated ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points. 
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, QTc.  
Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval and changes from baseline in corrected 
QT after treatment.  Categorical analysis will be conducted for the maximum change from 
baseline in corrected QT and the maximum post-baseline corrected QT interval.  
Shift tables will be provided for baseline vs worst on treatment corrected QT.  Shift tables 
will also be provided for ECG abnormality at baseline vs. on treatment.  Patients 
experiencing clinically-relevant morphological ECG changes will be summarized (including 
frequency and percentage). 
9.6. Interim Analysis 
The interim and the primary analyses for each endpoint will be performed based on the Full 
Analysis Set after all patients have been randomized in the study and the target number of 
events has occurred as described below.  A maximum of 4 distinct analyses cutoffs are 
planned in the study: 
• at the time when approximately 235 PFS events (70% of the expected 336 events) by 
BICR assessment have occurred in the PD-L1+ population (IA for PFS and IA1 for 
OS);   
• at the time when 336 PFS events by BICR assessment have occurred in the PD-L1+ 
population (primary analysis for PFS and IA2 for OS);   
• 15 months after the primary analysis for PFS (IA3 for OS); 
• at the time when 368 deaths have occurred in the PD-L1+ population (primary 
analysis for OS). 


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Table 9 displays the maximum number of analyses expected for each of the primary 
endpoints and the associated efficacy and futility boundaries.  The futility boundaries are 
non-binding but the study may be stopped for futility if at the time of the first interim 
analysis, both PFS and OS in the PD-L1+ population cross the corresponding futility 
boundaries.  If the efficacy boundary is crossed, for either of the primary endpoints, at the 
time of an interim analysis or at the time of the primary analysis then the primary objective 
of the study will have been demonstrated. 
Table 9. 
PFS and OS in the PD-L1+ population – Efficacy and Futility Boundaries 
Endpoint 
PFS in PD-L1+ 
OS in PD-L1 + 
Analysis 
IA1 
PA 
IA1 
IA2 
IA3 
PA 
Analysis cutoff 
trigger 
235 PFS 
events in 
PD-L1+ 
336 PFS 
events in 
PD-L1+ 
235 PFS 
events in 
PD-L1+ 
336 PFS 
events in 
PD-L1+ 
15 months 
after IA2 
368 deaths 
in PD-L1+ 
Number of events 
(Information 
fraction) 
235 (70%) 
336 (100%) 
125 (34%) 
195 (53%) 
294 (80%) 
368 
(100%) 
p-value (z-value) 
for efficacy 
<0.0006 
(<-3.2493) 
<0.0038 
(<-2.6682) 
<0.00007 
(<-3.7913) 
<0.0015 
(<-2.9686) 
<0.0093 
(<-2.3524) 
<0.0180 
(<-2.0975)   
p-value (z-value) 
for futility a 
>0.4059 
(>-0.2380) 
NA 
>0.6411 
(>0.3614)  
>0.3672 
(>-0.3394) 
>0.0879 
(>-1.3537) 
NA 
a Non-binding.  
IA1 = interim analysis 1, IA2 = interim analysis 2, IA3 = interim analysis 3, PA = primary analysis 
The observed number of events at the IAs may not match the planned number of events.  The efficacy and 
futility boundaries will be updated based on the actual number of observed events using the pre-specified 
α-and β-spending functions. 
 
Table 10 displays the analyses triggers for PFS and OS in the ‘all comers’ population, as well 
as the associated efficacy boundaries.  As described in Section 9.1, the significance level for 
the analyses of these endpoints is determined by the closed testing procedure.  


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Table 10. PFS and OS in the ‘All Comers’ Population – Efficacy Boundaries 
Endpoint 
PFS in ‘All Comers’ 
OS in ‘All Comers’ 
Analysis 
IA1 
PA 
IA1 
IA2 
IA3 
PA 
Analysis cutoff 
trigger 
235 PFS 
events in 
PD-L1+ 
336 PFS 
events in 
PD-L1+ 
235 PFS 
events in 
PD-L1+ 
336 PFS 
events in 
PD-L1+ 
15 months 
after IA2 
368 deaths 
in PD-L1+ 
Number of 
events a 
(Information 
fraction)  
343 (70%) 
490 (100%) 
182 (34%) 
283 (53%) 
427 (80%) 
534 
(100%) 
p-value 
(z-value) for 
efficacy b 
<0.0006 
(<-3.2478) 
<0.0038 
(<-2.6683) 
<0.00012 
(<-3.6656) 
<0.0020 
(<-2.8726) 
<0.0115 
(<-2.2727)  
<0.0212 
(<-2.0286)  
a Number of events expected under H13 for PFS (assuming a HR of 0.7) and H14 for OS (assuming a HR of 
0.75).  
b The p-values and z-values noted for OS are those associated with the scenario when both H02 and H03 are 
rejected. 
IA1 = interim analysis 1, IA2 = interim analysis 2, IA3 = interim analysis 3, PA = primary analysis 
The observed number of events at the IAs may not match the planned number of events.  The 
efficacy and futility boundaries will be updated based on the actual number of observed events 
using the pre-specified α-spending functions. 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  The efficacy and futility boundaries will be 
updated based on the actual number of observed events using the pre-specified α-and 
β-spending functions.  Therefore, the observed Z-test statistic at the interim analysis will be 
compared with the updated efficacy and futility boundaries.  If the study continues to final 
analysis, the p-value that will be used to declare statistical significance at the final analysis 
for each endpoint will be based on the actual number of events documented at the cut-off 
date for the final analysis and the α already spent at the interim analysis.  Further details will 
be provided in the Statistical Analysis Plan. 
If the results of the interim analysis indicate serious safety concerns, the sponsor, in 
conjunction with an external Data Monitoring Committee (E-DMC), will communicate with 
the Health Authorities regarding stopping the clinical trial. 
9.7. Data Monitoring Committee 
This study will use an external data monitoring committee (E-DMC). 


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The E-DMC will be responsible for ongoing monitoring of the safety and efficacy of patients 
in the study according to the charter.  The recommendations made by the E-DMC to alter the 
conduct of the study will be forwarded to Pfizer for final decision.  Pfizer will forward such 
decisions, which may include summaries of aggregate analyses of endpoint events and of 
safety data that are not endpoints, to regulatory authorities, as appropriate.  
The E-DMC will perform a preliminary review of safety data, without holding of 
recruitment, for the first 30 patients randomized in a 1:1 ratio and treated in the study, who 
have been followed for at least 6 weeks each after the first dose.  The E-DMC assessment 
will be conducted based on the available safety data of the first 30 patients and on all the 
available safety data of other patients treated up to the data cut-off.  Subsequently, the 
E-DMC will convene to monitor safety in the study approximately every 6 months after the 
first meeting.  
Recommendations for study conduct (continue as planned, continue with modifications, 
terminate) including whether the study has met the pre-specified minimal futility or efficacy 
criteria will be conveyed to the sponsor by the E-DMC chair. 
9.8. Cardiac Events Adjudication Committee 
An independent cardiac events adjudication committee will be established to review selected 
cardiac adverse events reported in the study in order to confirm the diagnosis and relationship 
to study treatment, as described in the relevant charter.  AEs that will be selected and any 
other relevant data for this review will be pre-specified in the cardiac events adjudication 
charter and endorsed by the committee.  
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 is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion. 
During study conduct and/or after study completion, the study site may be subject to review 
by the institutional review board (IRB)/ethics committee (EC), and/or to quality assurance 
audits performed by Pfizer, or companies working with or on behalf of Pfizer, and/or to 
inspection by appropriate regulatory authorities. 
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings. 


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It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
Japan only: After the combination of avelumab with axitinib is approved for treatment of 
aRCC by MHLW, this study will be conducted according to Good Post Marketing 
Surveillance Practices (GPSP) in addition to GCP.  
These changes are regulatory requirements only applied to Japan.  As per Japan regulation, 
once the investigational drug is approved by MHLW in Japan, the clinical trial should be 
conducted as a post-marketing clinical study.  Consequently, upon approval of the 
combination of avelumab with axitinib in Japan, references to Study B9991003 using the 
terms “clinical study” or “clinical trial” mentioned in the protocol will be interpreted as 
“post-marketing clinical study”. 
11. DATA HANDLING AND RECORD KEEPING 
11.1. Case Report Forms/Electronic Data Record 
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study. 
A CRF is required and should be completed for each included patient.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. 
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true.  Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry.  
In most cases, the source documents are the hospital's or the physician's patient chart.  In 
these cases data collected on the CRFs must match the data in those charts.  
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document. 


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11.2. Record Retention 
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer. 
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer.  
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.   
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met. 
12. ETHICS 
12.1. Institutional Review Board/Ethics Committee  
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, from the IRB/EC (in addition to the national completent 
authority).  Changes introduced to a clinical trial related documents, if classified as 
substantial, must also be approved by the IRB/EC (in addition to the national competent 
authority) before it can be implemented.  All correspondence with the IRB/EC should be 
retained in the investigator file.  Copies of IRB/EC approvals should be forwarded to Pfizer. 
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.  
12.2. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2013).  The Declaration of Helsinki 2013 will be complied with by the 
following provision: “ At the end of the study, Arm A patients who are still deriving clinical 
benefit from study treatment will be provided with an option for continued study treatment 
(eg, rollover study)” as described in Sections 3.1.1 and Section 6.4. 


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In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws. 
12.3. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law.  
When study data are complied for transfer to Pfizer and other authorized parties, patient 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study patients.  The study 
site will maintain a confidential list of patients who participated in the study, linking each 
patient’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of patients’ personal data consistent 
with applicable privacy laws. 
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws. 
The informed consent document(s) used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.   
The investigator must ensure that each study patient, or his or her legally acceptable 
representative, as allowed by local guideline/practice, is fully informed about the nature and 
objectives of the study and possible risks associated with participation.  
Whenever consent is obtained from patient’s parent(s), legal guardian or legally acceptable 
representative, the patient’s assent (affirmative agreement) must subsequently be obtained 
when the patient has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a patient’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the patient’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study patient does not provide 
his or her own consent, the source documents must record why the patient did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the patient’s legally acceptable representative, the consent 
signer’s relationship to the study patient (eg, parent, spouse), and that the patient’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each patient or the patient's legally acceptable representative before any 
study-specific activity is performed.  The investigator will retain the original of each patient's 
signed consent document. 


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12.4. Patient Recruitment 
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures. 
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study patients before such materials are used. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study patients against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of. 
13. DEFINITION OF END OF TRIAL 
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union (EU) is defined as the time at which it 
is deemed that a sufficient number of patients have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application (CTA) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State. 
13.2. End of Trial in All Other Participating Countries 
End of Trial in all other participating countries is defined as Last Subject Last Visit. 
14. SPONSOR DISCONTINUATION CRITERIA 
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of 
avelumab in combination with axitinib at any time. 
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating patients and 
the hospital pharmacy (if applicable) within 1 month.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible. 


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15. PUBLICATION OF STUDY RESULTS 
15.1. Communication of Results by Pfizer 
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 
www.clinicaltrials.gov 
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.  Primary completion date is defined as the date that the final patient was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome, whether the clinical study concluded according to the prespecified protocol 
or was terminated. 
EudraCT 
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations. 
www.pfizer.com 
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov. 
15.2. Publications by Investigators 
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed. 


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The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days. 
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results. 
If the study is part of a multicentre study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section. 
For all publications relating to the study, Institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA. 
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study patients, and the CSA will control as to all other 
issues. 


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55. Hodi FS, Bulter M, Oble DA, et al. Immnologic and clinical effects of antibody 
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tumor response to immunotherapy: immune-related response criteria using 
unidimensional measurements. Clin Cancer Res. 2013 Jul 15;19(14):3936-43. 
58. 2006.  Update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline.  J Clin Oncol 2006, 1:3187-3205. 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
63. Geisler BP, Raad RA, Esaian D, et al. Apical ballooning and cardiomyopathy in a 
melanoma patient treated with ipilimumab: a case of takotsubo-like syndrome. Journal 
for ImmunoTherapy of Cancer 2015, 3:4. 
64. Yervoy® Summary of Product Characteristics 
(http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Informati
on/human/002213/WC500109299.pdf). 
65. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in 
advanced renal-cellcarcinoma. NEJM 2015; 373:1803-13. 
66. McDermott D, Atkins M, Motzer RB et al. A phase II study of atezolizumab with or 
without bevacizumab vs sunitinib in untreated metastatic renal cell carcinoma patients. J 
Clin Oncol 2017; 35: suppl 6S, abstract 431. 
67. Jennison C, Turnbull BW. In: Group Sequential Methods with Applications to Clinical 
Trials. Chapman & Hall/CRC, Boca Raton, 2000. 


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


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Appendix 2.  Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 
Guidelines 
Adapted from E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1).  European Journal of Cancer 45 (2009) 228–247.34  
CATEGORIZING LESIONS AT BASELINE 
Measurable Lesions  
• Lesions that can be accurately measured in at least one dimension. 
• Lesions with longest diameter twice the slice thickness and at least 10 mm or greater 
when assessed by CT or MRI (slice thickness 5-8 mm). 
• Lesions with longest diameter at least 20 mm when assessed by Chest X-ray.  
• Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.  
• Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT. 
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest 
axis for all other measurable lesions.  
Non-measurable disease  
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques. 
• Bone disease: Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of 
measurability at baseline.  
• Previous local treatment: A previously irradiated lesion (or lesion subjected to other 
local treatment) is non-measurable unless it has progressed since completion of 
treatment. 


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Normal sites 
• Cystic lesions: Simple cysts should not be considered as malignant lesions and should 
not be recorded either as target or non-target disease.  Cystic lesions thought to 
represent cystic metastases can be measurable lesions, if they meet the specific 
definition above.  If non-cystic lesions are also present, these are preferred as target 
lesions. 
• Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease. 
RECORDING TUMOR ASSESSMENTS  
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to randomization and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.  
Target lesions 
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study.  
• If two target lesions coalesce the measurement of the coalesced mass is used.  If a 
large target lesion splits, the sum of the parts is used. 
• Measurements for target lesions that become small should continue to be recorded.  If 
the lesion is considered to have disappeared, 0 mm should be recorded; otherwise if a 
lesion is determined to be present but too small to measure, the lesion status will 
indicate “too small to measure and judged to be less than 10 mm” and 5 mm will be 
used in the calculation of the sum of the diameters. 
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded. 
Non-target disease  
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE (ie, Not Evaluable), 
PRESENT/NOT INCREASED, INCREASED.  Multiple non-target lesions in one organ may 


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be recorded as a single item on the case report form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION  
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist and the Sponsor to determine if substitution is 
possible.  If not, subsequent objective statuses are indeterminate.  
Target disease 
• Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed. 
• Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  All target lesions must be assessed.  
• Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, (smallest sum of diameters consider baseline and all 
assessments prior to the time point under evaluation), but enough that a previously 
documented 30% decrease no longer holds.  
• Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm.  
• Not Evaluable Progression has not been documented, and  
• One or more target measurable lesions have not been assessed or 
• Assessment methods used were inconsistent with those used at baseline or 
• One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure) or 
• One or more target lesions were excised or irradiated and have not reappeared or 
increased.  
Non-target disease 
• CR: Disappearance of all non-target lesions and normalization of tumor marker levels 
(if being followed).  All lymph nodes must be ‘normal’ in size (<10 mm short axis). 


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• Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits (if being followed).  
• PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare.  
• Not Evaluable Progression has not been determined and  
• one or more non-target sites were not assessed or  
• assessment methods used were inconsistent with those used at baseline or 
• one or more non-target lesions cannot be assessed (eg, poorly visible or unclear 
images) or 
• one or more non-target lesions were excised or irradiated and have not reappeared 
or increased.  
New Lesions  
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion. 
Supplemental Investigations 
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR. 
If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status.  
Subjective Progression 
Patients requiring discontinuation of treatment without objective evidence of disease 
progression should not be reported as PD on tumor assessment CRFs.  This should be 
indicated on the end of treatment CRF as off treatment due to Global Deterioration of Health 
Status.  Every effort should be made to document objective progression even after 
discontinuation of treatment.  


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Determination of Tumor Response by RECIST 
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  New lesions will also be recorded separately.  Determination of tumor response 
at each assessment based on target, non-target and new lesions is summarized in Table 11. 
Table 11. Objective Response Status at Each Assessment for Patients with 
Measurable Disease at Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Tumor Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD r not 
all evaluated 
No 
PR 
PR 
Non-PD* or not all 
evaluated 
No 
PR 
SD 
Non-PD* or not all 
evaluated  
No 
SD 
 Not all evaluated 
Non-PD 
No 
NE 
PD 
Any  
Yes or No 
PD 
Any  
PD 
Yes or No 
PD 
Any  
Any  
Yes** 
PD 
*Non-PD includes CR and Non-CR/Non-PD 
**New lesions must be unequivocal  
Determination of Best Overall Response 
The best overall response is the best response recorded from randomization until disease 
progression (taking as reference for progressive disease the smallest sum on study).  For CR 
and PR, the patient’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria.  CR and PR must be confirmed by 2 measurements at 
least 4 weeks apart.  In the case of SD, follow-up measurements must have met the SD 
criteria at least once after randomization at a minimum interval of 6 weeks. 
 


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Appendix 6. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) 
The NCI CTCAE (version 4.03, dated 14 June 2010) has been placed in the Study Reference 
Binder for this protocol.  Alternatively, the NCI CTCAE may be reviewed online at the 
following NCI website: 
http://ctep.cancer.gov/reporting/ctc.html 


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Appendix 7. Abbreviations and Definitions of Terms 
Ths is a list of abbreviations that may be used in the protocol  
ACTH  
 
Adrenocorticotropic hormone 
ADA  
 
Anti-Drug Antibody 
AE 
 
 
Adverse Event 
AESI  
 
Adverse Event of Special Interest 
AHFS  
 
American Hospital Formulary Service 
AIDS  
 
Acquired Immune Deficiency Syndrome 
ALT 
 
 
Alanine aminotransferase  
ANC  
 
Absolute Neutrophil Count 
ANSM  
 
Agence nationale de sécurité du médicaments et de produits de santé 
aRCC  
 
Advanced Renal Cell Cancer 
ASCO  
 
American Society of Clinical Oncology 
ASHP  
 
American Society of Hospital Pharmacists 
AST 
 
 
Aspartate Aminotransferase 
ATP 
 
 
Adenosine Triphosphate 
AUC  
 
Area Under the Curve 
BICR  
 
Blinded Independent Central Review 
BID 
 
 
Twice Daily 
BNP 
 
 
B-type natriuretic peptide  
BOR  
 
Best Overall Response 
BP 
 
 
Blood Pressure 
BUN  
 
Blood Urea Nitrogen 
CAP 
 
 
Chest, Abdomen, Pelvis 
CI 
 
 
Confidence Interval 
CL 
 
 
Clearance 
Cmax  
 
Maximum Plasma Concentration  
Cmin  
 
Minimum Plasma Concentration 
CK 
 
 
Creatinine Kinase 
CK-MB 
 
Creatine Kinase isoenzyme MB 
CR 
 
 
Complete Response 
CRF 
 
 
Case Report Form 
CT 
 
 
Computerized Tomography 
CTCAE 
 
Common Terminology Criteria for Adverse Events (US NCI) 
CYP1A2 
 
Cytochrome P450 enzyme-1A2 
CYP3A4/5 
 
Cytochrome P450 enzyme-3A4/5 
DLT 
 
 
Dose-Limiting Toxicity 
DNA  
 
Deoxyribonucleic Acid 
DR 
 
 
Duration of Response 
EC 
 
 
Ethics committee 
ECG  
 
Electrocardiogram 
ECHO  
 
Echocardiogram 
ECOG  
 
Easter Cooperative Oncology Group 
E-DMC 
 
External Data Monitoring Committee 


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ESMO  
 
European Society for Medical Oncology 
FACIT  
 
Functional Assessment of Chronic Illness Therapy 
FDG  
 
Fluorodeoxyglucose 
FDA  
 
Food and Drug Administration 
FFPE  
 
Formalin Fixed, Paraffin Embedded 
FH 
 
 
Fumarate Hydratase 
FSH 
 
 
Follicle-Stimulating Hormone 
GCP 
 
 
Good Clinical Practice 
GGT  
 
Gamma-Glutamyl Transferase 
GMP  
 
Good Manufacturing Practice 
GPSP  
 
Good Post Marketing Surveillance Practice 
HAV  
 
Hepatitis A Virus 
HBV  
 
Hepatitis B Virus 
HCV  
 
Hepatitis C Virus 
HDPE  
 
High Density Polyethylene 
HIF 
 
 
Hypoxia-Inducible Factor 
HIV 
 
 
Human Immunodeficiency Virus 
HRT  
 
Hormone Replacement Therapy 
IA 
 
 
Interim Analysis 
IB 
 
 
Investigator’s Brochure 
ICH 
 
 
International Committee Harmonization 
IFN 
 
 
Interferon 
IHC 
 
 
Immunohistochemistry 
IL-2 
 
 
Interleukin-2 
IND 
 
 
Investigational New Drug 
INR 
 
 
International Normalized Ratio 
IRB 
 
 
Institutional Review Board 
IUD 
 
 
Intrauterine Device 
IUS 
 
 
Intrauterine Hormone-Releasing System 
IV 
 
 
Intravenous 
LFT 
 
 
Liver Function Test 
LVEF  
 
Left Ventricular Ejection Fraction 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MHLW 
 
Ministry of Health, Labor and Welfare 
mRCC  
 
metastatic Renal Cell Carcinoma 
MRI 
 
 
Magnetic Resonance Imaging 
MTD  
 
Maximum Tolerated Dose 
mTPI  
 
Modified Toxicity Probability Interval 
mTOR  
 
Mammalian Target Of Rapamycin 
MUGA 
 
Multigated Acquisition 
Nab 
 
 
Neutralizing Antibodies 
NCI 
 
 
National Cancer Institute 
NSAID 
 
Nonsteroidal Anti-Inflammatory Drugs 
NSCLC 
 
Non-Small Cell Lung Cancer  
ORR  
 
Objective Response Rate 
OS 
 
 
Overall Survival 


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PACL  
 
Protocol Administrative Change Letter 
PD 
 
 
Pharmacodynamic 
PD 
 
 
Progressive Disease  
PD-1  
 
Programmed Death-1 
PDGF  
 
Platelet-Derived Growth Factor 
PDGFR 
 
Platelet-Derived Growth Factor Receptor 
PD-L1  
 
Programmed Death-Ligand 1 
PET 
 
 
Positron emission tomography 
PFS 
 
 
Progression-Free Survival 
PK 
 
 
Pharmacokinetics 
PO 
 
 
Per Os (by mouth) 
PR 
 
 
Partial Response 
PS 
 
 
Performance Status 
PT 
 
 
Prothrombin Time 
QD 
 
 
Every Day 
RCC  
 
Renal Cell Carcinoma  
RECIST 
 
Response Evaluation Criteria in Solid Tumors 
RNA  
 
Ribonucleic Acid 
RP2D  
 
Recommended Phase 2 Dose 
RSI 
 
 
Reference Safety Information 
SAE 
 
 
Serious Adverse Event 
SD 
 
 
Stable Disease 
SD 
 
 
Standard Deviation 
SOA  
 
Schedule of Activities 
SRSD  
 
Single Reference Safety Document 
t½ 
 
 
Plasma elimination half life 
T4 
 
 
Thyroxine 
TIL 
 
 
Tumor Infiltrating Lymphocytes  
TKI 
 
 
Tyrosine Kinase Inhibitor 
Tmax  
 
Time to maximum plasma concentration 
TSH 
 
 
Thyroid Stimulating Hormone 
TTR 
 
 
Time to Tumor Response 
ULN  
 
Upper Limit of Normal 
US 
 
 
United States 
VEGF  
 
Vascular Endothelial Growth Factor 
VEGFR 
 
Vascular Endothelial Growth Factor Receptor 
WBC  
 
White Blood Cell 
WHO  
 
World Health Organization 
WOCBP 
 
Women of Childbearing Potential  
VHL  
 
von Hippel-Lindau  


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Appendix 8. Treatment Recommendations for Symptoms of Infusion-Related Reactions 
Caused by Avelumab 
The following treatment recommendations for symptoms of avelumab infusion-related 
reactions may be modified based on local treatment standards and guidelines, as appropriate. 
For Grade 1 Symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated): 
• Decrease the avelumab infusion rate by 50% and monitor closely for any worsening. 
• Remain at bedside and monitor patient until recovery from symptoms. 
For Grade 2 Symptoms: (Moderate reaction; Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment (eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated for ≤24 hours): 
• Temporarily discontinued the avelumab infusion. 
• Treat based on emerging symptoms.  Treatment may include: 
• Normal saline IV; 
• H1 blockers, such as diphenhydramine 25 to 50 mg IV (or equivalent); 
• H2 blockers, such as ranitidine 50 mg IV (or equivalent); 
• NSAIDs, such as ibuprofen 600 mg (or equivalent); 
• Meperidine 12.5 to 50 mg IV; 
• Corticosteroids, such as hydrocortisone 100 to 500 mg IV (or equivalent); 
• Bronchodilators. 
• Remain at bedside and monitor patient until resolution of symptoms. 
• Resume infusion at 50% of previous rate once infusion related reaction has resolved 
or decreased to at least Grade 1 in severity, and monitor closely for any worsening. 


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For Grade 3 or Grade 4 Symptoms: (Severe reaction; Grade 3: prolonged [eg, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]; Grade 4: life-threatening consequences; urgent 
intervention indicated): 
• Stop the avelumab infusion immediately and disconnect infusion tubing from the 
patient. 
• Begin an IV infusion of normal saline, and treat the patient with one or more of the 
following: 
• Airway maintenance; 
• Oxygen; 
• Bronchodilators; 
• Epinephrine 0.01 mg/kg of a 1:1,000 (1 mg/mL) solution IM, up to a maximum 
dose of 0.5 mg; 
• H1 blockers, such as diphenhydramine 25 to 50 mg IV (or equivalent); 
• H2 blockers, such as ranitidine 50 mg IV (or equivalent); 
• Corticosteroids, such as hydrocortisone 100 to 500 mg IV (or equivalent). 
• Remain at bedside and monitor patient until recovery from symptoms.  
• Patients have to be withdrawn immediately from avelumab treatment and must not 
receive any further avelumab treatment. 

SAP_001.pdf: 
A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1
R E N A L C E L L C A R CI N O M A - J A V E LI N R E N A L 1 0 1
A P H A S E 3, M U L TI N A TI O N A L, R A N D O MI Z E D, O P E N -L A B E L,
P A R A L L E L -A R M S T U D Y O F A V E L U M A B ( M S B 0 0 1 0 7 1 8 C) I N C O M BI N A TI O N
WI T H A XI TI NI B (I N L Y T A ® ) V E R S U S S U NI TI NI B ( S U T E N T ® ) M O N O T H E R A P Y
I N T H E FI R S T- LI N E T R E A T M E N T O F P ATI E N T S WI T H A D V A N C E D R E N A L
C E L L C A R CI N O M A
S T A TI S TI C A L A N A L Y SI S P L A N – B 9 9 9 1 0 0 3
C o m p o u n d s:
M S B 0 0 1 0 7 1 8 C,  A G - 0 1 3 7 3 6, S U 0 1 1 2 4 8
C o m p o u n d N a me:
A vel u ma b , A xiti ni b, S u niti ni b
Versi o n :
5. 0
D ate:
1 6 -J ul- 2 0 1 8


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 2
T A B L E O F C O N T E N T S
LI S T O F T A B L E S ..................................................................................................................... 6
LI S T O F FI G U R E S ................................................................................................................... 7
A P P E N DI C E S ........................................................................................................................... 7
2. I N T R O D U C TI O N ............................................................................................................... 1 2
2. 1. St u d y  O bjecti ves ..................................................................................................... 1 3
2. 2. St u d y  Desi g n........................................................................................................... 1 4
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E F I NI TI O N S A N D 
C O N V E N TI O N S ................................................................................................................ 1 4
3. 1. Pri mar y  E n d p oi nt .................................................................................................... 1 4
3. 2. Sec o n dar y  E n d p oi nts...............................................................................................1 5
3. 2. 1. Safet y e n d p oi nts .......................................................................................... 1 5
3. 2. 2. Efficac y  e n d p oi nts...................................................................................... 1 5
3. 2. 3. Patie nt re p orte d o utc o mes ........................................................................... 1 6
3. 2. 4. P har mac o ki n etic e n d p oi nts ......................................................................... 1 7
3. 2. 5. I m m u n o ge nicit y e n d p oi nts ......................................................................... 1 7
3. 2. 6. Bi o mar ker e n d p oi nts ................................................................................... 1 7
3. 4. Baseli ne Varia bles ................................................................................................... 1 8
3. 4. 1. St u d y  dr u g, st u d y treat me nt a n d baseli ne defi niti o ns................................. 1 8
3. 4. 2. Baseli ne c haracteristics ............................................................................... 2 0
3. 5. Safet y E n d p oi nts ..................................................................................................... 2 0
3. 5. 1. A d verse e ve nts ............................................................................................ 2 0
4. A N A L Y SI S S E T S ............................................................................................................... 2 1
4. 1. F ull A nal y sis Set ..................................................................................................... 2 2
4. 2. Safet y A nal ys is Set.................................................................................................. 2 2
4. 3. Ot her A nal ys is Sets................................................................................................. 2 2
4. 3. 1. Per -pr ot oc ol a nal ysis set ............................................................................. 2 2
4. 3. 2. P K a nal y sis sets .......................................................................................... 2 3
4. 3. 3. Bi o mar ker a nal ys is set................................................................................ 2 3
4. 3. 4. I m m u n o ge nicit y a nal ysis set ....................................................................... 2 3
4. 3. 5. P R O a nal y sis set ......................................................................................... 2 3
C CI
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 3
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S .................................................... 2 3
5. 1. H y p ot heses a n d Decisi o n R ules .............................................................................. 2 3
5. 1. 1. H y p ot heses a n d sa m ple size deter mi nati o n ................................................ 2 4
5. 1. 2. Decisi o n r ules ............................................................................................. 2 6
5. 2. Ge ner al Met h o ds ..................................................................................................... 3 0
5. 2. 1. Data ha n dli n g after t he c ut -off date ............................................................ 3 0
5. 2. 2. P o oli n g of ce nters ....................................................................................... 3 0
5. 2. 3. Prese ntati o n of c o nti n u o us a n d q ualitati ve varia bles .................................. 3 0
5. 2. 4. Defi niti o n of st u d y da y ............................................................................... 3 1
5. 2. 5. Defi niti o n of start of ne w a nti -ca ncer dr u g t hera p y.................................... 3 1
5. 2. 6. Defi niti o n of start of ne w a nti -ca ncer t hera p y ............................................ 3 1
5. 2. 7. Defi niti o n of o n -treat me nt peri o d............................................................... 3 2
5. 2. 8. Sta n dar d deri vati o ns a n d re p orti n g c o n ve nti o ns ......................................... 3 2
5. 2. 9. U nsc he d ule d visits ...................................................................................... 3 2
5. 2. 1 0. A de q uate baseli ne t u m or assess me nt ........................................................ 3 3
5. 2. 1 1. A de q uate p ost -baseli ne t u m or assess me nt ................................................ 3 3
5. 3. Met h o ds t o Ma na ge Missi n g Data .......................................................................... 3 3
5. 3. 1. Missi n g data ................................................................................................ 3 3
5. 3. 1. 1. P har mac o ki netic c o nce ntrati o ns ................................................ 3 3
5. 3. 1. 2. P har mac o ki netic para meters ..................................................... 3 4
5. 3. 2. Ha n dli n g of i nc o m plete dates ..................................................................... 3 4
5. 3. 2. 1. Disease hist or y .......................................................................... 3 4
5. 3. 2. 2. A d verse e ve nts .......................................................................... 3 4
5. 3. 2. 3. Pri or a n d c o nc o mita nt me dicati o ns ........................................... 3 5
5. 3. 2. 4. E x p os ure .................................................................................... 3 5
5. 3. 3. I m p utat i o n r ules f or date of last c o ntact a n d efficac y assess me nts............ 3 6
5. 3. 3. 1. Date of last c o ntact .................................................................... 3 6
5. 3. 3. 2. Deat h date .................................................................................. 3 6
5. 3. 3. 3. T u m or assess me nts .................................................................... 3 7
5. 3. 3. 4. Date of start of ne w a nti -ca ncer t hera p y ................................... 3 7
6. A N A L Y S E S A N D S U M M A RI E S ...................................................................................... 3 9
6. 1. Pri mar y  E n d p oi nts................................................................................................... 3 9


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 4
6. 1. 1. Pr o gressi o n -free s ur vi val as assesse d by B I C R per R E CIS T v 1. 1 i n 
P D -L 1  p ositi ve patie nts.................................................................................... 3 9
6. 1. 1. 1. Pri mar y  a nalys is........................................................................ 3 9
6. 1. 2. O verall s ur vi val i n P D -L 1  p ositi ve patie nts ............................................... 4 2
6. 1. 2. 1. Pri mar y  a nalys is........................................................................ 4 2
6. 2. Sec o n dar y  E n d p oi nt(s)............................................................................................ 4 3
6. 2. 1. Safet y e n d p oi nts .......................................................................................... 4 3
6. 2. 2. Efficac y  e n d p oi nts...................................................................................... 4 3
6. 2. 2. 1. O verall s ur vi val f or patie nts u nselecte d f or P D-L 1 
e x pressi o n .......................................................................................... 4 4
6. 2. 2. 2. Pr o gressi o n -free s ur vi val as assesse d by B I C R per 
R E CI S T v 1. 1 f or patie nts u nselecte d f or P D-L 1 e x pressi o n ............. 4 4
6. 2. 2. 3. Se nsiti vit y  a nal yses f or pr o gressi o n-free s ur vi val..................... 4 4
6. 2. 2. 4. Se nsiti vit y  a nal yses f or o verall s ur vi val.................................... 4 7
6. 2. 2. 5. O bjecti ve res p o nse a n d t u m or s hri n ka ge ................................... 4 8
6. 2. 2. 6. Disease c o ntr ol .......................................................................... 5 1
6. 2. 2. 7. D urati o n of res p o nse ................................................................. 5 1
6. 2. 2. 8. Ti me t o res p o nse ....................................................................... 5 2
6. 2. 2. 9. Pr o gressi o n -free s ur vi val o n ne xt-li ne t hera p y ( P F S 2)............. 5 2
6. 2. 3. P har mac o ki netic e n d p oi nts ......................................................................... 5 4
6. 2. 4. P o p ulati o n p har mac o ki netic e n d p oi nts ....................................................... 5 5
6. 2. 5. Bi o mar ker e n d p oi nts ................................................................................... 5 5
6. 2. 6. E n d p oi nts f or i m m u n o ge nicit y  data of a vel u ma b....................................... 5 5
6. 2. 6. 1. Ti me t o a n d D urati o n of A D A a n d n A b res p o nse ..................... 5 7
6. 2. 6. 2. A D A titer ................................................................................... 5 8
6. 2. 6. 3. A nal y sis of P K, safety a n d efficac y b y i m m u n o ge nicit y  
stat us ..................................................................................................5 8
6. 3. Ot her E n d p oi nts ....................................................................................................... 6 0
6. 3. 2. P R O e n d p oi nts ............................................................................................ 6 2
6. 3. 2. 1. P R O i nstr u me nts ....................................................................... 6 3
6. 3. 2. 2. Sc ori n g pr oce d ure ..................................................................... 6 3
6. 3. 2. 3. I nstr u me nt c o m pleti o n rates ...................................................... 6 3
6. 3. 2. 4. Descri pti ve s u m maries o ver ti me .............................................. 6 3
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5
6. 3. 2. 5. Ti me -t o-e ve nt e n d p oi nts ........................................................... 6 3
6. 3. 2. 6. Bi nar y  e n d p oi nts ....................................................................... 6 4
6. 3. 2. 7. C o nti n u o us e n d p oi nts ................................................................ 6 4
6. 3. 2. 8. Se nsiti vit y  A nal yses..................................................................6 5
6. 4. S u bset a nal y ses........................................................................................................ 6 5
6. 5. Baseli ne a n d Ot her S u m maries a n d A nal ys es ......................................................... 6 7
6. 5. 1. Baseli ne s u m maries .................................................................................... 6 7
6. 5. 1. 1. De m o gra p hic c haracteristics..................................................... 6 7
6. 5. 1. 2. Me dical hist or y .......................................................................... 6 8
6. 5. 1. 3. Disease c haracteristics ...............................................................6 9
6. 5. 1. 4. Pri or a nti -ca ncer t hera pies ......................................................... 7 0
6. 5. 2. St u d y  c o n d uct a n d patie nt dis p ositi o n........................................................ 7 1
6. 5. 2. 1. Patie nt dis p ositi o n ..................................................................... 7 1
6. 5. 2. 2. Pr ot oc ol de viati o ns .................................................................... 7 2
6. 5. 3. St u d y  treat me nt c o m plia nce a n d e x p os ure ................................................. 7 2
6. 5. 3. 1. E x p os ure t o a vel u ma b ...............................................................7 3
6. 5. 3. 2. E x p os ure t o a xiti ni b .................................................................. 7 4
6. 5. 3. 3. E x p os ure t o s u niti ni b ................................................................. 7 4
6. 5. 3. 4. D ose re d ucti o ns ......................................................................... 7 5
6. 5. 3. 5. D ose escalati o ns ........................................................................ 7 5
6. 5. 3. 6. D ose i nterr u pti o ns ..................................................................... 7 6
6. 5. 3. 7. D ose dela y s ............................................................................... 7 6
6. 5. 3. 8. I nf usi o n rate re d ucti o ns ............................................................. 7 7
6. 5. 3. 9. I nf usi o n i nterr u pti o ns ................................................................ 7 7
6. 5. 4. C o nc o mita nt me dicati o ns a n d n o n -dr u g treat me nts ................................... 7 8
6. 5. 5. S u bse q ue nt a nti -ca ncer t hera pies ................................................................ 7 8
6. 6. Safet y S u m maries a n d A nal yses ............................................................................. 7 9
6. 6. 1. A d verse e ve nts ............................................................................................ 7 9
6. 6. 1. 1. All a d verse e ve nts ..................................................................... 8 0
6. 6. 1. 2. A d verse e ve nts lea di n g t o d ose re d ucti o n................................. 8 1
6. 6. 1. 3. A d verse e ve nts lea di n g t o i nterr u pti o n of st u d y treat me nt ....... 8 1
6. 6. 1. 4. A d verse e ve nts lea di n g t o disc o nti n uati o n of st u d y  
treat me nt............................................................................................ 8 2


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6
6. 6. 2. Deat hs ......................................................................................................... 8 3
6. 6. 3. Seri o us a d verse e ve nts ................................................................................ 8 3
6. 6. 4. Ot her si g nifica nt a d verse e ve nts .................................................................8 4
6. 6. 5. Ti me t o treat me nt disc o nti n uati o n or fail ure d ue t o t o xicit y ...................... 8 5
6. 6. 6. Treat me nt disc o nti n uati o n d ue t o t o xicit y .................................................. 8 5
6. 6. 7. L a b orat or y data........................................................................................... 8 6
6. 6. 7. 1. He mat ol o g y  a n d c he mistr y para meters..................................... 8 6
6. 6. 7. 2. Ot her la b orat or y  para meters...................................................... 8 9
6. 6. 8. Vital si g ns ................................................................................................... 8 9
6. 6. 9. M U G A/ E C H O ............................................................................................ 9 0
6. 6. 1 0. Electr ocar di o gra m ..................................................................................... 9 0
6. 6. 1 1 . P h ysical e xa mi nati o n ................................................................................ 9 2
6. 6. 1 2. E C O G perf or ma nce stat us ........................................................................ 9 2
7. I N T E RI M A N A L Y S E S ....................................................................................................... 9 2
7. 1. I ntr o d ucti o n ............................................................................................................. 9 2
7. 2. I nteri m A nal ys es a n d S u m maries ............................................................................ 9 3
7. 2. 1. I nteri m a nal ys is f or P F S i n P D-L 1  p ositi ve patie nts.................................. 9 3
7. 2. 2. I nteri m a nalys is f or P F S i n patie nts u nselecte d f or P D -L 1 e x pressi o n ...... 9 4
7. 2. 3. I nteri m a nal ys is f or O S i n P D-L 1  p ositi ve patie nts.................................... 9 4
7. 2. 4. I nteri m a nalys is f or O S i n patie nts u nselecte d f or P D -L 1 e x pressi o n ........ 9 5
8. R E F E R E N C E S .................................................................................................................... 9 7
9. A P P E N DI C E S ..................................................................................................................... 9 9
LI S T O F T A B L E S
Ta ble 1.
S u m mar y  of Maj or C ha n ges i n S A P A me n d me nts................................................8
Ta ble 2.
P K Para meters t o be Deter mi ne d f or A vel u ma b a n d A xiti ni b .............................1 7
Ta ble 3.
Bi o mar ker Defi niti o n a n d Deter mi nati o n ............................................................. 1 7
Ta ble 4.
Statistical A nal y ses by A nal ysis Set ..................................................................... 2 2
Ta ble 5.
P F S a n d O S i n P D -L 1  p ositi ve patie nts – Efficac y  a n d F utilit y B o u n daries .......2 8
Ta ble 6.
P F S a n d O S f or patie nts u nselecte d f or P D- L 1 e x pressi o n – Efficac y  
B o u n daries ............................................................................................................ 2 8
Ta ble 7
Si m ulate d c u m ulati ve pr o ba bilities t o st o p f or efficac y  or f utilit y at t he 
i nteri m or fi nal P F S a nal ysis i n P D-L 1 p ositi ve patie nts ................................ .....2 9


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7
Ta ble 8.
Si m ulate d c u m ulati ve pr o ba bilities t o st o p f or efficac y  or f utilit y at t he 
i nteri m or fi nal O S a nalyses i n P D -L 1  p ositi ve patie nts ...................................... 3 0
Ta ble 9.
O utc o me a n d e ve nt dates f or P F S a n d D R a nal y s es ............................................. 4 0
Ta ble 1 0 .
P F S Ce ns ori n g Reas o ns a n d Hierarc h y................................................................ 4 1
Ta ble 1 1 .
O S Ce ns ori n g Reas o ns a n d Hierarc h y.................................................................. 4 3
Ta ble 1 2.
P ossi ble O utc o mes f or I n vesti gat or vs BI C R ....................................................... 4 6
Ta ble 1 3.
P ossi ble B O R O utc o mes f or I n vesti gat or vs BI C R .............................................. 5 0
Ta ble 1 4 .
O utc o me , E ve nt Dates, Ce ns ori n g Reas o ns a n d Hierarc hy f or P F S 2 
A nal y ses................................................................................................................ 5 3
Ta ble 1 5 
Patie nts C haracterize d Base d o n A nti -Dr u g A nti b o d y  Res ults ( A D A 
Stat us) ................................................................................................................... 5 6
Ta ble 1 6 
Patie nts C haracterize d Base d o n Ne utralizi n g A nti b o d y  Res ults ( n A b 
Stat us) ................................................................................................................... 5 7
Ta ble 1 7.
O utc o me a n d e ve nt dates f or ir P F S a n d ir D R a nal y ses ........................................ 6 2
Ta ble 1 8. 
Case Defi niti o n f or ir A Es ..................................................................................... 9 9
Ta ble 1 9.
Case Defi niti o n f or I R Rs – I V St u d y Dr u gs A d mi nistere d Al o ne Or I n 
C o m bi nati o n Wit h N o n -I V St u d y Dr u gs............................................................ 1 0 1
LI S T O F FI G U R E S
Fi g ure 1 Testi n g Strate g y .........................................................................................................2 5
A P P E N DI C E S
A p pe n di x 1. I m m u ne - Relate d A d verse E ve nts........................................................................ 9 9
A p pe n di x 2. I nf usi o n Relate d Reacti o ns ............................................................................... 1 0 1


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 0
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 1
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 2
2. I N T R O D U C TI O N
T his S A P pr o vi des t he detaile d met h o d ol o g y  f or s u m mar y a n d statistical a nal yses of t he data 
c ollecte d i n st u d y B 9 9 91 0 0 3 .  T his d oc u me nt ma y m o dif y t he pla ns o utli ne d i n t he pr ot oc ol; 
h o we ver, a n y maj or m o dificati o ns of t he pri mar y e n d p oi nt defi niti o n or its a nal ys is will als o 
be reflecte d i n a pr ot oc ol a me n d me nt.
C CI




A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 4

T o e val uate t he p o p ulati o n p har mac o ki netics of a vel u ma b a n d a xiti ni b w he n 
a d mi nistere d i n c o m bi nati o n;

T o e val uate t he ti me t o treat me nt disc o nti n uati o n/fail ure d ue t o t o xicit y ;

T o e val uate t he pr o p orti o n of patie nts w h o disc o nti n ue d treat me nt d ue t o t o xicit y ;

T o e val uate ca n di date pre dicti ve bi o mar kers i n pre -treat me nt t u m or tiss ue t hat ma y  ai d 
i n t he i de ntificati o n of a patie nt s u b p o p ulati o n m ost li kel y t o be nefit fr o m treat me nt wit h 
a vel u ma b i n c o m bi nati o n wit h a xiti ni b a n d s u niti ni b m o n ot hera p y;

T o assess t he i m m u n o ge nicit y  of a vel u ma b w he n c o m bi ne d wit h a xiti ni b;

T o e val uate t he effects of a vel u ma b i n c o m bi nati o n wit h a xiti ni b a n d s u niti ni b 
m o n ot hera p y o n patie nt -re p orte d o utc o mes.
2. 2. St u d y Desi g n
T his is a P hase 3, m ulti nati o nal, m ultice nter, ra n d o mize d ( 1: 1), o pe n -la bel, parallel 2-ar m 
st u d y i n w hic h a p pr o xi matel y 8 3 0 patie nts , i ncl u di n g a mi ni m u m of 5 8 0 P D-L 1 p ositi ve 
patie nts , are pla n ne d t o be ra n d o mize d t o recei ve eit her a vel u ma b i n c o m bi nati o n wit h 
a xiti ni b or s u niti ni b m o n ot hera p y.

Ar m A: a vel u ma b pl us a xiti nib;

Ar m B: s u niti ni b.
Patie nts will be stratifie d acc or di n g t o E C O G P S ( 0 vs 1) a n d re gi o n ( U nite d States vs
Ca na da/ Wester n E ur o pe vs t he rest of t he w orl d).
Cr oss o ver bet wee n treat me nt ar ms will n ot be per mitte d .   
3. E N D P OI N T S A N D B A S E LI N E V A RI A B L E S: D E FI NI TI O N S A N D 
C O N V E N TI O N S
3. 1. Pri m ar y E n d p oi n t

P F S base d o n BI C R assess me nt per R E CIS T v 1. 1 f or P D- L 1 p ositi ve patie nts.
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 5
P F S is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he date of t he first 
d oc u me ntati o n of pr o gressi ve disease ( P D ) or deat h d ue t o a n y ca use, w hic he ver occ urs 
first.  

O S f or P D-L 1 p ositi ve patie nts.
O S is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he date of deat h d ue t o a ny 
ca use.
3. 2. Sec o n d ar y E n d p oi nts
3. 2. 1. S afet y e n d p oi nts

A d verse E ve nts ( A Es) as gra de d b y Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) v 4. 0 3;
A Es will be gra de d b y t he i n vesti gat or acc or di n g t o t he C T C A E v 4. 0 3 a n d c o de d usi n g 
t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A);

La b orat or y a b n or malities as gra de d b y N CI C T C A E v 4. 0 3;

Vital si g ns ( bl o o d press ure, p ulse rate) ;

Ti me t o treat me nt disc o nti n uati o n/fail ure d ue t o t o xicit y ;
Ti me t o treat me nt disc o nti n uati o n/fail ure d ue t o t o xicit y  is defi ne d as t he ti me fr o m first 
d ose of st u d y  treat me nt t o disc o nti n uati o n of st u d y treat me nt ( disc o nti n uati o n of eit her 
a vel u ma b or a xiti ni b f or ar m A) d ue t o a n a d verse e ve nt or deat h d ue t o st u d y treat me nt 
t o xicit y.

Treat me nt disc o nti n uati o n d ue t o t o xicit y .
Treat me nt disc o nti n uati o n d ue t o t o xicit y is defi ne d as t he disc o nti n uati o n of st u d y 
treat me nt ( disc o nti n uati o n of eit her a vel u ma b or a xiti ni b f or ar m A) d ue t o a n a d verse 
e ve nt or deat h d ue t o st u d y treat me nt t o xicit y.
3. 2. 2. Effic ac y e n d p oi nts

P F S b y  BI C R assess me nt per R E CIS T v 1. 1 f or patie nts u nsel ecte d f or P D-L 1 e x pressi o n.

O S f or patie nts u nselecte d f or P D-L 1 e x pressi o n

P F S base d o n I n vesti gat or assess me nt per R E CI S T v 1. 1 .

O bjecti ve Res p o nse ( O R), Disease C o ntr ol ( D C), Ti me t o T u m or Res p o nse ( T T R) a n d 
D urati o n of Res p o nse ( D R) base d o n BI C R assess me nt a n d base d o n I n vest i gat or 
assess me nt, per R E CI S T v 1. 1.
O R is defi ne d as c o m plete res p o nse ( C R), or partial res p o nse ( P R) acc or di n g t o R E CI S T 
v 1. 1, fr o m t he date of ra n d o mizati o n u ntil t he date of t he first d oc u me ntati o n of P D. B ot h 
C R a n d P R m ust be c o nfir me d b y  re peat assess me nts perf or me d n o less t ha n 4 wee ks 
after t he criteria f or res p o nse are first met.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 6
D C is defi ne d as C R, P R , n o n-C R/ n o n -P D or S D. B ot h C R a n d P R m ust be c o nfir me d b y 
re peat assess me nts perf or me d n o less t han 4 wee ks after t he criteria f or res p o nse are first 
met. Criteri a f or S D a n d n o n-C R/ n o n -P D m ust ha ve bee n met at least 6 wee ks after t he 
date of ra n d o mizati o n.
T T R is defi ne d, f or patie nts wit h a n O R , as t he ti me fr o m t he date of ra n d o mizati o n t o t he 
first d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R) w hic h is s u bse q ue ntl y c o nfir me d. 
D R is defi ne d, f or patie nts wit h a n O R , as t he ti me fr o m t he first d oc u me ntati o n of 
o bjecti ve res p o nse ( C R or P R) t o t he date of first d oc u me ntati o n of P D or deat h d ue t o 
a n y ca use.  

Pr o gressi o n - Free S ur vi val o n ne xt-li ne t hera py ( P F S 2).
P F S 2 is defi ne d as t he ti me fr o m ra n d o mizati o n t o disc o nti n uati o n of ne xt -li ne treat me nt,
sec o n d o bjecti ve disease pr o gressi o n, or deat h fr o m a n y ca use, w hic he ver occ urs first.

Meas ures of cli nical o utc o me ( P F S, O S, O R, D C, T T R, a n d D R) i n bi o mar ker -p ositi ve 
a n d bi o mar ker - ne gati ve s u b gr o u ps.
3. 2. 3. P atie nt re p orte d o utc o mes 

F A C T -Ki d ne y  Sy m pt o m I n de x ( F K SI - 1 9)
T he F K SI - 1 9 was de vel o pe d t o be part of t he F u ncti o nal Assess me nt of C hr o nic Ill ness 
T hera p y ( F A CI T) s ys te m. It is a n i nstr u me nt s pecificall y desi g ne d t o be a sta n d-al o ne 
i nstr u me nt t o meas ure sy m pt o ms a n d q ualit y  of life i n patie nts wit h a d va nce d ki d ne y  
ca ncer. It c o ntai ns 1 9 q uesti o ns, m ost of w hic h o verla p wit h t he F A C T -G q uesti o ns (Ra o 
et al. 2 0 0 9). T he F K SI -1 9 was de vel o pe d i n or der t o re prese nt t he sy m pt o ms a n d iss ues 
m ost i m p orta nt t o pe o ple recei vi n g treat me nt f or a R C C. 
A 9 -ite m s u bscale of t he F K SI k n o w n as t he F K SI-Disease Relate d S y m pt o ms s u bscale 
( F K SI-D R S) meas uri n g a d va nce d ki d ne y  ca ncer disease relate d sy m pt o ms was create d 
usi n g i n p uts fr o m o nc ol o gists a n d patie nts ( Cella 2 0 0 5). T his s u bscale i ncl u des t he 
foll o wi n g 9 ite ms: lac k of e ner g y, pai n, l osi n g wei g ht, b o ne pai n, fati g ue, s h ort ness of 
breat h, c o u g hi n g, b ot here d b y  fe vers, a n d he mat uria.

E ur o Q o L 5- Di me nsi o n ( E Q - 5 D)
T he E ur o Q ol E Q -5 D is a 6 -ite m patie nt-c o m plete d q uesti o n naire desi g ne d t o assess 
healt h stat us i n ter ms of a si n gle i n de x val ue or utilit y sc ore ( T he E ur o Q o L Gr o u p, 1 9 9 0) 
T here are t w o c o m p o ne nts t o t he E Q -5 D; a Healt h State Pr ofile w hic h has patie nts rate 
t heir le vel of pr o ble ms ( n o ne, sli g ht, m o derate, se vere, e xtre me/ u na ble) i n 5 areas 
( m o bilit y, self-care, us ual acti vities, pai n/ disc o mf ort, a n d a n xiety/ de pressi o n), a n d a 
Vis ual A nal o g ue Scale ( V A S) i n w hic h patie nts rate t heir o verall healt h stat us fr o m 0 
( w orst i ma gi na ble) t o 1 0 0 ( best i ma gi na ble). P u blis he d wei g hts are a vaila ble t hat all o w 
f or t he creati o n of a si n gle s u m mar y sc ore ( Ra bi n a n d de C harr o, 2 0 0 1). O verall sc ores 
ra n ge fr o m 0 t o 1, wit h l o w sc ores re prese nti n g a hi g her le vel of d ys f u ncti o n.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 7
3. 2. 4. P h ar m ac o ki netic e n d p oi nts

P K para meters i ncl u di n g tr o u g h c o nce ntrati o ns ( C tr o u g h) of a vel u ma b a n d tr o u g h
c o nce ntrati o ns ( C tr o u g h) a n d ma xi m u m c o nce ntrati o ns ( Cma x ) of a xiti ni b
T a ble 2.
P K P ar a meters t o be Deter mi ne d f or A vel u m a b a n d A xiti ni b
P a r a m eter
Defi niti o n
M e t h o d of Deter mi n ati o n
C ma x
a
Ma xi m u m o bser ve d plas ma c o nce ntrati o n 
O bser ve d directl y fr o m data
C tr o u g h
b
Pre d ose c o nce ntrati o n d uri n g m ulti ple 
d osi n g
O bser ve d directl y fr o m data
C ma x ( d n) a
D ose n or malize d C ma x
C ma x / D ose
a C ma x will be calc ulate d o nl y f or a xiti ni b
b C tr o u g h will be calc ulate d f or a vel u ma b a n d a xiti ni b
3. 2. 5. I m m u n o ge nicit y e n d p oi nts

A nti- dr u g a nti b o dies ( A D As; n A b ) of a vel u ma b w he n i n c o m bi nati o n wit h a xiti ni b.
3. 2. 6. Bi o m ar ker e n d p oi nts

T u m or tiss ue bi o mar ker stat us (i. e., p ositi ve or ne gati ve; base d o n, f or e xa m ple, P D -L 1  
e x pressi o n a n d/ or q ua ntitati o n of t u m or i nfiltrati n g C D 8 + T l y m p h oc y tes as assesse d b y 
i m m u n o hist oc he mistr y [I H C]; or base d o n e x pressi o n of a ge ne/ pr otei n or gr o u p of 
ge nes/ pr otei n  relati n g t o, or i n dicati ve of a n i m m u ne res p o nse wit hi n t he peri p he r y or 
t u m or micr oe n vir o n me nt).
T a ble 3.
Bi o m ar ker Defi niti o n a n d Deter mi n ati o n
P a r a m eter
Defi niti o n
M e t h o d of Deter mi n ati o n
P D -L 1 e x pressi o n
T he n u m ber of P D -L 1 p ositi ve cells a n d/ or 
q ualitati ve assess me nt of  P D -L 1 stai ni n g o n 
t u m or a n d i nfla m mat or y cells i n re gi o ns of 
i nterest t hat are defi ne d b y t u m or cell 
m o r p h ol o g y a n d t he prese nce or a bse nce of 
C D 8 + cells
Pat h ol o gist, assiste d b y i ma ge 
a nal ysis
T u m or i nfiltrati n g 
C D 8 + l y m p h oc ytes
T he n u m ber of C D 8 + cells per u nit area a n d 
t he perce nt of c o u nte d cells t hat are sc ore d as 
C D 8 + 
Pat h ol o gist, assiste d b y i ma ge 
a nal ysis
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 8
3. 4. B aseli ne V ari a bles
3. 4. 1. St u d y dr u g, st u d y tre at me nt a n d b aseli ne defi niti o ns
I n t his st u dy, ‘ st u d y dr u g’ refers t o a vel u ma b or a xiti ni b or s u niti ni b a n d ‘st u d y tre at me nt’ 
( or ‘tre at me nt ar m’) refers t o o ne of t he f oll o wi n g:

Ar m A = a vel u ma b pl us a xiti ni b ;

Ar m B = s u niti ni b.
Deter mi n ati o n of P D -L 1 st at us
D eter mi nati o n of P D-L 1 stat us will be perf or me d retr os pecti vely i n a ce ntral la b orat or y. 
P D -L 1  stat us will be assesse d usi n g a vali date d P D -L 1 I H C test kit ma n ufact ure d u n der G M P
s pecificati o ns, i n c o nj u ncti o n wit h a pre -s pecifie d sc ori n g al g orit h m a n d c ut off defi ni n g P D-
L 1 p ositi ve vers us ne gati ve stat us t hat will be esta blis he d pri or t o i nitiati o n of sc ori n g of P D -
L 1.
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 9
St art a n d e n d d ates of st u d y tre at me nt
F or Ar m A
T he date/ti me of first d ose of st u d y  treat me nt i n a c o m bi nati o n ar m is t he earliest date/ti me of 
t he first n o n-zer o d ose date/ti me f or t he st u d y  dr u gs i n t he c o m bi nati o n. 
T he date/ti me of last d ose of st u d y  treat me nt i n a c o m bi nati o n ar m is t he latest date/ti me of 
t he last n o n-zer o d ose date/ti me f or t he st u d y  dr u gs i n t he c o m bi nati o n.
F or Ar m B
T he date/ti me of first d ose of st u d y  treat me nt is t he earliest date/ti me of n o n-zer o d osi n g of 
t he st u d y dr u g.
T he date/ti me of last d ose of st u d y treat me nt is t he latest date/ ti me of n o n-zer o d osi n g of t he 
st u d y dr u g.
Defi niti o n of b aseli ne: 
Defi niti o n of baseli ne f or efficac y a n d P R O a nal yses 
T he last meas ure me nt pri or t o ra n d o mizati o n will ser ve as t he baseli ne meas ure me nt f or 
efficac y a n d P R O a nal yses. If s uc h a val ue is missi n g (si nce per pr ot oc ol t he first P R O 
assess me nt is pla n ne d t o occ ur pri or t o d osi n g o n C y cle 1 Da y 1), t he last meas ure me nt pri or 
t o t he first d ose of st u d y treat me nt will be use d as t he baseli ne meas ure me nt e xce pt f or 
a nal ys es of t u m or assess me nts data w here t he baseli ne assess me nt w o ul d be c o nsi dere d as 
missi n g. 
Defi niti o n of baseli ne f or i m m u n o ge nicit y  a nalys es
T he last a vaila ble assess me nt pri or t o t he start of treat me nt wit h a vel u ma b is defi ne d as 
‘ baseli ne’ res ult or ‘ baseli ne’ assess me nt.  If a n assess me nt is pla n ne d t o be perf or me d pri or 
t o t he first d ose of a vel u ma b i n t he pr ot oc ol a n d t he assess me nt is perf or me d o n t he sa me da y 
as t he first d ose of a vel u ma b, it will be ass u me d t hat it was perf or me d pri or t o a vel u ma b 
a d mi nistrati o n, if assess me nt ti me p oi nt is n ot c ollecte d or is missi n g.
Defi niti o n of baseli ne f or safet y a nal yses
T he last a vaila ble assess me nt pri or t o t he start of st u d y  treat me nt is defi ne d as ‘baseli ne ’
val ue or ‘baseli ne ’ assess me nt f or safet y a nalys es.  If a n assess me nt is pla n ne d t o be 
perf or me d pri or t o t he first d ose of st u d y  treat me nt i n t he pr ot oc ol a n d t he assess me nt is 
perf or me d o n t he sa me da y  as t he first d ose of st u d y treat me nt, it will be ass u me d t hat it was 
perf or me d pri or t o st u d y treat me nt a d mi nistrati o n, if assess me nt ti me p oi nt is n ot c ollecte d or 
is missi n g. If assess me nt ti me p oi nts are c ollecte d, t he o bser ve d ti me p oi nt will be use d t o 
deter mi ne pre -d ose o n st u d y  da y 1 f or baseli ne calc ulati o n. U nsc he d ule d assess me nts will be 
use d i n t he deter mi nati o n of baseli ne. H o we ver, if ti me is missi n g, a n u nsc he d ule d 
assess me nt o n st u d y d a y 1 will be c o nsi dere d t o ha ve bee n o btai ne d after st u d y treat me nt 
a d mi nistrati o n.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 2 0
Patie nts w h o start treat me nt a n d disc o nti n ue fr o m t he st u d y  o n t he sa me da y m a y ha ve t w o 
differe nt sets of data c ollecte d o n st u d y  da y 1 ( o ne d uri n g st u d y a n d o ne i n t he E n d of 
Treat me nt ( E O T) visit. Data re p orte d at t he E O T visit are n ot eli gi ble f or baseli ne selecti o n. 
If a sc he d ule d pre- d ose meas ure me nt act ually occ urre d p ost -d ose, t he n t he c orre s p o n di n g 
meas ure me nt will be treate d a n d a nal yz e d si milar t o a n u nsc he d ule d p ost- d ose meas ure me nt.
Baseli ne f or R R a n d Q T/ Q Tc i nter val assess me nts will be deri ve d fr o m t he visit w here b ot h 
R R a n d Q T are n ot missi n g. T ri plicate E C Gs are c ollecte d i n t he st ud y  a n d t he baseli ne f or 
eac h E C G meas ure me nt is t he a vera ge of t he pre -d ose re plicate meas ure me nts o n t he 
baseli ne da y . U nsc he d ule d assess me nts will n ot be i ncl u de d i n t he calc ulati o n of t he a vera ge. 
Q Tc B a n d Q Tc F will be deri ve d base d o n R R a n d Q T.  T he avera ge of t he re plicate 
meas ure me nts will be deter mi ne d after t he deri vati o n of t he i n di vi d ual para meter at eac h 
ti me p oi nt.
3. 4. 2. B aseli ne ch ar acteristics
Ra n d o mizati o n is stratifie d b y t he f oll o wi n g, as rec or de d i n t he I nteracti ve Res p o nse 
Tec h n ol o g y ( I R T) sys te m:

E C O G P S ( 0 vs 1);

Re gi o n ( U nite d States vs Ca na da/ Wester n E ur o pe vs t he rest of t he w orl d).
T he pri mar y  a nalys es of P F S a n d O S f or P D-L 1  p ositi ve patie nts, as well as t he sec o n dar y 
a nal ys es of P F S a n d O S f or patie nts u nselecte d f or P D-L 1  e x pressi o n will be stratifie d b y  
t hese ra n d o mizati o n stratificati o n fact ors.
Ot her b aseli ne c haracteristics (i ncl u di n g de m o gra p hics, p h y sical meas ure me nts, disease 
hist or y  a n d pri or a nti-ca ncer t hera pies) are descri be d i n Secti o n 6.5 . 1.  T hese baseli ne 
c haracteristics are n ot pla n ne d t o be i ncl u de d as stratificati o n varia bles or c o variates i n 
statistical m o dels u nless ot her wise s pecifie d i n Secti o n 6. 
3. 5. S afet y E n d p oi nts
3. 5. 1. A d verse eve nts
Tre at me nt -E m er ge nt A d verse E ve nts
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are t h ose e ve nts wit h o nset dates occ urri n g 
d uri n g t he o n -treat me nt peri o d f or t he first ti me, or if t he w orse ni n g of a n e ve nt is d uri n g t he 
o n-treat me nt peri o d. 
O n -tre at me nt peri o d is defi ne d as t he ti me fr o m t he first d ose of st u d y treat me nt t hr o u g h 
mi ni m u m ( 3 0 da y s + last d ose of st u d y treat me nt, start da y of ne w a nti-ca ncer dr u g t hera p y –
1 da y ). T he start da y  of ne w a nti-ca ncer dr u g t hera p y after t he first d ose of st u d y treat me nt is 
deri ve d as o utli ne d i n Secti o n 5. 2. 5 .


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 2 1
A d verse E ve nts of S peci al I nterest ( A E SIs)
A E SI s are i m m u ne-relate d a d verse e ve nts (ir A E) a n d i nf usi o n-relate d reacti o ns (IR Rs).  T he 
criteria f or classificati o n of a n A E as a n ir A E or I R R are descri be d i n A p pe n dices 1 a n d 2 , 
res pecti vely .
3- Tier A d verse E ve nts
It s h o ul d be rec o g nize d t hat m ost st u dies are n ot desi g ne d t o relia bly de m o nstrate a ca usal 
relati o ns hi p bet wee n t he use of a p har mace utical pr o d uct a n d a n a d verse e ve nt or a gr o u p of 
a d verse e ve nts. E xce pt f or select e ve nts i n u ni q ue sit uati o ns, st u dies d o n ot e m pl o y f or mal 
a dj u dicati o n pr oce d ures f or t he p ur p ose of e ve nt classif icati o n. As s uc h, safet y a nalys es are
ge nerall y c o nsi dere d as a n e x pl orat or y  a nalys is a n d its p ur p ose is t o ge nerate h yp ot heses f or 
f urt her i n vesti gati o n. T he 3-tier a p pr oac h facilitates t hese e x pl orat or y a nal yse s.
A d verse e ve nts a n d cl usters of a d verse e ve nts, of a n y  ca usality a n d treat me nt -relate d, will 
als o be s u m marize d f oll o wi n g a 3 -tier a p pr oac h.  U n der t his a p pr oac h, A Es are classifie d i nt o 
1 of 3 tiers.  
Tier -1 e ve nts : T hese are pre-s pecifie d e ve nts or cl usters of e ve nts of cli nical i m p orta nce a n d
will be descri be d i n t he Safet y Re vie w Pla n.   
Tier -2 e ve nts : T hese are e ve nts t hat are n ot Tier-1 b ut are “c o m m o n”.  A Me d D R A P T is 
defi ne d as a T ier-2 e ve nt if it is re p orte d b y  
a)
at least 1 0 % of patie nts wit h a n y  gra de i n a ny t reat me nt ar m, or
b)
at least 5 % of patie nts wit h G ra de 3, 4 or 5 i n a n y  treat me nt ar m.  
Tier -3 e ve nts : All ot her A Es t hat are classifie d neit her as T ier-1 n or T ier- 2.
4. A N A L Y SI S S E T S
Data f or all patie nts will be assesse d t o deter mi ne if patie nts meet t he criteria f or i ncl usi o n i n 
eac h a nal ys is p o p ulati o n pri or t o releasi n g t he data base a n d classificati o ns will be 
d oc u me nte d per Pfizer’s sta n dar d o perati n g pr oce d ures.
O nl y  patie nts w h o si g ne d i nf or me d c o nse nt will be i ncl u de d i n t he a nalys is sets bel o w.
Ta ble 4 s u m marizes t he use of t he a nal y sis sets f or efficac y, safety, baseli ne c haracteristics 
a n d e x p os ure. 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 2 2
T a ble 4.
St atistic al A n al yses b y A n al ysis Set
E n d p oi nts
F ull A n al ysis Set
Per Pr ot oc ol A n al ysis Set
S afet y A n al ysis Set
Baseli ne C haracteristics


Pri or a n d C o nc o mita nt 
T hera pies


E x p os ure

Efficac y: Pri mar y 


Efficac y: Sec o n dar y 

( ke y sec o n dar y o nl y*)
Safet y

* ke y sec o n dar y e n d p oi nts are O S a n d P F S f or patie nts u nselecte d f or P D-L 1 e x pressi o n
4. 1. F ull A n al ysis Set
T he f ull a nal ys is set ( F A S) will i ncl u de all ra n d o mize d patie nts.  Patie nts will be classifie d 
acc or di n g t o t he st u d y treat me nt assi g ne d at ra n d o mizati o n. 
4. 2. S afet y A n al ysis Set
T he safet y a nal ys is set will i ncl u de all patie nts w h o recei ve at least o ne d ose of st u d y dr u g. 
Patie nts will be classifie d acc or di n g t o t he st u d y treat me nt assi g ne d at ra n d o mizati o n u nless 
t he i nc orrect treat me nt(s) was/ were recei ve d t hr o u g h o ut t he d osi n g peri o d i n w hic h case 
patie nts will be classifie d acc or di n g t o t he first st u d y  treat me nt recei ve d. 
4. 3. Ot her A n al ysis Set s
4. 3. 1. Per -pr ot oc ol a n al ysis set
Per pr ot oc ol ( P P) a nal ys is set is a s u bset of t he F A S a n d will i ncl u de patie nts w h o d o n ot 
meet a n y of t he f oll o wi n g criteria t hat c o ul d i m pact t he ke y o bjecti ves of t he st u d y.  Patie nts 
w h o meet a n y of t he f oll o wi n g criteria will be e xcl u de d fr o m t he P P a nal ys is set. 

Patie nt di d n ot recei ve at least o ne d o se of t he ra n d o mize d st u d y treat me nt;

A p plic a ble o nly f or P F S: Patie nt wit h o ut 
a t u m or assess me nt ≥
6
wee ks 
after 
ra n d o mizati o n ( u nless P D b y  BI C R or deat h is o bser ve d bef ore t hat ti me i n w hic h case 
t he patie nt will n ot be e xclu de d fr o m t he P P a nal ysis set );

A p plic a ble o nly f or P F S: Patie nt wit h o ut meas ura ble disease at baseli ne b y BI C R ;

E C O G stat us > 1 ;

A n y  pri or t hera pies as defi ne d b y t he e xcl usi o n criteri o n 1 of t he st u d y pr ot oc ol:
-
Pri or s y ste mic t hera p y directe d at a d va nce d or metastatic R C C.
-
Pri or a dj u va nt or ne oa dj u va nt t hera p y f or R C C if disease pr o gressi o n or rela pse has 
occ urre d d uri n g or wit hi n 1 2 m o nt hs after t he last d ose of treat me nt.
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 2 3
-
Pri or i m m u n ot hera p y  wit h I L-2, I F N -, or a nti-P D -1, a nti -P D -L 1, a nti -P D -L 2 , 
a nti-C D 1 3 7, or a nti -c yt ot o xic T-l ym p h oc y t e-ass ociate d a nti ge n -4 ( C T L A -4) a nti b o d y  
(i ncl u di n g i pili m u ma b), or a ny ot her a nti b o d y or dr u g s pecificall y tar geti n g T -cell 
c o-sti m ulati o n or i m m u ne c hec k p oi nt pat h wa ys.
-
Pri or t hera p y wit h a xiti ni b a n d/ or s u niti ni b as well as a n y pri or t hera pies wit h ot her 
V E G F pat h wa y  i n hi bit ors. 
N ote t hat t he pr ot oc ol o nl y  re q uires t hat patie nts ha ve meas ura ble disease at baseli ne as per 
i n vesti gat or assess me nt. H o we ver, si nce P F S b y BIC R is a pri mar y  e n d p oi nt, “ patie nts
wit h o ut meas ura ble disease at baseli ne b y B I C R” will be use d as a criteri o n t o e xcl u de 
patie nts fr o m t he P P a nal ysis set f or t h e se nsiti vit y a nal ys is of t he P F S b y BI C R e n d p oi nt. 
4. 3. 2. P K a n al ysis set s
T he P K c o nce ntrati o n a nal y sis set is a s u bset of t he safety a nal ys is set a n d will i ncl u de 
patie nts w h o ha ve at least o ne p ost -d ose c o nce ntrati o n meas ure me nt a b o ve t he l o wer li mit of 
q ua ntitati o n ( L L Q) f or a vel u ma b or a xiti ni b. 
T he P K para meter a nal ys is set is a s u bset of t he safet y a nalys is set a n d will i ncl u de patie nts 
w h o ha ve at least o ne of t he P K para meters of i nterest f or a vel u ma b or a xiti ni b.
4. 3. 3. Bi o m ar ker a n al ysis set 
T he bi o mar ker a nal ys is set f or bi o mar kers t hat are meas ure d o nly at scree ni n g is a s u bset of 
t he safety a nal ys is set a n d will i ncl u de patie nts w h o ha ve at least o ne scree ni n g bi o mar ker 
assess me nt.
T he bi o mar ker a nal ys is set f or bi o mar kers t hat are meas ure d se q ue ntiall y is a s u bset of t he 
safety a nal ysis set a n d will i ncl u de patie nts w h o ha ve at least o ne baseli ne a n d o ne o n -
treat me nt bi o mar ker assess me nt f or t he sa me mar ker.
A nal y sis sets will be defi ne d se parately f or bl o o d -base d a n d t u m or tiss ue -base d bi o mar kers .
4. 3. 4. I m m u n o ge nicit y a n al ysis set
T he i m m u n o ge nicit y  a nal ysis set is a s u bset of t he safety a nal ysis set a n d will i ncl u de 
patie nts w h o ha ve at least o ne A D A/ n A b sa m ple c ollecte d for a vel u ma b i n Ar m A .
4. 3. 5. P R O a n al ysis set
T he P R O a nal ys is set will i ncl u de all ra n d o mize d patie nts ( F A S).  
5. G E N E R A L M E T H O D O L O G Y A N D C O N V E N TI O N S
5. 1. H y p ot heses a n d Decisi o n R ules
All refere nces t o P F S i n Secti o n 5. 1. 1 a n d Secti o n 5. 1. 2 refer t o P F S b y  BI C R assess me nt 
e ve n w he n n ot s pecificall y state d.


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5. 1. 1. H y p ot heses a n d s a m ple size deter mi n ati o n
T he f oll o wi n g statistical h y p ot heses will be teste d t o a d dress t he pri mar y  o bjecti ves:
H 0 1: H RP F S + ≥1 vs H 1 1: H RP F S + < 1
H 0 2: H RO S + ≥1 vs H 1 2: H RO S + < 1
w here H R P F S + a n d H R O S + are t he hazar d rati os ( Ar m A vs. Ar m B) of P F S a n d O S,
res pecti vely, i n P D - L 1 p ositi ve patie nts.
I n a d diti o n t he f oll o wi n g statistical h yp ot heses will be teste d t o a d dress t he sec o n dar y  
o bjecti ves:
H 0 3: H RP F S ≥1 vs H 1 3: H RP F S < 1
H 0 4: H RO S ≥1 vs H 1 4: H R O S < 1
w here H R P F S a n d H R O S are t he hazar d rati os ( Ar m A vs. Ar m B) of P F S a n d O S,
res pecti vely, f or patie nts u nselecte d f or P D-L 1 e x pressi o n .
O verall t y pe I -err or will be mai ntai ne d at or bel o w 1 -si de d 0. 0 2 5 by all ocati n g α = 0. 0 0 4 ( α1)
t o t he P F S c o m paris o n i n P D -L 1 + patie nts a n d b y all ocati n g α = 0. 0 2 1 ( α2) t o t he O S 
c o m paris o n i n P D - L 1 p ositi ve patie nts. A gate kee pi n g pr oce d ure will be use d t o all o w 
f urt her testi n g of P F S a n d O S f or patie nts u nselecte d f or P D-L 1 e x pressi o n as descri be d i n 
Fi g ur e 1 . T he si g nifica nce le vels f or eac h test will als o ta ke i nt o acc o u nt t he gr o u p se q ue ntial 
nat ure of t he desi g n.


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Fi g ure 1 Testi n g Str ate g y
A p pr o xi matel y  8 3 0 patie nts , i ncl u di n g a mi ni m u m of 5 8 0 P D-L 1  p ositi ve patie nts, will be 
ra n d o mize d t o t he treat me nt ar ms usi n g a 1: 1 ra n d o mizati o n, stratifie d b y E C O G P S ( 0 vs 1) 
a n d re gi o n ( U nite d States vs Ca na da/ Wester n E ur o pe vs t he rest of t he w orl d) .
F or t he pri mar y  P F S c o m paris o n, 3 3 6 P F S e ve nts b y BI C R assess me nt f or P D -L 1  p ositi ve 
patie nts will be re q uire d t o ha ve at least 9 0 % p o wer t o detect a hazar d rati o of 0. 6 5 usi n g a 1 -
si de d l o g-ra n k test at a si g nifica nce le vel of 0. 0 0 4, a n d a 2- l o o k gr o u p se q ue ntial desi g n wit h 
La n -De Mets ( O’Brie n -Fle mi n g) α- s pe n di n g f u ncti o n t o determi ne t he efficac y  b o u n dar y a n d 
a Ga m ma Fa mil y  (-1 5) β -s pe n di n g f u ncti o n t o deter mi ne t he n o n -bi n di n g f utilit y  b o u n dar y .
F or t he pri mar y  O S c o m paris o n, 3 6 8 O S e ve nts f or P D -L 1 p osit i ve patie nts will be re q uire d 
t o ha ve at least 9 0 % p o wer t o detect a hazar d rati o of 0. 7 0 usi n g a 1 -si de d l o g-ra n k test at a 
si g nifica nce le vel of 0. 0 2 1, a n d a 4- l o o k gr o u p -se q ue ntial desi g n wit h La n-De Mets ( O ’Brie n -
Fle mi n g) α- s pe n di n g f u ncti o n t o deter mi ne t he efficac y b o u n dar y a n d a Ga m ma Fa mil y (-3) 
β- s pe n di n g f u ncti o n t o deter mi ne t he n o n-bi n di n g f utilit y  b o u n dar y.
T he sa m ple size f or t his st u d y  is deter mi ne d base d o n t he f oll o wi n g: 
1.
t he me dia n P F S f or patie nts recei vi n g s u niti ni b is 1 1 m o nt hs (S ute nt S u m mar y  of Pr o d uct 
C haracteristics ) a n d t he me dia n P F S f or patie nts recei vi n g a vel u ma b i n c o m bi nati o n w it h 
a xiti ni b is 1 6. 9 m o nt hs f or P D -L 1 p osit i ve patie nts a n d 1 5. 7 m o nt hs f o r patie nts 
u nselecte d f or P D -L 1 e x pressi o n; t his, c orres p o n ds t o a hazar d rati o ( H R ) of 0. 6 5 a n d 0. 7, 
res pecti vely u n der t he e x p o ne ntial m o del ass u m pti o n ;
2.
t he me dia n O S f or patie nts recei vi n g s u niti ni b is 2 6. 4 m o nt hs (S ute nt S u m mar y  of 
Pr o d uct C haracteristics ) a n d t he me dia n O S f or patie nts recei vi n g a vel u ma b i n 
c o m bi nati o n wit h a xiti ni b is 3 7. 7 m o nt hs f or P D L 1 p ositi ve patie nts a n d 3 5. 2 m o nt hs f or 
patie nts u nselecte d f or P D -L 1 e x pressi o n; t his c orres p o n ds t o a H R of 0. 7 a n d 0. 7 5, 
res pecti vely u n der t he e x p o ne ntial m o del ass u m pti o n;


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3.
P F S dr o p -o ut rate of a p pr o xi matel y  1 5 % a n d O S dr o p-o ut rate of a p pr o xi matel y  5 %;
4.
7 0 % of t he ra n d o mize d patie nts are P D -L 1 p ositi ve;
5.
n o n- u nif or m patie nt accr ual acc o m plis he d o ver a 2 1 m o nt h peri o d.
T he sa m ple size of a p pr o xi matel y  8 3 0 patie nts will als o all o w a n assess me nt of P F S a n d O S
i n patie nts u nselecte d f or P D -L 1  e x pressi o n.
If H0 1 is rejecte d t he n P F S i n patie nts u nselecte d f or P D-L 1 e x pressi o n ca n be teste d a n d 4 9 0 
P F S e ve nt s b y BI C R assess me nt will be re q uire d t o ha ve at least 9 0 % p o wer t o detect a H R 
of 0. 7 0 usi n g a 1 -si de d l o g ra n k test at a si g nifica nce le vel of 0. 0 0 4, a n d a 2-l o o k gr o u p 
se q ue ntial desi g n wit h La n-De Mets ( O’Brie n -Fle mi n g) α-s pe n di n g f u ncti o n t o deter mi ne t he 
efficac y b o u n dar y.
If eit her H0 2 or H 0 3 are rejecte d, t he n O S i n patie nts u nselecte d f or P D -L 1 e x pressi o n ca n be 
teste d at t he s u m of t he si g nifica nce le vels ass ociate d wit h t he si g nifica nt H 0 2 a n d H 0 3 tests 
(see Fi g ure 1 ). Wit h 5 3 4 O S e ve nts, t he p o wer is 9 1 % (if b ot h H
0 2 a n d H 0 3 are rejecte d), 9 0 % 
(if H0 2 is rejecte d a n d H0 3 is n ot rejecte d) or 7 4 % (if H
0 2 is n ot rejecte d a n d H0 3 is rejecte d) t o 
detect a H R of 0. 7 5 usi n g a 1 -si de d l o g ra n k test at a si g nifica nce le vel of 0. 0 2 5, 0. 0 2 1 or 
0. 0 0 4, res pecti vely, a n d a 4- l o o k gr o u p se q ue ntial desi g n wit h L a n -De Mets ( O ’Brie n -
Fle mi n g) α- s pe n di n g f u ncti o n t o deter mi ne t he efficac y b o u n dar y.
T he data c ut off f or t he pri mar y  P F S a nal ys is will occ ur after t he target n u m ber of P F S e ve nts 
b y  BI C R assess me nt i n P D -L 1 p ositi ve patie nts has bee n reac he d a n d t he last patie nt 
ra n d o mize d i n t he st u d y has bee n f oll o we d f or at least 1 2 m o nt hs after ra n d o mizati o n.
T he data c ut off f or t he pri mar y  O S a nalys is will occ ur after t he tar get n u m ber of deat hs i n 
P D -L 1  p ositi ve patie nts has bee n reac he d.
T he st u d y  will be c o nsi dere d p ositi ve if t he stratifie d l o g-ra n k test f or eit her P F S or O S i n 
P D -L 1  p ositi ve patie nts is si g nifica nt at t he res pecti ve α le vels.
5. 1. 2. Decisi o n r ules
T he i nteri m a n d t he pri mar y  a nalys es f or eac h e n d p oi nt will be perf or me d base d o n t he F ull 
A nal y sis Set after all patie nts ha ve bee n ra n d o mize d i n t he st u d y a n d t he tar get n u m ber of 
e ve nts has occ urre d as descri be d bel o w.  A ma xi m u m of 4 disti nct a nal y ses c ut offs are 
pla n ne d i n t he st u d y :

at t he ti me w he n a p pr o xi matel y 2 3 5 P F S e ve nts ( 7 0 % of t he e x pecte d 3 3 6 e ve nts) b y 
BI C R assess me nt ha ve occ urre d i n P D -L 1 p ositi ve patie nts , a n d all patie nts ha ve bee n 
ra n d o mize d i n t he st u d y (I A f or P F S a n d I A 1 f or O S);  

at t he ti me w he n 3 3 6 P F S e ve nts b y BI C R assess me nt ha ve occ urre d i n P D -L 1 p ositi ve 
patie nts , a n d t he last patie nt ra n d o mize d i n t he st u d y  has bee n f oll o we d f or at least 
1 2 m o nt hs after ra n d o mizati o n ( pri mar y a nalys is f or P F S a n d IA 2 f or O S) ;    

1 5 m o nt hs after t he pri mar y  a nalys is f or P F S (IA 3 f or O S);


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
at t he ti me w he n 3 6 8 deat hs ha ve occ urre d i n P D -L 1 p ositi ve patie nts ( pri mar y a nalys is 
f or O S).
A ma xi m u m of t w o a nal y ses will be perf or me d f or P F S (i n P D -L 1  p ositi ve patie nts a n d i n 
patie nts u nselecte d f or P D -L 1 e x pressi o n) :
1.
a n i nteri m a nal ys is after all patie nts ha ve bee n ra n d o mize d i n t he st u d y a n d at least 
2 3 5 ( 7 0 %) of t he 3 3 6 P F S e ve nts i n P D-L 1  p ositi ve patie nts ha ve bee n d oc u me nte d 
b y  BI C R, a n d
2.
t he fi nal a nalys is f or P F S after all patie nts ra n d o mize d i n t he st u d y ha ve bee n 
f oll o we d f or 1 2 m o nt hs a n d at least 3 3 6 P F S e ve nts i n P D-L 1  p ositi ve patie nts ha ve 
bee n d oc u me nte d b y B I CR.
A ma xi m u m of f o ur a nal yses will be perf or me d f or O S (i n P D-L 1  p ositi ve patie nts a n d i n 
patie nts u nselecte d f or P D -L 1 e x pressi o n) : 
1.
a n i nteri m a nal ys is at t he ti me of t he i nteri m a nalys is f or P F S; 
2.
a n i nteri m a nal ys is at t he pr ojecte d ti me of t he fi nal a nalys is f or P F S; 
3.
a n i nteri m a nal ys is 1 5 m o nt hs after t he fi nal a nalysis f or P F S;
4.
a fi nal a nal ys is f or O S w he n 36 8 deat hs i n P D -L 1  p ositi ve patie nts are o bser ve d.
T o pr otect t he i nte grit y of t he st u d y a n d t o preser ve t he t y pe I err or rate, a gate kee pi n g testi n g 
strate gy is i m ple me nte d a n d t he si g nifica nce le vels f or t he i nteri m a n d fi nal efficac y a nalys es 
f or eac h e n d p oi nt will be deter mi ne d b y  usi n g t he La n- De Mets pr oce d ure wit h a n O’ Brie n-
Fle mi n g st o p pi n g b o u n dar y as descri be d i n Secti o n 5. 1. 1 .  
Ta ble 5 d is pla ys t he ma xi m u m n u m ber of a nalys es e x pecte d f or eac h of t he pri mar y  
e n d p oi nts a n d t he ass ociate d efficac y  a n d f utilit y b o u n daries if t he a nalys es are perf or me d at 
t he pla n ne d n u m ber of e ve nts as s h o w n i n t he ta ble.  T he f utilit y b o u n daries are n o n-bi n di n g 
b ut t he st u d y  ma y be st o p pe d f or f utilit y if at t he ti me of t he first i nteri m a nal ysis, b ot h P F S 
a n d O S i n P D -L 1  p ositi ve patie nts cr oss t he c orres p o n di n g f utilit y b o u n daries.   If t he 
efficac y b o u n dar y is cr osse d, f or eit her of t he pri mar y e n d p oi nts, at t he ti me of a n i nteri m 
a nal ys is or at t he ti me of t he pri mar y a nal ysis t he n t he pri mar y o bjecti ve of t he st u d y will 
ha ve bee n de m o nstrate d.


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T a ble 5.
P F S a n d O S i n P D -L 1 p ositi ve p atie nts – Effic ac y a n d F utilit y B o u n d aries
E n d p oi nt
P F S i n P D -L 1 p ositi ve 
p atie nts
O S i n P D -L 1 p ositi ve p atie nts
A n al ysis
I A 1
P A
I A 1 
I A 2 
I A 3
P A
A n alysis c ut off 
tri g ger
2 3 5 P F S 
eve nts i n 
P D -L 1 +
3 3 6 P F S 
eve nts i n 
P D -L 1 +
2 3 5 P F S 
eve nts i n 
P D -L 1 +
3 3 6 P F S 
eve nts i n 
P D -L 1 +
1 5 m o nt hs 
after I A 2
3 6 8 de at hs i n 
P D -L 1 +
N u m ber of e ve nts 
(I nf or mati o n 
fracti o n)
2 3 5 ( 7 0 %)
3 3 6 ( 1 0 0 %)
1 2 5 ( 3 4 %)
1 9 5 ( 5 3 %) 
2 9 4 ( 8 0 %)
3 6 8 ( 1 0 0 %)
p- val ue (z -val ue) 
f or efficac y
< 0. 0 0 0 6
( <-3. 2 4 9 3)                       
< 0. 0 0 3 8
( < -2. 6 6 8 2)                      
< 0. 0 0 0 0 7
( < -3. 7 9 1 3)              
< 0. 0 0 1 5
( < -2. 9 6 8 6)             
< 0. 0 0 9 3
( <-2. 3 5 2 4)             
< 0. 0 1 8 0   
( <-2. 0 9 7 5)          
p- val ue (z -val ue) 
f or f utilit y a
> 0. 4 0 5 9
( > -0. 2 3 8 0)                          
N A
> 0. 6 4 1 1              
( > 0. 3 6 1 4)             
> 0. 3 6 7 2                
( >-0. 3 3 9 4)               
> 0. 0 8 7 9                
( >-1. 3 5 3 7)               
N A
a N o n -bi n di n g.   
I A 1 = i nteri m a nal ysis 1, I A 2 = i nteri m a nal ysis 2, I A 3 = i nteri m a nal ysis 3, P A = pri mar y a nal ysis
T he o bser ve d n u m ber of e ve nts at t he I As ma y n ot matc h t he pla n ne d n u m ber of e ve nts. T he efficac y a n d 
f utilit y b o u n daries will be u p date d base d o n t he act ual n u m ber of o bser ve d e ve nts usi n g t he pre -s pecifie d α-
a n d β-s pe n di n g f u ncti o ns.
Ta ble 6 dis pla y s t he a nal yses tri g gers f or P F S a n d O S i n patie nts u nselecte d f or P D -L 1 
e x pressi o n , as well as t he ass ociate d efficac y b o u n daries if t he a nalys es are perf or me d at t he 
pla n ne d n u m ber of e ve nts as s h o w n i n t he ta ble . As descri be d i n Secti o n 5. 1. 1 , t he 
si g nifica nce le vel f or t he a nalys es of t hese e n d p oi nts is deter mi ne d b y  t he gate kee pi n g
pr oce d ure. 
T a ble 6. 
P F S a n d O S f or p atie nts u nselecte d f or P D- L 1 e x pressi o n – Effic ac y 
B o u n d aries
E n d p oi nt
P F S i n p atie nts 
u nselecte d f or P D -L 1 
e x pressi o n
O S i n p atie nts u nselecte d f or P D -L 1 e x pressi o n
A n al ysis
I A 1
P A
I A 1 
I A 2 
I A 3
P A
A n alysis c ut off 
tri g ger
2 3 5 P F S 
eve nts i n 
P D -L 1 +
3 3 6 P F S 
eve nts i n 
P D -L 1 +
2 3 5 P F S 
eve nts i n 
P D -L 1 +
3 3 6 P F S 
eve nts i n 
P D -L 1 +
1 5 m o nt hs 
after I A 2
3 6 8 de at hs 
i n P D-L 1 +
N u m ber of e ve nts a
(I nf or mati o n 
3 4 3 ( 7 0 %)
4 9 0 ( 1 0 0 %)
1 8 2 ( 3 4 %) 
2 8 3 ( 5 3 %) 
4 2 7 ( 8 0 %)
5 3 4 ( 1 0 0 %)


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E n d p oi nt
P F S i n p atie nts 
u nselecte d f or P D -L 1 
e x pressi o n
O S i n p atie nts u nselecte d f or P D -L 1 e x pressi o n
A n al ysis
I A 1
P A
I A 1 
I A 2 
I A 3
P A
A n alysis c ut off 
tri g ger
2 3 5 P F S 
eve nts i n 
P D -L 1 +
3 3 6 P F S 
eve nts i n 
P D -L 1 +
2 3 5 P F S 
eve nts i n 
P D -L 1 +
3 3 6 P F S 
eve nts i n 
P D -L 1 +
1 5 m o nt hs 
after I A 2
3 6 8 de at hs 
i n P D-L 1 +
fracti o n) 
p- val ue (z -val ue) 
f or efficac y b
< 0. 0 0 0 6
( <-3. 2 4 7 8)                       
< 0. 0 0 3 8
( < -2. 6 6 8 3)                      
< 0. 0 0 0 1 2
( < -3. 6 6 5 6)              
< 0. 0 0 2 0
( < -2. 8 7 2 6)             
< 0. 0 1 1 5
( <-2. 2 7 2 7)               
< 0. 0 2 1 2 
( <-2. 0 2 8 6)          
a N u m ber of e ve nts e x pecte d u n der H 1 3 f or P F S (ass u mi n g a H R of 0. 7) a n d H1 4 f or O S (ass u mi n g a H R of 
0. 7 5).   
b T he p -val ues a n d z -val ues n ote d f or O S are t h ose ass ociate d w it h t he sce nari o w he n b ot h H0 2 a n d H 0 3 are 
rejecte d.
I A 1 = i nteri m a nal ysis 1, I A 2 = i nteri m a nal ysis 2, I A 3 = i nteri m a nal ysis 3, P A = pri mar y a nal ysis
T he o bser ve d n u m ber of e ve nts at t he I As ma y n ot matc h t he pla n ne d n u m ber of e ve nts. T he efficac y a n d 
f utilit y b o u n daries will be u p date d base d o n t he act ual n u m ber of o bser ve d e ve nts usi n g t he pre -s pecifie d 
α- s pe n di n g f u ncti o ns.
Si nce t he o bser ve d n u m ber of e ve nts at t he i nteri m a nal y sis ma y n ot be e xactl y e q ual t o t he 
pla n ne d n u m ber of e ve nts, t he efficac y  a n d f utilit y b o u n daries will be u p date d base d o n t he 
act ual n u m ber of o bser ve d e ve nts usi n g t he pre -s pecifie d α-a n d β-s pe n di n g f u ncti o ns. 
T heref ore, t he o bser ve d Z -test statistic at t he i nteri m a nal ysis will be c o m pare d wit h t he 
u p date d efficac y  a n d, f or t he pri mar y e n d p oi nts, f utilit y b o u n daries.  If t he st u d y c o nti n ues t o 
fi nal anal ys is, t he p- val ue t hat will be use d t o declare statistical si g nifica nce at t he fi nal 
a nal ys is f or eac h e n d p oi nt will be base d o n t he act ual n u m ber of e ve nts d oc u me nte d at t he 
c ut- off date f or t he fi nal a nalys is, t he α alrea d y s pe nt at t he i nteri m a nalys is a n d t he 
gate kee pi n g testi n g strate g y . F urt her details are pr o vi de d i n Secti o n 7.  
Base d o n t he st o p pi n g b o u n daries defi ne d a b o ve a n d t he ti mi n g of t he i nteri m a n d fi nal 
a nal ys es as descri be d a b o ve, t he desi g n has t he f oll o wi n g o peratin g c haracteristics.
T a ble 7
Si m ul ate d c u m ul ati ve pr o b a bilities t o st o p f or effic ac y or f utilit y at t he 
i nteri m or fi n al P F S a n al ysis i n P D -L 1 p ositi ve p atie nts
Sce n ari o
L o o k
N u m ber 
of P F S 
e ve nts
C ale n d ar Ti me 
( mo nt hs)
P( Reject H 0 1)
P( Reject H 1 1)
H 0 1 is tr ue ( H R = 1)
I nteri m
2 3 5
2 3
0. 0 0 0 8
0. 5 9 3 3
Fi nal
3 3 6
2 9
0. 0 0 4 9 
0. 9 9 5 1
H 1 1 is tr ue ( H R =0. 6 5 )
I nteri m
2 3 5
2 5
0. 5 0 8 8 
0. 0 0 1 1
Fi nal
3 3 6
3 2
0. 8 9 1 8 
0. 1 0 8 2
Si m ulati o ns perf or me d i n E A S T 6. 3 wi t h n u m ber of si m ulati o ns = 1 0, 0 0 0 a n d see d =1 4 4 1 0 1 4


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T a ble 8. 
Si m ul ate d c u m ul ati ve pr o b a bilities t o st o p f or effic ac y or f utilit y at t he 
i nteri m or fi n al O S a n al yses i n P D -L 1 p ositi ve p atie nts
Sce n ari o
L o o k
N u m ber 
of O S 
e ve nts
C ale n d ar Ti me 
( mo nt hs)
P( Reject H 0 2)
P( Reject H 1 2)
H 0 2 is tr ue ( H R = 1)
I nteri m 1
1 2 5
2 3
0. 0 0 0 1
0. 3 6 6 8
I nteri m 2
1 9 5
2 9
0. 0 0 1 3
0. 6 5 5 4
I nteri m 3
2 9 4
4 1
0. 0 1 0 0 
0. 9 1 5 6
Fi nal
3 6 8
5 3
0. 0 1 9 8
0. 9 8 0 2
H 1 2 is tr ue ( H R = 0. 7 0)
I nteri m
1 2 5
2 5
0. 0 3 5 0
0. 0 0 9 8
I nteri m 2
1 9 5
3 2
0. 3 0 9 5
0. 0 2 2 6
I nteri m 3
2 9 4
4 6
0. 7 4 9 5 
0. 0 5 3 8
Fi nal
3 6 8
6 1
0. 8 9 4 3
0. 1 0 5 7
Si m ulati o ns perf or me d i n E A S T 6. 3 w it h n u m ber of si m ulati o ns = 1 0, 0 0 0 a n d see d = 2 5 6 4 1 0 5
5. 2. Ge ner al Met h o ds
As descri be d i n Secti o n 3. 4, i n t his st u d y  ‘tre at me nt ar m’ refers t o o ne of t he f oll o wi n g:

Ar m A = a vel u ma b pl us a xiti ni b;

Ar m B = s u niti ni b.
E n d p oi nts will be s u m marize d base d o n t he a nal y sis sets descri be d i n Ta ble 4 b y treat me nt 
ar m, u nless ot her wise s pecifie d.
5. 2. 1. D at a h a n dli n g after t he c ut -off d ate
Data after t he c ut -off date ma y  n ot u n der g o t he clea ni n g pr ocess an d will n ot be dis pla y e d i n 
a n y listi n gs or use d f or s u m mar y statistics, statistical a nalys es or i m p utati o ns.
5. 2. 2. P o oli n g of ce nters
I n or der t o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss ce nters.  
T he ‘ce nter’ fact or will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p a nal ys es d ue 
t o t he hi g h n u m ber of partici pati n g ce nters i n c o ntrast t o t he a ntici pate d s mall n u m ber of 
patie nts ra n d o mize d at eac h ce nter.
5. 2. 3. Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles
C o nti n u o us v aria bles will be s u m marize d usi n g descri pti ve statistics i.e., n u m ber of n o n -
missi n g val ues a n d n u m ber of missi n g val ues [i.e., n ( missi n g)], mea n, me dia n, sta n dar d 
de viati o n ( S D), mi ni m u m, ma xi m u m a n d first a n d t hir d q uartile ( Q 1 a n d Q 3). 
Q ualitati ve varia bles will be s u m marize d b y  fre q ue nc y c o u nts a n d perce nta ges. U nless 
ot her wise s pecifie d, t he calc ulati o n of pr o p orti o ns will i ncl u de t he missi n g cate g or y. 


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T heref ore c o u nts of missi n g o bser vati o ns will be i ncl u de d i n t he de n o mi nat or a n d pre se nte d 
as a se parate cate g or y.
I n case t he a nalys is refers o nl y t o certai n visits, perce nta ges will be base d o n t he n u m ber of 
patie nts still prese nt i n t he st u d y  at t hat visit, u nless ot her wise s pecifie d.
5. 2. 4. Defi niti o n of st u d y d a y
Start da y  of st u d y treat me nt is t he da y of t he first d ose of st u d y treat me nt.
T he st u d y  d a y f or assess me nts occ urri n g o n or after t he start of st u d y treat me nt (e. g., a d verse 
e ve nt o nset, t u m or meas ure me nt) will be calc ulate d as:
St u d y  d a y = Date of t he assess me nt/e ve nt - start of stu d y  treat me nt + 1. 
T he st u d y  d a y f or assess me nts occ urri n g pri or t o t he first d ose of st u d y treat me nt (e. g.,
baseli ne c haracteristics, me dical hist or y ) will be ne gati ve a n d calc ulate d as:
St u d y  d a y = Date of t he assess me nt/e ve nt - start of st u d y treat me nt.
T he st u d y  d a y will be dis pla ye d i n all rele va nt data listi n gs.
5. 2. 5. Defi niti o n of st art of ne w a nti -c a ncer dr u g t her a p y
Start date of ne w a nti -ca ncer dr u g t hera p y is use d t o deter mi ne t he e n d of t he o n -treat me nt 
peri o d (see Secti o n 5. 2. 7).
T he start date of ne w a nti -ca ncer dr u g t hera p y is t he earliest start date of a nti -ca ncer dr u g 
t hera py rec or de d i n t he ‘ F oll o w -u p Ca ncer T hera p y ’ e C R F pa ges t hat is after t he first d ose of 
st u d y treat me nt. W he n t he start date of a nti-ca ncer dr u g t hera p y is missi n g or partiall y 
missi n g, t he i m p utati o n r ules descri be d i n Secti o n 5. 3. 3. 4 s h o ul d be a p plie d usi n g o nl y  data 
fr o m t he ‘ F oll o w-u p Ca ncer T hera p y’  e C R F pa ges.
5. 2. 6. Defi niti o n of st art of ne w a nti -c a ncer t her a p y
Start date of ne w a nti -ca ncer t hera p y ( dr u g, ra diati o n, s ur ger y ) is use d f or ce ns ori n g i n 
efficac y a nalys es (see Secti o n 6. 1. 1 a n d Secti o n 6. 2. 2 ).
T he start date of ne w a nti -ca ncer t hera p y is t he earliest date after ra n d o mizati o n a m o n gst t he 
f oll o wi n g:

Start date of a nti -ca ncer dr u g t hera p y rec or de d i n t he ‘ F oll o w-u p Ca ncer T hera p y’ 
e C R F pa ges

Start date of ra diati o n t hera p y rec or de d i n ‘ C o nc o mita nt Ra diati o n T hera p y’, a n d 
‘ F oll o w-u p Ra diati o n T hera p y’ e C R F pa ges wit h ‘ Treat me nt I nte nt’ = ‘ C urati ve i n 
i nte nt’ 

S ur ger y  date rec or de d i n ‘ C o nc o mita nt S ur ger y’, a n d ‘ F oll o w-u p S ur ger y ’ e C R F 
pa ges w he n ‘ S ur ger y  O utc o me’ = ‘ Resecte d’ or ‘ Partiall y Resecte d’.  


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W he n start date of a nti -ca ncer t hera p y is missi n g or partiall y missi n g, t he i m p utati o n r ules 
descri be d i n Secti o n 5. 3. 3. 4 s h o ul d be a p plie d usi n g ‘ F oll o w-u p Ca ncer T hera p y’, 
‘ C o nc o mita nt Ra diati o n T hera py’, ‘ F oll o w -u p Ra diati o n T hera p y ’, ‘ C o nc o mita nt S ur ger y’, 
a n d ‘ F oll o w -u p S ur ger y ’ e C R F pa ges.
5. 2. 7. Defi niti o n of o n -tre at me nt peri o d
Safet y  e n d p oi nts will be s u m marize d base d o n t he o n-treat me nt peri o d u nless other wise 
s pecifie d.
O n -treat me nt peri o d is defi ne d as t he ti me fr o m t he first d ose of st u dy treat me nt t hr o u g h 
mi ni m u m ( 3 0 da y s + last d ose of st u d y treat me nt, start da y of ne w a nti-ca ncer dr u g t hera p y –
1 da y ).
Safet y  data c ollecte d o utsi de t he o n-treat me nt peri o d as descri be d a b o ve will be liste d a n d 
fla g ge d i n listi n gs b ut will n ot be s u m marize d.
5. 2. 8. St a n d ar d deri v ati o ns a n d re p orti n g c o n ve nti o ns
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da y s i nt o wee ks, m o nt hs or years:   
1 wee k = 7 da y s, 1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys.
De m o gra p hics a n d p h ys ical meas ure me nts:

A ge [ y ears]: 
-
( date of gi ve n i nf or me d c o nse nt - date of birt h + 1) / 3 6 5. 2 5
-
I n case of missi n g da y, da y o nly:  A ge [ years]: ( year/ m o nt h of gi ve n i nf or me d c o nse nt 
– ye ar/ m o nt h of birt h)
-
I n case o nly ye ar of birt h is gi ve n: A ge [ y ears]: ( year of gi ve n i nf or me d c o nse nt -
ye ar of birt h)
T he i nte ger part of t he calc ulate d a ge will be use d f or re p orti n g p ur p ose s. 

B MI  ( k g/ m2) = wei g ht ( k g)/[ hei g ht ( m)]2
F or re p orti n g c o n ve nti o ns, mea n a n d me dia n s h o ul d ge nerall y be dis pla ye d t o o ne m ore 
deci mal place t ha n t he ra w data a n d sta n dar d de viati o n s h o ul d be dis pla y e d t o t w o m ore 
deci mal places t ha n t he ra w data. Perce nta ges will be re p orte d t o o ne deci mal place. T he 
r o u n di n g will be perf or med t o cl osest i nte ger / first deci mal usi n g t he c o m m o n mi d -p oi nt 
bet wee n t he t w o c o nsec uti ve val ues. E. g. , 5. 1 t o 5. 4 will be r o u n de d t o a n i nte ger of 5, a n d 
5. 5 t o 5. 9 will be r o u n de d t o a n i nte ger of 6.
5. 2. 9. U nsc he d ule d visits
Ge nerall y , data c ollecte d at u nsc he d ule d visits will be i ncl u de d a n d a nalyz e d f or b ot h safet y 
a n d efficac y a nalys es i n t he sa me fas hi o n as t he data c ollecte d at sc he d ule d visits e xce pt 
w here ot her wise n ote d i n t he secti o ns t hat f oll o w. Descri pti ve statisti cs ( mea n, S D, me dia n, 


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mi ni m u m, ma xi m u m, q uartiles) b y  n o mi nal visit or ti me p oi nt f or safety e n d p oi nts s uc h as 
la b orat or y meas ure me nts, E C Gs a n d vital si g ns will i ncl u de o nl y data fr o m sc he d ule d visits.
5. 2. 1 0. A de q u ate b aseli ne t u m or assess me nt
A de q uate baseli ne is defi ne d usi n g t he f oll o wi n g criteria:

All baseli ne assess me nts m ust be wit hi n 2 8 da y s pri or t o a n d i ncl u di n g t he date of 
ra n d o mizati o n.

All d oc u me nte d lesi o ns m ust ha ve n o n- missi n g assess me nts (i.e. n o n- missi n g 
meas ure me nts f or tar get lesi o ns a n d n o n -mi ssi n g lesi o ns assess me nt stat us at baseli ne f or 
n o n- tar get lesi o ns).
5. 2. 1 1. A de q u ate p ost -b aseli ne t u m or assess me nt
A n a de q uate p ost -baseli ne assess me nt is defi ne d as a n assess me nt w here a res p o nse of C R, 
P R, S D, n o n -C R/ n o n -P D, or P D ca n be deter mi ne d (see Secti o n 6. 2. 2. 5).  Ti me p oi nts w here 
t he res p o nse is n ot e val ua ble ( N E ) or n o assess me nt was perf or me d will n ot be use d f or 
deter mi ni n g t he ce ns ori n g date.
5. 3.
Met h o ds t o M a n a ge Missi n g D at a
5. 3. 1. Missi n g d at a
U nless ot her wise s pecifie d, all data will be e val uate d as o bser ve d, a n d n o i m p utati o n met h o d 
f or missi n g val ues will be use d.
I n all patie nt data listi n gs i m p ute d val ues will be prese nte d.  I n all listi n gs i m p ute d 
i nf or mati o n will be fla g ge d.
Missi n g statistics, e. g. w he n t he y  ca n n ot be calc ulate d, s h o ul d be prese nte d as ‘ N D’ or ‘ N A’.  
F or e xa m ple, if N = 1, t he meas ure of varia bilit y ( S D) ca n n ot be c o m p ute d a n d s h o ul d be 
prese nte d as ‘ N D’ or ‘ N A’. 
5. 3. 1. 1. P h ar m ac o ki netic co nce ntr ati o ns
C o nce ntr ati o ns Bel o w t he Li mit of Q u a ntific ati o n
F or all calc ulati o ns, fi g ures a n d esti mati o n of i n di vi d ual p har mac o ki netic para meters, all 
c o nce ntrati o ns assa ye d as bel o w t he le vel of q ua ntificati o n ( B LQ) will be set t o zer o. I n l o g -
li near pl ots t hese val ues will n ot be re prese nte d.  T he B LQ val ues will be e xcl u de d fr o m 
calc ulati o ns of ge o m etric mea ns a n d t heir CI s. A state me nt si milar t o ‘ All val ues re p orte d as 
B L Q ha ve bee n re place d wit h zer o’ s h o ul d be i ncl u de d as a f o ot n ote t o t he a p pr o priate ta bles 
a n d fi g ures.
De vi ati o ns, Missi n g C o nce ntr ati o ns a n d A n o m al o us V al ues
I n s u m mar y ta bles a nd pl ots of me dia n pr ofiles, c o nce ntrati o ns will be set t o missi n g if o ne 
of t he f oll o wi n g cases is tr ue:
1.
A c o nce ntrati o n has bee n re p orte d as N D (i.e., n ot d o ne) or N S (i.e., n o sa m ple);


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2.
A de viati o n i n sa m pli n g ti me is of s ufficie nt c o ncer n or a c o nce ntrat i o n has bee n 
fla g ge d as a n o mal o us b y t he cli nical p har mac ol o gist.
S u m mar y  statistics will n ot be prese nte d at a partic ular ti me p oi nt if m ore t ha n 5 0 % of t he 
data are missi n g.  F or a nal y sis of p har mac o ki netic c o nce ntrati o ns, n o val ues will be i m p ute d 
f or missi n g data.
5. 3. 1. 2. P h ar m ac o ki netic p ar a meters
W het her act ual or n o mi nal P K sa m pli n g ti me will be use d f or t he deri vati o n of P K 
para meters will be deter mi ne d b y  t he res ults of i nteri m P K a nal yses.  If a P K para meter 
ca n n ot be deri ve d fr o m a patie nt’s c o nce ntrati o n data, t he para meter will be c o de d as N C 
(i.e., n ot calc ulate d).  N C val ues will n ot be ge nerate d be yo n d t he da y  t hat a patie nt 
disc o nti n ues.
I n s u m mar y ta bles, statistics will be calc ulate d by setti n g N C val ues t o missi n g. Statistics 
will n ot be prese nte d f or a partic ular treat me nt if m ore t ha n 5 0 % of t he data are N C.  F or 
statistical a nal yses (i.e., a nal ysis of varia nce), P K para meters c o de d as N C will als o be set t o 
missi n g.
If a n i n di vi d ual patie nt has a k n o w n biase d esti mate of a P K para meter ( d ue f or e xa m ple t o a 
de viati o n fr o m t he assi g ne d d ose le vel), t his will be f o ot n ote d i n s u m mar y  ta bles a n d will n ot 
be i ncl u de d i n t he calc ulati o n of s u m mar y statistics or statistical a nal ys es.
5. 3. 2. H a n dli n g of i nc o m plete d ates
5. 3. 2. 1. Dise ase hist or y
I nc o m plete dates f or dis ease hist or y (e. g., i nitial dia g n osis date, date of d oc u me nte d, l ocally 
a d va nce d, i n o pera ble or metastatic disease dia g n osis, date of res p o nse or pr o gressi o n i n pri or 
treat me nt) will be i m p ute d as f oll o ws:

If t he da y is missi n g, it will be i m p ute d t o t he 1 5 t h da y  of t he m o nt h. 

If b ot h da y a n d m o nt h are missi n g a n d t he year is pri or t o t he year of t he first st u d y 
treat me nt, t he m o nt h a n d da y will be i m p ute d as J ul y 1st.

If b ot h da y a n d m o nt h are missi n g a n d t he year is sa me as t he year of t he first st u d y 
treat me nt, t he m o nt h a n d da y will be i m p ute d as Ja n uar y 1st. 

If t he date is c o m pletel y missi n g, n o i m p utati o n will be perf or me d.
5. 3. 2. 2. A d verse eve nts
I nc o m plete A E -relate d dates will be i m p ute d as f oll o ws:

If t he A E o nset date is missi n g c o m pletel y, t he n t he o nset date will be re place d b y t he 
start of st u d y treat me nt.

If o nl y t he da y part of t he A E o nset date is missi n g, b ut t he m o nt h a n d year are e q ual t o 
t he start of st u d y treat me nt, t he n t he A E o nset date will be re place d b y t he start of st u d y 


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treat me nt. F or e xa m ple, if t he A E o nset date is --/J A N/ 2 0 1 5, a n d st u d y treat me nt start 
date is 1 5/J A N/ 2 0 1 5, t he n t he i m p ute d A E o nset date will be 1 5/J A N /2 0 1 5.

If b ot h t he da y a n d m o nt h of t he A E o nset date are missi n g b ut t he o nset year is e q ual t o 
t he start of st u d y treat me nt, t he n t he o nset date will be re place d b y t he start of st u d y 
treat me nt. F or e xa m ple, if A E o nset date is --/---/ 2 0 1 4, a n d st u d y treat me nt start date is 
1 9/ N O V/ 2 0 1 4, t he n t he i m p ute d A E o nset date will be 1 9/ N O V/ 2 0 1 4.

In all ot her cases t he missi n g o nset da y  or missi n g o nset m o nt h will be re place d b y 1.

I nc o m plete st o p date will be re place d b y t he last da y of t he m o nt h (if da y is missi n g 
o nl y ), if n ot res ulti n g i n a date later t ha n t he date of patie nt's deat h. I n t he latter case t he 
date of deat h will be use d t o i m p ute t he i nc o m plete st o p date. 

I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d.  If st o p date of A E is after 
t he d ate of c ut -off o utc o me of A E is o n g oi n g at c ut -off. 
5. 3. 2. 3. Pri or a n d c o nc o mit a nt me dic ati o ns
I nc o m plete pri or/c o nc o mita nt me dicati o n dates will be i m p ute d as f oll o ws:

If t he me dicati o n date is missi n g c o m pletel y, t he n t he me dicati o n date will be re place d b y 
t he start of st u d y treat me nt.

If t he da y of me dicati o n date is missi n g, b ut t he m o nt h a n d year are e q ual t o t he start of 
st u d y treat me nt, t he n t he me dicati o n date will be re place d by t he start of st u d y treat me nt. 
F or e xa m ple, if t he me dicati o n start date is --/J A N/ 2 0 1 5, a n d st u d y treat me nt start date is 
1 5/J A N/ 2 0 1 5, t he n t he i m p ute d me dicati o n start date will be 1 5/J A N /2 0 1 5. 

If b ot h t he da y a n d m o nt h of me dicati o n start date are missi n g b ut t he start year is e q ual 
t o t he start of st u d y treat me nt, t he n t he me dicati o n date will be re place d b y t he start of 
st u d y treat me nt. F or e xa m ple, if t he me dicati o n start date is --/---/ 2 0 1 4, a n d st u d y 
treat me nt start date is 1 9/ N O V/ 2 0 1 4, t he n t he i m p ute d me dicati o n start date will be 
1 9/ N O V/ 2 0 1 4.

I n all ot her cases t he missi n g me dicati o n da y  or missi n g me dicati o n m o nt h will be 
re place d by 1.

I nc o m plete st o p date will be re place d b y t he last da y of t he m o nt h (if da y is missi n g 
o nl y ), if n ot res ulti n g i n a date later t ha n t he date of patie nt's deat h. I n t he latter case t he
date of deat h will be use d t o i m p ute t he i nc o m plete st o p date. 

I n all ot her cases t he i nc o m plete me dicati o n st o p date will n ot be i m p ute d. 
5. 3. 2. 4. E x p os ure
N o i m p utati o n will be d o ne f or first d ose date.  Date of last d ose of st u d y  dr u g, if u n k n o w n or 
partiall y u n k n o w n , will be i m p ute d as f oll o ws:


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
If t he last date of st u d y dr u g is c o m pletel y missi n g a n d t here is n o E n d of T reat me nt 
e C R F pa ge a n d n o deat h date , t he patie nt s h o ul d be c o nsi dere d t o be o n g oi n g a n d use t he 
c ut-off date f or t he a nal ysis as t he last d o si n g date

If t he last date of st u d y dr u g is c o m pletel y or partiall y missi n g a n d t here is EIT H E R a n 
E n d of T reat me nt e C R F pa ge O R a deat h date a vaila ble ( wit hi n t he c ut-off date) , t he n 
i m p ute d last d ose date is:
= 3 1 D E C Y Y Y Y, if o nl y Year is a vaila ble a n d Year < Year of mi n ( E O T date, deat h date) 
= Last da y  of t he m o nt h, if b ot h Year a n d M o nt h are a vaila ble a n d Year = Year of mi n 
( E O T date, deat h date) a n d M o nt h < t he m o nt h of mi n ( E O T date, deat h date)
= mi n ( E O T date, deat h date), f or a ll ot her cases
5. 3. 3. I m p ut ati o n r ules f or d ate of l ast c o nt act a n d effic ac y assess me nts
5. 3. 3. 1. D ate of l ast c o nt act
T he date of last c o ntact will be deri ve d f or patie nts n ot k n o w n t o ha ve die d at t he a nal ys is 
c ut- off usi n g t he latest c o m plete date a m o n g t he f oll o wi n g:

All patie nt assess me nt dates ( bl o o d dra ws (la b orat or y , P K), vital si g ns, perf or ma nce 
stat us, E C G, t u m or assess me nts)

Start a n d e n d dates of a nti -ca ncer t hera pies a d mi nistere d after st u dy treat me nt 
disc o nti n uati o n

A E start a n d e n d dates

Last date of c o ntact c ollecte d o n t he ‘S ur vi val F oll o w - u p’ e C R F (d o n ot use date of 
s ur vi val f oll o w- u p assess me nt u nless stat us is ‘ali ve’)

St u d y  dr u g start a n d e n d dates

Ra n d o mizati o n date

Wit h dra wal of c o nse nt date

Date of disc o nti n uati o n o n dis p ositi o n e C R F pa ges ( d o n ot use if reas o n f or 
disc o nti n uati o n is l ost t o f oll o w -u p).
O nl y  dates ass ociate d wit h act ual e xa mi nati o ns of t he patie nt will be use d i n t he deri vati o n.  
Dates ass ociate d wit h a tec h nical o perati o n u nrelate d t o patie nt stat us s uc h as t he date a 
bl o o d sa m ple was pr ocesse d will n ot be use d. Assess me nt dates after t he c ut-off date will n ot 
be a p plie d t o deri ve t he last c o ntact date.
5. 3. 3. 2. De at h d ate
Missi n g or partial deat h dates will be i m p ute d base d o n t he last c o ntact date:

If t he date is missi n g it will be i m p ute d as t he da y  after t he date of last c o ntact 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 3 7

If t he da y or b ot h da y  a n d m o nt h is missi n g, deat h will be i m p ute d t o t he ma xi m u m of t he 
f ull ( n o n-i m p ute d) d a y  after t he date of last c o ntact a n d t he f oll o wi n g:
-
Missi n g da y :
1 st da y  of t he m o nt h a n d year of deat h
-
Missi n g da y  a n d m o nt h:
Ja n uar y 1st of t he ye ar of deat h
5. 3. 3. 3. T u m or assess me nts
All i n vesti gati o n dates (e. g. , X-ra y, C T sca n) m ust be c o m plete d wit h da y, m o nt h a n d year.
If t here are m ulti ple sca n dates ass ociate d wit h a n e valuati o n, i.e., ra di ol o gical assess me nts 
occ ur o ver a series of da y s rat her t ha n t he sa me da y, t he c h oice of date of assess me nt c o ul d 
i m pact t he date of pr o gressi o n a n d/ or date of res p o nse.  If t here are m ulti ple sca n dates 
ass ociate d wit h a n e val uati o n, t he earliest of t he sca n dates ass ociate d wit h t he e val uati o n 
will be use d as t he date of assess me nt.
If o ne or m ore i n vesti gati o n dates f or a n e val uati o n are i nc o m plete b ut ot her i n vesti gati o n 
dates are a vaila ble, t he i nc o m plete date(s) are n ot c o nsi dere d f o r calc ulati o n of t he 
assess me nt date a n d assess me nt date is calc ulate d as t he earliest of all i n vesti gati o n dates 
(e. g., X-ra y, C T-sca n).  
If all meas ure me nt dates f or a n e val uati o n ha ve n o da y  rec or de d, t he 1st of t he m o nt h is use d. 
If t he m o nt h is n ot c o m plete d, f or a n y of t he i n vesti gati o ns f or a n e val uati o n, t he res pecti ve 
assess me nt will be c o nsi dere d t o be at t he date w hic h is e xactl y bet wee n t he pre vi o us a n d t he 
f oll o wi n g assess me nt. If b ot h a pre vi o us a n d f oll o wi n g assess me nts are n ot a vaila ble, t his 
assess me nt will n ot be use d f or a n y calc ulati o ns.
5. 3. 3. 4. D ate of st art of ne w a nti -c a ncer t her a p y
I nc o m plete dates f or start date of ne w a nti -ca ncer t hera p y ( dr u g t hera p y, ra diati o n, s ur ger y) 
will be i m p ute d as f oll o ws a n d will be use d f or deter mi ni n g ce ns or i n g dates f or efficac y 
a nal ys es a n d i n t he deri vati o n of t he e n d of o n- treat me nt peri o d.  P D date bel o w refers t o P D 
date b y i n vesti gat or assess me nt.

T he e n d date of ne w a nti -ca ncer t hera p y will be i ncl u de d i n t he i m p utati o ns f or start date 
of ne w a nti -ca ncer t hera p y.  If t he e n d date of ne w a nti-ca ncer t hera p y is
o
c o m pletel y missi n g t he n it will be i g n ore d i n t he i m p utati o ns bel o w
o
partiall y  missi n g wit h o nl y year ( Y Y Y Y) a vaila ble t he n t he i m p utati o ns bel o w will 
c o nsi der 3 1 D E C Y Y Y Y as t he e n d date of t he ne w a nti-ca ncer t hera p y
o
partiall y  missi n g wit h o nl y m o nt h a n d year  a vaila ble t he n t he i m p utati o ns bel o w will 
c o nsi der t he last da y of t he m o nt h f or M M M Y Y Y Y as t he e n d date of t he ne w a nti-
ca ncer t hera p y

F or patie nts w h o ha ve n ot disc o nti n ue d st u d y treat me nt a t t he a nalys is c ut- off date, last 
d ose of st u d y  treat me nt is set t o t he a nalys is c ut- off date i n t he i m p utati o ns bel o w. 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 3 8

If t he start date of ne w a nti-ca ncer t hera p y is c o m pletel y or partiall y missi n g t he n t he 
i m p ute d start date of ne w a nti-ca ncer t hera p y is deri ve d as f oll o ws :
o
Start date of ne w a nti -ca ncer t hera p y is c o m pletel y missi n g
I m p ute d start date = mi n [ ma x( P D date + 1, last d ose of st u d y treat me nt + 1), e n d date 
of ne w a nti -ca ncer t hera p y]
o
O nl y  year ( Y Y Y Y) f or start of a nti- ca ncer t hera p y is a vail a ble
I F Y Y Y Y < Year of mi n [ ma x( P D date + 1, last d ose of st u d y treat me nt + 1), e n d 
date of ne w a nti -ca ncer t hera p y]  T H E N i m p ute d start date = 3 1 D E C Y Y Y Y; 
E L S E I F Y Y Y Y = Year of mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), 
e n d date of ne w a nti -ca ncer t hera p y]  
T H E N i m p ute d start date = mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), 
e n d date of ne w a nti -ca ncer t hera p y]
E L S E I F Y Y Y Y > Year of mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), 
e n d date of ne w a nti -ca ncer t hera p y]  
T H E N i m p ute d start date = 0 1J A N Y Y Y Y
o
B ot h Year ( Y Y Y Y) a n d M o nt h ( M M M) f or start of a nti- ca ncer t hera p y are a vaila ble
I F
Y Y Y Y = Year of mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), e n d 
date of ne w a nti -ca ncer t hera p y] , A N D
M M M
< M o nt h of mi n [ ma x( P D date + 1 da y , last d ose of st u d y treat me nt + 1 
da y ), e n d date of ne w a nti-ca ncer t hera p y]  
T H E N 
i m p ute d start date = D A Y ( Last da y of M M M) M M M Y Y Y Y ;
E L S E I F
Y Y Y Y = Year of mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), e n d 
date of ne w a n ti-ca ncer t hera p y] , A N D
M M M
= M o nt h of mi n [ ma x( P D date + 1 da y , last d ose of st u d y treat me nt + 1 
da y ), e n d date of ne w a nti-ca ncer t hera p y]  
T H E N 
i m p ute d start date = mi n [ ma x( P D date + 1 da y, last d ose of st u d y treat me nt + 1 
da y ), e n d date of ne w a nti-ca ncer t hera p y] );
E L S E I F
Y Y Y Y = Year of mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), e n d 
date of ne w a nti -ca ncer t hera p y] , A N D
M M M
> M o nt h of mi n [ ma x( P D date + 1 da y , last d ose of st u d y treat me nt + 1 
da y ), e n d date of ne w a nti-ca ncer t hera p y]  


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 3 9
T H E N 
i m p ute d start date = 0 1 M M M Y Y Y Y;
E L S E I F
Y Y Y Y < Year of mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), e n d 
date of ne w a nti -ca ncer t herap y ]
T H E N 
i m p ute d start date = D A Y ( Last da y of M M M) M M M Y Y Y Y;
E L S E I F
Y Y Y Y > Year of mi n [ ma x( P D date + 1, last d ose of st u d y  treat me nt + 1), e n d 
date of ne w a nti -ca ncer t hera p y]
T H E N 
i m p ute d start date = 0 1 M M M Y Y Y Y.
6. A N A L Y S E S A N D S U M M A RI E S
Refer t o Sect i o n 4 f or defi niti o ns of a nal ysis sets a n d Secti o n 5. 2 f or ge neral met h o d ol o g y. 
6. 1. Pri m ar y E n d p oi nts
6. 1. 1. Pr o gressi o n -free sur vi v al as assesse d b y BI C R per R E CI S T v 1. 1 i n P D -L 1 
p ositi ve p atie nts
6. 1. 1. 1. Pri m ar y a n al ysis
T he f oll o wi n g a nal ys es will be base d o n t he F A S usi n g t he strata assi g ne d at ra n d o mizati o n .
P D bel o w refers t o P D b y BI C R assess me nt.    
Pr o gressi o n -Free S ur vi val ( P F S) is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he 
date of t he first d oc u me ntati o n of P D or deat h d ue t o a n y  ca use, w hic he ver occ urs first.   
P F S data will be ce ns ore d o n t he date of t he last a de q uate t u m or assess me nt f or patie nts w h o 
d o n ot ha ve a n e ve nt ( P D or deat h), f or patie nts w h o start a ne w a nti -ca ncer t hera p y pri or t o 
a n e ve nt (see Secti o n 5. 2. 6) or f or patie nts wit h a n e ve nt after 2 or m ore missi n g t u m or 
assess me nts . Patie nts w h o d o n ot ha ve a n a de q uate baseli ne t u m or assess me nt or w h o d o n ot 
ha ve a n a de q uate p ost -baseli ne t u m or assess me nt will be ce ns ore d o n t he date of 
ra n d o mizati o n u nless deat h occ urre d o n or bef ore t he ti me of t he sec o n d pla n ne d t u m or 
assess me nt (i.e., ≤ 1 2 wee ks after t he date of ra n d o mizati o n) i n w hic h case t he deat h will be 
c o nsi dere d a n e ve nt. 
I n t his st u dy a ntit u m or acti vit y  will be assesse d t hr o u g h ra di ol o gical t u m or assess me nts 
c o n d ucte d at scree ni n g a n d e ver y  6 wee ks ( + 7 da ys wi n d o w all o we d) u ntil P D re gar dless of 
i nitiati o n of s u bse q ue nt a nti-ca ncer t hera p y.  After 1 8 m o nt hs fr o m t he date of 
ra n d o mizati o n, t u m or assess me nts will be c o n d ucte d less fre q ue ntly, i.e., at 1 2- wee k 
i nter vals ( + 7 da ys wi n d o w all o we d).


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 4 0
T he ce ns ori n g a n d e ve nt date o pti o ns t o be c o nsi dere d f or t he P F S a n d D R a nal ys is are 
prese nte d i n Ta ble 9.  
P F S ( m o nt hs) = [ date of e ve nt or ce ns ori n g– date of ra n d o mizati o n + 1]/ 3 0. 4 3 7 5
T a ble 9.  
O utc o me a n d e ve nt d ates f or P F S a n d D R a n al yses
Sce n ari o
D ate of e ve nt/ce ns ori n g
O utc o m e
N o a de q uate baseli ne assess me nt
Date of ra n d o mizati o n
Ce ns ore d a
P D or deat h 
-
After at m ost o ne missi n g or 
i na de q uate p ost-baseli ne t u m or 
assess me nt, O R
-
≤ 1 2 we e ks after t he date of 
ra n d o mizati o n
Date of P D or deat h
E ve nt
P D or deat h after 2 or m ore missi n g or 
i na de q uate p ost-baseli ne t u m or assess me nts
Date of last a de q uate t u mor
assess me nt b d oc u me nti n g n o P D 
bef ore ne w a nti -ca ncer t hera p y is 
gi ve n or misse d t u m or assess me nts
Ce ns ore d
N o P D a n d n o deat h
Date of last a de q uate t u mor
assess me nt b d oc u me nti n g n o P D 
bef ore ne w a nti -ca ncer t hera p y is 
gi ve n or misse d t u m or assess me nts
Ce ns ore d
Tr eat me nt disc o nti n uati o n d ue t o ‘ Disease 
pr o gressi o n’ wit h o ut d oc u me nte d 
pr o gressi o n
N ot a p plica ble
I nf or mati o n is i g n ore d. 
O utc o me is deri ve d base d 
o n d oc u me nte d 
pr o gressi o n o nl y.
N e w  a nti-ca ncer t hera p y gi ve n 
Date of last a de q uate t u mor
assess me nt b d oc u me nti n g n o P D
bef ore ne w  a nti -ca ncer t hera p y is 
gi ve n or m isse d t u m or assess me nts
Ce ns ore d
a H o w e ver if t he patie nt dies ≤1 2 we e ks after t he date of ra n d o mizati o n t he deat h is a n e ve nt wit h date o n deat h 
date
b  If t here are n o a de q uate p ost -baseli ne assess me nts pri or t o P D or deat h, t he n t he ti me wit h o ut a de q uate 
assess me nt s h o ul d be meas ure d fr o m t he date of ra n d o mizati o n; if t he criteria were met t he ce ns ori n g will be o n 
t he date of ra n d o mizati o n.
T he pri mar y  efficac y a nal ysis will c o mpare t he P F S ti me base d o n BI C R assess me nt bet wee n 
t he e x peri me ntal ar m a n d t he c o ntr ol ar m, a n d will be perf or me d usi n g a 1- si de d stratifie d 
l o g-ra n k test as descri be d i n Secti o n 5. 1. 
T he treat me nt effect will be esti mate d usi n g a C o x’s Pr o p orti o nal Hazar d m o del stratifie d b y  
t he ra n d o mizati o n strata t o calc ulate t he hazar d rati o. Eac h strat u m will defi ne a se parate 
baseli ne hazar d f u ncti o n ( usi n g t he ' S T R A T A' state me nt i n S A S P R O C P H R E G), i.e. f or t he 
i-t h strat u m t he hazar d f u ncti o n is e x presse d as: h(i;t) = h(i, 0;t) e x p( x ), w here h(i, 0;t) 
defi nes t he baseli ne hazar d f u ncti o n f or t he i -t h strat u m a n d x defi nes t he treat me nt ar m 
( 0 =c o ntr ol ar m , 1 = e x peri me ntal ar m ) a n d is t he u n k n o w n re gressi o n para meter.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 4 1
Ties will be ha n dle d b y re placi n g t he pr o p o rti o nal hazar ds m o del b y t he discrete l o gistic 
m o del ( Ties = Discrete o pti o n i n S A S P R O C P H R E G).
I n or der t o acc o u nt f or t he gr o u p se q ue ntial desi g n i n t his st u d y, t he re peate d CI ( R CI) 
met h o d (Je n nis o n a n d T ur n b ull, 2 0 0 0) will be use d t o c o nstr uct t he 2- si de d R CIs f or t he 
hazar d rati o at t he i nteri m a n d t he fi nal a nal ys es of P F S. In a d diti o n, t he u na dj uste d 9 5 % CIs 
f or t he hazar d rati o will als o be re p orte d at t he i nteri m a n d t he fi nal a nal yses f or P F S.
Ka pla n -Meier esti mates ( pr o d uct- li mit esti mates) will be prese nte d by treat me nt ar m t o get her 
wit h a s u m mar y  of ass ociate d statistics i ncl u di n g t he me dia n P F S ti me wit h 2- si de d 9 5 % CIs.  
I n partic ular, t he P F S rate at 6, 1 2, 1 8, 2 4, 3 0, 3 6 m o nt hs will be esti mate d wit h 
c orres p o n di n g 2- si de d 9 5 % CIs.  T he CIs f or t he me dia n will be calc ulate d acc or di n g t o 
Br o o k me y er a n d Cr o wle y a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts 
defi ne d a b o ve will be deri ve d usi n g t he l o g- l o g tra nsf or mati o n acc or di n g t o Kal bfleisc h a n d 
Pre ntice (c o nft ype =l o gl o g defa ult o pti o n i n S A S Pr oc LI F E T E S T) wit h bac k tra nsf or mati o n 
t o a CI o n t he u ntra nsf or me d scale. T he esti mate of t he sta n dar d err or will be c o m p ute d usi n g 
Gree n w o o d’s f or m ula.  
Fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h e ve nt t ype ( P D or d eat h) a n d 
ce ns ori n g reas o ns will be prese nte d b y treat me nt ar m. Reas o ns f or c e ns ori n g will be 
s u m marize d acc or di n g t o t he cate g ories i n Ta ble 1 0 f oll o wi n g t he hierarc hy s h o w n :
T a ble 1 0.
P F S Ce ns ori n g Re as o ns a n d Hier arc h y
Hier arc h y
C o n diti o n
Ce ns ori n g Re as o n
1
N o a de q uate baseli ne assess me nt
N o a de q uate baseli ne assess me nt
2
Start of ne w a nti -ca ncer t hera p y. 
Start of ne w a nti -ca ncer t hera p y
3 
E ve nt after 2 or m ore missi n g or i na de q uate p ost -baseli ne 
t u m or assess me nts/ date of ra n d o mizati o n
E ve nt after 2 or m ore missi n g 
assess me nts a
4
N o e ve nt a n d [ w it h dra wal of c o nse nt date ≥ date of 
ra n d o mizati o n O R E n d of st u d y ( E O S) = S u bject ref use d 
f urt her f oll o w-u p] 
Wit h dra w al of c o nse nt
5
N o e ve nt a n d l ost t o f oll o w -u p i n a n y dis p ositi o n pa ge 
L ost t o f oll o w -u p
6
N o e ve nt a n d [ E O S prese nt O R dis p ositi o n pa ge f or a n y 
e p oc h after scree ni n g sa ys patie nt will n ot c o nti n ue i nt o 
a n y s u bse q ue nt p hase of t he st u d y] a n d n o a de q uate p ost -
baseli ne t u m o r assess me nt 
N o a de q uate p ost -baseli ne t u m or 
assess me nt
7 
N o e ve nt a n d n o ne of t he c o n diti o ns i n t he pri or hierarc h y 
are met 
O n g oi n g wit h o ut a n e ve nt
a 2 or m ore missi n g or i na de q uate p ost -baseli ne t u m or assess me nts.   
T he P F S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a 
patie nt listi n g.
Ti me of F oll o w -U p f or P F S


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 4 2
A pl ot will be ge nerate d t o c o m pare pla n ne d a n d act ual relati ve da y  of t u m or assess me nts by 
treat me nt ar m. A Ka pla n-Meier pl ot f or P F S f oll o w -u p d urat i o n will als o be ge nerate d t o 
assess t he f oll o w-u p ti me i n t he treat me nt ar ms re versi n g t he P F S ce ns ori n g a n d e ve nt 
i n dicat ors.  Ka pla n - Meier esti mates ( pr o d uct-li mit esti mates) will be prese nte d b y treat me nt 
ar m t o get her wit h a s u m mar y of ass ociate d statistics i ncl u di n g t he me dia n ti me of f oll o w - u p 
f or P F S wit h 2 -si de d 9 5 % CIs.  I n partic ular, t he rate at 6, 1 2, 1 8, 2 4, 3 0, 3 6 m o nt hs will be 
esti mate d wit h c orres p o n di n g 2- si de d 9 5 % CIs.
6. 1. 2. O ver all sur vi v al i n P D -L 1 p ositi ve p atie nts
6. 1. 2. 1. Pri m ar y a n al ysis
T he f oll o wi n g a nal ys es will be base d o n t he F A S usi n g t he strata assi g ne d at ra n d o mizati o n.   
O verall s ur vi val ( O S) is defi ne d as t he ti me fr o m date of ra n d o mizati o n t o t he date of deat h 
d ue t o a n y ca use. Patie nts last k n o w n t o be ali ve will be ce ns ore d a t date of last c o ntact.
O S ( m o nt hs) = [ date of deat h or ce ns ori n g – date of ra n d o mizati o n + 1]/ 3 0. 4 3 7 5
T he pri mar y  a nalys is of O S will c o m pare t he O S ti me bet wee n t he e x peri me ntal ar m a n d t he 
c o ntr ol ar m, a n d will be perf or me d usi n g a 1- si de d stratifie d l o g-ra n k test as descri be d i n 
Secti o n 5. 1. 
T he treat me nt effect will be esti mate d usi n g a C o x’s Pr o p orti o nal Hazar d m o del stratifie d b y 
t he ra n d o mizati o n strata t o calc ulate t he hazar d rati o. Eac h strat u m will defi ne a se parate 
baseli ne hazar d f u ncti o n ( usi ng t he ' S T R A T A' state me nt i n S A S P R O C P H R E G), i.e. f or t he 
i-t h strat u m t he hazar d f u ncti o n is e x presse d as: h(i;t) = h(i, 0;t) e x p( x), w here h(i, 0;t) 
defi nes t he baseli ne hazar d f u ncti o n f or t he i -t h strat u m a n d x defi nes t he treat me nt ar m 
( 0 =c o ntr ol ar m, 1 = e x peri me ntal ar m ) a n d is t he u n k n o w n re gressi o n para meter.
Ties will be ha n dle d b y re placi n g t he pr o p orti o nal hazar ds m o del b y t he discrete l o gistic 
m o del ( Ties = Discrete o pti o n i n S A S P R O C P H R E G).
I n or der t o acc o u nt f or t he gr o u p se q ue ntial desi g n i n t his st u d y, t he re peate d CI ( R CI) 
met h o d, will be use d t o c o nstr uct t he 2 -si de d R CIs f or t he hazar d rati o at t he i nteri m a nd t he 
fi nal a nalys es of O S. I n a d diti o n, t he u na dj uste d 9 5 % CIs f or t he hazar d rati o will als o be 
re p orte d at t he i nteri m a n d t he fi nal a nalys es f or O S.
Ka pla n - Meier esti mates ( pr o d uct-li mit esti mates) will be prese nte d by treat me nt ar m t o get her 
wit h a s u m mar y  of ass ociate d statistics i ncl u di n g t he me dia n O S ti me wit h 2- si de d 9 5 % CIs.  
I n partic ular, t he OS rate at 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 6 0 m o nt hs will be esti mate d wit h 
c orres p o n di n g t w o -si de d 9 5 % CIs.  T he CIs f or t he me dia n will be calc ulate d acc or di n g t o 
Br o o k me yer a n d Cr o wle y a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts 
def i ne d a b o ve will be deri ve d usi n g t he l o g-l o g tra nsf or mati o n acc or di n g t o Kal bfleisc h a n d 
Pre ntice (c o nft ype =l o gl o g defa ult o pti o n i n S A S Pr oc LI F E T E S T) wit h bac k tra nsf or mati o n 
t o a CI o n t he u ntra nsf or me d scale. T he esti mate of t he sta n dar d err or will be c o m p ute d usi n g 
Gree n w o o d’s f or m ula.  


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Fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h a n e ve nt ( deat h) a n d ce ns ori n g reas o ns 
will be prese nte d b y treat me nt ar m. Reas o ns f or ce ns ori n g will be s u m marize d acc or di n g t o 
t he cate g ories i n Ta ble 1 1 f oll o wi n g the hierarc h y s h o w n .
T a ble 1 1.
O S Ce ns ori n g Re as o ns a n d Hier arc h y
Hier arc h y
C o n diti o n
Ce ns ori n g Re as o n
1
N o e ve nt a n d [ w it h dra wal of c o nse nt date ≥ date of 
ra n d o mizati o n O R E n d of st u d y ( E O S) = S u bject ref use d 
f urt her f oll o w-u p] 
Wit h dra w al of c o nse nt
2
N o e ve nt a n d [l ost t o f oll o w -u p i n a n y dis p ositi o n pa ge O R 
data c ut -of f date – last c o ntact date > 1 6 we e ks] 
L ost t o f oll o w -u p
3
N o e ve nt a n d n o ne of t he c o n diti o ns i n t he pri or hierarc h y 
are met 
Ali ve
T he O S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a 
patie nt listi n g.
Ti me of F oll o w -U p f or O S
A Ka pla n -Meier pl ot f or O S f oll o w -u p d urati o n will als o be ge nerate d t o assess t he f oll o w - u p 
ti me i n t he treat me nt ar ms re versi n g t he O S ce ns ori n g a n d e ve nt i n dicat ors. Ka pla n -Meier 
esti mates ( pr o d uct -li mit esti mates) will be prese nte d b y treat me nt ar m t o get her wit h a 
s u m mar y of ass ociate d statistics i ncl u di n g t he me dia n ti me of f oll o w -u p f or O S wit h 2 -si de d 
9 5 % CI s.  I n partic ular, t he rate at 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 6 0 m o nt hs will be esti mate d 
wit h c orres p o n di n g 2 -si de d 9 5 % CIs.
6. 2. Sec o n d ar y E n d p oi nt(s)
6. 2. 1. S afet y en d p oi nts
Refer t o Secti o n 6. 6.
6. 2. 2. Effic ac y en d p oi nts
T he f oll o wi n g a nal ys es will be base d o n t he F A S b y  treat me nt ar m u nless ot her wise 
s pecifie d.   Assess me nt of res p o nse will be ma de usi n g R E CIS T v 1. 1. 
A nal y ses f or t u m or-relate d e n d p oi nts will be perf or me d se parately base d o n BI C R 
assess me nts a n d base d o n i n vesti gat or assess me nt.  P F S b y  i n vesti gat or assess me nt will be
a nal yz e d as a sec o n dar y e n d p oi nt usi n g t he sa me met h o d ol o g y t hat is descri be d i n Secti o n 
6. 1. 1. 1 n o w referri n g t o P D b y  i n vesti gat or assess me nt i nstea d of P D b y BI C R assess me nt.
E n d p oi nts defi ne d i n Secti o ns 6. 2. 2. 5, 6. 2. 2. 6, 6. 2. 2. 7, 6. 2. 2. 8 a n d 6. 2. 2. 9 will be 
s u m marize d se parately f or P D -L 1 p ositi ve patie nts a n d f or patie nts u nselecte d f or P D -L 1 
e x pressi o n .


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6. 2. 2. 1. O ver all sur vi v al f or p atie nts u nselecte d f or P D-L 1 e x pressi o n
T he met h o d ol o g y descri be d i n Secti o n 6. 1. 2 f or O S i n P D -L 1  p ositi ve patie nts will be
foll o we d f or t he assess me nt of O S f or patie nts u nselecte d f or P D-L 1 e x pressi o n . A stratifie d 
l o g-ra n k test(1- si de d) stratifie d b y ra n d o mizati o n stratificati o n fact ors will be use d at t he 
i nteri m a n d/ or fi nal a nalyses at t he si g nifica nce le vel ass ociate d wit h t he testi n g strate g y  
o utli ne d i n Secti o n 5. 1. 1 f or t he testi n g of H0 4.
6. 2. 2. 2. Pr o gressi o n -free sur vi v al as assesse d b y BI C R per R E CI S T v 1. 1 f or p atie nts 
u nselecte d f or P D -L 1 e x pressi o n
T he met h o d ol o g y descri be d i n Secti o n 6. 1. 1 f or P F S b y BI C R assess me nt i n P D -L 1  p ositi ve 
patie nts will be f oll o we d f or P F S b y  BI C R assess me nt f or patie nts u nselecte d f or P D-L 1 
e x pressi o n . A stratifie d l o g-ra n k test (1- si de d) stratifie d b y ra n d o mizati o n stratificati o n 
fact ors will be use d at t he i nteri m a n d/ or fi nal a nal y ses at the si g nifica nce le vel ass ociate d
wit h t he testi n g strate g y o utli ne d i n Secti o n 5. 1. 1 f or t he testi n g of H0 3.
6. 2. 2. 3. Se nsiti vit y a n al yses f or p r o gressi o n -free sur vi v al
All se nsiti vit y a nalys es will be perf or me d f or P D -L 1  p ositi ve patie nts a n d f or patie nts 
u nselec te d f or P D-L 1 e x pressi o n .
T he f oll o wi n g se nsiti vit y a nal ys es will be perf or me d t o e x pl ore t he r o b ust ness of t he pri mar y  
a nal ys is res ults.  T hese a nal yses are re gar de d as p urel y e x pl orat or y. T he se nsiti vit y a nal yses 
will re peat t he pri mar y a nal ysis ( p-val ue , H R a n d 9 5 % CIs) descri be d i n Secti o n 6. 1. 1. 1 wit h 
t he m o dificati o ns bel o w:

P F S base d o n BI C R assess me nt a n d c o u nti n g all P D a n d deat hs as e ve nts re gar dless of  
missi n g assess me nts or ti mi n g of t he e ve nt 

P F S base d o n BI C R assess me nt o n t he P P a nal y sis set f or P F S

P F S base d o n BI C R assess me nt usi n g a n u nstratifie d a nal ys is

P F S base d o n BI C R assess me nt usi n g strata deri ve d acc or di n g t o e C R F data i nstea d of 
t h ose e ntere d i n I R T

P F S base d o n BI C R assess me nt m o dif y i n g t he ce ns ori n g r ules i n Ta ble 9 t o c o nsi der all 
deat hs as e ve nts

P F S base d o n BI C R assess me nt m o dif y i n g t he ce ns ori n g r ules i n Ta ble 9  wit h i nitiati o n 
of s u bse q ue nt a nti -ca ncer t hera pies n ot use d as a ce ns ori n g reas o n.
Met h o ds f or e v al u ati n g t he v ali dit y of m o del ass u m pti o ns
T he pr o p o rti o nal hazar ds ass u m pti o n will be c hec ke d vis uall y b y pl otti n g l o g(-l o g( P F S)) 
vers us l o g(ti me) wit hi n eac h ra n d o mizati o n strat u m.
Sc h oe nfel d resi d uals f or t he stratifie d C o x pr o p orti o nal re gressi o n m o del will be pl otte d t o 
i n vesti gate gra p hicall y vi olati ons fr o m t he pr o p orti o nal hazar ds ( P H) ass u m pti o n; a n o n -zer o 


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sl o pe is e vi de nce of de part ure fr o m P H .  T he P H ass u m pti o n will be f or mall y teste d usi n g 
Sc h oe nfel d’s resi d ual test ( Sc h oe nfel d, 1 9 8 0 ; T her nea u & Gra m bsc h, 2 0 0 0 ).  Lar ge 
de part ures fr o m P H will be e vi de nce d b y a p -val ue < 0. 0 5.
If t hese s h o w lar ge de part ures fr o m pr o p orti o nal hazar ds, t he n P F S b y BI C R assess me nt will 
als o be a nal yz e d base d o n restricte d mea n s ur vi val ti me ( R M S T) differe nces ( Z ha n g, 2 0 1 3 ). 
Restricte d Me a n S ur vi v al Ti me ( R M S T)
T he hazar d rati o esti mate fr o m t he C o x pr o p orti o nal hazar d m o del is r o uti nel y use d t o 
e m piricall y q ua ntif y t he bet wee n-ar m differe nce u n der t he ass u m pti o n t hat t he rati o of t he 
t w o hazar d f u ncti o ns is c o nsta nt o ver ti me.  W he n t his ass u m pti o n is pla usi ble, s uc h a rati o 
esti mate ma y ca pt ure t he relati ve differe nce bet wee n t w o s ur vi val c ur ves.  H o we ver, t he 
cli nical mea ni n g of s uc h a rati o esti mate is diffic ult, if n o t i m p ossi ble, t o i nter pret w he n t he 
u n derl y i n g P H ass u m pti o n is vi olate d (i.e., t he hazar d rati o is n ot c o nsta nt o ver ti me). 
T he R M S T is a r o b ust a n d cli nicall y  i nter preta ble s u m mar y meas ure of t he s ur vi val ti me 
distri b uti o n.  U nli ke me dia n s ur vi val ti me, it is esti ma ble e ve n u n der hea vy ce ns ori n g.  T here 
is a c o nsi dera ble b o dy of met h o d ol o gical researc h (e. g., R o y st o n a n d Par mar, 2 0 1 1;
U n o, Wei, et al., 2 0 1 4; Z ha n g, 2 0 1 3) a b o ut t he use of R M S T t o esti mate treat me nt effects as 
a n alter nati ve t o t he hazar d r ati o a p pr oac h.  
T he R M S T met h o d ol o g y is a p plica ble i n de pe n de ntl y  of t he P H ass u m pti o n a n d ca n be use d, 
at a mi ni m u m, as a se nsiti vit y a nal ys is t o e x pl ore t he r o b ust ness of t he pri mar y a nalys is 
res ults.  H o we ver, w he n lar ge de part ures fr o m t he P H ass u m pti on are o bser ve d, t he l o g -ra n k 
test is u n der p o were d t o detect differe nces bet wee n t he s ur vi val distri b uti o ns f or t he treat me nt 
ar ms, a n d a test of t he differe nce bet wee n t he R M S T f or t he e x peri me ntal ar m a n d t he 
c o ntr ol ar m ma y be m ore a p pr o priate t o deter mine s u peri orit y  of t he e x peri me ntal ar m 
c o m pare d t o t he c o ntr ol ar m wit h res pect t o t he ti me -t o-e ve nt e n d p oi nt.
I n partic ular, as it pertai ns t o t he c ut-off p oi nt ( τ) t o e val uate t he R M S T, it is n ote d t hat t he 
c ut-off p oi nt s h o ul d n ot e xcee d t he mi ni m u m of t he lar gest o bser ve d ti me f or b ot h treat me nt 
ar ms s o t hat t he R M S T of all treat me nt ar ms bei n g e val uate d ca n be a de q uatel y  esti mate d 
a n d c o m paris o n bet wee n treat me nts is feasi ble; τ s h o ul d be cli nicall y  mea ni n gf ul a n d cl oser 
t o t he e n d of t he st u dy f oll o w -u p s o t hat t he maj orit y  of s ur vi val o utc o mes will be c o vere d by 
t he ti me i nter val.  T he R M S T u p t o ti me τ ca n t he n be i nter prete d as t he e x pecte d s ur vi val 
ti me restricte d t o t he c o m m o n f oll o w-u p ti me τ a m o n g all patie nts.  T he selecti o n of τ s h o ul d 
e ns ure t hat t he R M S T e val uati o n will n ot g o be yo n d t he ma xi m u m ti me p oi nt w here t he 
e val uati o n ca n be perf or me d w hile als o ta ki n g i nt o acc o u nt a lar ge peri o d of ti me t hat is 
e x pecte d t o pr o vi de a mea ni n gf ul assess me nt of treat me nt effect.   T o a v oi d ar bitrar y 
selecti o n of t he c o m m o n c ut- off τ f or b ot h treat me nt ar ms, t hree sets of a nal y ses will be 
perf or me d:

τ1 = mi ni m u m of (lar gest o bser ve d s ur vi val ti me f or e x peri me ntal ar m, lar gest o bser ve d 
s ur vi val ti me f or c o ntr ol ar m).  

τ2 = mi ni m u m of (lar gest s ur vi val e ve nt ti me f or e x peri me ntal ar m, lar gest s ur vi val e ve nt 
ti me f or c o ntr ol ar m).


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
τ3 = mi d p oi nt bet wee n τ 1 a n d τ 2.
I n t his secti o n, ‘s ur vi val’ is mea nt t o de n ote P F S.
T he treat me nt effect bet wee n t he e x peri me ntal ar m a n d t he c o ntr ol ar m will be assesse d 
base d o n t he differe nce i n R M S T. T he ass ociate d 9 5 % CI f or t he differe nce i n mea ns a n d 1 -
si de d p- val ue will be ge nerate d. R M S T as a f u ncti o n of τ a n d t he ass ociate d treat me nt effect 
bet wee n t he e x peri me ntal ar m a n d t he c o ntr ol ar m will be pl otte d a gai nst ti me τ.
BI C R vs I n vesti g at or assess me nt
A s u m mar y  of t he BI C R assess me nt vers us i n vesti gat or assess me nt will be pr o vi de d 
i ncl u di n g n u m bers of c o nc or da nt a n d disc or da nt assess me nts as well as t he n u m ber of cases 
w here P F S e ve nt was assesse d at differe nt ti me p oi nts base d o n BI C R a n d i n vesti gat or 
assess me nts .
Ta ble 1 2 o utli nes t he p ossi ble o utc o mes b y  i n vesti gat or a n d BI C R ( A mit et al. 2 0 1 1). 
T a ble 1 2.
P ossi ble O utc o mes f or I n vesti g at or vs BI C R
BI C R
I n vesti g at or
E ve nt
N o E ve nt
E ve nt
a = a 1 + a 2 + a 3
b
N o E ve nt
c
d
a 1: n u m ber of a gree me nts o n ti mi n g a n d occ urre nce of e ve nt ; 
a 2: n u m ber of ti mes a gree me nt o n e ve nt b ut I N V declares e ve nt later t ha n BI C R; 
a 3: n u m ber of ti mes a gree me nt o n e ve nt b ut I N V declares e ve nt earlier t ha n BI C R; 
N = a + b +c + d. 
T he ti mi n g a gree me nt of e ve nt is defi ne d as a wi n d o w of + 7 d ays 
T he f oll o wi n g meas ure of disc or da nce will be calc ulate d f or eac h treat me nt ar m:

T otal E ve nt Discre pa nc y  Rate: ( b +c) / N

Earl y Discre pa nc y Rate ( E D R): (a 3 + b) / (a + b)

Late Discre pa nc y  Rate ( L D R): (a 2 +c) / (a 2 +a 3 + b +c)

O verall Discre pa nc y  Rate: (a 2 +a 3 + b +c) / N
T he E D R re prese nts t he p ositi ve pre dicti ve val ue of i n vesti gat or assess me nt a n d q ua ntifies 
t he fre q ue nc y wit h w hic h t he i n vesti gat or declares P F S e ve nt earlier t ha n BI C R wit hi n eac h
treat me nt ar m as a pr o p orti o n of t he t otal n u m ber of i n vesti gat or assesse d e ve nts.
T he L D R q ua ntifies t he fre q ue nc y  wit h w hic h t he i n vesti gat or declares P F S e ve nt later t ha n 
BI C R as a pr o p orti o n of t he t otal n u m ber of discre pa ncies wit hi n t he treat me nt ar m. 


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Disc or da nce metrics are calc ulate d f or eac h treat me nt ar m a n d, f or eac h metric, t he 
differe nce i n disc or da nce bet wee n t he e x peri me ntal a n d c o ntr ol ar ms is use d t o e val uate 
p ote ntial bias.  If t he disc or da nce is si milar acr oss t he treat me nt ar ms t he n t his s u g gests t he 
a bse nce of e val uati o n bias fa v ori n g a partic ular treat me nt ar m. A ne gati ve differe ntial 
disc or da nce f or E D R a n d/ or a p ositi ve differe ntial disc or da nce f or L D R ma y be i n dicati ve of 
i n vesti gat or e val uati o n bias i n fa v or of t he e x peri me ntal ar m ( A mit et al, 2 0 1 1).
E x pl or at or y a n al yses t o i n vesti g ate t he i m p act of p ote nti al pr o g n ostic or effect 
m o dif yi n g ( pre dicti ve) f act ors
See s u b gr o u ps as defi ne d i n Secti o n 6. 4.
M ulti varia ble C o x re gressi o n a nal y sis will be carrie d o ut t o assess a n d a dj ust t he treat me nt 
effect f or rele va nt baseli ne fact ors of p ote ntial pr o g n ostic i m pact. A ste p wise selecti o n 
pr oce d ure will ser ve t o i de ntif y  e x pla nat or y varia bles of p ote ntial pr o g n ostic val ues 
a d diti o nal t o t he ra n d o mizati o n strata w hic h will be i n cl u de d i n all m o dels d uri n g t he 
selecti o n pr oce d ure. T he C o x's Pr o p orti o nal Hazar d m o del is defi ne d as: 
h(t) = h( 0;t) e X b
w here h( 0;t) defi nes t he baseli ne hazar d f u ncti o n a n d X defi nes t he vect or of e x pla nat or y 
varia bles a n d b t he u n k n o w n vect or of re gre ssi o n para meters. 
I n t he ste p wise selecti o n pr oce d ure, varia bles are e ntere d i nt o a n d re m o ve d fr o m t he m o del 
i n s uc h a wa y t hat eac h f or war d selecti o n ste p ca n be f oll o we d b y o ne or m ore bac k war d 
eli mi nati o n ste ps. T he ste p wise selecti o n pr ocess ter mi nates if n o f urt her varia ble ca n be 
a d de d t o t he m o del or if t he varia ble j ust e ntere d i nt o t he m o del is t he o nl y  varia ble re m o ve d 
i n t he s u bse q ue nt bac k war d eli mi nati o n. T he le vel of si g nifica nce f or a n e x pla nat or y varia ble 
t o e nter t he m o del is set t o 0. 1 5 (p- val ue of Sc ore test) a n d t he si g nifica nce le vel f or 
re m o vi n g it is set t o 0. 4 0 ( p-val ue of Wal d test). T his a nal y sis will be perf or me d usi n g t he 
ste p wise selecti o n met h o d i n S A S ( Pr oc P H R E G). O nce t his pr oce d ure st o ps, t he fact or 
'treat me nt ar m' will be a d de d t o t he last selecte d m o del i n or der t o e val uate t he effect of 
treat me nt o n P F S ti me w he n a dj uste d f or t he selecte d e x pla nat or y varia bles. T he hazar d 
rati os of all selecte d e x pla nat or y varia bles a n d of treat me nt effects will be re p orte d i ncl u di n g 
2- side d 9 5 % CI s. N o i nteracti o ns will be c o nsi dere d. P ost-baseli ne fact ors will n ot be 
c o nsi dere d f or t he m o del .
6. 2. 2. 4. Se nsiti vit y a n al yses f or o ver all sur vi v al
All se nsiti vit y a nalys es will be perf or me d f or P D -L 1  p ositi ve patie nts a n d f or patie nts 
u nselecte d f or P D -L 1 e x pressi o n .
T he f oll o wi n g se nsiti vit y a nal ys es will be perf or me d t o e x pl ore t he r o b ust ness of t he pri mar y  
a nal ys is res ults f or O S.  T hese a nal yses are re gar de d as p urely e x pl orat or y. T he se nsiti vit y  
a nal ys es will re peat t he pr i mar y a nalys is ( p-val ue, H R a n d 9 5 % CIs) descri be d i n Secti o n 
6. 1. 2. 1 wit h t he m o dificati o ns bel o w:

P P a nal y sis set;


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
u nstratifie d;

usi n g strata deri ve d acc or di n g t o e C R F data i nstea d of t hat e ntere d i n I RT .
Met h o ds f or e v al u ati n g t he v ali dit y of m o del ass u m pti o ns
T he sa me met h o d ol o g y descri be d i n Secti o n 6. 2. 2. 3 f or P F S will be use d f or O S.
E x pl or at or y a n al yses t o i n vesti g ate t he i m p act of p ote nti al pr o g n ostic or effect 
m o dif yi n g ( pre dicti ve) f act ors
T he sa me met h o d ol o g y descri be d i n Secti o n 6. 2. 2. 3 f or PF S will be use d f or O S.
6. 2. 2. 5. O bjecti ve r es p o nse a n d tu m or shri n k a ge
Best o ver all res p o nse ( B O R) will be assesse d base d o n re p orte d o verall lesi o n res p o nses at 
differe nt e val uati o n ti me p oi nts fr o m t he date of ra n d o mizati o n u ntil t he first d oc u me ntati o n 
of P D , acc or di n g t o t he f oll o wi n g r ules .   O nl y  t u m or assess me nts perf or me d o n or bef ore t he 
start date of a n y f urt her a nti-ca ncer t hera pies will be c o nsi dere d i n t he assess me nt of B O R.  
Cli nical deteri orati o n will n ot be c o nsi dere d as d oc u me ntati o n of disease pr o gressi o n.

C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a part a n d bef ore first 
d oc u me ntati o n of P D . 

P R = at least t w o deter mi nati o ns of P R or better ( P R f oll o we d b y  P R or P R f oll o we d b y 
C R) at least 4 wee ks a part a n d bef ore first d oc u me ntati o n of P D (a n d n ot q ualif y i n g f or a 
C R). 

S D (a p plica ble o nl y t o patie nts wit h meas ura ble disease at baseli ne) = at least o ne S D 
assess me nt ( or better) ≥ 6 wee ks after t he date of ra n d o mizati o n a n d bef ore first 
d oc u me ntati o n of P D (a n d n ot q ualif yi n g f or C R or P R).   

N o n -C R/ n o n -P D (a p plica ble o nl y  t o patie nts wit h n o n-meas ura ble disease at baseli ne) = 
at least o ne n o n -C R/ n o n -P D assess me nt ( or better) ≥ 6 wee ks after t he date of 
ra n d o mizati o n a n d bef ore first d oc u me ntati o n of P D (a n d n ot q ualif yi n g f or C R or P R).

P D = first d oc u me ntati o n of P D ≤ 1 2 wee ks after t he date of ra n d o mizati o n (a n d n ot 
q ualif y i n g f or C R, P R, S D or n o n-C R/ n o n -P D). 

N E:  all ot her cases.  
A n o bjecti ve stat us of P R or S D ca n n ot f oll o w o ne of C R.  S D ca n f oll o w P R o nl y  i n t he rare 
case t hat t u m or i ncreases b y less t ha n 2 0 % fr o m t he na dir, b ut e n o u g h t hat a pre vi o usly 
d oc u me nte d 3 0 % decrease fr o m baseli ne n o l o n ger h ol ds.  I f t his occ urs, t he se q ue nce P R-
S D -P R is c o nsi dere d a c o nfir me d P R.  A se q ue nce of P R – S D – S D – P D w o ul d be a best 
resp o nse of S D if t he wi n d o w f or S D defi niti o n has bee n met.
O bjecti ve Res p o nse ( O R) is defi ne d as a B O R of c o m plete res p o nse ( C R) or partial 
res p o nse ( P R) acc or di n g t o R E CIS T v 1. 1.


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Patie nts w h o d o n ot ha ve a p ost -baseli ne ra di o gra p hic t u m or assess me nt d ue t o earl y 
pr o gressi o n, w h o recei ve a nti -t u m or t hera pies ot her t ha n t he st u d y  treat me nts pri or t o 
reac hi n g a C R or P R, or w h o die, pr o gress, or dr o p o ut f or a ny reas o n pri or t o reac hi n g a C R 
or P R will be c o u nte d as n o n -res p o n ders i n t he assess me nt of O R. Eac h patie nt will ha ve a n 
o bjecti ve res p o nse stat us ( 0: n o O R; 1: O R).  O R rate ( O R R) is t he pr o p orti o n of patie nts 
wit h O R i n t he a nal y sis set.
O R R b y  treat me nt ar m will be calc ulate d al o n g wit h t he 2 -si de d 95 % CI usi n g t he Cl o p per-
Pears o n met h o d (e xact CI f or a bi n o mial pr o p orti o n as c o m p ute d b y  defa ult b y t he F R E Q 
pr oce d ure usi n g t he E X A C T o pti o n). 
I n a d diti o n, t he fre q ue nc y ( n u m ber a n d perce nta ge) of patie nts wit h B O R of C R, P R, S D, 
n o n- C R/ n o n -P D (a p plica bl e o nl y t o patie nts wit h n o n-meas ura ble disease at baseli ne), P D 
a n d N E will be ta b ulate d. Patie nts wit h B O R of N E will be s u m marize d b y reas o n f or ha vi n g 
N E stat us. T he f oll o wi n g reas o ns will be use d:

N o baseli ne assess me nt 

N o p ost - baseli ne assess me nts d ue t o deat h

N o p ost -baseli ne assess me nts d ue t o ot her reas o ns 

All p ost -baseli ne assess me nts ha ve o verall res p o nse N E

Ne w a nti -ca ncer t hera p y starte d bef ore first p ost-baseli ne assess me nt

S D of i ns ufficie nt d urati o n ( < 6 wee ks after t he date of ra n d o mizati o n wit h o ut f urt her 
e val ua ble t u m or assess me nts )

P D t o o late ( > 1 2 wee ks after t he date of ra n d o mizati o n )
S pecial a n d rare cases w here B O R is N E d ue t o b ot h S D of i ns ufficie nt d urati o n a n d late P D 
will be classifie d as ‘ S D t o o earl y’ (i.e., S D of i ns ufficie nt d urati o n) .
T he ass ociati o n of st u d y treat me nt a n d O R will be teste d b y t he Ge neral Ass ociati o n Statistic 
of t he C oc hra n -Ma ntel -Hae nszel test ( C M H) wit h t he ra n d o mizati o n strata ta ke n i nt o 
acc o u nt . T he n ull hy p ot hesis of n o ass ociati o n i n a n y of t he ra n d o mizati o n strata is teste d 
a gai nst t he alter nati ve, w hic h s pecifies t hat t here is a n ass ociati o n bet wee n st u d y treat me nt 
a n d t u m or res p o nse at least i n o ne ra n d o mizati o n strat u m. T he C M H test will b e perf or me d at 
1- si de d al p ha le vel of 0. 0 2 5. 
T he stratifie d o d ds rati o i n ter ms of O R will als o be esti mate d al o n g wit h its 9 5 % CI  t o 
c o m pare st u d y treat me nts. T he o d ds rati o is defi ne d as t he o d ds of O R wit h e x peri me ntal
treat me nt di vi de d by t he o d ds of O R wit h c o ntr ol treat me nt. T he Bresl o w- Da y  test will be 
use d t o c hec k t he h o m o ge neit y  of t he o d ds rati o acr oss t he ra n d o mizati o n strata. It tests t he 
n ull h y p ot hesis t hat o d ds rati os i n all strata are e q ual a gai nst t he alter nati ve h y p ot hesis t hat at 
least i n o ne strat u m t he o d ds rati o is differe nt.
I n case t he n ull h yp ot hesis of h o m o ge neit y  of o d ds rati os acr oss strata is n ot rejecte d at t he 2-
si de d al p ha le vel of 0. 0 5, t he c o m m o n o d ds rati o will be deter mi ne d usi n g t he Ma ntel-


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Pa ge 5 0
Hae nszel esti mate ( b y t he F R E Q pr oce d ure usi n g C M H o pti o n i n S A S); if t he n ull h y p ot hesis 
of h o m o ge neit y  of o d ds rati o acr oss all strata is rejecte d, t he o d ds rati o per strat u m will be 
calc ulate d wit h t he c orres p o n di n g e xact CI.
BI C R vs I n vesti g at or Assess me nt:
Ta ble 1 3 o utli nes t he p o ssi ble B O R o utc o mes b y i n vesti gat or a n d BIC R. 
T a ble 1 3.
P ossi ble B O R O utc o mes f or I n vesti g at or vs BI C R
B O R
BI C R Assess me nt
C R
P R
S D
N o n -C R/ n o n -P D 
P D
N E
I n vesti g at or 
Assess me nt
C R
n 1 1
n 1 2
n 1 3
n 1 4
n 1 5
n 1 6
P R
n 2 1
n 2 2
n 2 3
n 2 4
n 2 5
n 2 6
S D
n 3 1
n 3 2
n 3 3
n 3 4
n 3 5
n 3 6
N o n -C R/ n o n -P D
n 4 1
n 4 2
n 4 3
n 4 4
n 4 5
n 4 6
P D
n 5 1
n 5 2
n 5 3
n 5 4
n 5 5
n 5 6
N E
n 6 1
n 6 2
n 6 3
n 6 4
n 6 5
n 6 6
∑ 
(  )
  is t he n u m ber of a gree me nts o n B O R bet wee n BI C R a n d I n vesti gat or 
∑
   ,   f or i ≠ j is t he n u m ber of disa gree me nts o n B O R bet wee n BI C R a n d I n vesti gat or 
N = ∑
   ,   T he f oll o wi n g meas ures of c o nc or da nce will be calc ulate d f or eac h treat me nt ar m:

C o nc or da nce rate f or B O R = ∑ 
(  )
  / 
C o nc or da nce rate f or res p o nse =  [∑
   + ∑
   ] / ,   ,   C o nc or da nce rates are calc ulate d f or eac h treat me nt ar m a n d, f or eac h metric, t he differe nce 
i n c o nc or da nce bet wee n t he e x peri me ntal a n d c o ntr ol ar ms are use d t o e val uate p ote ntial 
bias.  If t he c o nc or da nce is si milar a cr oss t he treat me nt ar ms t he n t his s u g gests t he a bse nce of 
e val uati o n bias fa v ori n g a partic ular treat me nt ar m.
T u m or S hri n k a ge fr o m B aseli ne:
T u m or s hri n ka ge will be s u m marize d as t he perce nt c ha n ge fr o m baseli ne i n tar get lesi o ns 
(s u m of l o n gest dia meter f or n o n-n o dal lesi o n a n d s h ort a xis f or n o dal lesi o n) per ti me p oi nt. 
It will be deri ve d as:

(( S u m of tar get lesi o ns at wee k X X – s u m of tar get lesi o ns at baseli ne)/s u m of tar get 
lesi o ns at baseli ne) × 1 0 0


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T he ma xi m u m re d ucti o n i n tar get lesi o ns fr o m base li ne will be deri ve d acr oss all t he p ost-
baseli ne assess me nts u ntil d oc u me nte d disease pr o gressi o n, e xcl u di n g assess me nts after start 
of s u bse q ue nt a nti -ca ncer t hera p y, as:

Mi ni m u m of ((s u m of tar get lesi o ns at wee k X X – s u m of tar get lesi o ns at baseli ne)/s u m
of tar get lesi o ns at baseli ne) × 1 0 0
A waterfall pl ot of ma xi m u m perce nt re d ucti o n i n t he s u m of l o n gest dia meter f or n o n -n o dal 
lesi o ns a n d s h ort a xis f or n o dal lesi o ns fr o m baseli ne will be create d by treat me nt ar m. T hese 
pl ots will dis pla y  t he best perce nta ge c ha n ge fr o m baseli ne i n t he s u m of t he dia meter of all 
tar get lesi o ns f or eac h patie nt wit h meas ura ble disease at baseli ne a n d at least o ne p ost -
baseli ne assess me nt.
6. 2. 2. 6. Dise ase co ntr ol
Disease C o ntr ol ( D C) is def i ne d as B O R of C R, P R , n o n-C R/ n o n -P D or S D .   B ot h C R a n d 
P R m ust be c o nfir me d b y re peat assess me nts perf or me d n o less t ha n 4 wee ks after t he 
criteria f or res p o nse are first met. D C rate ( D C R) is t he pr o p orti o n of patie nts wit h D C.
D C R will be s u m marize d b y  fre q ue nc y c o u nts a n d perce nta ges.
6. 2. 2. 7. D ur ati o n of res p o nse
D urati o n of Res p o nse ( D R) is defi ne d, f or patie nts wit h O R, as t he ti me fr o m t he first 
d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R) t o t he date of first d oc u me ntati o n of P D or 
deat h d ue t o a n y cause.  If a patie nt has n ot ha d a n e ve nt ( P D or deat h), D R is ce ns ore d at t he 
date of last a de q uate t u m or assess me nt. T he ce ns ori n g r ules f or D R are as descri be d f or P F S 
i n Ta ble 9.
D R ( m o nt hs) = [ date of e ve nt or ce ns ori n g – first date of O R + 1]/ 3 0. 4 3 7 5
Ka pla n -Meier esti mates ( pr o d uct- li mit esti mates) will be prese nte d by treat me nt ar m t o get her 
wit h a s u m mar y  of ass ociate d statistics i ncl u di n g t he me dia n D R ti me wit h 2- si de d 9 5 % CIs.  
I n partic ular, t he D R rate at 3, 6, 9, 1 2, 1 8, 2 4, 3 0 m o nt hs will be es ti mate d wit h 
c orres p o n di n g 2- si de d 9 5 % CIs.  T he CIs f or t he me dia n will be calc ulate d acc or di n g t o 
Br o o k me y er a n d Cr o wle y a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts 
defi ne d a b o ve will be deri ve d usi n g t he l o g- l o g tra nsf or mati o n accor di n g t o Kal bfleisc h a n d 
Pre ntice (c o nft ype =l o gl o g defa ult o pti o n i n S A S Pr oc LI F E T E S T) wit h bac k tra nsf or mati o n 
t o a CI o n t he u ntra nsf or me d scale. T he esti mate of t he sta n dar d err or will be c o m p ute d usi n g 
Gree n w o o d’s f or m ula.
D R will be dis pla y e d gra p hi call y a n d a nalyz e d usi n g Ka pla n - Meier met h o d ol o g y. If t he 
n u m ber of patie nts wit h O R is s mall, t he Ka pla n- Meier met h o d ma y  n ot pr o vi de relia ble 
esti mates.  In t his case, o nl y  descri pti ve statistics or listi n gs will be pr o vi de d.


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Pa ge 5 2
6. 2. 2. 8. Ti me t o res p o nse
Ti me t o res p o nse ( T T R) is defi ne d, f or patie nts wit h O R, as t he ti me fr o m t he date of 
ra n d o mizati o n t o t he first d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R) w hic h is 
s u bse q ue ntl y c o nfir me d. 
T T R (i n m o nt hs) = [f irst date of O R – date of ra n d o mizati o n + 1] / 3 0. 4 3 7 5
T T R will be s u m marize d usi n g si m ple descri pti ve statist ics ( mea n, S D, me dia n, mi n, ma x,
Q 1, Q 3).
6. 2. 2. 9. Pr o gressi o n -free s ur vi v al o n ne xt-li ne t her a p y ( P F S 2)
P F S 2 is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o disc o nti n uati o n of ne xt-li ne 
treat me nt after first o bjecti ve disease pr o gressi o n b y  i n vesti gat or assess me nt, sec o n d 
o bjecti ve disease pr o gressi o n b y  i n vesti gat or assess me nt after i nitiati o n of ne xt-li ne 
treat me nt, or deat h fr o m a n y ca use, w hic he ver occ urs first.   
P F S 2 ( m o nt hs) = [ date of e vent or ce ns ori n g – start date + 1]/ 3 0. 4 3 7 5
A patie nt will be c o nsi dere d t o ha ve a n e ve nt if 
1)
t he patie nt ha d o bjecti ve P D o n or pri or t o start of ne xt -li ne a nti-ca ncer treat me nt, A N D 
starte d ne xt -li ne a nti-ca ncer treat me nt, A N D ( ha d o bjecti ve P D after start of  ne x t-li ne 
a nti-ca ncer treat me nt O R disc o nti n ue d ne xt -li ne a nti-ca ncer treat me nt)
O R
2)
t he patie nt die d.
Ka pla n - Meier esti mates ( pr o d uct-li mit esti mates) will be prese nte d by treat me nt ar m t o get her 
wit h a s u m mar y  of ass ociate d statistics i ncl u di n g t he me dia n P F S 2 ti me wit h 2- si de d 9 5 % 
CI s.  I n partic ular, t he P F S 2 rate at 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 8, 6 0 m o nt hs will be esti mate d wit h 
c orres p o n di n g 2- si de d 9 5 % CIs.  T he CIs f or t he me dia n will be calc ulate d acc or di n g t o 
Br o o k me y er a n d Cr o wle y a n d t he CIs f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts 
defi ne d a b o ve will be deri ve d usi n g t he l o g- l o g tra nsf or mati o n acc or di n g t o Kal bfleisc h a n d 
Pre ntice (c o nft ype =l o gl o g defa ult o pti o n i n S A S Pr oc LI F E T E S T) wit h bac k tra nsf or mati o n 
t o a CI o n t he u ntra nsf or me d scale. T he esti mate of t he sta n dar d err or will be c o m p ute d usi n g 
Gree n w o o d’s f or m ula.
T he ce ns ori n g a n d e ve nt date o pti o ns t o be c o nsi dere d f or P F S 2, eac h c orres p o n di n g 
ce ns ori n g reas o n a n d its hierarc h y are prese nte d i n Ta ble 1 4. Fre q ue nc y  ( n u m ber a n d 
perce nta ge) of patie nts wit h a n e ve nt ( P D after ne xt li ne treat me nt, disc o nti n uati o n of ne xt -
li ne treat me nt or deat h ) a n d ce ns ori n g reas o ns will be prese nte d by treat me nt ar m.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5 3
T a ble 1 4.
O utc o me , E ve nt D ates , Ce ns or i n g Re as o ns a n d Hier arc h y f or P F S2
A n al yses
Sce n ari o
D ate of e ve nt/
ce ns ori n g
E ve nt /
Ce ns ori n g re as o n/
Ce ns ori n g hier arc h y
( N o P D a) a n d ( n o deat h )
Date of last a de q uate 
t u m or assess me ntb
d oc u me nti n g n o P D
Ce ns ore d /
N o P D/
1
( N o P Da) a n d deat h
Date of deat h
E ve nt ( Deat h )
(P D a date > N T X c start date) a n d ( n o deat h)
Start date of N T X c
Ce ns ore d /
Start of ne w a nti -ca ncer 
treat me nt bef ore P D/
2
(P D a date > N T X c start date) a n d deat h
Date of deat h
E ve nt ( Deat h)
( P Da date ≤ N T X c start date) a n d ( P D 2d date > 
N T X c start date)

If P D 2 date ≤ N T X c e n d date
Date of P D 2
E ve nt ( P D after start of ne xt 
li ne a nti -ca ncer treat me nt)

If P D 2 date > N T X c e n d date
E n d date of N T X c
E ve nt ( Disc o nti n uati o n of ne xt 
li ne a nti-ca ncer treat me nt)
( P Da date ≤N T X c start date) a n d ( n o P D 2d) a n d 
( n o deat h)

If N T X c e n d date is n o n-missi n g
E n d date of N T X c
E ve nt ( Disc o nti n uati o n of ne xt 
li ne a nti-ca ncer treat me nt)

Else if [ wit h dra wal of c o nse nt date ≥ date of 
ra n d o mizati o n O R E n d of st u d y ( E O S) = 
S u bject ref use d f urt her f oll o w- u p]
( Wit h dra wal of c o nse nt 
date) or ( E O S visit date 
w here s u bject ref usal of 
f urt her f oll o w-u p is 
rec or de d)
Ce ns ore d /
Wit h dra w al of c o nse nt/
3

Else if [l ost t o f oll o w -u p i n a n y dis p ositi o n 
pa ge]
Last c o ntact date
Ce ns ore d /
L ost t o f oll o w- u p/
4

Else if n o pri or c o n diti o ns are met
Last c o ntact date
Ce ns ore d /
O n g oi n g wit h o ut P F S 2 e ve nt/
5
( P Da a n d n o N T X c) a n d ( n o deat h)
Last c o ntact date
Ce ns ore d /
O n g oi n g wit h o ut P F S 2 e ve nt/
6
( P Da date ≤N T X c start date) a n d ( n o P D 2d) a n d 
deat h

If N T X c e n d date is n o n-missi n g
E n d date of N T X c
E ve nt ( Disc o nti n uati o n of ne xt 
li ne a nti-ca ncer treat me nt)

Else if t he pri or c o n diti o n is n ot met
Date of deat h
E ve nt ( Deat h)


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5 4
Sce n ari o
D ate of e ve nt/
ce ns ori n g
E ve nt /
Ce ns ori n g re as o n/
Ce ns ori n g hier arc h y
( P Da a n d n o N T X c) a n d deat h
Date of deat h
E ve nt ( Deat h)
a P D is t he first P D b y i n vesti gat or assess me nt per R E CI S T v 1. 1, w it h o ut c o nsi deri n g a n y ce ns ori n g r ules 
b If t here are n o a de q uate p ost -baseli ne assess me nts, t he n t he ce ns ori n g date is t he date of ra n d o mizati o n. If 
patie nt has i nitiate d ne xt -li ne a nti -ca ncer treat me nt, t he last a de q uate p ost -baseli ne assess me nt o n or pri or t o 
start date of ne xt-li ne a nti-ca ncer treat me nt will be c o nsi dere d.
c N T X is t he ne xt-li ne a nti-ca ncer treat me nt.
d P D 2 is t he first P D after i nitiati o n of ne xt -li ne a nti -ca ncer treat me nt b y  in vesti gat or assess me nt per R E CI S T 
v 1. 1, w it h o ut c o nsi deri n g a n y ce ns ori n g r ules.
T he P F S 2 ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a 
patie nt listi n g.
6. 2. 3. P h ar m ac o ki netic en d p oi nts
T he f oll o wi n g p har mac o ki netic a nal ys es will be base d o n t he P K a nal y ses set.  
C tr o u g h f or a vel u ma b a n d C tr o u g h a n d C ma x a xiti ni b will be s u m marize d descri pti vel y ( n, mea n, 
S D, C V, me dia n, mi ni m u m, ma xi m u m, ge o metric mea n, its ass ociate d C V, a n d 9 5 % 
c o nfi de nce i nter val) b y c ycle a n d da y .
D ose n or malize d para meters (e. g., C D N - Cma x , C D N - Ctr o u g h) will be re p orte d as a p pr o priate. 
T he tr o u g h c o nce ntrati o ns f or a vel u ma b a n d a xiti ni b will be pl otte d f or eac h d ose (if a xiti ni b 
is d ose titrate d) usi n g a b o x w his ker pl ot b y  c ycle a n d da y i n or der t o assess t he attai n me nt of 
stea d y state.
P har mac o ki netic para meters f or a vel u ma b a n d a xiti ni b will be ta ke n fr o m o bser ve d val ues or 
deri ve d fr o m plas ma c o nce ntrati o n -ti me data as descri be d i n Secti o n 3. 2. 4.
Prese ntat i o n of p har mac o ki netic data will i ncl u de:

Descri pti ve statistics ( n, mea n, S D, % C V, me dia n, mi ni m u m, ma xi m u m) of plas ma 
c o nce ntrati o ns will be prese nte d i n ta b ular f or m b y d ose le vel, c y cle, da y a n d n o mi nal 
ti me. A d diti o nall y si milar descri pti ve statistics will als o be ge nerate d f or d ose-
n or malize d a xiti ni b p har mac o ki netic para meters , if a p plica ble.

P har mac o ki netic para meters f or a vel u ma b a n d a xiti ni b will be liste d a n d s u m marize d b y  
c ycle a n d st u d y da y usi n g descri pti ve statistics ( n, mea n, S D, % C V, me dia n, mi ni m u m, 
ma xi m u m, ge o metric mea n a n d its ass ociate d % C V, a n d 9 5 % CI ). P K para meters wit h 
zer o val ues will be e xcl u de d fr o m t he calc ulati o n of ge o metric mea ns a n d its ass ociate d 
% C V. If a n i ntra patie nt d ose escalati o n or re d ucti o n occ urs, d ose -de pe n de nt P K 
para meters ( C ma x ) f or t hat patie nt ma y be d ose-n or malize d w he n it is k n o w n t hat t he dr u g 
e x hi bits li near P K wit hi n t he d ose ra n ge a n d ot her P K para meters will be re p orte d as 
esti mate d; or ma y o nl y be i ncl u de d i n descri pti ve statistics a n d s u m mar y pl ots up t o t he 
ti me of t he d ose c ha n ge. I n a d diti o n, d ose-n or malize d C ma x para meters will be 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5 5
s u m marize d (as descri be d a b o ve) usi n g data i n w hic h differe nt a vel u ma b a n d a xiti ni b 
d oses were a d mi nistere d.

B o x pl ots f or C ma x a n d C tr o u g h f or a xiti ni b will be ge nerate d. I n di vi d ual data p oi nts, t he 
ge o metric mea n a n d t he me dia n of t he para meter i n eac h treat me nt will be o verlai d o n t he 
b o x pl ots. I f a treat me nt ar m has li mite d e val ua ble P K data ( n < 4), matc hstic k pl ots 
s h o wi n g c ha n ges i n Cma x a n d C tr o u g h f or eac h dr u g i n i n di vi d ual patie nts will t he n be 
ge nerate d. T he ge o metric mea n of t he para meter i n eac h treat me nt will be o verlai d i n t he 
pl ots. I n a d diti o n, b o x pl ots f or d ose -n or malize d a xiti ni b  C ma x a n d C tr o u g h para meters will 
be create d usi n g data fro m patie nts i n Ar m A .

C tr o u g h f or a vel u ma b will be pl otte d f or eac h treat me nt ar m usi n g a b o x -w his ker pl ot b y  
c ycle a n d da y wit hi n c ycle i n or der t o assess t he attai n me nt of stea d y -state.
6. 2. 4. P o p ul ati o n p h ar m ac o ki netic en d p oi nts
P har mac o ki netic a n d p har mac o d y na mic data fr o m t his st u d y  ma y be a nal yze d usi n g 
m o deli n g a p pr oac hes a n d ma y  als o be p o ole d wit h data fr o m ot her st u dies t o i n vesti gate a n y 
ass ociati o n bet wee n a vel u ma b a n d a xiti ni b e x p os ure a n d bi o mar kers or si g nifica nt 
safety/ efficac y e n d p oi nts. T he res ults of t hese a nal yses, if perf or me d, ma y be re p orte d 
se paratel y.
6. 2. 5. Bi o m ar ker en d p oi nts
Bi o mar kers will be s u m marize d at all ti me p oi nts descri be d bel o w: 

S ol u ble pr otei ns: scree ni n g, C 1 D 1, C 2 D 1, C 3 D 1 a n d E O T. 

T u m or base d bi o mar kers, arc hi val F F P E T u m or Tiss ue Bl oc k: scree ni n g

T u m or base d bi o mar kers, de n o v o T u m or Bi o ps y : scree ni n g a n d E O T. 
S u m mar y  statistics, usi n g descri pti ve statistics ( mea n, S D, me dia n, Q 1, Q 3, mi ni m u m, a n d 
ma xi m u m), at eac h ti me p oi nt a n d perce nt c ha n g e fr o m t he val ue at scree ni n g if a vaila ble (f or 
c o nti n u o us mar kers) will be pr o vi de d se paratel y f or eac h treat me nt ar m. 
F or eac h defi ne d bi o mar ker or gr o u p t here of (s ig nat ure), patie nts ma y  be classifie d as 
p ositi ve, ne gati ve, or u n k n o w n acc or di n g t o sc or i n g al g orit h ms a n d c ut offs esta blis he d 
e xter nal t o t his st u d y. S u bset a nal ys es f or P F S b y BIC R assess me nt a n d O S will be 
perf or me d f or t he s u b gr o u ps defi ne d b y t hese c ut offs usi n g t he met h o d ol o g y descri be d i n 
Secti o n 6. 4.   If t here are fe wer t ha n 2 0 e ve nts i n a s u b gr o u p f or P F S b y  BI C R assess me nt or 
O S, o nl y  descri pti ve s u m maries will be pr o d uce d.
6. 2. 6. E n d p oi nts f or i m m u n o ge nicit y dat a of a vel u m a b 
All a nal y ses descri be d bel o w are perf or me d f or Ar m A o nl y . 
Bl o o d sa m ples f or a vel u ma b i m m u n o ge nicit y  testi n g will be c ollecte d wit hi n 2 h o urs bef ore 
t he start of t he a vel u ma b i nf usi o n o n Da y  1, Da y 1 5 a n d Da y 2 9 of Cycl e 1, o n Da y  1 a n d 
D a y  2 9 of Cycles 2 - 4, o n D a y  1 of Cycle 6, a n d t he n e ver y 2 c ycles t hereafter .  A n a d diti o nal 
sa m ple m ust be c ollecte d at 3 0 da ys after t he last d ose of a vel u ma b.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5 6
Sa m ples p ositi ve f or A D A will be a nal yz e d f or titer a n d ma y be a nalyz e d f or n A b.  As of t he 
fi nalizati o n of t his S A P, t he n A b assa y is n ot yet a vaila ble, t heref ore t he a nal yses of n A b data 
descri be d i n t he f oll o wi n g secti o ns will o nl y  be c o n d ucte d c o nti n ge nt u p o n assa y a n d data 
a vaila bilit y at t he ti me of re p orti n g.
Patie nts will be c haracterize d i nt o differe nt A D A cate g ories base d o n t he criteria defi ne d i n 
Ta ble 1 5.  
T a ble 1 5
P atie nts C h ar acterize d B ase d o n A nti - Dr u g A nti b o d y Res ults ( A D A St at us)
C ate g or y
Defi niti o n
S u bjects at Ris k ( De n o mi n at or f or 
I nci de nce)
A D A ne ver -p ositi ve 
N o p ositi ve A D A res ults at a n y ti me p oi nt; 
A D A -ne gati ve patie nts (titer < c ut p oi nt)
N u m ber of patie nts wit h at least o ne 
vali d A D A res ult at a n y ti me p oi nt
A D A e ver -p ositi ve 
At least o ne p ositi ve A D A res ult at a n y ti me 
p oi nt; A D A -p ositi ve patie nts (titer ≥ c ut p oi nt)
N u m ber of patie nts wit h at least o ne 
vali d A D A res ult at a n y ti me p oi nt
Baseli ne A D A 
p ositi ve
A p ositi ve A D A res ult at baseli ne
N u m ber of patie nts wit h vali d baseli ne 
A D A res ult
Treat me nt- b o oste d 
A D A
A p ositi ve A D A res ult at baseli ne a n d t he titer 
≥ 8 × baseli ne titer at least o nce after treat me nt 
wit h a vel u ma b
N u m ber of patie nts wit h vali d baseli ne 
A D A res ults a n d at least o ne vali d 
p ost -baseli ne A D A res ult
Treat me nt- i n d uce d 
A D A
Patie nt is A D A -ne gati ve at baseli ne a n d has at 
least o ne p ositi ve p ost-baseli ne A D A res ult; or 
if patie nt d oes n ot ha ve a baseli ne sa m ple, t he 
patie nt has at least o ne p ositi ve past -baseli ne 
A D A res ult
N u m ber of patie nts wit h at least o ne 
vali d p ost -baseli ne A D A res ult a n d 
wit h o ut p ositi ve baseli ne A D A res ult 
(i ncl u di n g missi n g, N R)
Tra nsie nt A D A 
res p o nse
If patie nts wit h treat me nt-i n d uce d A D A ha ve (a 
si n gle p ositi ve A D A res ult or d urati o n bet wee n 
first a n d last p ositi ve res ult < 1 6 wee ks) a n d 
A D A res ult at t he last assess me nt is n ot 
p ositi ve.
N u m ber of patie nts wit h at least o ne 
vali d p ost -baseli ne A D A res ult a n d 
wit h o ut p ositi ve baseli ne A D A res ult 
(i ncl u di n g mi ssi n g, N R)
Persiste nt A D A 
res p o nse
If patie nts wit h treat me nt-i n d uce d A D A ha ve 
d urati o n bet wee n first a n d last p ositi ve A D A 
res ult ≥1 6 w ee ks or a p ositi ve A D A res ult at 
t he last assess me nt
N u m ber of patie nts wit h at least o ne 
vali d p ost -baseli ne A D A res ult a n d 
wit h o ut p ositi ve baseli ne A D A res ult 
(i ncl u di n g missi n g, N R)
A D A: a nti - dr u g a nti b o d y, N R = n ot re p orta ble.
Patie nts will be c haracterize d i nt o differe nt n A b cate g ories base d o n t he criteria i n Ta ble 1 6. 
F or n A b, treat me nt -b o oste d is n ot a p plic a ble si nce n o titer res ult is a vaila ble.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5 7
T a ble 1 6
P atie nts C h ar acterize d B ase d o n Ne utr alizi n g A nti b o d y Res ults ( n A b 
St at us)
C ate g or y
Defi niti o n
S u bjects at Ris k ( De n o mi n at or f or 
I nci de nce)
n A b ne ver -p ositi ve 
N o p ositi ve n A b res ults at a n y ti me p oi nt
N u m ber of patie nts wit h at least o ne 
vali d A D A res ult at a n y ti me p oi nt
n A b e ver -p ositi ve 
At least o ne p ositi ve n A b res ult at a n y ti me 
p oi nt
N u m ber of patie nts wit h at least o ne 
vali d A D A res ult at a n y ti me p oi nt
Baseli ne n A b 
p ositi ve
A p ositi ve n A b res ult at baseli ne
N u m ber of patie nts wit h vali d baseli ne 
A D A res ult
Treat me nt- i n d uce d 
n A b
Patie nt is n ot n A b p ositi ve at baseli ne a n d  has 
at least o ne p ositi ve p ost -baseli ne n A b res ult; 
or if patie nt d oes n ot ha ve a baseli ne sa m ple, 
t he patie nt has at least o ne p ositi ve past-
baseli ne A D A res ult
N u m ber of patie nts wit h at least o ne 
vali d p ost -baseli ne A D A res ult a n d 
wit h o ut p ositi ve baseli ne n A b res ult 
(i ncl u di n g missi n g, N R)
Tra nsie nt n A b 
res p o nse
If patie nts wit h treat me nt-i n d uce d n A b ha ve (a 
si n gle p ositi ve n A b res ult or d urati o n bet wee n 
first a n d last p ositi ve res ult < 1 6 wee ks) a n d 
n A b res ult at t he last assess me nt is n ot 
p ositi ve.
N u m ber of patie nts wit h at least o ne 
A D A vali d p ost -baseli ne res ult a n d 
wit h o ut p o siti ve baseli ne n A b res ult 
(i ncl u di n g missi n g, N R)
Persiste nt n A b 
res p o nse
If patie nts wit h treat me nt-i n d uce d n A b ha ve 
d urati o n bet wee n first a n d last p ositi ve n A b 
res ult ≥1 6 w ee ks or a p ositi ve n A b res ult at 
t he last assess me nt
N u m ber of patie nts wit h at least o ne 
vali d p ost -baseli ne A D A res ult a n d 
wit h o ut p ositi ve baseli ne n A b res ult 
(i ncl u di n g missi n g, N R)
A D A = a nti dr u g a nti b o d y, n A b = ne utralizi n g a nti b o d y, N R = n o res ult.
T he n u m ber a n d perce nta ge of patie nts i n eac h A D A a n d n A b cate g or y  will be s u m marize d. 
6. 2. 6. 1. Ti me t o a n d D ur ati o n of A D A a n d n A b res p o nse 
T he A D A a n d n A b a nal yses descri be d bel o w will i ncl u de patie nts wit h treat me nt -i n d uce d 
A D A or n A b, res pecti vel y.  
Ti me ( w ee ks) t o A D A res p o nse is defi ne d as:
( Date of first p ositi ve A D A res ult – date of first d ose of a vel u ma b + 1)/ 7. 
Ti me t o A D A res p o nse will be s u m marize d usi n g si m ple descri pti ve statistics ( mea n, S D, 
me dia n, mi n, ma x. Q 1, Q 3).
D urati o n ( wee ks) of A D A res p o nse is defi ne d as:
( Date of last p ositi ve A D A res ult – date of first p ositi ve A D A res ult + 1)/ 7. 
D urati o n of A D A res p o nse will be ce ns ore d if: 

t he last A D A assess me nt is p ositi ve A N D patie nt is o n g oi n g treat me nt wit h a vel u ma b, or


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5 8

t he last A D A assessme nt is p ositi ve A N D patie nt disc o nti n ue d treat me nt wit h a vel u ma b 
A N D t he last pla n ne d A D A assess me nt ( 3 0 da y s after t he last d ose of a vel u ma b) is after 
t he c ut-off date.
Ti me t o n A b res p o nse a n d d urati o n of n A b res p o nse are defi ne d si milarl y base d o n firs t a n d 
last p ositi ve n A b res ult. 
Ka pla n - Meier esti mates ( pr o d uct-li mit esti mates) will be prese nte d t o get her wit h a s u m mar y 
of ass ociate d statistics i ncl u di n g t he me dia n A D A res p o nse ti me wit h 2 -si de d 9 5 % CIs.  
A D A res p o nse rates at differe nt ti me p oi nts will be esti mate d wit h c orres p o n di n g 2- si de d 
9 5 % CI s.  T he CIs f or t he me dia n will be calc ulate d acc or di n g t o Br o o k me y er a n d Cr o wle y
( 1 9 8 2) a n d t he CIs f or t he s ur vi val f u ncti o n esti mates will be deri ve d usi n g t he l o g-l o g 
tra nsf or mati o n acc or di n g t o Kal bflei sc h a n d Pre ntice ( 2 0 1 1) (c o nfty p e =l o gl o g defa ult o pti o n 
i n S A S Pr oc LI F E T E S T) wit h bac k tra nsf or mati o n t o a CI o n t he u ntra nsf or me d scale. T he 
esti mate of t he sta n dar d err or will be c o m p ute d usi n g Gree n w o o d’s f or m ula.
D urati o n of A D A res p o nse will be dis pl a ye d gra p hicall y a n d a nalyz e d usi n g Ka pla n -Meier 
met h o d ol o g y . If t he n u m ber of patie nts wit h A D A res p o nse is s mall, t he Ka pla n-Meier 
met h o d ma y  n ot pr o vi de relia ble esti mates.  I n t his case, o nly descri pti ve statistics or listi n gs 
will be pr o vi de d
As data per mit, t he a nal yses descri be d a b o ve will be re peate d f or patie nts wit h treat me nt -
i n d uce d n A b. 
6. 2. 6. 2. A D A titer
F or patie nts w h o are A D A e ver p ositi ve, t he ma xi m u m o bser ve d A D A titer f or a patie nt will 
be s u m marize d, o verall a n d b y  A D A s u bcate g ories ( baseli ne A D A p ositi ve, treat me nt -
b o oste d A D A, treat me nt -i n d uce d A D A, tra nsie nt A D A res p o nse, persiste nt A D A res p o nse) 
of patie nts ha vi n g eac h discrete ma xi m u m titer val ue will be ta b ulate d. T he de n o mi nat or t o 
calc ulate t he perce nta ges will be t he t otal n u m ber of pati e nts i n t he ass ociate d A D A 
s u bcate g or y. 
F or patie nts wit h treat me nt -i n d uce d A D A, a cr oss ta b ulati o n of d urati o n of A D A res p o nse 
a n d ma xi m u m A D A titer will be pr o vi de d. T he f oll o wi n g cate g ories f or d urati o n of A D A 
res p o nse will be use d: ≤1, > 1 t o ≤3, > 3 t o ≤5, > 5 t o ≤7, > 7 t o ≤1 3, > 1 3 t o ≤1 6, > 1 6 t o ≤2 5, 
> 2 5 wee ks. I n t his cate g orizati o n, t he ce ns ori n g i n d urati o n of A D A res p o nse is i g n ore d. 
6. 2. 6. 3. A n al ysis of P K, s afet y a n d effic ac y b y i m m u n o ge nicit y st at us
T he f oll o wi n g A D A a n d n A b stat us will be use d f or t he a nal ys es descri be d bel o w.
A D A 

A D A e ver -p ositi ve vers us A D A ne ver -p ositi ve 

A D A: treat me nt -i n d uce d A D A vers us A D A ne ver-p ositi ve or baseli ne A D A p ositi ve
n A b 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 5 9

n A b e ver - p ositi ve vers us n A b ne ver-p ositi ve 

n A b: treat me nt -i n d uce d n A b vers us n A b ne ver-p ositi ve or baseli ne n A b p ositi ve
Data listi n gs will i ncl u de i m m u n o ge nicit y  data t o get her wit h rele va nt P K, safety a n d efficac y 
data.
P K para meters a n d i m m u n o ge nicit y stat us
T he f oll o wi n g a nal ys es will i ncl u de patie nts i n b ot h t he i m m u n o ge nicit y a nal ys is set a n d i n
t he P K para meter a nal ysis set.  T he P K e n d p oi nt perti ne nt t o t he i m m u n o ge nicit y a nal yses is
C tr o u g h .
Bl o o d sa m ples f or a vel u ma b P K will be c ollecte d pre- d ose o n Da y  1, Da y 1 5 a n d Da y 2 9 of 
C y cle 1, o n Da y 1 a n d Da y 2 9 of C y cles 2-4, Da y 1 of C y cle 6, e ver y 2 c ycles after C ycle 6, 
a n d 1 m o nt h after e n d of a vel u ma b treat me nt.
C tr o u g h will be s u m marize d descri pti vel y ( n, mea n, S D, C V, me dia n, mi ni m u m, ma xi m u m,
ge o metric mea n, its ass ociate d C V, a n d 9 5 % CI ) b y n o mi nal ti me a n d A D A stat us. Li near -
li near a n d l o g-li near pl ots of mea n a n d me dia n f or C tr o u g h o ver n o mi nal ti me a n d b y A D A 
stat us will be prese nte d. 
A m o n g patie nts wit h treat me nt -i n d uce d A D A, a nal yses will be c o n d ucte d t o assess w het her 
C tr o u g h ha s a n y c ha n ges bef ore a n d after t he first p ositi ve A D A assess me nt. T o be i ncl u de d i n 
t his a nal ysis, patie nts m ust ha ve t he sa me P K para meter a vaila ble b ot h bef ore a n d after t he 
first p ositi ve A D A assess me nt.  Relati ve P K da y will be calc ulate d as:
( P K assess me nt n o mi nal da y) – (first p ositi ve A D A assess me nt n o mi nal da y ).
N o mi nal da y  is t he pr ot oc ol sc he d ule d ti mi n g f or a n assess me nt. F or e xa m ple, if C tr o u g h is 
c ollecte d o n Da y 1 of Cycle 2 a n d t he first p ositi ve A D A res ult is o bser ve d o n Da y  1 of 
C y cle 3, t he n t he relati ve P K da y  f or t his C tr o u g h is - 4 2. Li near-li near a n d l o g-li near pl ots of 
mea n a n d me dia n f or C tr o u g h o ver relati ve P K da y  will be prese nte d. 
As data per mit, t he a nal yses descri be d a b o ve will be re peate d f or n A b.
Safet y  a n d i m m u n o ge nicit y stat us
T he f oll o wi n g a nal ys es will i ncl u de patie nt s i n t he i m m u n o ge nicit y a nal ysis set.
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g will be 
prese nte d b y A D A stat us.

T E A Es, b y  S O C a n d P T 

T E A E s lea di n g t o d ose re d ucti o n of a vel u ma b, b y  S O C a n d P T

T E A E s lea di n g t o disc o nti n uati o n of avel u ma b , b y  S O C a n d P T


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 0

T E A E s lea di n g t o disc o nti n uati o n of st u d y treat me nt b y  S O C a n d P T

Gra de ≥ 3 T E A Es , b y  S O C a n d P T

S A Es , b y  S O C a n d P T

I R Rs, by P T
F or patie nts w h o ha d at least o ne I R R a n d ha ve treat me nt-i n d uce d A D A, ti me relate d t o first 
o nset of a n I R R (i nf usi o n 1, i nf usi o n 2, i nf usi o n 3, i nf usi o n 4 or later) will be s u m marize d 
ta ki n g i nt o acc o u nt w het her t he  I R R occ urre d o n or after t he first A D A p ositi ve assess me nt 
or w het her t he I R R occ urre d bef ore t he first A D A p ositi ve assess me nt.  
As data per mit, t he a nal yses descri be d a b o ve will be re peate d f or n A b.
Efficac y  a n d i m m u n o ge nicit y stat us
F or t he A D A e ver -p ositi ve patie nts, a listi n g will be pre pare d wit h patie nt I D, start a n d st o p 
of a vel u ma b treat me nt, date of first p ositi ve A D A res ult, ti me t o A D A res p o nse, d urati o n of 
A D A res p o nse, date of last A D A p ositi ve res ult, B O R, D R, P F S ti me or ce ns ori n g ti me a n d 
reas o n f or ce ns ori n g, a n d O S ti me or ce ns ori n g ti me a n d reas o n f or ce ns ori n g.   I f a p plica ble, 
date of first p ositi ve n A b res ult, ti me t o n A b res p o nse, d urati o n of n A b res p o nse, date of last 
n A b p ositi ve res ult will als o be prese nte d.  T u m or -relate d e n d p oi nts will be prese nte d base d 
o n BI C R as sess me nt a n d base d o n I n vesti gat or assess me nt. 
F or t he A D A e ver - p ositi ve patie nts, t he perce nt c ha n ge fr o m baseli ne i n tar get lesi o ns as well 
as t he first occ urre nce of a ne w lesi o n a n d patie nt off a vel u ma b treat me nt will be dis pla y e d 
a gai nst ti me p oi nt ( wee ks) i n a li ne pl ot. A d diti o nal s y m b ols will i n dicate t he first a n d last 
A D A p ositi ve res ult a n d, if a p plica ble, t he first a n d last n A b p ositi ve res ult. Pl ot will be 
prese nte d se paratel y base d o n BI C R assess me nt a n d base d o n I n vesti gat or assess me nt.   
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 1
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 2
6. 3. 2. P R O e n d p oi nts
All P R O a nal yses will be perf or me d f or P D - L 1 p ositi ve patie nts a n d f or patie nts u nselecte d 
f or P D-L 1 e x pressi o n a n d will be base d o n t he F A S.
C CI


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 3
6. 3. 2. 1. P R O instr u me nts 
Patie nt- re p orte d o utc o mes of H R Q o L will be e val uate d usi n g F A C T-Ki d ne y  S ym pt o m I n de x 
( F K SI- 1 9) a n d E Q - 5 D-5 L .  A 9-ite m s u bscale of t he F K SI- 1 9 k n o w n as t he F K SI - Disease 
Relate d S y m pt o ms s u bscale ( F K SI -D R S) meas ur es a d va nce d ki dn e y  ca ncer disease relate d 
s ym pt o ms .  
T he pri mar y  P R O e n d p oi nt will be t he ti me t o s ym pt o m deteri orati o n ( T T D) w hic h is defi ne d 
as t he ti me fr o m date of ra n d o mizati o n t o t he first ti me t he patie nt’s sc ore s h o ws a 3-p oi nt or 
greater decrease i n F K SI -D R S .
6. 3. 2. 2. Sc ori n g p r oce d ure
T he F K SI - 1 9 a n d E Q - 5 D-5 L  will be sc ore d acc or di n g t o t heir res pecti ve vali dati o n pa pers 
a n d user’s g ui des.  F or t he E Q - 5 D-5 L , utilit y sc ores will be c ollate d usi n g t he p u blis he d 
wei g hts (tariffs) f or t he U nite d Ki n g d o m ( U K).   Missi n g val ues i n t he i nstr u me nts will als o 
be ha n dle d f oll o wi n g t he g ui da nce fr o m t heir res pecti ve User Ma n uals.  
6. 3. 2. 3. I nstr u me nt c o m pleti o n r ates
F or eac h treat me nt ar m a n d at eac h ti me p oi nt, t he n u m ber a n d perce nta ge of patie nts w h o 
c o m plete t he F K SI - 1 9, F KSI -D R S a n d E Q- 5 D- 5 L will be s u m marize d, as will t he reas o ns 
f or n o n-c o m pleti o n of t hese meas ures.  A n i nstr u me nt is c o nsi dere d c o m plete if at least o ne 
ite m was a ns were d by t he patie nt.   
6. 3. 2. 4. Descri pti ve s u m m aries o ver ti me
Se parate ta bles will be use d t o s u m marize, f or eac h treat me nt ar m, t he mea n (a n d S D), a n d 
me dia n (a n d ra n ge) of a bs ol ute sc ores a n d c ha n ge fr o m baseli ne of t he F K SI -1 9, F K SI -D R S 
E Q - 5 D-5 L , a n d E Q- 5 D-5 L V A S at eac h ti me p oi nt.  A li ne c hart de picti n g t he mea ns al o n g 
wit h sta n dar d err or (S E ) err or bars o ver ti me will be pr o vi de d f or eac h scale i n eac h 
treat me nt ar m.  
6. 3. 2. 5. Ti me -t o-e ve nt e n d p oi nts
Ti me t o deteri or ati o n ( T T D) e n d p oi nt
A 3 -p oi nt c ha n ge fr o m baseli ne i n F K SI-D R S has bee n esta blis he d as cli nicall y  mea ni n gf ul.  
Ti me t o deteri orati o n ( T T D) is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he first 
ti me t he patie nt’s sc ore s h o ws a 3- p oi nt or greater decrease fr o m baseli ne i n F K SI-D R S.  
T T D data will be ce ns ore d at t he last ti me w he n a patie nt c o m plete d t he assess me nt f or 
patie nts w h o ha ve n ot deteri orate d.  
T he treat me nt effect o n T T D will be esti mate d usi n g a C o x’s Pr o p orti o nal Hazar d m o del 
stratifie d b y t he ra n d o mizati o n strata t o calc ulate t he hazar d rati o f or t he e x peri me ntal ar m vs 
c o ntr ol ar m. 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 4
Eac h strat u m will defi ne a se parate baseli ne hazar d f u ncti o n ( usi n g t he ' S T R A T A' state me nt 
i n S A S P R O C P H R E G), i.e. f or t he i-t h strat u m t he hazar d f u ncti o n is e x presse d as: h(i;t) = 
h(i, 0;t) e x p( x ), w here h(i, 0;t) defi nes t he baseli ne hazar d f u ncti o n f or t he i-t h strat u m a n d x 
defi nes t he treat me nt ar m ( 0 =c o ntr ol ar m, 1 = e x peri me ntal ar m) a n d is t he u n k n o w n 
re gressi o n para meter.
Ties will be ha n dle d b y re placi n g t he pr o p orti o nal hazar ds m o del b y t he discrete l o gistic 
m o del ( Ties = Discrete o pti o n i n S A S P R O C P H R E G).
Ka pla n - Meier esti mates ( pr o d uct-li mit esti mates) will be prese nte d by treat me nt ar m t o get her 
wit h a s u m mar y  of ass ociate d statistics i ncl u di n g t he me dia n T T D ti me wit h 2-si de d 9 5 % 
CI s.  T he CIs f or t he me dia n T T D will be calc ulate d acc or di n g t o Br o ok me yer a n d Cr o wle y  
( 1 9 8 2).
Ti me t o I m pr o ve me nt ( T TI) e n d p oi nt
A 3 -p oi nt c ha n ge fr o m baseli ne i n F K SI-D R S has bee n esta blis he d as cli nicall y  mea ni n gf ul.  
Ti me t o i m pr o ve me nt ( T TI) is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he first 
ti me t he patie nt’s sc ore s h o ws a 3 -p oi nt or greater i ncrease fr o m baseli ne i n F K SI-D R S.  
T TI  data will be ce ns ore d at t he last ti me w he n a patie nt c o m plete d t he assess me nt f or 
pa tie nts w h o ha ve n ot i m pr o ve d.  
T TI  will be a nalyz e d usi n g t he sa me met h o d ol o g y as T T D.
6. 3. 2. 6. Bi n ar y e n d p oi nts 
T he p r o p orti o n of patie nts w h o ha ve i m pr o ve d fr o m baseli ne at C ycle 5, defi ne d as a 3-p oi nt 
or greater i ncrease fr o m baseli ne i n F K SI-D R S, will be s u m marize d usi n g descri pti ve 
statistics as descri be d i n Secti o n 5. 2. 3 .  C hi-s q uare test will be use d t o c o m pare t he 
pr o p orti o ns bet wee n t he e x peri me ntal ar m a n d c o ntr ol ar m. Patie nts w h o di d n ot c o m plete 
t he first 5 c ycles of treat me nt a n d di d n ot s h o w i m pr o ve me nt pri or t o E O T will be c o u nte d as 
n ot ha vi n g i m pr o ve d .
6. 3. 2. 7. C o nti n u o us e n d p oi nts
Ra n d o m c oefficie nt m o dels will be carrie d o ut f or t he F K SI -1 9, F K SI -D R S E Q - 5 D-5 L , a n d 
E Q - 5 D-5 L V A S usi n g P R O C MI X E D. 
O utc o mes are P R O p ost- baseli ne sc ores a n d t he pre dict ors are t he c orres p o n di n g baseli ne 
P R O sc ore, treat me nt, ti me (treate d as a c o nti n u o us var ia ble), a n d treat me nt-b y -ti me 
i nteracti o n. I nterce pt a n d ti me are c o nsi dere d as ra n d o m effects partic ular t o eac h s u bject. 
All a vaila ble data f or eac h patie nt will be use d i n a nal ys es. All para meter esti mates will be 
o btai ne d usi n g restricte d ma xi m u m li ke li h o o d. T he u nstr uct ure d c o varia nce str uct ure will be 
use d t o defi ne c o varia nce bet wee n ra n d o m effects ( usi n g o pti o n “ T y pe = U N” as a part of t he 
R A N D O M state me nt i n P R O C MI X E D). F or t he de grees- of-free d o m calc ulati o ns t he 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 5
Ke n war d a n d R o ger al g orit h m will be use d ( usi n g o pti o n “ d df m = kr” as a part of t he 
M O D E L
state me nt i n P R O C MIX E D).   
6. 3. 2. 8. Se nsiti vit y A n al ys es   
S e nsiti vit y a nal yses base d o n a 2 -p oi nt , 4-p oi nt a n d 5-p oi nt decrease fr o m baseli ne i n F K SI-
D R S will be c o n d ucte d f or T T D ; si milarl y, se nsiti vit y a nal ys es  base d o n a 2 -p oi nt, 4 -p oi nt 
a n d 5-p oi nt i ncrease fr o m baseli ne i n F K SI-D R S will be c o n d ucte d f or T TI . Cu m ulati ve 
distri b uti o n f u ncti o n pl ots of t he c ha n ge fr o m baseli ne i n t he F K SI -D R S f or C y cle 2, 4, 6, 8 
a n d 1 0 will als o be prese nte d .
F or T T D a n d T TI, t he pri mar y a nal ys es will i ncl u de data fr o m baseli ne u p t o E O T 
assess me nt ( n ot i ncl u di n g E O T).  S e nsiti vit y a nal ys es f or t hese e n d p oi nts will i ncl u de all 
assess me nts fr o m baseli ne t o t he e n d of t he safet y f oll o w-u p peri o d.
6. 4. S u bset a n al yses
S u bset a nal y ses will be perf or me d f or P D - L 1 p ositi ve patie nts a n d f or patie nts u nselecte d f or 
P D -L 1  e x pressi o n .
S u bset a nal y ses will be perf or me d f or P F S, O R a n d D R per BIC R assess me nt a n d O S base d 
o n t he F A S f or t he s u b gr o u ps defi ne d bel o w. 
T he f oll o wi n g s u b gr o u ps will be defi ne d a n d use d f or a nal ys es:

Ra n d o mizati o n stratificati o n fact ors
-
E C O G P S 0 ( Refere nce) vs 1
-
Ge o gra p hical Re gi o n ( U nite d States ( Refere nce ) vs Ca na da/ Wester n E ur o pe vs Rest 
of t he W orl d)

A ge 
-
A ge < 6 5 ye ars ( Refere nce)
-
A ge ≥ 6 5 y ears 

Ge n der
-
Male ( Ref ere nce)
-
Fe male

Race
-
Ca ucasia n / W hite ( Ref ere nce)
-
Asia n
-
Blac k/ Africa n A merica n
-
Ot her


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 6

Et h nicit y
-
His pa nic/ Lati n o 
-
N o n -His pa nic/ Lati n o ( Ref ere nce)

P o ole d Ge o gra p hical Re gi o n 
-
N ort h A merica 
-
E ur o pe ( Ref ere nce )
-
Asia
-
Rest of t he W orl d 
(A ustral asia Lati n A merica , Africa a n d/ or Mi d dle East will be 
i ncl u de d as a d diti o nal s u b gr o u ps if i ncl u di n g > 1 0 % of t he o verall ra n d o mize d 
p o p ulati o n )

Ne p hrect o m y  at baseli ne
-
Yes ( Refere nce)
-
N o

M S K C C pr o g n ostic criteria at baseli ne
( detaile d i n S ecti o n 6. 5. 1. 3)
-
Fa v ora ble ( Refere nce)
-
I nter me diate
-
P o or

He n g pr o g n ostic criteria at baseli ne ( detaile d i n S ecti o n 6. 5. 1. 3)
-
Fa v ora ble ( Refere nce)
-
I nter me diate
-
P o or
S u bset a nal y ses f or P F S , O S a n d D R will use t he pri mar y ce ns ori n g r ules descri be d i n 
Secti o ns 6. 1. 1. 1 a n d 6. 1. 2. 1 . All t he s u b gr o u p a nal yses are e x pl orat or y. T reat me nt ar ms will 
be c o m pare d f or P F S a n d O S usi n g a 2- si de d u nstratifie d l o g-ra n k test f or eac h s u b gr o u p 
le vel a n d t he u nstratifie d H R a n d its c orres p o n di n g 9 5 % CI will be c o m p ute d per s u b gr o u p 
le vel. 
All t he s u b gr o u p a nal ys es will be e x pl orat or y; n o a dj ust me nt f or m ulti plicit y will be 
perf or me d.  I n t he case of a l o w n u m ber of patie nts wit hi n a cate g or y ( < 5 % of t he 
ra n d o mize d p o p ulati o n), t he cate g ories will be p o oled.
T o assess t he heter o ge neit y  of treat me nt effects f or P F S a n d O S acr oss t he s u b gr o u p le vels, 
t w o C o x re gressi o n m o del will be fitte d wit h P F S or O S, res pecti vel y , as t he de pe n de nt 
varia ble a n d s u b gr o u p, treat me nt, a n d wit h a n d wit h o ut t he treat me nt-b y -su b gr o u p 
i nteracti o n as e x pla nat or y varia bles. 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 7

M o del 1: fact ors + treat me nt + s u b gr o u p

M o del 2: fact ors + treat me nt + s u b gr o u p + treat me nt × s u b gr o u p- varia ble 
A p -val ue f or t he i nteracti o n test ( L i keli h o o d Rati o test) will be pr o vi de d t o get her wit h t he 
H R a n d c orres p o n di n g 9 5 % CI  f or t he i nteracti o n m o del para meter. 
T he H R f or P F S a n d O S a n d c orres p o n di n g 9 5 % CIs f or all s u b gr o u ps will als o be prese nte d 
i n a f orest pl ot.
T he O R R o d ds rati o f or eac h s u b gr o u p a n d c orres p o n di n g 9 5 % CIs will als o be prese nte d i n 
a f orest pl ot f or eac h treat me nt ar m.
6. 5. B aseli ne a n d Ot her S u m m aries a n d A n al yses
6. 5. 1. B aseli ne s u m m aries
T he f oll o wi n g a nal ys es will be perf or me d f or P D -L 1  p ositi ve patie nts a n d f or patie nts 
u nselecte d f or P D -L 1 e x pressi o n a n d will be base d o n t he F A S o verall a n d se paratel y b y
treat me nt ar m.
6. 5. 1. 1. De m o gr a p hic c h ar acteristics
De m o gra p hic c haracteristics a n d p h ysical meas ure me nts will be s u m marize d b y  treat me nt 
ar m usi n g t he f oll o wi n g i nf or mati o n fr o m t he ‘ Scree ni n g/ Baseli ne Visit’ eC R F pa ges.

De m o gra p hic c haracteristics 
-
Ge n der: Male, Fe male 
-
Race: W hite, Blac k or Africa n A merica n, Asia n, A merica n I n dia n or Alas ka Nati ve, 
Nati ve Ha waiia n or ot her Pacific Isla n der, Ot her, U n k n o w n
-
Et h nic ori gi n: His pa nic/ Lati n o ( Yes/ N o)
-
A ge ( y ears): s u m mar y statistics 
-
A ge cate g ories: 

< 6 5 y ears, ≥ 6 5 y ears 

< 6 5, 6 5- < 7 5, 7 5- < 8 5, ≥ 8 5 ye ars
-
P o ole d Ge o gra p hical Re gi o n (as a p plica ble): 

N ort h A merica 

E ur o pe

Asia


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 8

Rest of t he W orl d
(A ustralasia , Lati n A merica , Africa a n d/ or Mi d dle East will be 
i ncl u de d as a d diti o nal p o ole d ge o gra p hical re gi o ns if i ncl u di n g > 1 0 % of t he 
o verall ra n d o mize d p o p ulati o n)
-
Ge o gra p hic Re gi o n (as a p plica ble):

N ort h A merica

Lati n A merica

Wester n E ur o pe

Easter n E ur o pe

Mi d dle East

A ustral asia

Asia

Africa
-
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us: 0, 1, 2, 3, a n d 4 

P h y sical meas ure me nts
-
Hei g ht (c m)
-
Wei g ht ( k g)
-
B o d y  Mass I n de x ( B MI) ( k g/ m2)
Ce nter c o des will be use d f or t he deter mi nati o n of t he patie nt’s ge o gra p hic re gi o n.
T he listi n g of de m o gra p hics a n d baseli ne c haracteristics will i ncl u de t he f oll o wi n g 
i nf or mati o n: patie nt i de ntifier, treat me nt ar m, a ge, se x, race, et h nicity, hei g ht (c m), wei g ht 
( k g), B MI ( k g/ m2), a n d E C O G perf or ma nce stat us.
6. 5. 1. 2. Me dic al h ist or y
Me dical hist or y  will be c o de d usi n g t he m ost c urre nt a vaila ble versi o n of Me dical Dicti o nar y 
f or Re g ulat or y Acti vities ( Me d D R A) a n d will be s u m marize d fr o m t he ‘Me dical Hist or y ’
e C R F pa ge. Me dical hist or y will be s u m marize d as t he n u m bers a n d perce nta ges of patie nts 
b y Me d D R A preferre d ter m ( P T) as e ve nt cate g or y a n d Me d D R A pri mar y s yste m or ga n 
class ( S O C) as s u m mar y  cate g or y. Eac h patie nt will be c o u nte d o nl y o nce wit hi n eac h P T or 
S O C.
Me dical hist or y  will be dis pla ye d i n ter ms of fre q ue nc y ta bles: or dere d by pri mar y S O C a n d 
P T i n al p ha betical or der.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 6 9
6. 5. 1. 3. Dise ase ch ar acteristics
I nf or mati o n o n disease c haracteristics c ollecte d o n ‘Pri mar y  Dia g n osis’, ‘S u bsta nce A b use ’
a n d R E CIS T e C R F pa ge s will be s u m marize d o verall a n d b y treat me nt ar m. S u m mar y 
statistics will be prese nte d f or t he f oll o wi n g.
Fr o m t he ‘Pri mar y  Dia g n osis’ e C R F pa ge:

Site of pri mar y  t u m or

Pri mar y  dia g n osis (s u m marize all cate g ories c ollecte d i n t he ‘Pri mar y  Dia g n osis’ e C R F 
pa ge)

Ti me si nce i nitial dia g n osis t o date of ra n d o mizati o n ( m o nt hs), defi ne d as (date of 
ra n d o mizati o n – date of i nitial dia g n osis)/ 3 0. 4 3 7 5

Ti me si nce dia g n osis of l ocal/re gi o nal/ dista nt rec urre nce of disease ( m o nt hs), defi ne d as 
(date of ra n d o mizati o n –
date of dia g n osis of l ocal/re gi o nal/ dista nt rec urre nce of 
disease)/ 3 0. 4 3 7 5

T y pe of disease rec urre nce

Hist o pat h ol o gical a n d F ur h ma n gra de

T N M a n d AJ C C T N M, b ot h at i nitial dia g n osis a n d c urre nt sta ge

Pri or n e p hrect o m y

Me m orial Sl oa n -Ketteri n g Ca ncer Ce nter  (M S K C C) pr o g n ostic criteria ( M otzer et al., 
2 0 0 2) 
M S K C C pr o g n ostic criteria are base d o n t he detecti o n of fi ve ris k fact ors: E C O G P S ≥ 2, 
hi g h L D H ( > 1. 5 ti mes t he U L N), ser u m he m o gl o bi n < L L N, hi g h c orrecte d ser u m 
calci u m ( > 1 0 m g/ d L), ti me fr o m i nitial dia g n osis t o st u d y treat me nt start less t ha n o ne 
ye ar. Patie nts will be assi g ne d t o o ne of t he f oll o wi n g ris k gr o u ps:
-
Fa v ora ble ( 0 ris k fact ors)
-
I nter me diate ( 1 or 2 ris k fact ors)
-
P o or ( 3 or m ore ris k fact ors)

He n g pr o g n ostic criteria ( He n g et al., 2 0 0 9) 
He n g criteria are base d o n t he detecti o n of t he sa me ris k fact ors e val uate d b y  th e 
M S K C C criteria, e xce pt f or L D H, wit h t he a d diti o n of: a bs ol ute ne utr o p hils c o u nt > 
U L N, platelets c o u nt > U L N. Patie nts will be assi g ne d t o o ne of t he f oll o wi n g ris k 
gr o u ps:
-
Fa v ora ble ( 0 ris k fact ors)
-
I nter me diate ( 1 or 2 ris k fact ors)


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 0
-
P o or ( 3 or m ore ri s k fact ors)
Fr o m t he R E CI S T e C R F pa ge (s u m mar y will be prese nte d se parately base d o n i n vesti gat or 
assess me nt a n d BI C R assess me nt) :

Meas ura ble disease (lesi o ns) at baseli ne ( Yes, N o)

I n v ol ve d t u m or sites at baseli ne
Fr o m t he ‘S u bsta nce Use ’ e C R F pa ge:

S m o ki n g hist or y
-
Ne ver s m o ker vs c urre nt vs f or mer s m o ker 
-
S m o ki n g e x p os ure ( pac k -ye ars): 0, < 2 0, 2 0- < 4 0, ≥4 0 a n d s u m mar y  statistics
-
Years si nce q uitti n g: ne ver s m o ker, c urre nt s m o ker, < 5, 5- < 1 0, ≥1 0 a n d s u m mar y 
statistics
S pecificati o ns f or c o m p utati o n:

Ci garette e q ui vale nts are calc ulate d as f oll o ws: o ne ci gar is re gar de d e q ui vale nt t o 5 
ci garettes a n d 1 pi pe is re gar de d e q ui vale nt t o 3 ci garettes

D urati o n of nic oti ne c o ns u m pti o n [ y ears]:
(e n d of nic oti ne c o ns u m pti o n – start of nic oti ne c o ns u m pti o n + 1) / 3 6 5. 2 5

Pac k -years:
-
calc ulate ci garette e q ui vale nts per da y  usi n g t he c o n versi o n fact ors gi ve n a b o ve
-
c o n vert t o pac ks per da y w here 2 0 ci garettes are re gar de d as 1 pac k
-
pac k -ye ars = pac ks per da y × d urati o n of nic oti ne c o ns u m pti o n [ years]
Listi n g of disease hist or y will be pr o vi de d wit h all rele va nt data (as c ollecte d o n t he ‘Pri mar y  
Dia g n osis ’ a n d ‘S u bsta nce Use ’ e C R F pa ges) a n d deri ve d varia bles as a b o ve.
6. 5. 1. 4. Pri or a nti -ca ncer ther a pies
T he pri or a nti - ca ncer t hera pies are c ollecte d u n der t he ‘Pri or Ca ncer T hera p y ’, ‘ Pri or 
Ra diati o n T hera p y’ a n d ‘ Pri or S ur ger y ’ e C R F pa ges.
P ri or a nti-ca ncer t hera pies will be i ncl u de d i n t he listi n gs t hat f oll o w wit h a fla g t o i de ntif y 
pri or t hera pies . T hese will i ncl u de t he patie nt i de ntificati o n n u m ber, a n d all t he rele va nt 
c ollecte d data -fiel ds o n t he c orres p o n di n g e C R F pa ges.

Listi n g of a nti -ca ncer dr u g t hera pies 

Listi n g of a nti -ca ncer ra di ot hera p y 


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B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 1

Listi n g of a nti -ca ncer s ur geries
6. 5. 2. St u d y co n d uct a n d p atie nt d is p ositi o n
T he f oll o wi n g a nal ys es will be perf or me d base d o n t he F A S o verall a n d se paratel y b y
treat me nt ar m.
6. 5. 2. 1. P atie nt d is p ositi o n
T he perce nta ges bel o w will be calc ulate d base d o n t he n u m ber of patie nts i n t he F A S.

T otal n u m ber of patie nts scree ne d o verall

N u m ber of patie nts w h o disc o nti n ue d fr o m t he stu d y  pri or t o ra n d o mizati o n o verall a n d 
b y  t he mai n reas o n f or disc o nti n uati o n

N u m ber a n d perce nta ge of ra n d o mize d patie nts i n eac h of t he a nal ys is sets defi ne d i n 
Secti o n 4

N u m ber a n d perce nta ge of ra n d o mize d patie nts wit h st u d y dr u g o n g oi n g (se parately f or 
eac h st u d y dr u g i n Ar m A)

N u m ber a n d perce nta ge of ra n d o mize d patie nts w h o disc o nti n ue d st u d y dr u g o verall a n d 
b y  the mai n reas o n f or disc o nti n uati o n of st u d y dr u g (se parately f or eac h st u d y dr u g i n 
Ar m A)

N u m ber a n d perce nta ge of patie nts w h o e ntere d f o ll o w-u p

N u m ber a n d perce nta ge of patie nts w h o disc o nti n ue d  foll o w - u p o verall a n d b y  the mai n 
reas o n f or disc o nti n uati o n

N u m ber a n d perce nta ge of patie nts w h o e ntere d l o n g-ter m f oll o w- u p

N u m ber a n d perce nta ge of patie nts w h o disc o nti n ue d l o n g-ter m f oll o w- u p o verall a n d b y  
t he mai n reas o n f or disc o nti n uati o n.
T he res ults of t he ra n d o mizati o n al g orit h m (acc or di n g t o I RT ) will be s u m marize d as 
f oll o ws:

N u m ber 
a n d perce nta ge of ra n d o mize d patie nts o verall, b y  re gi o n ( E ur o pe, E E A 
(re q uire d b y  Eu dra C T), N ort h A merica, Lati n A merica, Mi d dle East, Asia, A ustralasia , 
Africa) , b y c o u ntr y wit hi n re gi o n 

N u m ber a n d perce nta ge of ra n d o mize d patie nts b y ce nter

N u m ber a n d perce nta ge of ra n d o mize d patie nts b y ra n d o mizati o n strata (I R T)

N u m ber a n d perce nta ge of ra n d o mize d patie nts b y ra n d o mizati o n strata (e C R F)

Cr oss ta b ulati o n: strat u m b y  I R T vs strat u m b y e C R F


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 2

Cr oss ta b ulati o n: patie nts ra n d o mize d ( Ar m A/ Ar m B/ n o ne) vs patie nts treate d (Ar m 
A/ Ar m B / n o ne)
I n ad diti o n, a cr oss ta b ulati o n of patie nts w h o ha ve disc o nti n ue d /are o n g oi n g treat me nt wit h
a vel u ma b vs patie nts w h o ha ve disc o nti n ue d /are o n g oi n g treat me nt wit h
a xiti ni b i n t he 
c o m bi nati o n ar m will als o be pr o vi de d. 
6. 5. 2. 2. Pr ot oc ol d e vi ati o ns
All pr ot oc ol vi olati o ns t hat i m pact t he s afet y of t he patie nts a n d/ or t he c o n d uct of t he st u d y 
a n d/ or its e val uati o n will be re p orte d. T hese i ncl u de:

Patie nts w h o are d ose d o n t he st u d y des pite n ot satisf yi n g t he i ncl usi o n criteria

Patie nts w h o de vel o p wit h dra wal criteria w hilst o n t he st u d y  b ut are n ot wit h dra w n

Patie nts w h o recei ve t he wr o n g treat me nt or a n i nc orrect d ose

Patie nts w h o recei ve a n e xcl u de d c o nc o mita nt me dicati o n

De viati o n s fr o m G C P.
T he i de ntificati o n of t hese a n d ot her C S R -re p orta ble de viati o ns will be base d o n t he 
i ncl usi o n/e xclusi o n criteria or ot her cri teria prese nte d i n t he pr ot oc ol.
6. 5. 3. St u d y tre at me nt co m pli a nce a n d ex p os ure
T he f oll o wi n g a nal ys es will be base d o n t he safet y  a nal ysis set b y treat me nt ar m.
C y cle defi niti o ns f or st u d y dr u gs t hat are a d mi nistere d i n c o m bi nati o n a p pl y t o all t he st u d y 
dr u gs i n t he c o m bi nati o n.  I .e., c ycle is patie nt -de pe n de nt, rat her t ha n st u d y -dr u g - de pe n de nt 
w he n st u d y  dr u gs are a d mi nistere d i n c o m bi nati o n.
F or C y cle X, act ual c ycle start date f or eac h patie nt is

t he earliest start date of d osi n g i n t he C y cle X da y  1 visit C R F e x p os ure pa ge, if t he 
patie nt recei ve d st u d y treat me nt o n t hat visit (i.e., a n y st u d y dr u g wit h d ose > 0 at t hat 
visit)

t he first d a y  of assess me nts i n t he C ycle X d a y  1 visit, if t he patie nt di d n ot recei ve st u d y 
treat me nt o n t hat visit (i.e., all st u d y dru gs ha d d ose = 0 at t hat visit).  Use start date i n t he 
e x p os ure pa ge if a vaila ble; if start date is n ot a vaila ble t he n use date of c ollecti o n of vital 
si g ns o n C ycle X da y 1 visit.
Act ual c y cle e n d date f or eac h patie nt is, 

f or all c ycles X e xce pt t he last c ycle, act ual c ycle e n d date = act ual c ycle ( X + 1) start date 
– 1 da y ;

f or t he last c ycle, act ual c ycle e n d date = act ual c ycle start date + 4 2 – 1 da y


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 3
C ycle d ur ati o n ( wee ks) = (act ual c ycle e n d date – act ual c ycle start date + 1)/ 7
W he n s u m marizi n g e x p os ure f or eac h st u d y dr u g, o nl y c ycles fr o m first d ose of st u d y 
treat me nt u ntil t he last c ycle wit h n o n-zer o d ose of st u d y dr u g ( Ar m B) or at least o ne of t he 
st u d y dr u gs ( Ar m A) s h o ul d be i ncl u de d.
E x p os ure will be s u m marize d ( per c y cle a n d/ or o verall) as d ose recei ve d (c u m ulati ve d ose, 
act ual d ose i nte nsit y) a n d as d ose recei ve d relati ve t o i nte n de d d ose (relati ve d ose i nte nsit y 
[ R DI]).
T he deri vati o ns bel o w are pr o vi de d f or t he f oll o wi n g :

A vel u ma b a d mi nistere d as a 1- h o ur I V i nf usi o n at a d ose of 1 0 m g/ k g o nce e ver y 2 
wee ks i n 6- wee k c y cles. 

A xiti ni b a d mi nistere d BI D P O at a d ose of 5 m g . 

S u niti ni b a d mi nistere d 5 0 m g P O Q D o n Sc he d ule 4/ 2 . 
A nal y sis of e x p os ure will be base d o n t he calc ulate d act ual d ose le vels:

A vel u ma b - t otal d ose / wei g ht 

A xiti ni b - t otal d ose

S u niti ni b - t otal d ose.
E x p os ure a n d c o m plia nce will be s u m marize d b y c ycle a n d o verall f or eac h st u d y dr u g i n 
eac h treat me nt ar m.
6. 5. 3. 1. E x p os ure t o a vel u m a b 
T he d ose le vel f or avel u ma b is calc ulate d as act ual d ose a d mi nistere d/ wei g ht ( m g/ k g). T he 
last a vaila ble wei g ht of t he patie nt o n or pri or t o t he da y of d osi n g will be use d.
I nte n de d d ur ati o n of tre at me nt wit h a vel u m a b ( wee ks) = 
(e n d date– date of first d ose of a vel u ma b + 1)/ 7 ,
w here e n d date = start date of last c y cle wit h n o n-zer o d ose of a vel u ma b + 4 2 – 1
D ur ati o n of e x p os ure t o a vel u m a b ( wee ks) = (last d ose date of a vel u ma b – first d ose date 
of a vel u ma b + 1 4)/ 7 
C u m ul ati ve d ose i n a c ycle or o verall is t he s u m of t he act ual d oses of a vel u ma b recei ve d i n 
a c ycle or o verall, res pecti vel y.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 4
Act u al D ose I nte nsit y ( DI)

B y  c ycle act ual DI ( m g / k g/6- wee k c y cle) = [c u m ulati ve d ose i n t he c ycle ( m g/ k g)]/[c ycle 
d urati o n ( wee ks)/ 6]

O verall act ual DI ( m g / k g/6- wee k c y cle) = [ o verall c u m ulati ve d ose ( m g/ k g)] / [i nte n de d 
d urati o n of treat me nt wit h a vel u ma b ( wee ks)/ 6 ]. 
Rel ati ve D ose I nte nsit y ( R DI)  

I nte n de d DI (m g/ k g/ 6- wee k c y cle ) = [i nte n de d c u m ulati ve d ose per c ycle] / [i nte n de d 
n u m ber of 6- wee ks i n a c y cle] = [ 3 0 ( m g/ k g)] / [ 1( 6- wee k c y cle)]  = 3 0 ( m g/ k g/6- wee k 
c ycle)

B y  c ycle R DI ( %) = 1 0 0 × [ b y c ycle act ual DI] / [i nte n de d DI]                                                            
= 1 0 0 × [ b y  c ycle act ual DI] / [3 0 ( m g/ k g/ 6 -wee k c y cle)]  

O verall R DI ( %) = 1 0 0 ×  [ o verall a ct ual DI] / [i nte n de d DI]                                                                
= 1 0 0 × [ o verall act ual DI] / [ 3 0 ( m g/ k g/ 6- wee k c ycle)]
6. 5. 3. 2. E x p os ure t o a xiti ni b
T he d ose le vel is calc ulate d as act ual d ose a d mi nistere d ( m g/ da y).  
I nte n de d d ur ati o n of tre at me nt wit h a xiti ni b ( wee ks) =
(last d ose date of a xiti ni b – first d ose date of a xiti ni b + 1)/ 7
D ur ati o n of e x p os ure t o a xiti ni b ( wee ks) = 
(last d ose date of a xiti ni b – first d ose date  of a xiti ni b + 1)/ 7
C u m ul ati ve d ose is t he s u m of t he act ual d oses of a xiti ni b recei ve d i n t he st u d y.  
Act u al D ose I nte nsit y ( DI)

O verall act ual DI ( m g/ wee k ) = [ o verall c u m ulati ve d ose ( m g)] / [i nte n de d treat me nt 
d urati o n ( wee ks)]
Rel ati ve D ose I nte nsit y ( R DI)

R DI  ( %) = 1 0 0 × [ o verall c u m ulati ve d ose] / [i nte n de d c u m ulati ve d ose per wee k × 
n u m ber of wee ks fr o m first d ose of st u d y  dr u g t o last d ose of a xiti ni b] 
= 1 0 0 × [ o verall c u m ulati ve d ose] / [ 7 × 2 × 5 × d urati o n of e x p os ure t o a xiti ni b]
6. 5. 3. 3. E x p os ure t o s u nit i ni b
T he d ose le vel is calc ulate d as act ual d ose a d mi nistere d ( m g/ da y).  
I nte n de d d ur ati o n of tre at me nt wit h s u niti ni b ( wee ks) = 
(e n d date– date of first d ose of s u niti ni b + 1)/ 7 ,


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 5
w here e n d date = start date of last c y cle wit h n o n-zer o d ose of s u niti ni b + 4 2 – 1
D ur ati o n of e x p os ure t o s u niti ni b ( wee ks) = (last d ose date of s u niti ni b – first d ose date of 
s u niti ni b + d )/ 7, w here d = 1 if t he patie nt disc o nti n ues s u niti ni b pri or t o t he e n d of t he last 
c ycle or d = 1 4 ot her wise (i.e. d = 1 if date of last d os e of s u niti ni b – date of first d ose of
s u niti ni b i n t he last c ycle < 2 8).
C u m ul ati ve d ose i n a c ycle or o verall is t he s u m of t he act ual d oses of s u niti ni b recei ve d i n a
c ycle or o verall, res pecti vel y.
Act u al D ose I nte nsit y ( DI)

B y  c ycle act ual DI ( m g / 6-wee k c ycle ) = [c u m ulati ve d ose i n t he c ycle ( m g)]/[c ycle 
d urati o n ( wee ks) / 6]

O verall act ual DI ( m g / 6-wee k c ycle) = [ o verall c u m ulati ve d ose ( m g)] / [i nte n de d 
d urati o n of treat me nt wit h s u niti ni b ( wee ks)/ 6]. 
Rel ati ve D ose I nte nsit y ( R DI)  

I nte n de d DI (m g/ 6- wee k c ycles) = [i nte n de d c u m ulati ve d ose per c ycle] / [i nte n de d 
n u m ber of 6- wee ks i n a c y cle] = [ 7 × 5 0 × 4 ( m g)] / [1 ( 6- wee k c y cle)]  = 1 4 0 0 ( m g/6- wee k
c ycle)

B y  c ycle R DI ( %) = 1 0 0 × [ b y c ycle act ual DI] / [i nte n de d DI]                                                            
= 1 0 0 × [ b y  c ycle act ual DI] / [1 4 0 0 ( m g/6- wee k c ycle)]  

O verall R DI ( %) = 1 0 0 ×  [ o verall act ual DI] / [i nte n de d DI]                                                                
= 1 0 0 ×  [ o verall act ual DI ] / [1 4 0 0 ( m g/6- wee k cyc le)]
6. 5. 3. 4. D ose re d ucti o ns 
A p plica ble t o a vel u ma b. D ose re d ucti o n is defi ne d as act ual n o n -zer o d ose < 9 0 % of t he 
pla n ne d d ose. 
A p plica ble t o a xiti ni b a n d s u niti ni b. D ose re d ucti o n is defi ne d as a c ha n ge t o a n o n -zer o d ose 
le vel l o wer t ha n t hat pla n ne d i n the pr ot oc ol.
T he n u m ber a n d perce nta ge of patie nts wit h at least o ne d ose re d ucti o n as well as a 
brea k d o w n of d ose re d ucti o ns ( 1, 2, 3, ≥4) will be s u m marize d . 
6. 5. 3. 5. D ose esc al ati o ns
A p plica ble t o a xiti ni b o nl y . D ose escalati o n is defi ne d as a c ha n ge t o a d ose le vel hi g her t ha n 
t hat pla n ne d i n t he pr ot oc ol.
N u m ber a n d perce nta ge of patie nts wit h at least o ne d ose escalati o n as well as a brea k d o w n 
of d ose escalati o n s ( 1, 2, ≥3 ) will be s u m marize d.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 6
6. 5. 3. 6. D ose i nterr u pti o ns
A p plica ble t o a xiti ni b a n d s u niti ni b.   
A n i nt err u pti o n is defi ne d a 0 m g d ose a d mi nistere d o n o ne or m ore da y s f or a xiti ni b or 
wit hi n t he d osi n g peri o d of a c y cle f or s u niti ni b. W hat f oll o ws defi nes h o w d ose 
i nterr u pti o ns will be c o u nte d i n t he case of m ulti ple d ose i nterr u pti o ns.

If a n i nterr u pti o n occ urs c o nsec uti vel y f or at least t w o da y s d ue t o t he sa me reas o n, t he n 
it will be c o u nte d o nl y o nce (e xa m ple: If t he act ual d ose o n d a y s 1- 3 is 1 0 m g a n d act ual 
d ose o n da y s 4- 5 is 0 m g a n d d ose i nterr u pti o n o n da y s 4- 5 is d ue t o A E, t he n t he t otal 
n u m ber of d ose i nterr u pti o ns is 1).

If a n i nterr u pti o n occ urs c o nsec uti vel y f or at least t w o da y s d ue t o differe nt reas o ns, t he n 
it will be c o u nte d f or eac h reas o n (e xa m ple: If t he act ual d ose o n da y s 1- 3 is 1 0 m g a n d 
act ual d ose o n d a y s 4- 5 is 0 m g a n d d ose i nterr u pti o n o n d a y  4 is d ue t o A E a n d d ose 
i nterr u pti o n o n d a y  5 is d ue t o d osi n g err or, t he n t he t otal n u m ber of d ose i nterr u pti o ns is 
2). 

If a n i nterr u pti o n occ urs f or m ore t ha n o ne d a y  due t o t he sa me reas o n, b ut t he d a y s are 
n ot c o nsec uti ve, i.e. t here is at least o ne d osi n g da y  in bet wee n, t he n eac h d ose 
i nterr u pti o n will be c o u nte d as a differe nt occ urre nce (e xa m ple: If t he act ual d ose o n da ys 
1, 3 a n d 5, is 1 0 m g a n d act ual d ose o n d a y s 2 a n d 4 is 0 m g, a n d d ose i nterr u pti o ns o n 
da y  2 a n d 4 are b ot h d ue t o d osi n g err or, t he t otal n u m ber of d ose i nterr u pti o ns is 2). 
A d ose i nterr u pti o n is n ot c o nsi dere d a d ose re d ucti o n or a d ose dela y.
T he n u m ber a n d perce nta ge of patie nts wit h d ose i nterr u pti o ns a n d t he c orres p o n di n g reas o ns 
will be s u m marize d.
6. 5. 3. 7. D ose d el a ys 
A p plica ble t o a vel u ma b a n d s u niti ni b .
A vel u m a b
D ose d ela y is t he differe nce bet wee n t he act ual ti me bet wee n t w o c o nsec uti ve n o n-zer o d oses 
a n d t he pla n ne d ti me bet wee n t he sa me t w o c o nsec uti ve n o n -zer o d oses. 
I n Cycl e 1, 
D ose Dela y  ( da ys) = da y of first d ose of a vel u ma b – 1. 
After t he first d ose of C ycle 1
D ose Dela y  ( da ys) = Date of d ose x of a vel u ma b – Date of d os e ( x-1) of a vel u ma b – 1 4.
S u niti ni b
D ose dela y  is t he differe nce bet wee n t he act ual ti me bet wee n t he last n o n-zer o d ose of a 
c ycle a n d t he act ual first n o n -zer o d ose of t he ne xt c ycle a n d t he pla n ne d ti me bet wee n t he 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 7
sa me t w o d oses.   D ose dela y is o nl y calc ulate d f or t he first d ose of s u niti ni b a d mi nistere d i n 
eac h c ycle.
I n Cycl e 1, 
D ose Dela y  f or D ose 1 ( da ys) = da y of first d ose of s u niti ni b – 1. 
I n Cycl e > 1
D ose Dela y  f or D ose x ( da ys) = Date of first d ose of s u niti ni b i n C ycle x – Date of first 
d ose of s u niti ni b i n C ycle ( x-1) – 4 2
D ose Dela y s will be gr o u pe d i nt o t he f oll o wi n g cate g ories

N o dela y  

1- 3 d a y s dela y

4- 6 da y s dela y

7 or m ore da y s dela y
F or e xa m ple, f or a vel u ma b, a d mi nistere d o n a 2 -wee k sc he d ule, if o ne patie nt recei ves 
a vel u ma b o n Da y 1, t he n t he ne xt a vel u ma b a d mi nistrati o n date will be o n Da y  1 5; h o we ver, 
if t he patie nt recei ves a vel u ma b at Da y 1 6 or 1 7, t his is c o nsi dere d as 1- 3 d a y s dela y.  
N o dela y  a n d 1-3 d a y s dela y will als o be s u m marize d t o get her.
T he n u m ber a n d perce nta ge of patie nts wit h dela ye d st u d y dr u g a d mi nistrati o n a n d ma xi m u m 
le n gt h of dela y, i.e., t he w orst case of dela y if patie nts ha ve m ulti ple d ose dela ys will be 
s u m marize d. 
6. 5. 3. 8. I nf usi o n r ate re d ucti o ns
A p plica ble t o a vel u ma b.   
T he n u m ber a n d perce nta ge of patie nts wit h at least o ne i nf usi o n rate re d ucti o n of ≥5 0 %
c o m pare d t o t he first i nf usi o n rate re p orte d i n t he eC R F as well as t he fre q ue nc y of patie nts 
wit h 1, 2, 3 or ≥4 i nf usi o n rate re d ucti o ns of ≥5 0 % or m ore will be s u m marize d .
6. 5. 3. 9. I nf usi o n i nterr u pti o ns
A p plica ble t o a vel u ma b.   
A n i nf usi o n i nterr u pti o n is defi ne d as a n i nf usi o n t hat is st o p pe d a n d re -starte d o n t he sa me 
da y  (i.e., f or a visit m ore t ha n o ne i nf usi o n start ti me a n d i nf usi o n e n d ti me are rec or de d).
T he n u m ber a n d perce nta ge of patie nts wit h at least o ne i nf usi o n i nterr u pti o n as well as t he 
fre q ue nc y of patie nts wit h 1, 2, 3, or ≥4 i nf usi o n i nterr u pti o ns will be s u m marize d.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 8
6. 5. 4. C o nc o mit a nt m e dic ati o ns a n d n o n- dr u g t re at me nts
T he f oll o wi n g a nal ys es will be base d o n t he safet y  a nal ysis set b y treat me nt ar m.
C o nc o mit a nt me dic ati o ns are me dicati o ns, ot her t ha n st u d y me dicati o ns, w hic h starte d 
pri or t o first d ose date of st u d y  treat me nt a n d c o nti n ue d o n o n-treat me nt peri o d as well as 
t h ose starte d d uri n g t he o n -treat me nt peri o d. Pri or me dic ati o ns are me dicati o ns, ot her t ha n 
st u d y me dicati o ns a n d pre -me dicati o ns f or stu d y dr u g, w hic h are starte d bef ore t he first d ose 
of st u d y treat me nt. 
Pri or a n d c o nc o mita nt me dicati o ns will be s u m marize d fr o m t he ‘ Ge neral C o nc o mita nt 
Me dicati o ns ’ e C R F pa ge. Pre -me dicati o ns f or st u d y dr u g will als o be s u m marize d se paratel y
fr o m t he ‘Pr e-Me dicati o n
Treat me nt ’ e C R F pa ge.
S u m mar y  of pri or me dicati o ns, s u m mar y of c o nc o mita nt me dicati o ns a n d s u m mar y of pre-
me dicati o ns will i ncl u de t he n u m ber a n d perce nta ge of patie nts b y A nat o mical T hera pe utic 
C he mical ( A T C) Classificati o n le vel 2 a n d prefer re d ter m. A patie nt will be c o u nte d o nl y 
o nce wit hi n a gi ve n dr u g class a n d wit hi n a gi ve n dr u g na me, e ve n if he/s he recei ve d t he 
sa me me dicati o n at differe nt ti mes. If a n y pri or or c o nc o mita nt me dicati o n is classifie d i nt o 
m ulti ple A T C classes, t he me dica ti o n will be s u m marize d se paratel y u n der eac h of t hese 
A T C classes. T he s u m mar y  ta bles will be s orte d o n decreasi n g fre q ue nc y of dr u g class a n d 
decreasi n g fre q ue nc y  of dr u g na me i n a gi ve n dr u g class. I n case of e q ual fre q ue nc y 
re gar di n g dr u g class (res pecti vely dr u g na me), al p ha betical or der will be use d. I n case a n y 
s pecific me dicati o n d oes n ot ha ve A T C classificati o n le vel 2 c o de d ter m, it will be 
s u m marize d u n der ‘U na vaila ble A T C classificati o n ’ cate g or y. 
A listi n g of pri or me dicati o ns a n d a listi n g of c o nc o mita nt me dicati o ns will be create d wit h 
t he rele va nt i nf or mati o n c ollecte d o n t he ‘Ge neral C o nc o mita nt Me dicati o ns’ e C R F pa ge.  A 
listi n g of pre- me dicati o ns will be create d wit h t he rele va nt i nf or mati o n c ollecte d o n t he ‘Pre -
Me dicati o n
Treat me nt ’ e C R F pa ge.
All c o nc urre nt pr oce d ures, w hic h were u n derta ke n a n y  ti me d uri n g t he o n-treat me nt peri o d, 
will be liste d acc or di n g t o t he e C R F pa ge ‘Ge neral N o n -dr u g Treat me nts ’. A listi n g of 
c o nc urre nt pr oce d ures will be create d wit h t he rele va nt i nf or mati o n c ollecte d o n t he ‘ Ge neral 
N o n -dr u g Treat me nts ’ e C R F pa ge.
6. 5. 5. S u bse q ue nt a nti -c a ncer ther a pies
T he f oll o wi n g a nal ys es will be base d o n t he F A S b y treat me nt ar m.
A nti-ca ncer treat me nt will be pr o vi de d i n a data listi n g wit h data retrie ve d fr o m ‘ F oll o w - u p 
Ca ncer T hera p y’, ‘ C o nc o mita nt Ra diati o n T hera p y ’, ‘ F oll o w- u p Ra diati o n T hera p y ’, 
‘ C o nc o mita nt S ur ger y’ a n d ‘F oll o w - u p S ur ger y ’ e C R F pa ges .
N u m ber a n d perce nta ge of patie nts wit h a n y a nti -ca ncer t hera p y after disc o nti n uati o n will be 
ta b ulate d o verall a n d by t y pe of t hera p y  base d o n t he data c ollecte d fr o m t he ‘F oll o w - u p 
Ca ncer T hera p y’ ‘ F oll o w-u p Ra diati o n T hera p y’  a n d ‘ F oll o w-u p S ur ger y ’ e C R F pa ge s. 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 7 9
6. 6. S afet y S u m m aries a n d A n al yses
T he Safet y A nal ysis Set will be t he pri mar y  p o p ulati o n f or safet y e val uati o ns. S u m maries of
A Es a n d ot her safet y para meters will be base d o n t he safet y a nal ys is set b y treat me nt ar m.  
6. 6. 1. A d verse eve nts
Treat me nt - e mer ge nt a d verse e ve nts ( T E A Es) are t h ose e ve nts wit h o nset dates occ urri n g 
d uri n g t he o n -treat me nt peri o d f or t he first ti me, or if t he w orse ni n g of a n e ve nt is d uri n g t he 
o n-treat me nt peri o d as defi ne d i n Secti o n 3. 5. 1.
All a nal y ses descri be d will be base d o n T E A Es (starte d d uri n g t he o n-treat me nt peri o d) if n ot 
ot her wise s pecifie d. T he A E listi n gs will i ncl u de all A Es ( w het he r treat me nt-e mer ge nt or 
n ot). A Es o utsi de t he o n -treat me nt peri o d will be fla g ge d i n t he listi n gs.

Rel ate d A d verse E ve nts : a d verse e ve nts wit h relati o ns hi p t o st u d y treat me nt (as 
rec or de d o n t he A E e C R F pa ge, Relati o ns hi p wit h st u d y treat me nt = Relate d) re p orte d b y 
t he i n vesti gat or a n d t h ose of u n k n o w n relati o ns hi p (i.e., n o a ns wer t o t he q uesti o n 
‘Relati o ns hi p wit h st u d y treat me nt’).  Relate d A Es are t h ose relate d t o at least o ne of t he 
st u d y dr u gs (i n Ar m A).

Seri o us A d verse E ve nts ( S A E): seri o us a d verse e ve nts (as rec or de d o n t he A E e C R F 
pa ge, Seri o us A d verse E ve nt = Yes).

A d verse E ve nts Le a di n g t o D ose Re d ucti o n : a d verse e ve nts lea di n g t o d ose re d ucti o n
of st u d y treat me nt (as rec or de d o n t he A E e C R F pa ge, Acti o n ta ke n wit h st u d y treat me nt 
= D ose re d uce d).

A d verse E ve nts Le a di n g t o I nterr u pti o n of St u d y Tre at me nt : a d verse e ve nts lea di n g 
t o i nterr u pti o n of st u d y treat me nt (as rec or de d o n t he A E e C R F pa ge, Acti o n ta ke n wit h 
st u d y treat me nt = Dr u g i nterr u pte d). T he e C R F d oes n ot all o w f or a clear se parati o n 
bet wee n i nterr u pti o n of a n i nf usi o n a n d dela y s of a d mi nistrati o n f or a pare nteral dr u g as 
b ot h are rec or de d usi n g t he sa me ter m o n t he e C R F (“ Dr u g i nterr u pte d”).   IR Rs will be 
e xcl u de d i n t he a nal ys is of A Es lea di n g t o Dr u g I nterr u pti o n i n case t he y o nl y  le d t o a n 
i nterr u pti o n of t he i nf usi o n.

A d verse E ve nts Le a di n g t o Per m a ne nt Tre at me nt Disc o nti n u ati o n:
a d verse e ve nts 
lea di n g t o per ma ne nt disc o nti n uati o n of st u d y treat me nt (as rec or de d o n t he A E e C R F 
pa ge, Acti o n ta ke n wit h st u d y  treat me nt = Dr u g wit h draw n).

A d verse E ve nts Le a di n g t o De at h: a d verse e ve nt lea di n g t o deat h (as rec or de d o n t he 
A E e C R F pa ge, O utc o me = Fatal, as well as A Es of Gra de 5).

I m m u ne- rel ate d A d verse 
E ve nts 
(ir A E): ir A Es (as i de ntifie d acc or di n g t o t he 
met h o d ol o g y  outli ne d i n A p pe n di x 1 f or a pre -s pecifie d searc h list of Me d D R A P Ts, 
d oc u me nte d i n t he Safet y  Re vie w Pla n a n d fi nalize d f or a nal ys is of t he c urre nt st u dies 
data pri or t o D B l oc k)

I nf usi o n-rel ate d Re acti o ns (I R R): I R Rs (as i de ntifie d acc or di n g t o t he met h o d ol o g y 
o utli ne d i n A p pe n di x 2 f or a pre -s pecifie d searc h list of Me d D R A P Ts, d oc u me nte d i n 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 0
t he Safet y  Re vie w Pla n a n d fi nalize d f or a nal ys is of t he c urre nt st u dies data pri or t o D B 
l oc k).
U nless ot her wise s pecifie d, A Es will be s u m marize d b y  n u m ber a n d perce nta ge of patie nts 
wit h t he A E i n t he cate g or y  of i nterest as descri be d a b o ve, b y treat me nt ar m, pri mar y S O C 
a n d P T i n decreasi n g fre q ue nc y  base d o n t he fre q ue ncies o bser ve d f or Ar m A . 
Eac h patie nt will be c o u nte d o nl y  o nce wit hi n eac h S O C or P T. If a patie nt e x perie nces m ore 
t ha n o ne A E wit hi n a S O C or P T f or t he sa me s u m mar y peri o d, o nly t he A E wit h t he 
str o n gest relati o ns hi p or t he w orst se verit y, as a p pr o priate, will be i ncl u de d i n t he s u m maries 
of relati o ns hi p a n d se verit y .
6. 6. 1. 1. All a d verse eve nts
A d verse e ve nts wil l be s u m marize d b y w orst se verit y (acc or di n g t o N CI-C T C A E versi o n 
4. 0 3) per patie nt, usi n g t he  latest versi o n of Me d D R A preferre d ter m ( P T) as e ve nt cate g or y  
a n d Me d D R A pri mar y syste m or ga n class ( S O C) b o d y ter m as B o d y S ys te m cate g or y. 
I n case a patie nt has e ve nts wit h missi n g a n d n o n -missi n g gra des, t he ma xi m u m of t he n o n -
missi n g gra des will be dis pla y e d. N o i m p utati o n of missi n g gra des will be perf or me d. 
T he f oll o wi n g ta bles will be create d: 

T he o verall s u m mar y  of A Es ta ble will i ncl u de t he fre q ue nc y (n u m ber a n d perce nta ge) of 
patie nts wit h eac h of t he f oll o wi n g b y  treat me nt ar m:
-
T E A Es
-
T E A Es, G ra de ≥ 3
-
Relate d T E A Es
-
Relate d T E A Es, G ra de ≥ 3
-
T E A Es lea di n g t o d ose re d ucti o n of a vel u ma b 
-
T E A Es lea di n g t o d ose re d ucti o n of a xiti ni b 
-
T E A Es lea di n g t o d ose re d ucti o n of s u niti ni b 
-
T E A Es lea di n g t o i nterr u pti o n of a vel u ma b
-
T E A Es lea di n g t o i nterr u pti o n of a xiti ni b
-
T E A Es lea di n g t o i nterr u pti o n of s u niti ni b
-
T E A Es lea di n g t o disc o nti n uati o n of a v el u ma b
-
T E A Es lea di n g t o disc o nti n uati o n of a xiti ni b
-
T E A Es lea di n g t o disc o nti n uati o n of s u niti ni b
-
T E A Es lea di n g t o disc o nti n uati o n of a n y  st u d y dr u g
-
T E A Es lea di n g t o disc o nti n uati o n of all st u d y  dr u gs


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 1
-
Relate d T E A Es lea di n g t o disc o nti n uati o n of a vel u ma b
-
Re late d T E A Es lea di n g t o disc o nti n uati o n of a xiti ni b
-
Relate d T E A Es lea di n g t o disc o nti n uati o n of s u niti ni b
-
Relate d T E A Es lea di n g t o disc o nti n uati o n of a n y  st u d y dr u g
-
Relate d T E A Es lea di n g t o disc o nti n uati o n of all st u d y  dr u gs
-
Seri o us T E A Es
-
Relate d Seri o us T E A Es 
-
T E A Es lea di n g t o deat h
-
Relate d T E A Es lea di n g t o de at h
-
ir A Es
-
I R Rs

T E A Es b y  S O C a n d P T a n d w orst gra de

R elate d T E A Es b y S O C a n d P T a n d w orst gra de 

T E A Es lea di n g t o deat h b y  S O C a n d P T

R elate d T E A Es lea di n g t o deat h b y S O C a n d P T

T E A Es E xcl u di n g S A Es, wit h fre q ue nc y  ≥ 5 % i n a n y treat me nt ar m b y  S O C a n d P T
6. 6. 1. 2. A d verse e ve nts le a di n g t o d ose re d ucti o n
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g will be 
prese nte d f or T E A Es lea di n g t o d ose re d ucti o n of eac h st u d y dr u g by treat me nt ar m:

T E A Es lea di n g t o d ose re d ucti o n of avel u ma b b y S O C a n d P T

T E A Es lea di n g t o d ose re d ucti o n of a xiti ni b b y  S O C a n d P T

T E A Es lea di n g t o d ose re d ucti o n of s u niti ni b b y  S O C a n d P T
. T he listi n g of all A Es lea di n g t o d ose re d ucti o n will als o be pr o vi de d wit h t he rele va nt 
i nf or mati o n. 
6. 6. 1. 3. A d verse e ve nts le a di n g t o i nterr u pti o n of st u d y tre at me nt
T he e C R F d oes n ot all o w f or a clear se parati o n bet wee n i nterr u pti o n of a n i nf usi o n a n d 
dela y s of a d mi nistrati o n f or a pare nteral dr u g as b ot h are rec or de d usi n g t he sa me ter m o n t he 
e C R F (“ Dr u g i nterr u pte d”).   I R Rs will be e xcl u de d i n t he a nal ys is of A Es lea di n g t o Dr u g 
I nterr u pti o n i n case t he y o nl y le d t o a n i nterr u pti o n of t he i nf usi o n (ie, di d n ot lea d t o a d ose 
re d ucti o n or a d ose dela y). 
As s uc h, A Es lea di n g t o i nterr u pti o n will be defi ne d as A Es i de ntifie d i n t he A E e C R F pa ge 
wit h a n acti o n ta ke n wit h st u d y  treat me nt of ‘ dr u g i nterr u pte d’ e xcl u di n g 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 2

I R Rs t hat occ urre d o n t he d a y  of i nf usi o n wit h ≥9 0 % of t he pla n ne d d ose gi ve n (ie I RRs 
t hat di d n ot lea d t o a d ose re d ucti o n) a n d s u bse q ue nt a d mi nistrati o n of st u d y dr u g ha d n o 
dela y (as defi ne d i n Secti o n 6. 5. 3. 7). T hese I R Rs will be c o nsi dere d as I R Rs lea di n g t o 
i nterr u pti o n of i nf usi o n.

I R Rs occ urri n g o n t he da y  after i nf usi o n a n d s u bse q ue nt d ose a d mi nistrati o n ha d n o 
dela y (as defi ne d i n Secti o n 6. 5. 3.7 ).
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g will be 
prese nte d f or T E A Es lea di n g t o i nterr u pti o n of eac h st u d y dr u g b y  treat me nt ar m:

T E A Es lea di n g t o i nterr u pti o n of a vel u ma b b y  S O C a n d P T

T E A Es lea di n g t o i nterr u pti o n of a xiti ni b b y  S O C a n d P T

T E A Es lea di n g t o i nterr u pti o n of s u niti ni b b y  S O C a n d P T
. T he listi n g of all A Es lea di n g t o i nterr u pti o n of st u d y  treat me nt will als o be pr o vi de d wit h 
t he rele va nt i nf or mati o n.
I n a d diti o n, t he fre q ue nc y ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g 
will be prese nte d f or T E A Es lea di n g t o i nterr u pti o n of eac h st u d y dr u g b y  treat me nt ar m:

T E A Es lea di n g t o b ot h i nterr u pti o n a n d d ose re d ucti o n of a vel u ma b b y  S O C a n d P T

T E A Es lea di n g t o b ot h i nterr u pti o n a n d d ose re d ucti o n of a xiti ni b b y  S O C a n d P T

T E A Es lea di n g t o b ot h i nterr u pti o n a n d d ose re d ucti o n of s u niti ni b b y  S O C a n d P T
T his s u m mar y  will ta ke i nt o acc o u nt P Ts wit h b ot h acti o ns as defi ne d i n Secti on 6. 6. 1, e ve n
t h o u g h t he acti o ns ma y be ca pt ure d f or differe nt P T rec or ds (ie, differe nt o nset f or t he P T 
wit h acti o n “ dr u g i nterr u pte d” a n d t he P T wit h acti o n “ d ose re d uce d”.
6. 6. 1. 4. A d verse eve nts le a di n g t o d isc o nti n u ati o n of st u d y tre at me nt
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g will be 
prese nte d f or T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of eac h st u d y  dr u g a n d st u d y 
treat me nt, by treat me nt ar m:

T E A Es lea di n g t o disc o nti n uati o n of avel u ma b b y S O C a n d P T

Relate d T E A Es lea di n g t o disc o nti n uati o n of a vel u ma b b y  S O C a n d P T

T E A Es lea di n g t o disc o nti n uati o n of a xiti ni b b y  S O C a n d P T

Relate d T E A Es lea di n g t o disc o nti n uati o n of a xiti ni b b y  S O C a n d P T

T E A Es lea di n g t o disc o nti n uati o n of s u niti ni b b y  S O C a n d P T

Relate d T E A Es lea di n g t o disc o nti n uati o n of s u niti ni b b y  S O C a n d P T

T E A Es lea di n g t o disc o nti n uati o n of a n y  st u d y dr u g b y S O C a n d P T 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 3

Relate d T E A Es lea di n g t o disc o nti n uati o n of a n y st u d y dr u g by S O C a n d P T

T E A Es lea di n g t o disc o nti n uati o n of all st u d y  dru gs b y  S O C a n d P T

Relate d T E A Es lea di n g t o disc o nti n uati o n of all st u d y  dr u gs by S O C a n d P T .
T he listi n g of all A Es lea di n g t o treat me nt disc o nti n uati o n will als o be pr o vi de d wit h t he 
rele va nt i nf or mati o n. 
6. 6. 2. De at hs
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts i n t he safety a nal ys is set w h o die d a n d 
w h o die d wit hi n 3 0 da y s after last d ose of st u d y treat me nt as well as t he reas o n f or deat h, 
will be ta b ulate d base d o n i nf or mati o n fr o m t he ‘N otice of Deat h ’ a n d ‘S ur vi val F oll o w -U p ’
e C R Fs, b y treat me nt ar m.  

All d eat hs 

Deat hs wit hi n 3 0 da y s after last d ose of st u dy treat me nt

Reas o n f or Deat h 
-
Disease pr o gressi o n
-
St u d y  treat me nt t o xicity
-
A E n ot relate d t o st u d y treat me nt
-
U n k n o w n
-
Ot her .
I n a d diti o n, date a n d ca use of deat h will be pr o vi de d i n i n di vi d ual patie nt data listi n g t o get her 
wit h selecte d d osi n g i nf or mati o n (st u d y  treat me nt recei ve d, date of first / last a d mi nistrati o n, 
d ose) a n d will i ncl u de t he f oll o wi n g i nf or mati o n:

A Es wit h fatal o utc o me (list preferre d ter ms of A Es wit h o utc o me = Fatal, as well as A Es 
of Gra de 5), 

Fla g f or deat h wit hi n 3 0 da y s of last d ose of st u d y treat me nt.
6. 6. 3. Seri o us a d verse eve nts
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he foll o wi n g will be 
prese nte d f or treat me nt -e mer ge nt S A Es b y treat me nt ar m:

S A Es b y  S O C a n d P T

R elate d S A Es b y S O C a n d P T
T he listi n gs of all S A Es will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or 
S A Es wit h o nset o utsi de of t he o n -treat me nt peri o d.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 4
6. 6. 4. Ot her si g nific a nt a d verse e ve nts
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g will be 
prese nte d f or ir A Es, b y treat me nt ar m:

ir A Es lea di n g t o deat h, b y Cl uster a n d P T

ir A Es, b y Cl uster a n d P T

ir A Es, G ra de ≥ 3, b y  Cl uster a n d P T

ir A Es lea di n g t o disc o nti n uati o n of a vel u ma b , b y Cl uster a n d P T 

ir A Es lea di n g t o disc o nti n uati o n of a xiti ni b, b y Cl uster a n d P T 

ir A Es lea di n g t o disc o nti n uati o n of s u niti ni b, b y Cl uster a n d P T 

ir A Es lea di n g t o disc o nti n uati o n of a n y st u d y dr u g , b y Cl uster a n d P T

ir A Es lea di n g t o disc o nti n uati o n of all st u d y dr u gs, b y Cl uster a n d P T

Seri o us ir A Es, b y Cl uster a n d P T
T he listi n g of all ir A Es will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or 
ir A Es wit h o nset o utsi de of t he on- treat me nt peri o d. 
T he fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g will be 
prese nte d f or I R Rs, b y  treat me nt ar m:

I R Rs lea di n g t o deat h, b y P T

I R Rs, by P T

I R Rs, G ra de ≥ 3, b y  P T

I R Rs lea di n g t o disc o nti n uati o n of a vel u ma b , b y P T 

Seri o us I R Rs, b y  P T

Ti me relate d t o first o nset of a n I RR (i nf usi o n 1, i nf usi o n 2, i nf usi o n 3, i nf usi o n 4 or 
later)
T he listi n g of all I R Rs will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or 
I R Rs wit h o nset o utsi de of t he o n-treat me nt peri o d.
I n a d diti o n, t he f oll o wi n g a nal ys es will be prese nte d f or T ier- 1 (ir A Es a n d I R Rs as defi ne d i n 
A p pe n dices 1 a n d 2 ) a n d T ier-2 e ve nts se parately. P- val ues a n d CIs f or ris k differe nce will 
be calc ulate d base d o n t he u nc o n diti o nal e xact met h o d b y  Sa nt ner a n d S nell ( 1 9 8 0). N o 
a d diti o nal a nal ys es will be prese nte d f or T ier-3 A Es. 

F re q ue nc y (n u m ber a n d perce nta ge) of patie nts wit h eac h of t he f oll o wi n g b y  treat me nt 
ar m a n d P T or Cl ustere d Ter m:


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 5
-
Tier - 2 A Es
-
Tier - 2 A Es G ra de ≥ 3

P oi nt esti mate f or ris k differe nce a n d 9 5 % CI  for ris k differe nce (e x peri me ntal ar m vs 
c o m parat or ar m) f or eac h of t he f oll o wi n g b y  P T or Cl ustere d Ter m:
-
irA Es
-
irA E s G ra de ≥ 3
-
Tier -2 A Es
-
Tier -2 A Es G ra de ≥ 3

2- si de d p -val ue ass ociate d wit h ris k differe nce (e x peri me ntal ar m vs c o m parat or ar m) f or 
eac h of t he f oll o wi n g b y P T or Cl ustere d Ter m:
-
irA Es
-
irA E s G ra de ≥ 3

T he p- val ues a n d CI s re p orte d are n ot a dj uste d f or m ulti plicit y  an d s h o ul d be use d f or 
scree ni n g p ur p oses o nl y .  The 9 5 % CI s are pr o vi de d t o hel p ga u ge t he precisi o n o f t he 
esti mates f or t he ris k differe nce a n d s h o ul d be use d f or esti mati o n p ur p oses o nl y .
6. 6. 5. Ti me t o tre at me nt disc o nti n u ati o n or f ail ure d ue t o t o xicit y
Ti me t o treat me nt disc o nti n uati o n or fail ure d ue t o t o xicit y ( here o n war ds referre d t o as ti me 
t o treat me nt fail ure ( T T F), f or si m plicit y) is defi ne d as t he ti me fr o m first d ose of st u d y 
treat me nt t o disc o nti n uati o n of st u d y treat me nt ( disc o nti n uati o n of eit her a vel u ma b or 
a xiti ni b f or ar m A) d ue t o a n a d verse e ve nt or deat h d ue t o st u d y  treat me nt t o xicit y.
T T F (i n m o nt hs) = [D ate of st u d y treat me nt disc o nti n uati o n – start date of st u d y treat me nt
+ 1]/ 3 0. 4 3 7 5
T T F will be s u m marize d usi n g si m ple descri pti ve statistics ( mea n, S D, me dia n, mi n, ma x. 
Q 1, Q 3).
6. 6. 6. Tre at me nt disc o nti n u ati o n d ue t o t o xicit y
Treat me nt disc o nti n uati o n d ue t o t o xicit y  is defi ne d as t he disc o nti n uati o n of st u d y treat me nt
( disc o nti n uati o n of eit her a vel u ma b or a xiti ni b f or ar m A) d ue t o a n a d verse e ve nt or deat h 
d ue t o st u d y treat me nt t o xicit y . T he n u m ber a n d perce nta ge of patie nts w h o disc o nti n ue 
treat me nt d ue t o t o xicit y  i n eac h treat me nt ar m will be esti mate d b y di vi di n g t he n u m ber of 
patie nts w h o meet t he a b o ve criteria b y t he n u m ber of patie nts i n t he safet y set.
T he c orres p o n di n g e xact 2 -si de d 9 5 % CIs will be pr o vi de d f or eac h treat me nt ar m, usi n g t he 
Cl o p per -Pears o n met h o d (e xact CI f or a bi n o mial pr o p orti o n as c o m p ute d b y  defa ult b y t he 
F R E Q pr oce d ure usi n g t he E X A C T o pti o n).


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 6
6. 6. 7. L a b or at or y d at a
6. 6. 7. 1. He m at ol o g y a n d che mistr y p ar a meters
La b orat or y  res ults will be classifie d acc or di n g t o t he N CI-C T C A E criteria versi o n 4. 0 3. N o n -
n u merical q ualifiers ( wit h t he e xce pti o n of fasti n g fla gs) will n ot be ta ke n i nt o c o nsi derati o n 
i n t he deri vati o n of C T C A E criteria (e. g., h yp o kale mia G ra de 1 a n d G ra de 2 are o nly 
disti n g uis he d b y  a n o n-n u merical q ualifier a n d t heref ore Gra de 2 will n ot be deri ve d). 
A d diti o nal la b orat or y  res ults t hat are n ot part of N CI-C T C A E will be prese nte d acc or di n g t o 
t he cate g ories: bel o w n or mal li mit, wit hi n n or mal li mits a n d a b o ve n or mal li mit (acc or di n g t o 
t he la b orat or y n or mal ra nges). 
Q ua ntitati ve data will be s u m marize d usi n g si m ple descri pti ve statistics ( mea n, S D, me dia n, 
Q 1, Q 3, mi ni m u m, a n d ma xi m u m) of act ual val ues a n d c ha n ges fr o m baseli ne f or eac h 
n o mi nal visit o ver ti me ( u nsc he d ule d meas ure me nts w o ul d t heref ore n ot be i n cl u de d i n t hese 
s u m maries as descri be d i n Secti o n 5. 2.9 ). E n d of T reat me nt visit la b orat or y res ults will be 
s u m marize d se parately. T he c ha n ges c o m p ute d will be t he differe nces fr o m baseli ne. 
Q ualitati ve data base d o n refere nce ra n ges will be descri be d acc or di n g t o t he cate g ories ( i.e.,
L o w, N or mal, Hi g h). 
A b n or malities classifie d acc or di n g t o N CI- C T C A E t o xicit y  gra di n g versi o n 4. 0 3 will be 
descri be d usi n g t he w orst gra de. F or t h ose para meters w hic h are gra de d wit h t w o t o xicities 
s uc h as p otassi u m ( hy p o kale mia/ h y per kale mia), t he t o xicities will be s u m marize d se paratel y . 
L o w directi o n t o xicit y  (e. g., h y p o kale mia) gra des at baseli ne a n d p ost baseli ne will be set t o 
0 w he n t he varia bles are deri ve d f or s u m marizi n g hi g h directi o n t o xicit y  (e. g.,
h y per kale mia ), a n d vice versa.  
F or W B C differe nti al c o u nts
(t otal ne utr o p hil [i ncl u di n g ba n ds], l ym p h oc y te, m o n oc yte, 
e osi n o p hil, a n d bas o p hil c o u nts), t he a bs ol ute val ue will be use d w he n re p orte d.  W he n o nl y  
perce nta ges are a vaila ble (t his is mai nl y  i m p orta nt f or ne utr o p hils a n d l y m p h oc y tes, beca use 
t he C T C A E gra di n g is base d o n t he a bs ol ute c o u nts), t he a bs ol ute val ue is deri ve d as f oll o ws: 
Deri ve d differe ntial a bs ol ute c o u nt = ( W B C c o u nt) × ( Differe ntial % val ue / 1 0 0)
If t he ra n ge f or t he differe ntial a bs ol ute co u nt is n ot a vaila ble ( o nl y ra n ge f or val ue i n % is 
a vaila ble) t he n Gra de 1 will be attri b ute d t o as f oll o ws: 

L y m p h oc y te c o u nt decrease d:  
-
deri ve d a bs ol ute c o u nt d oes n ot meet Gra de 2 -4 criteria, a n d
-
% val ue < % L L N val ue, a n d
-
deri ve d a bs ol ute c o u nt  ≥ 8 0 0/ m m 3

Ne utr o p hil c o u nt decrease d 
-
deri ve d a bs ol ute c o u nt d oes n ot meet Gra de 2 -4 criteria, a n d
-
% val ue < % L L N val ue, a n d


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 7
-
deri ve d a bs ol ute c o u nt  ≥ 1 5 0 0/ m m 3
F or c alci u m, C T C A E gra di n g is base d o n C orrecte d Calci u m a n d I o nize d Calci u m 
( C A LCI O). C orrecte d Calci u m is calc ulate d fr o m Al b u mi n a n d Calci u m as f oll o ws :
C orrecte d calci u m ( m m ol/ L ) = meas ure d t otal Calci u m ( m m ol/ L) + 0. 0 2 ( 4 0 - ser u m al b u mi n 
[ g/ L])
Li ver f u ncti o n tests : Ala ni ne a mi n otra nsferase ( A LT), as partate a mi n otra nsferase ( A S T), 
a n d t otal bil ir u bi n ( T BI LI) are use d t o assess p ossi ble dr u g i n d uce d li ver t o xicit y . T he rati os 
of test res ult o ver u p per li mit of n or mal ( U L N) will be calc ulate d a n d classifie d f or t hese 
t hree para meters d uri n g t he o n-treat me nt peri o d.   
S u m mar y  of li ver f u ncti o n tests will i ncl u de t he f oll o wi n g cate g ories.  T he n u m ber a n d 
perce nta ge of patie nts wit h eac h of t he f oll o wi n g d uri n g t he o n -treat me nt peri o d will be 
s u m marize d b y treat me nt ar m:

A L T ≥ 3 × U L N, A L T ≥ 5 × U L N, A L T ≥ 1 0 × U L N, A L T ≥ 2 0 × U L N

A S T ≥ 3 × U L N, A S T ≥ 5 × U L N, A S T ≥ 1 0 × U L N, A S T ≥ 2 0 × U L N

( A L T or A S T) ≥ 3 × U L N, ( A L T or A S T) ≥ 5 × U L N, ( A L T or A S T) ≥ 1 0 × U L N, ( A L T or 
A S T) ≥ 2 0 × U L N

T BI LI ≥ 2 × U L N

C o nc urre nt A L T ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N

C o nc urre nt A S T ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N

C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥2 × U L N 

C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N a n d A L P > 2 × U L N

C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N a n d (A L P ≤ 2 × U L N or 
missi n g ).
C o nc urre nt meas ure me nts are t h ose occ urri n g o n t he sa me date.
Cate g ories will be c u m ulati ve, i.e ., a patie nt wit h a n ele vati o n of A S T ≥1 0 × U L N will als o 
a p pear i n t he cate g ories ≥5 × U L N a n d ≥3 × U L N. Li ver f u ncti o n ele vati o n a n d p ossi ble H y ’s 
La w cases will be s u m marize d usi n g fre q ue nc y  c o u nts a n d perce nta ge s. 
A n e val uati o n of Dr u g -I nd uce d Seri o us He pat ot o xic it y (e DI S H) pl ot will als o be create d, 
wit h differe nt s y m b ols f or differe nt treat me nt ar ms, b y gra p hically dis pla y i n g

pea k ser u m A L T(/ U L N) vs pea k t otal bilir u bi n (/ U L N) i ncl u di n g refere nce li nes at 
A L T = 3 × U L N a n d t otal bilir u bi n = 2 × U L N . 

pea k ser u m A S T(/ U L N ) vs pea k t otal bilir u bi n (/ U LN) i ncl u di n g refere nce li nes at 
A S T = 3 × U L N a n d t otal bilir u bi n = 2 × U L N . 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 8
I n a d diti o n, a listi n g of all T BI LI, A L T, A S T a n d A LP val ues f or patie nts wit h a p ost -
baseli ne T BI LI ≥ 2 × U L N, A L T ≥ 3 × U L N or A S T ≥ 3 × U L N will be pr o vi de d.
P ar a meters wit h N CI -C T C gr a des a v ail a ble: 
T he la b orat or y  t o xicities will be ta b ulate d usi n g descri pti ve statistics ( n u m ber of patie nts a n d 
perce nta ges) d uri n g t he o n -treat me nt peri o d. T he de n o mi nat or t o calc ulate perce nta ges f or 
eac h la b orat or y para meter is t he n u m ber of patie nts e val ua ble f or C T C A E gra di n g (i.e. t h ose 
patie nts f or w h o m a Gra de 0, 1, 2, 3 or 4 ca n be deri ve d).

T he s u m mar y of la b orat or y para meters b y  CT C A E gra de ta ble will i ncl u de n u m ber a n d 
perce nta ge of patie nts wit h G ra de 1, 2, 3, 4, G rade 3/ 4 a n d a n y g ra de ( Gra des 1- 4) , 
la b orat or y a b n or malities d uri n g t he o n-treat me nt peri o d.

T he s hift ta ble will s u m marize baseli ne C T C A E gra de vers us t he w orst o n- treat me nt 
C T C A E gra de. T he hi g hest C T C A E gra de d uri n g t he o n- treat me nt peri o d is c o nsi dere d 
as t he w orst gra de f or t he s u m mar y . 
T he a b o ve a nal ys es a p pl y t o he mat ol o g y a n d c he mistr y e val uati o ns w hic h ca n be gra de d per 
C T C A E, i.e.:

He mat ol o g y : 
He m o gl o bi n ( H B), Le u k oc y tes ( w hite bl o o d cell decrease d), L y m p h oc y tes (l ym p h oc y te 
c o u nt i ncrease d/ decrease d), Ne utr o p hils / A bs ol ute Ne utr o p hils C o u nt ( A N C) ( ne utr o p hil 
c o u nt decrease d), Platelet C o u nt ( P LT) ( platelet c o u nt decrease d).

Ser u m C he mistr y :
Al b u mi n ( h yp oal b u mi ne mia), Al kali ne P h os p hatase (al kali ne p h os p hatase i ncrease d), 
Ala ni ne A mi n otra nsferase ( A L T) ( A L T i ncrease d), A m yl ase (ser u m a m yl ase i ncrease d), 
As partate A mi n otra nsferase ( A S T) ( A S T i ncrease d), T otal Bilir u bi n ( bl o o d bili ru bi n 
i ncrease d, C h olester ol (c h olester ol hi g h), Creati ni ne (creati ni ne i ncrease d), Creati ne 
Ki nase 
( C P K 
i ncrease d), 
P ot assi u m 
( h y p o kale mia/ 
h y per kale mia), 
S o di u m 
( h yp o natre mia/ 
h y per natre mia), 
Ma g nesi u m 
( hy p o ma g nese mia/ h y per ma g nese mia), 
Calci u m 
( h yp ocalce mia/ 
h y percalce mia), 
Gl uc ose 
( hy p o gl yc e mia/ h y per gl yce mia), 
Ga m ma 
Gl uta m yl  Tra nsferase ( G G T) ( G G T i ncrease d), Li pase (li pase i ncrease d), 
P h os p hates ( h y p o p h os p hate mia), Tri gl yc eri des ( h y pertri gl yceri de mia).
P ar a meters wit h N CI -C T C gr a des n ot a v ail a ble:
He mat ol o g y  a n d c he mistr y e val uati o ns w hic h ca n n ot be gra de d per C T C A E criteria will be 
s u m marize d as fre q ue nc y ( n u m ber a n d perce nta ge) of patie nts wit h: 

s hifts fr o m baseli ne n or mal t o at least o ne res ult a b o ve n or mal d uri n g o n-treat me nt peri o d 

s hifts fr o m baseli ne n or mal t o at least o ne res ult bel o w n or mal d uri n g o n- treat me nt 
peri o d
I n t his st u dy, t hese a p pl y t o t he f oll o wi n g para meters: 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 8 9

He mat ol o g y : A bs ol ute M o n oc ytes, A bs ol ute E osi n o p hils, A bs ol ute Bas o p hils

Ser u m C he mistr y : C hl ori de, T otal Urea, Uric Aci d, T otal Pr otei n, C- Reacti ve Pr otei n, 
Lactate De h y dr o ge nase ( L D H) , B-t ype natri uretic pe pti de ( B N P), tr o p o ni n, a n d C K-M B
6. 6. 7. 2. Ot her la b or at or y p ar a meters
All ot her para meters c ollecte d o n t he e C R F will be liste d i n de dicate d listi n gs prese nti n g all 
c orres p o n di n g c ollecte d i nf or mati o n o n t he e C R F. 

C oa g ulati o n: acti vate d partial t hr o m b o plasti n ti me (a P T T), pr ot hr o m bi n ti me ( P T),  
i nter nati o nal n or malize d rati o (I N R),  a n d P T T.

Uri nal y sis: all uri nalys is para meters

H C V, H B V testi n g

H or m o ne tests: T S H, free T 4, A C T H

A N C A, A N A, R F 

Pre g na nc y  test
T he listi n gs of la b orat or y res ults will be pr o vi de d f or all la b orat or y  para meters. T he listi n gs 
will be s orte d b y  para meters a n d assess me nt dates or visits f or eac h patie nt. La b orat or y 
val ues t hat are o utsi de t he n or mal ra n ge will als o be fla g ge d i n t he data listi n gs, al o n g wit h 
c orres p o n di n g n or mal ra n ges.  A listi n g of C T C A E g ra di n g will als o be ge nerate d f or t h ose 
la b orat or y tests. 
I n a d diti o n, listi n gs of a b n or mal val ues will be pr o vi de d f or he mat ol o gy, c he mistr y, 
uri nal y sis, c oa g ulati o n para meters. If t here is at least o ne a b n or mal assess me nt f or a n y 
para meter, all t he data f or t hat la b orat or y  para meter will be i ncl u de d i nt o t he listi n g. 
F or all tests n ot me nti o ne d a b o ve b ut prese nt i n t he cli nical data, a listi n g of patie nts wit h at 
least o ne res ult f or t he rele va nt test will be pr o vi de d.
6. 6. 8. Vit al si g ns
Wei g ht f or t he p ur p oses of d ose cal c ulati o n will be rec or de d at scree ni n g a n d wit hi n 3 da y s 
pre -d ose Da y  1 of eac h c ycle. Hei g ht will be meas ure d at scree ni n g o nl y.
Vital si g n s u m maries will i ncl u de all vital si g n assess me nts fr o m t he o n -treat me nt peri o d.  
All vital si g n assess me nts will be liste d, a n d t h ose c ollecte d o utsi de t he o n-treat me nt peri o d 
will be fla g ge d i n t he listi n g. 
All vital si g n para meters will be s u m marize d usi n g descri pti ve statistics ( mea n, S D, me dia n, 
Q 1, Q 3, mi ni m u m, a n d ma xi m u m) of act ual val ues a n d c ha n ges fr o m basel i ne f or eac h visit 
o ver ti me. E n d of Treat me nt visit will be s u m marize d se paratel y. T he c ha n ges c o m p ute d will 
be t he differe nces fr o m baseli ne. 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 0
6. 6. 9. M U G A/ E C H O
L V E F % will be s u m marize d usi n g si m ple descri pti ve statistics ( mea n, S D, me dia n, Q 1, Q 3, 
mi ni m u m, a n d ma xi m u m) of act ual val ues a n d c ha n ges fr o m baseli ne f or eac h n o mi nal visit 
o ver ti me.  I n a d diti o n, L V E F % will be s u m marize d as fre q ue nc y ( n u m ber a n d perce nta ge) 
of patie nts wit h: 

a s hift fr o m baseli ne n or mal t o at least o ne res ult bel o w t he i nstit uti o nal l o wer li mit of 
n or mal d uri n g t he o n -treat me nt peri o d

≥1 0 -p oi nt decrease fr o m baseli ne i n L V E F % d uri n g t he o n -treat me nt peri o d

≥1 0- p oi nt decrease fr o m baseli ne i n L V E F % t o a p ost -baseli ne val ue < L L N d uri n g t he 
o n-treat me nt peri o d

≥1 5- p oi nt decrease fr o m baseli ne i n L V E F % d uri n g t he o n -treat me nt peri o d

≥1 5- p oi nt decrease fr o m baseli ne i n L V E F % t o a p ost -baseli ne val ue < L L N d uri n g t he 
o n-treat me nt peri o d.
Cli nicall y  si g nifica nt fi n di n gs will be liste d.
6. 6. 1 0. Electr oc ar di o gr a m
E C G s u m maries will i ncl u de all E C G assess me nts fr o m t he o n -treat me nt peri o d.  All E C G 
assess me nts will be liste d, a n d t h ose c ollecte d o utsi de t he o n-treat me nt peri o d will be fla g ge d 
i n t he listi n g. Q Tc B a n d Q Tc F will be deri ve d base d o n R R a n d Q T (see bel o w) . T he 
a vera ge of t he re plicate meas ure me nts s h o ul d be deter mi ne d after t he deri vati o n of t he 
i n di vi d ual para meter at eac h ti me p oi nt.
Selecti n g Pri m ar y Q T C orrecti o n f or He art R ate
T he a nal ys is of Q T data is c o m plicate d b y t he fact t hat t he Q T i nter val is hi g hl y c orrelate d 
wit h heart rate.  Beca use of t his c orrelati o n, f or m ulas are r o uti nel y use d t o o btai n a c orrecte d 
val ue, de n ote d Q Tc, w hic h is i n de pe n de nt of heart rate. T his Q Tc i nter val is i nte n de d t o 
re prese nt t he Q T i nter val at a sta n dar dize d heart rate. Se veral c orrecti o n f or m ulas ha ve bee n 
pr o p ose d i n t he literat ure. F or t his a nal y sis we will use s o me of t h ose met h o ds of c orrecti o n, 
as descri be d bel o w. T he Q T i nter val c orrecte d f or heart rate b y t he Bazett’s f or m ula, Q Tc B, 
is defi ne d as 
R R
Q T
Q Tc B 
,
t he Q T i nter val c orrecte d f or heart rate by t he Fri dericia’s f or m ula, Q Tc F, is defi ne d as 
3 R R
Q T
Q Tc F

,
w here R R re prese nts t he R R i nter val of t he E C G, i n sec o n ds , a n d ca n be esti mate d as 
6 0/ Heart Rate .  


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 1
Alt h o u g h Bazett’s c orre cti o n is t he hist orical sta n dar d, it d oes n ot perf or m well w he n heart 
rate fl uct uates. Fri dericia’s f or m ula ma y perf or m better u n der t hese c o n diti o ns. If Q Tc B a n d 
Q Tc F met h o ds d o n ot a de q uatel y c orrect f or H R a n d t here are a s ufficie nt n u m ber of patie nts 
(e. g. > 3 0) wit h baseli ne E C Gs, a n alter nate c orrecti o n t o ac hie ve t he g oal of getti n g 
u nc orrelate d Q Tc a n d R R is base d o n a li near re gressi o n met h o ds w hic h yiel ds, t he oretically, 
u nc orrelate d Q Tc a n d R R.
Li near re gressi o n met h o d:

Fit a m o del Q T = a + b × R R t o baseli ne data 

Use t he esti mate d sl o pe,  
^
b , t o c orrect Q T

C orrecte d Q T f or heart rate will be c o m p ute d as f oll o ws:
Q Tc P = Q T + 
^
b × ( 1- R R )
Data will be s u m marize d usi n g Q Tc F a n d Q Tc B. H o we ver, if t hese are n ot a p pr o priate f or 
t he data set d ue t o a n o bser ve d lar ge c orrelati o n bet wee n c orrecte d Q T a n d H R usi n g t he 
baseli ne assess me nts, t he res ults will als o be s u m marize d usi n g Q Tc P.  
E C G S u m m aries
T he f oll o wi n g a nal ys es will be perf or me d f or eac h a p plica ble E C G para meters ( R R, P R, 
Q R S, Q T, ve ntric ular rate -de n ote d as H R i n w hat f oll o ws -, a n d Q Tc) by treat me nt ar m, 
d uri n g t he o n -treat me nt peri o d. T he de n o mi nat or t o calc ulate perce nta ges f or eac h cate g or y  
is t he n u m ber of patie nts e val ua ble f or t he cate g or y.

Pears o n c orrelati o n bet wee n Q T a n d H R, Q Tc ( Q Tc B, Q Tc F a n d, if a p plica ble, Q Tc P) 
a n d H R usi n g i n di vi d ual ( n o n-a vera ge d) baseli ne assess me nts 

F or eac h of t he E C G para meters ( H R, a n d Q T, Q Tc, Q R S, P R i nter vals), descri pti ve 
statistics at baseli ne, at eac h p ost -baseli ne ti me p oi nt a n d c ha n ges fr o m baseli ne at eac h 
p ost -baseli ne ti me p oi nt 

Fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h n ota ble E C G val ues acc or di n g t o t he 
f oll o wi n g cate g ories:           
-
Q T/ Q Tc i ncrease fr o m baseli ne > 3 0 ms,  > 6 0 ms
-
Q T/ Q Tc > 4 5 0 ms, > 4 8 0 ms, > 5 0 0 ms
-
H R ≤ 5 0 b p m a n d decrease fr o m baseli ne ≥ 2 0 b p m
-
H R ≥ 1 2 0 b p m a n d i ncrease fr o m baseli ne ≥ 2 0 b p m
-
P R ≥ 2 2 0 ms a n d i ncrease fr o m baseli ne ≥ 2 0 ms
-
Q R S ≥ 1 2 0 ms 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 2
Patie nts wit h n ota ble E C G i nter val val ues a n d q ualitati ve E C G a b n or m alities will be liste d 
f or eac h patie nt a n d ti me p oi nt a n d t he c orres p o n di n g n ota ble val ues a n d a b n or malit y 
fi n di n gs will be i ncl u de d i n t he listi n gs.
U nsc he d ule d E C G meas ure me nts will n ot be use d i n c o m p uti n g t he descri pti ve statistics f or 
c ha n ge fr o m bas eli ne at eac h p ost -baseli ne ti me p oi nt. H o we ver, t he y  will be use d i n t he 
a nal ys is of n ota ble E C G c ha n ges a n d t he s hift ta ble a nalys is of n ota ble Q T para meters.
6. 6. 1 1. P h ysic al ex a mi n ati o n
N u m ber a n d perce nta ge of patie nts wit h a b n or mal fi n di n gs i n p h y sical e xa minati o n will be 
s u m marize d b y b o d y sys te m.
6. 6. 1 2. E C O G p erf or m a nce st at us
T he E C O G s hift fr o m baseli ne t o hi g hest sc ore d uri n g t he o n- treat me nt peri o d will be 
s u m marize d b y  treat me nt ar m. E C O G perf or ma nce stat us wit h s hift fr o m E C O G = 0 or 1 t o 
E C O G 2 or hi g her will als o be prese nte d i n a data listi n g.
7. I N T E RI M A N A L Y S E S
7. 1. I ntr o d ucti o n
T he i nteri m a nal ys es will be perf or me d b y a n i n de pe n de nt statisticia n. T he g oals of t he 
i nteri m a nal yses are t o all o w early st o p pi n g of t he st u d y f or f utilit y or efficac y.  T he i nteri m 
a nal ys is of P F S a n d O S will be perf or me d as descri be d i n Secti o ns 5. 1. 1 a n d 5. 1. 2 usi n g t he 
met h o d ol o g y  descri be d i n Secti o n 6. 1. 1 f or P F S a n d Secti o n 6. 1. 2 f or O S.  
At t he ti me of t he i nteri m a nal ys is f or P F S i n P D -L 1 p ositi ve patie nts , t he first i nteri m 
a nal ys is f or O S i n P D -L 1  p ositi ve patie nts will be perf or me d. 
If t he i nteri m a nalys is f or P F S i n P D -L 1  p ositi ve patie nts cr osses t he pre-s pecifie d b o u n dar y 
f or efficac y, t he i nteri m a nal ysis f or P F S f or patie nts u nselecte d f or P D-L 1 e x pressi o n will be 
perf or me d at t he sa me ti me. If t he i nteri m a nal y sis f or P F S f or patie nts u nselecte d f or P D-L 1 
e x pressi o n or t he first i nteri m a nal ys is f or O S i n P D -L 1 p ositi ve patie nts cr oss t he pre-
s pecifie d b o u n daries f or efficac y, t he n t he first i nteri m a nalys is f or O S f or patie nts u nselecte d 
f or P D-L 1 e x pressi o n will be perf or me d at t he sa me ti me.
U n bli n de d res ults fr o m t he i nteri m a nal ys es will n ot be c o m m u nicate d t o t he S p o ns or ’s 
cli nical tea m or t o a n y part y  i n v ol ve d i n t he st u d y c o n d uct (a part fro m t he i n de pe n de nt 
statisticia n a n d E-D M C me m bers) u ntil t he E- D M C has deter mi ne d t hat eit her (i) P F S i n P D -
L 1 p ositi ve patie nts a nal ysis has cr osse d t he pre-s pecifie d b o u n dar y f or efficac y or (ii) O S i n 
P D -L 1  p ositi ve patie nts a nal ysis has cr osse d t he pre-s pecifie d b o u n dar y f or efficac y or (iii) 
t he st u d y nee ds t o be ter mi nate d d ue t o a n y ca use, i ncl u di n g f utilit y or safet y reas o ns.  
F urt her details will be descri be d i n t he E- D M C c harter.
At t he ti me of fi nal a nal ysis f or P F S i n P D -L 1  p ositi ve patie nts, t he sec o n d i nteri m a nal ysis
f or O S i n P D -L 1  p ositi ve patie nts will be perf or me d. If t he fi nal a nal ys is f or P F S i n P D -L 1  
p ositi ve patie nts cr osses t he pre-s pecifie d b o u n dar y f or efficac y, t he fi nal a nal ysis f or P F S i n


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 3
patie nts u ns electe d f or P D-L 1 e x pressi o n will be perf or me d at t he sa me ti me. If t he fi nal
a nal ys is f or P F S i n patie nts u nselecte d f or P D -L 1  e x pressi o n or t he sec o n d i nteri m a nal ysis 
f or O S i n P D -L 1  p ositi ve patie nts cr oss t he pre -s pecifie d b o u n daries f or efficac y, t he n t he 
sec o n d i nteri m a nalys is f or O S f or patie nts u nselecte d f or P D-L 1 e x pressi o n will be 
perf or me d at t he sa me ti me.
T he t hir d i nteri m a nal ys is f or O S i n P D-L 1  p ositi ve patie nts will be perf or me d 1 5 m o nt hs 
after t he fi nal a nal ys is f or P F S. If t he t hir d i nteri m a nalys is f or O S i n P D-L 1 p ositi ve patie nts 
cr osses t he pre-s pecifie d b o u n dar y f or efficac y, t he t hir d i nteri m a nalys is f or OS f or patie nts 
u nselecte d f or P D -L 1 e x pressi o n will be perf or me d at t he sa me ti me.
All patie nts will c o nti n ue t o be f ol l o we d f or O S u ntil t he fi nal O S a nal ysis ( or earlier if O S i n 
patie nts u nselecte d f or P D -L 1 e x pressi o n reac hes statistical si g nifica nce at a n i nteri m 
a nal ys is).
7. 2. I nteri m A n al yses a n d S u m m aries
At eac h a nal ys is ti me p oi nt, t he critical b o u n daries f or t he gr ou p se q ue ntial test will be 
deri ve d fr o m t he pre defi ne d s pe n di n g f u ncti o n(s) as descri be d i n Secti o n 5. 1 . T he 
calc ulati o ns of b o u n daries will be perf or me d usi n g E A S T.
7. 2. 1. I nteri m a n al ysis f or P F S i n P D-L 1 p ositi ve p atie nts
T hr o u g h o ut t his secti o n, refere nces t o P F S pertai n t o P F S b y  BIC R assess me nt i n P D -L 1  
p ositi ve patie nts.
Let u(t 1) a n d u (tF ) de n ote t he u p per critical b o u n dar ies base d o n t he test statistics Z 1 a n d Z F
f or efficac y at t he i nteri m a n d t he fi nal a nal ysis, res pecti vel y, a n d let l(t1) a n d l(tF ) de n ote t he 
l o wer critical b o u n dar y f or f utilit y at t he i nteri m a n d fi nal a nal ys is, res pecti vel y.  F or t he 
fi nal a nalys is, l(tF ) = u(tF ). 
T he c ritical val ues u(t1) a n d l(t1) f or t he i nteri m a nal ysis of P F S are deter mi ne d s uc h as
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



   a n d   
)
(
))
(
(
1
1
1
t
t
l
Z
Pa



,
w here P 0 a n d P a de n ote t he pr o ba bilit ies u n der t he n ull h y p ot hesis a n d t he alter nati ve 
h y p ot hes is, res pecti vely, a n d w here
)
( 1t

a n d
)
( 1t

de n ote t he α a n d β s pe nt, res pecti vel y,
base d o n t h e pre defi ne d s pe n di n g f u ncti o ns at i nf or mati o n fracti o n t1 (t1 is calc ulate d as t he 
rati o of t he n u m ber of P F S e ve nts o bser ve d at t he ti me of t he c ut-off f or t he i nteri m a nal ysis 
a n d t he t otal n u m ber of P F S e ve nts tar gete d f or t he fi nal a nal ys is). 
T he b o u n dar y  f or t he fi nal efficac y a nalys is will be calc ulate d s uc h t hat
0 0 4
.0
)
),
(
(
)
(
1
1
0
1




F
F
u
Z
t
u
Z
P
t

As descri be d i n Secti o n 5. 1. 2, i f t he n u m ber of P F S e ve nts i n t he fi nal a nal ysis de viates fr o m 
t he tar get n u m ber of P F S e ve nts, t he fi nal a nal ys is criteria will be deter mi ne d as a b o ve ta ki n g 
i nt o acc o u nt t he act ual al p ha s pe nt at t he i nteri m a nal ysis a n d t he act ual c orrelati o n bet wee n 


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 4
t he t w o test statistics Z 1 a n d Z F , s o t hat t he o verall 1 -si de d si g nifica nce le vel acr oss all 
a nal ys es a n d c o m paris o ns is preser ve d at 0.0 0 4. 
7. 2. 2. I nteri m a n al ysis f or P F S i n p atie nts u nselecte d f or P D -L 1 e x pressi o n
T hr o u g h o ut t his secti o n, refere nces t o P F S pertai n t o P F S b y  BIC R assess me nt i n patie nts 
u nselecte d f or P D -L 1 e x pressi o n.
T he i nteri m a nal ys is f or P F S f or patie nts u nselecte d f or P D -L 1 e x pressi o n will be perf or me d 
if H 0 1 is rejecte d. N o f utilit y  a nalys is will be perf or me d f or P F S i n patie nts u nselecte d f or 
P D -L 1  e x pressi o n .
Let u(t 1) a n d u (tF ) de n ote t he u p per critical b o u n dar ies base d o n t he test statistics Z1 a n d Z F
f or efficac y at t he i nteri m a n d t he fi nal a nal ysis, res pecti vel y.
T he c ritical val ues u(t1) f or t he i nteri m a nalys is of P F S are deter mi ne d s uc h as
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



,
w here P 0 de n ote t he pr o ba bilit ies u n der t he n ull h y p ot hesis , a n d w here
)
( 1t

de n ote t he α 
s pe nt, base d o n t he pre defi ne d s pe n di n g f u ncti o ns at i nf or mati o n fracti o n t1 (t1 is calc ulate d 
as t he rati o of t he n u m ber of P F S e ve nts o bser ve d at t he ti me of t he c ut-off f or t he i nteri m 
a nal ys is a n d t he t otal n u m ber of P F S e ve nts tar gete d f or t he fi nal a nal ys is). 
T he b o u n dar y  f or t he fi nal efficac y a nalys is will be calc ulate d s uc h t hat
0 0 4
.0
)
),
(
(
)
(
1
1
0
1




F
F
u
Z
t
u
Z
P
t

As descri be d i n Secti o n 5. 1. 2, i f t he n u m ber of P F S e ve nts i n t he fi nal a nal ysis de viates fr o m 
t he tar get n u m ber of P F S e ve nts, t he fi nal a nal ys is criteria will be deter mi ne d as a b o ve ta ki n g 
i nt o acc o u nt t he act ual al p ha s pe nt at t he i nteri m a nal ysis a n d t he act ual c orrelati o n bet wee n 
t he t w o test statistics Z 1 a n d Z F , s o t hat t he o verall 1 -si de d si g nifica nce le vel acr oss all 
a nal ys es a n d c o m paris o ns is preser ve d at 0. 00 4. 
7. 2. 3. I nteri m a n al ysis f or O S i n P D-L 1 p ositi ve p atie nts
T hr o u g h o ut t his secti o n, refere nces t o O S pertai n t o O S i n P D -L 1  p ositi ve patie nts.
Let u(t i) a n d u (tF ) de n ote t he u p per critical b o u n dar ies base d o n t he test statistics Z i a n d Z F
f or efficac y at t he it h i nteri m a n d t he fi nal a nalys is, res pecti vely, a n d let l(ti) a n d l(tF ) de n ote 
t he l o wer critical b o u n dar y f or f utilit y at t he it h i nteri m a n d fi nal a nal ys is, res pecti vel y, w here 
i = 1, 2, 3. F or t he fi nal a nal y sis, l(t F ) = u(tF ).
I n w hat f oll o ws P 0 a n d P a de n ote t he pr o ba bilit ies u n der t he n ull h y p ot hesis a n d t he 
alter nati ve h y p ot hesis res pecti vel y , a n d
)
( it

a n d
)
( it

de n otes res pecti vely t he α a n d β s pe nt
base d o n t he pre defi ne d s pe n di n g f u ncti o n s at i nf or mati o n fracti o n ti (ti is calc ulate d as t he 
rati o of t he n u m ber of O S e ve nts o bser ve d at t he ti me of t he c ut-off f or t he i t h i nteri m 
a nal ys is a n d t he t otal n u m ber of O S e ve nts tar gete d f or t he fi nal a nalys is).


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 5
T he c ritical val ues u(t1) a n d l(t 1) f or t he 1 st i nteri m a nalys is of O S are deter mi ne d s uc h as
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



a n d   
)
(
))
(
(
1
1
1
t
t
l
Z
Pa



,
Critical b o u n daries f or t he a d diti o nal i nteri m a nal yses a n d t he fi nal a nalys is of O S are 
calc ulate d rec ursi vel y as f oll o ws
u(t 2) is deri ve d s uc h t hat 
)
(
))
(
),
(
(
)
(
2
2
2
1
1
0
1
t
t
u
Z
t
u
Z
P
t






,
l(t 2) is deri ve d s uc h t hat  
)
(
))
(
),
(
(
)
(
2
2
2
1
1
1
t
t
l
Z
t
l
Z
P
t
a






,
u(t 3 ) is deri ve d s uc h t hat 
)
(
))
(
),
(
),
(
(
)
(
3
3
3
2
2
1
1
0
2
t
t
u
Z
t
u
Z
t
u
Z
P
t







,
l(t 3) is deri ve d s uc h t hat  
)
(
))
(
),
(
),
(
(
)
(
3
3
3
2
2
1
1
2
t
t
l
Z
t
l
Z
t
l
Z
P
t
a







T he b o u n dar y  f or t he fi nal efficac y a nalys is is deri ve d s uc h t hat
'
)
),
(
),
(
),
(
(
)
(
3
3
2
2
1
1
0
3








F
F
u
Z
t
u
Z
t
u
Z
t
u
Z
P
t
w here α’ = 0. 0 2 1 f or t he a nal ys is of O S i n P D -L 1  p ositi ve patie nts.
As descri be d i n Secti o n 5. 1. 2, if t he n u m ber of O S e ve nts i n t he fi nal a nal ysis de viates fr o m 
t he tar get n u m ber of O S e ve nts, t he fi nal a nal ys is criteria will be deter mi ne d as a b o ve ta ki n g 
i nt o acc o u nt t he act ual al p ha s pe nt at t he i nteri m a nal yses a n d t he act ual c orrelati o n bet wee n 
t he t hree test statistics Z i (i = 1, 2, 3) a n d Z F , s o t hat t he o verall 1- si de d si g nifica nce le vel 
acr oss all a nal yses a n d c o m paris o ns is preser ve d at 0.0 2 1. 
7. 2. 4. I nteri m a n al ysis f or O S i n p atie nts u nselecte d f or P D -L 1 e x pressi o n
T hr o u g h o ut t his secti o n, refere nces t o O S pertai n t o O S i n patie nts u nselecte d f or P D-L 1 
e x pressi o n.
T he i nteri m a nal ys is f or O S f or patie nts u nselecte d f or P D -L 1 e x pressi o n will be perf or me d 
acc or di n g t o t he testi n g strate g y descri be d i n Secti o n 7. 1 a n d i n S ecti o n 5. 1. 1. N o f utilit y  
a nal ys is will be perf or me d f or O S f or patie nts u nselecte d f or P D- L 1 e x pressi o n .
Let u(t i) a n d u (tF ) de n ote t he u p per critical b o u n dar ies base d o n t he test statistics Z i a n d Z F
f or efficac y at t he it h i nteri m a n d t he fi nal a nalys is, res pecti vely, w here i = 1, 2 , 3.
I n w hat f oll o ws P 0 de n ote t he pr o ba bilit y u n der t he n ull h y p ot hesis a n d
)
( it

de n ote t he α
s pe nt base d o n t he pre defi ne d s pe n di n g f u ncti o n s at i nf or mati o n fracti o n ti (ti is calc ulate d as 
t he rati o of t he n u m ber of O S e ve nts o bser ve d at t he ti me of t he c ut-off f or t he i t h i nteri m 
a nal ys is a n d t he t otal n u m ber of O S e ve nts tar gete d f or t he fi nal a nalys is).
T he c ritical val ue u(t1) f or t he 1 st i nteri m a nal ysis of O S are deter mi ne d s uc h as
)
(
))
(
(
1
1
1
0
t
t
u
Z
P



,


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 6
Critical b o u n daries f or t he a d diti o nal i nteri m a nal yses a n d t he fi nal a nalys is of O S are 
calc ulate d rec ursi vel y as f oll o ws
u(t 2) is deri ve d s uc h t hat 
)
(
))
(
),
(
(
)
(
2
2
2
1
1
0
1
t
t
u
Z
t
u
Z
P
t






,
u(t 3 ) is deri ve d s uc h t hat 
)
(
))
(
),
(
),
(
(
)
(
3
3
3
2
2
1
1
0
2
t
t
u
Z
t
u
Z
t
u
Z
P
t







T he b o u n dar y  f or t he fi nal efficac y a nalys is is deri ve d s uc h t hat
'
)
),
(
),
(
),
(
(
)
(
3
3
2
2
1
1
0
3








F
F
u
Z
t
u
Z
t
u
Z
t
u
Z
P
t
w here α’ = 0. 0 2 5 or 0. 0 2 1 or 0. 0 0 4 f or t he a nal ys is of O S i n patie nts u nselecte d f or P D-L 1 
e x pressi o n as deter mi ne d acc or di n g t o t he testi n g strate g y  descri be d i n Secti o n 5. 1. 1.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 7
8. R E F E R E N C E S
1.
A mit O, et al.  Bli n de d i n de pe n de nt ce ntral r e vie w of pr o gressi o n i n ca ncer cli nical 
trials: Res ults fr o m a meta-a nal ys is a n d rec o m me n dati o n fr o m a P h R M A w or ki n g 
gr o u p. E ur o pea n J o ur nal of Ca ncer 4 7: 1 7 7 2 -1 7 7 8, 2 0 1 1.
2.
Br o o k me y er R, Cr o wle y JJ. A c o nfi de nce i nter val f or t he me dia n s ur vi val ti me. 
Bi o metr ics. 3 8: 2 9- 4 1, 1 9 8 2.
3. 
Cl o p per CJ, Pears o n E S ( 1 9 3 4). T he use of c o nfi de nce or fi d ucial li mits ill ustrate d i n 
t he case of t he bi n o mial.  Bi o metri ka; 2 6, 4 0 4- 4 1 3.
4.
E ur o Q ol --a ne w facilit y f or t he meas ure me nt of healt h-relate d q ualit y of life. T he 
E ur o Q ol Gr o u p. Healt h P olic y . 1 9 9 0 Dec; 1 6 ( 3): 1 9 9- 2 0 8.
5.
He n g D Y C, Xie W, Re ga n M M, Warre n M A, G ols ha y a n A R, Sa hi C, Ei gl BJ, R uet her 
J D, C he n g T, N ort h S, Ve n ner P, K n o x JJ, C hi K N, K oll ma n ns ber ger C, Mc Der m ott 
D F, O h W K, At ki ns M B, B u k o ws ki R M, Ri ni BI , C h o ueiri T K. Pr o g n ostic Fact ors f or 
O verall S ur vi val i n Patie nts Wit h Metastatic Re nal Cell Carci n o ma Treate d Wit h 
Vasc ular E n d ot helial Gr o wt h Fact or – Tar gete d A ge nts: Res ults Fr o m a L ar ge, 
M ultice nter St u d y . J o ur nal of Cli nical O nc ol o g y. 2 7: 5 7 9 4-5 7 9 9, 2 0 0 9.
6.
Je n nis o n C, T ur n b ull B W. In: Gr o u p Se q ue ntial Met h o ds wit h A p plicati o ns t o Cli nical
Trials. C ha p ma n & Hall/ C R C, B oca Rat o n, 2 0 0 0.
7.
Kal bfleisc h J D, Pre ntice, R L . Statistical A nalys is of Fail ure Ti me Data, 2n d E diti o n. 
H o b o ke n, Wile y  Interscie nce  
8.
Ka pla n E L, Meier P. N o n para metric esti mati o n fr o m i nc o m plete o bser vati o ns. J A m 
Stat Ass oc. 5 3: 4 5 7 - 8 1, 1 9 5 8.
9.
M otzer RJ, Baci k J, M ur p h y  B A, R uss o P, Maz u m dar M. I nterfer o n-Alfa as a 
c o m parati ve treat me nt f or cli nical i nterfer o n -alfa as a c o m parati ve treat me nt f or cli nical 
cell carci n o ma. J o ur nal of Cli nical O nc ol o g y. 2 0: 2 8 9- 2 9 6, 2 0 0 2.
1 0.
Ra bi n R, de C harr o F. E Q - 5 D: a meas ure of healt h stat us fr o m t he E ur o Q ol Gr o u p. A n n 
Me d. 2 0 0 1 J ul; 3 3 ( 5): 3 3 7- 4 3. Re vie w.
1 1.
Ra o D 1, B utt Z, R ose n bl o o m S, R o bi ns o n D Jr, V o n R oe n n J, K uzel T M, Ce lla D. A. 
C o m paris o n of t he Re nal Cell Carci n o ma -S y m pt o m I n de x ( R C C -SI ) a n d t he F u ncti o nal 
Assess me nt of Ca ncer T hera p y- Ki d ne y  S ym pt o m I n de x ( F K SI). J Pai n S y m pt o m 
Ma na ge. 2 0 0 9 A u g; 3 8( 2): 2 9 1 -8 d oi: 1 0. 1 0 1 6/j.j pai ns y m ma n. 2 0 0 8. 0 8. 0 1 3. E p u b 2 0 0 9
1 2.
R o y st o n P, Par mar M K. T he use of restricte d mea n s ur vi val ti me t o esti mate t he 
treat me nt effect i n ra n d o mize d cli nical trials w he n t he pr o p orti o nal hazar ds ass u m pti o n 
is i n d o u bt. Statistics i n m e dici ne, 2 0 1 1 3 0 ( 1 9), p p. 2 4 0 9- 2 4 2 1


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 8
1 3.
Sa nt ner TJ, S nell M K. ( 1 9 8 0). S mall -sa m ple c o nfi de nce i nter vals f or p 1-p 2 a n d p 1/ p 2 
i n 2 x 2 c o nti n ge nc y ta bles. J o ur n al of t he A meric a n St atistic al Ass oci ati o n , 7 5: 3 8 6–
3 9 4
1 4.
Sc h oe nfel d D. C hi -s q uare d g o o d ness- of-fit tests f or t he pr o p orti o nal hazar ds re gressi o n 
m o del. Bi o metri ka 1 9 8 0; 6 7: 1 4 5 - 5 3.
1 5.
S ute nt S u m mar y  of Pr o d uct C haracteristics, Pfizer I nc.
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y / E P A R-
Pr o d uct _I nf or mati o n/ h u ma n/ 0 0 0 6 8 7/ W C 5 0 0 0 5 7 7 3 7. p df .
1 6.
T her nea u T M, Gra m bsc h P M. M o deli n g S ur vi val Data: E xte n di n g t he C o x M o del. 
Statistics f or Bi ol o g y  a n d Healt h 2 0 0 0.
1 7.
U n o H, et al.. M o vi n g Be y o n d t he Hazar d Rati o i n Q ua ntif y i n g t he Bet wee n-Gr o u p 
Differe nce i n S ur vi val A nal y sis. J Cli n O nc ol 2 0 1 4; 3 2.
1 8.
Z ha n g X. C o m paris o n of restricte d mea n s ur vi val ti mes bet wee n treat me nts base d o n a 
stratifie d C o x m o del. D OI 1 0. 1 5 1 5/ ba ms- 2 0 1 3-0 1 0 1 Bi o -Al g orit h ms a n d Me d -S y ste ms 
2 0 1 3; 9( 4): 1 8 3 – 9.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 9 9
9. A P P E N DI C E S
A p pe n di x 1. I m m u ne-Rel ate d A d verse E ve nts
T he Me d D R A P Ts a n d cl usters f or ir A Es are defi ne d i n t he Safet y Re vie w Pla n ( S R P) f or 
a vel u ma b.
I m m u ne-relate d A Es (ir A Es) will be pr o gra m maticall y i de ntifie d as o utli ne d i n Ta ble 1 8.   
T his case defi niti o n is hierarc hical, i.e., eac h ste p is o nl y  c hec ke d f or patie nts a n d e ve nts t hat 
ha ve alrea d y met t he pri or ste p.   
T a ble 1 8.
C ase Defi niti o n f or ir A Es
Ste p
Selecti o n Criteri a
A d diti o n al N otes
1
E ve nt selecte d base d o n a list of pre -
s pecifie d Me d D R A P Ts wit hi n cl usters.  
T hese are i ncl u de d i n t he S R P as Tier 1 
e ve nts (I m m u ne -me diate d x x x x).  If A E 
matc hes t he list t he n it is i n f or t he ne xt ste p
2
A E o nset d uri n g 1 st st u d y dr u g a d mi nistrati o n 
or a n yti me t hereafter t hr o u g h 9 0 da ys after 
last d ose of st u d y treat me nt .
T his is re gar dless of sta rt of ne w a nti-ca ncer dr u g 
t hera p y a n d re gar dless of T E A E classificati o ns
3
A ns wer i n t he A E eC R F pa ge t o ‘ Was 
a n ot her treat me nt gi ve n beca use of t he 
occ urre nce of t he e ve nt’ is ‘ Y E S’
4
A E treate d wit h c ortic oster oi ds or ot her 
i m m u n os u p pressa nt t hera p y.  
F or e n d ocri n o pat hies o nl y: A E re q uire d 
h or m o ne re place me nt
L o o k i n t he c o n me d pa ges f or A E i de ntifiers t hat 
matc h t he A Es fr o m Ste p 3.  F or eac h of s uc h A Es if 
A) O R B) O R C) bel o w  are met t he n t he A E is i n f or 
t he ne xt ste p
A)
c o n me d A T C c o de is i n ( H 0 2 A, H 0 2 B,  D 0 7, 
A 0 1 A C, S 0 1 B A, S 0 1 B B, L 0 4 A A,  L 0 4 A B,  
L 0 4 A C,   L 0 4 A D,  L 0 4 A X , A 0 7 E A ) a n d A E P T 
is i n a n y of t he ir A E cl usters.
B)
c o n me d A T C c o de is i n ( H 0 3 A, H 0 3 B) a n d A E 
P T is i n o ne of t he ir A E cl usters  ass ociate d wit h 
“I m m u ne -me diate d e n d ocri n o pat hies”
C)
c o n me d A T C c o de is A 1 0 A a n d A E P T is i n t he 
ir A E cl uster ass ociate d wit h “I m m u ne-me diate d 
e n d ocri n o pat hies: T y pe I Dia betes Mellit us”


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 0 0
5
A)
N o clear eti ol o g y ( ot her t ha n i m m u ne 
me diate d eti ol o g y)
B)
Hist o pat h ol o g y / bi o ps y c o nsiste nt wit h 
i m m u ne-me diate d e ve nt
E ve nt is i n if 
[ A ns wer t o 5 B 1 a n d 5 B 2 is Y E S  (re gar dless 
of a ns wer t o 5 A)]
O R
[ A ns wer t o 5 B 1 is Y E S A N D a ns wer t o 5 B 2 
is N O A N D a ns wer t o 5 A is N O] 
O R
[ A ns wer t o 5 B 1 is N O A N D a ns wer t o 5 A is 
N O]
A)
Fr o m  t he A E e C R F pa ge
Is t he A E clearl y relate d t o a n eti ol o g y ot her t ha n 
i m m u ne-me diate d eti ol o g y?    Yes / N o
If a ns wer is Yes, c hec k all t hat a p pl y:
U n derl yi n g mali g na nc y / pr o gressi ve disease.
Ot her me dical c o n diti o ns. 
Pri or or c o nc o mita nt me dicati o ns / pr oce d ures.  
Ot her.  S pecif y.
B)
Fr o m  t he A E e C R F pa ge
B 1) Was t here a pat h ol o g y / hist ol o g y e val uati o n 
perf or me d t o i n vesti gate t he A E?  Y/ N
B 2) If a ns wer t o t he a b o ve is Yes, d oes t he 
pat h ol o g y/ hist ol o g y e val uati o n c o nfir ms a n 
i m m u ne me diate d mec ha nis m f or t he A E?  Y/ N
B 3) If pat h ol o g y / hist ol o g y e val uati o n 
perf or me d t o i n vesti gate t he A E, pr o vi de 
s u m mar y of rele va nt fi n di n gs of t he pat h ol o g y 
/ hist ol o g y re p ort.  ( Free Te xt)
T he data set ass ociate d wit h ir A Es ma y  be refi ne d base d o n me dical re vie w.  T he fi nal data 
set i ncl u di n g a n y c ha n ges base d o n me dical re vie w (e. g., a d diti o n of cases t hat are n ot 
selecte d by t he pr o gra m matic al g orit h m) will be t he basis of t he ir A E a nal yses.


A vel u ma b
B 9 9 9 1 0 0 3 ( M S B 0 0 1 0 7 1 8 C , A G -0 1 3 7 3 6, S U 0 1 1 2 4 8 ) Statistical A nal ysis Pla n
Pa ge 1 0 1
A p pe n di x 2. I nf usi o n Rel ate d Re acti o ns
F or defi ni n g a n A E as I RR t he o nset of t he e ve nt i n relati o n t o t he i nf usi o n of st u d y  dr u g a n d 
ti me t o res ol uti o n of t he e ve nt will be c o nsi dere d. 

All A Es i de ntifie d b y  t he Me d D R A P T q uer y descri bi n g si g ns a n d s ym pt o ms will be 
c o nsi dere d p ote ntial I R Rs w he n o nset is o n t he da y  of a vel u ma b i nf usi o n ( d uri n g or 
after i nf usi o n) a n d t he e ve nt res ol ve d wit h e n d date wit hi n 2 da ys after o nset. 

All A Es i de n tifie d b y t he Me d D R A P Ts of I nf usi o n relate d reacti o n, Dr u g 
h y perse nsiti vit y , A na p hylactic reacti o n, H y perse nsiti vit y , T ype 1 h y p erse nsiti vit y, 
will be c o nsi dere d p ote ntial I R Rs w he n o nset is o n t he da y  of a vel u ma b i nf usi o n 
( d uri n g or after t he i nf usi o n) or t he da y after t he a vel u ma b i nf usi o n (irres pecti ve of  
res ol uti o n date).
T he list of Me d D R A P Ts f or ‘I R Rs SI G N S a n d S Y M P T O M S’ a n d P Ts ‘I R Rs C O R E’ are 
defi ne d i n t he S R P f or a vel u ma b. 
I nf usi o n-relate d reacti o ns (IR Rs) will be pr o gra m maticall y  i de ntifie d as o utli ne d i n Ta ble 1 9
a n d will be i de ntifie d f or I V dr u gs o nl y.     
T a ble 1 9 .
C ase Defi niti o n f or I R Rs – I V St u d y Dr u gs A d mi nistere d Al o ne Or I n 
C o m bi n ati o n Wit h N o n -I V St u d y Dr u gs
C o n diti o n
Selecti o n criteri o n
If A E meets [ 1 A N D 2] O R [ 3 A N D ( 4 A O R 4 B)]  t he n A E is classifie d as a n I R R
1
P T is i ncl u de d i n t he ‘I R Rs SI G N S a n d S Y M P T O M S’ list 
2

A E o nset date = date of i nf usi o n of st u d y dr u g A N D

A E ti mi n g relate d t o st u d y dr u g (‘ D U RI N G’, ‘ A F T E R’) A N D

A E o utc o me i n (‘ R E C O V E R E D/ R E S O L V E D’, ‘ R E C O V E R E D/ R E S O L V E D WI T H 
S E Q U E L A E’, ‘ R E C O V E RI N G/ R E S O L VI N G’)  A N D

A E  e n d date – A E o nset date < = 2 
3
P T is i ncl u de d i n t he ‘I R Rs C O R E’ list 
4 A

A E o nset date = date of i nf usi o n of st u d y dr u g A N D

A E ti mi n g relate d t o st u d y dr u g i n (‘ D U RI N G’, ‘ A F T E R’)
4 B
A E o nset o n t he da y after i nf usi o n