Conditions: Non-Small Cell Lung Cancer Urothelial Cancer
Keywords: Cancer non-small cell lung cancer non small cell lung cancer NSCLC lung cancer urothelial cancer bladder cancer Avelumab Bavencio Axitinib Inlyta
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 61
Healthy volunteers: no

Brief summary:
This is a Phase 2 study to evaluate the safety and efficacy of avelumab in combination with axitinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior platinum containing therapy, and in treatment naïve patients with advanced or metastatic urothelial cancer, who are ineligible for cisplatin containing chemotherapy for their advanced disease.

Detailed description:

Arms:
arm 1: Avelumab administered at 800 mg IV every two weeks in combination with axitinib, 5 mg PO BID.

Interventions: intervention 1: Avelumab (MSB0010718C) intervention 2: Axitinib (AG-013736)
Intervention descriptions: intervention 1: IV treatment: Avelumab administered at 800 mg IV every two weeks intervention 2: Oral treatment: Axitinib given 5 mg PO BID

Protocol document:
Prot_000.pdf: 
MSB0010718C, AG-013736 
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A PHASE 2, OPEN LABEL STUDY TO EVALUATE SAFETY AND CLINICAL 
ACTIVITY OF AVELUMAB (BAVENCIO®) IN COMBINATION WITH AXITINIB 
(INLYTA®) IN PATIENTS WITH ADVANCED OR METASTATIC PREVIOUSLY 
TREATED NON-SMALL CELL LUNG CANCER OR TREATMENT NAÏVE 
CISPLATIN-INELIGIBLE UROTHELIAL CANCER
Javelin Medley VEGF
Investigational Product Number:
MSB0010718C, AG-013736
Investigational Product Name:
Avelumab, Axitinib
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2017-004345-24
Protocol Number:
B9991027
Phase:
2a
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this information in 
confidence and not copy or disclose it to others (except where required by applicable law) or use it for 
unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer must be 
promptly notified.
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 1
07 March 2018
The following change to the original protocol 
was requested by the US FDA:
A footnote was added to Table 4, for guidance 
related to patients with non-small cell lung 
cancer (NSCLC) who may develop risk factors 
for pulmonary hemorrhage while on treatment.
In addition, the following changes were
implemented:
Changes were made to the Schedule of
Activities: To clarify that smoking history is 
being collected as part of the 
Medical/Oncological History and to clarify the 
time intervals for blood pressure and pulse 
readings.
Section 5.5.5.2: Text updated for clarification 
that blood pressure monitoring devices will be 
provided to patients. 
Section 7.1.5: Text updated to clarify the time 
interval for blood pressure and pulse readings.
Original protocol
19 December 2017
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs). 


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
LIST OF FIGURES ...................................................................................................................8
APPENDICES ...........................................................................................................................8
PROTOCOL SUMMARY.........................................................................................................9
SCHEDULE OF ACTIVITIES................................................................................................13
1. INTRODUCTION ...............................................................................................................17
1.1. Mechanism of Action/Indication.............................................................................17
1.2. Background and Rationale ......................................................................................17
1.2.1. Urothelial Cancer........................................................................................17
1.2.2. NSCLC .......................................................................................................19
1.2.3. Avelumab (BAVENCIO®, MSB0010718C)..............................................20
1.2.3.1. Avelumab Clinical Experience..................................................20
1.2.3.3. Clinical Experience in Patients with Locally Advanced or 
Metastatic UC....................................................................................23
1.2.3.4. Pharmacokinetics of Avelumab Fixed Dosing..........................24
1.2.4. Axitinib (INLYTA®, AG 013736)..............................................................25
1.2.5. Clinical Experience with Axitinib in NSCLC ............................................26
1.2.6. Clinical Experience of Combination Therapy of Avelumab Plus 
Axitinib ............................................................................................................26
1.2.7. Study Rationale for Tumor Types Under Evaluation.................................28
1.2.8. Summary of Benefit/Risk Assessment .......................................................29
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................32
3. STUDY DESIGN.................................................................................................................33
4. PATIENT ELIGIBILITY CRITERIA.................................................................................33
4.1. Inclusion Criteria.....................................................................................................34
4.2. Exclusion Criteria....................................................................................................36
4.3. Lifestyle Requirements ...........................................................................................40
4.3.1. Contraception..............................................................................................40
4.4. Sponsor’s Qualified Medical Personnel..................................................................40
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5. STUDY TREATMENTS.....................................................................................................41
5.1. Allocation to Treatment ..........................................................................................41
5.2. Treatment Duration .................................................................................................42
5.3. Patient Compliance .................................................................................................42
5.3.1. IV Administered Investigational Product...................................................42
5.3.2. P.O. Administered Investigational Product ................................................42
5.4. Investigational Product Supplies.............................................................................42
5.4.1. Dosage Form(s) and Packaging..................................................................43
5.4.1.1. Avelumab ..................................................................................43
5.4.1.2. Axitinib......................................................................................43
5.4.2. Preparation and Dispensing........................................................................43
5.4.2.1. Avelumab ..................................................................................43
5.4.2.2. Axitinib......................................................................................44
5.5. Administration.........................................................................................................44
5.5.1. Avelumab....................................................................................................44
5.5.2. Axitinib.......................................................................................................45
5.5.3. Treatment After Initial Evidence of Radiologic Disease Progression........45
5.5.4. Food Requirements.....................................................................................46
5.5.5. Recommended Dose Modifications............................................................46
5.5.5.1. Intrapatient Axitinib Dose Escalation and Dose Reduction......47
5.5.5.2. Management of Axitinib-Related Hypertension .......................48
5.5.5.3. Axitinib Dose Modifications and Avelumab Infusion 
Omissions for Treatment-Related Toxicity.......................................48
5.5.5.4. Special Precautions for Avelumab Administration...................54
5.5.5.5. Management of Avelumab Infusion-Related Reactions ...........54
5.5.5.6. Management of Avelumab Immune-Related Adverse 
Events ................................................................................................56
5.6. Investigational Product Storage ..............................................................................63
5.7. Investigational Product Accountability...................................................................64
5.8. Destruction of Investigational Product Supplies.....................................................64
5.9. Concomitant Treatment(s).......................................................................................65
5.9.1. Inhibitors and Inducers of Cytochrome P450 (CYP) Enzymes..................65
5.9.2. Hematopoietic Growth Factors...................................................................66


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5.9.3. Concomitant Surgery..................................................................................66
5.9.4. Concomitant Radiotherapy.........................................................................67
5.9.5. Other Prohibited Concomitant Medications and Therapies........................67
5.10. Rescue Medications and Supportive Care.............................................................68
5.10.1. Supportive Care Guidelines......................................................................68
6. STUDY PROCEDURES .....................................................................................................68
6.1. Screening.................................................................................................................68
6.1.1. Tumor Biospecimens..................................................................................69
6.2. Study Treatment Period...........................................................................................69
6.3. Patient Withdrawal/End of Treatment.....................................................................69
6.3.1. Withdrawal of Consent...............................................................................70
6.3.2. Lost to Follow-up .......................................................................................71
6.4. Short-Term Follow-up.............................................................................................71
6.5. Long-Term Follow-up.............................................................................................71
7. ASSESSMENTS..................................................................................................................72
7.1. Safety Assessment...................................................................................................72
7.1.1. Pregnancy Testing ......................................................................................72
7.1.2. Contraceptive Check...................................................................................73
7.1.3. Adverse Events...........................................................................................73
7.1.4. Laboratory Safety Assessments..................................................................73
7.1.5. Physical Examinations and Vital Signs......................................................75
7.1.6. (12-Lead) Electrocardiogram Measurements .............................................75
7.1.7. Left Ventricular Ejection Fraction by MUGA Scan or 
Echocardiogram ...............................................................................................75
7.2. Pharmacokinetics Assessments...............................................................................76
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis ...........................76
7.2.2. Collection of Axitinib Pharmacokinetic Samples.......................................76
7.2.3. Collection of Avelumab Pharmacokinetic Samples ...................................77
7.3. Immunogenicity Assessment...................................................................................77
7.4. Translational and Pharmacodynamic Assessments.................................................77
7.4.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies..................78
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7.6. Tumor Assessments.................................................................................................79
8. ADVERSE EVENT REPORTING......................................................................................81
8.1. Requirements...........................................................................................................81
8.1.1. Additional Details On Recording Adverse Events on the CRF..................82
8.1.2. Eliciting Adverse Event Information..........................................................82
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Patient Withdrawal Section) ............................................................................82
8.1.4. Time Period for Collecting AE/SAE Information......................................82
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................83
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF.................83
8.1.5. Causality Assessment .................................................................................83
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................84
8.2. Definitions...............................................................................................................84
8.2.1. Adverse Events...........................................................................................84
8.2.2. Abnormal Test Findings .............................................................................85
8.2.3. Serious Adverse Events ..............................................................................85
8.2.4. Hospitalization............................................................................................86
8.3. Severity Assessment................................................................................................87
8.4. Special Situations ....................................................................................................87
8.4.1. Protocol-Specified Serious Adverse Events...............................................87
8.4.2. Potential Cases of Drug-Induced Liver Injury............................................88
8.4.3. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................89
8.4.3.1. Exposure During Pregnancy......................................................89
8.4.3.2. Exposure During Breastfeeding ................................................91
8.4.3.3. Occupational Exposure .............................................................91
8.4.4. Medication Errors .......................................................................................91
8.4.4.1. Medication Errors......................................................................91
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................92
9.1. Analysis Sets ...........................................................................................................92
9.1.1. Full Analysis Set.........................................................................................92
9.1.2. Safety Analysis Set.....................................................................................92
9.1.3. Pharmacokinetics Analysis Set...................................................................92


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9.1.4. Immunogenicity Analysis Set.....................................................................93
9.1.5. Biomarker Analysis Set..............................................................................93
9.2. Sample Size Determination.....................................................................................93
9.3. Efficacy Analysis ....................................................................................................94
9.3.1. Analysis of the Primary Endpoint...............................................................94
9.3.2. Analysis of the Secondary Efficacy Endpoints ..........................................94
9.4. Analysis of Pharmacokinetics and Pharmacodynamics ..........................................95
9.4.1. Analysis of Pharmacokinetics of Investigational Products ........................95
9.4.2. Population Pharmacokinetic Analysis or 
Pharmacokinetic/Pharmacodynamic (PK/Pharmacodynamic) Modeling........95
9.4.3. Analysis of Immunogenicity Data of Avelumab........................................95
9.5. Analyses for Secondary 
 Biomarker Endpoints ............................96
9.6. Safety Analysis........................................................................................................96
9.6.1. Adverse Events...........................................................................................96
9.6.2. Laboratory Test Abnormalities...................................................................96
9.6.3. Electrocardiogram.......................................................................................96
9.7. Analysis of Other Endpoints ...................................................................................97
9.8. Interim Analysis ......................................................................................................97
9.9. Data Monitoring Committee ...................................................................................97
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................97
11. DATA HANDLING AND RECORD KEEPING .............................................................98
11.1. Case Report Forms/Electronic Data Record .........................................................98
11.2. Record Retention...................................................................................................98
12. ETHICS..............................................................................................................................99
12.1. Institutional Review Board/Ethics Committee......................................................99
12.2. Ethical Conduct of the Study ................................................................................99
12.3. Patient Information and Consent...........................................................................99
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................100
13. DEFINITION OF END OF TRIAL.................................................................................100
13.1. End of Trial in a Member State...........................................................................100
13.2. End of Trial in All Other Participating Countries...............................................100
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................100
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15. PUBLICATION OF STUDY RESULTS........................................................................101
15.1. Communication of Results by Pfizer ..................................................................101
15.2. Publications by Investigators ..............................................................................102
16. REFERENCES ................................................................................................................103
LIST OF TABLES
Table 1.
Study B9991002 Treatment-Related (Avelumab- and/or Axitinib-Related) 
Adverse Events by Preferred Term.......................................................................27
Table 2.
Study B9991002 Immune Related Adverse Events by Preferred Term...............28
Table 3.
Axitinib Dose Levels ............................................................................................47
Table 4.
Axitinib Dose Modifications and Avelumab Infusion Omissions for 
Investigational Product Related Toxicity .............................................................49
Table 5.
Treatment Modification for Symptoms of Infusion Related Reactions 
Caused by Avelumab............................................................................................55
Table 6.
Management of Avelumab Immune Related Adverse Events..............................56
Table 7.
Required Laboratory Tests ...................................................................................74
Table 8.
Sample Size and Exact 95% CI for ORR .............................................................94
Table 9.
Objective Response Status at each Evaluation...................................................119
Table 10.
Overall Responses Derived From Changes in Target, Non-target, and New 
Lesions................................................................................................................121
LIST OF FIGURES
Figure 1.
Study Schema .......................................................................................................33
APPENDICES
Appendix 1. ECOG Performance Status................................................................................111
Appendix 2. National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) ..................................................................................112
Appendix 3. Treatment Recommendations for Symptoms of Avelumab 
Infusion-Related Reactions.................................................................................113
Appendix 4. Response Evaluation Criteria in Solid Tumors Version 1.1 .............................115
Appendix 6. Abbreviations....................................................................................................122
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PROTOCOL SUMMARY 
Avelumab is a human immunoglobulin (Ig) G1 monoclonal antibody (mAb) directed against 
programmed death-ligand 1 (PD-L1).  Avelumab selectively binds to PD-L1 and 
competitively blocks its interaction with programmed death receptor 1 (PD-1), thereby 
interfering with this key immune checkpoint inhibition pathway.  In March 2017, avelumab 
received accelerated approval by the United States (US) Food and Drug Administration 
(FDA) as the first treatment for metastatic Merkel cell carcinoma (MCC).  In May 2017, 
avelumab received accelerated approval by the US FDA for the treatment of patients with 
locally advanced or metastatic urothelial cancer (UC) with disease progression during or 
following platinum-containing chemotherapy, or within 12 months of neoadjuvant or
adjuvant platinum-containing chemotherapy.  Avelumab is currently being investigated as 
single agent and in combination with other anti-cancer therapies in patients with locally 
advanced or metastatic solid tumors and various hematological malignancies.
With evolving data it is becoming evident that combination immunotherapy strategies will be 
necessary to achieve enhanced anti-tumor activity for patients who do not experience disease 
control with single-agent immune checkpoint inhibitors.1 Growing nonclinical and clinical 
evidence suggest that the combination of checkpoint inhibition plus anti-angiogenic agents 
may potentially improve anti-tumor activity and patient outcomes compared to results seen 
with single agents.  Vascular endothelial growth factor (VEGF) can exert 
immunosuppressive effects in tumors by inhibiting maturation of dendritic cells, promoting 
immune suppressive cell infiltration and enhancing immune checkpoint molecule 
expression.62 Likewise, immunosuppressive cells such as myeloid derived suppressor cells 
secrete pro-angiogenic factors VEGF and matrix metalloproteinase (MMP) which directly 
promote angiogenesis growth63 and induce resistance to anti-VEGF therapy.  Given the 
immunomodulatory and anti-angiogenic properties of anti-VEGF therapies, including 
axitinib,62-66 potential synergy with anti-VEGF therapy in combination with immune 
checkpoint blockade may increase clinical efficacy in patients with advanced or metastatic 
non-small cell lung cancer (NSCLC) who have received at least one prior 
platinum-containing therapy, and in treatment naïve patients with advanced or metastatic UC, 
who are ineligible for cisplatin-containing chemotherapy for their advanced disease. 
Study Objectives
Primary Objective

To evaluate the Objective Response Rate (ORR) based on Investigator assessment, 
per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of avelumab in 
combination with axitinib in patients with advanced or metastatic NSCLC who have 
received at least one prior platinum-containing therapy and in treatment naïve patients 
with advanced or metastatic UC, who are ineligible for cisplatin-containing 
chemotherapy for their advanced disease.


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Secondary Objectives
To evaluate the following in patients with advanced or metastatic NSCLC who have received 
at least one prior platinum-containing therapy and in treatment naïve patients with advanced 
or metastatic UC, who are ineligible for cisplatin-containing chemotherapy for their 
advanced disease:
•
The safety and tolerability of avelumab in combination with axitinib;
•
The anti-tumor activity of avelumab in combination with axitinib;
•
The pharmacokinetics of avelumab and axitinib when administered in combination;
•
Candidate predictive and/or early response biomarkers in pre-treatment tumor tissue 
and pre- and post-treatment blood samples that may aid in the identification of a 
patient subpopulation most likely to benefit from treatment with avelumab in 
combination with axitinib.  Assessments may include but are not limited to tumor 
mutational burden, immune repertoire and PD-L1 expression within the tumor 
microenvironment;
•
The immunogenicity of avelumab when combined with axitinib.
Study Endpoints
Primary Endpoint
Confirmed Objective Response (OR) based on Investigator assessment per RECIST v1.1.77
Secondary Endpoints
•
Adverse events (AEs) as characterized by type, severity as graded by National Cancer 
Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.03, 
(Appendix 2), timing, seriousness, and relationship to study treatments;
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•
Laboratory abnormalities as characterized by type, severity (as graded by NCI 
CTCAE v.4.03) and timing;
•
Time-to-event endpoints including time to tumor response (TTR), duration of 
response (DR), progression-free survival (PFS) based on Investigator assessment per 
RECIST v1.1, and overall survival (OS);
•
Pharmacokinetic parameters including trough and maximum concentrations (Ctrough,
Cmax) of avelumab and axitinib;
•
Tumor tissue biomarker status (ie, positive or negative based on, for example, PD-L1 
expression and/or quantitation of tumor mutational burden as well as characterization 
of the immune repertoire in peripheral blood and/or tumor);
•
Anti-drug antibody (ADA) titers and neutralizing antibodies (NAb) against avelumab. 
Study Design
This is an open-label, multi-center, Phase 2 study to evaluate the safety and efficacy of 
avelumab in combination with axitinib in patients with advanced or metastatic NSCLC who 
have received at least one prior platinum-containing therapy, and in treatment naïve patients 
with advanced or metastatic UC, who are ineligible for cisplatin-containing chemotherapy for 
their advanced disease.
Approximately 40 patients will be enrolled in each tumor cohort, NSCLC and UC. 
Study Treatment
Avelumab 800 mg fixed dose will be administered as a 1-hour (hr) intravenous (IV) infusion 
every 2 weeks (Q2W), on Day 1 and Day 15 of each 28 day cycle. 
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Axitinib will be administered at 5 mg by mouth (PO) twice daily (BID), with or without 
food, on a continuous dosing schedule (see Section 5.5.2).
Treatment with study drugs may continue until confirmed disease progression, patient 
refusal, patient lost to follow up, unacceptable toxicity, or the study is terminated by the
sponsor, whichever comes first (see Section 6.3).
Patients who develop disease progression on study treatment but are otherwise continuing to 
derive clinical benefit from study treatment will be eligible to continue with avelumab 
combined with axitinib, single-agent avelumab, or single-agent axitinib provided that the 
treating physician has determined that the benefit/risk for doing so is favorable.
Statistical Methods
The primary objective is to assess the ORR of avelumab in combination with axitinib in 
patients with advanced or metastatic NSCLC who have received at least one prior 
platinum-containing therapy and in treatment naïve patients with advanced or metastatic UC, 
who are ineligible for cisplatin-containing chemotherapy for their advanced disease.  The 
primary endpoint is confirmed OR, which is defined as a complete response (CR) or partial 
response (PR) per RECIST v1.1 by Investigator from the first dose of study treatment until 
disease progression (PD) 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.  ORR is defined as the proportion of treated patients with confirmed CR or PR per 
Investigator’s assessment according to RECIST v1.1. 
Approximately 40 patients will be enrolled from each of 2 tumor type cohorts: NSCLC and 
UC.  Thus, a total of approximately 80 patients will be enrolled. 
With 40 treated patients per tumor type cohort, ORR can be estimated with a maximum 
standard error of 0.079.  Further, assuming beta (0.5, 0.5) prior:

NSCLC cohort: if 15 responders (out of 40 patients, ORR of 37.5%) are observed, the 
probability of a true ORR 30% (considered a clinically relevant effect above 
single-agent checkpoint inhibition,39-43 [Section 1.2.2]) will be 80% (85.0%).

UC cohort: if 19 responders (out of 40 patients, ORR of 47.5%) are observed, the 
probability of a true response rate 40% (considered a clinically relevant effect above 
single-agent checkpoint inhibition,25,26 [Section 1.2.1]) will be 80% (83.4%). 


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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 on the schedule of activities table, in order to 
conduct evaluations or assessments required to protect the well-being of the patient.
Visit Identifiers1
Screening
Study Treatment (1 cycle = 28 days)
End of
Treatment/Withdrawal3
Post-TreatmentFollow-Up
28 Days
Prior to
Enrollment
Cycle 1 and higher
Short-Term4
Long-Term4
Day 12
(3 days for cycle 
2)
Day 15 (3 days)
Day 30, Day 60, Day 90
(3 days)
Every 12 weeks
(14 days)
ClinicalAssessments
Informed Consent5
X
Medical/OncologicalHistory6
X
BaselineSigns/Symptoms7
X
Physical Examination8
X
X
X
X
X
Contraception Check9
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Vital Signs10
X
X
X
X
X
Home Blood Pressure Monitoring11
X, continuously monitoring
Laboratory Studies
Hematology12
X
X
X
X
X
Blood Chemistry13
X
X
X
X
X
Coagulation12
X
X
X
X
X
Thyroid Function Tests14
X
Cycle 1, then Q8W
X
X
ACTH15
X
Cycle 1, then Q8W
X
X
HBV, HCV Tests16
X
If clinically indicated
Serum/Urine Pregnancy Test(for women 
of childbearing potential only)17
X
X
X
X
Urinalysis18
X
If clinically indicated
X
If clinically indicated
LVEF by MUGA Scan or 
Echocardiogram19
X
Cycle 2, then Q12W
X
X (Day 30 only)
12-Lead ECG20
X
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X


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Visit Identifiers1
Screening
Study Treatment (1 cycle = 28 days)
End of
Treatment/Withdrawal3
Post-TreatmentFollow-Up
≤28 Days
Prior to
Enrollment
Cycle 1 and higher
Short-Term4
Long-Term4
Day 12
(±3 days for cycle 
≥2)
Day 15 (±3 days)
Day 30, Day 60, Day 90
(±3 days)
Every 12 weeks
(±14 days)
Disease Assessments
Tumor Assessments21
X
Q8W after first dose of study drug for 1 year from start of study treatment, and then Q12W thereafter until PD regardless 
of discontinuation of study treatment or initiation of subsequent anti cancer therapy.
Survival22
X
X
Other Clinical Assessments
Follow-up for Axitinib Dosing
Compliance23
X (D5 ±3 days)
Concomitant Medications/Treatments24
X
X
X
X
X
Adverse Events25
X, continuously monitored and recorded
X
X
New Anti-cancer Therapy26
X
X
Enrollment/StudyTreatment27
Avelumab28
X
X
Axitinib28
X(continuous daily dosing)
Other Samplings
Pharmacokinetics for axitinib29
X (Cycle 2 only)
X (Cycles 1 and 2)
Pharmacokinetics for avelumab30
X (Cycle 1 and 2)
X (Cycles 1,3,6,9 and 12)
Translational and Pharmacodynamic 
Biospecimens32
X
X 
(Cycles 1,2,3 and 4)
X
Mandatory Archival or de novo
FFPE Tumor Tissue33
X
X
(optional)
Anti-Avelumab Antibodies and
NeutralizingAntibodies34
X (Cycle 1 and 2)
X
(Cycles 1, 3, 6, 9, and 12)
X
X (Day 30 only)
Saliva Sample35
X (Cycle 1 only)
ACTH=adrenocorticotropic hormone; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FFPE=formalin-fixed and paraffin-embedded; 
HBV=hepatitis B virus; HCV=hepatitis C virus; LVEF=left ventricular ejection fraction; MUGA=multi-gated acquisition; QXW=every X weeks.
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Footnotes for Schedule of Activities
1.
Visit Identifiers: All assessments should be performed prior to the start of study treatment unless otherwise indicated. Acceptable time windows for performing each
assessment are described in the column headers.
2.
Visit window: -3 days visit window is allowed for all laboratory assessments on Day 1 of each cycle except for serum/urine pregnancy test.
3.
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 8 weeks.
4.
Short- and Long-Term Follow-up: All patients will be followed for safety every 30 days (3 days) through 90 days after the last dose of investigational product or until the
time of initiation of new anti-cancer treatment.  Beyond the 90 days until the end of the study, all patients will be followed every 12 weeks (14 days) for survival, and new
systemic anti-cancer treatment will also be recorded.
5.
Informed Consent: Must be obtained prior to undergoing any study-specific procedure.
6.
Medical/Oncological History: To include information on prior systemic therapy regimens, surgery, locoregional therapy, radiation therapy and smoking history.
7.
Baseline Signs/Symptoms: To be recorded pre-dose for all patients on Cycle 1 Day 1.  Patients will be asked about any signs and symptoms experienced within the 14 days
prior to study enrollment.
8.
Physical Examination: Includes an examination of major body systems and weight (height included at Screening only).
9.
Contraception Check: See Section 4.3 and Section 7.1.1.
10. Vital Signs: Blood pressure and pulse rate should be taken with the patient in the supine or seated position after the patient has been lying down or sitting quietly for at least 5 minutes.
Two blood pressure readings will be taken at least 1 hour apart at each clinic visit. See Section 7.1.5.
11. Home Blood Pressure Monitoring: All patients will receive home blood pressure monitoring devices and blood pressure will be monitored at home.  See Section 5.5.5.2 for 
further details.
12. Hematology and Coagulation: Required tests are listed in Table 7.  May also be performed when clinically indicated.
13. Blood Chemistry: Full chemistry panel (required tests are listed in Table 7) is required as follows: Screening, Day 1 of each Cycle, End of Treatment and Short-Term
Follow-up.  Core chemistry panel (required tests are listed in Table 7) is required as follows: Day 15 of each Cycle.  May also be performed when clinically indicated.
14. Thyroid Function Tests: May also be performed when clinically indicated. See Table 7.
15. ACTH: May also be performed when clinically indicated. See Table 7.
16. HBV, HCV Tests: Performed at Screening and as clinically indicated.
17. Serum/Urine Pregnancy Test (for women of childbearing potential only): See Section 4.1 for criteria for defining women of non-childbearing potential.  Results of the 
pregnancy test should be available prior to the beginning of each cycle.  See Section 7.1.1.
18. Urinalysis: Required at Screening, at Cycle 1 Day 1, when clinically indicated and at the End of Treatment.  If protein 2+ by semiquantitative method (eg, urine dipstick), 
protein will have to be quantified by 24-hour urine collection.  See Table 7.
19. LVEF by MUGA Scan or Echocardiogram: For the evaluation of the LVEF, the technique used at screening will also be consistently used for the following assessments 
throughout the study.
20. 12-Lead Electrocardiogram (ECG): See Section 7.1.6 for details.  ECG measurements will be obtained at Screening, as clinically indicated and End of Treatment.  
Clinically significant abnormal findings in baseline ECGs will be recorded as medical history.  


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21. Tumor Assessments: Baseline scans must be performed within 28 days prior to first dose of study drug.  Anti-tumor activity will be assessed through radiological tumor 
assessments conducted at baseline, then every 8 weeks from first dose of study drug for 1 year from start of study treatment, and then every 12 weeks thereafter until PD 
regardless of discontinuation of study treatment or initiation of subsequent anti-cancer therapy. See Section 7.6 for additional information.
22. Survival: All patients will be followed for survival and subsequent anti-cancer therapies every 12 weeks (±14 days) until death, end of the study or patient withdrawal of
consent, whichever comes first.  For patients refusing to go back to the site a telephone contact is acceptable.
23. Follow-up for Axitinib 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.
24. 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.
25. Adverse Events: Adverse events should be documented and recorded at each visit using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) v. 4.03.  See Section 8.1.4 for guidance on the time period for collecting and reporting AE and SAEs.  If a patient begins a new anti-cancer therapy, the recording
period for non-serious AEs ends at the time the new treatment is started; however, SAEs must continue to be recorded on the CRF during the active collection period.
26. New Anti-cancer Therapy: If a patient begins a new anti-cancer therapy, the AE reporting period for non-serious AEs ends at the time the new treatment is started.  Death
must be reported if it occurs during the SAE reporting period after the last dose of study drug, irrespective of any intervening treatment.
27. Enrollment: Managed by an Interactive Response Technology (IRT) system operated by Pfizer, Inc.  See Section 5.1 for information regarding the IRT system.  
Investigational product administration must begin within 3 calendar days after enrollment.
28. Study Treatment: Axitinib will be given orally (PO) twice daily (BID) on a continuous schedule. Avelumab will be given as a 1-hour (-10/+20 minutes) intravenous (IV)
infusion every 2 weeks (see Section 5).  Laboratory safety assessments must be performed and results reviewed by the treating physician prior to each study drug 
administration.
29. Pharmacokinetics for axitinib: PK samples for axitinib (3 mL) will be collected at pre-dose and 2-4 hours post-dose on Cycle 1 Day 15 and Cycle 2 Day 1 and Day 15.  
Details are outlined in Section 7.2.
30. Pharmacokinetics for avelumab: Blood samples (3.5 mL) for avelumab PK will be collected in all patients: pre-dose and at the end of infusion on Cycle 1 Day 1 and Day 15, 
Cycle 2 Day 1.  After that, trough (pre-dose) samples will be collected at Day 15 of Cycles 3, 6, 9, and 12.  Pre-dose samples can be taken up to 2 hours prior to the start of
avelumab infusion.  Details are outlined in Section 7.2.
32. Translational and Pharmacodynamic Biospecimens:
 
 
 
  One 10 mL of blood red-top serum BD Vacutainer® for serum 
preparation will be collected on Cycle 1, Day 1, pre-dose.  See Section 7.4.
33. Mandatory Archival or de novo FFPE Tumor Tissue: See Section 6.1.1 and Section 7.4.1.
34. Anti-Avelumab Antibodies (Anti-Drug Antibodies, ADAs) and Neutralizing Antibodies (NAb): One blood sample (3.5 mL) for anti-avelumab antibodies will be collected
pre-dose on Cycle 1 Day 1 and Day 15, Cycle 2 Day 1, and Day 15 of Cycles 3, 6, 9 and 12, End of Treatment, and Short Term follow up Day 30.  All samples should be drawn
within 2 hours before start of avelumab infusion.  See Section 7.3.
35. Saliva Sample: Unless prohibited by local regulations or ethics committee decision, collect a saliva sample optimized for DNA analysis before the first dose of study drug 
treatment.  See Section 7.4 and Laboratory Manual.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
The study will investigate avelumab in combination with axitinib in patients with advanced 
or metastatic NSCLC who have received at least one prior platinum-containing therapy, and 
in treatment naïve patients with advanced or metastatic UC, who are ineligible for 
cisplatin-containing chemotherapy for their advanced disease.
The mechanisms of action of each investigational product are described in Section 1.2.3 and 
Section 1.2.4.
1.2. Background and Rationale 
1.2.1. Urothelial Cancer 
UC includes tumors originating from the urothelial cells lining the bladder, renal pelvis,
ureter, and urethra.2  Bladder cancer alone accounts for 90% of UC,2 and is the ninth most
prevalent cancer worldwide, with approximately 430,000 new cases diagnosed and
165,000 deaths attributed to this disease each year.3-5  The incidence and mortality of bladder 
cancer have remained unchanged over the last 24 years.6  Approximately 30% of patients 
with newly diagnosed UC present with muscle-invasive UC of the bladder,7 a high-grade,
typically aggressive disease requiring multimodal therapy including radical cystectomy and 
chemotherapy.2,8,9  Metastatic disease is observed in 5% of patients at the time of diagnosis;8
those patients who are diagnosed with localized muscle invasive tumor and treated with 
radical cystectomy alone usually develop metastatic disease within 2 years of the initial 
diagnosis.10,11
Combination chemotherapy with cisplatin-based regimens is the standard of care for first-line 
locally advanced or metastatic UC.12-16  However, up to 50% of patients are ineligible or 
“unfit” to receive cisplatin due to age- or disease-associated renal dysfunction, poor 
performance status or other existing co-morbidities such as hearing loss, neuropathy and 
heart failure.17-19  Standard treatment options for these treatment naïve, cisplatin-ineligible 
patients have included carboplatin-based regimens20 and single- or double-agent 
chemotherapy depending on patient presentation and performance status.21,22  While no direct 
comparison of cisplatin- versus carboplatin-based regimens has been conducted, only 
cisplatin containing regimens have shown survival benefit in patients with advanced or 
metastatic UC.14-16,23,24  Cisplatin-based regimens have a median OS of 14-15 months15,16
while gemcitabine plus carboplatin is associated with a median OS of 9 months and 21% 
treatment discontinuation due to treatment-related toxicity.20  Consequently, due to the 
survival differences of the platinum-based regimens, there is an unmet medical need for 
improvements in clinical efficacy and treatment tolerability in cisplatin-ineligible for patients 
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Blocking the PD-1/PD-L1 pathway has shown therapeutic benefit for many tumor types, 
including UC. Remarkable breakthroughs in second-line systemic treatment have led to the 
approvals of five immune checkpoint (PD-1/PD-L1) inhibitors, including avelumab 
(Bavencio®), in the US and Europe (EU) for single agent use in patients with UC who have 
progressed during or following platinum-containing chemotherapy or progressed within 
12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.2  
 
 
 
  Please see 
Section 1.2.3.3 for detailed data with avelumab in patients with metastatic or locally 
advanced UC, who have progressed during or following platinum-containing chemotherapy 
or progressed within 12 months of neoadjuvant or adjuvant treatment with 
platinum-containing chemotherapy.
Furthermore, two immune checkpoint inhibitors, atezolizumab, PD-L1 mAb, (Tecentriq®) 
and pembrolizumab, PD-1 mAb, (Keytruda®), gained approval in the US and EU as 
single-agent, first-line therapy options for cisplatin-ineligible patients with advanced or 
metastatic UC.25,26  Results from the IMvigor 210 cohort 1 (N=119 treated), a single-arm, 
Phase 2 study testing the safety and efficacy of atezolizumab monotherapy in patients with 
cisplatin-ineligible UC, showed an ORR of 23% (95% CI: 16-31%) and median OS of 
15.6 months (95% CI: 10.4 months to not estimable).26  The most common treatment-related 
AEs were fatigue (30%), diarrhea (12%) and pruritus (11%).  In another Phase 2, single-arm 
study (KEYNOTE-052, N=370 treated), pembrolizumab monotherapy also showed 
anti-tumor activity and acceptable safety in patients with treatment naïve, cisplatin-ineligible 
UC.25  ORR was 24% (95% CI: 20-29%) and 6 month OS rate was 67% (95% CI: 62-73%).  
Common treatment-related AEs included fatigue (15%), pruritus (14%) and rash (9%). 
VEGF blockade has been extensively studied in first- and second-line UC.27  To date, 
monotherapy studies, including tyrosine kinase inhibitors (TKIs) sunitinib, pazopanib and 
sorafenib as well as aflibercept, an antibody-based VEGF recombinant fusion protein, have 
not shown single-agent clinical activity.27  Combination studies with chemotherapy have 
been more encouraging though toxicity and tolerability concerns have adversely impacted 
risk/benefit considerations.  Bevacizumab in combination with cisplatin- and 
carboplatin-based regimens both demonstrated impressive efficacy with median OS of 
19.1 months and 13.9 months, respectively.28,29  However, significant Grade ≥3 hematologic 
treatment-related toxicity in addition to vascular thrombotic events (VTE) were noted in both 
studies.  Likewise, sunitinib in combination with cisplatin plus gemcitabine showed ORR 
ranging from 49 to 64% but was also poorly tolerated.30,31  Conversely, pazopanib plus 
paclitaxel was studied in a heavily pretreated patient population (N=28 evaluable patients) 
where ORR was 54% (95% CI: 33.9-72.5%) with median PFS of 6.2 months and median OS 
10.0 months and was generally well-tolerated.32  The most common Grade ≥3 AEs were 
fatigue (13%) and anemia (13%).  Most recently, results from the Phase 3 study (RANGE) 
testing ramucirumab, a vascular endothelial growth factor receptor-2 (VEGFR-2) antibody, 
plus docetaxel compared to placebo plus docetaxel in previously treated patients with UC 
were reported by Petrylak et al at the European Society for Medical Oncology (ESMO) 
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2017 annual meeting.  A statistically significant improvement was observed for PFS, median 
4.07 months vs 2.76 months, respectively, (hazard ratio [HR]=0.757, 95% CI: 0.607–0.943, 
p=0.0118), thus potentially providing another therapy option for second-line UC.33
1.2.2. NSCLC
NSCLC is the most common cause of fatal malignancy globally, most often diagnosed in 
advanced stages, where surgery and local radiotherapy are no longer curative.5,34  Standard 
therapy in later stages of disease is primarily palliative in nature, involving the use of 
cytotoxic chemotherapy with or without radiation therapy or immunotherapy.35,36  Targeted 
therapies such as TKIs may be used for appropriate patients.  In spite of these treatments, 
5-year survival is only about 17.0% for advanced-stage NSCLC patients, highlighting the 
need for novel therapies and treatment regimens.37
Single-agent chemotherapy has been the standard of care for second- and third-line therapy 
for patients with advanced NSCLC in whom prior platinum-based therapy failed.37,38  
However, a new treatment paradigm has emerged based on five randomized studies that 
evaluated immune checkpoint inhibitor monotherapy compared to single-agent 
chemotherapy.39-43  Results across these studies consistently demonstrated clinically 
meaningful improvements in OS with medians ranging from 9.2 to 13.8 months for 
checkpoint inhibitors versus 6.0 to 9.6 for chemotherapy.39-43  ORR ranged from 14% to 
20% and importantly, extended duration of response was observed varying from 
14.3 -17.2 months to not reached (NR) compared to 5.6 to 8.4 months for chemotherapy.  
Efficacy was independent of PD-L1 expression though trends toward greater benefit were 
seen among higher levels of PD-L1 expression.  Both squamous and nonsquamous 
histologies derived clinical benefit.  Safety profiles were consistent among the trials with low 
grade (Grade 1 or 2) fatigue, nausea and decreased appetite being the most commonly 
reported AEs.39-43  In addition, substantially fewer treatment-related Grade 3 AEs and 
treatment-related discontinuations were reported, indicating single agent checkpoint 
inhibitors are generally well tolerated and the AE profile is quite different compared with 
chemotherapy.  Indeed, a recent updated 2-year safety and survival analysis from the 
CHECKMATE 017 and 057 studies showed long-term benefit with nivolumab compared to 
docetaxel in squamous cell histology, 2-year OS rate of 23% (95% CI, 16-30%) versus 
8% (95% CI, 4-13%) and nonsquamous histology, 2-year OS rate of 29% (95% CI, 24-34%) 
versus 16% (95% CI, 12-20%).44  No new safety signals were identified. 
Anti-angiogenic therapy has demonstrated anti-tumor activity in advanced NSCLC.  
Bevacizumab (Avastin), a mAb targeting VEGF, was the first approved anti-angiogenic 
agent in advanced NSCLC for front-line therapy in combination with chemotherapy based on 
the Eastern Cooperative Oncology Group (ECOG) 4599 trial which compared bevacizumab 
plus paclitaxel/carboplatin vs paclitaxel/carboplatin alone in treatment naïve patients with 
nonsquamous histology.45  Significant improvements in PFS (median 6.2 months vs 
4.5 months, HR= 0.66, p<0.001), response rate (RR) (35% vs 15%, p<0.001) and OS 
(median 12.3 months vs 10.3 months, HR= 0.79, p=0.003) were observed in the bevacizumab 
arm versus chemotherapy arm.  The experimental regimen was well-tolerated though higher 
rates of Grade 3 bleeding were observed in the bevacizumab arm compared to the 


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chemotherapy doublet, (4.4% vs 0.7%, p<0.001).  Subset analyses from an earlier Phase 2 
study with bevacizumab plus paclitaxel/carboplatin identified clinical features such as 
squamous histology, cavitary tumors and centrally located tumors with close proximity to 
major blood vessels as risk factors for life-threatening bleeding and as a result, were 
excluded in later bevacizumab trials.46  Ramucirumab (Cyramza), a mAb targeting 
VEGRF-2, was recently approved in combination with docetaxel for second-line treatment of 
NSCLC based on results from the REVEL study.47  In this Phase 3, randomized, 
double-blind study, ramucirumab plus docetaxel was compared to docetaxel/placebo in 
patients who progressed during or after a platinum-doublet regimen; both squamous and 
nonsquamous histologies were included.  Median OS in the ramucirumab arm was 
10.5 months versus 9.1 months for the placebo arm (HR, 0.86; 95% CI: 0.75-0.98; 
p=0.023).47  The most common Grade 3 AEs were hypertension, fatigue and hematologic 
neutropenia, febrile neutropenia and leukopenia.  Though the ramucirumab arm had more 
bleeding/hemorrhage events of any grade compared to the placebo arm (29% vs 15%), the 
number of Grade 3 events were the same in both arms. 
Recent data also demonstrated anti-tumor activity of anti-angiogenic TKIs in patients with 
advanced NSCLC.48  In a Phase 3 (LUME-Lung1), randomized, double-blind study, 
nintedanib, a multi-kinase TKI with anti-VEGFR-2, fibroblast growth factor receptor (FGFR) 
and platelet-derived growth factor receptor (PDGFR) and activity, was evaluated in 
combination with docetaxel compared to placebo/docetaxel in second-line patients with 
advanced NSCLC.49  PFS, the primary endpoint, was significantly improved in the 
nintedanib arm compared to the placebo arm, median 3.4 months versus 2.7 months 
(HR=0.79, 95% CI: 0.68-0.92, p=0.019).  In pre-specified sub-group analyses, OS was 
significantly improved in the nintedanib combination for all patients with adenocarcinoma 
histology compared to placebo, median 12.6 months versus 10.3 months (HR=0.83, 
95% CI: 0.70-0.99, p=0.0359) and for patients with adenocarcinoma who progressed within 
9 months after starting first-line treatment, median 10.9 months compared to 7.9 months 
(HR=0.75, 95% CI: 0.60-0.92, p=0.0073).49  
Clinical experience with axitinib in NSCLC is described in Section 1.2.5.
1.2.3. Avelumab (BAVENCIO, MSB0010718C)
Avelumab (MSB0010718C) is a human Ig G1 mAb directed against PD-L1.  Avelumab 
selectively binds to PD-L1 and competitively blocks its interaction with PD-1, thereby 
interfering with this key immune checkpoint inhibition pathway.  For complete details of the 
in vitro and nonclinical studies, refer to the avelumab Investigator’s Brochure (IB).50
1.2.3.1. Avelumab Clinical Experience
Avelumab is being developed jointly by Pfizer and Merck KGaA/EMD Serono, and is being 
studied in Phase 1, 2, and 3 clinical protocols in a variety of adult cancers, including NSCLC, 
gastric cancer, Merkel cell carcinoma (MCC), renal cell carcinoma (RCC), ovarian cancer, 
UC, head and neck cancer, classic Hodgkin’s Lymphoma and non-Hodgkin’s Lymphoma, as 
single agent or in combination with chemotherapy, TKIs, or other immune-modulating 
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On 23 March 2017, avelumab received accelerated approval from the FDA for the treatment 
of adults and pediatric patients 12 years and older with metastatic MCC, including those who 
have not received prior chemotherapy.  In addition, on 09 May 2017, avelumab was also 
approved by the FDA for the treatment of patients with locally advanced or metastatic 
urothelial carcinoma who experience disease progression during or after platinum-containing 
chemotherapy, or who experience disease progression with 12 months of neoadjuvant or 
adjuvant treatment with platinum-containing chemotherapy.
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1.2.3.3. Clinical Experience in Patients with Locally Advanced or Metastatic UC
On 09 May 2017, avelumab received FDA approval for the treatment of patients with locally
advanced or metastatic UC who have disease progression during or following 
platinum-containing chemotherapy or have disease progression within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
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1.2.3.4. Pharmacokinetics of Avelumab Fixed Dosing 
To date, avelumab has been administered at the clinically active, safe, and tolerable dose of 
10 mg/kg every 2 weeks (Q2W) to more than 1700 patients across multiple indications.  
Avelumab was originally dosed on a mg/kg basis in order to reduce inter-subject variability 
in drug exposure.  However, emerging data for monoclonal antibodies, including the 
marketed PD-1 and PD-L1 immune checkpoint inhibitors nivolumab, pembrolizumab and 
atezolizumab, reveal that body weight-based dosing regimens do not result in less variability 
in measures of exposure over fixed (ie, body-weight independent) dosing regimens.53-55  
Additionally, fixed dosing offers the advantages of less potential for dispensing errors, 
shorter dose preparation times in a clinical setting, and greater ease of administration.
Population pharmacokinetic (PK) analysis was conducted based on the acquired data across 
3 single-agent avelumab studies in 1827 patients with 14 different types of cancer.  PK 
simulations suggest that exposures to avelumab across the available range of body weights 
are similar, less variable with 800 mg Q2W compared with 10 mg/kg Q2W; exposures were 
similar near the population median weight.  Low-weight subjects tended toward marginally 
lower exposures relative to the rest of the population when weight-based dosing was used, 
and marginally higher exposures when fixed dosing was applied.  However, the implications 
of these exposure differences are not expected to be clinically meaningful at any weight 
across the whole population.  Furthermore, the 800 mg Q2W dosing regimen is expected to 
result in Ctrough >1 μg/mL required to maintain avelumab serum concentrations at 
>90% target occupancy (TO) throughout the entire Q2W dosing interval in all weight 
categories.
Therefore, in this clinical trial, a fixed dosing regimen of 800 mg administered as a 1-hour IV 
(-10 min/+20 min) infusion will be utilized for avelumab on Days 1 and 15 of each cycle. 
Complete information for avelumab may be found in the SRSD, which for this study is the 
avelumab IB.50
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1.2.4. 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).56
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.  In additional kinase assays, axitinib showed potent 
and ATP competitive inhibition of the VEGFRs 1, 2, and 3 and PDGFR-, 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-TAG2 transgenic mice model and demonstrated anti-tumor efficacy 
including marked cytoreductive anti-tumor activity in multiple tumor models implanted in 
athymic mice.
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.  
Following twice daily 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 SRSD, which for this study is the 
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1.2.5. Clinical Experience with Axitinib in NSCLC
Axitinib has been evaluated in NSCLC as monotherapy and in combination with platinum-
and taxane-based regimens.58,59  In Schiller et al, axitinib single-agent activity was evaluated 
in a Phase 2, open-label study among 32 patients with squamous or nonsquamous histology; 
23 patients had received 1 previous systemic therapy.  Axitinib was well-tolerated and 
demonstrated preliminary single-agent activity with an ORR of 9%, a disease control rate of 
41% and median OS of 14.8 months (95% CI: 10. 7 months-not estimable).59  The most 
common treatment-related events were fatigue, anorexia, diarrhea, nausea and hypertension.  
In a Phase 1 dose escalation study, axitinib at 5 mg BID was examined in combination with 
cisplatin- and carboplatin-based regimens among patients with advanced solid tumors.  A 
total of 17 patients with NSCLC, including a squamous cell expansion cohort, received the 
axitinib plus carboplatin-based regimen; objective responses were observed in 5 patients with 
NSCLC.58  No Grade 3 events of hemoptysis were noted.
In a Phase 2, open-label, single-arm study, 38 first-line patients with squamous cell NSCLC 
were treated with six cycles of axitinib plus cisplatin-based regimen and continued on 
maintenance axitinib monotherapy.60  ORR was 39.5% and median OS was 14.2 months.  
The most frequent Grade 3 AEs were hypertension, neutropenia, fatigue and anemia.  
Pulmonary hemorrhage was observed in 3 patients including one Grade 5 event. 
In another Phase 2 study, 170 treatment naïve patients with nonsquamous cell NSCLC were 
randomized to receive axitinib/pemetrexed/cisplatin, modified axitinib 
dosing/pemetrexed/cisplatin or pemetrexed/cisplatin alone.61  Although axitinib arms did not 
show a statistically significant difference in ORR, it was numerically higher in the axitinib 
arms compared to chemotherapy alone, 45.5% for the standard axitinib arm, 39.7% in the 
modified axitinib dosing arm and 26.3% for the pemetrexed/cisplatin arm; median OS was 
17.0 months, 14.7 months and 15.9 months, respectively.  Gastrointestinal AEs (vomiting, 
nausea), fatigue and neutropenia were common among all treatment arms.  
Grade 3 hypertension was observed in the axitinib arms and Grade 3 fatigue in the 
chemotherapy alone arm. 
1.2.6. Clinical Experience of Combination Therapy of Avelumab Plus Axitinib
Study B9991002 is a Phase 1b, open-label, multicenter, multiple-dose trial of the 
combination of avelumab with axitinib in treatment-naïve patients with aRCC.  A 
dose-finding phase preceded the dose-expansion phase of the trial.  The study objectives 
were to identify a tolerable dose of the combination for further studies, to evaluate the 
anti-tumor activity of the combination, and to investigate candidate predictive biomarkers 
(ClinicalTrials.gov Identifier: NCT02493751).  One regimen was evaluated in the 
dose-finding phase (a 7-day lead-in period with axitinib 5 mg oral twice daily (BID) followed 
by avelumab 10 mg/kg intravenously (IV) Q2W in combination with axitinib 5 mg oral 
BID).  The maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) 
were determined to be avelumab 10 mg/kg IV Q2W with axitinib 5 mg oral BID.  In the dose 
expansion phase, both a 7-day lead in period with axitinib 5 mg oral BID followed by 
avelumab 10 mg/kg IV Q2W in combination with axitinib 5 mg oral BID (10 patients) and 
avelumab 10 mg/kg IV Q2W in combination with axitinib 5 mg oral BID (39 patients) were 


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evaluated.  No differences in safety and efficacy were apparent when reviewing the data from 
the 16 patients who received lead-in axitinib (6 patients in the dose-finding cohort and 
10 patients in the dose expansion cohort) and the 39 patients in the dose-expansion cohort 
who did not receive axitinib lead-in; data from both cohorts were therefore analyzed together. 
As of 13 April 2017, per the investigator’s assessment of response according to 
RECIST v.1.1, 32/55 (58.2%) patients had a confirmed objective response 
(95% CI: 44.1-71.3).  A total of 3/55 (5.5%) patients developed a CR, 29/55 (52.7%) patients 
had a PR, and 11/55 (20%) patients had stable disease (SD) as best overall response (BOR).  
An objective response of SD or better (disease control) was achieved in 43/55 (78.2%) 
patients.  Response occurred at the time of the first tumor assessment in 20/32 patients and, at 
the data cut-off date, responses were ongoing in 24/32 patients.  The probability of an 
ongoing response (ie, no disease progression or death) at 12 months was 75.0% 
(95% CI: 54.3–87.3).  A total of 45/54 (83%) patients experienced tumor shrinkage (1 patient 
died prior to the first oncologic assessment).
The most frequent treatment-related adverse events (TRAEs), ie, those reported for 20% of 
patients, and any Grade 5 TRAEs are shown in Table 1.  A total of 32 (58.2%) patients had a 
TRAE of Grade 3 severity: 26 (47.3%) patients had Grade 3 TRAEs, 5 (9.1%) patients had 
a Grade 4 TRAE, and 1 (1.8%) patient had a Grade 5 TRAE (myocarditis).  The autopsy of 
the patient with a Grade 5 TRAE indicated immune myocarditis.
Table 1.
Study B9991002 Treatment-Related (Avelumab- and/or Axitinib-Related) 
Adverse Events by Preferred Term
N=55
n (%)
All
Grades
Grade
3
Grade
4
Grade
5
Any TRAE
53 (96.4)
26 (47.3)
5 (9.1)
1 (1.8)
Diarrhoea
32 (58.2)
2 (3.6)
0
0
Hypertension
26 (47.3)
16 (29.1)
0
0
Dysphonia
26 (47.3)
0
0
0
Fatigue
25 (45.5)
2 (3.6)
0
0
PPE syndrome
17 (30.9)
4 (7.3)
0
0
ALT increased
16 (29.1)
4 (7.3)
0
0
Rash
16 (29.1)
1 (1.8)
0
0
AST increased
14 (25.5)
1 (1.8)
0
0
Hypothyroidism
14 (25.5)
0
0
0
Amylase increased
13 (23.6)
3 (5.5)
1 (1.8)
0
Decreased appetite
13 (23.6)
1 (1.8)
0
0
Mucosal inflammation
13 (23.6)
1 (1.8)
0
0
IRR
11 (20.0)
1 (1.8)
0
0
Lipase increased
11 (20.0)
1 (1.8)
3 (5.5)
0
Nausea
11 (20.0)
1 (1.8)
0
0
Myocarditis
1 (1.8)
0
0
1 (1.8)
Table includes any grade TRAEs observed in 20% of patients and Grade 5 TRAEs observed in any patient.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; IRR=infusion-related 
reaction: N/n=number of patients/number of patients with TRAEs; PPE=palmar-plantar erythrodysethesia; 
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A total of 23 (41.8%) patients experienced an immune-related AE (irAE) (Table 2).  The 
most frequent irAE was hypothyroidism (12 [21.8%] patients).  Five (5, 9.1%) patients 
experienced a total of 7 irAEs of Grade 3 severity: Grade 3 ALT increased in 
2 (3.6%) patients, Grade 3 drug eruption, rash, AST increased, and diarrhoea each in 
1 (1.8%) patient, and Grade 5 myocarditis in 1 (1.8%) patient.
Table 2.
Study B9991002 Immune Related Adverse Events by Preferred Term
n (%)
N=55
All Grades
Grade 3
Grade 4
Grade 5
Any irAE
23 (41.8)
4 (7.3)
0
1 (1.8)
Hypothyroidism
12 (21.8)
0
0
0
Blood TSH increased
1 (1.8)
0
0
0
Hyperthyroidism
3 (5.5)
0
0
0
Pruritus
1 (1.8)
0
0
0
Rash papular
1 (1.8)
0
0
0
Dermatitis acneiform
1 (1.8)
0
0
0
Drug eruption
1 (1.8)
1 (1.8)
0
0
Rash
2 (3.6)
1 (1.8)
0
0
Rash pustular
1 (1.8)
0
0
0
Hepatitis (ALT increased)
3 (5.5)
2 (3.6)
0
0
Hepatitis (AST increased)
2 (3.6)
1 (1.8)
0
0
Diarrhoea
1 (1.8)
1 (1.8)
0
0
Adrenal insufficiency
1 (1.8)
0
0
0
Myocarditis
1 (1.8)
0
0
1 (1.8)
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; irAE=immune-related 
adverse event; N=number of patients; TSH=thyroid stimulating hormone.
In conclusion, for this patient population, the safety profile of the combination was tolerable, 
manageable, and consistent with the known safety profiles of avelumab50 and axitinib57 when 
administered as monotherapy.
This combination is being evaluated in the Phase 3 study B9991003 (NCT02684006): A 
Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer 
(JAVELIN Renal 101).
1.2.7. Study Rationale for Tumor Types Under Evaluation 
With evolving data it is becoming evident that combination immunotherapy strategies will be 
necessary to achieve enhanced anti-tumor activity for patients who do not experience disease 
control with single-agent immune checkpoint inhibitors.1 Growing nonclinical and clinical 
evidence suggest that the combination of checkpoint inhibition plus antiangiogenic agents 
may potentially improve anti-tumor activity and patient outcomes compared to results seen 
with single agents. VEGF can exert immunosuppressive effects in tumors by inhibiting 
maturation of dendritic cells, promoting immune suppressive cell infiltration and enhancing 
immune checkpoint molecule expression.62  Likewise, immunosuppressive cells such as 
myeloid derived suppressor cells secrete pro-angiogenic factors VEGF and MMP which 
directly promote angiogenesis growth63 and induce resistance to anti-VEGF therapy.  Given 
the immunomodulatory and anti-angiogenic properties of anti-VEGF therapies, including 


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axitinib,62-66 potential synergy with anti-VEGF therapy in combination with immune 
checkpoint blockade may increase clinical efficacy in patients with advanced or metastatic 
NSCLC who have received at least one prior platinum-containing therapy and in treatment 
naïve patients with advanced or metastatic UC, who are ineligible for cisplatin-containing 
chemotherapy for their advanced disease.
The two tumor types selected for the study are responsive to monotherapy checkpoint 
inhibition which is available as standard-of-care for these indications.  In addition, avelumab 
has shown preliminary evidence of clinical activity as monotherapy in these tumor types 
(NSCLC51 and UC67); see Section 1.2.3.2 and Section 1.2.3.3 respectively).  Furthermore, 
NSCLC and UC have demonstrated sensitivity to anti-VEGFR-2 inhibition in combination 
with chemotherapy.33,45,47,49  However, despite these therapies, substantial clinical unmet 
needs exist as the majority of patients experience disease progression during the course of 
their treatment.
Recently, cabozantinib, a multi-kinase TKI for VEGFR2, mesenchymal-epithelial transition
factor (MET) and AXL, in combination with nivolumab ± ipilumumab showed preliminary 
anti-tumor activity and a manageable safety profile in heavily pretreated, advanced 
genitourinary (GU) malignancies.68  ORR for evaluable patients was 33% with a median PFS 
of 5.9 months (95% CI: 4.5-10.1 months) and median OS of 20 months 
(95% CI: 10.6 months-undefined).  Of the 42 patients treated, 15 patients (13 evaluable) with 
advanced UC demonstrated an ORR of 38%.68  Other ongoing anti-VEGF plus immune 
checkpoint combination trials include ramucirumab plus pembrolizumab which is being 
evaluated in multiple tumor cohorts including second-line UC and previously treated 
NSCLC.  In the UC cohort, preliminary results for 24 treated patients showed anti-tumor 
activity with a RR of 8% and SD of 42%; median PFS was 1.87 months 
(95% CI: 1.28-3.38 months).69  Among 27 patients in the NSCLC cohort, ORR was 30%, 
median PFS was 9.7 months (95% CI: 4.6-11.5 months) and the OS rate at 6 months was 
84.9%.70  There were no new safety signals for either cohort. 
1.2.8. Summary of Benefit/Risk Assessment
An evaluation of the anticipated benefits and risks as required in Article 3(2)(a) of Directive 
2001/20/EC (cf. Article 6(3)(b) of Directive 2001/20/EC) has been conducted.
The benefit-risk relationship has been carefully considered in the planning of this trial.  
Avelumab demonstrated clinical activity in patients with advanced solid tumors, including 
NSCLC (first-line and second-line or higher), breast cancer, CRPC, UC and ovarian cancer
 
 
 
  Infusion-related reactions, 
including hypersensitivity and irAEs/autoimmune disorders, have been identified as 
important risks for avelumab.  Respective risk mitigation measures have been implemented 
in all ongoing clinical studies with avelumab, including this clinical trial protocol.  These 
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include guidelines for treatment interruption and discontinuation in case of irAEs, as well as 
mandatory pre-treatment with an antihistamine and acetaminophen prior to the first 
4 avelumab infusions (Cycles 1-2) and as clinically indicated thereafter.
Thus far, avelumab has demonstrated a manageable safety profile and significant anti-tumor 
activity in various tumor types.50
Axitinib is approved multi-nationally for the treatment of advanced RCC after failure of one 
prior systemic therapy.  The adverse events reported for axitinib are well characterized in 
clinical studies and considered tolerable and manageable (see Section 1.2.4).  Furthermore, 
axitinib demonstrated acceptable toxicity profile as a monotherapy or in combination with 
other agents. 
The combination of avelumab with axitinib is currently being tested in study B9991002, as 
described in Section 1.2.6.  Overall, the safety profile of the combination appears 
manageable and in line with that of individual agents.  One case of fatal myocarditis has 
occurred in a patient after 19 days of treatment with the combination and 5 days after the 
second dose of avelumab.  
 
 
 
 
  
Severe or fatal myocarditis has also been reported in literature with pembrolizumab 
single-agent,71,72 nivolumab single-agent,73 nivolumab in combination with ipilimumab,74
and ipilimumab single-agent,75 either as single adverse events or in the context of more 
complex autoimmume syndromes.  For ipilimumab, myocarditis (including with fatal 
outcome) is reported in the prescribing information with a frequency <1%.76  Guidelines 
about the management of suspect or confirmed cases of myocarditis and relevant avelumab 
management instructions have been included in Table 6.
This combination is being evaluated in the Phase 3 Study B9991003 (NCT02684006): A 
Study of Avelumab With Axitinib Versus Sunitinib In Advanced Renal Cell Cancer 
(JAVELIN Renal 101).
Based on the manageable safety profiles of avelumab and axitinib and its’ enhanced 
anti-tumor activity in advanced RCC, the anticipated benefit-risk relationship of avelumab 
given in combination with axitinib is expected to be favorable for investigation in patients 
with advanced or metastatic NSCLC who have received at least one prior 
platinum-containing therapy, and in treatment naïve patients with advanced or metastatic UC, 
who are ineligible for cisplatin-containing chemotherapy for their advanced disease. 
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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective:
Primary Endpoint:
•
To evaluate the ORR based on Investigator 
assessment, per RECIST v1.1 of avelumab in 
combination with axitinib in patients with advanced 
or metastatic NSCLC who have received at least one 
prior platinum-containing therapy and in treatment 
naïve patients with advanced or metastatic UC, who 
are ineligible for cisplatin-containing chemotherapy 
for their advanced disease.
•
Confirmed OR based on Investigator assessment 
per RECIST v1.1.77
Secondary Objectives:
Secondary Endpoints:
To evaluate the following in patients with advanced or 
metastatic NSCLC who have received at least one prior 
platinum-containing therapy and in treatment naïve 
patients with advanced or metastatic UC, who are 
ineligible for cisplatin-containing chemotherapy for their 
advanced disease:
•
The safety and tolerability of avelumab in 
combination with axitinib;
•
The anti-tumor activity of avelumab in combination 
with axitinib;
•
The pharmacokinetics of avelumab and axitinib 
when administered in combination;
•
Candidate predictive and/or early response 
biomarkers in pre-treatment tumor tissue and pre-
and post-treatment blood samples that may aid in the 
identification of a patient subpopulation most likely 
to benefit from treatment with avelumab in 
combination with axitinib.  Assessments may include 
but are not limited to tumor mutational burden, 
immune repertoire and PD-L1 expression within the 
tumor microenvironment;
•
The immunogenicity of avelumab when combined 
with axitinib.
•
AEs as characterized by type, severity as graded 
by NCI CTCAE v.4.03, (Appendix 2), timing, 
seriousness, and relationship to study treatments;
•
Laboratory abnormalities as characterized by 
type, severity (as graded by NCI CTCAE v.4.03) 
and timing;
•
Time-to-event endpoints including TTR, DR, 
PFS based on Investigator assessment per 
RECIST v1.1, and OS;
•
Pharmacokinetic parameters including trough 
and maximum concentrations (Ctrough, Cmax)
of avelumab and axitinib;
•
Tumor tissue biomarker status (ie, positive or 
negative based on, for example, PD-L1 
expression and/or quantitation of tumor 
mutational burden as well as characterization of 
the immune repertoire in peripheral blood and/or 
tumor);
•
ADA titers and NAb against avelumab. 
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3. STUDY DESIGN
This is an open-label, multi-center, Phase 2 study to evaluate the safety and efficacy of 
avelumab in combination with axitinib in patients with advanced or metastatic NSCLC who 
have received at least one prior platinum-containing therapy, and in patients with advanced 
or metastatic UC, who are treatment naïve and ineligible for cisplatin-containing 
chemotherapy for their advanced disease.
Approximately 40 patients will be enrolled in each cohort, NSCLC and UC.  See Figure 1. 
Figure 1.
Study Schema
Patients will receive avelumab 800 mg IV Q2W on Days 1 and 15 of each 28 day cycle in 
combination with axitinib 5 mg PO BID on a continuous dosing schedule.  Treatment with 
study drugs may continue until confirmed disease progression, patient refusal, patient lost to 
follow up, unacceptable toxicity, or the study is terminated by the sponsor, whichever comes 
first (see Section 6.3).
Patients who develop disease progression on study treatment but are otherwise continuing to 
derive clinical benefit from study treatment will be eligible to continue with avelumab 
combined with axitinib, single-agent avelumab, or single-agent axitinib provided that the 
treating physician has determined that the benefit/risk for doing so is favorable.
4. PATIENT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate patients are enrolled.  The following 
eligibility criteria are designed to select patients for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular patient is suitable for this protocol. 
An eligibility worksheet will be provided to the Investigator and site personnel in order to 
document the review of inclusion and exclusion criteria for each patient.  The eligibility 
worksheet will be sent to the Sponsor for approval in order to complete enrollment, which 
defines enrollment into the study, for each patient.


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4.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Diagnosis: 
a.
NSCLC Cohort: Histologically or cytologically confirmed diagnosis of NSCLC 
that is locally advanced or metastatic: 

No activating EGFR mutations, Anaplastic lymphoma kinase (ALK)
translocations/rearrangements, or c-ros oncogene 1 (ROS1)
translocations/rearrangements where testing is standard of care. 

Have received at least 1 prior platinum-based chemotherapy regimen for 
locally advanced or metastatic NSCLC. 

No more than 2 prior lines of systemic therapy for locally advanced or 
metastatic disease. 

If disease progression occurred during or within 6 months after 
neoadjuvant/adjuvant chemotherapy or radiotherapy-chemotherapy, the 
regimen is counted as 1 prior treatment regimen towards the allowed limit of
prior treatment regimens. 

Checkpoint inhibitor naïve.
b. UC Cohort: Histologically or cytologically confirmed diagnosis of transitional 
cell carcinoma (TCC) of the urothelium (if mixed, more than 50% TCC 
component) including bladder, urethra, ureters, or renal pelvis that is locally 
advanced or metastatic: 

No prior systemic treatment for locally advanced or metastatic disease.  Prior 
neoadjuvant or adjuvant therapy is permitted if disease progression occurred 
>12 months after the completion of therapy. 

Checkpoint inhibitor naïve. 

Ineligible for receiving cisplatin-containing front-line chemotherapy based at 
least one of the following criteria:19
i. ECOG performance status (PS) 2; 
ii. Renal dysfunction (defined as creatinine-clearance <60 ml/min); 
iii. Grade 2 peripheral neuropathy;


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iv. Grade 2 hearing loss (hearing loss measured by audiometry of 
25 decibels at two contiguous frequencies).
2.
Measurable disease by RECIST v1.1 with at least 1 measurable lesion that has not 
previously been irradiated.
3. Availability of an archival formalin-fixed and paraffin-embedded (FFPE) tumor tissue 
block from primary diagnosis specimen or metastatic specimen (if available).  If a 
FFPE tissue block cannot be provided, then 15 unstained slides (10 minimum) will be 
acceptable.  If such an archived sample is not available, a de novo (ie, fresh) tumor 
sample must be obtained prior to study enrollment (see Section 6.1.1).
4. ECOG PS: 0 or 1.  For UC patients, ECOG PS 2 is permitted as part of 
cisplatin-ineligibility criteria.
5. Age 18 years.
6. Estimated life expectancy of at least 90 days.
7. Adequate hepatic function defined by:
a.
Total serum bilirubin 1.5 × the upper limit of normal range (ULN);
b. AST and ALT 2.5 × ULN; for subjects with documented metastatic disease to 
the liver, AST and ALT levels 5 × ULN.
8. Adequate bone marrow function including: 
a.
Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109/L;
b. Platelets 100,000/mm3 or 100 x 109/L;
c.
Hemoglobin 9 g/dL (5.6 mmol/L) (may have been transfused).
9. Adequate renal function defined by:
a.
Estimated creatinine clearance 30 mL/min as calculated using the 
Cockcroft-Gault (CG) equation.
b. Urinary protein <2+ by urine dipstick.  If dipstick is 2+, then 24-hour urinary 
protein <2 g per 24 hours.
10. Left ventricular ejection fraction (LVEF) lower limit of normal (LLN) as assessed
by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO).


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11. No evidence of uncontrolled hypertension as documented by 2 baseline blood
pressure readings taken at least 1 hour apart.  The baseline systolic blood pressure
readings must be 140 mm Hg, and the baseline diastolic blood pressure readings
must be 90 mm Hg.  Patients whose hypertension is controlled by antihypertensive
therapies are eligible.
12. Evidence of a personally signed and dated informed consent document indicating that
the patient has been informed of all pertinent aspects of the study.
13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and 
other study procedures.
14. Female patients of childbearing potential must have negative serum pregnancy or 
urine pregnancy test at screening.  Female patients of non-childbearing potential must 
meet at least 1 of the following criteria:
a.
Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; status may be confirmed with a serum follicle-stimulating 
hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are considered to be 
of childbearing potential.
4.2. Exclusion Criteria
Patients with any of the following characteristics/conditions will not be included in the study:
1. Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
anti-OX-40, anti-glucocorticoid induced tumor necrosis factor (TNF) receptor 
(GITR), anti-lymphocyte activation gene-3 (LAG-3), anti-T cell immunoglobulin and 
mucin (TIM-3) domain, or anti-cytotoxic T lymphocyte-associated protein 
4 (CTLA-4) antibody (including ipilimumab). 
2. Prior treatment with an anti-VEGF pathway TKI; prior use of anti-VEGF pathway 
mAb is permitted. 
3. Patients with newly diagnosed brain metastases or 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 enrollment, have discontinued 
corticosteroid treatment for these metastases for at least 14 days prior to study 
enrollment, and are neurologically stable.


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4. Diagnosis of any other malignancy within 5 years prior to study enrollment. 
Adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the 
bladder, breast, or cervix, or low grade (Gleason 6) prostate cancer on surveillance 
without any plans for treatment intervention (eg, surgery, radiation, or castration) are
allowed.
5. Radiologically documented evidence of major blood vessel invasion or encasement 
by cancer (ie, invasion into the fat plane between the vessel wall and tumor) or 
intratumor cavitation, regardless of tumor histology. 
6. Current use of immunosuppressive medication at the time of study enrollment, 
EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid 
injection (eg, intra-articular injection); b. Systemic corticosteroids at physiologic 
doses 10 mg/day of prednisone or equivalent; c. Steroids as premedication for 
hypersensitivity reactions.
7. Active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent.  Patients with diabetes type I, vitiligo, psoriasis, or 
hypo- or hyperthyroid disease not requiring immunosuppressive treatment are 
eligible.
8. Prior organ transplantation including allogenic stem-cell transplantation.
9. Active infection requiring systemic therapy.
10. Known history of testing positive for human immunodeficiency virus (HIV) or 
known acquired immunodeficiency syndrome.
11. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
12. Administration of a live vaccine within 28 days prior to study enrollment.
13. Known prior severe hypersensitivity to the investigational products or any component 
in their formulations, including known severe hypersensitivity reactions to 
monoclonal antibodies (NCI CTCAE v4.03 Grade 3).
14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, 
alopecia, sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a 
safety risk based on Investigator's judgment are acceptable.  For UC patients, 
Grade 2 peripheral neuropathy is permitted as part of cisplatin-ineligibility criteria.
15. NCI CTCAE Grade 3 hemorrhage within 28 days prior to study enrollment.
16. Hemoptysis (1/2 teaspoon of bright red blood episode with cough) within 28 days 
prior to enrollment. 


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17. Evidence of inadequate wound healing.
18. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days prior to enrollment.
19. Any of the following in the previous 6 months prior to study enrollment: deep vein 
thrombosis or symptomatic pulmonary embolism.
20. Any of the following within the 12 months prior to study enrollment: 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.
21. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2 or prolongation of the QTc 
interval to >500 msec.
22. Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus 
extending to the heart.
23. Spinal cord compression unless the patient has good pain control attained through 
therapy, and there is stabilization or recovery of neurological function for the 4 weeks
prior to first dose of study drug. 
24. Known history of immune-mediated colitis, inflammatory bowel disease,
immune-mediated pneumonitis, pulmonary fibrosis.
25. 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 3 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.
26. Major surgery 28 days or major radiation therapy 14 days prior to study 
enrollment.  Prior palliative radiotherapy (10 fractions) to metastatic lesion(s) is 
permitted, provided it has been completed at least 48 hours prior to study enrollment.  
Port placement is considered to be minor surgery. 


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27. 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
first dose of study drug (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, diltiazem, and conivaptan).  The topical use of these 
medications (if applicable), such as 2% ketoconazole cream, is allowed.
28. Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, 
including their administration within 10 days prior to first dose of study drug 
(eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentin, 
clevidipine, St John’s wort).
29. 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 or Factor Xa inhibitors is allowed.
30. Participation in other studies involving investigational drug(s) within 28 days prior to
study enrollment.
31. Other severe acute or chronic medical 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.
32. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the Investigator, or 
patients who are Pfizer employees, including their family members, directly involved 
in the conduct of the study.
33. Pregnant female patients; breastfeeding female patients; fertile male patients and 
female patients of childbearing potential who are unwilling or unable to use 2 
methods of contraception (at least one of which is considered to be highly effective 
with low user dependency as defined in Section 4.3.1) as outlined in this protocol for 
the duration of the study and for at least 30 days after the last dose of avelumab (90 
days for males) and 90 days after the last dose of axitinib.


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4.3. Lifestyle Requirements 
4.3.1. Contraception
In this study, fertile male patients and female patients who are of childbearing potential as 
applicable to the study will receive avelumab for which the teratogenic risk is currently 
unknown in combination with axitinib, which has been associated with demonstrated 
teratogenicity.  Patients who are, in the opinion of the investigator, sexually active and at risk 
for pregnancy with their partner(s) must agree to use 2 methods of contraception (at least one 
of which is considered to be highly effective with low user dependency as defined below) 
throughout the study and for at least 30 days after the last dose of avelumab (90 days for 
male patients) and 90 days after the last dose of axitinib.  The investigator or his or her 
designee, in consultation with the patient, will confirm that the patient has selected 
2 appropriate methods of contraception (at least one of which is considered to be highly 
effective with low user dependency as defined below) for the individual patient and his/her 
partner(s) and will confirm that the patient has been instructed in their consistent and correct 
use.  At time points indicated in the Schedule of Activities, the investigator or designee will 
inform the patient of the need to use 2 methods of contraception consistently and correctly 
and document the conversation, and the patient’s affirmation, in the patient’s chart.  In 
addition, the investigator or designee will instruct the patient to call immediately if 1 or both 
of the selected contraception methods is discontinued or if pregnancy is known or suspected 
in the patient or partner.
Highly effective methods of contraception with low user dependency include (applies to 
female patients at risk for pregnancy with their male partners):
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, inserted, injected, implanted), provided the patient or male patient’s 
female partner plans to remain on the same treatment throughout the entire study and 
has been using that hormonal contraceptive for an adequate period of time to ensure 
effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male sterilization with absence of sperm in the postvasectomy ejaculate.
4. Bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure
(provided that occlusion has been confirmed in accordance with the device’s label).
4.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Manual. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, patients are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational product identifiers, patient study numbers, 
contact information for the investigator site, and contact details for a contact center in the 


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event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
patient’s participation in the study.  The contact number can also be used by investigator staff 
if they are seeking advice on medical questions or problems; however, it should be used only 
in the event that the established communication pathways between the investigator site and 
the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the patient directly, and if a patient calls that number, he or 
she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).  
For this study, the investigational products are avelumab and axitinib.
5.1. Allocation to Treatment
At the time that a patient has signed informed consent and entered screening, the site should 
contact the interactive response technology (IRT) system to obtain the patient identification 
number. 
Once a patient has met all eligibility criteria, assignment of patient enrollment number, 
patient enrollment, and allocation of investigational product will be managed by the IRT 
system.  The site will need to contact the IRT system to enroll the patient and to obtain the 
study drug allocation information.  At the time of enrollment, site personnel (study 
coordinator or specified designee) will be required to enter into or select information from 
the IRT system including, but not limited to, the user’s identification and password, the 
protocol number, and the patient enrollment number.  The IRT system will then provide a 
treatment assignment and dispensable unit (DU) or vial or bottle number for each 
investigational product to be dispensed.  The IRT system will also provide a confirmation 
report containing the patient number and DU or vial or bottle numbers assigned.  The 
confirmation report must be stored in the site’s files. 
Study treatment must be initiated preferably on the day of enrollment, but no later than
3 calendar days after enrollment.
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.


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5.2. Treatment Duration
Patients will continue to receive study treatment until objective disease progression assessed 
by investigator (see Section 5.5.3 for guidance on treatment beyond progression), patient 
refusal, unacceptable toxicity, global deterioration of health status requiring discontinuation
or until the study is terminated by the Sponsor, whichever occurs first.
5.3. Patient Compliance
5.3.1. IV Administered Investigational Product
For avelumab, the site will complete the required dosage Preparation Record located in the 
Investigational Product Manual.  The use of the Preparation Record is preferred, but it does 
not preclude the use of an existing appropriate clinical site documentation system.  The 
existing clinical site's documentation system should capture all pertinent /required 
information on the preparation and administration of the dose.  This may be used in place of 
the Preparation Record after approval from the Pfizer monitor. 
The information related to each trial drug administration, including the date, time, and dose 
of study drug, will be recorded on the case report form (CRF).  The Investigator will ensure 
that the information entered into the CRF regarding drug administration is accurate for each 
patient.  Any reason for noncompliance should be documented.
Non-compliance is defined as a patient missing >1 infusion of any investigational product for 
non-medical reasons.  If 1 infusion is missed and the interval between the subsequent 
infusion and the last administered treatment is longer than 4 weeks for nonmedical reasons, 
the criteria of insufficient compliance will have been met as well. 
5.3.2. P.O. Administered Investigational Product
For axitinib, patients will be required to return all unused study treatment at the beginning of 
each cycle.  The number of tablets returned by the patient at the end of the cycle will be 
counted, documented, and recorded for drug accountability.  Treatment compliance (reported 
as a percent) will be defined as the number of tablets taken during the study divided by the 
expected number of tablets multiplied by 100%.  Tablets that are not returned will be 
considered to have been taken unless reported otherwise by the patient.  Drug diary records 
will be provided to the patients as an aid for the recording of study treatment compliance. 
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 dosing instructions.  If needed, the patient will be re-trained.  The same follow-up 
process will be applied in case the dose of axitinib is modified during the treatment period.
5.4. Investigational Product Supplies
Avelumab and axitinib 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 


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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.
5.4.1. Dosage Form(s) and Packaging
5.4.1.1. Avelumab
Avelumab is a sterile, clear and colorless to slightly yellow solution intended for IV 
administration.  Avelumab is formulated as a 20 mg/mL solution and will be supplied by the 
sponsor in single-use glass vials, stoppered with a rubber septum and sealed with an 
aluminum polypropylene flip-off seal.
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.
5.4.1.2. 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.
5.4.2. 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 
investigational agents.
5.4.2.1. 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 Instructions 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.


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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 Instructions 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.
5.4.2.2. 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.
5.5. Administration
All investigational products will be administered on an outpatient basis.
5.5.1. Avelumab
The Drug Administration Instructions within the IP Manual contains specific instructions for 
avelumab dose calculation, reconstitution, preparation of the infusion fluid, and 
administration.
Avelumab will be administered Q2W on Days 1 and 15 of each 28 day cycle after all 
procedures/assessments have been completed as described in the Schedule of Activities table.  
After Cycle 1, Day 1, avelumab may be administered up to 3 days before or after the 
scheduled Days 1 and 15 of each dose.
Avelumab will be administered as an 800 mg fixed dose via a 1-hour infusion.  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 CRF.


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In order to mitigate avelumab infusion-related reactions, patients must be premedicated 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab.  Premedication 
should be administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity of prior infusion reactions.  Premedication will include an antihistamine 
(for example, 25-50 mg diphenhydramine IV or oral equivalent), and paracetamol 
(acetaminophen) (eg, 500-650 mg IV or oral equivalent).  This regimen may be modified 
based on local treatment standards and guidelines, as appropriate, provided it does not 
include systemic corticosteroids. 
Avelumab dose reduction for toxicity management is not permitted, however next 
administration may be omitted due to persisting toxicity or treatment may be discontinued as 
described in Table 4 and Section 5.5.5.  Possible modifications of the infusion rate for the 
management of infusion-related reactions related to avelumab are described in 
Section 5.5.5.5.
5.5.2. Axitinib
Axitinib will be administered at 5 mg PO BID, with our without food, 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 5.5.5).  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 any time 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, 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 3 and Table 4.
5.5.3. Treatment After Initial Evidence of Radiologic Disease Progression
Immunotherapeutic agents such as avelumab may produce anti-tumor effects by potentiating 
endogenous cancer-specific immune responses.  Following immunotherapy, a clinical 
response may occur later than would typically be expected following treatment with a 
cytotoxic agent.  In addition, this response may occur after an initial increase in tumor burden 
or even after the appearance of new lesions. 


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If radiologic imaging shows disease progression, tumor assessment should be repeated 
4 weeks later in order to confirm the observation.  Patients may continue to receive 
avelumab and axitinib at the Investigator’s discretion while waiting for confirmation of PD if
they are clinically stable as defined by the following criteria:

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.
Before continuation of treatment after initial PD, the patient must be re-consented via 
informed consent addendum and informed that by continuing to receive the investigational 
products on study, the patient may be foregoing approved therapy with possible clinical 
benefit(s).
If repeat imaging does not confirm PD, treatment with avelumab and axitinib may be 
continued. 
If the repeat imaging confirms PD, patients should discontinue from all investigational 
products.  However, according to the Investigator’s clinical judgment and after discussion 
between the Investigator and the Sponsor, if a patient with evidence of PD is still 
experiencing clinical benefit, the patient may be eligible for continued treatment with axitinib 
and avelumab.  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. 
If the patient is subsequently found to have further disease progression either radiologically 
according to RECIST v 1.1 or clinically, then treatment with axitinib and avelumab should be 
permanently discontinued.
5.5.4. 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]).
5.5.5. Recommended Dose Modifications
Every effort should be made to administer investigational product on the planned dose and 
schedule.


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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 avelumab, no dose modifications are permitted in this study, but next infusion may be 
omitted based on persisting toxicity, as outlined in Table 4.  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 dose level for intrapatient dose modification is listed in Table 3.
5.5.5.1. Intrapatient Axitinib Dose Escalation and Dose Reduction
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 3 (unless the patient’s blood pressure [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.
Table 3.
Axitinib Dose Levels
Dose Level
Dose
+2
10 mg BID
+1
7 mg BID
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 4.  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 3 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.


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5.5.5.2. Management of Axitinib-Related Hypertension
Patients will be issued BP monitoring devices including cuffs (provided by the sponsor) for
home monitoring and instructed to measure their BP at least once daily (before taking the 
morning dose of axitinib).  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.78,79  To treat an increase in BP, standard antihypertensives in 
accordance to local standard of care may be used except diltiazem (eg, thiazide or 
thiazide-like diuretics, angiotensin II receptor blockers, angiotensin converting-enzyme 
inhibitors, and dihydropyridine (DHP) calcium channel blockers, beta blockers, etc.).78,79
Dose modification for axitinib in case of hypertension is described in Table 4.
5.5.5.3. Axitinib Dose Modifications and Avelumab Infusion Omissions for
Treatment-Related Toxicity
Recommended axitinib dose modifications and avelumab infusion omissions in case of drug
related toxicity are shown in Table 4. 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.


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Table 4.
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product Related Toxicity
Toxicity
NCI CTCAE
Severity Grade
Axitinib
Avelumab
Dose Modification
TreatmentModification
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 or if the same Grade 3 toxicity recurs
(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 or urine protein
creatinine (UPC) ratio.  Dosing may continue while waiting for test
<2 g proteinuria/
24 hour or UPC <2

Continue at the same dose level.


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Table 4.
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
(continued)
Toxicity
NCI CTCAE
Severity Grade
Axitinib
Avelumab
Dose Modification
TreatmentModification
2 g proteinuria/
24 hours or UPC 2

Withhold until proteinuria is <2 g/24 hours or
UPC <2.

Repeat 24-hour urine collection or UPC for
proteinuria and creatinine clearance (interval at
investigator discretion) until proteinuria is
<2 g/24 hours or UPC <2.

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 5.5.5.2 for monitoring/management of
axitinib-related hypertension.

Continue as per schedule.
2 systolic BP readings
separated by at least
hour show systolic
pressure >150 mm Hg
OR
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 5.5.5.2 for monitoring/management
of axitinib-related hypertension.

Continue as per schedule.


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Table 4.
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
(continued)
Toxicity
NCI CTCAE
Severity Grade
Axitinib
Avelumab
Dose Modification
TreatmentModification
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 Hg
and adjust antihypertensive medication.

Then, reduce by 1 dose level and resume
treatment.

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 5.5.5.2 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 5.5.5.2 for monitoring/management
of axitinib-related hypertension.

Continue as per schedule.


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Table 4
Axitinib Dose Modifications and Avelumab Infusion Omissions for Investigational Product-Related Toxicity 
(continued)
Toxicity
NCI CTCAE
Severity Grade
Axitinib
Avelumab
Dose Modification
TreatmentModification
Infusion-related
Reaction
Grade 1-4

Continue at the same dose level.
See Section 5.5.5.5 and Table 5.
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 5.5.5.6 and Table 6.
Stevens-Johnson
syndrome
Grade 3-4

Permanentdiscontinuation

Permanentdiscontinuation
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
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 or if the same Grade 3
toxicity recurs (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).


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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.
For NSCLC patients: 
Patients with NSCLC who develop symptomatic brain metastases, tumor encasing vasculature, patients on anticoagulants, and patients with hemoptysis or any 
other relevant risk factors for pulmonary hemorrhage (such as bleeding diathesis) while on study treatment should be discussed with the sponsor and have 
treatment with axitinib permanently discontinued. However, if brain metastases are successfully treated, or if a patient no longer needs anticoagulation, or 
bleeding disorder resolves, then treatment could be restarted at the discretion of the investigator and upon discussion with the sponsor.


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5.5.5.4. Special Precautions for Avelumab Administration
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. 
If an allergic reaction occurs, the patient must be treated according to the best available 
medical practice. 
In order to mitigate avelumab infusion-related reactions, patients have to be premedicated 
approximately 30 to 60 minutes prior to the first 4 infusions of avelumab.  Premedication 
should be administered for subsequent avelumab doses based upon clinical judgment and 
presence/severity of prior infusion reactions.  Premedication will include an antihistamine 
(for example, 25-50 mg diphenhydramine IV or oral equivalent), and paracetamol 
(acetaminophen) (eg, 500-650 mg, IV or oral equivalent).  This regimen may be modified 
based on local treatment standards and guidelines, as appropriate, however, the prophylactic 
administration of systemic corticosteroids is not permitted.
Following avelumab infusions, patients must be observed for 30 minutes post-infusion for 
potential infusion-related reactions.  Patients should be instructed to report any delayed 
reactions to the investigator immediately.
Treatment recommendations for the management of infusion-related reactions and severe
hypersensitivity reactions are outlined in Section 5.5.5.5 and Table 5, 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 5.5.5.6.
5.5.5.5. Management of Avelumab Infusion-Related Reactions
Since avelumab is administered IV, infusion-related reactions may occur.  Symptoms of 
infusion-related reactions include but are not limited to fever, chills, flushing, hypotension, 
dyspnea, wheezing, back pain, abdominal pain, and urticaria.  Management of 
infusion-related reactions should follow the guidelines set forth 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 (for example, 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.

If a Grade 2 infusion related reaction does 
not improve or worsens following the 
decrease in infusion rate and appropriate 
symptomatic treatment the infusion should 
not be resumed for that day. 
Grade 3 or Grade 4 – severe or life-threatening

Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae.

Grade 4: Life-threatening consequences; 
urgent intervention indicated.

Stop the avelumab infusion immediately 
and disconnect infusion tubing from the 
subject.

Subjects have to be withdrawn immediately 
from avelumab treatment and must not 
receive any further avelumab treatment.
IV: intravenous; NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse Event; 
NSAIDs: nonsteroidal anti-inflammatory drugs.
*If avelumab infusion rate has been decreased by 50% due to an infusion reaction, it must remain decreased 
for the next scheduled infusion.  If no infusion reaction is observed at the next scheduled infusion, the 
infusion rate may be returned to baseline at subsequent infusions.
Additional Modifications for Patients with Grade 2 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.


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5.5.5.6. 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 high grade AE (Grade 3 to 4);

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 some 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 5.5.5.6.
For overlapping potential immune-related toxicities, follow the specific management
recommendations described in Table 6.
Table 6.
Management of Avelumab Immune Related Adverse Events
Gastrointestinal irAEs
Severity of Diarrhea/Colitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Diarrhea: <4 stools/day over 
Baseline
Colitis: asymptomatic 
Continue avelumab therapy.
Symptomatic treatment 
(eg, loperamide).
Close monitoring for worsening 
symptoms.
Educate subject to report worsening 
immediately.
If worsens:
Treat as Grade 2, 3 or 4. 
Grade 2 
Diarrhea: 4 to 6 stools per day over 
Baseline; IV fluids indicated 
<24 hours; not interfering with ADL
Colitis: abdominal pain; blood in 
stool 
Withhold avelumab therapy.
Symptomatic treatment.
If improves to Grade 1: 
Resume avelumab therapy.
If persists >5-7 days or recurs:
Treat as Grade 3 or 4.


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Grade 3 to 4
Diarrhea (Grade 3): 7 stools per 
day over Baseline; incontinence; IV 
fluids 24 h; interfering with ADL
Colitis (Grade 3): severe abdominal 
pain, medical intervention indicated, 
peritoneal signs
Grade 4: life-threatening, 
perforation
Withhold avelumab for 
Grade 3.
Permanently discontinue 
avelumab for Grade 4 or 
recurrent Grade 3.
1.0 to 2.0 mg/kg/day 
prednisone IV or equivalent
Add prophylactic antibiotics 
for opportunistic infections.
Consider lower endoscopy.
If improves: 
Continue steroids until Grade 1, then 
taper over at least 1 month; resume 
avelumab therapy following steroids 
taper (for initial Grade 3). 
If worsens, persists >3 to 5 days, or 
recurs after improvement:
Add infliximab 5 mg/kg (if no 
contraindication).  Note: infliximab 
should not be used in cases of 
perforation or sepsis. 
Dermatological irAEs
Grade of Rash
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1 to 2 
Covering 30% body surface area 
Continue avelumab therapy.  
Symptomatic therapy (for 
example, antihistamines, 
topical steroids).
If persists >1 to 2 weeks or recurs: 
Withhold avelumab therapy.
Consider skin biopsy.
Consider 0.5-1.0 mg/kg/day 
prednisone or equivalent.  Once 
improving, taper steroids over at least 
1 month, consider prophylactic 
antibiotics for opportunistic infections, 
and resume avelumab therapy 
following steroids taper.
If worsens: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Covering >30% body 
surface area; 
Grade 4: Life threatening 
consequences 
Withhold avelumab for 
Grade 3.
Permanently discontinue for 
Grade 4 or recurrent Grade 3. 
Consider skin biopsy.
Dermatology consult.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
If improves to Grade 1: 
Taper steroids over at least 1 month; 
resume avelumab therapy following 
steroids taper (for initial Grade 3).


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Pulmonary irAEs
Grade of Pneumonitis
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Radiographic changes only 
Consider withholding 
avelumab therapy.
Monitor for symptoms every
2 to 3 days.
Consider Pulmonary and 
Infectious Disease consults.
Re-assess at least every 3 weeks
If worsens: 
Treat as Grade 2 or Grade 3 to 4. 
Grade 2
Mild to moderate new symptoms 
Withhold avelumab therapy.
Pulmonary and Infectious 
Disease consults.
Monitor symptoms daily; 
consider hospitalization.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
Consider bronchoscopy, lung 
biopsy.
Re-assess every 1 to 3 days 
If improves: 
When symptoms return to Grade 1, 
taper steroids over at least 1 month, 
and then resume avelumab therapy 
following steroids taper.
If not improving after 2 weeks or 
worsening: 
Treat as Grade 3 to 4. 
Grade 3 to 4
Grade 3: Severe new symptoms; 
New/worsening hypoxia;
Grade 4: Life-threatening 
Permanently discontinue 
avelumab therapy.
Hospitalize.
Pulmonary and Infectious 
Disease consults.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
Consider bronchoscopy, lung 
biopsy.
If improves to Grade 1: 
Taper steroids over at least 1 month 
If not improving after 48 hours or 
worsening: 
Add additional immunosuppression 
(for example, infliximab, 
cyclophosphamide, IV 
immunoglobulin, or mycophenolate 
mofetil).
Hepatic irAEs
Grade of Liver Test Elevation
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Grade 1 AST or ALT > ULN to 
3.0 x ULN and/or Total bilirubin 
> ULN to 1.5 x ULN 
Continue avelumab therapy.
Continue liver function monitoring 
If worsens:
Treat as Grade 2 or 3 to 4. 


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Grade 2
AST or ALT >3.0 to 5 x ULN 
and/or total bilirubin >1.5 to 
3 x ULN 
Withhold avelumab therapy.
Increase frequency of 
monitoring to every 3 days.
If returns to Grade 1:
Resume routine monitoring; resume 
avelumab therapy.
If elevation persists >5 to 7 days or 
worsens: 
Treat as Grade 3 to 4.
Grade 3 to 4
AST or ALT >5 x ULN and/or total 
bilirubin >3 x ULN 
Permanently discontinue 
avelumab therapy.
Increase frequency of 
monitoring to every 1 to 
2 days.
1.0 to 2.0 mg/kg/day 
prednisone or equivalent.
Add prophylactic antibiotics 
for opportunistic infections.
Consult gastroenterologist/ 
hepatologist.
Consider obtaining MRI/CT 
scan of liver and liver biopsy 
if clinically warranted.
If returns to Grade 1: 
Taper steroids over at least 1 month 
If does not improve in >3 to 5 days, 
worsens or rebounds: 
Add mycophenolate mofetil 1 gram (g) 
twice daily.
If no response within an additional 
3 to 5 days, consider other 
immunosuppressants per local 
guidelines.
Renal irAEs
Grade of Creatinine Increased 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 1
Creatinine increased > ULN to 
1.5 x ULN
Continue avelumab therapy.
Continue renal function 
monitoring
If worsens:
Treat as Grade 2 to 3 or 4.
Grade 2 to 3
Creatinine increased >1.5 and 
6 x ULN
Withhold avelumab therapy.
Increase frequency of monitoring to 
every 3 days.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
If returns to Grade 1:
Taper steroids over at least 
1 month, and resume avelumab 
therapy following steroids taper.
If worsens: 
Treat as Grade 4.


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Grade 4
Creatinine increased >6 x ULN
Permanently discontinue avelumab 
therapy.
Monitor creatinine daily.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Consider renal biopsy.
Nephrology consult.
If returns to Grade 1:
Taper steroids over at least 
1 month.
Cardiac irAEs
Myocarditis
Initial Management
Follow-up Management
New onset of cardiac signs or 
symptoms and / or new laboratory 
cardiac biomarker elevations 
(eg, troponin, CK-MB, BNP) or 
cardiac imaging abnormalities 
suggestive of myocarditis 
Withhold avelumab therapy.
Hospitalize.
In the presence of life threatening cardiac 
decompensation, consider transfer to a 
facility experienced in advanced heart 
failure and arrhythmia management.
Cardiology consult to establish etiology 
and rule-out immune-mediated 
myocarditis.
Guideline based supportive treatment as 
per cardiology consult.*
Consider myocardial biopsy if 
recommended per cardiology consult.
If symptoms improve and 
immune-mediated etiology 
is ruled out, re-start 
avelumab therapy.
If symptoms do not 
improve/worsen, viral 
myocarditis is excluded, and 
immune-mediated etiology 
is suspected or confirmed 
following cardiology 
consult, manage as 
immune-mediated 
myocarditis.
Immune-mediated myocarditis
Permanently discontinue avelumab.
Guideline based supportive treatment as 
appropriate as per cardiology consult.*
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Once improving, taper 
steroids over at least 
1 month.
If no improvement or 
worsening, consider 
additional 
immunosuppressants 
(eg, azathioprine, 
cyclosporine A).


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*Local guidelines, or eg, ESC or AHA guidelines 
ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines
AHA guidelines website: 
http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001
Endocrine irAEs
Endocrine Disorder
Initial Management
Follow-up Management
Grade 1 or Grade 2 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Continue avelumab therapy.
Endocrinology consult if needed.
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
Type I diabetes mellitus) as 
appropriate.
Rule-out secondary endocrinopathies 
(ie, hypopituitarism / hypophysitis).
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate.
Grade 3 or Grade 4 
endocrinopathies 
(hypothyroidism, 
hyperthyroidism, adrenal 
insufficiency, type I diabetes 
mellitus)
Withhold avelumab therapy.
Consider hospitalization.
Endocrinology consult.
Start thyroid hormone replacement 
therapy (for hypothyroidism), 
anti-thyroid treatment (for 
hyperthyroidism), corticosteroids (for 
adrenal insufficiency) or insulin (for 
type I diabetes mellitus) as 
appropriate. 
Rule-out secondary endocrinopathies 
(ie, hypopituitarism / hypophysitis).
Resume avelumab once 
symptoms and/or laboratory 
tests improve to Grade 1 
(with or without hormone 
replacement/suppression).
Continue hormone 
replacement/suppression and 
monitoring of endocrine 
function as appropriate.


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Hypopituitarism/Hypophysitis 
(secondary endocrinopathies)
If secondary thyroid and/or adrenal 
insufficiency is confirmed 
(ie, subnormal serum FT4 with 
inappropriately low TSH and/or low 
serum cortisol with inappropriately 
low ACTH):

Refer to endocrinologist for 
dynamic testing as indicated and 
measurement of other hormones 
(FSH, LH, GH/IGF-1, PRL, 
testosterone in men, estrogens in 
women).

Hormone 
replacement/suppressive therapy 
as appropriate.

Perform pituitary MRI and visual 
field examination as indicated.
If hypophysitis confirmed:

Continue avelumab if mild 
symptoms with normal MRI. 
Repeat the MRI in 1 month.

Withhold avelumab if moderate, 
severe or life-threatening 
symptoms of hypophysitis and/or 
abnormal MRI. Consider 
hospitalization. Initiate 
corticosteroids (1 to 2 mg/kg/day 
prednisone or equivalent) 
followed by corticosteroids taper 
during at least 1 month.

Add prophylactic antibiotics for 
opportunistic infections.
Resume avelumab once 
symptoms and hormone tests 
improve to Grade 1 (with or 
without hormone 
replacement).
In addition, for hypophysitis 
with abnormal MRI, resume 
avelumab only once 
shrinkage of the pituitary 
gland on MRI/CT scan is 
documented.
Continue hormone 
replacement/suppression 
therapy as appropriate.
Other irAEs (not described above)
Grade of other irAEs 
(NCI-CTCAE v4)
Initial Management
Follow-up Management
Grade 2 or Grade 3 clinical signs 
or symptoms suggestive of a 
potential irAE
Withhold avelumab therapy pending 
clinical investigation.
If irAE is ruled out, manage 
as appropriate according to 
the diagnosis and consider 
re-starting avelumab therapy.
If irAE is confirmed, treat as 
Grade 2 or 3 irAE.
Grade 2 irAE or first occurrence 
of Grade 3 irAE
Withhold avelumab therapy.
1.0 to 2.0 mg/kg/day prednisone or 
equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Specialty consult as appropriate.
If improves to Grade 1: 
Taper steroids over at least 
1 month and resume 
avelumab therapy following 
steroids taper.


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Recurrence of same Grade 3 
irAEs
Permanently discontinue avelumab 
therapy.
1.0 to 2.0 mg/kg/day
prednisone or equivalent.
Add prophylactic antibiotics for 
opportunistic infections.
Specialty consult as appropriate.
If improves to Grade 1: 
Taper steroids over at least 
1 month.
Grade 4 
Permanently discontinue avelumab 
therapy.
1.0 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.
5.6. 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 products should be stored in their original containers and in accordance with 
the labels. 
See the IP manual for storage conditions of the product once reconstituted and/or diluted (for 
avelumab only).
Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the product label.


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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 evaluation for 
excursions should be available.  The intent is to ensure that the minimum and maximum 
temperature is checked each business day to confirm that no excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order. 
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery.  The site should actively pursue options for returning the product to the storage 
conditions described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation. 
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 products 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. 
5.7. Investigational Product Accountability 
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record.  All bottles of study drug must be 
returned to the investigator by the patient at every visit and at the end of the trial.
5.8. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the investigator site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.


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5.9. Concomitant Treatment(s)
Medications or vaccinations specifically prohibited in the exclusion criteria are also not 
allowed during the active treatment period.
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 
discretion of the treating physician.
Concomitant medications and treatments, including herbal supplements, will be recorded 
from 28 days prior to the start of study treatment(s) and up to 90 days after the last dose of 
study treatment(s).  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, as well as non-drug supportive interventions 
(eg, transfusions).
Concurrent anti-cancer therapy with agents other than study treatments 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, and 
immune-related events are reported in Section 5.5.5.5 and Section 5.5.5.6, respectively.
5.9.1. Inhibitors and Inducers of Cytochrome P450 (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.
The concomitant use of strong CYP3A4/5 inhibitors (eg, ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin, diltiazem and voriconazole) should be avoided.  Selection of an alternate 
concomitant medication with no or minimal CYP3A4/5 inhibition potential is recommended.  
Although axitinib dose adjustments have not been studied in patients receiving strong 
CYP3A4/5 inhibitors, a dose reduction of approximately half is recommended, as this dose 
reduction is predicted to adjust the axitinib area under the plasma concentration vs time curve 
(AUC) to the range observed without inhibitors.  The subsequent doses can be increased or 
decreased based on individual safety and tolerability.  If co-administration of the strong 
inhibitor is discontinued, the INLYTA dose should be returned (after 3 to 5 half-lives of the 
inhibitor) to that used prior to initiation of the strong CYP3A4/5 inhibitor.


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If coadministration of the strong CYP3A4/5 inhibitor is discontinued, the axitinib dose 
should be re-escalated (after 10 days) to that used prior to initiation of the strong CYP3A4/5 
inhibitor.
Coadministration of axitinib 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 and 
should be avoided if possible.  Consider a dose increase if axitinib must be dosed with a 
CYP3A4/5 inducer.
If coadministration of the strong CYP3A4/5 inducer is discontinued, the axitinib 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.
5.9.2. Hematopoietic Growth Factors
Granulocyte colony stimulating factor may be used in agreement with American Society of
Clinical Oncology (ASCO) guidelines80 or as allowed per local guidance.
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. 
5.9.3. Concomitant Surgery
Caution is advised on theoretical grounds for any surgical procedures during the study. 
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
major surgery, assuming the wound has completely healed and there are no wound healing
complications (eg, delayed healing, wound infection or fistula).
There is no evidence suggesting that treatment with avelumab increases surgical risk.  
Postoperatively, the decision to reinitiate investigational products should be discussed with 
the Sponsor. 
In the case that a surgical procedure is required for palliative care, all attempts should be 
made to rule out disease progression beforehand. 


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5.9.4. Concomitant Radiotherapy
Palliative radiotherapy to specific sites of disease is permitted if considered medically 
necessary by the treating physician.  All attempts should be made to rule out disease 
progression in the event of increased localized pain.  If palliative radiotherapy is needed to 
control bone pain, the sites of bone disease should be present at baseline; otherwise, bone 
pain requiring radiotherapy will be considered as a sign of disease progression.  Study 
treatment should be withheld for the entire duration of palliative radiotherapy and can be 
restarted upon recovery from any radiotherapy-related toxicities, but no sooner than 48 hours 
after radiotherapy completion. 
5.9.5. Other Prohibited Concomitant Medications and Therapies
Patients are prohibited from receiving the following therapies during the treatment phase of 
this trial: 

Anti-cancer systemic chemotherapy or biological therapy.

Immunotherapy not specified in this protocol. 

Investigational agents other than investigational products. 

Radiation therapy (with the exception noted above in the Concomitant Radiotherapy 
Section 5.9.4).

Immunosuppressive drugs, unless otherwise indicated for the treatment of irAEs 
(see).  See below Clarification Regarding Steroid Use.

Other experimental pharmaceutical products.

Any vaccine therapies for the prevention of infectious disease (eg, human papilloma 
virus vaccine) except for inactivated vaccines (eg, influenza vaccine).

Herbal remedies with immunostimulating properties (eg, mistle toe extract) or those 
known to potentially interfere with major organ function (eg, hypericin).

Bisphosphonate or denosumab treatment unless it has been initiated more than 
14 days prior to enrollment. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
Restrictions for Steroid Use: Data indicate that corticosteroids have an adverse effect on 
T-cell function and that they inhibit and damage lymphocytes.81,82  Furthermore, as for all 
immunotherapies intended to augment T-cell-mediated immunity, there is a risk that 
concomitant immunosuppressives such as steroids will counteract the intended benefit.  
However, studies with anti-CTLA-4 compounds indicate that short term use of steroids can 
be employed without compromising clinical outcomes.82  Therefore, the use of steroids 
during this trial is restricted as follows:


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
Therapeutic use: for the treatment of infusion-related reactions and for the treatment 
of irAEs, steroids are permitted according to the modalities indicated in Table 6.

Physiologic use: replacement for adrenal insufficiency at doses equivalent to 10 mg 
prednisone daily are acceptable.

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection) are permitted. 
5.10. Rescue Medications and Supportive Care
5.10.1. 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.88

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.89  
Patients should be strongly encouraged to maintain liberal oral fluid intake. 

Anti-infectives: Patients with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating Investigator for a given infectious condition, according to standard 
institutional practice.  Prophylactic administration should be considered for the cases 
outlined in Table 6.

Anti-inflammatory or narcotic analgesics may be offered as needed. 

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).


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6.1.1. Tumor Biospecimens
Archived tumor tissue from the most recent primary or metastatic tumor biopsy or resection 
is required to be available.  If there is no archived tumor available, then a de novo (ie, fresh) 
tumor sample should be obtained prior to study enrollment.
For any sample of tumor tissue, one FFPE tissue block should be provided if available and 
permitted by local laws and policies.  If one or more blocks cannot be provided for these 
reasons, then sections must be freshly cut (ie, cut no more than 30 days prior to shipment to 
the central laboratory), 4-5 m thick and mounted on positively-charged microscope slides 
(SuperFrost Plus glass slides are recommended).  Fifteen slides (minimum 10) should be 
provided. 
A minimum 18 gauge core needle should be used in biopsies in order to maximize the quality 
and value of obtained tissue; a minimum of 3 separate cores is requested for each biopsy 
procedure.  Tumor tissue from cytologic sampling (eg, fine needle aspiration, including 
FFPE cell pellet material) is not adequate and should not be submitted. 
Additional information on tumor biospecimen collection procedures is included in the Study 
Manual.
6.2. Study Treatment Period
For treatment period procedures, see the Schedule of Activities.
6.3. Patient Withdrawal/End of Treatment
For End of Treatment visit procedures, please see Schedule of Activities and Section 7.
Patients may withdraw from study treatment or the study overall at any time at their own 
request, or they may be withdrawn at the discretion of the Investigator or Sponsor for safety 
or behavioral reasons, or the inability of the patient to comply with the protocol-required 
schedule of study visits or procedures at a given study site. 
Reasons for withdrawal of study treatment may include:

Objective disease progression.  However, patients with disease progression who are 
continuing to derive clinical benefit from the study treatment will be eligible to 
continue study treatment, provided that the treating physician has determined that the 
benefit/risk for doing so is favorable (See Section 5.5.3 for details and exceptions); 

Global deterioration of health status requiring discontinuation;

Unacceptable toxicity.  If the unacceptable toxicity is attributed to 1 of the 
investigational products, the Investigator may continue treatment with the other 
investigational product(s); 

Pregnancy;


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
Significant protocol violation;

Lost to follow-up;

Patient refused further treatment;

Study terminated by Sponsor;

Death.
Reasons for withdrawal from the study may include:

Study terminated by Sponsor;

Lost to follow-up;

Refused further follow-up;

Death.
If a patient does not return for a scheduled visit, every effort should be made to contact the 
patient.  All attempts to contact the patient and information received during contact attempts 
must be documented in the patient’s medical record.  In any circumstance, every effort 
should be made to document patient outcome, if possible.  The Investigator should inquire 
about the reason for withdrawal, request that the patient return for a final visit, if applicable, 
and follow-up with the patient regarding any unresolved AEs.
If the patient refuses further visits, the patient should continue to be followed for survival 
unless the patient withdraws consent for disclosure of future information or for further 
contact.  In this case, no further study specific evaluations should be performed, and no 
additional data should be collected.  The Sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
6.3.1. Withdrawal of Consent
Patients who request to discontinue receipt of study treatment will remain in the study and 
must continue to be followed for protocol specified follow-up procedures.  The only 
exception to this is when a patient specifically withdraws consent for any further contact with 
him or her or persons previously authorized by the patient to provide this information.  
Patients should notify the investigator in writing of the decision to withdraw consent from 
future follow-up, whenever possible.  The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of investigational product (in which case the withdrawal of consent form is not 
applicable) or also from study procedures and/or posttreatment study follow-up (in which 
case a withdrawal of consent form should be provided and signed).  In the event that vital 
status (whether the patient is alive or dead) is being measured, publicly available information 


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should be used to determine vital status only as appropriately directed in accordance with 
local law.
6.3.2. Lost to Follow-up 
All reasonable efforts must be made to locate patients to determine and report their ongoing 
status.  This includes follow-up with persons authorized by the patient as noted above.  Lost 
to follow-up is defined by the inability to reach the patient after a minimum of 2 documented 
phone calls, faxes, or e-mails as well as lack of response by the patient to 1 registered mail 
letter.  All attempts should be documented in the patient’s medical records.  If it is 
determined that the patient has died, the site will use locally permissible methods to obtain 
the date and cause of death.  If the investigator’s use of a third-party representative to assist 
in the follow-up portion of the study has been included in the patient’s informed consent, 
then the investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the patient’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If, after all attempts, the patient remains lost to follow-up, then 
the last-known-alive date as determined by the investigator should be reported and 
documented in the patient’s medical records.
6.4. Short-Term Follow-up
For follow-up procedures see the Schedule of Activities and ASSESSMENTS section. 
In Short-term Follow-up, patients should be evaluated up to 90 days (30 days, 60 days, and 
90 days 3 days) after last dose of investigational product(s) for safety or until the time of
initiation of new anti-cancer treatment.  Patients continuing to experience study drug-related 
toxicity following discontinuation of investigational products will continue to be followed at 
least every 4 weeks regardless of initiation of new anti-cancer treatment until resolution or 
determination, in the clinical judgment of the Investigator, that no further improvement is 
expected.  Physical examination, ECOG status, vital signs, and safety laboratory 
measurements are not required for patients who initiate new anti-cancer treatment, unless the 
patient continues to experience toxicity following discontinuation of the investigational 
products.  Contraception check and serum/urine pregnancy tests are required up to 30 days 
after last dose of avelumab (90 days for male patients) and 90 days after last dose of axitinib 
for all patients who enter Short-term Follow-up regardless of initiation of subsequent 
anti-cancer therapy. 
6.5. Long-Term Follow-up
Following completion of the Short-term Follow-up period, all patients will be followed for 
survival and subsequent anti-cancer treatments every 12 weeks (14 days) until death, end of 
the study, or patient withdrawal of consent, whichever comes first; new systemic anti-cancer 
treatment will also be recorded.  These visits may be conducted in-clinic or by remote contact 
(eg, telephone). 


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Patients whose disease has not progressed at the time of End of Treatment will continue to 
undergo disease assessments every 8 weeks for 1 year from the start of study treatment and 
then every 12 weeks thereafter until documented disease progression regardless of 
discontinuation of study treatment or initiation of subsequent anti-cancer therapy
(see Section 7.6). 
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the Investigator that may make it unfeasible to 
perform the test.  In these cases the Investigator will take all steps necessary to ensure the 
safety and well-being of the patient.  When a protocol-required test cannot be performed, the 
Investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible.  The 
study team will be informed of these incidents in a timely fashion.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
7.1. Safety Assessment
Safety assessments will include collection of AEs, Serious Adverse Events (SAEs), vital 
signs and physical examination, electrocardiogram (ECG) (12-lead), LVEF by MUGA scan
or Echocardiogram, laboratory assessments, including pregnancy tests, and verification of 
concomitant treatments.  See also Schedule of Activities. 
7.1.1. Pregnancy Testing
For female patients of childbearing potential, a serum or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, and assayed in a certified laboratory, will be performed on 
2 occasions prior to starting study treatments; once at the start of screening and once at the 
baseline visit, immediately before study drugs administration.  Following a negative 
pregnancy test result at screening, appropriate contraception must be commenced and another 
negative pregnancy test result will then be required at the baseline visit before the patient 
may receive the investigational products.  Additional pregnancy tests (serum or urine) will be 
repeated at every treatment cycle, on the day of dosing (results should be available prior to 
dosing), during the active treatment period, at the end of treatment, during follow-up for at 
least 90 days after the last dose of axitinib or for at least 30 days after last dose of avelumab 
and additionally whenever 1 menstrual cycle is missed or when potential pregnancy is 
otherwise suspected.  Additional pregnancy tests may also be undertaken if requested by 
IRBs/ECs or if required by local regulations.  In the case of a positive confirmed pregnancy, 
the patient will be withdrawn from administration of investigational product but should 
remain in the study.  See also Schedule of Activities.


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7.1.2. Contraceptive Check
Fertile male patients and female patients who are of childbearing potential, who are, in the 
opinion of the Investigator, sexually active and at risk for pregnancy with their partner(s), 
will need to affirm that they meet the criteria for correct use of 2 of the selected methods of 
contraception (at least one of which is considered to be highly effective with low user 
dependency as defined in Section 4.3.1).  The Investigator or his or her designee will discuss 
with the patient the need to use 2 contraception methods consistently and correctly and 
document such conversation in the patient’s chart.  In addition, the Investigator or his or her 
designee will instruct the patient to call immediately if one or both selected contraception 
methods are discontinued, or if pregnancy is known or suspected in the patient or the 
patient’s partner.  Patients who are, in the opinion of the Investigator, sexually active and at 
risk for pregnancy with their partner(s) must agree to use 2 methods of contraception (at least 
one of which is considered to be highly effective with low user dependency as defined in 
Section 4.3.1) throughout the study for at least 90 days after last dose of axitinib or at least 
30 days after the last dose of avelumab (90 days for male patients).  See Section 4.3.1 for 
more details.
7.1.3. Adverse Events
Assessment of adverse events will include the type, incidence, severity (graded by NCI 
CTCAE version 4.03), timing, seriousness, and relatedness.
7.1.4. Laboratory Safety Assessments
Hematology and blood chemistry will be drawn at the time points described in the Schedule 
of Activities and analyzed at local laboratories.  Laboratory safety assessments may also be 
performed when clinically indicated.  The required laboratory tests are listed in Table 7. 
Laboratory safety assessments must be performed and results reviewed by the treating 
physician prior to study treatment administration.


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Table 7.
Required Laboratory Tests
Hematology
Hemoglobin
Platelets
WBC
Absolute Neutrophils
Absolute Lymphocytes
Absolute Monocytes
Absolute Eosinophils
Absolute Basophils
Percentages allowed only if Absolute not available
Chemistry 
(*denotes core chemistry panel)
ALT
AST
Alkaline Phosphatase
Sodium*
Potassium
Magnesium
Chloride
Calcium
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
Urinalysis
Protein, glucose, blood
Pregnancy Tests
For female patients of childbearing potential, serum or urine
Thyroid Function Tests:
TSH, free T4
Coagulation Tests
PT or INR
Other Tests: 
ACTH, HBV, HCV serology
° For potential Hy's Law cases, in addition to repeating AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, 
prothrombin time (PT)/INR, alkaline phosphatase, total bile acids, and acetaminophen levels.
ACTH=adrenocorticotropic hormone, ALT=alanine aminotransferase, AST=aspartate aminotransferase, 
BUN=blood urea nitrogen, CRP=C-reactive protein, GGT=gamma-glutamyltransferase, HBV= hepatitis B 
virus, HCV= hepatitis C virus, INR=international normalized ratio, LDH=lactate dehydrogenase, 
TSH=thyroid-stimulating hormone, WBC=white blood cell


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7.1.5. Physical Examinations and Vital Signs
Patients will have a physical examination to include major body systems, supine or sitting 
blood pressure, pulse rate, body temperature, assessment of ECOG performance status, 
weight, and height (height will be measured at screening only) at the time points described in 
the Schedule of Activities. Blood pressure and pulse rate should be taken after the patient has 
been lying down or sitting quietly for at least 5 minutes. 
7.1.6. (12-Lead) Electrocardiogram Measurements
A standard 12-lead (with a 10-second rhythm strip) tracing will be used for all ECGs.  It is 
preferable that the machine used has a capacity to calculate the standard intervals 
automatically. 
A single ECG is to be performed at Screening, as clinically indicated and EOT.  Clinically 
significant abnormal findings in baseline ECGs will be recorded as medical history. If the 
QTc is prolonged (>500 msec, ie, CTCAE Grade 3), then a triplicate ECG (3 consecutive 
12-lead ECGs approximately 2 minutes apart) will be collected to confirm the original 
measurement.  If the mean QTc of the triplicate ECG is >500 msec then the ECGs will be 
re-evaluated by a qualified person at the site for confirmation as soon as the finding is made, 
including verification that the machine reading is accurate.  If manual reading verifies a QTc 
of >500 msec, immediate correction for reversible causes (including electrolyte 
abnormalities, hypoxia and concomitant medications for drugs with the potential to prolong 
the QTc interval) should be performed.  In addition, single ECGs should be repeated hourly 
for at least 3 hours until the QTc interval falls below 500 msec.  If QTc interval reverts to 
less than 500 msec, and in the judgment of the investigator(s) and sponsor is determined to 
be due to cause(s) other than investigational product, treatment may be continued with 
regular ECG monitoring as clinically indicated.  If in that timeframe the QTc intervals rise 
above 500 msec the investigational product will be held until the QTc interval decreases to 
500 msec.  If the QTc interval has still not decreased to <500 msec after 2-weeks, or if at
any time a patient has a QTc interval >515 msec or becomes symptomatic, the patient will be 
removed from the study.
Each episode of prolongation of the QTc interval will be evaluated by a specialist to 
determine if due to the investigational product or due to other potential precipitating factors 
(eg, change in patient clinical condition, effect of concurrent medication, electrolyte 
disturbance).
If a patient experiences any cardiac or neurologic AEs (especially syncope, dizziness, 
seizures, or stroke), an ECG in triplicate should be obtained at the time of the event. 
7.1.7. Left Ventricular Ejection Fraction by MUGA Scan or Echocardiogram
For the evaluation of LVEF, both MUGA and Echocardiogram are acceptable.  The same 
technique used at screening must be consistently used for the following assessments 
throughout the study. Please see Schedule of Activities. 


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7.2. Pharmacokinetics Assessments
7.2.1. Blood Sample Collection for Pharmacokinetic Analysis
Blood samples will be collected for PK analysis of avelumab and axitinib into the appropriate 
tubes as outlined in the Schedule of Activities, Section 7.2.2 and Section 7.2.3.  PK sampling 
schedule may be modified based on emerging PK data.  Blood for PK samples will be drawn 
from the arm contralateral to the drug infusion. 
All efforts will be made to obtain the PK samples at the scheduled nominal time relative to 
dosing.  However, with the exception of samples where nominal time coincides with end of 
infusion, samples obtained within ±10% of the nominal time (eg, within 3 minutes of a 
30 minute sample) will not be captured as a protocol deviation, as long as the exact time of 
the sample collection is noted on the source document and data collection tool (eg, CRF).  
For samples where nominal time coincides with end of infusion, a sample collected within 
10 min post end of infusion will not be captured as a protocol deviation.  If the infusion of 
avelumab is interrupted due to AE, any PK samples scheduled during the time of the dosing 
interruption are not required.  If a scheduled blood sample collection cannot be completed for 
any reason, the missed sample time may be re-scheduled with agreement of clinical 
investigators, patient and Sponsor.
•
Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site prior to initiation of the trial.
•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
The samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulted in compromised 
sample integrity, will be considered a protocol deviation.
 
 
 
 
7.2.2. Collection of Axitinib Pharmacokinetic Samples
At each time point for axitinib, a 3 mL whole blood sample will be collected into an
appropriately labeled K3EDTA (tripotassium edetic acid [ethylenediaminetetraacetic acid])
tube to provide a minimum of 1 mL plasma for axitinib PK analysis.
C
C
I


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7.2.3. Collection of Avelumab Pharmacokinetic Samples
A 3.5 mL whole blood sample will be collected into a Serum Separator Tube (SST) at the 
designated times to provide serum for avelumab PK analysis.  Pre-dose samples can be taken
up to 2 hours prior to the start of avelumab infusion.
7.3. Immunogenicity Assessment
Blood samples (3.5 mL whole blood) will be collected for assessment of avelumab ADAs 
into an appropriately labeled SST.  Predose ADA samples will be collected within 2 hours 
prior to dosing.  Further details can be found in the Lab Manual.  This assessment will take 
place at regular intervals during the treatment and follow-up periods as described in the 
Schedule of Activities. 
A tiered ADA testing strategy will be used: all samples that are positive in the screening 
assay will be confirmed for antibody specificity.  Confirmed positive samples will be further 
characterized for titer and tested in the NAb assay, if appropriate.
•
Details regarding the collection, processing, storage and shipping of the blood 
samples will be provided to the investigator site prior to initiation of the trial.
•
Samples will be analyzed using a validated analytical method in compliance with 
Pfizer standard operating procedures.
•
The samples must be processed and shipped as indicated to maintain sample integrity.  
Any deviations from the processing steps (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulted in compromised 
sample integrity, will be considered a protocol deviation.
7.4. Translational and Pharmacodynamic Assessments
Whole blood samples 
 
one 10 mL, red-top serum Becton Dickinson (BD) Vacutainer® tube for serum 
preparation) will be collected at the designated times for secondary 
 
assessments which may include immune repertoire analysis, and/or epigenetic or proteomic 
profiles, unless prohibited by local regulation or by decision of the IRB or EC.  
 
CCI
CCI
CCI
CCI


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Unless prohibited by local regulations or ethics committee decision, a saliva sample will be 
collected on Cycle 1, Day 1 before the first dose of study drug treatment to be used as a 
germline control to assist in identifying and profiling tumor mutations. 
7.4.1. Archived Tumor Biospecimens and De Novo Tumor Biopsies
Archived tumor tissue samples and de novo biopsies of primary and/or 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.
Markers that may be analyzed include, but may not necessarily be limited to, the 
presence/absence of tumor-infiltrating CD8+ T lymphocytes and/or expression of PD-L1, 
within the tumor microenvironment and tumor mutational burden.
CCI
CCI


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7.6. Tumor Assessments 
The decision for body areas to be scanned will depend on the disease under study and the 
extent of disease.  Tumor assessments must include all known or suspected disease sites.  
The minimum recommended body areas to be scanned depending upon malignancy are 
detailed in the Imaging Manual. 
Baseline scans must be performed within 28 days prior to first dose of study drug. 
Anti-tumor activity will be assessed through radiological tumor assessments conducted at 
baseline, then every 8 weeks from first dose of study drug for 1 year from start of study 
treatment, and then every 12 weeks thereafter until PD regardless of discontinuation of study 
treatment or initiation of subsequent anti-cancer therapy, as specified in the Schedule of 
Activities. In addition, radiological tumor assessments will be conducted whenever PD is 
suspected (eg, symptomatic deterioration). 
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The schedule of tumor assessments should be fixed according to the calendar regardless of 
treatment schedule or treatment delays or interruptions due to toxicity. 
Imaging may include chest, abdomen and pelvis computed tomography (CT) or magnetic 
resonance imaging (MRI) scans. 
Brain CT or MRI scans are required at baseline for all patients with stable brain lesions and 
for those for whom brain metastasis is suspected.  If stable brain metastases are present at 
baseline, brain imaging should be repeated at each tumor assessment.  Otherwise, brain 
imaging will be conducted post- baseline only when clinically indicated.
Bone imaging using bone scan (bone scintigraphy) (preferred method) or other methods 
considered standard of care locally such as 18-fluorodeoxyglucose positron emission 
tomography (18F-FDG-PET/CT) or CT or MRI is required at baseline.  Bone lesion(s) 
identified at baseline by bone scan will be further assessed by diagnostic CT or MRI as per 
local practice (where bone scans are not used as a routine restaging tool) and subsequently 
re-assessed by diagnostic CT or MRI as per the tumor assessment schedule as an alternative 
to bone scans.  Bone scans will only be repeated during study as clinically indicated 
(ie, patient describes new or worsening bone pain, or has increasing alkaline phosphatase 
level or other signs and symptoms of new/progressing bone metastases), at the time of
confirmation of CR, and at every other tumor assessment visit (ie, every 16 weeks during the 
first 12 months of study treatment and every 32 weeks thereafter) if considered local standard 
of care.
The CT and MRI scans should be performed with contrast agents unless contraindicated for 
medical reasons.  The same imaging technique used to characterize each identified and 
reported lesion at baseline will be employed in the following tumor assessments.
Assessment of response will be made using RECIST v1.1 (Appendix 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.
In case CR or PR is observed, tumor assessments must be confirmed on repeated imaging at 
least 4 weeks after initial documentation.  If radiologic imaging shows PD, then the tumor 
assessment should be repeated after at least 4 weeks to confirm PD.  See Section 5.5.3 for 
treatment after initial evidence of PD.  If the patient begins a new anti-cancer therapy prior to 
confirmation of PD, then the confirmatory assessment is not required. 
All patients’ files and radiologic images must be available for source verification and for 
potential peer review.  All radiographic images will be collected and stored by an 
independent third-party imaging laboratory, according to instructions in the Imaging Manual. 
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8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy, 
exposure via breastfeeding, 
occupational exposure 
(regardless of whether 
associated with an AE)
All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and illnesses, must be provided.  In the case of a 


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patient death, a summary of available autopsy findings must be submitted as soon as possible 
to Pfizer Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
8.1.1. Additional Details On Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study patient.  In addition, each study patient will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Patient 
Withdrawal Section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a patient withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each patient begins from the time the patient provides informed consent, which 
is obtained before the patient’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 90 calendar days after the last administration of the investigational product.
For patients who are screen failures, the active collection period ends when screen failure 
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8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a patient during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a patient after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, SAEs occurring during the above-indicated 
active collection period must still be reported to Pfizer Safety irrespective of any intervening 
treatment.
8.1.4.2. Recording Non-Serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
If a patient begins a new anti-cancer therapy, the recording period for non-serious AEs ends 
at the time the new treatment is started; however, SAEs must continue to be recorded on the 
CRF during the above-indicated active collection period.
Death must be reported if it occurs during the SAE reporting period after the last dose of
study drug, irrespective of any intervening treatment.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE; generally the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 


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In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study 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 signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

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 recorded as AEs 
in the appropriate section of the CRF.  Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as AEs.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention; 
and/or

Test result leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
recording as an AE.
8.2.3. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the patient or may require intervention to prevent one of the other AE outcomes, the 
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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Progression of the malignancy under study (including signs and symptoms of progression) 
should not be reported as an SAE unless the outcome is fatal within the active collection 
period.  Hospitalization due to signs and symptoms of disease progression should not be 
reported as an SAE.  If the malignancy has a fatal outcome during the study or within the 
active collection period, then the event leading to death must be recorded as an AE on the 
CRF, and as an SAE with Common Terminology Criteria for Adverse Events (CTCAE) 
Grade 5 (see the Severity Assessment section).
8.2.4. 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 is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating clinical 
AE is not in itself an SAE. Examples include:

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, patient has no place to sleep);

Administrative admission (eg, for yearly physical examination);


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
Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual patient;

Admission exclusively for the administration of blood products.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
GRADE
Clinical Description of Severity
0 
No change from normal or reference range (This grade is not included in the 
Version 4.03 CTCAE document but may be used in certain circumstances.)
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the patient's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol-Specified Serious Adverse Events
There are no protocol-specified SAEs in this study.  All SAEs will be reported to Pfizer 
Safety by the investigator as described in previous sections, and will be handled as SAEs in 
the safety database. 


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8.4.2. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some patients, transaminase elevations are a harbinger of a more 
serious potential outcome.  These patients fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Patients who experience a transaminase elevation above 3 times the upper limit of 
normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the patient’s 
individual baseline values and underlying conditions.  Patients who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Patients with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available;

For patients with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 


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The patient should return to the investigator 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 
In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a co-formulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.3. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.3.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product.


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
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 

If a patient or patient’s partner becomes or is found to be pregnant during the 
patient’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must 
submit information regarding environmental exposure to a Pfizer product in a 
pregnant woman (eg, a patient reports that she is pregnant and has been exposed to a 
cytotoxic product by inhalation or spillage) to Pfizer Safety using the EDP 
supplemental form.  This must be done irrespective of whether an AE has occurred 
and within 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 Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
pre-procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion.

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 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.


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
Additional information regarding the EDP may be requested by the sponsor.  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 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.
8.4.3.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.3.3. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a patient enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.4. Medication Errors 
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
8.4.4.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong patient, or at the wrong time, or at the wrong dosage strength. 


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Medication errors include:

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.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by Pfizer.  
This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint and/or its analysis will also be reflected in a protocol 
amendment.
This section describes the data analysis and statistical methods for the combination of 
avelumab and axitinib.
9.1. Analysis Sets
9.1.1. Full Analysis Set
The full analysis set includes all patients who receive at least 1 dose of study treatment.
9.1.2. Safety Analysis Set
The safety analysis set includes all patients who receive at least 1 dose of study treatment.  In 
this non-randomized study, the full analysis set and the safety analysis set are identical.
9.1.3. Pharmacokinetics Analysis Set
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration above the lower limit of quantitation 
(LLQ) for avelumab or axitinib.
The PK parameter analysis set is a subset of the safety analysis set and will include treated 
patients who have at least one of the PK parameters of interest for avelumab or axitinib.


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9.1.4. Immunogenicity Analysis Set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose ADA/NAb sample collected for avelumab.
9.1.5. Biomarker Analysis Set
The biomarker analysis set is a subset of the safety analysis set and will include patients who 
have at least one baseline biomarker assessment. Analysis sets will be defined separately for 
blood-based and tumor tissue-based biomarkers.
9.2. Sample Size Determination
The primary objective is to assess the ORR of avelumab in combination with axitinib in 
patients with advanced or metastatic NSCLC who have received at least one prior 
platinum-containing therapy and in treatment naïve patients with advanced or metastatic UC, 
who are ineligible for cisplatin-containing chemotherapy for their advanced disease.
Approximately 40 patients will be enrolled from each of 2 tumor type cohorts: NSCLC, and 
UC.  Thus, a total of approximately 80 patients will be enrolled. 
With 40 treated patients per tumor type cohort, ORR can be estimated with a maximum 
standard error of 0.079.  Assuming a beta (0.5, 0.5) prior,

NSCLC cohort: if 15 responders (out of 40 patients, ORR of 37.5%) are observed, the 
probability of a true ORR 30% (considered a clinically relevant effect above 
single-agent checkpoint inhibition,39-43 [Section 1.2.2]) will be 80% (85.0%). 

UC cohort: if 19 responders (out of 40 patients, ORR of 47.5%) are observed, the 
probability of a true response rate 40% (considered a clinically relevant effect above 
single-agent checkpoint inhibition25,26 [Section 1.2.1]) will be 80% (83.4%). 
Table 8 provides the exact 95% confidence intervals for ORR based on different observed 
number of responders in a given tumor type cohort.


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Table 8.
Sample Size and Exact 95% CI for ORR
Number of Patients
Number of Responders
Observed ORR
Exact 95% CI for ORR
40
4
10.0%
(2.8% - 23.7%)
6
15.0%
(5.7% - 29.8%)
8
20.0%
(9.1% - 35.6%)
10
25.0%
(12.7% - 41.2%)
12
30.0%
(16.6% - 46.5%)
14
35.0%
(20.6% - 51.7%)
16
40.0%
(24.9% - 56.7%)
18
45.0%
(29.3% - 61.5%)
20
50.0%
(33.8% - 66.2%)
24
60.0%
(43.3% - 75.1%)
28
70.0%
(53.5% - 83.4%)
CI=confidence interval; ORR=objective response rate.
9.3. Efficacy Analysis 
All efficacy analyses will be performed based on the full analysis set for each tumor type 
cohort separately.
9.3.1. Analysis of the Primary Endpoint
The primary endpoint is confirmed OR based on Investigator assessment per RECIST v1.1. 
OR is defined as a CR or PR per RECIST v 1.1 from the first dose of study treatment until 
disease progression 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.  ORR 
is defined as the proportion of patients with a confirmed CR or confirmed PR based on 
Investigator’s assessment per RECIST v 1.1.  Confirmed responses are those that persist on 
repeat tumor assessments for at least 4 weeks after initial documentation or response.  
Otherwise, the patient will be counted as a non-responder in the assessment of ORR.  
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 assessment of 
ORR.  The two-sided exact 95% CIs for ORR will be calculated.
9.3.2. Analysis of the Secondary Efficacy Endpoints
PFS is defined as the time from first dose of study treatment (ie, start date) to the date of 
disease progression by RECIST v 1.1 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 an adequate baseline tumor assessment or who do not have any adequate 
post-baseline tumor assessments will be censored on the date of first dose of study treatment 
unless death occurred on or before the time of the second planned tumor assessment in which 
case the death will be considered an event.


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TTR is defined for patients with confirmed objective response (CR or PR) as the time from 
the first dose of study treatment to the first documentation of objective tumor response.
DR is defined for patients with confirmed objective response (CR or PR) as the time from the 
first documentation of objective tumor response to the first documentation of objective tumor 
progression or to death due to any cause, whichever occurs first.
OS is defined as the time from the first dose of study treatment to the date of death.  Patients 
without an event (death) will be censored at the date of last contact.
TTR will be summarized using simple descriptive statistics (eg, median and range).  DR, 
PFS, and OS will be analyzed using Kaplan-Meier methods.  Point estimates will be 
presented with 95% CIs.  In addition, progression date, death date, date of first response, and 
last tumor assessment date will be listed, along with BOR, TTR, DR, PFS and OS.
9.4. Analysis of Pharmacokinetics and Pharmacodynamics
9.4.1. Analysis of Pharmacokinetics of Investigational Products
PK data analyses will include descriptive summary statistics (n, mean, SD, coefficient of 
variation (CV), median, minimum, maximum, geometric mean and its associated CV) of the 
pre-dose trough (Ctrough) and post-dose (Cmax) concentrations for each investigational product 
by cycle, day and by dose level.
Other PK parameters may be determined if deemed appropriate.  The summary data may be 
compared with the historical data of avelumab and axitinib as single agents to assess the 
effect of avelumab on the PK of axitinib and the effect of axitinib on the PK of avelumab.  
The analysis and population modeling analysis report (PMAR), if performed, will be outlined 
in the statistical analysis plan (SAP).
The trough concentrations for avelumab and axitinib will be plotted versus time for each dose 
using a box whisker plot by cycle and day in order to assess the attainment of steady state.
9.4.2. Population Pharmacokinetic Analysis or Pharmacokinetic/Pharmacodynamic 
(PK/Pharmacodynamic) Modeling
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab and axitinib exposure and biomarkers or significant safety 
endpoints.  The results of these analyses, if performed, may be reported separately.
9.4.3. Analysis of Immunogenicity Data of Avelumab
ADA and NAb data will be listed and summarized for each dosing interval for avelumab.  
The percentage of patients with positive ADA and NAb will each be summarized by cohort 
and for all cohorts combined.  For patients with positive ADA, the magnitude (titer), time of 
onset, and duration of ADA response will also be described, if data permit.  The effect of 
ADA on avelumab concentrations and pharmacokinetics will be evaluated, if data permit.


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9.5. Analyses for Secondary 
 Biomarker Endpoints
For continuous measurement biomarker results, summary statistics (eg, the mean, standard 
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate.  
Appropriate change from baseline measurements will be provided.
For discrete measurement biomarkers (eg, tumor marker status), frequencies and percentages 
of categorical biomarker measures will be determined at baseline and on-treatment/end of 
treatment time points.  Shift tables may also be provided.
Data from biomarker assays may be analyzed using graphical methods and descriptive 
statistics such as Fisher’s exact test, Wilcoxon rank-sum test, Kaplan-Meier estimates, and 
linear regression as appropriate.  The statistical approaches will explore the correlations of 
biomarker results with pharmacokinetic parameters and measures of anti-tumor efficacy, 
such as tumor response and progression free survival.
9.6. Safety Analysis
9.6.1. Adverse Events
AEs will be graded by the investigator according to the CTCAE version 4.03 and coded 
using the Medical Dictionary for Regulatory Activities (MedDRA).  The focus of AE 
summaries will be on Treatment Emergent Adverse Events, those with initial onset or 
increasing in severity after the first dose of study treatment.  The number and percentage of 
patients who experienced any AE, SAE, treatment-related AE, and treatment-related SAE 
will be summarized according to worst toxicity grades. 
9.6.2. Laboratory Test Abnormalities
The laboratory results will be graded according to the CTCAE version 4.03 severity grade 
whenever applicable.  The number and percentage of patients who experienced laboratory 
test abnormalities will be summarized according to worst toxicity grade observed for each 
laboratory test.
For laboratory tests without CTCAE grade definitions, results will be categorized as normal, 
abnormal, or not done.
Shift tables will be provided to examine the distribution of laboratory toxicities.
9.6.3. Electrocardiogram
Baseline ECG measurements will be summarized by tumor type cohort.  Interval 
measurements from clinically indicated on-treatment ECGs will be included in the outlier 
analysis (categorical analysis) as individual values obtained at unscheduled time points.
QT intervals will be corrected for heart rate (QTc) using standard correction factors 
[ie, Fridericia’s (default correction), Bazett’s, and possibly a study specific factor, as 
appropriate].  Data will be summarized and listed for QT, HR, RR, PR, QRS, and QTc. 
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Descriptive statistics (n, mean, median, standard deviation, minimum, and maximum) will be 
used to summarize the absolute corrected QT interval.
9.7. 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. 
9.8. Interim Analysis
No formal interim analysis will be conducted for this study.  However, as this is an 
open-label, non-randomized study, the Sponsor may conduct unblinded reviews of the data 
during the course of the study for the purpose of efficacy and safety assessment, facilitating 
PK/Pharmacodynamic modeling, and/or to support clinical development.
9.9. Data Monitoring Committee
An external independent Data Safety Monitoring Committee will not be established for the 
study.  For the purpose of this protocol, Pfizer procedures for periodic safety review will be 
applied by an internal safety review team with medical and statistical capabilities to review 
individual and summary data collected in the safety and clinical databases.  Procedures 
include:

Surveillance for SAEs according to regulatory guidelines;

Discussions between the investigators and the sponsor of AEs and laboratory tests 
alterations seen at each dose level will be performed in an ongoing manner at regular 
teleconferences and/or meetings to determine the safety profile and risk/benefit ratio 
and decide if further enrollment is appropriate.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 


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


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


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


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


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


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Galsky MD, Hahn NM, Rosenberg J, et al.  A consensus definition of patients with 
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randomised phase 3 trial. Lancet 2014;384 (9944):665-73.


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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.
From: Oken MM, Creech RH, Tormey DC et al.  Toxicity and response criteria of the 
Eastern Cooperative Oncology Group.  Am J Clin Oncol.  1982; 5: 649–655.


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Appendix 2. 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


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


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
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.


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


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
Normal nodes: Nodes with short axis <10 mm are considered normal and should not 
be recorded or followed either as measurable or non-measurable disease.
RECORDING TUMOR ASSESSMENTS 
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate. 
Target lesions
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, 
representative of all involved organs, should be identified as target lesions at baseline.  
Target lesions should be selected on the basis of size (longest lesions) and suitability for 
accurate repeated measurements.  Record the longest diameter for each lesion, except in the 
case of pathological lymph nodes for which the short axis should be recorded.  The sum of 
the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions 
at baseline will be the basis for comparison to assessments performed on study. 
If two target lesions coalesce the measurement of the coalesced mass is used.  If a large target 
lesion splits, the sum of the parts is used.
Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise a default value of 5 mm should be recorded.
NOTE: When nodal lesions decrease to <10 mm (normal), the actual measurement 
should still be recorded.
Non-target disease 
All non-measurable disease is non-target.  All measurable lesions not identified as target 
lesions are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT 
INCREASED, INCREASED.  Multiple non-target lesions in one organ may be recorded as a 
single item on the case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple 
liver metastases’).
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION 
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case 
must be discussed with the radiologist to determine if substitution is possible.  If not, 
subsequent objective statuses are indeterminate. 


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Target disease

Complete Response (CR): Complete disappearance of all target lesions with the 
exception of nodal disease.  All target nodes must decrease to normal size (short axis 
<10 mm).  All target lesions must be assessed.

Partial Response (PR): Greater than or equal to 30% decrease under baseline of the 
sum of diameters of all target measurable lesions.  The short diameter is used in the 
sum for target nodes, while the longest diameter is used in the sum for all other target 
lesions.  All target lesions must be assessed. 

Stable: Does not qualify for CR, PR or Progression.  All target lesions must be 
assessed.  Stable can follow PR only in the rare case that the sum increases by less 
than 20% from the nadir, but enough that a previously documented 30% decrease no 
longer holds. 

Objective Progression (PD): 20% increase in the sum of diameters of target 
measurable lesions above the smallest sum observed (over baseline if no decrease in 
the sum is observed during therapy), with a minimum absolute increase of 5 mm. 

Indeterminate.  Progression has not been documented, and 

One or more target measurable lesions have not been assessed; 
or

Assessment methods used were inconsistent with those used at baseline;
or

One or more target lesions cannot be measured accurately (eg, poorly visible 
unless due to being too small to measure);
or

One or more target lesions were excised or irradiated and have not reappeared or 
increased. 
Non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker 
levels.  All lymph nodes must be ‘normal’ in size (<10 mm short axis).

Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level 
above the normal limits. 


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
PD: Unequivocal progression of pre-existing lesions.  Generally the overall tumor 
burden must increase sufficiently to merit discontinuation of therapy.  In the presence 
of SD or PR in target disease, progression due to unequivocal increase in non-target 
disease should be rare. 

Indeterminate: Progression has not been determined and one or more non-target sites 
were not assessed or assessment methods were inconsistent with those used at 
baseline.
New Lesions 
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example due to its small size, continued assessment will clarify the etiology.  
If repeat assessments confirm the lesion, then progression should be recorded on the date of 
the initial assessment.  A lesion identified in an area not previously scanned will be 
considered a new lesion.
Supplemental Investigations
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR.
If progression determination depends on a lesion with an increase possibly due to necrosis, 
the lesion may be investigated with biopsy or fine needle aspirate to clarify status. 
Objective/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. 
When both target and non-target lesions are present, individual assessments will be recorded 
separately.  Determination of tumor response at each assessment is summarized in table 
Table 9.


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Table 9.
Objective Response Status at each Evaluation
Target Lesions
Non-Target Lesions
New Lesions
Tumor Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Indeterminate or 
Missing
No
PR
PR
Non-CR/Non-PD,
Indeterminate or 
Missing 
No
PR
SD
Non-CR/Non-PD, 
Indeterminate or 
Missing
No
SD
Indeterminate or 
Missing
Non-PD
No
Indeterminate
PD
Any response
Yes or No
PD
Any response
PD
Yes or No
PD
Any response
Any response
Yes
PD
Determination of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest sum on study).  
For CR and PR, the patient’s best response assignment will depend on the achievement of 
both measurement 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 study entry at a minimum interval of 8 weeks.


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Appendix 6. Abbreviations 
This following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
ACTH
adrenocorticotropic hormone
ADA
anti-drug antibody
ADL
activities of daily living
AE
adverse event
AHFS
American Hospital Formulary Service
ALK
Anaplastic lymphoma kinase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASHP
American Society of Hospital Pharmacists
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
Area under the curve
BD
Becton Dickinson
BID
twice daily
BNP
B-type natriuretic peptide
BOR
best overall response
BP
blood pressure 
BUN
blood urea nitrogen
CG
Cockcroft-Gault
CI
confidence interval
CK
creatine kinase
CPK
creatinine phosphokinase
CR
complete response
CRF
case report form
CRP
C-reactive protein
CRPC
castration resistant prostate cancer
CSA
clinical study agreement
CSF
cerebrospinal fluid
CSR
clinical study report
CT
computed tomography
CTA
clinical trial application
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T lymphocyte-associated protein 4
CT SAE 
Clinical Trial Serious Adverse Event
CV
coefficient of variation
CYP
Cytochrome P450
DHP
dihydropyridine 
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Abbreviation
Term
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DR
duration of response
DU
Dispensable unit
EC
ethics committee
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
ESMO
European Society for Medical Oncology
EU
European Union
EudraCT
European Clinical Trials Database
FDG-PET
fluorodeoxyglucose positron emission tomography
FDA
Food and Drug Administration
FGFR
fibroblast growth factor receptor
FSH
follicle-stimulating hormone
FFPE
formalin-fixed and paraffin-embedded
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GH
growth hormone
GITR
glucocorticoid induced tumor necrosis factor receptor 
GMP
Good Manufacturing Practice
GVHD
graft versus host disease
GU
genitourinary
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HDPE
high-density polyethylene 
HR
hazard ratio
IB
Investigator brochure
ICH
International Conference on Harmonisation
ID
identification
IERC
Independent Endpoint Review Committee 
Ig
immunoglobulin
IHC
immunohistochemistry
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
ir
immune related
irAE
immune-related adverse event


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Abbreviation
Term
IRB
institutional review board
IRR
infusion-related reaction
IRT
interactive response technology
IUD
intrauterine device
IV
intravenous
JM
juxta membrane 
K3EDTA
tripotassium ethylenediaminetetraacetic acid
LAG-3
lymphocyte activation gene-3
LDH
lactate dehydrogenase
LFT
liver function test
LH
luteinizing hormone
LSLV
last subject last visit
LLN
lower limit of normal
LLQ
lower limit of quantitation 
LSLV
last patient last visit 
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MCC
Merkel Cell Carcinoma
MedDRA
Medical Dictionary for Regulatory Activities
MET
mesenchymal-epithelial transition factor 
MMP
matrix metalloproteinase
MRI
magnetic resonance imaging
MTD
Maximum tolerated dose
MUGA
multigated acquisition
N/A
not applicable
NAb
Neutralizing Antibody
NCI
National Cancer Institute
NR
Not reached
NSAIDs
nonsteroidal anti-inflammatorydrugs
NSCLC
Non-Small Cell Lung Cancer
OR
objective response
ORR
objective response rate
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Abbreviation
Term
OS
overall survival
PCD
primary completion date
PD
progressive disease
PFS
progression free survival 
PD-1
Programmed Death-1
PDGFR
Platelet-Derived Growth Factor Receptor
PD-L1
Programmed Death-Ligand 1
PI
principal investigator
PK
pharmacokinetic
PMAR
population modeling analysis report 
PO
per Os (by mouth)
PR
partial response
PS
Performance status
PT
prothrombin time
PTs
preferred terms
Q2W
every 2 weeks 
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumor
RNA
ribonucleic acid
ROS1
c-ros oncogene 1
RP2D
recommended Phase 2 dose
RR
Response rate
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOA
schedule of activities
SRSD
single reference safety document
SST
serum separator tube
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
TCC
Transitional cell carcinoma
TEAE
treatment emergent adverse event
TIM-3
T cell immunoglobulin and mucin domain
TKI
tyrosine kinase inhibitor
TNF
Tumor necrosis factor
TO
Target occupancy
TRAE
Treatment related adverse events
TSH
thyroid stimulating hormone
TTP
time to progression
TTR
time to response
UC
urothelial cancer
ULN
upper limit of normal


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Abbreviation
Term
US
United States
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor
VTE
vascular thrombotic events
WBC
white blood cell
WHO
World Health Organization

SAP_001.pdf: 
Avelumab
B9991027 (MSB0010718C, AG-013736) Statistical Analysis Plan    
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A PHASE 2, OPEN LABEL STUDY TO EVALUATE SAFETY AND CLINICAL 
ACTIVITY OF AVELUMAB (BAVENCIO) IN COMBINATION WITH AXITINIB
(INLYTA) IN PATIENTS WITH ADVANCED OR METASTATIC PREVIOUSLY
TREATED NON-SMALL CELL LUNG CANCER OR TREATMENT NAÏVE
CISPLATIN-INELIGIBLE UROTHELIAL CANCER
JAVELIN MEDLEY VEGF
STATISTICAL ANALYSIS PLAN – B9991027
Compounds:
MSB0010718C
AG-013736
Compound Name:
Avelumab
Axitinib
Version:
3.0
Date:
15-Dec-2020
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................5
LIST OF FIGURES ...................................................................................................................6
APPENDICES ...........................................................................................................................6
1. VERSION HISTORY............................................................................................................7
2. INTRODUCTION .................................................................................................................9
2.1. Study Objectives .......................................................................................................9
2.2. Study Design ...........................................................................................................10
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................10
3.1. Primary Endpoint ....................................................................................................10
3.2. Secondary Endpoints...............................................................................................11
3.2.1. Safety endpoints..........................................................................................11
3.2.2. Efficacy endpoints ......................................................................................11
3.2.3. Pharmacokinetic endpoints.........................................................................11
3.2.4. Immunogenicity endpoints .........................................................................12
3.2.5. Biomarker endpoints...................................................................................12
3.4. Baseline Variables...................................................................................................12
3.4.1. Study drug, study treatment and baseline definitions.................................12
3.4.2. Baseline characteristics...............................................................................13
3.5. Safety Endpoints .....................................................................................................13
3.5.1. Adverse events............................................................................................13
4. ANALYSIS SETS ...............................................................................................................14
4.1. Full Analysis Set .....................................................................................................14
4.2. Safety Analysis Set..................................................................................................14
4.3. Other Analysis Set...................................................................................................14
4.3.1. PK analysis sets ..........................................................................................14
4.3.2. Biomarker analysis set................................................................................14
4.3.3. Immunogenicity analysis set.......................................................................15
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................15
5.1. Hypotheses and Decision Rules ..............................................................................15
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5.1.1. Hypotheses and sample size determination................................................15
5.1.2. Decision rules .............................................................................................16
5.2. General Methods .....................................................................................................16
5.2.1. Data handling after the cut-off date............................................................16
5.2.2. Pooling of centers .......................................................................................16
5.2.3. Presentation of continuous and qualitative variables..................................16
5.2.4. Definition of study day...............................................................................17
5.2.5. Definition of start of new anti-cancer drug therapy....................................17
5.2.6. Definition of start of new anti-cancer therapy............................................17
5.2.7. Definition of on-treatment period...............................................................18
5.2.8. Standard derivations and reporting conventions.........................................18
5.2.9. Unscheduled visits......................................................................................18
5.2.10. Adequate baseline tumor assessment........................................................19
5.2.11. Adequate post-baseline tumor assessment................................................19
5.3. Methods to Manage Missing Data ..........................................................................19
5.3.1. Missing data................................................................................................19
5.3.1.1. Pharmacokinetic concentrations................................................19
5.3.1.2. Pharmacokinetic parameters .....................................................20
5.3.2. Handling of incomplete dates .....................................................................20
5.3.2.1. Disease history ..........................................................................20
5.3.2.2. Adverse events ..........................................................................20
5.3.2.3. Prior and concomitant medications...........................................21
5.3.2.4. Exposure....................................................................................21
5.3.3. Imputation rules for date of last contact and efficacy assessments ............22
5.3.3.1. Date of last contact....................................................................22
5.3.3.2. Death date..................................................................................22
5.3.3.3. Tumor assessments....................................................................22
5.3.3.4. Date of start of new anti-cancer therapy ...................................23
6. ANALYSES AND SUMMARIES ......................................................................................25
6.1. Primary Endpoint ....................................................................................................25
6.1.1. Objective response as assessed by the Investigator per RECIST v1.1.......25
6.1.1.1. Primary analysis ........................................................................25
6.2. Secondary Endpoints...............................................................................................26


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6.2.1. Safety endpoints..........................................................................................26
6.2.2. Efficacy endpoints ......................................................................................26
6.2.2.1. Tumor shrinkage from baseline.................................................27
6.2.2.2. Duration of response .................................................................27
6.2.2.3. Time to response .......................................................................29
6.2.2.4. Progression-free survival...........................................................29
6.2.2.5. Overall Survival ........................................................................31
6.2.3. Pharmacokinetic endpoints.........................................................................32
6.2.4. Population pharmacokinetic endpoints.......................................................33
6.2.5. Biomarker endpoints...................................................................................33
6.2.6. Endpoints for immunogenicity data of avelumab.......................................34
6.2.6.1. Time to and Duration of ADA and nAb response.....................36
6.2.6.2. ADA titer...................................................................................37
6.2.6.3. Analysis of PK and safety by immunogenicity status...............37
6.4. Subset Analyses.......................................................................................................39
6.5. Baseline and Other Summaries and Analyses.........................................................40
6.5.1. Baseline summaries ....................................................................................40
6.5.1.1. Demographic characteristics .....................................................40
6.5.1.2. Medical history..........................................................................41
6.5.1.3. Disease characteristics...............................................................41
6.5.1.4. Prior anti-cancer therapies.........................................................42
6.5.2. Study conduct and patient disposition........................................................43
6.5.2.1. Patient disposition .....................................................................43
6.5.2.2. Protocol deviations....................................................................43
6.5.3. Study treatment compliance and exposure .................................................44
6.5.3.1. Exposure to avelumab ...............................................................44
6.5.3.2. Exposure to axitinib ..................................................................45
6.5.3.3. Dose reductions.........................................................................46
6.5.3.4. Dose escalations ........................................................................46
6.5.3.5. Dose interruptions .....................................................................46
6.5.3.6. Dose delays ...............................................................................46
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6.5.3.7. Infusion rate reductions.............................................................47
6.5.3.8. Infusion interruptions ................................................................47
6.5.4. Concomitant medications and non-drug treatments ...................................47
6.5.5. Subsequent anti-cancer therapies................................................................48
6.6. Safety Summaries and Analyses .............................................................................48
6.6.1. Adverse events............................................................................................48
6.6.1.1. All adverse events .....................................................................49
6.6.1.2. Adverse events leading to dose reduction.................................50
6.6.1.3. Adverse events leading to interruption of study treatment .......51
6.6.1.4. Adverse events leading to discontinuation of study 
treatment............................................................................................51
6.6.2. Deaths .........................................................................................................52
6.6.3. Serious adverse events................................................................................52
6.6.4. Other significant adverse events.................................................................53
6.6.5. Laboratory data...........................................................................................53
6.6.5.1. Hematology and chemistry parameters.....................................53
6.6.5.2. Other laboratory parameters......................................................56
6.6.6. Vital signs...................................................................................................56
6.6.7. Electrocardiogram.......................................................................................56
6.6.8. MUGA/ECHO............................................................................................56
7. INTERIM ANALYSES.......................................................................................................57
7.1. Introduction .............................................................................................................57
7.2. Interim Analyses and Summaries............................................................................57
8. REFERENCES ....................................................................................................................58
9. APPENDICES .....................................................................................................................59
LIST OF TABLES
Table 2.
PK Parameters to be Determined for Avelumab and Axitinib .................11
Table 3.
Biomarker Definition and Determination.................................................12
Table 4.   
Sample Size and Exact 95% CI for ORR .................................................15
Table 5.
Outcome and Event Dates for DR Analyses.............................................28
Table 6.
DR Censoring Reasons and Hierarchy .....................................................29
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Table 7.
Outcome and Event Dates for PFS Analyses ...........................................30
Table 8.
PFS Censoring Reasons and Hierarchy....................................................31
Table 9.
OS Censoring Reasons and Hierarchy......................................................32
Table 10 
Patients Characterized Based on Anti-Drug Antibody Results 
(ADA Status) ............................................................................................35
Table 11 
Patients Characterized Based on Neutralizing Antibody Results 
(nAb Status)..............................................................................................36
Table 12.  
Case Definition for irAEs .........................................................................59
Table 13.  
Case Definition for IRRs – IV Study Drugs Administered Alone Or 
In Combination With Non-IV Study Drugs..............................................61
LIST OF FIGURES
Figure 1.
Study Design Schema...............................................................................10
APPENDICES
Appendix 1. Immune-Related Adverse Events........................................................................59
Appendix 2. Infusion Related Reactions .................................................................................61


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1. VERSION HISTORY
This Statistical Analysis Plan (SAP) for study B9991027 is based on the protocol amendment 
1 dated 07MAR2018 and Protocol Administrative Change Letters dated 01JUN2018 and 
14DEC2018.  
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2. INTRODUCTION
This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in study B9991027.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment.
Statistical analyses will be performed using cleaned eCRF data as well as non-CRF data (ie,
pharmacokinetics data, immunogenicity data, and biomarker data).  The primary (also the 
final) analysis of the data will be performed after last patient last visit (LPLV). 
Additional analyses of the data may be performed for publication or regulatory reporting 
purposes.
2.1. Study Objectives
Primary Objective
To evaluate the Objective Response Rate (ORR) based on Investigator assessment, per 
Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 of avelumab in 
combination with axitinib in patients with advanced or metastatic non-small cell lung cancer 
(NSCLC) who have received at least one prior platinum-containing therapy and in treatment 
naïve patients with advanced or metastatic urothelial cancer (UC), who are ineligible for 
cisplatin-containing chemotherapy for their advanced disease.
Secondary Objectives
To evaluate the following in patients with advanced or metastatic NSCLC who have received 
at least one prior platinum-containing therapy and in treatment naïve patients with advanced 
or metastatic UC, who are ineligible for cisplatin-containing chemotherapy for their 
advanced disease:
•
The safety and tolerability of avelumab in combination with axitinib;
•
The anti-tumor activity of avelumab in combination with axitinib;
•
The pharmacokinetics (PK) of avelumab and axitinib when administered in combination;
•
Candidate predictive and/or early response biomarkers in pre-treatment tumor tissue and 
pre- and post-treatment blood samples that may aid in the identification of a patient 
subpopulation most likely to benefit from treatment with avelumab in combination with 
axitinib. Assessments may include but are not limited to tumor mutational burden,
immune repertoire and PD-L1 expression within the tumor microenvironment;
•
The immunogenicity of avelumab when combined with axitinib.
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2.2. Study Design
This is an open-label, multi-center, Phase 2 study to evaluate the safety and efficacy of 
avelumab in combination with axitinib in patients with advanced or metastatic NSCLC who 
have received at least one prior platinum-containing therapy, and in patients with advanced 
or metastatic UC, who are treatment naïve and ineligible for cisplatin-containing 
chemotherapy for their advanced disease.
Patients will receive avelumab 800 mg intravenous (IV) every 2 weeks (Q2W) on Days 1 and 
15 of each 28-day cycle in combination with axitinib 5 mg by mouth (PO) twice daily (BID) 
on a continuous dosing schedule.    
Approximately 40 patients will be enrolled in each cohort, NSCLC and UC (Figure 1).   
Figure 1.
Study Design Schema 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint
•
Confirmed Objective Response (OR) based on Investigator assessment per RECIST v1.1.
OR is defined as complete response (CR) or partial response (PR) according to RECIST 
v1.1 from the date of first dose of study treatment until the date of the first documentation
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of progressive disease (PD). Both CR and PR must be confirmed by repeat assessments 
performed no less than 4 weeks after the criteria for response are first met.
3.2. Secondary Endpoints
3.2.1. Safety endpoints

Adverse events (AEs) as characterized by type, severity as graded by National Cancer
Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v4.03, 
timing, seriousness, and relationship to study treatments;
AEs will be graded by the investigator according to the CTCAE v4.03 and coded using 
the Medical Dictionary for Regulatory Activities (MedDRA)

Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE 
v4.03) and timing.
3.2.2. Efficacy endpoints

Time-to-event endpoints including time to tumor response (TTR), duration of response 
(DR), progression-free survival (PFS) based on Investigator assessment per RECIST
v1.1, and overall survival (OS).
DR is defined, for patients with OR, as the time from the first documentation of objective 
response (CR or PR) to the date of first documentation of PD or death due to any cause.  
TTR is defined, for patients with an OR, as the time from the date of first dose of study 
treatment to the first documentation of objective response (CR or PR) which is
subsequently confirmed. 
PFS is defined as the time from the date of first dose of study treatment to the date of the 
first documentation of PD or death due to any cause, whichever occurs first.
OS is defined as the time from the date of first dose of study treatment to the date of 
death due to any cause.
3.2.3. Pharmacokinetic endpoints

Pharmacokinetic parameters including trough and maximum concentrations (Ctrough, Cmax)
of avelumab and axitinib.
Pharmacokinetic parameters (Cmax and Ctrough after single dose and at steady state). 
Table 2.
PK Parameters to be Determined for Avelumab and Axitinib
Parameter
Definition
Method of Determination
Cmax
Maximum observed plasma concentration 
Observed directly from data
Ctrough
Pre-dose observed plasma concentration 
Observed directly from data
Cmax(dn)
Dose normalized Cmax for axitinib
Cmax / Dose
Ctrough(dn)
Dose normalized Ctrough for axitinib
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3.2.4. Immunogenicity endpoints
•
Anti-drug antibody (ADA) titers and neutralizing antibodies (nAb) against avelumab.
3.2.5. Biomarker endpoints
•
Tumor tissue biomarker status (ie, positive or negative based on, for example, PD-L1
expression and/or quantitation of tumor mutational burden as well as characterization of 
the immune repertoire in peripheral blood and/or tumor).
Table 3.
Biomarker Definition and Determination
Parameter
Definition
Method of Determination
PD-L1 expression
Assessment of the proportion (%) of tumor 
cells and immune cells displaying PD-L1 
staining of any intensity within the tumor 
microenvironment
Pathologist, assisted by image 
analysis
Immune repertoire
Determination of the identity and abundance 
of individual T cell clones in peripheral blood 
and/or tumor tissue samples at baseline and
on-treatment 
TCR sequencing
Tumor mutational 
burden
Determination/estimation of the frequency of 
mutations (total and non-synonymous) present 
in baseline tumor derived nucleic acid 
samples
Whole exome or genome 
sequencing and/or RNAseq
3.4. Baseline Variables
3.4.1. Study drug, study treatment and baseline definitions
In this study, ‘study drug’ refers to avelumab or axitinib and ‘study treatment’ (or 
‘treatment group’) refers to one of the following:
•
NSCLC Cohort: avelumab 800 mg IV Q2W plus axitinib 5 mg PO BID;
•
UC Cohort: avelumab 800 mg IV Q2W plus axitinib 5 mg PO BID.
Start and end dates of study treatment:
The date/time of first dose of study treatment in a combination group is the earliest date/time 
of the first non-zero dose date/time for the study drugs in the combination. 
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The date/time of last dose of study treatment in a combination group is the latest date/time of 
the last non-zero dose date/time for the study drugs in the combination.
Definition of baseline: 
Definition of baseline for efficacy analyses and for safety analyses
The last available assessment prior to the start of study treatment is defined as ‘baseline’
value or ‘baseline’ assessment for safety and efficacy analyses.  If an assessment is planned 
to be performed prior to the first dose of study treatment in the protocol and the assessment is 
performed on the same day as the first dose of study treatment, it will be assumed that it was 
performed prior to study treatment administration, if assessment time point is not collected or 
is missing. If assessment time points are collected, the observed time point will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be 
used in the determination of baseline. However, if time is missing, an unscheduled 
assessment on study day 1 will be considered to have been obtained after study treatment 
administration.
Patients who start treatment and discontinue from the study on the same day may have two 
different sets of data collected on study day 1 (one during study and one in the End of 
Treatment (EOT) visit. Data reported at the EOT visit are not eligible for baseline selection. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
Definition of baseline for immunogenicity analyses
The last available assessment prior to the start of treatment with avelumab is defined as 
‘baseline’ result or ‘baseline’ assessment.  If an assessment is planned to be performed prior 
to the first dose of avelumab in the protocol and the assessment is performed on the same day 
as the first dose of avelumab, it will be assumed that it was performed prior to avelumab 
administration, if assessment time point is not collected or is missing.
3.4.2. Baseline characteristics
Baseline characteristics (including demographics, disease history and prior anti-cancer 
therapies) are described in Section 6.5.1.  These baseline characteristics are not planned to be 
included as stratification variables or covariates in statistical models unless otherwise 
specified in Section 6. 
3.5. Safety Endpoints
3.5.1. Adverse events
Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
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On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day). The start day of new anti-cancer drug therapy after the first dose of study treatment is 
derived as outlined in Section 5.2.5.
Adverse Events of Special Interest (AESIs)
AESIs are immune-related adverse events (irAE) and infusion-related reactions (IRRs).  The 
criteria for classification of an AE as an irAE or IRR are described in Appendix 1 and 
Appendix 2, respectively.
4. ANALYSIS SETS
Data for all patients will be assessed to determine if patients meet the criteria for inclusion in 
each analysis population prior to releasing the database and classifications will be 
documented per Pfizer’s standard operating procedures.
Only patients who signed informed consent will be included in the analysis sets below.
4.1. Full Analysis Set
The FAS will include all patients who receive at least one dose of study drug.  Patients will 
be classified according to the study treatment actually received.  If a patient receives more 
than one treatment the patient will be classified according to the first study treatment 
received. 
4.2. Safety Analysis Set
The safety analysis set will include all patients who receive at least one dose of study drug.  
Patients will be classified according to the study treatment actually received.  If a patient 
receives more than one study treatment, the patient will be classified according to the first
study treatment received. In this non-randomized study, the FAS and the safety analysis set 
are identical. 
4.3. Other Analysis Set
4.3.1. PK analysis sets
The PK concentration analysis set is a subset of the safety analysis set and will include 
patients who have at least one post-dose concentration measurement above the lower limit of 
quantitation (LLQ) for avelumab or axitinib. 
The PK parameter analysis set is a subset of the safety analysis set and will include patients 
who have at least one of the PK parameters of interest for avelumab or axitinib.
4.3.2. Biomarker analysis set 
Biomarker analysis set is a subset of the safety analysis set and will include patients who 
have at least one baseline biomarker assessment. Analysis sets will be defined separately for 
blood-based and tumor tissue-based biomarkers.


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4.3.3. Immunogenicity analysis set
The immunogenicity analysis set is a subset of the safety analysis set and will include 
patients who have at least one ADA/nAb assessment collected for avelumab.
5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
5.1.1. Hypotheses and sample size determination
There is no formal hypothesis testing in this study.  Approximately 40 patients will be 
enrolled from each of 2 tumor type cohorts: NSCLC, and UC. Thus, a total of approximately 
80 patients will be enrolled. Within each treatment group, ORR will be estimated and the 2-
sided exact 95% confidence intervals (CIs) will be calculated.
With 40 treated patients per tumor type cohort, ORR can be estimated with a maximum 
standard error of 0.079. Further, assuming beta (0.5, 0.5) prior:

NSCLC Cohort: if 15 responders (out of 40 patients, ORR of 37.5%) are observed, the 
probability of a true ORR ≥ 30% (considered a clinically relevant effect above single-
agent checkpoint inhibition) will be ≥80% (85.0%). 

UC Cohort: if 19 responders (out of 40 patients, ORR of 47.5%) are observed, the 
probability of a true response rate ≥ 40% (considered a clinically relevant effect above 
single-agent checkpoint inhibition) will be ≥80% (83.4%).   
Table 4 provides the exact 95% CI for ORR based on different observed number of 
responders in a given tumor type cohort.
Table 4.   Sample Size and Exact 95% CI for ORR
Number of Patients 
Number of Responders
Observed ORR
Exact 95% CI for 
ORR
40
4
10.0%
( 2.8% - 23.7%)
6
15.0%
( 5.7% - 29.8%)
8
20.0%
( 9.1% - 35.6%)
10
25.0%
(12.7% - 41.2%)
12
30.0%
(16.6% - 46.5%)
14
35.0%
(20.6% - 51.7%)
16
40.0%
(24.9% - 56.7%)
18
45.0%
(29.3% - 61.5%)
20
50.0%
(33.8% - 66.2%)
24
60.0%
(43.3% - 75.1%)
28
70.0%
(53.5% - 83.4%)
CI=confidence interval; ORR=objective response rate.


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5.1.2. Decision rules
There are no formal decision rules in this study.
5.2. General Methods
As described in Section 3.4.1, in this study ‘treatment group’ (ie, cohort) refers to one of 
the following:

NSCLC Cohort: avelumab 800 mg IV Q2W plus axitinib 5 mg PO BID;

UC Cohort: avelumab 800 mg IV Q2W plus axitinib 5 mg PO BID.
Baseline characteristics, disposition and efficacy data will be summarized based on the FAS 
by treatment group.
Other safety data, exposure data, concomitant medications and non-drug treatments will be 
summarized based on the safety analysis set by treatment group. 
PK data will be summarized based on the PK analysis set by treatment group and for all 
treatment groups combined.
Biomarker data will be summarized based on the biomarker analysis set by treatment group.
Immunogenicity data will be summarized based on the immunogenicity analysis set by 
treatment group and for all treatment groups combined.
5.2.1. Data handling after the cut-off date
Data after the cut-off date may not undergo the cleaning process and will not be displayed in 
any listings or used for summary statistics, statistical analyses or imputations.
5.2.2. Pooling of centers
In order to provide overall estimates of treatment effects, data will be pooled across centers.  
The ‘center’ factor will not be considered in statistical models or for subgroup analyses due 
to the high number of participating centers in contrast to the anticipated small number of 
patients treated at each center.
5.2.3. Presentation of continuous and qualitative variables
Continuous variables will be summarized using descriptive statistics ie, number of non-
missing values and number of missing values [ie, n (missing)], mean, median, standard 
deviation (SD), minimum, maximum and first and third quartile (Q1 and Q3).
Qualitative variables will be summarized by frequency counts and percentages. Unless 
otherwise specified, the calculation of proportions will include the missing category. 
Therefore, counts of missing observations will be included in the denominator and presented 
as a separate category.


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In case the analysis refers only to certain visits, percentages will be based on the number of 
patients still present in the study at that visit, unless otherwise specified.
5.2.4. Definition of study day
Start day of study treatment is the day of the first dose of study treatment.
The study day for assessments occurring on or after the start of study treatment (eg, adverse 
event onset, tumor measurement) will be calculated as:
Study day = Date of the assessment/event - start of study treatment + 1. 
The study day for assessments occurring prior to the first dose of study treatment (eg,
baseline characteristics, medical history) will be negative and calculated as:
Study day = Date of the assessment/event - start of study treatment.
The study day will be displayed in all relevant data listings.
5.2.5. Definition of start of new anti-cancer drug therapy
Start date of new anti-cancer drug therapy is used to determine the end of the on-treatment 
period (see Section 5.2.7).
The start date of new anti-cancer drug therapy is the earliest start date of anti-cancer drug 
therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF pages that is after the first dose of 
study treatment. When start date of anti-cancer drug therapy is missing or partially missing, 
the imputation rules described in Section 5.3.3.4 should be applied using only data from the 
‘Follow-up Cancer Therapy’ eCRF pages.
5.2.6. Definition of start of new anti-cancer therapy
Start date of new anti-cancer therapy (drug, radiation, surgery) is used for censoring in 
efficacy analyses (see Section 6.1.1 and Section 6.2.2).
The start date of new anti-cancer therapy is the earliest date after the first dose of study 
treatment amongst the following:

Start date of anti-cancer drug therapy recorded in the ‘Follow-up Cancer Therapy’ eCRF 
pages

Start date of radiation therapy recorded in ‘Concomitant Radiation Treatment’, and 
‘Follow-up Radiation Treatment’ eCRF pages with ‘Treatment Intent’ = ‘Curative in 
intent’ 

Surgery date recorded in ‘On-Study Anti-Cancer Surgery’, and ‘Follow-up Anti-Cancer 
Surgery’ eCRF pages when ‘Surgery Outcome’ = ‘Resected’ or ‘Partially Resected’.  
When start date of anti-cancer therapy is missing or partially missing, the imputation rules
described in Section 5.3.3.4 should be applied using ‘Follow-up Cancer Therapy’, 


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‘Concomitant Radiation Treatment’, ‘Follow-up Radiation Treatment’, ‘On-Study Anti-
Cancer Surgery’, and ‘Follow-up Anti-Cancer Surgery’ eCRF pages.
5.2.7. Definition of on-treatment period
Safety endpoints will be summarized based on the on-treatment period unless otherwise 
specified.
On-treatment period is defined as the time from the first dose of study treatment through 
minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy –
1 day).
Safety data collected outside the on-treatment period as described above will be listed and 
flagged in listings but not summarized.
5.2.8. Standard derivations and reporting conventions
The following conversion factors will be used to convert days into weeks, months or years:   
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
Demographics and physical measurements:

Age [years]: 
-
(date of given informed consent - date of birth + 1) / 365.25
-
In case of missing day, day only: Age [years]: (year/month of given informed consent 
– year/month of birth)
-
In case only year of birth is given: Age [years]: (year of given informed consent -
year of birth)
The integer part of the calculated age will be used for reporting purposes. 
For reporting conventions, mean and median should generally be displayed one more 
decimal place than the raw data and standard deviation should be displayed to two more 
decimal places than the raw data. Percentages will be reported to one decimal place. The 
rounding will be performed to closest integer / first decimal using the common mid-point
between the two consecutive values. Eg, 5.1 to 5.4 will be rounded to an integer of 5, and 5.5 
to 5.9 will be rounded to an integer of 6.
5.2.9. Unscheduled visits
Generally, data collected at unscheduled visits will be included and analyzed for both safety 
and efficacy analyses in the same fashion as the data collected at scheduled visits except 
where otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, 
minimum, maximum, quartiles) by nominal visit or time point for safety endpoints such as 
laboratory measurements, ECGs and vital signs will include only data from scheduled visits
(if such analyses are performed).


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5.2.10. Adequate baseline tumor assessment
Adequate baseline is defined using the following criteria:

All baseline assessments must be within 31 days prior to and including the date of first 
dose of study treatment.

All documented lesions must have non-missing assessments (ie, non-missing 
measurements for target lesions and non-missing lesions assessment status at baseline for 
non-target lesions).
5.2.11. Adequate post-baseline tumor assessment
An adequate post-baseline assessment is defined as an assessment where a response of CR, 
PR, SD, non-CR/non-PD, or PD can be determined (see Section 6.1.1.1).  Time points where 
the response is not evaluable (NE) or no assessment was performed will not be used for 
determining the censoring date.
5.3. Methods to Manage Missing Data
5.3.1. Missing data
Unless otherwise specified, all data will be evaluated as observed, and no imputation method 
for missing values will be used.
In all patient data listings imputed values will be presented.  In all listings imputed 
information will be flagged.
Missing statistics, eg when they cannot be calculated, should be presented as ‘ND’ or ‘NA’.  
For example, if N=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘ND’ or ‘NA’. 
5.3.1.1. Pharmacokinetic concentrations
Concentrations Below the Limit of Quantification
For all calculations, figures and estimation of individual pharmacokinetic parameters, all 
concentrations assayed as below the level of quantification (BLQ) will be set to zero. In log-
linear plots these values will not be represented. The BLQ values will be excluded from 
calculations of geometric means and their CIs. A statement similar to ‘All values reported as 
BLQ have been replaced with zero’ should be included as a footnote to the appropriate tables 
and figures.
Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, concentrations will be set to missing if one 
of the following cases is true:
1. A concentration has been reported as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged as anomalous by the clinical pharmacologist.


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Summary statistics will not be presented at a particular time point if more than 50% of the 
data are missing.  For analysis of pharmacokinetic concentrations, no values will be imputed 
for missing data.
5.3.1.2. Pharmacokinetic parameters
Whether actual or nominal PK sampling time will be used for the derivation of PK 
parameters will be determined by the results of interim PK analyses.  If a PK parameter is 
missing, the parameter will be coded as NC (ie, not calculated).  NC values will not be 
generated beyond the day that a patient discontinues.
In summary tables, statistics will be calculated by setting NC values to missing. Statistics 
will not be presented for a particular treatment if more than 50% of the data are NC.  For 
statistical analyses (ie, analysis of variance), PK parameters coded as NC will also be set to 
missing.
If an individual patient has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this will be footnoted in summary tables and will not 
be included in the calculation of summary statistics or statistical analyses.
5.3.2. Handling of incomplete dates
5.3.2.1. Disease history
Incomplete dates for disease history (eg, initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows:

If the day is missing, it will be imputed to the 15th day of the month. 

If both day and month are missing and the year is prior to the year of the first study 
treatment, the month and day will be imputed as July 1st.

If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st. 

If the date is completely missing, no imputation will be performed.
5.3.2.2. Adverse events
Incomplete AE-related dates will be imputed as follows:

If the AE onset date is missing completely, then the onset date will be replaced by the 
start of study treatment.

If only the day part of the AE onset date is missing, but the month and year are equal to 
the start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start 
date is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015.

If both the day and month of the AE onset date are missing but the onset year is equal to 
the start of study treatment, then the onset date will be replaced by the start of study 


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treatment. For example, if AE onset date is --/---/2014, and study treatment start date is 
19/NOV/2014, then the imputed AE onset date will be 19/NOV/2014.

In all other cases the missing onset day or missing onset month will be replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete stop date will not be imputed.  If stop date of AE is after 
the date of cut-off outcome of AE is ongoing at cut-off. 
5.3.2.3. Prior and concomitant medications
Incomplete prior/concomitant medication dates will be imputed as follows:

If the medication date is missing completely, then the medication date will be replaced by 
the start of study treatment.

If the day of medication date is missing, but the month and year are equal to the start of 
study treatment, then the medication date will be replaced by the start of study treatment. 
For example, if the medication start date is --/JAN/2015, and study treatment start date is 
15/JAN/2015, then the imputed medication start date will be 15/JAN/2015. 

If both the day and month of medication start date are missing but the start year is equal 
to the start of study treatment, then the medication date will be replaced by the start of 
study treatment. For example, if the medication start date is --/---/2014, and study 
treatment start date is 19/NOV/2014, then the imputed medication start date will be 
19/NOV/2014.

In all other cases the missing medication day or missing medication month will be 
replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case the 
date of death will be used to impute the incomplete stop date. 

In all other cases the incomplete medication stop date will not be imputed. 
5.3.2.4. Exposure
No imputation will be done for first dose date.  Date of last dose of study drug, if unknown or 
partially unknown, will be imputed as follows:

If the last date of study drug is completely missing and there is no End of Treatment 
eCRF page and no death date, the patient should be considered to be ongoing and use the 
cut-off date for the analysis as the last dosing date

If the last date of study drug is completely or partially missing and there is EITHER an 
End of Treatment eCRF page OR a death date available (within the cut-off date), then 
imputed last dose date is:
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date) 


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= Last day of the month, if both Year and Month are available and Year = Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date)
= min (EOT date, death date), for all other cases.
5.3.3. Imputation rules for date of last contact and efficacy assessments
5.3.3.1. Date of last contact
The date of last contact will be derived for patients not known to have died at the analysis 
cut-off using the latest complete date among the following:

All patient assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments)

Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation

AE start and end dates

Last date of contact collected on the ‘Survival Follow-up’ eCRF (do not use date of 
survival follow-up assessment unless status is ‘alive’)

Study drug start and end dates

Withdrawal of consent date

Date of discontinuation on disposition eCRF pages (do not use if reason for 
discontinuation is lost to follow-up).
Only dates associated with actual examinations of the patient will be used in the derivation.  
Dates associated with a technical operation unrelated to patient status such as the date a 
blood sample was processed will not be used. Assessment dates after the cut-off date will not 
be applied to derive the last contact date.
5.3.3.2. Death date
Missing or partial death dates will be imputed based on the last contact date:

If the date is missing it will be imputed as the day after the date of last contact 

If the day or both day and month is missing, death will be imputed to the maximum of the 
full (non-imputed) day after the date of last contact and the following:
-
Missing day:
1st day of the month and year of death
-
Missing day and month:
January 1st of the year of death
5.3.3.3. Tumor assessments
All investigation dates (eg, X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, ie, radiological assessments 
occur over a series of days rather than the same day, the choice of date of assessment could 
impact the date of progression and/or date of response.  If there are multiple scan dates 


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associated with an evaluation, the earliest of the scan dates associated with the evaluation 
will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the
assessment date and assessment date is calculated as the earliest of all investigation dates (eg,
X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and the 
following assessment. If both a previous and following assessments are not available, this 
assessment will not be used for any calculations.
5.3.3.4. Date of start of new anti-cancer therapy
Incomplete dates for start date of new anti-cancer therapy (drug therapy, radiation, surgery) 
will be imputed as follows and will be used for determining censoring dates for efficacy
analyses and in the derivation of the end of on-treatment period.  PD date below refers to PD 
date by investigator assessment.

The end date of new anti-cancer therapy will be included in the imputations for start date 
of new anti-cancer therapy.  If the end date of new anti-cancer therapy is
o
completely missing then it will be ignored in the imputations below
o
partially missing with only year (YYYY) available then the imputations below will 
consider 31DECYYYY as the end date of the new anti-cancer therapy
o
partially missing with only month and year available then the imputations below will 
consider the last day of the month for MMMYYYY as the end date of the new anti-
cancer therapy

For patients who have not discontinued study treatment at the analysis cut-off date, last 
dose of study treatment is set to the analysis cut-off date in the imputations below. 

If the start date of new anti-cancer therapy is completely or partially missing, then the 
imputed start date of new anti-cancer therapy is derived as follows:
o
Start date of new anti-cancer therapy is completely missing
Imputed start date = min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
o
Only year (YYYY) for start of anti-cancer therapy is available
IF YYYY < Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy] THEN imputed start date = 31DECYYYY; 
ELSE IF YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 


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THEN imputed start date = min [max (PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy]
ELSE IF YYYY > Year of min [max (PD date + 1, last dose of study treatment + 1), 
end date of new anti-cancer therapy] 
THEN imputed start date = 01JANYYYY
o
Both Year (YYYY) and Month (MMM) for start of anti-cancer therapy are available
IF
YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM < Month of min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM = Month of min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy]);
ELSE IF
YYYY = Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy], AND
MMM > Month of min [max (PD date + 1 day, last dose of study treatment + 1 
day), end date of new anti-cancer therapy] 
THEN 
imputed start date = 01 MMM YYYY;
ELSE IF
YYYY < Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]
THEN 
imputed start date = DAY (Last day of MMM) MMM YYYY;
ELSE IF
YYYY > Year of min [max (PD date + 1, last dose of study treatment + 1), end 
date of new anti-cancer therapy]


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THEN 
imputed start date = 01 MMM YYYY.
6. ANALYSES AND SUMMARIES
Refer to Section 4 for definitions of analysis sets and Section 5.2 for general methodology. 
6.1. Primary Endpoint
6.1.1. Objective response as assessed by the Investigator per RECIST v1.1 
6.1.1.1. Primary analysis
The following analyses will be based on the FAS by treatment group.   Assessment of 
response will be made using RECIST v1.1.  Assessments below refer to investigator 
assessment.  
Best overall response (BOR) will be assessed based on reported overall lesion responses at 
different evaluation time points from the date of first dose of study treatment until the first 
documentation of PD, according to the following rules. Only tumor assessments performed 
on or before the start date of any further anti-cancer therapies will be considered in the 
assessment of BOR.  Clinical deterioration will not be considered as documentation of
disease progression.
BOR Based on Confirmed Responses:

CR = at least two determinations of CR at least 4 weeks apart and before first 
documentation of PD

PR = at least two determinations of PR or better (PR followed by PR or PR followed by 
CR) at least 4 weeks apart and before first documentation of PD (and not qualifying for a 
CR) 

SD (applicable only to patients with measurable disease at baseline) = at least one SD 
assessment (or better) ≥ 6 weeks after the date of first dose of study treatment and before 
first documentation of PD (and not qualifying for CR or PR).

Non-CR/non-PD (applicable only to patients with non-measurable disease at baseline) = 
at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after the date of first dose 
of study treatment and before first documentation of PD (and not qualifying for CR or 
PR).

PD = first documentation of PD ≤ 12 weeks after the date of first dose of study treatment
(and not qualifying for CR, PR, SD or non-CR/non-PD).

NE:  all other cases.
An objective status of PR or SD cannot follow one of CR.  SD can follow PR only in the 
rare case that tumor increases by less than 20% from the nadir, but enough that a previously 
documented 30% decrease from baseline no longer holds.  If this occurs, the sequence PR-


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SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best 
response of SD if the window for SD definition has been met.
Objective Response (OR) is defined as confirmed BOR of CR or PR according to RECIST 
v1.1.
Patients who do not have a post-baseline radiographic tumor assessment due to early 
progression, who receive anti-cancer therapies other than the study treatments prior to 
reaching a CR or PR, or who die, progress, or drop out for any reason prior to reaching a CR 
or PR will be counted as non-responders in the assessment of OR. Each patient will have an 
objective response status (0: no OR; 1: OR).  OR rate (ORR) is the proportion of patients 
with OR in the analysis set.
ORR by treatment group will also be calculated along with the 2-sided 95% CI using the 
Clopper-Pearson method 2 (exact CI for a binomial proportion as computed by default by the 
FREQ procedure using the EXACT option). 
In addition, the frequency (number and percentage) of patients with a confirmed BOR of CR, 
PR, SD, non-CR/non-PD (applicable only to patients with non-measurable disease at 
baseline), PD, and NE will be tabulated. Patients with confirmed BOR of NE will be 
summarized by reason for having NE status. The following reasons will be used:

No baseline assessment 

No post-baseline assessments due to death (i.e., death prior to 8 weeks after first dose of 
study treatment)

No post-baseline assessments due to other reasons

All post-baseline assessments have overall response NE

New anti-cancer therapy started before first post-baseline assessment

SD of insufficient duration (<6 weeks after the date of first dose of study treatment
without further evaluable tumor assessments)

PD too late (>12 weeks after the date of first dose of study treatment)
Special and rare cases where BOR is NE due to both SD of insufficient duration and late PD 
will be classified as ‘SD too early’ (ie, SD of insufficient duration).
6.2. Secondary Endpoints
6.2.1. Safety endpoints
Refer to Section 6.6.
6.2.2. Efficacy endpoints
The following analyses will be based on the FAS by treatment group.   Assessment of 
response will be made using RECIST v1.1. Tumor-related endpoints will be analyzed based 
on investigator assessment.  


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6.2.2.1. Tumor shrinkage from baseline
Tumor shrinkage will be summarized as the percent change from baseline in target lesions 
(sum of longest diameter for non-nodal lesion and short axis for nodal lesion) per time point. 
It will be derived as:

((Sum of target lesions at week XX – sum of target lesions at baseline)/sum of target 
lesions at baseline) × 100
The maximum reduction in target lesions from baseline will be derived across all the post-
baseline assessments until documented disease progression, excluding assessments after start 
of subsequent anti-cancer therapy, as:

Minimum of ((sum of target lesions at week XX – sum of target lesions at baseline)/sum 
of target lesions at baseline) × 100
A waterfall plot of maximum percent reduction in the sum of longest diameter for non-nodal 
lesions and short axis for nodal lesions from baseline will be created by treatment group. 
These plots will display the best percentage change from baseline in the sum of the diameters
of all target lesions for each patient with measurable disease at baseline and at least one post-
baseline assessment.
6.2.2.2. Duration of response
Duration of Response (DR) is defined, for patients with OR, as the time from the first 
documentation of objective response (CR or PR) to the date of first documentation of PD or 
death due to any cause.  If a patient has not had an event (PD or death), DR is censored at the 
date of last adequate tumor assessment. The censoring rules for DR are as described in Table 
5.
DR (months) = [date of event or censoring– first date of OR +1]/30.4375


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Table 5.
Outcome and Event Dates for DR Analyses
Scenario
Date of event/censoring
Outcome
PD or death 
-
After at most one missing or inadequate 
post-baseline tumor assessment, OR
-
≤ 16 weeks after the date of first dose of 
study treatment
Date of PD or death
Event
PD or death 
-
After 2 or more missing or inadequate 
post-baseline tumor assessments
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored
No PD and no death
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments 
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived 
based on documented 
progression only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment a documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the first dose of study treatment; if the criteria were met the censoring will 
be on the first dose of study treatment.
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median DR time with 2-sided 
95% CIs.  In particular, the DR rates at 2, 4, 6, 8, 10, 12, 15, 18, and 24 months will be 
estimated with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982)1 and the CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc
LIFETEST) with back transformation to a CI on the untransformed scale. The estimate of the 
standard error will be computed using Greenwood’s formula.
DR will be displayed graphically and analyzed using Kaplan-Meier methodology. If the 
number of patients with OR is small, the Kaplan-Meier method may not provide reliable 
estimates.  In this case, only descriptive statistics or listings will be provided.
Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories in Table 6  following the hierarchy shown.


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Table 6.
DR Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
Start of new anti-cancer therapy   
Start of new anti-cancer therapy
2 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of randomization
Event after 2 or more missing 
assessments a
3
No event and [withdrawal of consent date ≥ date of 
randomization OR End of study (EOS) = Patient refused 
further follow-up] 
Withdrawal of consent
4
No event and lost to follow-up in any disposition page 
Lost to follow-up
5
No event and [EOS present OR disposition page for any 
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
6 
No event and none of the conditions in the prior hierarchy
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
6.2.2.3. Time to response
Time to response (TTR) is defined, for patients with OR, as the time from the date of first 
dose of study treatment to the first documentation of objective response (CR or PR) which is 
subsequently confirmed. 
TTR (in months) = [first date of OR – date of first dose of study treatment +1]/30.4375
TTR will be summarized using simple descriptive statistics (mean, SD, median, min, max. 
Q1, Q3).
6.2.2.4. Progression-free survival
Progression-free survival (PFS) is defined as the time from the date of first dose of study 
treatment to the date of the first documentation of PD or death due to any cause, whichever 
occurs first.   
PFS data will be censored on the date of the last adequate tumor assessment for patients who 
do not have an event (PD or death), for patients who start a new anti-cancer therapy prior to 
an event (see Section 5.2.6) or for patients with an event after 2 or more missing tumor 
assessments.   Patients who do not have an adequate baseline tumor assessment or who do 
not have an adequate post-baseline tumor assessment will be censored on the date of first 
dose of study treatment unless death occurred on or before the time of the second planned 
tumor assessment (ie ≤ 16 weeks after the date of first dose of study treatment) in which case 
the death will be considered an event. 
In this study antitumor activity will be assessed through radiological tumor assessments 
conducted at screening and every 8 weeks (± 7 days) for 1 year from start of study treatment, 
and then every 12 weeks (± 7 days) thereafter until PD regardless of discontinuation of study 
treatment or initiation of subsequent anti-cancer therapy.  


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The censoring and event date options to be considered for the PFS analysis are presented in
Table 7.  
PFS (months) = [date of event or censoring– date of first dose of study treatment +1]/30.4375
Table 7.
Outcome and Event Dates for PFS Analyses
Scenario
Date of event/censoring
Outcome
No adequate baseline assessment
Date of first dose of study 
treatment a
Censored a
PD or death 
-
After at most one missing or 
inadequate post-baseline tumor 
assessment, OR
-
≤16 weeks after the date of first dose 
of study treatment
Date of PD or death
Event
PD or death 
-
After 2 or more missing or 
inadequate post-baseline tumor 
assessments
Date of last adequate tumor 
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
No PD and no death
Date of last adequate tumor
assessment b documenting no PD 
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
Treatment discontinuation due to ‘Disease 
progression’ without documented progression
Not applicable
Information is ignored. 
Outcome is derived 
based on documented 
progression only.
New anti-cancer therapy given 
Date of last adequate tumor 
assessment b documenting no PD
before new anti-cancer therapy is 
given or missed tumor assessments
Censored
a However if the patient dies ≤16 weeks after the date of first dose of study treatment the death is an event with 
date on death date
b  If there are no adequate post-baseline assessments prior to PD or death, then the time without adequate 
assessment should be measured from the date of first dose of study treatment; if the criteria were met the 
censoring will be on the date of first dose of study treatment
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median PFS time with 2-sided 
95% CIs.  In particular, the PFS rates at 2, 4, 6, 8, 10, 12, 15, 18, and 24 months will be 
estimated with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated
according to Brookmeyer and Crowley (1982)1 and the CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc 
LIFETEST) with back transformation to a CI on the untransformed scale. The estimate of the 
standard error will be computed using Greenwood’s formula.  


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Frequency (number and percentage) of patients with each event type (PD or death) and 
censoring reasons will be presented by treatment group. Reasons for censoring will be 
summarized according to the categories Table 8 following the hierarchy shown.
Table 8.
PFS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No adequate baseline assessment
No adequate baseline assessment
2
Start of new anti-cancer therapy 
Start of new anti-cancer therapy
3 
Event after 2 or more missing or inadequate post-baseline 
tumor assessments/date of first dose of study treatment
Event after missing assessments a
4
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = Patient
refused further follow-up] 
Withdrawal of consent
5
No event and lost to follow-up in any disposition page 
Lost to follow-up
6
No event and [EOS present OR disposition page for any
epoch after screening says patient will not continue into 
any subsequent phase of the study] and no adequate post-
baseline tumor assessment 
No adequate post-baseline tumor 
assessment
7 
No event and none of the conditions in the prior hierarchy 
are met 
Ongoing without an event
a 2 or more missing or inadequate post-baseline tumor assessments.   
The PFS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for PFS
A plot will be generated to compare planned and actual relative day of tumor assessments by 
treatment group. A Kaplan-Meier plot for PFS follow-up duration will also be generated to 
assess the follow-up time in the treatment groups reversing the PFS censoring and event 
indicators, including the median time of follow-up for PFS with 2-sided 95% CIs.  
6.2.2.5. Overall Survival
Overall survival (OS) is defined as the time from the date of first dose of study treatment to 
the date of death due to any cause. Patients last known to be alive will be censored at date of 
last contact.
OS (months) = [date of death or censoring– date of first dose of study treatment +1]/30.4375
Kaplan-Meier estimates (product-limit estimates) will be presented by treatment group 
together with a summary of associated statistics including the median OS time with 2-sided 
95% CIs.  In particular, the OS rates at 2, 4, 6, 8, 10, 12, 15, 18, 24 and 30 months will be 
estimated with corresponding 2-sided 95% CIs.  The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982)1 and the CIs for the survival function 
estimates at the time points defined above will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option in SAS Proc 


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LIFETEST) with back transformation to a CI on the untransformed scale. The estimate of the 
standard error will be computed using Greenwood’s formula.  
Frequency (number and percentage) of patients with an event (death) and censoring reasons 
will be presented by treatment group. Reasons for censoring will be summarized according to 
the categories in Table 9 following the hierarchy shown.
Table 9.
OS Censoring Reasons and Hierarchy
Hierarchy
Condition
Censoring Reason
1
No event and [withdrawal of consent date ≥ date of first 
dose of study treatment OR End of study (EOS) = Patient
refused further follow-up] 
Withdrawal of consent
2
No event and [lost to follow-up in any disposition page OR 
data cut-off date – last contact date > 14 weeks] 
Lost to follow-up
3
No event and none of the conditions in the prior hierarchy 
are met 
Alive
The OS time or censoring time and the reasons for censoring will also be presented in a 
patient listing.
Time of Follow-Up for OS
A Kaplan-Meier plot for OS follow-up duration will also be generated to assess the follow-up 
time in the treatment groups reversing the OS censoring and event indicators, including the 
median time of follow-up for OS with 2-sided 95% CIs.  
6.2.3. Pharmacokinetic endpoints
The following pharmacokinetic analyses will be based on the PK analyses set by treatment 
group and for all patients.  
Pharmacokinetic parameters (Ctrough and Cmax) for avelumab and axitinib will be calculated 
from observed concentrations. Dose normalized concentrations (eg, CDN- Cmax, CDN-
Ctrough) for axitinib will be reported as appropriate. 
Presentation of pharmacokinetic data will include:

Pharmacokinetic plasma concentrations for avelumab and axitinib will be listed and 
summarized in tabular form by treatment group, cycle, study day and nominal time using 
descriptive statistics (n, mean, SD, %CV, median, minimum, maximum, geometric mean 
and its associated %CV, and 95% CI). For axitinib, if an intrapatient dose escalation or 
reduction occurs, dose-dependent PK parameters (Ctrough and Cmax) for that patient may be 
dose-normalized when the dose is confirmed within the linear range and other PK 
parameters will be reported as estimated; or may only be included in descriptive statistics 
and summary plots up to the time of the dose change. In addition, the dose-normalized 
axitinib Cmax and Ctrough parameter will be summarized (as described above).


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
Box plots for Ctrough and Cmax for avelumab and axitinib will be generated. Individual data 
points, the geometric mean and the median of the parameter in each treatment will be 
overlaid on the box plots. If a treatment group has limited evaluable PK data (n<4), 
matchstick plots showing changes in Ctrough and Cmax for each drug in individual patients 
will then be generated. The geometric mean of the parameter in each treatment will be 
overlaid in the plots. In addition, box plots for dose-normalized axitinib Cmax and Ctrough
parameters will be created using data pooled across treatment groups.

Ctrough and Cmax for avelumab will be plotted for each treatment group using a box-
whisker plot by cycle and day within cycle in order to assess the attainment of steady-
state.

Observed concentrations of avelumab and axitinib from this study may be compared with 
the historical observed concentrations when each drug is administered alone.
6.2.4. Population pharmacokinetic endpoints
Pharmacokinetic and pharmacodynamic data from this study may be analyzed using 
modeling approaches and may also be pooled with data from other studies to investigate any 
association between avelumab and axitinib exposure and biomarkers or significant 
safety/efficacy endpoints. The results of these analyses, if performed, may be reported 
separately.
6.2.5. Biomarker endpoints
Secondary biomarker endpoints include PD-L1 expression, tumor mutational burden, and 
immune repertoire in peripheral blood and/or tumor. 
Biomarker data will be analyzed based on the biomarker analysis sets as defined in Section 
4.3.2. Data will be presented by treatment group.
Biomarkers values at screening will be listed and summarized.
For these biomarker endpoints, patients may be classified as positive, negative, or some other 
category according to scoring algorithms and cut-offs established from internal or external 
sources. If no external standards exist, patients may be stratified using the median, quartiles 
and tertiles.  Patients whose status cannot be determined are not considered to have screening 
biomarker assessment per the biomarker analysis set definition, and therefore will be 
excluded from the analyses.   
For continuous measurement biomarker results, summary statistics (eg, the mean, standard
deviation, median, percent of coefficient of variation, and minimum/maximum levels) will be 
determined at baseline and on-treatment/end of treatment time points, as appropriate.
Appropriate change from baseline measurements will be provided.
For discrete measurement biomarker results (eg, tumor marker status), frequencies and
percentages of categorical biomarker measures will be determined at baseline and on-
treatment/end of treatment time points.  Shift tables may also be provided.


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Clinical responses will be summarized by treatment group and by biomarker status
following the methodology outlined in Section 6.1.1.1. The number of responders (patients 
with BOR of CR or PR) will be tabulated relative to biomarker classifications using a 
contingency table and a Fisher’s exact test will be performed.
DR, PFS and OS (if meaningful) will be summarized by treatment group and by biomarker 
status following the methodology outlined in Sections 6.2.2.2, 6.2.2.4 and 6.2.2.5.
6.2.6. Endpoints for immunogenicity data of avelumab 
All analyses described below are performed by treatment group and for all treatment groups 
combined. 
Blood samples for avelumab immunogenicity testing will be collected pre-dose on Cycle 1 
Day 1 and Day 15, Cycle 2 Day 1, and Day 15 of Cycles 3, 6, 9 and 12, as well as at the end 
of treatment and Day 30 follow-up visit. All samples should be drawn within 2 hours before 
start of avelumab infusion.
Samples positive for ADA will be analyzed for titer and may be analyzed for nAb.  The 
analyses of nAb data described in the following sections will be conducted contingent upon 
data availability at the time of reporting. 
Patients will be characterized into different ADA categories based on the criteria defined in 
Table 10.  


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Table 10
Patients Characterized Based on Anti-Drug Antibody Results (ADA Status)
Category
Definition
Patients at Risk (Denominator for 
Incidence)
ADA never-positive 
No positive ADA results at any time point; 
ADA-negative patients (titer < cutpoint)
Number of patients with at least one 
valid ADA result at any time point
ADA ever-positive 
At least one positive ADA result at any time 
point; ADA-positive patients (titer ≥ cutpoint)
Number of patients with at least one 
valid ADA result at any time point
Baseline ADA 
positive
A positive ADA result at baseline
Number of patients with valid baseline 
ADA result
Treatment-boosted 
ADA
A positive ADA result at baseline and the titer 
≥ 8×baseline titer at least once after treatment 
with avelumab
Number of patients with valid baseline 
ADA results and at least one valid 
post-baseline ADA result
Treatment-induced 
ADA
Patient is ADA-negative at baseline and has at 
least one positive post-baseline ADA result; or 
if patient does not have a baseline sample, the 
patient has at least one positive post-baseline 
ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Transient ADA 
response
If patients with treatment-induced ADA have (a 
single positive ADA result or duration between 
first and last positive result <16 weeks) and 
ADA result at the last assessment is not 
positive.
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
Persistent ADA 
response
If patients with treatment-induced ADA have 
duration between first and last positive ADA 
result ≥16 weeks or a positive ADA result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline ADA result 
(including missing, NR)
ADA: anti-drug antibody, NR = not reportable.
Patients will be characterized into different nAb categories based on the criteria in Table 11. 
For nAb, treatment-boosted is not applicable since no titer result is available.


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Table 11
Patients Characterized Based on Neutralizing Antibody Results (nAb 
Status)
Category
Definition
Patients at Risk (Denominator for 
Incidence)
nAb never-positive 
No positive nAb results at any time point
Number of patients with at least one 
valid ADA result at any time point
nAb ever-positive 
At least one positive nAb result at any time 
point
Number of patients with at least one 
valid ADA result at any time point
Baseline nAb 
positive
A positive nAb result at baseline
Number of patients with valid baseline 
ADA result
Treatment-induced
nAb
Patient is not nAb positive at baseline and has 
at least one positive post-baseline nAb result; 
or if patient does not have a baseline sample, 
the patient has at least one positive post-
baseline ADA result
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
Transient nAb 
response
If patients with treatment-induced nAb have (a 
single positive nAb result or duration between
first and last positive result <16 weeks) and 
nAb result at the last assessment is not
positive.
Number of patients with at least one 
ADA valid post-baseline result and 
without positive baseline nAb result 
(including missing, NR)
Persistent nAb 
response
If patients with treatment-induced nAb have 
duration between first and last positive nAb 
result ≥16 weeks or a positive nAb result at 
the last assessment
Number of patients with at least one 
valid post-baseline ADA result and 
without positive baseline nAb result 
(including missing, NR)
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result.
The number and percentage of patients in each ADA and nAb category will be summarized. 
6.2.6.1. Time to and Duration of ADA and nAb response 
The ADA and nAb analyses described below will include patients with treatment-induced 
ADA or nAb, respectively.  
Time (weeks) to ADA response is defined as:
(Date of first positive ADA result – date of first dose of avelumab + 1)/7. 
Time to ADA response will be summarized using simple descriptive statistics (mean, SD, 
median, min, max. Q1, Q3).
Duration (weeks) of ADA response is defined as:
(Date of last positive ADA result – date of first positive ADA result + 1)/7. 
Duration of ADA response will be censored if: 

the last ADA assessment is positive AND patient is ongoing treatment with avelumab, or


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
the last ADA assessment is positive AND patient discontinued treatment with avelumab 
AND the last planned ADA assessment (day 30 follow-up visit) is after the cut-off date.
Time to nAb response and duration of nAb response are defined similarly based on first and 
last positive nAb result. 
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary 
of associated statistics including the median ADA response time with 2-sided 95% CIs.  
ADA response rates at different timepoints will be estimated with corresponding 2-sided 
95% CIs.  The CIs for the median will be calculated according to Brookmeyer and Crowley
(1982)1 and the CIs for the survival function estimates will be derived using the log-log 
transformation according to Kalbfleisch and Prentice (2002)3 (conftype=loglog default option 
in SAS Proc LIFETEST) with back transformation to a CI on the untransformed scale. The 
estimate of the standard error will be computed using Greenwood’s formula.
Duration of ADA response will be displayed graphically and analyzed using Kaplan-Meier 
methodology. If the number of patients with ADA response is small, the Kaplan-Meier 
method may not provide reliable estimates.  In this case, only descriptive statistics or listings 
will be provided
As data permit, the analyses described above will be repeated for patients with treatment-
induced nAb. 
6.2.6.2. ADA titer
For patients who are ADA ever positive, the maximum observed ADA titer for a patient will 
be summarized, overall and by ADA subcategories (baseline ADA positive, treatment-
boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response) 
of patients having each discrete maximum titer value will be tabulated. The denominator to 
calculate the percentages will be the total number of patients in the associated ADA 
subcategory. 
For patients with treatment-induced ADA, a cross tabulation of duration of ADA response 
and maximum ADA titer will be provided. The following categories for duration of ADA 
response will be used: ≤1, >1 to ≤3, >3 to ≤5, >5 to ≤7, >7 to ≤13, >13 to ≤16, >16 to ≤25, 
>25 weeks. In this categorization, the censoring in duration of ADA response is ignored. 
6.2.6.3. Analysis of PK and safety by immunogenicity status
The following ADA and nAb status will be used for the analyses described below.
ADA 

ADA ever-positive versus ADA never-positive 

ADA: treatment-induced ADA versus ADA never-positive or baseline ADA positive


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nAb 

nAb ever-positive versus nAb never-positive 

nAb: treatment-induced nAb versus nAb never-positive or baseline nAb positive
PK parameters and immunogenicity status
The following analyses will include patients in both the immunogenicity analysis set and in 
the PK parameter analysis set.  The PK endpoints pertinent to the immunogenicity analyses 
are Ctrough and Cmax.  
Blood samples for avelumab PK will be collected pre-dose and post-dose on Cycle 1 Day 1 
and Day 15, Cycle 2 Day 1, and pre-dose on Day 15 of Cycles 3, 6, 9 and 12.
Ctrough and Cmax will be summarized descriptively (n, mean, SD, CV, median, minimum,
maximum, geometric mean, its associated CV, and 95% CI) by nominal time and ADA 
status. Linear-linear box plots of mean and median for Ctrough and Cmax over nominal time and 
by ADA status will be presented, as data permit.
Among patients with treatment-induced ADA, analyses will be conducted to assess whether 
Ctrough and Cmax have any changes before and after the first positive ADA assessment. To be 
included in this analysis, patients must have the same PK parameter available both before 
and after the first positive ADA assessment.  Relative PK day will be calculated as:
(PK assessment nominal day) – (first positive ADA assessment nominal day).
Nominal day is the protocol scheduled timing for an assessment. For example, if Ctrough is 
collected on Day 1 of Cycle 2 and the first positive ADA result is observed on Day 1 of 
Cycle 3, then the relative PK day for this Ctrough is -28. 
As data permit, the analyses described above will be repeated for nAb.
Safety and immunogenicity status
The following analyses will include patients in the immunogenicity analysis set.
The frequency (number and percentage) of patients with each of the following will be 
presented by ADA status.

TEAEs, by SOC and PT 

TEAEs leading to dose reduction of avelumab, by SOC and PT

TEAEs leading to discontinuation of avelumab, by SOC and PT

TEAEs leading to discontinuation of study treatment by SOC and PT


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•
Grade ≥ 3 TEAEs, by SOC and PT
•
SAEs, by SOC and PT
•
IRRs, by PT
For patients who had at least one IRR and have treatment-induced ADA, time related to first 
onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or later) will be summarized 
taking into account whether the IRR occurred on or after the first ADA positive assessment 
or whether the IRR occurred before the first ADA positive assessment.  
As data permit, the analyses described above will be repeated for nAb.
6.4. Subset Analyses
OR and DR (if meaningful) will also be summarized for patients in the following subsets:
Within each cohort:
•
Baseline PD-L1 status: Positive, Negative.
NSCLC cohort:
•
Histology: Non-Squamous, Squamous;
•
Number of previous systemic therapies: 1, ≥2.
UC cohort:
CCI


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
Baseline ECOG performance status (PS): ≤1, ≥2.
In the case of a low number of patients within a category (<10 patients), the category may not 
be summarized.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Baseline summaries
The following analyses will be based on the FAS by treatment group.
6.5.1.1. Demographic characteristics
Demographic characteristics will be summarized by treatment group using the following 
information from the ‘Screening/Baseline Visit’ eCRF pages.

Demographic characteristics 
-
Gender: Male, Female 
-
Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiracial, Not Reported.
-
Ethnic origin: 

Hispanic or Latino 

Not Hispanic or Latino
-
Age (years): summary statistics 
-
Age categories: 

< 65 years, ≥ 65 years 

< 65, 65-<75, 75-<85, ≥ 85 years
-
Pooled Geographical Region (as applicable): 

North America 

Europe

Asia

Rest of the World (Australasia, Latin America, Africa and/or Middle East will be 
included as additional pooled geographical regions if including > 10% of the 
overall treated population)
-
Geographic Region (as applicable):

North America

Latin America

Western Europe

Eastern Europe

Middle East


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
Australasia

Asia

Africa
-
Eastern Cooperative Oncology Group (ECOG) Performance Status: 0, 1, 2, 3, and 4 
Center codes will be used for the determination of the patient’s geographic region.
The listing of demographics and baseline characteristics will include the following 
information: patient identifier, treatment group, age, sex, race, ethnicity and ECOG 
performance status.
6.5.1.2. Medical history
Medical history will be coded using the most current available version of Medical Dictionary 
for Regulatory Activities (MedDRA) and will be summarized from the ‘Medical History’
eCRF page. Medical history will be summarized as the numbers and percentages of patients 
by MedDRA preferred term (PT) as event category and MedDRA primary system organ 
class (SOC) as summary category. Each patient will be counted only once within each PT or 
SOC.
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and 
PT in alphabetical order.
For the UC cohort, the reasons for ineligibility for cisplatin-containing front-line 
chemotherapy will be summarized using information collected on ‘Oncology Stratification 
By Inclusion Criteria’ and ‘ECOG Performance Status’ eCRF pages:  

Baseline ECOG PS 2;

Renal dysfunction (defined as creatinine-clearance <60 ml/min) at baseline;

Grade ≥2 peripheral neuropathy at baseline;

Grade ≥2 hearing loss (hearing loss measured by audiometry of 25 decibels at two 
contiguous frequencies) at baseline.
6.5.1.3. Disease characteristics
Information on disease characteristics collected on ‘Primary Diagnosis’ and RECIST eCRF 
pages will be summarized by treatment group. Summary statistics will be presented for the 
following.
From the ‘Primary Diagnosis’ eCRF page:

Site of primary tumor

Primary diagnosis (summarize all categories collected in the ‘Primary Diagnosis’ eCRF 
page)


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
Time since initial diagnosis to date of first dose of study treatment (months), defined as 
(date of first dose of study treatment – date of initial diagnosis)/30.4375
From the RECIST eCRF page:

Measurable disease (lesions) at baseline (Yes, No)

Involved tumor sites at baseline
Listing of disease history will be provided with all relevant data (as collected on the ‘Primary 
Diagnosis’ eCRF page) and derived variables as above.
6.5.1.4. Prior anti-cancer therapies
The prior anti-cancer therapies are collected under the ‘Prior Cancer Therapy’, ‘Prior 
Radiation Therapy’ and ‘Prior Anti-Cancer Surgery’ eCRF pages.
The number and percentage of patients in each of the following anti-cancer therapy 
categories will be tabulated:

Patients with at least one type of prior anti-cancer therapy

Patients with at least one prior anti-cancer drug therapy

Patients with at least one prior anti-cancer radiotherapy

Patients with at least one prior anti-cancer surgery
Prior anti-cancer drug therapy will be summarized as follows based on the number and 
percentage of patients with the following:

At least one prior anti-cancer drug therapy

Number of prior anti-cancer drug therapy regimens: missing, 1, 2, 3, ≥4

Intent of Drug Therapy: Neo-Adjuvant, Adjuvant, Advanced – Metastatic, Locoregional
Disease-Recurrence

Best response: CR, PR, SD, PD, Unknown, Not applicable.
Best response is derived 
from the last treatment regimen.
The prior anti-cancer drug therapies will also be summarized based on the number and 
percentage of patients by the drug class and preferred term. A patient will be counted only 
once within a given drug class and within a given drug name, even if he/she received the 
same medication at different times. The summary will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal 
frequency regarding drug class (respectively drug name), alphabetical order will be used.
Prior anti-cancer drug therapies will be included in the listing that follow with a flag to 
identify prior therapies. These will include the patient identification number, and all the 
relevant collected data-fields on the corresponding eCRF pages.

Listing of anti-cancer drug therapies 


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6.5.2. Study conduct and patient disposition
The following analyses will be performed based on the FAS by treatment group.
6.5.2.1. Patient disposition
The percentages below will be calculated based on the number of patients in the FAS.

Total number of patients screened overall

Number of patients who discontinued from the study prior to treatment with study drug 
overall and by the main reason for discontinuation

Number and percentage of treated patients in each of the analysis sets defined in Section 
4

Number and percentage of patients with study drug ongoing (separately for each study 
drug administered in combination)

Number and percentage of treated patients who discontinued study drug overall and by 
the main reason for discontinuation of study drug (separately for each study drug 
administered in combination)

Number and percentage of patients who entered follow-up

Number and percentage of patients who discontinued follow-up overall and by the main 
reason for discontinuation
In addition, the following will be summarized:

Number and percentage of treated patients overall, by region (Europe, EEA (required by 
EudraCT), North America, Latin America, Middle East, Asia, Australasia, Africa), by 
country within region 

Number and percentage of treated patients by center
In addition, a cross tabulation of patients who have discontinued/are ongoing treatment with 
avelumab vs patients who have discontinued/are ongoing treatment with axitinib will also be 
provided. 
6.5.2.2. Protocol deviations
All protocol violations that impact the safety of the patients and/or the conduct of the study 
and/or its evaluation will be reported. These include:

Patients who are dosed on the study despite not satisfying the inclusion criteria

Patients who develop withdrawal criteria whilst on the study but are not withdrawn

Patients who receive the wrong treatment or an incorrect dose

Patients who receive an excluded concomitant medication

Deviations from GCP.


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The identification of these and other CSR-reportable deviations will be based on the 
inclusion/exclusion criteria or other criteria presented in the protocol.
6.5.3. Study treatment compliance and exposure
The following analyses will be based on the safety analysis set by treatment group.
Cycle definitions for study drugs that are administered in combination apply to all the study 
drugs in the combination.  Ie, cycle is patient-dependent, rather than study-drug-dependent 
when study drugs are administered in combination.  
For Cycle X, actual cycle start date for each patient is

the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the 
patient received study treatment on that visit (ie, any study drug with dose>0 at that visit)

the first day of assessments in the Cycle X day 1 visit, if the patient did not receive study 
treatment on that visit (ie, all study drugs had dose=0 at that visit).  Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs on Cycle X day 1 visit.
Actual cycle end date for each patient is, 

for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date 
– 1 day;

for the last cycle, actual cycle end date = actual cycle start date + 28 (in days) – 1 day
Cycle duration (weeks) = (actual cycle end date – actual cycle start date + 1)/7
When summarizing exposure for each study drug, only cycles from first dose of study 
treatment until the last cycle with non-zero dose of at least one of the study drugs should be 
included. 
Exposure may be summarized (per cycle and/or overall) as dose received (cumulative dose, 
actual dose intensity) and as dose received relative to intended dose (relative dose intensity 
[RDI]).  
The formulae below should be applied to each study drug separately even when study drugs 
are administered in combination.
The derivations below are provided for the following study drugs (administered alone or in 
combination):

Avelumab administered as a 1-hour IV infusion at a dose of 800 mg once every 2 weeks 
in 4-week cycles. 

Axitinib administered orally at a dose of 5 mg BID. 
6.5.3.1. Exposure to avelumab 
The dose level for avelumab is calculated as actual dose administered (mg). 


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Intended duration of treatment with avelumab (weeks) = 
(end date–date of first dose of avelumab +1)/7, 
where end date = start date of last cycle with non-zero dose of avelumab + 28 – 1
Duration of exposure to avelumab (weeks) = 
(last dose date of avelumab – first dose date of avelumab + 14)/7  
Cumulative dose is the sum of the actual doses of avelumab received.  
Actual Dose Intensity (DI)

Overall actual DI (mg/4-week cycle) = [overall cumulative dose (mg)] / [intended 
duration of treatment with avelumab (weeks)/4].  
Relative Dose Intensity (RDI)  

Intended DI (mg/4-week cycle) = [intended cumulative dose per cycle] / [intended 
number of 4-weeks in a cycle] = [2 x 800 (mg)] / [1 (4-week cycle)] = 1600 (mg/4-week 
cycle)

Overall RDI (%) = 100 × [overall actual DI] / [intended DI]                                                                
= 100 × [overall actual DI] / [1600 (mg/4-week cycle)] 
6.5.3.2. Exposure to axitinib
The dose level is calculated as actual dose administered (mg/day).  
Intended duration of treatment with axitinib (weeks) =
(last dose date of axitinib– date of first dose of axitinib +1)/7, 
Duration of exposure to axitinib (weeks) = 
(last dose date of axitinib – first dose date of axitinib + 1)/7  
Overall cumulative dose is the sum of the actual doses of axitinib received in the study.  
Actual Dose Intensity (DI)

Overall actual DI (mg/week) = [overall cumulative dose (mg)] / [intended treatment 
duration (weeks)]   
Relative Dose Intensity (RDI)  

RDI (%) = 100 × [overall cumulative dose] / [intended cumulative dose per week × 
number of weeks from first dose of study drug to last dose of study drug] 
= 100 × [overall cumulative dose] / [7 ×2 × 5 × duration of exposure to axitinib in 
weeks]


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6.5.3.3. Dose reductions 
Applicable to avelumab.  Dose reduction is defined as actual non-zero dose < 90% of the 
planned dose.
Applicable to axitinib.  Dose reduction is defined as a change to a non-zero dose level lower 
than that planned in the protocol.
The number and percentage of patients with at least one dose reduction as well as a 
breakdown of the number of dose reductions (1, 2, 3, ≥4) will be summarized. 
6.5.3.4. Dose escalations
Applicable to axitinib only.
Dose escalation is defined as a change to a dose level higher than that planned in the 
protocol.
Number and percentage of patients with at least one dose escalation as well as a breakdown 
of dose escalations (1, 2, 3, ≥4) will be summarized.
6.5.3.5. Dose interruptions
Applicable to axitinib only.  
An interruption is defined a 0 mg dose administered on one or more days for axitinib. What 
follows defines how dose interruptions will be counted in the case of multiple dose 
interruptions.

If an interruption occurs consecutively for at least two days, then it will be counted only 
once (example: If the actual dose on days 1-3 is 10 mg and actual dose on days 4-5 is 0 
mg, then the total number of dose interruptions is 1).

If an interruption occurs for more than one day, but the days are not consecutive, ie there 
is at least one dosing day in between, then each dose interruption will be counted as a 
different occurrence (example: If the actual dose on days 1, 3 and 5, is 10 mg and actual 
dose on days 2 and 4 is 0 mg, the total number of dose interruptions is 2). 
A dose interruption is not considered a dose reduction.
The number and percentage of patients with dose interruptions and the corresponding reasons 
will be summarized.
6.5.3.6. Dose delays 
Applicable to avelumab only.
Dose Delay is the difference between the actual time between two consecutive non-zero 
doses and the planned time between the same two consecutive non-zero doses. 
For Cycle 1 Dose 1:
Dose Delay (days) = day of the first day of study drug -1


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After Cycle 1 Dose 1:
Dose Delay for Dose x (days) = Date of Dose x – Date of Dose (x-1) – Planned days 
between two consecutive doses= Date of Dose x – Date of Dose (x-1) – 14. 
Dose delays will be grouped into the following categories: 

No delay 

1-3 days delay

4-6 days delay

7 or more days delay
For example, for avelumab, administered on a 2-week schedule, if one patient receives 
avelumab on Day 1, then the next avelumab administration date will be on Day 15; however, 
if the patient receives avelumab at Day 16 or 17 or 18, this is considered as 1-3 days delay.  
No delay and 1-3 days delay will also be summarized together. 
The number and percentage of patients with delayed study drug administration and maximum 
length of delay, ie, the worst case of delay if patients have multiple dose delays will be 
summarized. 
6.5.3.7. Infusion rate reductions
Applicable to avelumab only.
The number and percentage of patients with at least one infusion rate reduction of ≥50% 
compared to the first infusion rate reported in the eCRF as well as the frequency of patients 
with 1, 2, 3 or ≥4 infusion rate reductions of ≥50% will be summarized.
6.5.3.8. Infusion interruptions
Applicable to avelumab only. 
An infusion interruption is defined as an infusion that is stopped and re-started on the same 
day (ie, for a visit more than one infusion start time and infusion end time are recorded).
The number and percentage of patients with at least one infusion interruption as well as the 
frequency of patients with 1, 2, 3, or ≥4 infusion interruptions will be summarized.
6.5.4. Concomitant medications and non-drug treatments
The following analyses will be based on the safety analysis set by treatment group.
Concomitant medications are medications, other than study drugs, which started prior to 
first dose date of study treatment and continued during the on-treatment period as well as 
those started during the on-treatment period. Prior medications are medications, other than 
study drugs and pre-medications for study drug, which are started before the first dose of 
study treatment. 


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Concomitant medications will be summarized from the ‘General Concomitant Medications’ 
eCRF page. 
Summary of concomitant medications will include the number and percentage of patients by 
Anatomical Therapeutic Chemical (ATC) Classification level 2 and preferred term. A patient 
will be counted only once within a given drug class and within a given drug name, even if 
he/she received the same medication at different times. If any concomitant medication is 
classified into multiple ATC classes, the medication will be summarized separately under 
each of these ATC classes. The summary tables will be sorted on decreasing frequency of 
drug class and decreasing frequency of drug name in a given drug class. In case of equal
frequency regarding drug class (respectively drug name), alphabetical order will be used. In 
case any specific medication does not have ATC classification level 2 coded term, it will be 
summarized under ‘Unavailable ATC classification’ category. 
6.5.5. Subsequent anti-cancer therapies
The following analyses will be based on the FAS by treatment group.
Anti-cancer drug treatment will be provided in a data listing with data retrieved from 
‘Follow-up Cancer Therapy’ eCRF page. 
Number and percentage of patients with any anti-cancer therapy after discontinuation will be 
tabulated overall and by type of therapy based on the data collected from the ‘Follow-up 
Cancer Therapy’, ‘Follow-up Radiation Treatment’ and ‘Follow-up Anti-Cancer Surgery’ 
eCRF pages. 
6.6. Safety Summaries and Analyses
The Safety Analysis Set will be the primary population for safety evaluations. Summaries of
AEs and other safety parameters will be based on the safety analysis set by treatment group.  
6.6.1. Adverse events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring 
during the on-treatment period as defined in Section 3.5.1.
All analyses described below will be based on TEAEs (started during the on-treatment 
period) if not otherwise specified. The AE listings will include all AEs (whether treatment-
emergent or not). AEs outside the on-treatment period will be flagged in the listings.

Related Adverse Events: adverse events with relationship to study treatment (as 
recorded on the AE eCRF page, Relationship with study treatment = Related) reported by 
the investigator and those of unknown relationship (ie, no answer to the question 
‘Relationship with study treatment’). Related AEs are those related to any study drug (ie, 
at least one of the study drugs).

Serious Adverse Events (SAE): serious adverse events (as recorded on the AE eCRF 
page, Serious Adverse Event = Yes).


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
Adverse Events Leading to Dose Reduction: adverse events leading to dose reduction
of study treatment (as recorded on the AE eCRF page, Action taken with study treatment 
= Dose reduced).

Adverse Events Leading to Interruption of Study Treatment: adverse events leading 
to interruption of study treatment (as recorded on the AE eCRF page, Action taken with 
study treatment = Drug interrupted). The eCRF does not allow for a clear separation 
between interruption of an infusion and delays of administration for a parenteral drug as 
both are recorded using the same term on the eCRF (“Drug interrupted”).   IRRs will be 
excluded in the analysis of AEs leading to Drug Interruption in case they only led to an 
interruption of the infusion.

Adverse Events Leading to Permanent Treatment Discontinuation: adverse events 
leading to permanent discontinuation of study treatment (as recorded on the AE eCRF 
page, Action taken with study treatment = Drug withdrawn).  

Adverse Events Leading to Death: adverse event leading to death (as recorded on the 
AE eCRF page, Outcome = Fatal, as well as AEs of Grade 5).

Immune-related Adverse Events (irAE): irAEs (as identified according to the 
methodology outlined in Appendix 1 for a pre-specified search list of MedDRA PTs, 
documented in the Safety Review Plan and finalized for analysis of the current study data 
prior to DB lock)

Infusion-related Reactions (IRR): IRRs (as identified according to the methodology 
outlined in Appendix 2 for a pre-specified search list of MedDRA PTs documented in the 
Safety Review Plan and finalized for analysis of the current study data prior to DB lock).
Unless otherwise specified, AEs will be summarized by number and percentage of patients 
with the AE in the category of interest as described above, by treatment group, primary SOC 
and PT in decreasing frequency. 
Each patient will be counted only once within each SOC or PT. If a patient experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries 
of relationship and severity.
6.6.1.1. All adverse events
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 
4.03) per patient, using the latest version of MedDRA preferred term (PT) as event category 
and MedDRA primary system organ class (SOC) body term as Body System category. 
In case a patient has events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. No imputation of missing grades will be performed. 
The following tables will be created: 

The overall summary of AEs table will include the frequency (number and percentage) of 
patients with each of the following by treatment group:


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-
TEAEs
-
TEAEs, Grade ≥ 3
-
Related TEAEs
-
Related TEAEs, Grade ≥ 3
-
TEAEs leading to dose reduction of avelumab 
-
TEAEs leading to dose reduction of axitinib
-
TEAEs leading to interruption of avelumab
-
TEAEs leading to interruption of axitinib
-
TEAEs leading to discontinuation of avelumab
-
TEAEs leading to discontinuation of axitinib
-
TEAEs leading to discontinuation of any study drug
-
TEAEs leading to discontinuation of all study drugs
-
Related TEAEs leading to discontinuation of avelumab
-
Related TEAEs leading to discontinuation of axitinib
-
Related TEAEs leading to discontinuation of any study drug
-
Related TEAEs leading to discontinuation of all study drugs
-
Serious TEAEs
-
Related Serious TEAEs 
-
TEAEs leading to death
-
Related TEAEs leading to death
-
irAEs
-
IRRs 

TEAEs by SOC and PT and worst grade

Related TEAEs by SOC and PT and worst grade

TEAEs leading to death by SOC and PT

Related TEAEs leading to death by SOC and PT
6.6.1.2. Adverse events leading to dose reduction
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to dose reduction of each study drug by treatment group:

TEAEs leading to dose reduction of avelumab by SOC and PT

TEAEs leading to dose reduction of axitinib by SOC and PT


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The listing of all AEs leading to dose reduction will also be provided with the relevant 
information. 
6.6.1.3. Adverse events leading to interruption of study treatment
The eCRF does not allow for a clear separation between interruption of an infusion and 
delays of administration for a parenteral drug as both are recorded using the same term on the 
eCRF (“Drug interrupted”).   IRRs will be excluded in the analysis of AEs leading to Drug 
Interruption in case they only led to an interruption of the infusion (ie, did not lead to a dose 
reduction or a dose delay). 
As such, AEs leading to interruption will be defined as AEs identified in the AE eCRF page 
with an action taken with study treatment of ‘drug interrupted’ excluding 

IRRs that occurred on the day of infusion with ≥90% of the planned dose given (ie IRRs 
that did not lead to a dose reduction) and subsequent administration of study drug had no 
delay (as defined in Section 6.5.3.6). These IRRs will be considered as IRRs leading to 
interruption of infusion.

IRRs occurring on the day after infusion and subsequent dose administration had no 
delay (as defined in Section 6.5.3.6).
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to interruption of each study drug by treatment group:

TEAEs leading to interruption of avelumab by SOC and PT

TEAEs leading to interruption of axitinib by SOC and PT
The listing of all AEs leading to interruption of study treatment will also be provided with the
relevant information.
In addition, the frequency (number and percentage) of patients with each of the following 
will be presented for TEAEs leading to both interruption and dose reduction of each study 
drug by treatment group:

TEAEs leading to both interruption and dose reduction of avelumab by SOC and PT

TEAEs leading to both interruption and dose reduction of axitinib by SOC and PT
This summary will take into account PTs with both actions as defined in Section 6.6.1, even
though the actions may be captured for different PT records (ie, different onset for the PT 
with action “drug interrupted” and the PT with action “dose reduced”.  
6.6.1.4. Adverse events leading to discontinuation of study treatment
The frequency (number and percentage) of patients with each of the following will be 
presented for TEAEs leading to permanent discontinuation of each study drug and study 
treatment, by treatment group:

TEAEs leading to discontinuation of avelumab by SOC and PT


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
Related TEAEs leading to discontinuation of avelumab by SOC and PT

TEAEs leading to discontinuation of axitinib by SOC and PT

Related TEAEs leading to discontinuation of axitinib by SOC and PT

TEAEs leading to discontinuation of any study drug by SOC and PT

Related TEAEs leading to discontinuation of any study drug by SOC and PT

TEAEs leading to discontinuation of all study drugs by SOC and PT

Related TEAEs leading to discontinuation of all study drugs by SOC and PT
The listing of all AEs leading to treatment discontinuation will also be provided with the 
relevant information. 
6.6.2. Deaths
The frequency (number and percentage) of patients in the safety analysis set who died and 
who died within 30 days after last dose of study treatment as well as the reason for death, 
will be tabulated based on information from the ‘Notice of Death’ and ‘Survival Follow-Up’
eCRFs, by treatment group.  

All deaths 

Deaths within 30 days after last dose of study treatment

Reason for Death 
-
Disease progression
-
Study treatment toxicity
-
AE not related to study treatment
-
Unknown
-
Other.
In addition, date and cause of death will be provided in individual patient data listing together 
with selected dosing information (study treatment received, date of first / last administration, 
dose) and will include the following information:

AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as AEs 
of Grade 5), 

Flag for death within 30 days of last dose of study treatment.
6.6.3. Serious adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for treatment-emergent SAEs by treatment group:

SAEs by SOC and PT


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
Related SAEs by SOC and PT
The listings of all SAEs will also be provided with the relevant information with a flag for 
SAEs with onset outside of the on-treatment period.
6.6.4. Other significant adverse events
The frequency (number and percentage) of patients with each of the following will be 
presented for irAEs, by treatment group:

irAEs leading to death, by Cluster and PT

irAEs, by Cluster and PT

irAEs, Grade ≥ 3, by Cluster and PT

irAEs leading to discontinuation of avelumab, by Cluster and PT 

Serious irAEs, by Cluster and PT
The listing of all irAEs will also be provided with the relevant information with a flag for 
irAEs with onset outside of the on-treatment period. 
The frequency (number and percentage) of patients with each of the following will be 
presented for IRRs, by treatment group:

IRRs leading to death, by PT

IRRs, by PT

IRRs, Grade ≥ 3, by PT

IRRs leading to discontinuation of avelumab, by PT 

Serious IRRs, by PT

Time related to first onset of an IRR (infusion 1, infusion 2, infusion 3, infusion 4 or 
later).  
The listing of all IRRs will also be provided with the relevant information with a flag for 
IRRs with onset outside of the on-treatment period.
6.6.5. Laboratory data
6.6.5.1. Hematology and chemistry parameters
Laboratory results will be classified according to the NCI-CTCAE criteria version 4.03. Non-
numerical qualifiers (with the exception of fasting flags) will not be taken into consideration 
in the derivation of CTCAE criteria (eg, hypokalemia Grade 1 and Grade 2 are only 
distinguished by a non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to 
the categories: below normal limit, within normal limits and above normal limit (according to 
the laboratory normal ranges). 


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Abnormalities classified according to NCI-CTCAE toxicity grading version 4.03 will be 
described using the worst grade. For those parameters which are graded with two toxicities 
such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (eg, hypokalemia) grades at baseline and post baseline will be set to 0 
when the variables are derived for summarizing high direction toxicity (eg, hyperkalemia), 
and vice versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported.  When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because 
the CTCAE grading is based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) × (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased:  
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 800/mm3

Neutrophil count decreased 
-
derived absolute count does not meet Grade 2-4 criteria, and
-
% value < % LLN value, and
-
derived absolute count  ≥ 1500/mm3
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium 
(CALCIO). Corrected Calcium is calculated from Albumin and Calcium as follows
Corrected calcium (mmol/L) = measured total Calcium (mmol/L) + 0.02 (40 - serum 
albumin [g/L])
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. The ratios 
of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and 
percentage of patients with each of the following during the on-treatment period will be 
summarized by treatment group:

ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN

AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN

(ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) ≥ 10×ULN, (ALT or 
AST) ≥ 20×ULN


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
TBILI ≥ 2×ULN

Concurrent ALT ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent AST ≥ 3×ULN and TBILI ≥ 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN 

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and ALP > 2×ULN

Concurrent (ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or 
missing)
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, ie, a patient with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. Liver function elevation and possible Hy’s 
Law cases will be summarized using frequency counts and percentages. 
An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying

peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at
ALT=3×ULN and total bilirubin =2×ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at
AST=3×ULN and total bilirubin =2×ULN . 
In addition, a listing of all TBILI, ALT, AST and ALP values for patients with concurrent 
(ALT or AST) ≥ 3×ULN and TBILI ≥ 2×ULN and (ALP ≤ 2×ULN or missing) will be 
provided.
Parameters with NCI-CTC grades available: 
The laboratory toxicities will be tabulated using descriptive statistics (number of patients and 
percentages) during the on-treatment period. The denominator to calculate percentages for 
each laboratory parameter is the number of patients evaluable for CTCAE grading (ie those 
patients for whom a Grade 0, 1, 2, 3 or 4 can be derived).

The shift table will summarize baseline CTCAE grade versus the worst on-treatment 
CTCAE grade. The highest CTCAE grade during the on-treatment period is considered 
as the worst grade for the summary. 

The number and percentage of patients with newly occurring or worsening laboratory 
abnormalities during the on-treatment period will be summarized by worst grade on-
treatment (Grade 1, 2, 3, 4, Grade 3/4 and any grade (Grades 1-4)).


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The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, ie:

Hematology: 
Hemoglobin (HB), Leukocytes (white blood cell decreased), Lymphocytes (lymphocyte 
count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) (neutrophil 
count decreased), Platelet Count (PLT) (platelet count decreased).

Serum Chemistry:
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine 
Kinase 
(CPK 
increased), 
Potassium 
(hypokalemia/ 
hyperkalemia), 
Sodium 
(hyponatremia/ 
hypernatremia), 
Magnesium 
(hypomagnesemia/hypermagnesemia), 
Calcium (hypocalcemia/ hypercalcemia), Glucose (hypoglycemia/hyperglycemia), 
Gamma Glutamyl Transferase (GGT) (GGT increased), Lipase (lipase increased), 
Phosphates (hypophosphatemia), Triglycerides (hypertriglyceridemia).
6.6.5.2. Other laboratory parameters
The listings of laboratory results will be provided for all laboratory parameters. The listings 
will be sorted by parameters and assessment dates or visits for each patient. Laboratory 
values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges.  A listing of CTCAE grading will also be generated for those 
laboratory tests. 
6.6.6. Vital signs
Weight will be recorded at screening and pre-dose Days 1 and 15 of each cycle, End of 
Treatment, and short-term follow-up (30, 60, and 90 days post treatment). Height will be 
measured at screening only.
Vital sign summaries will include all vital sign assessments from the on-treatment period.  
All vital sign parameters will be summarized using descriptive statistics (mean, SD, median, 
Q1, Q3, minimum, and maximum) of actual values and changes from baseline for each visit 
over time. End of Treatment visit will be summarized separately. The changes computed will 
be the differences from baseline. 
6.6.7. Electrocardiogram
Patients with qualitative ECG abnormalities will be listed for each patient and time point and 
the corresponding abnormality finding will be included in the listing.
6.6.8. MUGA/ECHO
In addition, LVEF% will be summarized as frequency (number and percentage) of patients 
with: 


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
a shift from baseline normal to at least one result below the institutional lower limit of 
normal during the on-treatment period

≥10-point decrease from baseline in LVEF% during the on-treatment period

≥10-point decrease from baseline in LVEF% to a post-baseline value < LLN during the 
on-treatment period

≥15-point decrease from baseline in LVEF% during the on-treatment period

≥15-point decrease from baseline in LVEF% to a post-baseline value < LLN during the 
on-treatment period
7. INTERIM ANALYSES
There is no formal interim analysis planned for this study.
7.1. Introduction
Not applicable.
7.2. Interim Analyses and Summaries
Not applicable.


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8. REFERENCES
1.
Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. 
Biometrics. 38: 29-41, 1982.
2.
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial.  Biometrika; 26, 404-413, 1934
3.
Kalbfleisch JD, Prentice, RL. Statistical Analysis of Failure Time Data, 2nd Edition. 
Hoboken, Wiley Interscience.  2002.
4.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am 
Stat Assoc. 53: 457-81, 1958.


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9. APPENDICES
Appendix 1. Immune-Related Adverse Events
The MedDRA PTs and clusters for irAEs are defined in the SRP for avelumab.
Immune-related AEs (irAEs) will be programmatically identified as outlined in Table 12. 
Unless otherwise noted, this case definition is hierarchical, ie, each step is only checked for 
patients and events that have already met the prior step.  
Table 12.  Case Definition for irAEs
Step
Selection Criteria
Additional Notes
1
Event selected based on a list of pre-
specified MedDRA PTs within clusters.  
These are included in the SRP as Tier1 
events (Immune-mediated xxxx).  If AE 
matches the list, then it is in for the next step
2
AE onset during 1st study drug administration 
or anytime thereafter through 90 days after 
last dose of study treatment.
This is regardless of start of new anti-cancer drug 
therapy and regardless of TEAE classifications
3
Answer in the AE eCRF page to ‘Was 
another treatment given because of the 
occurrence of the event’ is ‘YES’
Steps 3 and 4 will be checked concurrently.  Step 5 
will be checked if the criteria in Step 4 is met, 
irrespective of whether the Criteria in Step 3 is met.
4
AE treated with corticosteroids or other 
immunosuppressant therapy.  
For endocrinopathies only: AE required 
hormone replacement
Look in the conmed pages for AE identifiers that 
match the AEs from Step 3.  For each of such AEs if 
A) OR B) OR C) below are met then the AE is in for 
the next step
A) conmed ATC code is in (H02A, H02B, H02C, 
D07, A01AC, S01BA, S01BB, L04AA, L04AB,
L04AC, L04AD, L04AX, A07EA) and AE PT is 
in any of the irAE clusters.
B) conmed ATC code is in (H03A, H03B) and AE 
PT is in one of the irAE clusters associated with
“Immune-mediated endocrinopathies”
C) conmed ATC code is A10A and AE PT is in the 
irAE cluster associated with “Immune-mediated 
endocrinopathies: Type I Diabetes Mellitus”


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


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Appendix 2. Infusion Related Reactions
For defining an AE as IRR the onset of the event in relation to the infusion of study drug and 
time to resolution of the event will be considered. 

All AEs identified by the MedDRA PT query describing signs and symptoms will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after
infusion) and the event resolved with end date within 2 days after onset. 

All AEs identified by the MedDRA PTs of Infusion related reaction, Drug 
hypersensitivity, Anaphylactic reaction, Hypersensitivity, Type 1 hypersensitivity, will be 
considered potential IRRs when onset is on the day of study drug infusion (during or after 
the infusion) or the day after the study drug infusion (irrespective of resolution date).
The list of MedDRA PTs for ‘IRRs SIGNS and SYMPTOMS’ and PTs ‘IRRs CORE’ are 
defined in the SRP for avelumab. 
Infusion-related reactions (IRRs) will be programmatically identified as outlined in Table 13
and will be identified for IV drugs only.     
Table 13.  Case Definition for IRRs – IV Study Drugs Administered Alone Or In 
Combination With Non-IV Study Drugs
Condition
Selection criterion
If AE meets [1 AND 2] OR [3 AND (4A OR 4B)] then AE is classified as an IRR
1
PT is included in the ‘IRRs SIGNS and SYMPTOMS’ list 
2

AE onset date = date of infusion of study drug AND

AE timing related to study drug (‘DURING’, ‘AFTER’) AND

AE outcome in (‘RECOVERED/RESOLVED’, ‘RECOVERED/RESOLVED WITH 
SEQUELAE’, ‘RECOVERING/RESOLVING’) AND

AE end date – AE onset date ≤2 
3
PT is included in the ‘IRRs CORE’ list 
4A

AE onset date = date of infusion of study drug AND

AE timing related to study drug in (‘DURING’, ‘AFTER’)
4B
AE onset on the day after infusion